Faculty Profiles - TANUMA Junichi

Papers - TANUMA Junichi

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下顎歯肉への転移を契機に診断に至った膵癌の1例

須田大亮, 船山昭典, 新美奏恵, 佐久間英伸, 齋藤大輔, 林孝文, 丸山智, 田沼順一, 小林正治

日本口腔腫瘍学会誌 36 ( 4 ) 89 - 95 2024.12

Language：Japanese Publisher：(一社)日本口腔腫瘍学会

口腔領域の転移性腫瘍は比較的まれであり,なかでも膵癌の口腔転移は極めて少ない。今回われわれは下顎歯肉への転移性腫瘍を契機に膵癌の診断に至った1例を経験したので報告する。患者は57歳女性。既往歴として糖尿病と腰椎椎間板ヘルニアがあった。左側下顎第二大臼歯遠心の歯肉腫脹と出血を自覚し近医歯科で消炎処置を受けたが,1ヵ月経過しても改善しなかったため,消炎と智歯抜歯の依頼で当科を紹介受診した。左側下顎第二大臼歯遠心歯肉に10×5mmの隆起性の腫瘤を認め,造影CTでは造影性を認めた。細胞診の結果はLow grade squamous intraepithelial lesion(LSIL)で,生検ではAdenocarcinomaの診断であった。免疫組織化学ではCK7,CK20,MUC1が陽性,CDX2,PAX8,MUC2が陰性で,膵癌,胃癌,大腸癌等の転移性腫瘍が疑われたためPET/CTによる全身検索を行った。膵尾部のFDG集積を伴う腫瘤と腹膜播種病変,両肺と肝臓の多発結節,脊椎や骨盤に多発するFDG集積を認め,診断は膵癌ならびに多発転移疑いであった。当院消化器内科に対診し膵臓の超音波内視鏡下穿刺吸引法EUS-FNAによりAdenocarcinomaの確定診が得られた。ゲムシタビン・ナブパクリタキセル併用療法を行ったがその後,BSCの方針となり,初診の131日後に死亡した。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J02382&link_issn=&doc_id=20241224140002&doc_link_id=10.5843%2Fjsot.36.89&url=https%3A%2F%2Fdoi.org%2F10.5843%2Fjsot.36.89&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Development and Characterization of a Three-Dimensional Organotypic In Vitro Oral Cancer Model with Four Co-Cultured Cell Types, Including Patient-Derived Cancer-Associated Fibroblasts Reviewed

Yuka Aizawa, Kenta Haga, Nagako Yoshiba, Witsanu Yortchan, Sho Takada, Rintaro Tanaka, Eriko Naito, Tatsuya Abé, Satoshi Maruyama, Manabu Yamazaki, Jun-ichi Tanuma, Kazuyo Igawa, Kei Tomihara, Shinsaku Togo, Kenji Izumi

Biomedicines 12 ( 10 ) 2373 - 2373 2024.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Background/Objectives: Cancer organoids have emerged as a valuable tool of three-dimensional (3D) cell cultures to investigate tumor heterogeneity and predict tumor behavior and treatment response. We developed a 3D organotypic culture model of oral squamous cell carcinoma (OSCC) to recapitulate the tumor–stromal interface by co-culturing four cell types, including patient-derived cancer-associated fibroblasts (PD-CAFs). Methods: A stainless-steel ring was used twice to create the horizontal positioning of the cancer stroma (adjoining normal oral mucosa connective tissue) and the OSCC layer (surrounding normal oral mucosa epithelial layer). Combined with a structured bi-layered model of the epithelial component and the underlying stroma, this protocol enabled us to construct four distinct portions mimicking the oral cancer tissue arising in the oral mucosa. Results: In this model, α-smooth muscle actin-positive PD-CAFs were localized in close proximity to the OSCC layer, suggesting a crosstalk between them. Furthermore, a linear laminin-γ2 expression was lacking at the interface between the OSCC layer and the underlying stromal layer, indicating the loss of the basement membrane-like structure. Conclusions: Since the specific 3D architecture and polarity mimicking oral cancer in vivo provides a more accurate milieu of the tumor microenvironment (TME), it could be crucial in elucidating oral cancer TME.

File： biomedicines-12-02373-v2.pdf

DOI： 10.3390/biomedicines12102373

Ladinin-1 in actin arcs of oral squamous cell carcinoma is involved in cell migration and epithelial phenotype Reviewed

Tatsuya Abé, Manabu Yamazaki, Motohiro Nozumi, Satoshi Maruyama, Kaori Takamura, Riuko Ohashi, Yoichi Ajioka, Jun-ichi Tanuma

Scientific Reports 14 22778 2024.10

Cell-cell interaction determines cell fate of mesoderm-derived cell in tongue development through Hh signaling Reviewed

Kawasaki M, Kawasaki K, Sari FT, Kudo T, Nihara J, Kitamura M, Nagai T, Utama V, Ishida Y, Meguro F, Kesuma A, Fujita A, Nishimura T, Kogure Y, Maruyama S, Tanuma J, Kakihara Y, Maeda T, Ghafoor S, Khonsari RH, Corre P, Sharpe PT, Cobourne M, Franco B, Ohazama A

eLife 13 e85042 2024.10

広範な骨膜反応を呈した非細菌性下顎骨骨髄炎の1例

須田大亮, 船山昭典, 佐久間英伸, 齋藤大輔, 羽賀健太, 林孝文, 丸山智, 田沼順一, 小林正治

日本口腔科学会雑誌 73 ( 3 ) 272 - 273 2024.9

下顎歯肉癌を発症したBloom症候群の1例

船山昭典, 竹内涼子, 齋藤大輔, 須田大亮, 羽賀健太, 西山秀昌, 林孝文, 山崎学, 田沼順一, 小林正治

日本口腔科学会雑誌 73 ( 2 ) 207 - 207 2024.9

広範な骨膜反応を呈した非細菌性下顎骨骨髄炎の1例

須田大亮, 船山昭典, 佐久間英伸, 齋藤大輔, 羽賀健太, 林孝文, 丸山智, 田沼順一, 小林正治

日本口腔科学会雑誌 73 ( 3 ) 272 - 273 2024.9

頭頸部扁平上皮癌におけるmRNAスプライシングシグネチャーと病理学的意義の探索(Alternative splicing signatures of mRNA in head and neck squamous cell carcinoma and pathological significance)

阿部達也, 凌一葦, 奥田修二郎, 山崎学, 丸山智, 田沼順一

日本癌学会総会記事 83回 P - 2222 2024.9

Targeting CD36-Mediated Lipid Metabolism by Selective Inhibitor-Augmented Antitumor Immune Responses in Oral Cancer Reviewed

Mayu Takaichi, Hidetake Tachinami, Danki Takatsuka, Amirmoezz Yonesi, Kotaro Sakurai, Muhammad Irfan Rasul, Shuichi Imaue, Shin-Ichi Yamada, Muhammad Ruslin, Manabu Yamazaki, Jun-Ichi Tanuma, Makoto Noguchi, Kei Tomihara

International Journal of Molecular Sciences 25 ( 17 ) 9438 - 9438 2024.8

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

The fatty acid receptor CD36 is expressed on various malignant cells and is suggested to contribute to tumor progression. CD36 is also expressed by several immune cells and involved in immune responses and may be a potential target in cancer immunotherapy. In this study, we investigated whether the selective inhibition of CD36 can inhibit tumor progression and facilitate an antitumor immune response in oral squamous carcinoma cells (OSCCs). We assessed the effects of sulfosuccinimidyl oleate sodium (SSO), a CD36 inhibitor, on the proliferation apoptosis and alteration in tumor cell surface expression levels of immune accessory molecules in vitro. We also assessed whether SSO-treated OSCCs could promote a T cell response via a Mixed Lymphocyte Reaction (MLR) assay. We also investigated the direct antitumor effects and immunomodulatory effects of SSO using a mouse oral cancer OSCC model. SSO treatment significantly inhibited OSCC proliferation, increased apoptotic cell death, and upregulated the cell surface expression of several immune accessory molecules, including CD83, MHC-Class II, and PD-L1. SSO-treated OSCCs augmented T cell proliferation following MLR. In vivo SSO administration significantly attenuated mouse tumor growth with an increased proportion of immune cells, including CD4+ T, CD8+ T, and dendritic cells; it also decreased the proportion of immune suppressive cells, such as myeloid-derived suppressor and regulatory T cells. These results suggest that the selective inhibition of CD36 can induce direct and indirect antitumor effects by facilitating host antitumor immune responses in OSCCs.

File： ijms-25-09438.pdf

DOI： 10.3390/ijms25179438

Oral Focal Mucinosis of the Tongue: Case Report and Review of the Literature Reviewed

Ryota Kobayashi, Hideaki Hirai, Satoshi Maruyama, Jun-ichi Tanuma, Kei Tomihara

Cureus 16 ( 8 ) 2024.8

The effects of carbon-ion beam irradiation on three-dimensional in vitro models of normal oral mucosa and oral cancer: development of a novel tool to evaluate cancer therapy Reviewed

Eriko Naito, Kazuyo Igawa, Sho Takada, Kenta Haga, Witsanu Yortchan, Orakarn Suebsamarn, Ryota Kobayashi, Manabu Yamazaki, Jun-ichi Tanuma, Tsuyoshi Hamano, Takashi Shimokawa, Kei Tomihara, Kenji Izumi

In Vitro Cellular & Developmental Biology - Animal 2024.8

PAK4 inhibition augments anti-tumour effect by immunomodulation in oral squamous cell carcinoma. Reviewed International journal

Danki Takatsuka, Hidetake Tachinami, Nihei Suzuki, Manabu Yamazaki, Amirmoezz Yonesi, Mayu Takaichi, Shuichi Imaue, Shin-Ichi Yamada, Jun-Ichi Tanuma, Makoto Noguchi, Kei Tomihara

Scientific reports 14 ( 1 ) 14092 - 14092 2024.6

Language：English Publishing type：Research paper (scientific journal)

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumours, warranting novel treatments. Here, we examined the therapeutic efficacy of inhibiting p21 activated kinase 4 (PAK4) in OSCC and determined its immunomodulatory effect by focusing on the enhancement of anti-tumour effects. We examined PAK4 expression in OSCC cells and human clinical samples and analysed the proliferation and apoptosis of OSCC cells following PAK4 inhibition in vitro. We also investigated the effects of in vivo administration of a PAK4 inhibitor on immune cell distribution and T-cell immune responses in OSCC tumour-bearing mice. PAK4 was detected in all OSCC cells and OSCC tissue samples. PAK4 inhibitor reduced the proliferation of OSCC cells and induced apoptosis. PAK4 inhibitor significantly attenuated tumour growth in mouse and was associated with increased proportions of IFN-γ-producing CD8+ T-cells. Furthermore, PAK4 inhibitor increased the number of dendritic cells (DCs) and up-regulated the surface expression of various lymphocyte co-stimulatory molecules, including MHC-class I molecules, CD80, CD83, CD86, and CD40. These DCs augmented CD8+ T-cell activation upon co-culture. Our results suggest that PAK4 inhibition in OSCC can have direct anti-tumour and immunomodulatory effects, which might benefit the treatment of this malignancy.

File： s41598-024-64126-0.pdf

DOI： 10.1038/s41598-024-64126-0

Rapamycin Induces Phenotypic Alterations in Oral Cancer Cells That May Facilitate Antitumor T Cell Responses Invited Reviewed

Amirmoezz yonesi, Kei Tomihara, Danki Takatsuka, Hidetake Tachinami, Manabu Yamazaki, Amir Reza Younesi Jadidi, Mayu Takaichi, Shuichi Imaue, Kumiko Fujiwara, Shin-ichi Yamada, Jun-ichi Tanuma, Makoto Noguchi

Biomedicines 2024.5

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

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

Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 36 ( 4 ) 624 - 631 2024.4

口腔扁平上皮癌における異所性核酸受容分子の発現解析(Expression of heterotopic nucleic acid-sensing molecules in oral squamous cell carcinoma)

山崎学, 阿部達也, 丸山智, 田沼順一

日本病理学会会誌 113 ( 1 ) 351 - 351 2024.2

良性および悪性唾液腺腫瘍の診断におけるCD73免疫組織化学的検索(CD73 immunohistochemical analysis for the diagnosis of benign and malignant salivary gland tumors)

丸山智, 山崎学, 阿部達也, 田沼順一

日本病理学会会誌 113 ( 1 ) 351 - 351 2024.2

頭頸部扁平上皮癌における選択的スプライシングシグネチャーによる予後予測(Prediction of prognosis by alternative splicing signature in head and neck squamous cell carcinoma)

阿部達也, 凌一葦, 奥田修二郎, 山崎学, 丸山智, 田沼順一

日本病理学会会誌 113 ( 1 ) 296 - 296 2024.2

Wnt/β-catenin-C-kit axis may play a role in adenoid cystic carcinoma prognostication Reviewed

Shinsuke Fujii, Kana Hasegawa, Takashi Maehara, Kari J Kurppa, Kristiina Heikinheimo, Kristy A. Warner, Satoshi Maruyama, Yudai Tajiri, Jacques E. Nör, Jun-ichi Tanuma, Shintaro Kawano, Tamotsu Kiyoshima

Pathology - Research and Practice 254 155148 - 155148 2024.1

Comparing the Diagnostic Accuracy of Ultrasonography, CT, MRI, and PET/CT in Cervical Lymph Node Metastasis of Oral Squamous Cell Carcinoma Reviewed

Masaki Takamura, Yutaka Nikkuni, Takafumi Hayashi, Kouji Katsura, Hideyoshi Nishiyama, Manabu Yamazaki, Satoshi Maruyama, Jun-ichi Tanuma

Biomedicines 11 ( 12 ) 3119 - 3119 2023.11

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

(1) Background: In oral cancer staging, ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-[fluorine-18]fluoro-D-glucose (FDG) with positron emission tomography/computed tomography (PET/CT) are routinely used in clinical practice. The present study is a retrospective examination of the diagnostic accuracy of cervical lymph node metastasis using US, CT, MRI, and PET/CT, with histopathological diagnosis as a reference, to compare the different diagnostic imaging modalities. (2) Methods: The participants included 16 patients with oral squamous cell carcinoma who underwent US-, CT-, MRI-, and PET/CT-based preoperative diagnostic imaging and simultaneous primary lesion resection and neck dissection, including 82 level regions and 424 lymph nodes. We compared the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of each imaging modality based on the imaging results and the pathology results of metastasis. (3) Results: Of the four diagnostic imaging modalities, PET/CT exhibited the highest sensitivity but the lowest specificity and accuracy. US, CT, and MRI had high specificities. Comparing each level region and lymph node showed that differences were observed in PET/CT. (4) Conclusions: PET/CT to diagnose lymph node metastasis requires a comprehensive evaluation because it produces more false positives than other diagnostic imaging modalities. Using US, CT, and MRI, which have excellent spatial resolution, improves diagnostic accuracy at the lymph node level.

File： biomedicines-11-03119-v2.pdf

DOI： 10.3390/biomedicines11123119

Hypoxia-Induced Biosynthesis of the Extracellular Matrix Molecules, Perlecan and Fibronectin, Promotes the Growth of Pleomorphic Adenoma Cells In Vitro Models Reviewed

Satoshi Maruyama, Manabu Yamazaki, Tatsuya Abé, Jun Cheng, Takashi Saku, Jun-ichi Tanuma

Biomedicines 11 ( 11 ) 2981 - 2981 2023.11

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Salivary pleomorphic adenoma is histopathologically characterized by its colorful stroma with myxoid, chondroid, and hyaline appearances, due to enhanced biosynthesis of extracellular matrix (ECM) molecules and poor vascularity. Thus, pleomorphic adenoma cells embedded in the stroma typically survive under hypoxic conditions. We determined the expression kinetics of ECM molecules, such as perlecan and fibronectin (FN), under hypoxia in SM-AP1 cells which are duct epithelial differentiated cells, and in SM-AP4 cells, which are myoepithelial differentiated cells, cloned from pleomorphic adenoma of the parotid gland. We investigated hypoxia-inducible factor-1α (HIF-1α)-inducing pathways through a variety of ECM molecules in association with their cellular proliferation and migration. We observed that hypoxic conditions with elevated HIF-1α protein levels induced increased expression of perlecan and FN in SM-AP cells than in controls. Moreover, perlecan and FN knockdown reduced the proliferation of SM-AP1 and SM-AP4 cells under hypoxia. Further, SM-AP1 cell migration was enhanced by both perlecan and FN knockdown, whereas SM-AP4 cell migration was increased by perlecan knockdown and inhibited by fibronectin knockdown. The results indicated that pleomorphic adenoma cells can survive under hypoxic conditions by promoting cell proliferation via enhanced synthesis of ECM molecules. Overall, ECM molecules may be a new anti-tumor target under hypoxic conditions.

File： biomedicines-11-02981.pdf

DOI： 10.3390/biomedicines11112981

同種死細胞により誘導される口腔扁平上皮癌細胞の活性化メカニズム(Dead cancer cell-induced activation mechanisms of oral squamous cell carcinoma cells)

山崎学, 阿部達也, 丸山智, 田沼順一

日本癌学会総会記事 82回 233 - 233 2023.9

頭頸部扁平上皮癌における特異的選択的スプライシングの探索データベース解析とロングリード-ケンシング(Alternative splicing in head and neck squamous cell carcinoma: public database exploration and long-read sequencing)

阿部達也, 凌一葦, 奥田修二郎, 山崎学, 丸山智, 田沼順一

日本癌学会総会記事 82回 1083 - 1083 2023.9

Solitary central osteoma of the mandible with unusual clinicoradiological presentations: A case report and literature review Reviewed

Nyein Nyein Chan, Manabu Yamazaki, Hidenobu Sakuma, Takafumi Hayashi, Tadaharu Kobayashi, Jun‐ichi Tanuma

Oral Science International ( 20 ) 132 - 138 2023.7

Masticatory muscle tendon-aponeurosis hyperplasia that was initially misdiagnosed for polymyositis: a case report and review of the literature Reviewed

Wataru Katagiri, Daisuke Saito, Satoshi Maruyama, Makiko Ike, Hideyoshi Nisiyama, Takafumi Hayashi, Jun-ichi Tanuma, Tadaharu Kobayashi

Maxillofacial Plastic and Reconstructive Surgery 45 ( 18 ) 2023.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

Masticatory muscle tendon-aponeurosis hyperplasia (MMTAH) is a relatively newly identified clinical condition that manifests as trismus with a square-shaped mandible. Herein, we report a case of MMATH that was initially misdiagnosed for polymyositis due to trismus and simultaneous lower limb pain, with literature review.

Case presentation

A 30-year-old woman had a history of lower limb pain after exertion for 2 years. Initial physical examination had been performed at the Department of General Medicine in our hospital. There was also redness in the hands and fingers. Although polymyositis was suspected, it was denied. The patient visited our department for right maxillary wisdom tooth extraction.

Clinical examination revealed that the patient had a square-shaped mandible. The maximal mouth opening was 22 mm. There was no temporomandibular joint pain at the time of opening. Furthermore, there was awareness of clenching while working. Panoramic radiography revealed developed square mandibular angles with flattened condyles. Computed tomography showed enlarged masseter muscles with high-density areas around the anterior and lateral fascia. Magnetic resonance imaging also showed thickened tendons and aponeuroses on the anterior surface and inside bilateral masseter muscles. Finally, the patient was diagnosed with MMTAH. Bilateral aponeurectomy of the masseter muscles with coronoidectomy and masseter muscle myotomy was performed under general anesthesia. The maximum opening during surgery was 48 mm. Mouth opening training was started on day 3 after surgery. Histopathological examination of the surgical specimen showed that the muscle fibers were enlarged to 60 μm. Immunohistochemistry testing for calcineurin, which was associated with muscle hypertrophy due to overload in some case reports, showed positive results. Twelve months after surgery, the mouth self-opening and forced opening were over 35 mm and 44 mm, respectively.

Conclusions

Herein, we report a case of MMATH. Lower limb pain due to prolonged standing at work and overload due to clenching were considered risk factors for symptoms onset of MMATH.

File： Masticatory.pdf

DOI： 10.1186/s40902-023-00386-6

Other Link： https://link.springer.com/article/10.1186/s40902-023-00386-6/fulltext.html

Cholesterol Is a Regulator of CAV1 Localization and Cell Migration in Oral Squamous Cell Carcinoma Invited Reviewed

Nyein Nyein Chan, Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Kenta Haga, Masami Kawaharada, Kenji Izumi, Tadaharu Kobayashi, Jun-ichi Tanuma

International Journal of Molecular Sciences 24 ( 7 ) 6035 2023.3

唾液腺多形腺腫由来細胞は低酸素環境下にてCD73による増殖及び遊走能を亢進する

丸山智, 山崎学, 阿部達也, Chan Nyein Nyein, 田沼順一

日本病理学会会誌 112 ( 1 ) 292 - 292 2023.3

口腔扁平上皮癌におけるladinin-1と細胞極性・上皮性格制御

阿部達也, 山崎学, 丸山智, Chan Nyein Nyein, 田沼順一

日本病理学会会誌 112 ( 1 ) 289 - 289 2023.3

頭頸部癌特異的スプライシングイベントの探索

阿部達也, 山崎学, 丸山智, Chan Nyein Nyein, 田沼順一

日本病理学会会誌 112 ( 1 ) 291 - 291 2023.3

Liquid‐based cytology for differentiating two cases of pemphigus vulgaris from oral squamous cell carcinoma Reviewed International journal

Maruyama S, Yamazaki M, Abé T, Kato Y, Kano H, Sumita Y, Tomihara K, Tanuma J

Diagnostic Cytopathology 51 ( 5 ) 1 - 6 2023.2

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

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.

File： Diagnostic Cytopathology - 2023 - Maruyama - Liquid%E2%80%90based cytology for differentiating two cases of pemphigus vulgaris from.pdf

DOI： 10.1002/dc.25117

口底部に生じた異所性胃腸管嚢胞の1例

齋藤直朗, 丸山智, 加藤祐介, 竹内涼子, 田沼順一, 小林正治

日本口腔外科学会雑誌 69 ( 1 ) 27 - 31 2023.1

Language：Japanese Publisher：(公社)日本口腔外科学会

4歳5ヵ月女児。既往として出生前診断で指摘されていた口底部の嚢胞様病変に対し、生後3日に開窓術が施行され、病理組織学的に類表皮嚢胞と診断された。今回、3歳9ヵ月時に開窓部からの出血を主訴に当科へ受診となった。数日後に出血が治まったため、いったん終診となったが、4歳2ヵ月頃より唾仙痛様症状が出現したため再診した。口腔内所見および画像所見を踏まえて、開窓術後の変化を伴う口底部類表皮嚢胞と診断され、5歳時に全身麻酔下で嚢胞摘出術が行われた。その結果、病理組織学的に異所性胃腸管嚢胞と確定診断された。術後3年経過現在、再発なく、経過良好である。

Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01073&link_issn=&doc_id=20230201450005&doc_link_id=10.5794%2Fjjoms.69.27&url=https%3A%2F%2Fdoi.org%2F10.5794%2Fjjoms.69.27&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

天疱瘡2例のLBC法における細胞像の検討

丸山智, 山崎学, 阿部達也, 田沼順一

新潟県臨床細胞学会会報 ( 37 ) 54 - 54 2022.12

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

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

diagnotics 12 ( 2398 ) 2398 - 2398 2022.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：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.

File： diagnostics-12-02398.pdf

DOI： 10.3390/diagnostics12102398

Clinicopathologic factors influencing the screening accuracy of oral cytology: A retrospective cohort study Reviewed International journal

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 2022.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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.

File： ol_24_5_13505_PDF.pdf

DOI： 10.3892/ol.2022.13505

Oral cytology can easily spot serious diseases Invited

Dental Outlook 140(3) ( 9 ) 500 - 508 2022.9

Metastasis of pulmonary adenocarcinoma to the oral cavity: A case report and literatures review of the last 30 years Reviewed

Masami Kawaharada, Satoshi Maruyama, Tatsuya Abé, Takafumi Hayashi, Tadaharu Kobayashi, Jun‐ichi Tanuma

Oral Science International 1 - 6 2022.9

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley

File： Oral Science International - 2022 - Kawaharada - Metastasis of pulmonary adenocarcinoma to the oral cavity A case report.pdf

DOI： 10.1002/osi2.1130

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/osi2.1130

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

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 2022.9

Novel cytological model for the identification of early oral cancer diagnostic markers: The carcinoma sequence model. Invited Reviewed International journal

Masami Kawaharada, Manabu Yamazaki, Satoshi Maruyama, Tatsuya AbÉ, Nyein Nyein Chan, Taiichi Kitano, Tadaharu Kobayashi, Takeyasu Maeda, Jun-Ichi Tanuma

Oncology letters 23 ( 3 ) 76 2022.3

Language：English Publishing type：Research paper (scientific journal)

Most oral squamous cell carcinomas (OSCCs) arise from a premalignant lesion, oral epithelial dysplasia; however, useful markers for the early detection of OSCC are lacking. The present study aimed to establish a novel experimental model to observe changes in the sequential expression patterns of mRNAs and proteins in a rat model of tongue cancer using liquid-based cytology techniques. Cytology specimens were collected at 2, 5, 8, 11, 14, 17 and 21 weeks from rats treated with 4-nitroquinoline 1-oxide to induce tongue cancer. The expression of candidate biomarkers was examined by performing immunocytochemistry and reverse transcription-quantitative PCR. The percentage of positively stained nuclei was calculated as the labeling index (LI). All rats developed OSCC of the tongue at 21 weeks. The mRNA expression levels of bromodomain protein 4 (Brd4), c-Myc and Tp53 were upregulated during the progression from negative for intraepithelial lesion or malignancy to squamous cell carcinoma (SCC). Brd4- and c-Myc-LI increased in low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion and SCC specimens. p53-LI was significantly increased in SCC specimens. This novel experimental model allowed the observation of sequential morphological changes and the expression patterns of mRNAs and proteins during carcinogenesis. Combining immunocytochemistry with cytology-based diagnoses may potentially improve the diagnostic accuracy of OSCC.

File： ol_23_3_13196_PDF.pdf

DOI： 10.3892/ol.2022.13196

口腔上皮の反応異型と上皮内扁平上皮癌

田沼順一

病理と臨床 40 ( 3 ) 281 - 283 2022.3

Melanotic neuroectodermal tumor of infancy in the mandible: A case report. Reviewed International journal

Ryoko Takeuchi, Akinori Funayama, Yohei Oda, Tatsuya Abé, Manabu Yamazaki, Satoshi Maruyama, Takafumi Hayashi, Jun-Ichi Tanuma, Tadaharu Kobayashi

Medicine 100 ( 50 ) e28001 2021.12

Language：English Publishing type：Research paper (scientific journal)

RATIONALE: Melanocytic neuroectodermal tumor of infancy (MNTI) is a rare benign pigmented neoplasm that arises from the neural crest and has an aggressive growth pattern. It is predominantly seen in infants under 1 year of age, and the most common site of involvement is the maxilla. The currently accepted treatment is removal by surgical resection. Herein, we report a case of MNTI that involved the anterior alveolar ridge of the mandible in a 6-month-old infant. PATIENT CONCERNS: A case of a 6-month-old male child with a huge mass in the anterior alveolar ridge of the mandible. DIAGNOSIS: The tumor was diagnosed using histopathological and immunohistochemical techniques on the biopsy specimen obtained following incisional biopsy. Based on the findings, a final diagnosis of MNTI was established. INTERVENTIONS: Radical resection of the tumor was performed, after determining the extent of resection by referring to the mandibular 3D model created using the pre-operative CT data. OUTCOMES: The postoperative course was uneventful, and no recurrence has been observed to date for more than 4 years after surgery. LESSONS: This case emphasizes that early diagnosis and radical surgery are critical to the effective treatment, as MNTI exhibits rapid and destructive growth. It also requires careful and close follow-up because of high recurrence rates.

File： Melanotic_neuroectodermal_tumor_of_infancy_in_the.24.pdf

DOI： 10.1097/MD.0000000000028001

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders in the oral cavity: a clinicopathologic study of 4 cases and literature review Reviewed

Masami Kawaharada, Satoshi Maruyama, Tatsuya Abé, Manabu Yamazaki, Akira Kurokawa, Wataru Katagiri, Ritsuo Takagi, Takafumi Hayashi, Tadaharu Kobayashi, Jun-ichi Tanuma

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 132 ( 6 ) 687 - 697 2021.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

Objectives: Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OI-LPD) have been reported as one of the adverse effects of immunosuppressive therapy. The aim of this study was to describe the clinicopathologic and immunohistochemical features of OI-LPD in the oral cavity. Study Design: Immunohistochemistry was performed to describe the immunohistochemical features in our 4 cases. The results were analyzed along with 62 cases of oral OI-LPD in the English and Japanese literature to define clinical and pathologic characteristic features. Results: In our immunohistochemical analysis, Epstein-Barr virus (EBV)–positive OI-LPD showed a higher percentage of mouse double minute 2–positive cells than EBV-negative samples. A literature survey revealed that OI-LPD (including the present cases) arises primarily in the gingiva, followed by the tongue, and usually occurs with a male-to-female ratio of 1:1.9. The rate of EBV positivity was 93.8%. Further, 31 of 66 patients had osteonecrosis of the jaw and 24 of 31 patients had taken multiple immunosuppressive drugs in combination. Conclusions: We can therefore conclude that the overexpression of mouse double minute 2 in OI-LPD is associated with EBV infection, and the combination of multiple immunosuppressive drugs may be a risk factor for osteonecrosis of the jaw.

File： 1-s2.0-S2212440321004648-main.pdf

DOI： 10.1016/j.oooo.2021.05.015

Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression Reviewed International journal

Kenta Haga, Manabu Yamazaki, Satoshi Maruyama, Masami Kawaharada, Ayako Suzuki, Emi Hoshikawa, Nyein Nyein Chan, Akinori Funayama, Toshihiko Mikami, Tadaharu Kobayashi, Kenji Izumi, Jun-ichi Tanuma

Translational Oncology 14 ( 12 ) 101236 - 101236 2021.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

Cancer-associated fibroblasts (CAFs) have important roles in promoting cancer development and progression. We previously reported that high expression of sex-determining region Y (SRY)-box9 (SOX9) in oral squamous cell carcinoma (OSCC) cells was positively correlated with poor prognosis. This study developed three-dimensional (3D) in vitro models co-cultured with OSCC cells and CAFs to examine CAF-mediated cancer migration and invasion in vitro and in vivo. Moreover, we performed an immunohistochemical analysis of alpha-smooth muscle actin and SOX9 expression in surgical specimens from 65 OSCC patients. The results indicated that CAFs promote cancer migration and invasion in migration assays and 3D in vitro models. The invading OSCC cells exhibited significant SOX9 expression and changes in the expression of epithelial-mesenchymal transition (EMT) markers, suggesting that SOX9 promotes EMT. TGF-β1 signalling inhibition reduced SOX9 expression and cancer invasion in vitro and in vivo, indicating that TGF-β1-mediated invasion is dependent on SOX9. In surgical specimens, the presence of CAFs was correlated with SOX9 expression in the invasive cancer nests and had a significant impact on regional recurrence. These findings demonstrate that CAFs promote cancer migration and invasion via the TGF-β/SOX9 axis.

File： 1-s2.0-S193652332100228X-main.pdf

DOI： 10.1016/j.tranon.2021.101236

Response to Letter to the Editor “Ectomesenchymal chondromyxoid tumour on the lateral border of the tongue: some historical and clinical considerations”

K. Sakurai, K. Nakamori, M. Yamazaki, J.-i. Tanuma

International Journal of Oral and Maxillofacial Surgery 2021.10

Spindle cell squamous cell carcinoma exhibiting prominent neutrophil phagocytosis: a case report. International journal

Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Yoshimasa Sumita, Yuji Katsumi, Yutaka Nikkuni, Takafumi Hayashi, Jun-Ichi Tanuma

Journal of medical case reports 15 ( 1 ) 438 - 438 2021.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Spindle cell squamous cell carcinoma is an uncommon variant of squamous cell carcinoma; its diagnosis is sometimes challenging because it histopathologically resembles neoplastic or reactive spindle cell lesions of mesenchymal origins. Here, we report a rare case of spindle cell squamous cell carcinoma exhibiting prominent neutrophil phagocytosis. CASE PRESENTATION: A 69-year-old Japanese man presented with pain and a polypoid mass on the lower left gingiva. He had received chemoradiotherapy for squamous cell carcinoma of the buccal mucosa 15 years prior to this consultation. In addition, he was treated for mandibular osteonecrosis 6 years after chemoradiotherapy without evidence of cancer recurrence. A biopsy revealed atypical spindle or pleomorphic cells scattered in the edematous and fibrin-rich stroma; however, no malignant squamous components were apparent. These atypical cells frequently contained neutrophils within their cytoplasm that formed cell-in-cell figures. Immunohistochemically, the atypical cells were negative for cytokeratins, epithelial membrane antigen, and E-cadherin, but positive for p63, vimentin, and p53. Although these findings suggested spindle cell squamous cell carcinoma, it was difficult to reach a definitive diagnosis. Based on a clinical diagnosis of a malignant tumor, the patient underwent a hemimandibulectomy. The surgically resected specimen had a typical spindle cell squamous cell carcinoma histology consisting of biphasic spindle cells and conventional squamous cell carcinoma components. Moreover, the surgical specimen also exhibited spindle tumor cells that frequently included neutrophils, around which intense staining for lysosomal-associated membrane protein 1 and cathepsin B was observed. This suggested that the cell-in-cell figures represent active neutrophil phagocytosis by tumor cells, and not emperipolesis. CONCLUSION: The presence of neutrophil phagocytosis may be a potent indicator of malignancy.

File： s13256-021-03066-z.pdf

DOI： 10.1186/s13256-021-03066-z

Central mucoepidermoid carcinoma arising directly from a glandular odontogenic cyst of the mandible: a case report. Reviewed International journal

Satoshi Maruyama, Taisuke Mori, Manabu Yamazaki, Tatsuya Abé, Eijitsu Ryo, Hiroyuki Kano, Go Hasegawa, Jun-Ichi Tanuma

Diagnostic pathology 16 ( 1 ) 61 - 61 2021.7

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Central mucoepidermoid carcinoma (MEC) is a rare salivary gland tumor that affects the jawbone. Glandular odontogenic cyst (GOC) is also a rare odontogenic developmental cyst with glandular differentiation. GOC shares some histological features with central MEC, and a pre-existing GOC can develop into central MEC. Here, we present a rare case of central MEC developed directly from a pre-existing GOC of the mandible. CASE PRESENTATION: A 67-year-old Japanese man presented with a cystic lesion in the right third molar region. Histologically, the biopsy specimen demonstrated both typical findings of a GOC component lined with non-keratinized squamous epithelium and a recognizable component of central MEC consisting of polycystic nests with mucous cells, intermediate cells, and epidermoid cells in the cyst wall. The results from the immunohistochemistry for cytokeratin (CK) profiling demonstrated that, while both central MEC and GOC expressed CKs 7, 14, 18, and 19, CK13 was interestingly exclusively expressed in GOC. Fluorescence in-situ hybridization (FISH) revealed the rearrangement of the Mastermind like (MAML)-2 gene in both the MEC and GOC components. CONCLUSIONS: Our case suggests that central MEC and GOC may be in the same spectrum of diseases caused by the rearrangement of the MAML-2 gene. However, given that the expression profile of CK13 was completely different between central MEC and GOC, they can be considered as separate tumors. Overall, we demonstrated a rare case in which central MEC may have originated directly from the GOC.

File： maruyama.pdf

DOI： 10.1186/s13000-021-01124-0

A comparative study between CT, MRI, and intraoral US for the evaluation of the depth of invasion in early stage (T1/T2) tongue squamous cell carcinoma Reviewed

Masaki Takamura, Taichi Kobayashi, Yutaka Nikkuni, Kouji Katsura, Manabu Yamazaki, Satoshi Maruyama, Jun-ichi Tanuma, Takafumi Hayashi

Oral Radiology 38 ( 1 ) 114 - 125 2021.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

<title>Abstract</title><sec>
<title>Objectives</title>
This study aimed to clarify the accuracy of intraoral ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) in preoperative image depth of invasion (DOI) measurement of T1/T2 tongue cancer through comparison with histopathological measurements.

</sec><sec>
<title>Methods</title>
Imaging of the primary lesions was performed at our hospital; the lesions were classified into T1 and T2 based on the 8th edition of the AJCC/UICC, and surgery performed. There was histopathological confirmation of lesions as squamous cell carcinoma in 48 patients with tongue cancer. T3 and T4 cases, cases in which preoperative chemotherapy and radiation therapy were performed, and cases where biopsy was performed before imaging were excluded. The radiological DOI in US, CT, and MRI and the histopathological DOI as base were comparatively investigated and statistical analyses were performed by Bland–Altman analysis and Spearman's rank correlation coefficient.

</sec><sec>
<title>Results</title>
Bland–Altman analysis showed that the US radiological DOI was overestimated by an average of 0.2 mm compared to the histopathological DOI, while CT and MRI radiological DOI were overestimated by an average of 2–3 mm. The comparison of CT and MRI revealed that the difference between the MRI and histopathological DOI, as well as the 95% limit of agreement, were smaller than those of the CT radiological DOI.

</sec><sec>
<title>Conclusions</title>
US is the most accurate preoperative diagnostic tool for T1 and T2 squamous cell carcinoma; CT and MRI tend to have an overestimation of about 2–3 mm and so caution is required.

</sec>

File： Takamura2021_Article_AComparativeStudyBetweenCTMRIA.pdf

DOI： 10.1007/s11282-021-00533-7

Other Link： https://link.springer.com/article/10.1007/s11282-021-00533-7/fulltext.html

Identification and characterization of R2TP in the development of oral squamous cell carcinoma. International journal

Tetsuo Kiguchi, Yoshito Kakihara, Manabu Yamazaki, Kouji Katsura, Kenji Izumi, Jun-Ichi Tanuma, Takashi Saku, Ritsuo Takagi, Makio Saeki

Biochemical and biophysical research communications 548 161 - 166 2021.4

Language：English Publishing type：Research paper (scientific journal)

R2TP is a well-conserved molecular chaperone complex, composed of Pontin, Reptin, RPAP3, and PIH1D, in eukaryotes. Recent studies have suggested an involvement of R2TP in cancer development. However, it remains unclear if it is related to the development of oral squamous cell carcinoma (OSCC), which is the most common type of oral cancer. Here, we identify and investigate the function of R2TP in OSCC development. Immunohistochemical analysis reveals that all of the R2TP components are strongly expressed in normal oral epithelia and OSCC tissues, where actively proliferating cells are abundant. Co-immunoprecipitation assay identifies that R2TP components form a protein complex in OSCC-derived HSC4-cells. Knockdown experiments show that all R2TP components, except for RPAP3, are required for the cell proliferation and migration of HSC-4 cells. Furthermore, we reveal that Pontin contributes to a gain-of-function (GOF) activity of mutp53-R248Q in HSC-4 cells by regulating phosphorylation levels of mutp53 at Ser15 and Ser46. To our knowledge, this study is the first to report the functional involvement of R2TP and its components in the malignant characteristics of OSCC cells.

DOI： 10.1016/j.bbrc.2021.02.074

Bethesda system for oral cytology：differentiation points for NILM, LSIL, HSIL and SCC Invited Reviewed

Jun-ichi Tanuma

38 ( 2 ) 136 - 145 2021.4

Low-grade myofibroblastic sarcoma of the tongue with difficulty of diagnosis: a case report and review of the literature. Reviewed

Kawaharada M, Katagiri W, Maruyama S, Nishiyama H, Hayashi T, Kobayashi T, Tanuma J

Journal of Oral and Maxillofacial Surgery, Medicine and Pathology 33 ( 1 ) 93 - 97 2021.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

We describe a case of low-grade myofibroblastic sarcoma (LGMS) on the dorsum of the tongue. A 41-year-old Japanese man noticed that a mass on the dorsal surface of the tongue had been present for 8 months. Computed tomography showed a homogeneously enhancing mass measuring 16 x 14 mm in the midline of the tongue. Magnetic resonance imaging showed a homogeneously enhancing mass with an almost clear margin on post-contrast T1-weighted imaging. The lesion was homogeneous with high signal intensity on T2-weighted imaging. The patient underwent excisional biopsy. Histologically, the tumor had an indistinct margin and was composed of spindle-shaped cells arranged in cellular fascicles. The cell nuclei showed signs of mild atypia. Positive staining for desmin and less strong staining for a-smooth muscle actin revealed that the tumor cells were myofibroblasts or smooth muscle cells. The tumor cells were negative for h-caldesmon. The MIB-1 labeling index of the tumor was 4.9 %. Thus, based on the histopathological, immunohistochemical and imaging findings, the tumor was finally diagnosed as LGMS. We reviewed the literature on the immunohistochemistry of LGMS. We suggest that immunohistochemistry is helpful in the differential diagnosis of LGMS.

File： kawaharada.pdf

DOI： 10.1016/j.ajoms.2020.07.011

Corrigendum to “An ectomesenchymal chondromyxoid tumour on the lateral border of the tongue” [Int J Oral Maxillofac Surg 49 (2020) 1290–1203] (International Journal of Oral … Maxillofacial Surgery (2020) 49(10) (1290–1293), (S0901502720301399), (10.1016/j.ijom.2020.04.010))

K. Sakurai, K. Nakamori, M. Yamazaki, J. I. Tanuma

International Journal of Oral and Maxillofacial Surgery 2021

Language：English Publishing type：Research paper (scientific journal) Publisher：Churchill Livingstone

The authors regret that although we stated “four cases with lesions involving the floor of the mouth and two with lesions involving the hard palate have been reported”, none actually involved the oral floor. We erroneously called the base of the tongue as the floor of the mouth. Therefore, we would like to correct this to “four cases with lesions involving the base of the tongue and two with lesions involving the hard palate have been reported”. The authors would like to apologise for any inconvenience caused.

DOI： 10.1016/j.ijom.2021.05.021

口腔細胞診のベセスダシステムとLBC法の標本作製 Invited

田沼順一

細胞検査士会報 68 ( 1 ) 3 - 7 2020.12

17年を経過して再減量手術を行った上顎骨線維性異形成症の1例

伊藤元貴, 児玉泰光, 大貫尚志, 高村真貴, 林孝文, 阿部達也, 田沼順一, 小林正治, 高木律男

新潟歯学会雑誌 50 ( 2 ) 79 - 85 2020.12

Language：Japanese Publisher：新潟歯学会

線維性異形成症(FD)は正常な骨組織が線維性結合組織で置換され増殖することを特徴とする非腫瘍性骨病変である。骨格成長後にはFDの増殖が静止するとされているが、成人期でも増大をきたすことがある。今回、上顎骨FDの減量手術後再増大をきたし、再び減量手術が必要となった症例を経験したので報告する。患者は42歳の男性。25歳の時に上顎骨FDの減量手術を施行されるも受診が途絶え、再増大による顔面非対称をきたしたため17年後に当科初診となった。顔面非対称改善と病変増大による機能障害の予防のため、右側上顎骨頬側と口蓋側の2回に分けて減量手術を行った。削除量の目安としてCT画像から3次元実体モデルを利用してサージカルガイドを制作し、術中の対称性確認と手術時間の短縮を行った。術後3年経過した現在、明らかな再増大はない。今回もあくまで減量手術であり、病巣の残遺に伴う病態変化の可能性についての患者教育とともに長期の経過管理が重要と考えられた。(著者抄録)

Frequent Germline and Somatic Single Nucleotide Variants in the Promoter Region of the Ribosomal RNA Gene in Japanese Lung Adenocarcinoma Patients Reviewed International journal

Riuko Ohashi, Hajime Umezu, Ayako Sato, Tatsuya Abé, Shuhei Kondo, Kenji Daigo, Seijiro Sato, Norikazu Hara, Akinori Miyashita, Takeshi Ikeuchi, Teiichi Motoyama, Masashi Kishi, Tadahiro Nagaoka, Keiko Horiuchi, Atsushi Shiga, Shujiro Okuda, Tomoki Sekiya, Aya Ohtsubo, Kosuke Ichikawa, Hiroshi Kagamu, Toshiaki Kikuchi, Satoshi Watanabe, Jun-Ichi Tanuma, Peter Schraml, Takao Hamakubo, Masanori Tsuchida, Yoichi Ajioka

Cells 9 ( 11 ) 2409 - 2409 2020.11

Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called “ribosomopathies,” including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions −248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p < 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

File： cells-09-02409-v2.pdf

DOI： 10.3390/cells9112409

前舌腺に発生した腺癌NOSの1例

三上俊彦, 船山昭典, 西山秀昌, 山崎学, 田沼順一, 小林正治

日本口腔外科学会雑誌 66 ( 11 ) 553 - 558 2020.11

Language：Japanese Publisher：(公社)日本口腔外科学会

52歳女。舌の違和感を主訴に近医を受診し、右側舌腫瘍を指摘された。他院のMRIで腫瘍性病変を認められ、当科での加療を勧められて来院した。右側舌下面粘膜下に15×15×15mm大の比較的境界明瞭な弾性硬の腫瘤を認めた。画像所見からは腺系腫瘍が示唆され、良悪性を含めた病理組織学的診断目的に生検を行ったが、組織型の確定には至らず、舌癌の診断のもと全身麻酔下に舌部分切除術を施行した。切除標本の病理組織所見は、淡明細胞の胞巣状増殖が主体ながら、粘液産生を示す二相性腺管がわずかに混在していたことから、鑑別疾患として筋上皮癌、上皮筋上皮癌、多型腺癌、明細胞癌が挙げられた。免疫染色によって筋上皮癌、上皮筋上皮癌、多型腺癌は否定され、EWSR1遺伝子のFISH解析によって明細胞癌も否定されたため腺癌NOS(not otherwise specified)と診断した。術後4年の現在まで再発・転移は認めていない。

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01073&link_issn=&doc_id=20201130470003&doc_link_id=10.5794%2Fjjoms.66.553&url=https%3A%2F%2Fdoi.org%2F10.5794%2Fjjoms.66.553&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Rac1-dependent phagocytosis of apoptotic cells by oral squamous cell carcinoma cells: A possible driving force for tumor progression. Reviewed International journal

Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Masayuki Tsuneki, Hiroko Kato, Kenji Izumi, Jun-Ichi Tanuma, Jun Cheng, Takashi Saku

Experimental cell research 392 ( 1 ) 112013 - 112013 2020.7

Language：English Publishing type：Research paper (scientific journal)

Apoptotic cell death frequently occurs in human cancer tissues including oral squamous cell carcinoma (SCC), wherein apoptotic tumor cells are phagocytosed not only by macrophages but also by neighboring tumor cells. We previously reported that the engulfment of apoptotic SCC cells by neighboring SCC cells frequently occurs at the invading front. Therefore, we hypothesized that the phagocytosis of these apoptotic cells by tumor cells contributes to disease progression. Herein, using cultured oral SCC cells, we aimed to confirm whether tumor cells actually phagocytose apoptotic cells and to examine whether cellular activities are regulated by the phagocytosis of apoptotic cells. Co-culture experiments showed that living cells could ingest apoptotic cells into phagolysosomes. NSC23766, an inhibitor of Rac1, which is a key regulator of phagocytic cup formation in professional phagocytes, dramatically suppressed the phagocytosis of apoptotic cells by living cells. Additionally, cell migration and the secretion of DKK1, a tumor-promoting protein, were enhanced by co-culture with apoptotic cells, whereas NSC23766 inhibited these effects. These results show that tumor cells can actively phagocytose apoptotic neighbors in a Rac1-dependent manner and that such activity increases their migration. The regulation of apoptotic cell phagocytosis thus represents new directions for therapeutic intervention for oral cancer.

File： 1-s2.0-S0014482720302354-main.pdf

DOI： 10.1016/j.yexcr.2020.112013

An ectomesenchymal chondromyxoid tumour on the lateral border of the tongue. Reviewed International journal

K Sakurai, K Nakamori, M Yamazaki, J-I Tanuma

International journal of oral and maxillofacial surgery 2020.5

Language：English

Ectomesenchymal chondromyxoid tumour (ECT) is an extremely rare intraoral mesenchymal tumour. Most of these tumours have been identified on the anterior aspect of the dorsal surface of the tongue. ECT is difficult to diagnose because of its rarity. We report a case of ECT arising on the lateral border of the tongue in a 67-year-old woman. The tumour, measuring 20 × 10 mm in size, was surgically removed. Histopathologically, the tumour was composed of small polygonal cells arranged in sheets, with a myxoid or hyalinized stroma. The tumour boundary was clear; however, the tumour showed a multinodular structure expanding along the tongue surface without obvious capsule. Careful examination revealed the tumour nodule to be spreading in a skip lesion-like fashion away from the main part of the tumour in the striated muscle layer. Although there was no evidence of recurrence at 18 months after the surgery, our observations suggest that surgery for ECT resection with a safety margin is more appropriate than enucleation.

File： 1-s2.0-S0901502720301399-main.pdf

DOI： 10.1016/j.ijom.2020.04.010

The usefulness of oral LBC for oral disease-Fast, cheap, and accurate of oral cytology- Invited Reviewed

Jun-ichi Tanuma

Niigata Dental Journal 50 ( 1 ) 1 - 6 2020.1

Masseter muscle hypertrophy: A case report Reviewed

Masayuki Tsuneki, Satoshi Maruyama, Manabu Yamazaki, Kanae Niimi, Tadaharu Kobayashi, Hideyoshi Nishiyama, Takafumi Hayshi, Jun-ichi Tanuma

JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY MEDICINE AND PATHOLOGY 31 ( 6 ) 428 - 431 2019.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Masseter muscle hypertrophy is defined as the unilateral or bilateral expansion of the masseter muscle, and little is known about its etiology. Here we report a case of masseter muscle hypertrophy in a female patient in her 20 s who complained of facial asymmetry. Because of the hemifacial overgrowth of the right-side maxillofacial region from birth, she was thought to have congenital hemifacial hyperplasia. After orthodontic treatment and osteotomy, the patient underwent debulking of the right masseter muscle. Histologically, the surgical specimens exhibited thick masseter muscle fibers arranged irregularly. Masseter muscle cells exhibited diameters in the range of 20-60 mu m.

File： 1-s2.0-S2212555819301905-main.pdf

DOI： 10.1016/j.ajoms.2019.08.005

Cytoplasmic expression of SOX9 as a poor prognostic factor for oral squamous cell carcinoma. Reviewed International journal

Yoshimasa Sumita, Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Jun Cheng, Ritsuo Takagi, Jun-Ichi Tanuma

Oncology reports 40 ( 5 ) 2487 - 2496 2018.11

Language：English Publishing type：Research paper (scientific journal)

Transcription factor SRY‑box 9 (SOX9) is a key regulator of chondrocyte differentiation and sex determination, and it is also involved in the progression of various types of human cancer. However, its putative association with oral squamous cell carcinoma (OSCC) remains elusive. The aim of the present study was to investigate the expression profiles of SOX9 in various oral epithelial lesions, including OSCC. We performed immunohistochemical analysis of SOX9 expression in surgical specimens of OSCC, which simultaneously exhibited different grades of epithelial lesions, and analyzed the correlation between SOX9 expression and several clinicopathological factors. Moreover, we performed immunofluorescent staining, western blot analysis and real‑time reverse transcription‑polymerase chain reaction to assess SOX9 expression in OSCC HSC‑3 (a metastatic cell line) and HSC‑4 (a non‑metastatic cell line) cell lines. In surgical specimens, SOX9 expression was detected in the nuclei of proliferating cells in areas with epithelial dysplasia and carcinoma in situ, but not in areas with normal epithelia. Nuclear SOX9 expression was observed in most SCC cells. Notably, cytoplasmic SOX9 expression was confirmed only in some SCC cells; however, cytoplasmic SOX9 expression was significantly and positively correlated with poor clinical outcomes. Both protein and mRNA expression of SOX9 were significantly higher in the HSC‑3 cell line than that in the HSC‑4 line. Notably, however, only HSC‑3 cells exhibited cytoplasmic localization of SOX9 expression. Our findings indicate that SOX9 may be involved in the tumorigenesis and progression of OSCC. Furthermore, its cytoplasmic expression represents a potential predictive biomarker for tumor aggressiveness and OSCC prognosis.

File： 2018SOX9 oncology report.pdf

DOI： 10.3892/or.2018.6665

A case of glandular odontogenic cyst arising in the maxillary premolar region. Reviewed

Tanaka S, Kaneko Y, Inagaki Y, Nagayama M, Tanuma J, Sumitomo S

Jpn. J. Oral Maxillofac. Surg 64 ( 10 ) 577 - 581 2018.10

口腔の液状検体細胞診の可能性 Invited Reviewed

田沼順一

1 ( 1 ) 1 - 2 2018.6

口腔扁平上皮癌におけるSOX9細胞質発現は予後不良と関連する

田沼順一, 高木律男, 隅田賢正

新潟歯学会雑誌 48 ( 1 ) 55 - 56 2018.6

Gorham-Stout disease: Progressive massive osteolysis of the mandible Reviewed

Makoto Matsubara, Makoto Adachi, Jun-ichi Tanuma, Yasunori Muramatsu, Shinichiro Sumitomo

Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 ( 2 ) 147 - 151 2016.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ltd

Gorham-Stout disease (GSD) is an extremely rare massive osteolytic bone disease, and the pathogenesis and etiology are unknown. It is characterized by the uncontrolled proliferation of distended, thin-walled vascular and lymphatic channels within bone, which leads to resorption and replacement of the bone with angiomas and/or fibrosis.A 35-year-old man had complained of masticatory disturbance caused by mandibular teeth mobility and mandibular swelling for several years. He suffered from an eating disorder because of the severe mobility of his mandibular teeth, and he presented at our hospital for consultation. He had swelling and grade III mobility without pain
his skin was normal in color with a 70 mm × 50 mm lesion of elastic and firm texture at the submental region. The ill-defined mandibular bone destruction was seen radiographically. Magnetic resonance imaging (MRI) showed that the lesion occupied the submental region and inside the mandibular bone, and these lesions were isolated. The biopsy results suggested a diagnosis of lymphangioma. The patient received radical surgery, and histological examination suggested lymphangioma. We diagnosed GSD because massive osteolysis of the mandible associated with lymphangioma was seen in the lesion. The postoperative course was uneventful, with no local recurrence 36 months after surgery. Given the rarity of this disease entity, there is no standard therapy. The details of this case are presented, and diagnostic and management considerations are described.

File： 1-s2.0-S2212555815002008-main-2.pdf

DOI： 10.1016/j.ajoms.2015.09.007

Inflammatory Myofibroblastic Tumor Mimicking Apical Periodontitis. Reviewed International journal

Makoto Adachi, Kazuki Kiho, Genta Sekine, Takahisa Ohta, Makoto Matsubara, Takakazu Yoshida, Akitoshi Katsumata, Jun-ichi Tanuma, Shinichiro Sumitomo

Journal of endodontics 41 ( 12 ) 2079 - 82 2015.12

Language：English Publishing type：Research paper (scientific journal)

Inflammatory myofibroblastic tumors (IMTs) are rare. IMTs of the head and neck occur in all age groups, from neonates to old age, with the highest incidence occurring in childhood and early adulthood. An IMT has been defined as a histologically distinctive lesion of uncertain behavior. This article describes an unusual case of IMT mimicking apical periodontitis in the mandible of a 42-year-old man. At first presentation, the patient showed spontaneous pain and percussion pain at teeth #28 to 30, which continued after initial endodontic treatment. Panoramic radiography revealed a radiolucent lesion at the site. Cone-beam computed tomographic imaging showed osteolytic lesions, suggesting an aggressive neoplasm requiring incisional biopsy. Histopathological examination indicated an IMT. The lesion was removed en bloc under general anesthesia, and the patient manifested no clinical evidence of recurrence for 24 months. Lesions of nonendodontic origin should be included in the differential diagnosis of apical periodontitis. Every available diagnostic tool should be used to confirm the diagnosis. Cone-beam computed tomographic imaging is very helpful for differential diagnosis in IMTs mimicking apical periodontitis.

File： 1-s2.0-S0099239915008316-main.pdf

DOI： 10.1016/j.joen.2015.09.006

A case of sinonasal undifferentiated carcinoma treated without radical resection Reviewed

Takahisa Ohta, Masayuki Motohashi, Yasunori Muramatsu, Shinichiro Sumitomo, Jun-ichi Tanuma, Michio Shikimori

Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 27 ( 2 ) 216 - 220 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ltd

Sinonasal undifferentiated carcinoma (SNUC) is a rare and highly aggressive neoplasm of the paranasal sinuses. SNUC is characterized by rapid expansion with high rates of recurrence and metastasis to cervical lymph nodes and distant sites. The patient was a 65-year-old woman who complained of persistant pain at the right maxilla. She had undergone endodontic therapy at the right first molar by her primary dentist. Imaging studies, including computed tomography (CT) and magnetic resonance imaging (MRI), showed a lesion occupying the right maxillary sinus and extending into the nasal cavity and ethmoid sinus. A malignant tumor of the maxillary sinus was suspected, and a biopsy was performed. The lesion was diagnosed as sinonasal undifferentiated carcinoma. The patient was treated with chemoradiation therapy. After 4 cycles of chemoradiation therapy, CT and MRI showed shrinkage of the lesion and changes consistent with necrosis. Histological examination of a repeat biopsy specimen after the 4 cycles of chemoradiation did not contain tumor cells. 2 more cycles of chemoradiation therapy were added. Six months after the initial diagnosis, CT finding suggested residual tumor in the ethmoid sinus. We performed another biopsy and the histopathological analysis was negative for tumor. The patient has been followed for 33 months since completing chemoradiation therapy, and there has not been any further evidence of disease.

File： 1-s2.0-S2212555813001828-main.pdf

DOI： 10.1016/j.ajoms.2013.10.001

Establishment of a novel dwarf rat strain: cartilage calcification insufficient (CCI) rats. Reviewed

Masami Tanaka, Minoru Watanabe, Izuru Yokomi, Naoki Matsumoto, Katsuko Sudo, Hitoshi Satoh, Tsuneo Igarashi, Azusa Seki, Hitoshi Amano, Kiyoshi Ohura, Kakei Ryu, Shunichi Shibata, Motohiko Nagayama, Jun-ichi Tanuma

Experimental animals 64 ( 2 ) 121 - 8 2015

Language：English Publishing type：Research paper (scientific journal)

Rats with dwarfism accompanied by skeletal abnormalities, such as shortness of the limbs, tail, and body (dwarf rats), emerged in a Jcl-derived Sprague-Dawley rat colony maintained at the Institute for Animal Experimentation, St. Marianna University Graduate School of Medicine. Since the dwarfism was assumed to be due to a genetic mutation based on its frequency, we bred the dwarf rats and investigated their characteristics in order to identify the causative factors of their phenotypes and whether they could be used as a human disease model. One male and female that produced dwarf progeny were selected, and reproduction was initiated by mating the pair. The incidence of dwarfism was 25.8% among the resultant litter, and dwarfism occurred in both genders, suggesting that it was inherited in an autosomal recessive manner. At 12 weeks of age, the body weights of the male and female dwarf rats were 40% and 57% of those of the normal rats, respectively. In soft X-ray radiographic and histological examinations, shortening and hypoplasia of the long bones, such as the tibia and femur, were observed, which were suggestive of endochondral ossification abnormalities. An immunohistochemical examination detected an aggrecan synthesis disorder, which might have led to delayed calcification and increased growth plate thickening in the dwarf rats. We hypothesized that the principal characteristics of the dwarf rats were systemically induced by insufficient cartilage calcification in their long bones; thus, we named them cartilage calcification insufficient (CCI) rats.

DOI： 10.1538/expanim.14-0072

Establishment of a novel dwarf rat strain: cartilage calcification insufficient (CCI) rats.

Masami Tanaka, Minoru Watanabe, Izuru Yokomi, Naoki Matsumoto, Katsuko Sudo, Hitoshi Satoh, Tsuneo Igarashi, Azusa Seki, Hitoshi Amano, Kiyoshi Ohura, Kakei Ryu, Shunichi Shibata, Motohiko Nagayama, Jun-ichi Tanuma

Experimental animals 64 ( 2 ) 121 - 8 2015

Language：English Publishing type：Research paper (scientific journal)

Rats with dwarfism accompanied by skeletal abnormalities, such as shortness of the limbs, tail, and body (dwarf rats), emerged in a Jcl-derived Sprague-Dawley rat colony maintained at the Institute for Animal Experimentation, St. Marianna University Graduate School of Medicine. Since the dwarfism was assumed to be due to a genetic mutation based on its frequency, we bred the dwarf rats and investigated their characteristics in order to identify the causative factors of their phenotypes and whether they could be used as a human disease model. One male and female that produced dwarf progeny were selected, and reproduction was initiated by mating the pair. The incidence of dwarfism was 25.8% among the resultant litter, and dwarfism occurred in both genders, suggesting that it was inherited in an autosomal recessive manner. At 12 weeks of age, the body weights of the male and female dwarf rats were 40% and 57% of those of the normal rats, respectively. In soft X-ray radiographic and histological examinations, shortening and hypoplasia of the long bones, such as the tibia and femur, were observed, which were suggestive of endochondral ossification abnormalities. An immunohistochemical examination detected an aggrecan synthesis disorder, which might have led to delayed calcification and increased growth plate thickening in the dwarf rats. We hypothesized that the principal characteristics of the dwarf rats were systemically induced by insufficient cartilage calcification in their long bones; thus, we named them cartilage calcification insufficient (CCI) rats.

DOI： 10.1538/expanim.14-0072

Potential for using lectin sugar chains as diagnostic markers in oral precancerous lesions Reviewed

Michiko Ehara, Juna Nakao, Motohiko Nagayama, Masaaki Shiota, Kiyoko F. Aoki-Kinoshita, Jun-ichi Tanuma

GLYCOBIOLOGY 24 ( 11 ) 1214 - 1215 2014.11

Hypomineralized Enamel of Dens Invaginatus: Its distinct images and pathogenesis of the Type III invagination using micro-focusing computed tomography Reviewed

Maiko Yamada, Motohiko Nagayama, Akitoshi Katsumata, Satoshi Kawano, Keika Gen, Michiko Ehara, Juna Nakao, Jun-ichi Tanuma, Takakazu Yoshida

JOURNAL OF HARD TISSUE BIOLOGY 23 ( 4 ) 449 - 453 2014.10

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL HARD TISSUE BIOLOGY

Dens invaginatus (DI) is one of the rare developmental tooth anomaly, and generally resulting from invagination of the inner enamel epithelium into the dental papilla before calcification. However, it remains unclear whether the invaginated enamel mineralizaion is lower than outer enamel, the association with the resistance to invaginated enamel caries and the inflammatory lesions mediated their invagination. Because of the difficulties of treating and the tendency of their inflammatory lesions mediated their malformed structures, teeth extracted from the patients with DI, were collected in our hospital and analyzed by three-dimensional micro-focusing computed tomography (mu CT) to clarify the differences of the invaginated enamel in mineral density (MD), and to find their pathogenesis of tooth anomaly and associated inflammatory lesions by histological analysis. The teeth were fixed with 10% formaldehyde and analyzed by mu CT, decalcified specimens were performed to histological (HE) and immunohistochemistry for cytokeratin AE1/AE3. All invaginated teeth enamel showed extremely lower MD than did the outer enamel. Interestingly there were no carious lesions in the invaginated enamel. HE showed thin reduced enamel epithelium on the surface of invaginated enamel and cytokeratin AE1/AE3 markedly showed positive their cellular matrix. The persistent reduced enamel epithelium of the invaginated enamel indicates delayed or inhibited maturation after tooth eruption. This failure of maturation results in lower MD but resistance to enamel caries. However, the structural abnormalities of DI teeth may allow bacteria to enter the interior of the tooth through the invagination, causing pulpitis or apical periodontitis. (243 words)

File： 23_449.pdf

DOI： 10.2485/jhtb.23.449

Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis. Reviewed International journal

Hirohiko Suwa, Masato Hirano, Kouji Kawarada, Motohiko Nagayama, Michiko Ehara, Tomonari Muraki, Hayase Shisa, Aiko Sugiyama, Masahiro Sugimoto, Hiroshi Hiai, Motoo Kitano, Jun-Ichi Tanuma

Oncology reports 31 ( 1 ) 3 - 12 2014.1

Language：English Publishing type：Research paper (scientific journal)

Susceptibly to the induction of rat tongue cancer (TC) by oral 4-nitroquinoline 1-oxide (4NQO) exposure is a polygenic trait. Among several quantitative trait loci identified by crosses between TC-susceptible Dark Agouti (DA) rats and TC-resistant Wistar-Furth (WF) rats, we focused on tongue cancer susceptibility locus (Tcas3) of chromosome 4. We examined tongue carcinogenesis in the reciprocal congenic strains DA.WF-Tcas3 and WF.DA-Tcas3 and in their parental strains. The Tcas3DA allele, and not the Tcas3WF allele, significantly favored tumor latency, incidence and TC number/size. In genomic DNA of TCs induced in (DA x WF) F1 rats, the resistant Tcas3WF allele was frequently and selectively lost, particularly in larger tumors. Thus, we searched the possible candidate genes in the Tcas3 region using microarray analysis of TCs in F1 rats and revealed significant upregulation of 2 cancer-related genes, parathyroid hormone-like hormone (Pthlh) and Kras2. The relevance of the WF allele of Pthlh as a cancer modifier was indicated by 3 single nucleotide polymorphisms specific to this strain. In contrast, no consistent strain-specific variations were found in Kras2. Moreover, the plasma Ca2+ level was consistently higher in DA rats when compared to the level in WF rats bearing TCs; moreover, the Pthlh-mRNA expression level was >30-fold higher in TCs when compared to this level in the normal tongue mucosa. Immunostaining experiments showed strong PTHrP protein expression in TCs of DA rats, and the signal was intensified in larger TCs. Kras2 was also upregulated in TCs, but to a lesser degree than PTHrP. Thus, Pthlh is a promising candidate modifier gene in the development and progression of rat TCs.

DOI： 10.3892/or.2013.2859

Intraneural perineurioma arising in the lateral border of the tongue. Reviewed International journal

Masato Hirano, Tomonori Muraki, Motohiko Nagayama, Michiko Ehara, Kouji Kawarada, Hirohiko Suwa, Motoo Kitano, Jun-ichi Tanuma

Pathology international 63 ( 12 ) 619 - 21 2013.12

Basaloid squamous cell carcinoma of the tongue: a case report. Reviewed

Matsui R, Tanuma J, Kwashima K, Miyahara M, Semba I, Sugihara K

Oral Medicine & Oral Pathology 15 117 - 122 2011.2

FGFR4 polymorphism, TP53 mutation, and their combinations are prognostic factors for oral squamous cell carcinoma. Reviewed International journal

Jun-Ichi Tanuma, Toshiyuki Izumo, Masato Hirano, Yoshitaka Oyazato, Fumiya Hori, Eri Umemura, Hayase Shisa, Hiroshi Hiai, Motoo Kitano

Oncology reports 23 ( 3 ) 739 - 44 2010.3

Language：English Publishing type：Research paper (scientific journal)

The genotype of the fibroblast growth factor receptor 4 (FGFR4) gene and TP53 mutation have been reported as prognostic factors for cancers of the head and neck, bladder, breast and colon. To determine whether they are applicable for oral squamous cell carcinoma (OSCC), we investigated these two genes in OSCC samples from 150 patients who had undergone radical surgery and in 100 cancer-free individuals. In OSCC, the FGFR4 Gly388Arg polymorphism and the presence or absence of mutation in TP53 did not show a significant association with the clinicopathological features of the tumors at surgery. However, the FGFR4 Arg388 allele, as well as mutations in TP53, was found to be closely associated with poor prognosis. Moreover, these two parameters synergistically affected the survival of OSCC patients. During 60 months of observation after radical surgery, a majority of patients with homozygous Arg388 FGFR4 plus mutated TP53 died of cancer, whereas >90% patients carrying homozygous Gly388 FGFR4 plus wild-type TP53 survived. Therefore, the FGFR4 Gly388Arg polymorphism and TP53 mutations, as well as their combinations, are excellent predictors of the prognosis for OSCC patients.

DOI： 10.3892/or-00000692

Tumor lymphangiogenesis correlates with lymph node metastasis and clinicopathologic parameters in oral squamous cell carcinoma. Reviewed International journal

Mayumi Miyahara, Jun-Ichi Tanuma, Kazumasa Sugihara, Ichiro Semba

Cancer 110 ( 6 ) 1287 - 94 2007.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Lymphatic vessel density (LVD) and microvessel density (MVD) are important parameters for assessing the malignant potential of tumors and patient survival. In this report, the authors defined LVD as the density of D2-40-positive lymphatic vessels and MVD as the density of CD105-positive microvessels per unit area of tissue. It was reported previously that vascular endothelial growth factor C (VEGF-C) is a major modulator of LVD and MVD. The objectives of this study were to clarify the clinical and prognostic significance of both LVD and MVD in oral squamous cell carcinoma (OSCC) and to elucidate the lymphangiogenic and angiogenic activities of VEGF-C in cancer tissues. METHODS: In total, 110 OSCC tissue samples were evaluated for LVD, MVD, and expression of VEGF-C using immunohistochemistry. Correlations among these parameters and clinicopathologic factors were examined. RESULTS: LVD was significantly higher in tumors that had very high expression of VEGF-C compared with tumors that had no/weak expression of VEGF-C. LVD correlated well with lymph node metastasis (P < .001). MVD was correlated significantly with positive lymph node metastasis (P < .001) but not with VEGF-C expression. In contrast, high expression of VEGF-C was correlated significantly with advanced tumor status (P = .041). Survival rates were lower in patients who had higher LVD (P < .001), higher MVD (P = .0028), and strong VEGF-C expression (P = .048). CONCLUSIONS: Lymphangiogenesis predominantly influenced metastasis-free survival. The current results suggested that LVD is a more useful tool than MVD and VEGF-C for deciding on therapeutic strategies in patients with OSCC.

DOI： 10.1002/cncr.22900

DRH strains: genetic resistance to chemical hepatocarcinogenesis. Reviewed

Hiai H, Liu H, Omi N, Tanuma J, Higashi K

Trends in Cancer Research 2 127 - 134 2007.4

Pleomorphic adenoma presenting low T-2 signal-intensity on magnetic resonance imaging Reviewed

H. Indo, S. Suenaga, E. Nozoe, N. Nakamura, J. Tanuma, I. Semba, H. J. Majima

DENTOMAXILLOFACIAL RADIOLOGY 35 ( 5 ) 380 - 382 2006.9

Language：English Publishing type：Research paper (scientific journal) Publisher：BRITISH INST RADIOLOGY

We report an unusual case of pleomorphic adenoma of the submandibular gland in a 48-year-old female. The present case appeared as a relatively homogeneous, low to intermediate signal-intensity on the T-2 weighted magnetic resonance (MR) images. To our knowledge, the MR feature of low T-2 signal-intensity of pleomorphic adenoma has not been reported in the literature.

DOI： 10.1259/dmfr/21157218

Selective loss of resistant alleles at p15INK4B and p16INK4A genes in chemically-induced rat tongue cancers. Reviewed International journal

Kotaro Ogawa, Jun-ichi Tanuma, Masato Hirano, Yoshikazu Hirayama, Ichiro Semba, Hayase Shisa, Motoo Kitano

Oral oncology 42 ( 7 ) 710 - 7 2006.8

Language：English Publishing type：Research paper (scientific journal)

We previously reported that susceptibility to 4-nitroquinoline 1-oxide (4NQO)-induced tongue cancer in Dark-Agouti (DA) and Wistar/Furth (WF) rats was determined by a number of quantitative trait loci. In this article, we further scrutinized one of the quantitative trait loci at a suggestive level on rat chromosome 5. Analyzing a DNA panel of 130 (DAxWF) F2 rats treated with 4NQO showed a quantitative trait loci, containing p15INK4B and p16INK4A. To study the possible relevance of these genes in the development of tongue cancer, we examined 45 4NQO-induced tongue cancers in 100 (DAxWF) F1 rats for loss of heterozygosity. The incidence of loss of heterozygosity at p15INK4B and p16INK4A genes in large advanced tongue cancers was 37.8% and 40.0%, respectively, and the WF allele was selectively lost. Accumulation of loss of heterozygosity and methylation of the promoter regions in the tumour suppressor genes in advanced tumours suggests that they may play a role in tongue cancer progression.

DOI： 10.1016/j.oraloncology.2005.11.011

Immunohistological evaluation of Ki-67, p63, CK 19 and pS3 expression in oral epithelial dysplasias Reviewed

T. Takeda, K. Sugihara, Y. Hirayama, M. Hirano, J-I Tanuma, I. Semba

JOURNAL OF ORAL PATHOLOGY & MEDICINE 35 ( 6 ) 369 - 375 2006.7

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

BACKGROUND: Oral squamous cell carcinoma develops through a multistep of genetic mutations, and the process can be morphologically recognized as oral epithelial dysplasia. To evaluate the hypothesis that distributional alterations of proliferating and stem cells may be a useful index to estimate the grading and development of epithelial dysplasia, we examined the distribution patterns according to stratified cell layers.
METHODS: Sixty-two oral dysplasia cases according to the histological grades were immunohistologically examined and the nuclear expression of Ki-67 and p63 antigens was counted according to epithelial layers as labeling index.
RESULTS: The Ki-67 labeling index in the basal and suprabasal layers and that of p63 in the basal layer showed a significant difference between low- and high-grade groups of epithelial dysplasia.
CONCLUSION: The architectural alteration of proliferating cell and stem cell distribution in the layers of epithelial dysplasias may provide useful information to evaluate the grading of oral epithelial dysplasias.

Immunohistological evaluation of Ki-67, p63, CK19 and p53 expression in oral epithelial dysplasias Reviewed

T. Takeda, K. Sugihara, Y. Hirayama, M. Hirano, J. I. Tanuma, I. Semba

Journal of Oral Pathology and Medicine 35 ( 6 ) 369 - 375 2006.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Oral squamous cell carcinoma develops through a multistep of genetic mutations, and the process can be morphologically recognized as oral epithelial dysplasia. To evaluate the hypothesis that distributional alterations of proliferating and stem cells may be a useful index to estimate the grading and development of epithelial dysplasia, we examined the distribution patterns according to stratified cell layers. METHODS: Sixty-two oral dysplasia cases according to the histological grades were immunohistologically examined and the nuclear expression of Ki-67 and p63 antigens was counted according to epithelial layers as labeling index. RESULTS: The Ki-67 labeling index in the basal and suprabasal layers and that of p63 in the basal layer showed a significant difference between low- and high-grade groups of epithelial dysplasia. CONCLUSION: The architectural alteration of proliferating cell and stem cell distribution in the layers of epithelial dysplasias may provide useful information to evaluate the grading of oral epithelial dysplasias. © Blackwell Munksgaard 2006 · All rights reserved.

DOI： 10.1111/j.1600-0714.2006.00444.x

A speed congenic rat strain bearing the tongue cancer susceptibility locus Tscc1 from Dark-Agouti rats. Reviewed International journal

Masato Hirano, Jun-Ichi Tanuma, Yoshikazu Hirayama, Masanobu Ohyama, Ichiro Semba, Shinya Wakusawa, Hayase Shisa, Hiroshi Hiai, Motoo Kitano

Cancer letters 231 ( 2 ) 185 - 91 2006.1

Language：English Publishing type：Research paper (scientific journal)

We previously reported that Dark-Agouti (DA) rats are highly susceptible to 4-nitroquinoline 1-oxide (4NQO)-induced tongue cancer (TC), whereas Wistar/Furth (WF) rats are barely susceptible. Linkage analysis of reciprocal (DAxWF)F2 rats demonstrated five quantitative trait loci, Tongue squamous cell carcinoma 1-5 (Tscc1-5) determining the size and number of the TCs. The major susceptibility locus Tscc1 is mapped on rat chromosome 19. In the present study, we used a marker-assisted speed congenic procedure to construct WF.DA-Tscc1 (WF-T1D) rats, i.e. WF rats carrying a DA-derived Tscc1 chromosomal segment, and evaluated the effect of a single Tscc1 on 4NQO-induced tongue carcinogenesis. In WF-T1D rats, the incidence, number and size of 4NQO-induced TCs were significantly higher than those in WF rats, indicating that the introgressed segment contains one of the susceptibility loci for 4NQO-induced TCs from DA rats. Detection of a single nucleotide polymorphism in NQO1, one of the Tscc1 candidate genes, enabled us to map NQO1 in the Tscc1 segment between D19Wox8 and D19Wox7 on chromosome 19. Possible relevance of NQO1 polymorphism to TC susceptibility is discussed.

DOI： 10.1016/j.canlet.2005.01.043

FGFR4 Gly388Arg polymorphism and prognosis of breast and colorectal cancer. Reviewed International journal

Monica Spinola, Vera Piera Leoni, Jun-Ichi Tanuma, Angela Pettinicchio, Milo Frattini, Stefano Signoroni, Roberto Agresti, Riccardo Giovanazzi, Silvana Pilotti, Lucio Bertario, Fernando Ravagnani, Tommaso A Dragani

Oncology reports 14 ( 2 ) 415 - 9 2005.8

Language：English Publishing type：Research paper (scientific journal)

A functional Gly388Arg variation in the FGFR4 gene has been reported to be associated with breast and colorectal cancer prognostic parameters. To further examine the functional role of this genetic polymorphism at the population level, we assessed the presence of the Arg388 allele in 142 breast carcinoma patients, 179 colorectal carcinoma patients and 220 general population controls with respect to an association with cancer prognosis and/or risk. No significant association with cancer risk, survival or any other prognostic parameters was observed in either breast or colorectal cancer. A pooled analysis of the present and published data on nodal status by FGFR4 genotypes revealed no association in either breast cancer [odds ratio (OR), 1.0; 95% confidence interval (CI), 0.7-1.4; 702 subjects] or colorectal cancer (OR, 1.4; 95% CI, 0.6-3.4; 260 cases). Thus, the FGFR4 polymorphism may not be relevant in predicting nodal involvement of breast cancer or colon cancer patients.

Genetic predisposition to 4NQO-induced tongue carcinogenesis in the rat Reviewed

J Tanuma, M Hirano, Y Hirayama, Semba, I, K Ogawa, H Shisa, H Hiai, M Kitano

MEDICAL PRINCIPLES AND PRACTICE 14 ( 5 ) 297 - 305 2005

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Objective: This study aims to elucidate the genetic basis of predisposition to 4-nitroquinoline1-oxide (4NQO)-induced tongue cancers (TCs). Materials and Methods: We have reported that inbred Dark-Agouti (DA) strain rats were highly susceptible to 4NQO-induced TCs, whereas Wistar/Furth (WF) rats were resistant to tongue squamous cell carcinomas induced by oral administration of 4NQO. Using size and number of the tumours as quantitative parameters, responsible host loci were analysed by an interval mapping of F-2 intercross of DA and WF given carcinogenic regimen. Also, loss of heterozygosity (LOH) at these loci was analysed in tongue cancers in (DA x WF) F-1. Results: We identified and mapped 5 significant quantitative trait loci (QTL), the Tongue squamous cell carcinoma 1-5 (Tscc1-5), and several other suggestive QTL that determine susceptibility to 4NQO-induced TC. Study of TCs induced in (DA x WF)F-1 rats revealed a high frequency of LOH in the chromosomal regions of Tscc2, 3, and 4 and also of suggestive QTL on chromosomes 5 and 6. The fact that LOH was found only in larger TCs indicates that LOH occurred in the process of tumour progression. In most LOH, the allele of the resistant WF strain was lost, suggesting that these loci may encode tumour suppressor genes. In larger TCs, in addition to LOH, point mutations and the methylation of possible candidate genes were accumulated. Conclusion: These observations indicate that the 4NQO-induced TC in the rat is a multifactorial disease of a polygenic trait. This model will be useful to understand the complicated genetic basis of predisposition to oral cancers. Copyright (C) 2005 S. Karger AG, Basel.

DOI： 10.1159/000086926

Analysis of human cytomegalovirus UL144 variability in low-passage clinical isolates in Japan. Reviewed International journal

Tsugiya Murayama, Masataka Takegoshi, Junichi Tanuma, Yoshito Eizuru

Intervirology 48 ( 2-3 ) 201 - 6 2005

Language：English Publishing type：Research paper (scientific journal)

To explore a possible role for viral genes as determinants of virulence, portions of the UL144 tumor necrosis factor-like receptor gene and the UL55 envelope glycoprotein B gene from 42 patients with congenital human cytomegalovirus (HCMV) infection or other diseases were sequenced. Of the 42 patients, 16 (38%) had UL144 group 1 [group 1A, 15 of 16 (94%); group 1B, 1 of 16 (6%); group 1C, 0 of 16 (0%)], 5 patients (12%) had UL144 group 2, and 21 patients (50%) had UL144 group 3. Although group 1C was not found in Japan strains (0%), it was found in USA strains (22%). Other HCMV polymorphisms should be further evaluated for their potential relevance to neonatal infection, and acquired immunodeficiency syndrome-associated HCMV diseases.

DOI： 10.1159/000081749

Genetic predisposition to 4NQO-induced tongue carcinogenesis in the rat Reviewed

J Tanuma, M Hirano, Y Hirayama, Semba, I, K Ogawa, H Shisa, H Hiai, M Kitano

MEDICAL PRINCIPLES AND PRACTICE 14 ( 5 ) 297 - 305 2005

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Objective: This study aims to elucidate the genetic basis of predisposition to 4-nitroquinoline1-oxide (4NQO)-induced tongue cancers (TCs). Materials and Methods: We have reported that inbred Dark-Agouti (DA) strain rats were highly susceptible to 4NQO-induced TCs, whereas Wistar/Furth (WF) rats were resistant to tongue squamous cell carcinomas induced by oral administration of 4NQO. Using size and number of the tumours as quantitative parameters, responsible host loci were analysed by an interval mapping of F-2 intercross of DA and WF given carcinogenic regimen. Also, loss of heterozygosity (LOH) at these loci was analysed in tongue cancers in (DA x WF) F-1. Results: We identified and mapped 5 significant quantitative trait loci (QTL), the Tongue squamous cell carcinoma 1-5 (Tscc1-5), and several other suggestive QTL that determine susceptibility to 4NQO-induced TC. Study of TCs induced in (DA x WF)F-1 rats revealed a high frequency of LOH in the chromosomal regions of Tscc2, 3, and 4 and also of suggestive QTL on chromosomes 5 and 6. The fact that LOH was found only in larger TCs indicates that LOH occurred in the process of tumour progression. In most LOH, the allele of the resistant WF strain was lost, suggesting that these loci may encode tumour suppressor genes. In larger TCs, in addition to LOH, point mutations and the methylation of possible candidate genes were accumulated. Conclusion: These observations indicate that the 4NQO-induced TC in the rat is a multifactorial disease of a polygenic trait. This model will be useful to understand the complicated genetic basis of predisposition to oral cancers. Copyright (C) 2005 S. Karger AG, Basel.

DOI： 10.1159/000086926

Expressions of junB and c-fos are enhanced in 4-nitroquinoline 1-oxide-induced rat tongue cancers Reviewed

M Ohyama, Y Hirayama, J Tanuma, M Hirano, Semba, I, H Shisa, H Hiai, K Sugihara, M Kitano

PATHOLOGY INTERNATIONAL 54 ( 1 ) 35 - 40 2004.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Activator protein-1 (AP-1) is a transcription factor activated in many tumors. Using 4-nitroquinoline 1-oxide (4NQO)-induced rat tongue cancers (TC), the present study investigated the expression levels of genes that encode the components of AP-1, the jun gene family (c-jun, junB and junD) and the fos gene family (c-fos, fra-1, fra-2 and fosB). Expression levels of junB and c-fos mRNAs in TC were significantly elevated compared with those in epithelial tissue of control rat tongue, although only c-fos mRNA levels tended to be elevated in dysplastic tongue epithelium. Histologically, all 4NQO-induced rat TC were well-differentiated squamous cell carcinomas. Immunostaining for JunB and c-Fos proteins was positive in the nuclei of tumor cells of all TC. It is noteworthy that JunB was negative, but c-Fos was positive in the dysplastic tongue epithelium of the 4NQO-treated rats. Immunostaining for both proteins was negative in tongue mucosal epithelium of control rats. There were no mutations in the coding regions of either junB or c-fos in all the TC examined. These results suggest the possibility that the expressions of junB and c-fos were enhanced stepwise in 4NQO-induced carcinogenesis of rat tongue, and that the coexpression of JunB and c-Fos might play an important role in the establishment of TC.

DOI： 10.1046/j.1440-1827.2003.01587.x

Expressions of junB and c-fos are enhanced in 4-nitroquinoline 1-oxide-induced rat tongue cancers. Reviewed International journal

Masanobu Ohyama, Yoshikazu Hirayama, Jun-ichi Tanuma, Masato Hirano, Ichiro Semba, Hayase Shisa, Hiroshi Hiai, Kazumasa Sugihara, Motoo Kitano

Pathology international 54 ( 1 ) 35 - 40 2004.1

Language：English Publishing type：Research paper (scientific journal)

Activator protein-1 (AP-1) is a transcription factor activated in many tumors. Using 4-nitroquinoline 1-oxide (4NQO)-induced rat tongue cancers (TC), the present study investigated the expression levels of genes that encode the components of AP-1, the jun gene family (c-jun, junB and junD) and the fos gene family (c-fos, fra-1, fra-2 and fosB). Expression levels of junB and c-fos mRNAs in TC were significantly elevated compared with those in epithelial tissue of control rat tongue, although only c-fos mRNA levels tended to be elevated in dysplastic tongue epithelium. Histologically, all 4NQO-induced rat TC were well-differentiated squamous cell carcinomas. Immunostaining for JunB and c-Fos proteins was positive in the nuclei of tumor cells of all TC. It is noteworthy that JunB was negative, but c-Fos was positive in the dysplastic tongue epithelium of the 4NQO-treated rats. Immunostaining for both proteins was negative in tongue mucosal epithelium of control rats. There were no mutations in the coding regions of either junB or c-fos in all the TC examined. These results suggest the possibility that the expressions of junB and c-fos were enhanced stepwise in 4NQO-induced carcinogenesis of rat tongue, and that the coexpression of JunB and c-Fos might play an important role in the establishment of TC.

DOI： 10.1046/j.1440-1827.2003.01587.x

SCCA2-like Serpins Mediate Genetic Predisposition to Skin Tumors. Reviewed

Gariboldi M, Peissel B, Fabbri A, Saran A, Zaffarouni D, Falvella FS, Spinola M, Tanuma J, Cataltepe S, Hayashizaki Y, Okazaki Y, Dragani TA

Cancer Res 63 1871 - 1875 2003.5

Carcinogenesis modifier loci in rat tongue are subject to frequent loss of heterozygosity. Reviewed International journal

Jun-ichi Tanuma, Hiroshi Hiai, Hayase Shisa, Masato Hirano, Ichiro Semba, Shigetaka Nagaoka, Motoo Kitano

International journal of cancer 102 ( 6 ) 638 - 42 2002.12

Language：English Publishing type：Research paper (scientific journal)

Rats of the DA strain are highly susceptible to 4NQO-induced TCs, whereas WF rats are barely susceptible. In (DA x WF)F2 rats, 5 QTL, Tscc1-5, are responsible for most of the phenotypic variations, though they do not account for all of the phenotypic differences between WF and DA rats. Analysis of 40 tongue tumors >5 mm in diameter from (DA x WF)F1 rats for LOH at the Tscc loci revealed a high frequency of LOH in chromosomal regions where the Tscc2, -3 and -4 loci map. In most cases of LOH, the allele of the barely susceptible WF strain was lost, suggesting that these loci in the WF strain encode tumor-suppressor genes. Analysis of the same tumors for somatic mutations in oncogenes indicated frequent alteration of Ha-ras, which maps in the Tscc3 region, but rare mutation of the p15(INK4B) and p16(INK4A) genes or the p53 and Msh2 genes. Frequent LOH was also found on rat chromosomes 5 (RNO5) and 6 (RNO6). Tumors of large size accumulated LOH at multiple loci, suggesting the involvement of Tscc loci in tumor progression.

Carcinogenesis modifier loci in rat tongue are subject to frequent loss of heterozygosity. Reviewed

Jun-ichi Tanuma

International journal of cancer 102 638 - 642 2002.12

Language：English Publishing type：Research paper (scientific journal)

Rats of the DA strain are highly susceptible to 4NQO-induced TCs, whereas WF rats are barely susceptible. In (DA x WF)F2 rats, 5 QTL, Tscc1-5, are responsible for most of the phenotypic variations, though they do not account for all of the phenotypic differences between WF and DA rats. Analysis of 40 tongue tumors >5 mm in diameter from (DA x WF)F1 rats for LOH at the Tscc loci revealed a high frequency of LOH in chromosomal regions where the Tscc2, -3 and -4 loci map. In most cases of LOH, the allele of the barely susceptible WF strain was lost, suggesting that these loci in the WF strain encode tumor-suppressor genes. Analysis of the same tumors for somatic mutations in oncogenes indicated frequent alteration of Ha-ras, which maps in the Tscc3 region, but rare mutation of the p15(INK4B) and p16(INK4A) genes or the p53 and Msh2 genes. Frequent LOH was also found on rat chromosomes 5 (RNO5) and 6 (RNO6). Tumors of large size accumulated LOH at multiple loci, suggesting the involvement of Tscc loci in tumor progression.

DOI： 10.1002/ijc.10751

Solitary fibrous tumor in the mental region Reviewed

M Hirano, J Tanuma, T Shimoda, K Sugihara, M Tsuneyoshi, M Kitano

PATHOLOGY INTERNATIONAL 51 ( 11 ) 905 - 908 2001.11

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Solitary fibrous tumor (SFT) is a rare, benign, soft tissue tumor that most commonly occurs in the pleura; however, it has recently been described in other sites of the body. To date, eight examples of oral SFT have been reported. This paper is a description of the first case of an SFT occurring as a soft tissue tumor in the mental region. Histologically, the tumor was composed predominantly of rather uniform spindle-shaped fibroblastic cells arranged in vague fascicles or in a haphazard fashion, intermingled with abundant collagen fibers. Immunohistochemically, the tumor cells were positive for CD34 and vimentin, and weakly positive for muscle actin and alpha -smooth muscle actin. The diagnosis of SFT may be difficult as this tumor shares a number of histological features with other soft tissue tumors. Awareness of its occurrence in the oral cavity is important so that confusion with other spindle cell neoplasms can be avoided.

DOI： 10.1046/j.1440-1827.2001.01290.x

Five quantitative trait loci affecting 4-nitroquinoline 1-oxide-induced tongue cancer in the rat Reviewed

J Tanuma, K Fujii, M Hirano, H Matsuuchi, H Shisa, H Hiai, H Kitano

JAPANESE JOURNAL OF CANCER RESEARCH 92 ( 6 ) 610 - 616 2001.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BUSINESS CENTER ACADEMIC SOCIETIES JAPAN

In our previous study, Dark-Agouti (DA) rats were found to be highly susceptible to 4-nitroquinoline 1-oxide (4NQO)-induced tongue carcinoma (TC), whereas Wistar/Furth (WF) rats were barely susceptible. Interval mapping analysis of reciprocal backcross rats showed two quantitative trait loci (QTL) on rat chromosomes (RNO) 1 and 19, In the present study, a composite interval mapping analysis was applied to 4NQO-induced TC in 130 (DAxWF) F2 rats, demonstrating five independent QTL, Tongue squamous cell carcinoma 1-5 (Tscc1-5), responsible for phenotypic differences in the size and number of TCs in the two strains. Two of these QTL were mapped on RNO1, and the others were mapped on RNO4, 14, and 19. The DA allele at these loci consistently yielded semidominant susceptibility to TC, Out of the five loci detected in this F2 generation, Tscc1 and 2 were identical to Stc1 and Rtc1 described in our previous study, but the other three were novel. We propose a new nomenclature consistent with their function. Genome-nide screening of the F2 progeny also suggested the presence of three additional QTL on RNO5, 6, and 10, The possible roles of these loci in tongue carcinogenesis are discussed.

Biological and genetic characterization of a human immunodeficiency virus strain resistant to CXCR4 antagonist T134 Reviewed

K. Kanbara, S. Sato, J. I. Tanuma, H. Tamamura, K. Gotoh, M. Yoshimori, T. Kanamoto, M. Kitano, N. Fujii, H. Nakashima

AIDS Research and Human Retroviruses 17 ( 7 ) 615 - 622 2001

Language：English Publishing type：Research paper (scientific journal)

The chemokine receptors CXCR4 and CCR5 are considered to be potential targets for the inhibition of HIV-1 replication. We have reported that T134 and T140 inhibited X4 HIV-1 infection specifically because they acted as CXCR4 antagonists. In the present study, we have generated a T134-resistant virus (trHIV-1NL4-3) in a cell culture with gradually increasing concentrations of the compound. The EC50 of T134 against trHIV-1NL4-3 recovered after 145 passages was 15 times greater than that against wild-type HIV-1NL4-3. This adapted virus was resistant to other CXCR4 antagonists, T140, AMD3100, and ALX40-4C, and SDF-1
from 10 to 145 times greater than that against wild-type HIV-1NL4-3. On the other hand, T134, T140, and ALX40-4C were still active against AMD3100-resistant viruses (arHIV-1018A). The trHIV-1NL4-3 contained the following mutations in the V3 loop of gp120: N269K, Q278T, R279K, A284V, F285L, V286Y, I288T, K290E, N293D, M294I, and Q296K
an insertion of T at 290
and Δ274-275 (SI). In addition, many other mutations were recognized in the V1, V2, and V4 domains. Thus, resistance to T134 may be the consequence of amino acid substitutions in the envelope glycoprotein of X4 HIV-1. The trHIV-1NL4-3 could not utilize CCR5 as an HIV infection coreceptor, although many amino acid substitutions were recognized. The trHIV-1NL4-3 acquired resistance to vMIP II, which could inhibit both X4 and R5 HIV-1 infection. However, neither the ligands of CCR5, RANTES, and MIP-1α, nor a CCR5 low molecular antagonist, TAK-779, were able to influence the infection of trHIV-1NL4-3. Those results indicated that alternation of coreceptor usage of trHIV-1NL4-3 was not induced.

DOI： 10.1089/088922201300119716

Solitary fibrous tumor in the mental region. Reviewed

Hirano M, Tanuma J, Shimoda T, Sugihara K, Tsuneyoshi M, Kitano M

Pathology International 51 905 - 908 2000.3

Polygenetic susceptibility and resistance to 4-nitroquinoline 1-oxide-induced tongue carcinomas in the rat Reviewed

Jun-Ichi Tanuma, Motoo Kitano, Hayash Shisa, Hiroshi Hiai

Journal of Experimental Animal Science 41 ( 1-2 ) 68 - 77 2000

Language：English Publishing type：Research paper (international conference proceedings) Publisher：Urban und Fischer Verlag Jena

Oral administration of 4-nitroquinoline 1-oxide (4NQO) to rats induced a high incidence of tongue carcinomas (TCs). The inbred Dark-Agouti (DA) strain of rats showed much higher susceptibility to 4NQO-induced TCs than the Wistar-Furth (WF) strain. Our previous study on crosses between the two strains postulated a semidominant susceptibility gene in DA and a semidominant resistance gene in WF rats. This hypothesis was confirmed by the genetic analysis of the backcrosses to either parent with PCR-based microsatellite assay. Using the number of TCS with &gt
5 mm diameter as a quantitative parameter, we mapped a quantitative trait locus Stc1 (Susceptibility to TC) favouring TC development near the locus D19Mit9 on Chr. 19 with a peak LOD scare of 6.08. Two other regions in Chr. 3 and Chr. 14 showed weak linkage for susceptibility, but were not statistically significant. On the other hand, another quantitative trait locus Rtc1 (Resistance to TC) providing resistance to TCs was mapped on Chr. 1 between the loci of D1Mit1 and D1Mit3 with a peak LOD score of 3.30. Quantitative parameters such as the number of tumours in the tongue or upper alimentary tract, the frequency of larger tumours and their maximum size were closely correlated and principally determined by Stc1 and Rtc1. Therefore the susceptibility to 4NQO-induced TCs in crosses between DA and WF is explained by the combinations of genotypes at these two loci. Possible candidate genes for Stc1 and Rtc1 are discussed.

DOI： 10.1016/S0939-8600(00)80034-6

Mutation of p53 gene during 4NQO-induced tongue carcinogenesis in the Dark-Agouti rat. Reviewed

Kitano Motoo, Hirayama Yoshikazu, Tanuma Jun-ichi, Li Tie-Jun, HiranoMasato, Semba Ichiro

Reports of Kagoshima University Project. 3 ( * ) p137 - 144 1999

Propyinitrosourea-induced T-lymphomas in LEXF RI strains of rats: Genetic analysis Reviewed

L. M. Lu, H. Shisa, J. I. Tanuma, H. Hiai

British Journal of Cancer 80 ( 5-6 ) 855 - 861 1999

Language：English Publishing type：Research paper (scientific journal) Publisher：Churchill Livingstone

Oral administration of propylnitrosourea (PNU) in drinking water induces high incidence of lympho-haemopoietic malignancies in rats. Previously we reported that F344 strain rats were highly susceptible to T-lymphomas, and LE/Stm rats, to erythro- or myeloid leukaemias. For analysis of the genetic factors determining types of diseases, we have established LEXF recombinant inbred strains of rats comprising 23 substrains, each derived from intercross between F344 and LE/Stm rats. Rats of 23 LEXF substrains were given PNU, and the development of tumours was observed. The overall incidence of haemopoietic tumours ranged from 100% to 66.7%, and the fractions of T-lymphomas, from 100% to 4%, showing a continuous spectrum. Based on the genetic profile published as a strain distribution pattern table for the LEXF, we screened the potential quantitative trait loci involved in determination of the types of disease and length of the latency period. Statistical calculation was performed using the Map Manager QT software developed by Manly. Four loci, on chromosome 4, 7, 10 and 18, were suggested to associate with the T-lymphoma susceptibility and three loci, on chromosome 1, 5 and 16, with the length of the latency period. These putative loci were further examined in backcross (F344 x LE)F1 x LE. Among seven loci suggested by the recombinant inbred study, three loci, on chromosome 5, 7 and 10, were significantly associated with T-lymphomas and another locus on chromosome 1, just weakly. These observations indicate that PNU-induced lymphomagenesis is a multifactorial genetic process involving a number of loci linked with susceptibility and resistance.

DOI： 10.1038/sj.bjc.6690432

Random nuclear p53 overexpression pattern in tamoxifen-mediated endometrial carcinoma Reviewed

Y Kuwashima, M Kurosumi, Y Kobayashi, J Tanuma, K Suemasu, Y Higashi, T Kasamatsu, K Shiromizu, K Kishi

INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY 17 ( 2 ) 135 - 139 1998.4

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

In a previous paper, we suggested that tamoxifen (TAM)-mediated endometrial carcinogenesis may not involve estrogenic pathways because of random estro en receptor positivity among endometrial carcinomas with and without TAM treatment for breast cancer. DNA adduct formation (reported in rat liver and human endometrium) was considered to be a more plausible mechanism for TAM-mediated carcinogenesis. To examine the reported correlation between DNA adduct formation and p53, the present study examined p53 expression in the endometrial carcinomas reported in the previous study. Seven endometrial adenocarcinomas associated with long-term TAM treatment for breast carcinoma and 4 carcinomas without TAM treatment but with history of breast carcinoma were immunohistochemically investigated for nuclear p53 expression. The bcl-2 product was also examined. Diffuse and intense nuclear reactivity for p53 protein was present in only one TAM-related case. Essentially, no differences were observed in the bcl-2 staining patterns of TAM-treated and untreated patients with cancer. Thus, p53 overexpression in endometrial carcinomas occurring in patients with breast cancer seems to be not specific for TAM-treated patients, and, if DNA adduct formation has any role in this type of endometrial carcinogenesis, it may not be related preferentially to p53 gene alteration. Further studies are needed to understand the precise mechanism(s) of the endometrial carcinogenesis.

Quantitative trait loci affecting 4NQO-induced tongue carcinogenesis in the rat Reviewed

Tanuma J, Shisa H, Hiai H, Yamada Y, Kamoto T, Hirayama Y, Matsuuchi H, Kitano M

Cancer Research 58 ( 8 ) 1660 - 1664 1998.3

Language：English Publishing type：Doctoral thesis

The incidence of tongue carcinomas (TCs) induced by oral administration of 4-nitroquinoline 1-oxide in rats is strain dependent. The inbred Dark-Agouti (DA) strain showed a much higher susceptibility to large mass-forming infiltrative TCs than did the Wistar-Furth (WF) strain. Our previous study (M. Kitano et al, Jpn. J. Cancer Res., 87: 1097-1101, 1996) on crosses between these two strains postulated a dominant susceptibility gene in DA and a dominant resistance gene in WF rats. The present study mapped these loci by analyzing the backcrosses to each parent with simple sequence repeat polymorphisms. Five quantitative parameters were analyzed: (a) the number of TCs > 5 mm in diameter; (b) the total number of TCs per rat; (c) the diameter of the largest TCs (DTCmax values); (d) the number of non-TC cancers per rat; and (e) and the number of cancers of any site per rat. All of these parameters were closely correlated (P < 0.0001). DA rats had a semidominant gene (Stc1) favoring the development of 4-nitroquinoline 1-oxide-induced cancers on chromosome 19, closely linked to D19Mit9. Peak linkage was observed 4 cM distal from D19Mit9, with a logarithm of the odds (lod) score of 5.72 for

Inverse correlation between bcl-2 expression and cell growth fraction in human Endometrial adenocarcinoma tissue. Reviewed

Kuwashima Y, Kobayashi Y, Kurozumi M, Tanuma J, Shiromizu K, Kishi K

Anticancer Res 17 3773 - 3776 1997.8

Genetic controls of the susceptibility and resistance to 4NQO-induced tongue carcinomas in the rats. Reviewed

Kitano M, Hirayama Y, Tanuma J, Matsuuchi H, Miura Y, Li T-J, Semba I, Kokubu T, Hatano H, Tada M, Kobayashi Y, Shisa H

Jpn. J. Cancer Res 87 1097 - 1101 1997.6

Occurrence of apoptotic DNA fragmentation in quiescent and proliferating cells in human endometrial adenocarcinoma tissues and the influence of apoptosis-suppressing effects of bcl-2 products. Reviewed

Kuwashima Y, Kobayashi Y, Kawarai A, Kurozumi M, Tanuma J, Shiromizu K, Kishi K

Anticancer Res 17 3737 - 3741 1997.5

The LEXF: A new set of rat recombinant inbred strains between LE/Stm and F344 Invited Reviewed

Hayase Shisa, Lingmin Lu, Hideki Katoh, Atsuko Kawarai, Jun-Ichi Tanuma, Yoshibumi Matsushima, Hiroshi Hiai

Mammalian Genome 8 ( 5 ) 324 - 327 1997.5

Language：English Publishing type：Research paper (scientific journal)

A new set of rat RI strains consisting of 11 independent strains and 13 of their substrains was established by inbreeding F2 rats between F344/DuCrj and LE/Stm. The strain distribution pattern was examined for 66 microsatellite loci, 8 biochemical genetic markers, 2 histocompatibility loci, and 2 coat color genes. A rat salivary protein gene Spe1 was newly mapped on Chr 1.

DOI： 10.1007/s003359900432

Tamoxifen mediated human endometrial carcinogenesis may not involve estrogenic pathways: A preliminary note Reviewed

Y Kuwashima, M Kurosumi, Y Kobayashi, J Tanuma, K Suemasu, Y Higashi, T Kasamatsu, K Shiromizu, M Matsuzawa, K Kishi

ANTICANCER RESEARCH 16 ( 5A ) 2993 - 2996 1996.9

Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

Seven cases of endometrial adenocarcinoma patients who had experienced long-term tamoxifen treatments as adjuvant therapy of breast carcinoma, were investigated with respect to estrogen receptor (ER) status. Four cases of endometrial adenocarcinoma without tamoxifen treatment but with a previous history of breast carcinoma were investigated for comparison. One of the 7 and two of the 4 cases were positive for ER immunohistochemically. Thus, the frequency of ER positivity in secondary endometrial adenocarcinoma seemed to be at random among tamoxifen-treated and non-treated br east cancer patients. These results suggest that tamoxifen-mediated human endometrial carcinogenesis may not involve estrogenic pathway(s) but may involve other carcinogenic mechanisms such as DNA adduct formation as shown in rat liver tumorigenesis.

Expression of bcl-2 and Apoptotic DNA Fragmentation in Human Endometrial Adenocarcinoma cells. Reviewed

Kuwashima Y, Kobayashi Y, Kawarai A, Kurozumi M, Uehara T, Tanuma J, Shiromizu K, Matsuzawa M, Kishi K

Anticancer Res 16 3221 - 3224 1996.5

Evaluation of Apoptosis in human endometrial adenocarcinoma: Comparison of Neck and Labelling Le(y) Antigen Immunostaining Method. Reviewed

Kuwashima Y, Kobayashi Y, Kawarai A, Kurozumi M, Tanuma J, Shiromizu K, Matsuzawa K, Kishi K

Anticancer Res 16 3225 - 3228 1996.5

Immunohistochemical detection of ras p21 oncoprotein in undifferentiated and well-differentiated epithelial carcinomas of the human ovary Reviewed

Y. Kuwashima, H. Shisa, T. Uehara, M. Kurosumi, Y. Kobayashi, J. Tanuma, K. Shiromizu, M. Matsuzawa, K. Kishi

Anticancer Research 15 ( 6 B ) 2847 - 2850 1995

Language：English Publishing type：Research paper (scientific journal)

Expression of ras p21 oncoproteins in human ovarian carcinomas was examined immunohistochemically by using a monoclonal antibody(clone RAS 10) with respect to the degree of their histological differentiation. To achieve this, the intensity of staining for the protein was compared between undifferentiated and well differentiated carcinomas, i.e. extreme subtypes of common epithelial carcinomas. The former was composed of 8 'solid' carcinomas and the latter
11 serous, 8 mucinous, 4 endometrioid and 4 clear cell carcinomas. All the cases examined, including both undifferentiated and well-differentiated carcinomas, showed a positive reaction to this antibody. Staining intensity and the number of positive cells somewhat varied among the cases. Additionally, 2 cases of ovarian epithelial tumors of low malignant potential (I,MP) were stained with this antibody. Both the cases were positive, but the number of positive cells seemed to be rather less than than that found in the carcinoma groups. Thus, no differences in ras p21 expression were observed between the cases examined in spite of the differences in the degree of differentiation of the epithelial ovarian carcinomas. However
the possibility remained that the number of positive cells could be an indicator of malignant potential, enabling us to distinguish LMPs from carcinomas. Thus immunodetection of ras p21 could not provide an additional means for the histological differentiation of ovarian cancer although the evaluation of basement membrane integrity and cell proliferation kinetics as reported previously was useful in differential diagnosis and in understanding the biology of ovarian undifferentiated carcinomas.

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