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天野　雄介 (ｱﾏﾉ ﾕｳｽｹ)

  • 病理学講座（統合病理学部門）　准教授
Last Updated :2023/03/07

研究者情報

学位

  • 博士(歯学)（2010年03月 日本大学）

ホームページURL

J-Global ID

研究キーワード

  • 人体病理   口腔癌   

研究分野

  • ライフサイエンス / 人体病理学
  • ライフサイエンス / 実験病理学

所属学協会

  • 日本頭頸部癌学会   日本癌学会   日本臨床口腔病理学会   日本臨床細胞学会   日本病理学会   

研究活動情報

論文

  • Yusuke Amano, Atsushi Kihara, Masayo Hasegawa, Tamaki Miura, Daisuke Matsubara, Noriyoshi Fukushima, Hiroshi Nishino, Yoshiyuki Mori, Toshiro Niki
    Frontiers in medicine 9 859144 - 859144 2022年 
    Background: Stromal patterns (SP), especially desmoplastic reactions, have recently gained attention as indicators of malignant potential in cancer. In this study, we explored the clinicopathological and prognostic significance of the SP in oral squamous cell carcinoma (OSCC). Materials and Methods: We reviewed 232 cases of surgically resected OSCC that were not treated with neoadjuvant chemoradiotherapy. We categorized the SP of the OSCC into four groups: immune/inflammatory (84 cases), mature (14 cases), intermediate (78 cases), or immature (56 cases). Results: The SP category was significantly associated with various clinicopathological factors, such as the histological grade, lymphovascular invasion, neural invasion, and a diffuse invasion pattern. For each of the factors, the immune/inflammatory type was associated with favorable categories, while the immature type was associated with unfavorable categories (p ≤ 0.001). The SP category was also shown to be a prognostic predictor: the 5-year relapse-free survival (RFS) rate was 72.0% for the immune/inflammatory type, 66.7% for the intermediate/mature type, and 31.2% for the immature type (p < 0.0001), and the 5-year overall survival (OS) rate was 85.1% for the immune/inflammatory type, 76.4% for the intermediate/mature type, and 50.0% for the immature type (p < 0.0001). In multivariate analyses, the SP category was identified as an independent prognostic factor for RFS and OS. Conclusion: Our SP categorization method provides valuable prognostic information in OSCC.
  • Yusuke Amano, Daisuke Matsubara, Atsushi Kihara, Hiroshi Nishino, Yoshiyuki Mori, Toshiro Niki
    Pathology 2021年09月 
    Methylthioadenosine phosphorylase (MTAP) is a rate-limiting enzyme in the methionine salvage pathway, which recycles one carbon unit that is lost during polyamine synthesis back into the methionine cycle. Although MTAP deficiency has been reported in various tumours, MTAP is overexpressed and might promote oncogenesis in other cancers, including prostate and colon cancer. Currently, little is known about the MTAP status of oral squamous cell carcinoma (OSCC). In this study, we immunohistochemically examined the expression of MTAP in surgically resected oral epithelial dysplasia (OED, n=7), carcinoma in situ (CIS) (n=16), and OSCC (n=118). In the normal epithelium, MTAP was only weakly expressed in the cytoplasm of the basal layer cells. In OED, CIS, and OSCC, MTAP was uniformly expressed in the cytoplasm of the dysplastic and cancer cells. In addition to cytoplasmic MTAP expression, 45 of 118 cases (38.1%) exhibited increased nuclear expression of MTAP in the cancer cells at the invasive front. Statistical analysis showed that the concomitant nuclear and cytoplasmic expression of MTAP was associated with a high budding score (p=0.0023); poor differentiation (p=0.0044); aggressive invasion patterns (p=0.0001); and features of epithelial-to-mesenchymal transition (EMT), such as loss of E-cadherin expression (p=0.0003) and upregulated expression of vimentin (p=0.0002), slug (p=0.0002), and laminin 5 (p<0.0001). High expression of protein arginine methyltransferase 1 or 5, the functions of which are reported to be inhibited in MTAP-deficient cancer, was associated with the concomitant nuclear and cytoplasmic expression of MTAP (p<0.0001). Concomitant nuclear and cytoplasmic expression of MTAP was marginally significantly associated with worse 5-year relapse-free survival (p=0.045). These findings suggest that MTAP not only plays a role in the oncogenesis of OSCC, but that it might also make it more aggressive by inducing EMT through its activity in the methionine salvage pathway.
  • Yusuke Amano, Kentaro Tsuji, Atshushi Kihara, Daisuke Matsubara, Noriyoshi Fukushima, Hiroshi Nishino, Toshiro Niki
    Medicine 100 2 e24011  2021年01月 
    RATIONALE: Salivary duct carcinoma (SDC) is a rare and highly aggressive cancer with a poor prognosis. SDC demonstrates a potential for invasive growth with early regional and distant metastasis to organs, such as bone, lung, liver, and brain. Because, adrenal gland metastasis from SDC is rare, its treatment options are not well established. Herein, we report a case of SDC metastasis from the parotid gland to the adrenal gland, which was successfully treated by surgery. PATIENT CONCERNS: The patient had an abnormal but painless lump on the right parotid gland. The size of the mass had increased over a period of 3 years. The patient underwent complete removal of the right parotid gland and radical neck dissection followed by adjuvant radiotherapy and chemotherapy. Two years later, a mass was identified in the left adrenal gland by computed tomography. As no local recurrence or metastasis to other organs was observed, the patient underwent adrenalectomy. DIAGNOSES: Metastasis of SDC in the adrenal gland was confirmed by histopathological examination of the adrenalectomized specimen. INTERVENTIONS: After adrenalectomy, the patient was followed-up without adjuvant therapy. OUTCOMES: The patient was well and alive during the 13-month postoperative follow-up period without any complications. LESSONS: Surgical resection of solitary metastatic lesion may show a survival benefit with metastatic SDC.
  • Yusuke Amano, Mio Sakaguchi-Tamba, Yumiko Sasaki, Hisashi Oshiro, Noriyoshi Fukushima, Takashi Fujita, Shinobu Masuda, Toshiro Niki
    Medicine 99 42 e22665  2020年10月 [査読有り][通常論文]
     
    INTRODUCTION: Breast adenomyoepithelioma (AME) is a rare tumor composed of myoepithelial cells and ductal or luminal cells. Most cases of AME are benign, but rare cases in which either or both cell types exhibited malignant features have been reported. Due to its rarity, no diagnostic criteria for malignancy have been established for AME. PATIENT CONCERNS: A 64-year-old woman presented with a mass in her right breast. Fine-needle aspiration cytology and biopsy examinations revealed lesions composed of spindle-shaped cells and round epithelial cells. AME was suspected, and partial mastectomy was performed. DIAGNOSIS: The tumor specimen showed AME, which mainly consisted of spindle-shaped myoepithelial cells with slight atypia, admixed with tubular luminal cells and small areas of atypical intraductal proliferative lesions. No apparent features of malignancy, such as necrosis or invasion, were seen in the myoepithelial cells or the luminal or intraductal component. However, the atypical intraductal component exhibited focal nuclear atypia, a cribriform pattern, and moderate to strong membranous human epidermal growth factor receptor 2 (HER2) immunoreactivity. HER2 amplification was detected in focal regions of the atypical intraductal component by fluorescence in situ hybridization (FISH), which resulted in a diagnosis of AME with ductal carcinoma in situ. OUTCOMES: The patient did not receive further therapy and was free from tumor recurrence at 23 months after the operation. CONCLUSION: HER2 FISH might be useful for evaluating suspected AME tumors for malignancy when an atypical ductal lesion that lacks definitive features of malignancy is encountered.
  • 天野 雄介, 鈴木 智子, 大城 久, 松原 大祐, 福嶋 敬宣, 森 良之, 仁木 利郎
    臨床検査栃木 14 2 133 - 138 (一社)栃木県臨床検査技師会 2019年04月 [査読有り][招待有り]
     
    口腔領域の細胞診は、ブラシや綿棒などで粘膜を擦過して細胞を採取するので、侵襲性が少なく、繰り返し実施可能である。そのため、口腔癌検診や初診時のスクリーニング目的に実施されることが多い。口腔粘膜疾患細胞診の判定区分について解説し、口腔潜在的悪性疾患(紅板症、白板症、口腔扁平苔癬)、口腔上皮性異形成、扁平上皮癌(上皮内癌含む)における病理学的および細胞学的な項目を中心に概説した。
  • 病理アトラス 口腔上皮異形成の病理
    天野 雄介, 仁木 利郎
    別冊Bio Clinica: 慢性炎症と疾患 7 3 1 - 4 (株)北隆館 2018年10月 [査読無し][招待有り]
  • Yusuke Amano, Daisuke Matsubara, Taichiro Yoshimoto, Tomoko Tamura, Hiroshi Nishino, Yoshiyuki Mori, Toshiro Niki
    Pathology International 2018年06月 [査読有り][通常論文]
  • Yusuke Amano, Sumie Ohni, Taku Homma, Tsutomu Yamada, Masahiko Sugitani, Hidetaka Shiraiwa, Noboru Kitamura, Masami Takei
    Pathology international 66 6 351 - 3 2016年06月 [査読有り][通常論文]
  • 天野 雄介, 廣谷 ゆかり, 中西 陽子, 辻村 隆介, 若松 賀代美, 植村 史子, 桂 義久, 杉谷 雅彦, 根本 則道
    日大医学雑誌 74 3 113 - 116 日本大学医学会 2015年06月 [査読有り][通常論文]
     
    今回、我々は頭皮皮膚原発と考えられた血管肉腫の胸水浸潤例を経験した。症例は70歳代の男性で、頭部腫瘤を切除され血管肉腫と診断された。術後6ヵ月後に胸水細胞診が施行され腫瘍細胞は、大小の集塊や、印環様細胞、細胞質内小腺腔構造、細胞相互封入像(Pair cell)、および複数細胞からなる細胞封入像(渦巻き様構造)として認められた。免疫組織化学的にCD31、D2-40、Vimentinに陽性であった。上記所見と臨床所見より血管肉腫の胸水浸潤と診断した。(著者抄録)
  • 天野 雄介, 杉谷 雅彦, 伊豆 麻未, 西巻 はるな, 本間 琢, 鈴木 淳子, 関 利美, 増田 しのぶ, 根本 則道
    診断病理 32 2 178 - 182 (一社)日本病理学会 2015年04月 [査読有り][通常論文]
     
    小児の縦隔に発生したHistiocytic sarcomaの1例を経験したので報告する。患者は4歳男児、感冒様症状が出現したため近医を受診したところ、画像上縦隔の拡大が指摘された。診断目的で臨床的に転移巣と考えられた頭部皮膚の生検が施行された。組織学的には、真皮から皮下組織にかけて結節性病変が認められ、中等大の類円形細胞の増殖から構成されていた。免疫染色ではCD45LCA、CD68、CD163陽性、CD1a、CD3、CD20、CD79a、CD246、MPO、lysozyme陰性であり、HE像と併せ、Histiocytic sarcomaと診断した。(著者抄録)
  • Amano Yusuke, Ohni Sumie, Ishige Toshiyuki, Homma Taku, Yamada Tsutomu, Nishimori Nobuyuki, Nemoto Norimichi
    日大医学雑誌 74 2 73 - 77 NIHON UNIVERSITY MEDICAL ASSOCIATION 2015年 [査読有り]
     
    Herein, we present a case report of the metastasis of a clear cell renal cell carcinoma (ccRCC) with an eosinophilic cell component to the skin of the submandibular region. An eosinophilic component has not been reported previously in the histological findings of ccRCC. The patient was a 74yearold man who had a painless papula in the right submandibular region. Six years earlier, he had undergone nephrectomy and had been diagnosed with stage 1 ccRCC (pT1a, N0, M0). At the current presentation, the dermis in the resected specimen was composed of a clear cell neoplasm with glycogen deposits. Upon immunohistochemical analysis, the clear cells were found to be positive for CD10 and vimentin. As these findings were similar to those from the nephrectomy specimen, the cutaneous lesion on the skin of the submandibular region was confirmed to be a lesion of the metastatic ccRCC. Even when a lowstage ccRCC with an eosinophilic cell component is diagnosed, critical pathological and clinical examinations are needed because distant metastases may occur to the head and neck region, as in this case. Furthermore, when a skin tumor is found in the head and neck region, metastatic RCC must be considered in the differential diagnosis.
  • 天野 雄介, 楠美 嘉晃, 山田 勉, 樋口 雄将, 戸井 輝夫, 増田 毅, 浅川 剛志, 池田 稔, 森永 正二郎, 根本 則道
    診断病理 30 4 326 - 329 (一社)日本病理学会 2013年10月 [査読有り][通常論文]
     
    50代後半女性の顎下部に、径約15cmの腫瘤を認め、切除された。病理組織では紡錘形細胞が粘液腫様基質を伴い増生し、一部に扁平上皮化生を認める多形腺腫がみられ、これと移行するように異型の高度な紡錘形細胞が密に増殖する肉腫様の病変がみられ、破骨型巨細胞の出現も目立った。免疫染色では、肉腫様の腫瘍細胞は筋上皮の形質を示し、多形腺腫由来筋上皮癌と診断した。高い増殖能と被膜浸潤を伴い、術後早期に局所再発と肺転移巣の増大により死亡した。多形腺腫由来筋上皮癌は悪性度が高く、正確に診断する必要があると考えられた。(著者抄録)
  • Yusuke Amano, Yoshitake Cho, Manabu Matsunawa, Kazuo Komiyama, Makoto Makishima
    The Journal of steroid biochemistry and molecular biology 114 3-5 144 - 51 2009年04月 [査読有り][通常論文]
     
    The active form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], is a potent ligand for the nuclear receptor vitamin D receptor (VDR) and induces myeloid leukemia cell differentiation. The cardiotonic steroid bufalin enhances vitamin D-induced differentiation of leukemia cells and VDR transactivation activity. In this study, we examined the combined effects of 1,25(OH)(2)D(3) and bufalin on differentiation and VDR target gene expression in human leukemia cells. Bufalin in combination with 1,25(OH)(2)D(3) enhanced the expression of VDR target genes, such as CYP24A1 and cathelicidin antimicrobial peptide, and effectively induced differentiation phenotypes. An inhibitor of the Erk mitogen-activated protein (MAP) kinase pathway partially inhibited bufalin induction of VDR target gene expression. 1,25(OH)(2)D(3) treatment induced transient nuclear expression of VDR in HL60 cells. Interestingly, bufalin enhanced 1,25(OH)(2)D(3)-induced nuclear VDR expression. The MAP kinase pathway inhibitor increased nuclear VDR expression induced by 1,25(OH)(2)D(3) and did not change that by 1,25(OH)(2)D(3) plus bufalin. A proteasome inhibitor also enhanced 1,25(OH)(2)D(3)-induced CYP24A1 expression and nuclear VDR expression. Bufalin-induced nuclear VDR expression was associated with histone acetylation and VDR recruitment to the CYP24A1 promoter in HL60 cells. Thus, the Na(+),K(+)-ATPase inhibitor bufalin modulates VDR function through several mechanisms, including Erk MAP kinase activation and increased nuclear VDR expression.
  • Yusuke Amano, Kazuo Komiyama, Makoto Makishima
    Journal of oral science 51 1 11 - 20 2009年03月 [査読有り][通常論文]
     
    1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3); 1,25-dihydroxycholecalciferol or calcitriol] is the active form of vitamin D(3), a lipid-soluble vitamin that plays a role in calcium and bone metabolism. Recently, vitamin D(3) has been shown to function in cancer prevention, immunity and cardiovascular regulation. 1,25(OH)(2)D(3) exhibits physiological and pharmacological effects by activating the vitamin D receptor (VDR), a transcription factor of the nuclear receptor superfamily. 1,25(OH)(2)D(3) plays a role in maintaining oral health through its effects on bone and mineral metabolism and innate immunity, and several VDR gene polymorphisms have been reported to be associated with periodontal disease. VDR ligands should prove to be useful in the treatment and prevention of periodontal disease.

講演・口頭発表等

  • 口腔癌におけるHippo pathwayタンパクの発現(The role of hippo pathway protein expression in oral cancer)
    天野 雄介, 松原 大祐, 木原 淳, 吉本 多一郎, 福嶋 敬宜, 仁木 利郎
    日本病理学会会誌 2022年03月 (一社)日本病理学会
  • 口腔扁平上皮癌におけるHippo pathwayタンパク発現の役割
    天野 雄介, 松原 大祐, 木原 淳, 吉本 多一郎, 仁木 利郎
    日本癌学会総会記事 2021年09月 (一社)日本癌学会
  • 口腔扁平上皮癌における腫瘍間質の組織学的評価
    天野 雄介, 木原 淳, 長谷川 雅世, 三浦 珠希, 松原 大祐, 福嶋 敬宜, 仁木 利郎
    日本病理学会会誌 2021年03月 (一社)日本病理学会
  • 口腔扁平上皮癌における腫瘍間質の組織学的評価
    天野 雄介, 木原 淳, 松原 大祐, 森 良之, 西野 宏, 仁木 利郎
    頭頸部癌 2020年07月 (一社)日本頭頸部癌学会
  • 口腔癌におけるMTAP発現の意義(The role of MTAP expression in oral cancer)
    天野 雄介, 松原 大祐, 木原 淳, 仁木 利郎
    日本病理学会会誌 2020年03月 (一社)日本病理学会
  • 口腔癌におけるリン酸化YAPの発現(Expressions of YAP and phospho-YAP(S127) in oral cancer)
    天野 雄介, 松原 大祐, 木原 淳, 吉本 多一郎, 仁木 利郎
    日本癌学会総会記事 2019年09月 (一社)日本癌学会
  • 口腔癌におけるYAP発現の役割(The role of YAP expression in oral cancer)
    天野 雄介, 松原 大祐, 木原 淳, 吉本 多一郎
    日本病理学会会誌 2019年04月 (一社)日本病理学会
  • 口腔癌におけるYAPの役割(The role of YAP expression in oral squamous cell carcinoma)
    天野 雄介, 松原 大祐, 木原 淳, 吉本 多一郎, 仁木 利郎
    日本癌学会総会記事 2018年09月 (一社)日本癌学会
  • 胎児型肺腺癌との鑑別を要したHNF-4α陽性肺腺癌の一例
    天野 雄介, 木原 淳, 吉本 多一郎, 松原 大祐, 遠藤 俊輔, 萩原 弘一, 仁木 利郎
    日本病理学会会誌 2018年04月 (一社)日本病理学会

MISC

  • Atsushi Kihara, Yusuke Amano, Noriyoshi Fukushima, Hiroyuki Fujiwara, Toshiro Niki Histopathology 2022年04月 
    AIMS: The pathological diagnosis of undifferentiated and dedifferentiated endometrial carcinomas (UC/DCs) is prognostically important. However, undifferentiated components may be confused with other subtypes, particularly grade 3 endometrioid carcinomas (G3ECs). ZEB1 has recently been identified as a promising marker because it is frequently expressed in the undifferentiated components of UC/DCs, but not in other carcinomas. Therefore, we herein evaluated the diagnostic utility of ZEB1 with an emphasis on distinguishing between UC/DCs and G3ECs using an expanded cohort of endometrial carcinomas and carcinosarcomas. METHODS AND RESULTS: Immunostaining for ZEB1 was performed on whole-tissue sections of 19 UC/DCs, 194 non-UC/DC endometrial carcinomas, and 29 carcinosarcomas. Staining was defined as negative (<5%), focal (5-50%), and diffuse expression (>50%). ZEB1 was expressed in 84% of the undifferentiated components of UC/DCs (diffuse in 14, focal in two). Focal expression was observed in eight non-UC/DC endometrial carcinomas and diffuse expression in seven, with the latter comprising G3ECs (4/76), serous carcinoma (1/37), clear cell carcinoma (1/21), and neuroendocrine carcinoma (1/3). Epithelial differentiation was morphologically and immunohistochemically less evident in G3ECs and neuroendocrine carcinoma with diffuse ZEB1 expression. All carcinosarcomas showed diffuse ZEB1 expression in their sarcomatous components. CONCLUSION: Immunostaining for ZEB1 was sufficiently sensitive to detect undifferentiated components. Diffuse ZEB1 expression showed high specificity for distinguishing between undifferentiated components and G3ECs; however, ZEB1 expression was not entirely specific to UC/DCs. The integration of ZEB1 into the diagnosis of UC/DCs requires careful examinations to exclude other tumours, such as less differentiated G3ECs, neuroendocrine carcinomas, and carcinosarcomas.
  • Hirokazu Matsuura, Akira Saito, Yusuke Amano, Kazue Morishima, Hideki Sasanuma, Alan Kawarai Lefor, Naohiro Sata International journal of surgery case reports 94 107085 -107085 2022年04月 
    INTRODUCTION AND IMPORTANCE: Intussusception is invagination of the bowel and is rare in adults, representing only 5% of all cases of intussusception. Duodenal intussusception is also very rare. To the best of our knowledge, there is only one previous report of a malignant tumor in the fourth portion of the duodenum as the lead point of intussusception (Vaibhav et al., 2021 [1]). This reports a duodenal-duodenal intussusception caused by a malignant tumor in the third portion of the duodenum. CASE PRESENTATION: A 36-year-old woman with abdominal pain was diagnosed with duodenal intussusception by abdominal ultrasonography and computed tomography scan. Double balloon endoscopy showed that the intussusception had spontaneously reduced, and a tumor was found in the third portion of the duodenum. Open resection was performed because of the tumor location. Pathologic examination revealed adenocarcinoma with an adenoma of the duodenum. The patient had no evidence of recurrence for 4 years after resection. CLINICAL DISCUSSION: This patient had a primary duodenal malignancy and presented with intussusception, Duodenal intussusception is a rare condition requiring prompt intervention, usually requiring surgery. In this patient, since endoscopic resection was difficult, partial resection of duodenum was performed by open surgery assisted by double balloon enteroscopy. The pathological diagnosis of the resected specimen was primary duodenal malignancy. CONCLUSION: This is a report of adult duodenal intussusception caused by a primary duodenal malignancy. This rare condition posed an intriguing challenge for the optimal operative approach.
  • Atsushi Kihara, Yusuke Amano, Daisuke Matsubara, Noriyoshi Fukushima, Hiroyuki Fujiwara, Toshiro Niki Human pathology 116 12 -21 2021年10月 
    SMARCA4-deficient uterine sarcoma (SMARCA4-DUS) was recently proposed as a new entity of uterine sarcoma. Reported cases of SMARCA4-DUS showed the loss of SMARCA4 and SMARCA2 expression. However, the prevalence of their deficiency in uterine mesenchymal tumors remains unclear. This study immunohistochemically examined the expression of SMARCA4, SMARCA2, and SMARCB1 in 206 uterine mesenchymal tumors and detected a round cell tumor with the loss of SMARCA4 and SMARCA2 and a low-grade endometrial stromal sarcoma with SMARCA4 deficiency. The remaining 204 cases, including 170 smooth muscle tumors, 22 endometrial stomal nodule/sarcomas, seven undifferentiated uterine sarcomas, two adenosarcomas, one uterine tumor resembling ovarian sex cord tumor, and two perivascular epithelioid cell tumors, retained the expression of both SMARCA4 and SMARCA2. All tumors retained SMARCB1 expression. The round cell tumor with the loss of SMARCA4 and SMARCA2 was composed of diffuse small round cell growth with follicle-like spaces, which resembled small cell carcinoma of the ovary, hypercalcemic type. Immunohistochemically, the tumor showed the proficient expression of mismatch repair proteins and wild-type p53 expression, which favored SMARCA4-DUS; however, the tumor harbored the PIK3CA mutation, and thus, was reclassified as undifferentiated endometrial carcinoma. In conclusion, SMARCA4, SMARCA2, and SMARCB1 were rarely deficient in uterine mesenchymal tumors. SMARCA4 immunohistochemistry has potential in the diagnosis of SMARCA4-DUS with the exclusion of some tumors showing its deficiency, such as endometrial stromal sarcoma and undifferentiated carcinoma. Undifferentiated carcinoma may show an indistinguishable morphology and immunophenotype from SMARCA4-DUS, and thus, molecular analysis is required for their distinction in diagnostic practice.
  • Kosuke Matsuzono, Younhee Kim, Hiroyuki Honda, Yuhei Anan, Masato Tsunoda, Yusuke Amano, Noriyoshi Fukusima, Toru Iwaki, Tetsuyuki Kitamoto, Shigeru Fujimoto The American journal of gastroenterology 2020年11月
  • Atsushi Kihara, Yusuke Amano, Daisuke Matsubara, Noriyoshi Fukushima, Hiroyuki Fujiwara, Toshiro Niki The American journal of surgical pathology 44 (12) 1712 -1724 2020年09月 [査読無し][通常論文]
     
    Switch/sucrose nonfermenting complex subunits, such as BRG1, INI1, and ARID1B, are inactivated in a subset of endometrial undifferentiated carcinoma and dedifferentiated carcinoma (DC). Limited information is currently available on their prevalence in other subtypes or the nosological status of endometrial carcinoma with their deficiencies. This study immunohistochemically examined the expression status of BRG1, INI1, and ARID1B using 570 archived cases of endometrial carcinoma and carcinosarcoma resected at a single institution. We identified 1 BRG1-deficient undifferentiated carcinoma, 8 BRG1/INI1/ARID1B-deficient DC, and 3 BRG1-deficient clear-cell carcinomas. None of the cases of endometrioid and serous carcinomas or carcinosarcoma showed deficiencies of these subunits. We then compared 8 BRG1/INI1/ARID1B-deficient DC with 6 BRG1/INI1/ARID1B-intact DC and 28 carcinosarcomas, the latter of which was often confused with DC. Histologically, BRG1/INI1/ARID1B-intact and BRG1/INI1/ARID1B-deficient DC shared a monotonous solid appearance with rhabdoid and epithelioid cells and a myxoid stroma; however, abrupt keratinization and cell spindling was absent in BRG1/INI1/ARID1B-deficient tumors. The median overall survival of patients with BRG1/INI1/ARID1B-deficient DC was 3.8 months, which was worse than those with BRG1/INI1/ARID1B-intact DC (P=0.008) and with carcinosarcoma (P=0.004). BRG1/INI1/ARID1B-deficient DC may be a separate entity with an aggressive behavior to be distinguished from BRG1/INI1/ARID1B-intact DC and carcinosarcoma. Regarding clear-cell carcinoma (n=12), BRG1 deficiency appeared to be mutually exclusive with abnormal ARID1A, BRM, and p53 expression. Further studies are needed to clarify whether BRG1 deficiency plays a role in the pathogenesis of clear-cell carcinoma.
  • Atsushi Kihara, Kazuya Takahashi, Ayataka Ishikawa, Yusuke Amano, Daisuke Matsubara, Hiroaki Kanda, Naohiro Sata, Noriyoshi Fukushima, Toshiro Niki Medical molecular morphology 53 (3) 177 -182 2020年09月 [査読無し][通常論文]
     
    We herein report a variant case of desmoplastic small round cell tumor (DSRCT) showing limited desmoplasia and confusing immunohistochemical findings. A 26-year-old male was referred for multiple abdominal masses. Laparoscopic biopsy showed only the solid proliferation of small round cells, and he was initially diagnosed with small cell carcinoma. At autopsy, the tumor spread diffusely throughout the abdominal and pelvic cavities. Although the tumor was composed of a predominantly solid pattern of small round cells, multiple samples revealed a fibrous stroma in limited areas only. While immunohistochemistry showed the diffuse expression of desmin, CD99, and bcl-2, epithelial differentiation was unclear with few cytokeratin-positive cells and no staining for the epithelial membrane antigen. Although fluorescence in situ hybridization analysis indicated the EWSR1 gene rearrangement, we were unable to exclude Ewing sarcoma considering the morphological and immunohistochemical findings. The diagnosis of DSRCT was confirmed with a reverse transcription-polymerase chain reaction for EWSR1-WT1 fusion transcripts. DSRCT must be included in a differential diagnosis of small round cell tumors even if desmoplasia is not immediately detected, and thorough sampling and a molecular analysis are mandatory.
  • Hikaru Watanabe, Reiji Koide, Misato Yokose Ozawa, Younhee Kim, Kumiko Miura, Tadashi Ozawa, Kosuke Matsuzono, Takafumi Mashiko, Ryota Tanaka, Yusuke Amano, Katsuya Nagatani, Kojiro Sato, Shigeru Fujimoto Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 41 (7) e889-e890 2020年08月 [査読無し][通常論文]
  • Daisuke Matsubara, Taichiro Yoshimoto, Manabu Soda, Yusuke Amano, Atsushi Kihara, Toko Funaki, Takeshi Ito, Yuji Sakuma, Tomoki Shibano, Shunsuke Endo, Koichi Hagiwara, Shumpei Ishikawa, Masashi Fukayama, Yoshinori Murakami, Hiroyuki Mano, Toshiro Niki Cancer science 111 (6) 2183 -2195 2020年06月 [査読無し][通常論文]
     
    Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in thyroid transcription factor-1 (TTF-1)/NK2 homeobox 1 (NKX2-1)-positive terminal respiratory unit (TRU) types and rarely in non-TRU types. To elucidate the molecular characteristics of the major subtypes of non-TRU-type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non-TRU types). A characteristic of non-TRU-type cell lines was the strong expression of TFF-1 (trefoil factor-1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF-1 was positive in 31 cases (13%). Expression of TFF-1 was frequently detected in invasive mucinous (14/15, 93%), enteric (2/2, 100%), and colloid (1/1, 100%) adenocarcinomas, less frequent in acinar (5/24, 21%), papillary (7/120, 6%), and solid (2/43, 5%) adenocarcinomas, and negative in micropapillary (0/1, 0%), lepidic (0/23, 0%), and microinvasive adenocarcinomas or adenocarcinoma in situ (0/9, 0%). Expression of TFF-1 correlated with the expression of HNF4-α and MUC5AC (P < .0001, P < .0001, respectively) and inversely correlated with that of TTF-1/NKX2-1 (P < .0001). These results indicate that TFF-1 is characteristically expressed in non-TRU-type adenocarcinomas with gastrointestinal features. The TFF-1-positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. Expression of TFF-1 correlated with tumor spread through air spaces, and a poor prognosis in advanced stages. Moreover, the knockdown of TFF-1 inhibited cell proliferation and soft-agar colony formation and induced apoptosis in a TFF-1-high and KRAS-mutated lung adenocarcinoma cell line. These results indicate that TFF-1 is not only a biomarker, but also a potential molecular target for non-TRU-type lung adenocarcinomas.
  • 齋藤 晶, 鯉沼 広治, 田原 真紀子, 森 和亮, 井上 賢之, 宮永 明子, 秋山 陽一郎, 天野 雄介, 堀江 久永, 佐田 尚宏 日本消化器外科学会雑誌 53 (1) 22 -29 2020年01月 [査読無し][通常論文]
     
    症例は45歳の男性で,多発血管炎性肉芽腫症に対して当院アレルギー・リウマチ科で薬剤療法を開始した.開始後12日目に下腹部痛が出現し,腹部CTにて消化管穿孔と診断し緊急手術を施行した.小腸間膜対側に10mm以下の発赤を20ヶ所認め,うち2ヶ所の穿孔部を含む3ヶ所を部分切除した.術後経過は良好で,9日目に薬剤療法を再開した小腸穿孔部の病理組織学的検査所見では,血管壁への炎症細胞の浸潤を認め,多発血管炎性肉芽腫症に伴う消化管穿孔と診断した.術後53日目に絞扼性イレウスが疑われ緊急手術を施行したが,明らかな絞扼性イレウスや穿孔の所見は認めなかった.その後の経過は良好で,薬剤療法を再開,継続中である.今回の検討から多発血管炎性肉芽腫症に伴う消化管穿孔は重症化しやすく,潰瘍性病変が多発する傾向にあり,ときに再穿孔を来すことがわかった.これらを十分理解し,患者・家族へ説明し,治療にあたることが必要である.(著者抄録)
  • 中枢神経原発と考えられ、その後他臓器浸潤がみられた悪性リンパ腫の一例
    柳田 美樹, 二階堂 貴章, 郡 俊勝, 鈴木 智子, 渡邊 温子, 天野 雄介, 大城 久, 福嶋 敬宜 自治医科大学臨床検査技師年報 (42) 52 -55 2019年12月 [査読無し][通常論文]
     
    症例は60歳代女性で、2週間程度で亜急性進行性の多発脳神経障害と錐体路・小脳・全感覚路の障害を認めた。頭部MRI所見より中枢神経系原発悪性リンパ腫(PCNSL)と考えられたが、脳幹部位であったため生検による組織診断が不可能で、脳脊髄液細胞診においても確定には至らなかった。ステロイド治療により病変の縮小と造影効果の消失を認めたが、約半年後に症状の急速な悪化がみられた。MRIで病変の広がりを認め、鎖骨上窩や腹腔内リンパ節の腫大、右腎周囲・脾・膵・腸管周囲の腫瘤、胸腹水貯留がみられ、再発/浸潤が疑われた。その後の治療で寛解になっている。当院の過去10年間において脳生検または手術を施行したPCNSLは34例で、全脳腫瘍に対して4.9%と少なく、全例においてDLBCLであった。さらに脳脊髄液細胞診を行い、悪性リンパ腫が疑われた症例は2例であった。脳生検または手術を施行しなかったPCNSLの症例は今回の症例のみで、他臓器転移があった症例は他に1例みられた。
  • 病理解剖室・臓器保管倉庫におけるホルマリン対策
    小瀬川 順幸, 二階堂 貴章, 本望 一昌, 飛田野 清美, 芳賀 美子, 天野 雄介, 福嶋 敬宜 自治医科大学臨床検査技師年報 (42) 56 -63 2019年12月 [査読無し][通常論文]
     
    当院では開院当初(1974年)からの旧病理解剖室と2016年にリニューアル移転した現在の新病理解剖室において、ホルマリン濃度が0.1ppm以下の第1管理区分を目標とした環境改善対策を旧剖検室で1回、新剖検室で3回、合わせて4回実施した。本稿では、対策前後の作業環境改善結果について報告した。当院の旧剖検室はホルマリン環境対策を一切行っていなかった。旧倉庫は病理レポートの保管棚と同じスペースにあり、切り出し台、ホルマリン原液ストック場と床に直置きした臓器保管用ホルマリンバケツ置き場が混在していた。2013年に旧解剖室と旧倉庫のホルマリン対策を初めて行い、それを参考に2016年に新解剖室・臓器保管倉庫のリニューアルが実施され、1階の旧剖検室から地下1階の新剖検室に場所を移した。リニューアル移転時のホルマリン環境測定結果は、第1管理区分に至らなかった。新解剖室では切り出し臓器時にホルマリン吸収シートを使用したり、新倉庫で保管容器のビニール袋使用による二重密閉・パッキン付き容器への変更・ホルマリン吸着ビーズを使用したりと工夫を重ね、最終的には何とか第1管理区分を達成できた。旧剖検室では、ホルマリン臭がするのが当たり前との意識で剖検業務をこなしていた。現在の新剖検室は旧剖検室に比べてホルマリン臭はかなり軽減されてはいる。しかし現在第1管理区分を達成していても、ホルマリン臭がきつくなる場面も多々あり、ホルマリン濃度の低減への根本的な解決にはなっていないと思われる。
  • Tadashi Ozawa, Ryota Tanaka, Risa Nagaoka, Yuhei Anan, Younhee Kim, Kosuke Matsuzono, Takafumi Mashiko, Reiji Koide, Haruo Shimazaki, Keisuke Ohtani, Yusuke Amano, Kensuke Kawai, Shigeru Fujimoto Data in brief 27 104648 -104648 2019年12月 [査読無し][通常論文]
     
    Data presented in this article are related to our article entitled "Unilateral posterior reversible encephalopathy syndrome: A case report" [1]. Cases of Posterior Reversible Encephalopathy Syndrome (PRES) involving unilateral lesions are very rare. We searched the PubMed database using keywords such as PRES, unilateral, and asymmetric and found a small number of cases to include in our review. We summarized the characteristics of these reported cases of unilateral PRES, including our case.
  • Atsushi Kihara, Yusuke Amano, Taichiro Yoshimoto, Daisuke Matsubara, Noriyoshi Fukushima, Hiroyuki Fujiwara, Toshiro Niki The American journal of surgical pathology 43 (11) 1526 -1535 2019年11月 [査読無し][通常論文]
     
    Atypical polypoid adenomyoma (APA) is a polypoid lesion that is comprised of atypical endometrial glands and fibromuscular stroma, which pathologists often confuse with myoinvasive endometrioid carcinoma. Here, we characterized the immunohistochemical and molecular features of the stromal components of APA to find distinct markers between APA and myoinvasive endometrioid carcinoma. First, we examined the immunohistochemical expression and gene mutations that were previously investigated in uterine and breast fibroepithelial lesions using 12 cases of APA. α-smooth muscle actin was diffusely positive in the stromal component in all cases, whereas desmin and h-caldesmon were focally expressed in 8 cases. Positive expression was also observed in 9 cases for CD10, 12 cases for estrogen receptor, 3 cases for HMGA2, and 3 cases for MDM2. All cases showed normal p53 expression and negative staining of HMGA1 and nuclear β-catenin. No mutations in MED12 exon 2 and the TERT promoter were found in any cases. p16 was positive in all cases and showed diffuse expression in 10 cases. We assessed stromal p16 expression in 84 cases of myoinvasive endometrioid carcinoma. The stromal p16 status was negative in all myoinvasive carcinomas, but there was 1 case with focal staining. There was a significant difference in stromal p16 expression between APA and myoinvasive endometrioid carcinoma (P<0.001). Stromal p16 expression was more suggestive of APA than myoinvasive endometrioid carcinoma among endometrial fibroepithelial lesions.
  • Ayaka Ishihara, Shuji Hatakeyama, Jun Suzuki, Yusuke Amano, Teppei Sasahara, Masaki Toshima, Yuji Morisawa BMC infectious diseases 19 (1) 848 -848 2019年10月 [査読無し][通常論文]
     
    BACKGROUND: Pegylated liposomal doxorubicin plays an important role in the treatment of patients with severe refractory human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). High cumulative doses of conventional doxorubicin exceeding 500 mg/m2 are known to cause cardiac toxicity. However, the safe cumulative dose of pegylated liposomal doxorubicin is unclear. CASE PRESENTATION: A 40-year-old Japanese man with HIV infection presented with pain, edema, and multiple skin nodules on both legs which worsened over several months. He was diagnosed with HIV-associated KS. He received long-term pegylated liposomal doxorubicin combined with antiretroviral therapy for advanced, progressive KS. The cumulative dose of pegylated liposomal doxorubicin reached 980 mg/m2. The patient's left ventricular ejection fraction remained unchanged from baseline during treatment. After he died as a result of cachexia and wasting, caused by recurrent sepsis and advanced KS, an autopsy specimen of his heart revealed little or no evidence of histological cardiac damage. We also conducted a literature review focusing on histological changes of the myocardium in patients treated with a cumulative dose of pegylated liposomal doxorubicin exceeding 500 mg/m2. CONCLUSIONS: This case report and literature review suggest that high (> 500 mg/m2) cumulative doses of pegylated liposomal doxorubicin may be used without significant histological/clinical cardiac toxicity in patients with HIV-associated KS.
  • Tadashi Ozawa, Ryota Tanaka, Risa Nagaoka, Yuhei Anan, Younhee Kim, Kosuke Matsuzono, Takafumi Mashiko, Reiji Koide, Haruo Shimazaki, Keisuke Ohtani, Yusuke Amano, Kensuke Kawai, Shigeru Fujimoto Clinical neurology and neurosurgery 185 105493 -105493 2019年10月 [査読無し][通常論文]
  • Taichiro Yoshimoto, Daisuke Matsubara, Manabu Soda, Toshihide Ueno, Yusuke Amano, Atsushi Kihara, Takashi Sakatani, Tomoyuki Nakano, Tomoki Shibano, Shunsuke Endo, Koichi Hagiwara, Masashi Fukayama, Kaori Denda-Nagai, Tatsuro Irimura, Hiroyuki Mano, Toshiro Niki Cancer science 110 (9) 3006 -3011 2019年09月 [査読無し][通常論文]
     
    Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell-cell and cell-matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O-glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness.
  • 佐々木 裕美子, 藤田 崇史, 天野 雄介, 田中 宏幸, 田中 昌宏, 佐田 尚宏 臨牀と研究 96 (5) 595 -597 2019年05月 [査読無し][通常論文]
     
    35歳女性。発赤と疼痛を伴う左乳房腫瘤を主訴に近医を受診、左乳腺炎として抗菌薬CFPN-PI(Cefcapene pivoxil)を投与されるも改善せず、当科へ紹介となった。乳房超音波では左乳房AC領域にプローブのスケールを超える境界不明瞭な低エコー腫瘤がみられ、内部は不均一で一部嚢胞様構造を呈していた。また、乳房MRIではダイナミック造影で左乳房AC領域を中心に最大径95mmの造影効果を伴う腫瘤を認め、内部には複数のリング状濃染される結節性病変を認めた。以上、これらの所見のほか、乳房膿様分泌液からの細菌培養により、本症例はCorynebacterium属感染による巨大肉芽腫性乳腺炎を考え、抗菌薬であるLVFXの内服とドレナージによる感染コントロールを行い、次いで少量のステロイド内服を開始したところ、左乳房腫瘤は徐々に蝕知されなくなり、治癒が得られた。
  • Tadahide Noguchi, Yasushi Sugiura, Naruo Okada, Yoshiyuki Tsuchiya, Jun-Ichi Hyasaka, Ken-Ichi Sasaguri, Shunji Sarukawa, Akifumi Fujita, Yusuke Amano, Yoshiyuki Mori Journal of medical case reports 13 (1) 58 -58 2019年03月 [査読無し][通常論文]
     
    BACKGROUND: Osteosarcomas of the head and neck region are rare entities that comprise < 10% of all osteosarcomas. Multimodality treatment of patients with osteosarcoma is well-established for osteosarcoma in long bones, and the benefits of chemotherapy in long bones are clearly known. However, there is no consensus regarding the effects of chemotherapy in cases of head and neck osteosarcoma. The prognostic factor for head and neck osteosarcoma is complete tumor resection with negative margin, which is a radical surgery. However, a clear margin may be difficult to achieve in the head and neck region. CASE PRESENTATION: We present a case of a 69-year-old Japanese woman who developed osteosarcoma of the condyle within the masticator space and infratemporal fossa, which was treated with radical surgery using a modified preauricular and transmandibular approach. Although we recommended adjuvant treatment after surgery, the patient refused this treatment. There was no evidence of local recurrence or distant metastasis through 30 months of follow-up. CONCLUSIONS: Our modified preauricular and transmandibular approach allowed access to the masticator space and infratemporal fossa, thereby increasing complete resection of the tumor and resulting in minimal functional and cosmetic deficits.
  • Kumiko Mito, Yusuke Amano, Hisashi Oshiro, Daisuke Matsubara, Noriyoshi Fukushima, Shigeru Ono Medicine 98 (4) e14211 2019年01月 [査読無し][通常論文]
     
    RATIONALE: Liver heterotopia associated with congenital diaphragmatic hernia (CDH) is a rare condition; to the best of our knowledge, only 17 cases have been reported to date. The histogenesis and clinicopathological features are largely unknown. We herein report 2 cases of liver heterotopia associated with CDH along with 17 cases described in the literature to shed light on their clinicopathological characteristics. PATIENT CONCERNS: Case 1 was a vaginally delivered male newborn who presented with respiratory distress immediately after birth. Case 2 was a female fetus who was found to have left-sided CDH during gestation. DIAGNOSIS: In case 1, a chest X-ray revealed left-sided CDH. In case 2, magnetic resonance imaging performed at 33 weeks of gestation revealed left-sided CDH. INTERVENTIONS: Case 1 underwent diaphragmatic patch repair surgery 3 days after birth. Histopathological examination following surgery in case 1 revealed the presence of ectopic liver tissue in the hernia sac. Case 2 was delivered by Cesarean section, and diaphragmatic patch surgery was performed 3 days after birth. During surgery, an isolated nodule was identified on the peritoneal side of the border of the defective foramen of the diaphragm. Histopathological examination following surgery in case 2 confirmed the presence of an epidermal cyst in the hernia sac. In addition, the isolated nodule was histopathologically found to be ectopic liver tissue. OUTCOMES: In Case 1, CDH recurred at 6 months after surgery, and a second patch repair surgery was performed. The surgically removed hernia sac was found to contain microscopic ectopic liver tissue on histopathology. Case 1 recovered well after surgery, and there was no critical change during the 10-month postoperative period. Case 2 recovered well after surgery, and there was no critical change during the 20-month postoperative period. LESSONS: There were no secondary pathological conditions associated with the presence of ectopic liver in CDH, such as torsion, infarction, rupture, intra-abdominal bleeding, or tumorization. Our observations suggest that liver heterotopia is a rare but asymptomatic condition in patients with CDH.
  • Daisuke Matsubara, Manabu Soda, Taichiro Yoshimoto, Yusuke Amano, Yuji Sakuma, Azusa Yamato, Toshihide Ueno, Shinya Kojima, Tomoki Shibano, Yasuyuki Hosono, Masahito Kawazu, Yoshihiro Yamashita, Shunsuke Endo, Koichi Hagiwara, Masashi Fukayama, Takashi Takahashi, Hiroyuki Mano, Toshiro Niki Cancer science 108 (9) 1888 -1896 2017年09月 [査読無し][通常論文]
     
    The major driver mutations of lung cancer, EGFR mutations and EML4-ALK fusion, are mainly detected in terminal respiratory unit (TRU)-type lung adenocarcinomas, which typically show lepidic and/or papillary patterns, but are rarely associated with a solid or invasive mucinous morphology. In order to elucidate the key genetic events in non-TRU-type lung cancer, we carried out whole-exome sequencing on 43 non-TRU-type lung adenocarcinomas based on morphology (17 acinar, nine solid, and two enteric adenocarcinomas, and 15 adenocarcinomas with a mucinous morphology). Our analysis identified mutations in TP53 (16/43, 37.2%), KRAS (13/43, 30.2%), and NKX2-1/TTF-1 (7/43; 16.3%) as the top three significantly mutated genes, while the EGFR mutation was rare (1/43, 2.3%) in this cohort. Eight NKX2-1/TTF-1 mutations (five frameshift, two nonsense, and one missense) were identified, with one case harboring two distinct NKX2-1/TTF-1 mutations (one missense and one frameshift). Functional assays with the NK2 homeobox 1 (NKX2-1)/thyroid transcription factor 1 (TTF-1) mutants revealed that none of them retain the activity as a transcriptional factor. Histologically, invasive mucinous adenocarcinomas accounted for most of the NKX2-1/TTF-1 mutations (five cases), as well as one enteric and one acinar adenocarcinoma. Immunohistochemistry showed that the cohort was largely divided into TTF-1-postive/hepatocyte nuclear factor 4-α (HNF4-α)-negative and TTF-1-negative/HNF4-α-positive groups. NKX2-1/TTF-1 mutations were exclusively found in the latter, in which the gastrointestinal markers, mucin 5AC and cytokeratin 20, were frequently expressed. Bisulfite sequencing revealed that the NKX2-1/TTF-1 gene body was highly methylated in NKX2-1/TTF-1-negative cases, including those without the NKX2-1/TTF-1 mutations. The genetic or epigenetic inactivation of NKX2-1/TTF-1 may play an essential role in the development and aberrant differentiation of non-TRU-type lung adenocarcinomas.
  • Natsuki Shima, Takamasa Murosaki, Takao Nagashima, Masahiro Iwamoto, Yusuke Amano, Naomi Nakano, Mamitaro Ohtsuki, Seiji Minota Internal medicine (Tokyo, Japan) 56 (15) 2063 -2066 2017年 [査読無し][通常論文]
     
    A 68-year-old man presented with polyarthritis, proximal muscle weakness, and erythema of the face, arms, neck, and anterior chest that resembled the V-neck sign. Initially, dermatomyositis (DM) was considered because of the erythema, polyarthritis, and muscle weakness. He also had mediastinal and hilar lymphadenopathy on contrast-enhanced computed tomography. Unexpectedly, a biopsy of the forehead skin revealed numerous multinucleated giant cells. A biopsy of a solitary nodule on the dorsum of his right middle finger revealed similar multinucleated giant cells with ground-glass cytoplasm, leading to the diagnosis of multicentric reticulohistiocytosis (MRH). Although MRH is rare, it should be remembered that MRH can mimic DM.
  • Tomoyuki Nakano, Yoshihiko Kanai, Yusuke Amano, Taichiro Yoshimoto, Daisuke Matsubara, Tomoki Shibano, Tomoko Tamura, Sachiko Oguni, Shizuka Katashiba, Takeshi Ito, Yoshinori Murakami, Masashi Fukayama, Takashi Murakami, Shunsuke Endo, Toshiro Niki PloS one 12 (8) e0181342 2017年 [査読無し][通常論文]
     
    Decreased cell-substratum adhesion is crucially involved in metastasis. Previous studies demonstrated that lung cancer with floating cell clusters in histology is more likely to develop metastasis. In the present study, we investigated whether cancer cells in long-term, three-dimensional low attachment cultures acquire high metastatic potential; these cells were then used to examine the mechanisms underlying metastasis. Two KRAS-mutated adenocarcinoma cell lines (A549 and H441) were cultured and selected on ultra-low attachment culture dishes, and the resulting cells were defined as FL (for floating) sublines. Cancer cells were inoculated into NOD/SCID mice via an intracardiac injection, and metastasis was evaluated using luciferase-based imaging and histopathology. In vitro cell growth (in attachment or suspension cultures), migration, and invasion were assayed. A whole genomic analysis was performed to identify key molecular alterations in FL sublines. Upon detachment on low-binding dishes, parental cells initially formed rounded spheroids with limited growth activity. However, over time in cultures, cells gradually formed smaller spheroids that grew slowly, and, after 3-4 months, we obtained FL sublines that regained prominent growth potential in suspension cultures. On ordinary dishes, FL cells reattached and exhibited a more spindle-shaped morphology than parental cells. No marked differences were observed in cell growth with attachment, migration, or invasion between FL sublines and parental cell lines; however, FL cells exhibited markedly increased growth potential under suspended conditions in vitro and stronger metastatic abilities in vivo. A genomic analysis identified epithelial-mesenchymal transition (EMT) and c-Myc amplification in A549-FL and H441-FL cells, respectively, as candidate mechanisms for metastasis. The growth potential of FL cells was markedly inhibited by lentiviral ZEB1 knockdown in A549-FL cells and by the inhibition of c-Myc through lentiviral knockdown or the pharmacological inhibitor JQ1 in H441-FL cells. Long-term three-dimensional low attachment cultures may become a useful method for investigating the mechanisms underlying metastasis mediated by decreased cell-substratum adhesion.
  • Hiromichi Takahashi, Katsuhiro Miura, Masaru Nakagawa, Masahiko Sugitani, Yusuke Amano, Daisuke Kurita, Masashi Sakagami, Shimon Ohtake, Yoshihito Uchino, Hitomi Kodaira, Noriyoshi Iriyama, Sumiko Kobayashi, Atsuko Hojo, Yujin Kobayashi, Yukio Hirabayashi, Machiko Kusuda, Yoshihiro Hatta, Tomohiro Nakayama, Masami Takei Leukemia & lymphoma 57 (12) 2784 -2790 2016年12月 [査読有り][通常論文]
     
    Co-expression of MYC and BCL2 proteins in diffuse large B-cell lymphoma (DLBCL), or 'double-expressor lymphoma' (DEL), results in poor patient prognosis, but the significance of DEL when aggressive treatments are applied remains uncertain. We performed a retrospective analysis of 40 patients with de novo DLBCL, who were categorized as being at high/high-intermediate risk according to the age-adjusted International Prognostic Index. Patients underwent an R-Double-CHOP regimen, a dose-intensified immunochemotherapy with or without consolidative high-dose chemotherapy followed by autologous stem cell transplantation. According to immunohistochemical analysis, 10 (25%) patients were categorized as having DEL, showing positivity for MYC (≥40%) and BCL2 (≥50%). The 3 year progression-free survival and overall survival of the DEL group were significantly worse compared with those of the non-DEL group (30% vs. 63%, p = 0.019 and 40% vs. 82%, p = 0.006, respectively). These results suggest that advanced DEL may need discrete treatment strategies.
  • Makoto Sano, Taku Homma, Emiko Hayashi, Hiroko Noda, Yusuke Amano, Ryusuke Tsujimura, Tsutomu Yamada, Brian Quattrochi, Norimichi Nemoto Virchows Archiv : an international journal of pathology 465 (5) 531 -8 2014年11月 [査読有り][通常論文]
     
    Undifferentiated (anaplastic) carcinoma with rhabdoid features is a rare and aggressive subtype of pancreatic carcinoma. Here, we report the clinical, histological, and immunohistochemical phenotypes in six autopsy cases of anaplastic carcinoma with rhabdoid features. The patients ranged between 44 and 76 years of age (median, 61 years) and consisted of four males and two females. All patients except one case died within 3 months of diagnosis, as these tumors were found at an advanced stage and were chemoresistant. At autopsy, tumor masses measuring 4-22 cm in maximum diameter were mainly located in the pancreatic body and tail. Microscopically, all cases showed anaplastic carcinoma with rhabdoid features that were discohesive with round to polygonal eosinophilic cytoplasm with occasional inclusions, and that had vesicular nuclei, and prominent nucleoli. Immunohistochemistry showed that the rhabdoid cells, particularly the inclusions, were strongly positive for pan-cytokeratin (AE1/AE3) and vimentin. Meanwhile, downregulation or aberrant cytoplasmic localization with focal aggregation of E-cadherin, β-catenin, and EMA were frequently observed in the rhabdoid cells. Moreover, the intracytoplasmic inclusions were labeled with selective autophagy-related molecules including p62/SQSTM1, ubiquitin, and kelch-like ECH-associated protein 1 (KEAP1). In addition, nuclear factor erythroid 2-related factor 2 (NRF2) and overexpression of its target molecule multidrug resistance-associated protein 1 (MRP1) were commonly observed in the rhabdoid cells. Therefore, these results suggest that p62-mediated aggregation of ubiquitinated intermediate filaments and membranous proteins is an important phenomenon in the rhabdoid phenotype. Indeed, the ubiquitinated aggregates of p62 and KEAP1 would induce activation of NRF2 and upregulation of MRP1, leading to potential chemoresistance of anaplastic carcinoma with rhabdoid features.
  • Kenji Mishima, Hiroko Inoue, Tatsuaki Nishiyama, Yo Mabuchi, Yusuke Amano, Fumio Ide, Makoto Matsui, Hiroyuki Yamada, Gou Yamamoto, Junichi Tanaka, Rika Yasuhara, Takashi Sakurai, Masaichi-Chang-Il Lee, Kan Chiba, Hidetoshi Sumimoto, Yutaka Kawakami, Yumi Matsuzaki, Kazuo Tsubota, Ichiro Saito Stem cells (Dayton, Ohio) 30 (9) 1925 -37 2012年09月 [査読有り][通常論文]
     
    Stem cell-based therapy has been proposed as a promising strategy for regenerating tissues lost through incurable diseases. Side population (SP) cells have been identified as putative stem cells in various organs. To examine therapeutic potential of SP cells in hypofunction of exocrine glands, SP cells isolated from mouse exocrine glands, namely, lacrimal and salivary glands, were transplanted into mice with irradiation-induced hypofunction of the respective glands. The secretions from both glands in the recipient mice were restored within 2 months of transplantation, although the transplanted cells were only sparsely distributed and produced no outgrowths. Consistent with this, most SP cells were shown to be CD31-positive endothelial-like cells. In addition, we clarified that endothelial cell-derived clusterin, a secretory protein, was an essential factor for SP cell-mediated recovery of the hypofunctioning glands because SP cells isolated from salivary glands of clusterin-deficient mice had no therapeutic potential, whereas lentiviral transduction of clusterin restored the hypofunction. In vitro and in vivo studies showed that clusterin had an ability to directly inhibit oxidative stress and oxidative stress-induced cell damage. Thus, endothelial cell-derived clusterin possibly inhibit oxidative stress-induced hypofunction of these glands.
  • Manabu Matsunawa, Yusuke Amano, Kaori Endo, Shigeyuki Uno, Toshiyuki Sakaki, Sachiko Yamada, Makoto Makishima Toxicological sciences : an official journal of the Society of Toxicology 109 (1) 50 -8 2009年05月 [査読無し][通常論文]
     
    Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon produced by cigarette combustion, is implicated as a causative agent in smoking-related cancer and atherosclerosis. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], a potent ligand for the nuclear receptor vitamin D receptor (VDR), has been shown to decrease the risk of osteoporosis, some types of cancer and cardiovascular disease, suggesting an opposing effect of vitamin D3 to cigarette smoking. In this study, we investigated the effects of BaP on the vitamin D3 signaling pathway. BaP effectively enhanced the 1,25(OH)2D3-dependent induction of cytochrome P450 24A1 (CYP24A1) in human monocyte/macrophage-derived THP-1 cells and breast cancer MCF-7 cells. BaP combination was less or not effective on mRNA expression of CD14, arachidonate 5-lipoxygenase, and cathelicidin antimicrobial peptide in THP-1 cells. BaP also increased the expression of CYP24A1 induced by a non-vitamin D VDR ligand, lithocholic acid acetate. Another aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, enhanced CYP24A1 expression by 1,25(OH)2D3 in THP-1 cells. Treatment of cells with an AhR antagonist and a protein synthesis inhibitor inhibited the enhancing effect of BaP on CYP24A1 induction, indicating that the effects of BaP are mediated by AhR activation and de novo protein synthesis. BaP pretreatment increased 1,25(OH)2D3-dependent recruitment of VDR and retinoid X receptor to the CYP24A1 promoter. Analysis of 1,25(OH)2D3 metabolism showed that BaP enhanced the hydroxylation of 1,25(OH)2D3 by CYP24A1 in THP-1 cells. Thus, AhR activation by BaP stimulates vitamin D3 catabolism. Modulation of vitamin D signaling by AhR may represent a mechanism underlying cigarette smoking-related diseases.
  • Naoyuki Matsumoto, Hidero Ohki, Shotaro Mukae, Yusuke Amano, Daisuke Harada, Satoshi Nishimura, Kazuo Komiyama Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 106 (4) e29-34 2008年10月 [査読有り][通常論文]
     
    We report an unusual case of gingival anaplastic large-cell lymphoma (ALCL) that occurred in a 76-year-old Japanese woman who showed marked gingival swelling in both the maxilla and mandible. Although the patient received caries and periodontal therapy at the outpatient clinic of our dental hospital, the gingival swelling remained and she was referred to the oral surgery department, where a biopsy of the gingiva was performed. The specimens showed proliferation of large atypical and amphophilic epithelioid cells beneath the covering epithelium. Immunohistochemical analysis of the proliferating cells revealed positivity for CD30 and T-cell markers, such as CD45RB, as well as CD45RO antibodies, and they were weakly positive for the granzyme B antibody. In contrast, the tumor cells were negative for all B-cell markers as well as for CD3, CD56, S-100 protein, epithelial membrane antigen, and p80(NPM/ALK) antibodies. Based on the clinical and histopathologic features, the lesion was diagnosed as an ALCL in both the upper and the lower gingiva. This is an extremely rare case, in which a specific subtype of T-cell lymphoma appeared in the oral cavity.
  • 三木 裕香子, 迎 章太郎, 天野 雄介, 金子 泰英, 岡崎 泰尋, 大木 秀郎, 鶴田 正, 松本 光彦, 小宮山 一雄 日大歯学 80 (2) 109 -115 2006年06月 [査読無し][通常論文]
     
    ヒト口腔癌細胞株HSC-3を用い,分泌型phospholipase A2(sPLA2)とcyclooxygenase(COX)-2の発現と増殖能およびprostaglandin E2(PGE2)産生を解析し,その意義について検討した.HSC-3におけるsPLA2(-II A,-V,-X),COX-1およびCOX-2の発現をRT-PCRと免疫組織化学で検索した.ついで,HSC-3にsPLA2またはCOX-2特異的inhibitorを加え,細胞増殖をMTT法で,PGE2産生量をELISA法で測定した.RT-PCRによりsPLA2-X,COX-1およびCOX-2のmRNA発現を認めたが,sPLA2-II A,-Vは検出されなかった.免疫組織化学によりsPLA2-X,COX-1およびCOX-2はHSC-3細胞質に陽性を示した.HSC-3の細胞増殖は各inhibitor添加により,濃度依存的,経時的に抑制された.またPGE2産生も,各inhibitor添加により低下した.以上より,口腔扁平上皮癌におけるsPLA2の発現を検討したところ,sPLA2-Xが主要なサブタイプであることを明らかにした.また,sPLA2,COX-2の発現が,口腔扁平上皮癌の細胞増殖およびPGE2産生の調節因子の一つであることを示した.本研究の結果,両酵素の機能制御による口腔癌治療の応用の可能性が示された(著者抄録)
  • Hidero Ohki, Mitsuhiko Matsumoto, Mitsuharu Hasegawa, Osamu Shimizu, Shotaro Mukae, Yusuke Amano, Kazuo Komiyama Journal of oral science 47 (4) 219 -22 2005年12月 [査読有り][通常論文]
     
    A 54-year-old male presented with the complaint of a painful sore on the left side of his tongue. Our examination found an ulcer 15 x 20 mm in size on the left edge of the tongue, with peripheral indurations. The lesion was diagnosed histopathologically as squamous cell carcinoma (T2N0M0). Consequently, the lesion was surgical removed and radical neck dissection was performed. Four months after the operation, two unusual cyst-like lesions were identified in the parapharyngeal space by CT and MRI. A biopsy specimen revealed recurrent carcinoma with a cyst-like structure. The route of the tumor metastasis into the parapharyngeal space was obscured, but it was speculated that the excessive lymph accumulation was due to a lymphatic occlusion caused by the surgical procedure, proliferation of the metastatic carcinoma, or stagnation and accumulation of tissue fluid caused by parapharyngeal invasion by the recurrent lesion.

共同研究・競争的資金等の研究課題

  • 組織形態に基づく口腔扁平上皮癌における癌微小環境の解析
    日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2022年04月 -2025年03月 
    代表者 : 天野 雄介
  • PRMT5の口腔癌EMT機構における役割の解析
    日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2019年04月 -2022年03月 
    代表者 : 天野 雄介
  • 頭頸部癌の発癌・進展におけるPRMT5の機能解析
    日本学術振興会：科学研究費助成事業 若手研究(B)
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 天野 雄介
     
    タンパク質アルギニンメチル基転移酵素(Protein arginine methyltransferases; PRMT)5は, 種々の癌でPRMT5 の遺伝子発現およびタンパクの増加が示され, oncogenic な性格を有することが明らかになりつつある. 術前治療が行われずに外科的切除された頭頸部癌 59症例と上皮異形成9症例を用いて, 免疫組織化学的にPRMT5の発現を検討した.1)正常上皮では, 基底層付近の細胞質に弱陽性細胞を認めた. 2)上皮異形成では, 異型細胞の細胞質主体に正常上皮に比して強く染色される陽性細胞を認めた. HNCの胞巣中心部では, 細胞質に局在するのに対して, 浸潤先進部では核と細胞質に局在する傾向を認めた.3) 2)の結果を踏まえて, 口腔癌浸潤先進部の形態学的分類である山本・小浜(YK)分類を用いPRMT5の局在を, 連続標本を作製して詳細に検討した. 先進部が胞巣状を示すYK-1~3に相当す る23症例は, 22症例が細胞質に局在し, 1症例が核と細胞質に局在した. 一方, 紡錘形ないしびまん性を示すYK-4C, 4Dに相当する36症例では, 25症例が細胞質に局在し, 11症例が核と細胞質に局在した. すなわち, YK-4C, 4Dの症例では, YK-1~3の症例に比して有意に核と細胞質に局在した(YK1~3 vs YK4, p=0.0147). PRMT5が核と細胞質に局在する症例では, 上皮系マーカーであるCytokeratin (CK) 17とE-cadherinの発現が細胞質に局在する症例に比して, 減弱していた (p=0.0002, 0.0016). また, YK-4の症例でも同様に, CK17とE-cadherinの発現がYK-1~3の症例に比して減弱していた(p=0.0296, 0.0065).

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