Faculty Profiles - KUNISADA Toshiyuki

Masato Ise, Eiji Nakata, Yoshimi Katayama, Masanori Hamada, Toshiyuki Kunisada, Tomohiro Fujiwara, Ryuichi Nakahara, Shouta Takihira, Kohei Sato, Yoshiteru Akezaki, Masuo Senda, Toshifumi Ozaki

Healthcare (Basel, Switzerland) 9 ( 5 ) 2021.5

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

Psychological distress is common in patients with soft tissue and bone tumors. We first investigated its frequency and the associated risk factors in patients with pre-operative bone and soft tissue tumors. Participants included 298 patients with bone and soft tissue tumors who underwent surgery in our institution between 2015 and 2020. Psychological distress was evaluated by the Distress and Impact Thermometer (DIT) that consists of two types of questions (questions about the severity of the patient's distress (DIT-D) and its impact (DIT-I)). We used a cut-off point of 4 on the DIT-D and 3 on the DIT-I for screening patients with psychological distress. We therefore investigated: (1) the prevalence of psychological distress as assessed with DIT or distress thermometer (DT), which can be decided by DIT-D ≥ 4, (2) what are the risk factors for the prevalence of psychological distress, and (3) what is the number of patients who consulted a psychiatrist for psychological distress in patients with pre-operative bone and soft tissue tumors. With DIT and DT, we identified 64 patients (21%) and 95 patients (32%), respectively, with psychological distress. Multivariate logistic regression revealed that older age, sex (female), malignancy (malignant or intermediate tumor), a lower Barthel Index, and higher numeric rating scale were risk factors for psychological distress. Two patients (3%) consulted a psychiatrist after surgery. In conclusion, careful attention to psychological distress is needed, especially for female patients, older patients, and those with malignant soft or bone tissue tumors who have more than moderate pain.

DOI： 10.3390/healthcare9050566

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脊椎転移に対する集学的治療麻痺を認めない脊椎SREに対する保存的治療の成績

中田英二, 国定俊之, 藤原智洋, 尾崎敏文

The Japanese Journal of Rehabilitation Medicine 58 ( 特別号 ) JSY39 - 1 2021.5

Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma. Reviewed International journal

Yusuke Mochizuki, Hiroshi Tazawa, Koji Demiya, Miho Kure, Hiroya Kondo, Tadashi Komatsubara, Kazuhisa Sugiu, Joe Hasei, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 70 ( 5 ) 1405 - 1417 2021.5

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

Immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1) antibody have recently improved clinical outcome in certain cancer patients; however, osteosarcoma (OS) patients are refractory to PD-1 blockade. Oncolytic virotherapy has emerged as novel immunogenic therapy to augment antitumor immune response. We developed a telomerase-specific replication-competent oncolytic adenovirus OBP-502 that induces lytic cell death via binding to integrins. In this study, we assessed the combined effect of PD-1 blockade and OBP-502 in OS cells. The expression of coxsackie and adenovirus receptor (CAR), integrins αvβ3 and αvβ5, and programmed cell death ligand 1 (PD-L1) was analyzed in two murine OS cells (K7M2, NHOS). The cytopathic activity of OBP-502 in both cells was analyzed using the XTT assay. OBP-502-induced immunogenic cell death was assessed by analyzing the level of extracellular ATP and high-mobility group box protein B1 (HMGB1). Subcutaneous tumor models for K7M2 and NHOS cells were used to evaluate the antitumor effect and number of tumor-infiltrating CD8+ cells in combination therapy. K7M2 and NHOS cells showed high expression of integrins αvβ3 and αvβ5, but not CAR. OBP-502 significantly suppressed the viability of both cells, in which PD-L1 expression and the release of ATP and HMGB1 were significantly increased. Intratumoral injection of OBP-502 significantly augmented the efficacy of PD-1 blockade on subcutaneous K2M2 and NHOS tumor models via enhancement of tumor-infiltrating CD8+ T cells. Our results suggest that telomerase-specific oncolytic virotherapy is a promising antitumor strategy to promote the efficacy of PD-1 blockade in OS.

DOI： 10.1007/s00262-020-02774-7

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脊椎転移に対する集学的治療麻痺を認めない脊椎SREに対する保存的治療の成績

中田英二, 国定俊之, 藤原智洋, 尾崎敏文

The Japanese Journal of Rehabilitation Medicine 58 ( 特別号 ) JSY39 - 1 2021.5

Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma. Reviewed International journal

Suguru Yokoo, Tomohiro Fujiwara, Aki Yoshida, Koji Uotani, Takuya Morita, Masahiro Kiyono, Joe Hasei, Eiji Nakata, Toshiyuki Kunisada, Shintaro Iwata, Tsukasa Yonemoto, Koji Ueda, Toshifumi Ozaki

Cancers 13 ( 8 ) 2021.4

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

The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1+CD9+ EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume (p = 0.003). Furthermore, serum levels of MCT1+CD9+ EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival (p = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1+CD9+ EVs and indicates the therapeutic potential of MCT1 in SS.

DOI： 10.3390/cancers13081823

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Immunotherapy for sarcomas. Reviewed International journal

Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Tastuo Ito, Shota Takihira, Toshifumi Ozaki

Japanese journal of clinical oncology 51 ( 4 ) 523 - 537 2021.4

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

Sarcomas are a heterogeneous group of malignancies of mesenchymal origin; their molecular and genomic mechanisms differ with regard to histology. These characteristics lead to the presentation of varied immunological profiles based on the tumor microenvironment. Various immunotherapies are considered for the treatment of sarcoma. These treatments are performed either in isolation or in combination with other methods such as cytotoxic chemotherapy or the use of molecular target agents. Among these, two recently emerging immunotherapies include T-cell receptor gene therapy and immune checkpoint inhibitor therapy, which are expected to be effective for many types of sarcoma. A sarcoma with a disease-specific translocation and a limited number of mutations, such as synovial sarcoma, expresses high levels of self-antigens, like the New York esophageal squamous cell carcinoma 1, which has been targeted in T-cell receptor gene therapy. On the other hand, sarcomas with a greater number of mutations, such as undifferentiated pleomorphic sarcomas, myxofibrosarcoma and dedifferentiated liposarcomas, can be good candidates for immune checkpoint inhibitors. Among immune checkpoint inhibitor therapies, programmed cell death-1 blockade (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte-associated antigen 4 blockade (ipilimumab) have been investigated most often in sarcoma. Although the sole use of immune checkpoint inhibitors provides limited efficacy, combined immunotherapy with immune checkpoint inhibitors or molecular target agents, especially antiangiogenic agents, has shown moderate results against some types of sarcoma, such as the alveolar soft part sarcoma. Several clinical trials utilizing immunotherapy, including T-cell receptor gene therapy and immune checkpoint inhibitors, in sarcomas are under progress. By clarifying the tumor microenvironment and biomarker-predictive capacity of immunotherapy in sarcomas, better clinical trials can be designed; this could lead to improved outcomes for immunotherapy in sarcoma.

DOI： 10.1093/jjco/hyab005

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【骨・軟部腫瘍のマネジメント(その1)】総論診療体制サルコーマセンター設立と腫瘍内科医との連携集約化と地域連携

国定俊之, 中田英二, 藤原智洋, 久保寿夫, 西森久和, 田端雅弘, 尾崎敏文

別冊整形外科 ( 79 ) 7 - 12 2021.4

Language：Japanese Publisher：(株)南江堂

＜文献概要＞はじめにわが国では歴史的に整形外科が中心となって肉腫(サルコーマ)の治療方針を決め,主に手術と化学療法を担当してきた.一方,欧米では腫瘍内科が肉腫の化学療法を担当することが一般的であり,わが国の治療状況とは大きく異なる.肉腫治療例の増加とともに進行例が増加し,新規治療薬も開発され,整形外科医のみで治療していくことがむずかしくなってきた.また,化学療法以外にも,肉腫の診断,手術には多くの診療科の協力が必要で,多職種による集学的医療チームによる治療が重要である.当院では肉腫患者によりよい治療を提供する目的で,2014年4月に大学病院の診療部門としては日本ではじめてサルコーマセンターを設立した.本稿では,当院サルコーマセンターの活動を紹介する.

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【骨・軟部腫瘍のマネジメント(その1)】治療総論免疫療法肉腫における免疫療法

中田英二, 藤原智洋, たき平将太, 国定俊之, 尾崎敏文

別冊整形外科 ( 79 ) 149 - 157 2021.4

Language：Japanese Publisher：(株)南江堂

＜文献概要＞はじめに肉腫における免疫療法の歴史は古く,1891年,William Coley博士は切除不能で転移性の肉腫の患者において免疫療法の効果を最初に示した.その後,免疫調節薬,ワクチンなどさまざまな免疫療法が開発され,最近は免疫チェックポイント阻害薬(immune-check point inhibitor:ICI)や活性化自己リンパ球輸注療法などの有望な治療法が登場している(表1).本稿では肉腫の免疫療法についてレビューを行う.

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【骨・軟部腫瘍のマネジメント(その1)】診断組織・遺伝子診断肉腫におけるがんゲノム医療の意義

中田英二, 藤原智洋, 国定俊之, 尾崎敏文, 遠西大輔, 冨田秀太, 平沢晃, 二川摩周, 武田達明

別冊整形外科 ( 79 ) 75 - 83 2021.4

Language：Japanese Publisher：(株)南江堂

＜文献概要＞はじめにがんにはさまざまな遺伝子異常を認め,同一のがん種でも発現する遺伝子が異なることが少なくない.最近,次世代シークエンサー(next generation sequencer:NGS)を用いて遺伝子異常を同時多重性(マルチプレックス)に検出するがん遺伝子パネルが登場した.がんゲノム医療では,がん遺伝子パネルで同定した遺伝子変異に基づいて薬剤を選択する,精密医療(precision medicine)が行われる.本稿では,肉腫におけるゲノム医療の意義について述べる.

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【骨・軟部腫瘍のマネジメント(その1)】診断組織・遺伝子診断骨・軟部腫瘍におけるリキッドバイオプシーの開発

藤原智洋, 中田英二, 国定俊之, 尾崎敏文

別冊整形外科 ( 79 ) 63 - 69 2021.4

Language：Japanese Publisher：(株)南江堂

＜文献概要＞はじめに-リキッドバイオプシーとはリキッドバイオプシーとは,血液,尿,唾液などの体液中に含まれる細胞,核酸,蛋白質,代謝物などの生体分子の解析から病態の把握をめざす病態診断技術の総称である.この用語は,2010年代に血液中に存在する循環腫瘍細胞(circulating tumor cells:CTC)の検出による診断法に与えられたものであり,その後,核酸,蛋白質,代謝物などのさまざまな生体分子を対象とした解析法に対しても用いられるようになっている.現在では,循環腫瘍DNA(circulating tumor DNA:ctDNA),疾患特異的なマイクロRNA(microRNA:miRNA)などの核酸分子や,癌細胞由来のエクソソームの検出による疾患診断法の開発が精力的にすすめられている(図1).リキッドバイオプシーは非侵襲的かつ簡便に施行することができ,同一症例に対して繰り返し施行することが可能であるため,診断だけでなく治療効果や予後の予測に有用であり,次世代の診断技術の基盤として期待が集まっている.骨・軟部腫瘍には,消化器癌,前立腺癌,婦人科癌などの存在診断,治療効果予測,再発リスクの予測,術後再発のモニタリングなどに用いられる血液腫瘍マーカーがきわめて少ない.2012年の『軟部腫瘍診療ガイドライン』では,「臨床検査値で異常を示す腫瘍は?」というクリニカルクエスチョンに対して「軟部腫瘍で特異的な腫瘍マーカーは一般的にはない」と記載されている.癌腫と同様に乳酸脱水素酵素(LDH)の上昇を認めることがあるが,一般的には腫瘍サイズの大きな高悪性度軟部肉腫,あるいは多発性に転移して進行した軟部肉腫に限られる.このような背景から,肉腫細胞由来の生体分子を用いたリキッドバイオプシーの開発は,骨・軟部腫瘍の診療における新しいブレイクスルーとなる可能性があり,研究開発が精力的に行われている.本稿では,リキッドバイオプシーの骨・軟部腫瘍における研究開発の動向を生体分子別に述べ,本法の将来展望について論じる.

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Role of Tumor-Associated Macrophages in Sarcomas. Reviewed International journal

Tomohiro Fujiwara, John Healey, Koichi Ogura, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Miho Kure, Hiroshi Tazawa, Eiji Nakata, Toshiyuki Kunisada, Toshiyoshi Fujiwara, Toshifumi Ozaki

Cancers 13 ( 5 ) 2021.3

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

Sarcomas are complex tissues in which sarcoma cells maintain intricate interactions with their tumor microenvironment. Tumor-associated macrophages (TAMs) are a major component of tumor-infiltrating immune cells in the tumor microenvironment and have a dominant role as orchestrators of tumor-related inflammation. TAMs promote tumor growth and metastasis, stimulate angiogenesis, mediate immune suppression, and limit the antitumor activity of conventional chemotherapy and radiotherapy. Evidence suggests that the increased infiltration of TAMs and elevated expression of macrophage-related genes are associated with poor prognoses in most solid tumors, whereas evidence of this in sarcomas is limited. Based on these findings, TAM-targeted therapeutic strategies, such as inhibition of CSF-1/CSF-1R, CCL2/CCR2, and CD47/SIRPα, have been developed and are currently being evaluated in clinical trials. While most of the therapeutic challenges that target sarcoma cells have been unsuccessful and the prognosis of sarcomas has plateaued since the 1990s, several clinical trials of these strategies have yielded promising results and warrant further investigation to determine their translational benefit in sarcoma patients. This review summarizes the roles of TAMs in sarcomas and provides a rationale and update of TAM-targeted therapy as a novel treatment approach for sarcomas.

DOI： 10.3390/cancers13051086

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Papers - KUNISADA Toshiyuki