Updated on 2021/12/16

写真a

 
NASU Yasutomo
 
Organization
Administrative Center Director
Position
Director
External link

Degree

  • (BLANK) ( Okayama University )

  • (BLANK)

Research Areas

  • Life Science / Urology

Professional Memberships

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Committee Memberships

  • 一般社団法人吉備高原オープンイノベーション協会   理事  

    2021.7   

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  • 特定非営利活動法人せとうち臨床遺伝研究会   監事  

    2020.12   

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  • 吉備高原都市スーパーシティ推進協議会   理事、副会長  

    2020.12   

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  • 第4回日本地域医療連携システム学会   会長  

    2020.12   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会財務委員会   委員  

    2020.11   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会会則検討委員会   委員長  

    2020.11   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会倫理・COI委員会   委員  

    2020.11   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会総会賞選考委員会   委員長  

    2020.11   

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    Committee type:Academic society

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  • 第34回日本泌尿器内視鏡学会総会   会長  

    2020.11   

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    Committee type:Academic society

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  • 日本学術会議   連携会員  

    2020.10   

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  • 第7回泌尿器画像診断・治療技術研究会   会長  

    2019.9   

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    Committee type:Academic society

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  • (公財)岡山医学振興会   監事  

    2019.6   

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  • (公財)ウエスコ学術振興財団   選考委員  

    2019.6   

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  • 岡山県医用工学研究会   顧問  

    2019.4   

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  • 日本泌尿器科学会知的財産管理委員会   委員  

    2019.4 - 2021.12   

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    Committee type:Academic society

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  •   日本泌尿器科学会 監事  

    2019.4 - 2021.4   

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    Committee type:Academic society

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  • 日本泌尿器科学会医療賞選考委員会   委員  

    2019.4 - 2021.4   

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    Committee type:Academic society

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  • 日本泌尿器腫瘍学会広報委員会   委員  

    2019.4 - 2021.3   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会医工連携・新技術検討委員会   委員  

    2018.11   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会Innovation Award選考委員会   副委員長  

    2018.11   

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    Committee type:Academic society

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  • 医薬品医療機器総合機構 科学委員会専門部会   委員  

    2018.11 - 2020.10   

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  • 認定NPO法人岡山医師研修支援機構   理事  

    2018.6   

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  • 日本泌尿器科学会専門医制度審議会専門研修委員会   委員  

    2018.6   

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    Committee type:Academic society

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  • 日本泌尿器科学会専門医制度審議会   委員  

    2018.4   

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    Committee type:Academic society

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  • 第4回日本泌尿器癌局所療法研究会   会長  

    2018.2   

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    Committee type:Academic society

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  • 文部科学省地域イノベーション・エコシステム形成プログラム   山口地域事業アドバイザー  

    2017.12   

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  • 第23回日本遺伝子細胞治療学会   会長  

    2017.7   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会泌尿器腹腔鏡ガイドライン作成委員会   小委員長  

    2017.5 - 2020.11   

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    Committee type:Academic society

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  • 泌尿器科紀要編集委員会   委員  

    2017.4   

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  • 日本泌尿器腫瘍学会総務/広報委員会   委員  

    2017.4 - 2019.3   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会ロボット支援手術委員会   委員  

    2016.11   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会学術委員会   副委員長  

    2016.11 - 2020.11   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会財務委員会   委員長  

    2016.11 - 2020.11   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会倫理・COI委員会   副委員長  

    2016.11 - 2020.11   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会総会賞選考委員会   委員  

    2016.11 - 2020.11   

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    Committee type:Academic society

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  • 日本泌尿器内視鏡学会総務委員会   委員  

    2016.11 - 2020.11   

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  • 日本泌尿器内視鏡学会阿曽賞選考委員会   委員  

    2016.11 - 2018.11   

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    Committee type:Academic society

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  • ARO協議会   理事  

    2016.8   

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  • 日本泌尿器内視鏡学会   代議員  

    2016.5   

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    Committee type:Academic society

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  • 高知大学   非常勤講師  

    2016.5 - 2021.7   

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  •   日本泌尿器腫瘍学会 代議員  

    2016.4   

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  • ARO協議会TRセンター運営戦略連絡会   幹事  

    2016.4   

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  • 日本泌尿器科学会学会賞・坂口賞選考委員会   委員  

    2016.4 - 2018.4   

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    Committee type:Academic society

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  • 日本遺伝子治療学会財務委員会   委員  

    2015.10   

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  •   日本性機能学会 代議員  

    2015.9   

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  • 西日本泌尿器科   編集委員  

    2015.7 - 2022.3   

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    Committee type:Academic society

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  • 大阪大学第二特定認定再生医療等委員会   委員  

    2015.6   

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  •   西日本泌尿器科学会 理事  

    2015.6 - 2022.3   

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  • 日本泌尿器科学会国際委員会   委員  

    2015.4 - 2021.4   

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    Committee type:Academic society

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  • 日本泌尿器科学会男女共同参画委員会   委員  

    2015.4 - 2019.4   

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  • 日本泌尿器科学会利益相反委員会   委員  

    2015.4 - 2019.4   

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    Committee type:Academic society

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  • 日本泌尿器科学会生殖・ゲノム委員会   委員  

    2015.4 - 2019.4   

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  • 日本泌尿器科学会選挙管理委員会   委員  

    2015.4 - 2017.4   

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  • 日本泌尿器内視鏡学会プロクター認定制度委員会   委員  

    2014.11 - 2016.11   

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    Committee type:Academic society

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  • 特定非営利活動法人臨床研究推進ネットワークジャパン   理事  

    2014.4 - 2020.3   

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  • 第3回日本泌尿器病理研究会   会長  

    2014.3   

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    Committee type:Academic society

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  • 医薬品医療機器総合機構   専門委員  

    2013.10   

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  •   日本泌尿器内視鏡学会 事務局長  

    2012.11 - 2016.11   

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  • 日本泌尿器内視鏡学会阿曽賞選考委員会   委員長  

    2012.11 - 2016.11   

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  • 日本泌尿器内視鏡学会編集委員会   委員  

    2012.11 - 2016.11   

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  • 日本泌尿器内視鏡学会ロボット支援手術部会医事小委員会   委員長  

    2012.11 - 2016.11   

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  • 日本泌尿器内視鏡学会ロボット支援手術部会   副部会長  

    2012.11 - 2016.11   

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  • 日本泌尿器内視鏡学会将来検討委員会   副委員長  

    2012.11 - 2016.11   

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  • 日本泌尿器内視鏡学会学術委員会   委員長  

    2012.11 - 2014.11   

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  •   日本泌尿器科学会 代議員(西部)  

    2012.10   

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  •   日本遺伝子細胞治療学会 理事  

    2011.7   

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  • 厚生労働省 厚生科学審議会   専門委員  

    2011.2 - 2021.6   

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    Committee type:Government

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  •   日本泌尿器内視鏡学会 理事  

    2010.10   

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  • 日本泌尿器内視鏡学会将来検討委員会   委員長  

    2010.10 - 2012.11   

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  •   泌尿器科分子・細胞研究会 世話人  

    2010.4   

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  • (独)理化学研究所分子イメージング科学研究センターマイクロドーズ臨床試験推進検討委員会   委員  

    2010.2 - 2011.7   

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  • 科学研究費委員会   専門委員  

    2009.12   

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  •   西日本泌尿器科学会 評議員  

    2008.11   

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  • 日本泌尿器内視鏡学会学術委員会   委員  

    2006.10 - 2010.10   

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  • 日本泌尿器内視鏡学会広報委員会   委員  

    2004.11 - 2012.11   

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  • 日本泌尿器内視鏡学会国際委員会   委員  

    2004.11 - 2012.11   

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    Committee type:Academic society

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Papers

  • Presence of decoy cells for 6 months on urine cytology efficiently predicts BK virus nephropathy in renal transplant recipients

    Takanori Sekito, Motoo Araki, Kasumi Yoshinaga, Yuki Maruyama, Takuya Sadahira, Shingo Nishimura, Koichiro Wada, Masami Watanabe, Toyohiko Watanabe, Katsuyuki Tanabe, Hidemi Takeuchi, Hiroshi Morinaga, Masashi Kitagawa, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada, Hiroyuki Yanai, Yasutomo Nasu

    International Journal of Urology   28 ( 12 )   1240 - 1246   2021.12

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1111/iju.14679

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/iju.14679

  • Impact of paclitaxel, cisplatin, and gemcitabine as first-line chemotherapy in cisplatin-fit and -unfit patients with advanced/metastatic urothelial carcinoma. International journal

    Satoshi Katayama, Yasuyuki Kobayashi, Atsushi Takamoto, Kohei Edamura, Takuya Sadahira, Takehiro Iwata, Shingo Nishimura, Tomoko Sako, Koichiro Wada, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Urologic oncology   39 ( 10 )   731.e25-731.e32   2021.10

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    PURPOSE: This study aimed to clarify the efficacy and toxicity of first-line combination treatment with paclitaxel, cisplatin, and gemcitabine (PCG) for advanced/metastatic urothelial carcinoma (UC) in cisplatin-unfit patients compared with cisplatin-fit patients. METHODS: We conducted a retrospective study of patients who received first-line PCG. Using international consensus criteria, patients were classified into cisplatin-fit and -unfit groups. Cisplatin-unfit patients received PCG with adjustment of the cisplatin dose after assessing 24-hour urinary creatinine clearance, without modifying the administration interval. RESULTS: From 2008 to 2017, 50 patients received first-line PCG, of whom 30 and 20 were classified into the cisplatin-fit and -unfit groups. After a median follow-up of 15.0 months, the median overall survival (OS) and progression-free survival (PFS) were 15.0 and 9.8 months in all patients, 15.0 and 10.0 months in the cisplatin-fit group, and 13.2 and 9.3 months in the cisplatin-unfit group, respectively. There was no significant difference in OS (hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 0.69-2.54) or PFS (HR: 1.38, 95% CI: 0.74-2.55) between the groups. The overall response rate and complete response rate were 58% (95% CI: 43.2-71.8) and 32% (95% CI: 19.5-46.7) in all patients, and 55% (95% CI: 31.5-76.9) and 35% (95% CI: 15.4-59.2) in the cisplatin-unfit group, respectively. The common grade 3 of 4 adverse events experienced were neutropenia (78%), followed by thrombocytopenia (56%), anemia (46%), and febrile neutropenia (16%). The 24-hour urinary creatinine clearance did not differ significantly between the groups after one, two, or three courses of PCG. CONCLUSIONS: We found no significant difference regarding OS and PFS between the cisplatin-fit patients with a full dose of cisplatin and -unfit patients with cisplatin-dose-adjusted chemotherapy. In select cisplatin-unfit patients, PCG with dose adjustment of cisplatin may be useful for treating advanced/metastatic UC without any significant adverse events or impaired renal function compared with cisplatin-fit patients with a full dose of cisplatin.

    DOI: 10.1016/j.urolonc.2021.02.029

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  • Impact of Sarcopenia on Erectile Function after Nerve-Sparing Robot-Assisted Radical Prostatectomy. International journal

    Yosuke Mitsui, Takuya Sadahira, Yuki Maruyama, Ryota Sato, Acosta Gonzalez Herik Rodrigo, Koichiro Wada, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    The world journal of men's health   39 ( 4 )   673 - 682   2021.10

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    PURPOSE: To determine the impact of sarcopenia on erectile functional outcomes after a nerve-sparing (NS) robot-assisted radical prostatectomy (RARP) using patient-reported validated questionnaires. MATERIALS AND METHODS: In this retrospective study, RARP was performed on 841 patients at Okayama University Hospital, of which 132 underwent NS RARP. Erectile functional outcomes were assessed using the 5-item version of the International Index of Erectile Function (IIEF-5) and the Expanded Prostate Cancer Index Composite before and 1, 3, 6, and 12 months after surgery. Automated measurement of skeletal muscle at L3 was achieved using volume analyzer software and normalizing for height (cm²/m²) to calculate skeletal muscle index (SMI). Patients who had an IIEF-5≤4 comprised the group with erectile dysfunction (ED), and those with an IIEF-5≤5 made up the non-ED group. RESULTS: This study enrolled 95 patients of median age 65 years with a preoperative IIEF-5 of 16. There were no significant differences between patients with and without sarcopenia among those with preoperative IIEF-5. Postoperatively, in the ED group, SMI and preoperative IIEF-5 were significantly lower than in the non-ED group. Multiple linear regression analysis revealed that (1) both SMI and preoperative IIEF-5 were independent predictors of ED, and (2) sarcopenia and preoperative IIEF-5 were predictors of ED at 12 months after NS RARP. CONCLUSIONS: Patients with sarcopenia can have worse erectile functional outcomes after NS RARP. Sarcopenia and a lower preoperative IIEF-5 score may be predictive of postoperative ED.

    DOI: 10.5534/wjmh.200036

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  • Blood concentrations of tacrolimus upon conversion from rabeprazole to vonoprazan in renal transplant recipients: Correlation with cytochrome P450 gene polymorphisms. International journal

    Shogo Watari, Motoo Araki, Jun Matsumoto, Kasumi Yoshinaga, Takanori Sekito, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Koichiro Wada, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Shinji Kitamura, Hitoshi Sugiyama, Noritaka Ariyoshi, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Drug metabolism and pharmacokinetics   40   100407 - 100407   2021.10

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    We evaluated the impact of vonoprazan on blood concentrations of tacrolimus via a retrospective analysis of 52 renal transplant recipients who took tacrolimus and converted from rabeprazole to vonoprazan between August 2018 and September 2019. We compared tacrolimus trough levels upon conversion among groups that were classified based on cytochrome P450 (CYP) gene polymorphisms. CYP3A5 groups were heterozygous or homozygous for CYP3A5∗1 and CYP3A5∗3 alleles. CYP2C19 genotypes were classified as extensive (∗1/∗1), intermediate (∗1/∗2 and ∗1/∗3) or poor metabolizers (∗2/∗2, ∗2/∗3 and ∗3/∗3). Tacrolimus trough levels increased only 0.3 ng/mL upon conversion in the CYP3A5∗3/∗3 group: 5.8 [3.4-7.2] vs 6.1 [3.8-7.9]; p = 0.06. No statistically significance changes in tacrolimus levels also occurred in the CYP3A5∗1/∗1 or CYP3A5∗1/∗3 groups. Subgroup analyses of CYP3A5∗3/∗3 demonstrated low changes for all three CYP2C19 subgroups: 5.2 [4.3-6.5] vs 6.2 [4.3-7.9]; p = 0.07, 6.1 [3.4-7.2] vs 6.7 [4.6-7.9]; p = 0.12 and 5.4 [3.6-6.5] vs 4.7 [3.8-6.3]; p = 1.00, respectively. Conversion to vonoprazan thus resulted in little increase of tacrolimus trough levels, even in the group predicted to be most susceptible (CYP3A5∗3/∗3 and 2C19∗1/∗1), thus supporting the safety of concomitant use of vonoprazan with tacrolimus.

    DOI: 10.1016/j.dmpk.2021.100407

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  • A clinical trial evaluating the usefulness of tailored antimicrobial prophylaxis using rectal-culture screening media prior to transrectal prostate biopsy: A multicenter, randomized controlled trial

    Sadahira T, Maruyama Y, Hiyama Y, Kitano H, Yamada H, Goto T, Kondo T, Shigemura K, Mitsui Y, Iwata T, Edamura K, Araki M, Watanabe M, Takenaka T, Teishima J, Miyata Y, Ishikawa K, Takaoka E, Miyazaki J, Takahashi S, Masumori N, Kiyota H, Fujisawa M, Yamamoto S, Sakuma T, Kusumi N, Ichikawa T, Watanabe T, Nasu Y, Tsugawa M, Nasu Y, Wada K

    Acta Med. Okayama   75 ( 5 )   663 - 667   2021.10

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  • Intraluminal diamond-like carbon coating with anti-adhesion and anti-biofilm effects for uropathogens: A novel technology applicable to urinary catheters. International journal

    Shogo Watari, Koichiro Wada, Motoo Araki, Takuya Sadahira, Daiki Ousaka, Susumu Oozawa, Tatsuyuki Nakatani, Yuichi Imai, Junichi Kato, Reiko Kariyama, Toyohiko Watanabe, Yasutomo Nasu

    International journal of urology : official journal of the Japanese Urological Association   28 ( 12 )   1282 - 1289   2021.9

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    OBJECTIVES: To examine anti-adhesion and anti-biofilm effects of a diamond-like carbon coating deposited via a novel technique on the inner surface of a thin silicon tube. METHODS: Diamond-like carbon coatings were deposited into the lumen of a silicon tube with inner diameters of 2 mm. The surface of the diamond-like carbon was evaluated using physicochemical methods. We used three clinical isolates including green fluorescent protein-expressing Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. We employed a continuous flow system for evaluation of both bacterial adhesion and biofilm formation. Bacterial adhesion assays consisted of counting the number of colony-forming units and visualization of adhered bacterial cells by scanning electron microscope to evaluate the diamond-like carbon-coated/uncoated samples. The biofilm structure was analyzed by confocal laser scanning microscopy on days 3, 5, 7 and 14 for green fluorescent protein-expressing Pseudomonas aeruginosa. RESULTS: The smooth and carbon-rich structure of the intraluminal diamond-like carbon film remained unchanged after the experiments. The numbers of colony-forming units suggested lower adherence of green fluorescent protein-expressing Pseudomonas aeruginosa and Escherichia coli in the diamond-like carbon-coated samples compared with the uncoated samples. The scanning electron microscope images showed adhered green fluorescent protein-expressing Pseudomonas aeruginosa cells without formation of microcolonies on the diamond-like carbon-coated samples. Finally, biofilm formation on the diamond-like carbon-coated samples was lower until at least day 14 compared with the uncoated samples. CONCLUSIONS: Intraluminal diamond-like carbon coating on a silicone tube has anti-adhesion and anti-biofilm effects. This technology can be applied to urinary catheters made from various materials.

    DOI: 10.1111/iju.14675

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  • Comparison of inflammation-based prognostic scores as predictors of survival outcomes in patients with germ cell tumors

    Yoshinaga K, Sadahira T, Maruyama Y, Mitsui Y, Iwata T, Wada K, Araki M, Watanabe T, Nasu Y

    Investing Cline Urol   62 ( 1 )   47 - 55   2021.9

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  • Nationwide surveillance of bacterial pathogens isolated from patients with acute uncomplicated cystitis in 2018: Conducted by the Japanese Research Group for Urinary Tract Infections (JRGU)

    Wada K, Yokoyama T, Uno S, Araki M, Sadahira T, Maruyama Y, Acosta H, Nakajima H, Hiyama Y, Kunishima Y, Togo Y, Nukaya T, Yamada H, Shigemura K, Ito S, Tanimura M, Kobayashi K, Kitano H, Teishima J, Yasuda M, Uehara S, Hamasuna R, Watanabe T, Nakagawa T, Hayami H, Miyazaki J, Takahashi S, Masumori N, Ishikawa K, Kiyota H, Fujisawa M, Arakawa S, Nasu Y, Yamamoto S

    J Infect Chemother   1169 ( 1180 )   2021.8

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  • The Cell Cycle Checkpoint Gene, RAD17 rs1045051, Is Associated with Prostate Cancer Risk.

    Jingkai Sun, Wenfeng Lin, Qixu Wang, Akiko Sakai, Ruizhi Xue, Masami Watanabe, Chunxiao Liu, Takuya Sadahira, Yasutomo Nasu, Abai Xu, Peng Huang

    Acta medica Okayama   75 ( 4 )   415 - 421   2021.8

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    Human RAD17, as an agonist of checkpoint signaling, plays an essential role in mediating DNA damage. This hospital-based case-control study aimed to explore the association between RAD17 rs1045051, a missense sin-gle nucleotide polymorphism (SNP), and prostate cancer risk. Subjects were 358 prostate cancer patients and 314 cancer-free urology patients undergoing treatment at the Zhujiang Hospital of Southern Medical University in China. RAD17 gene polymorphism rs1045051 was evaluated by the SNaPshot method. Compared with the RAD17 gene polymorphism rs1045051 AA genotype, there was a higher risk of prostate cancer for the CC gen-otype (adjusted odds ratio [AOR] = 1.731, 95% confidence interval [95%CI] = 1.031-2.908, p = 0.038). Compared with the A allele, the C allele was significantly associated with the disease status (AOR = 1.302, 95%CI = 1.037-1.634, p = 0.023). All these findings indicate that in the SNP rs1045051, both the CC genotype and C allele may have a substantial influence on the prostate cancer risk.

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  • Successful deceased donor kidney transplantation to a recipient with a history of COVID-19 treatment. International journal

    Kasumi Yoshinaga, Motoo Araki, Koichiro Wada, Kou Hasegawa, Takanori Sekito, Shuji Miyake, Shogo Watari, Yuki Maruyama, Takuya Sadahira, Shingo Nishimura, Katsuyuki Tanabe, Hidemi Takeuchi, Yuri Nakashima, Masaru Kinomura, Herik Acosta, Yosuke Mitsui, Risa Kubota, Hirochika Nakajima, Kohei Edamura, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Fumio Otsuka, Jun Wada, Yasutomo Nasu

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 7 )   1097 - 1101   2021.7

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    CASE PRESENTATION: A 49-year-old Asian male, who had undergone hemodialysis for >16 years, complained of a fever, dysgeusia and dysosmia, and was diagnosed with COVID-19 pneumonia based on severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (SARS-CoV-2 PCR) and computed tomography (CT). Treatment was started with oral favipiravir and ciclesonide inhalation. On the 10th day of treatment, the patient had a persistent high fever and a chest CT showed exacerbation of pneumonia, so dexamethasone was intravenously started. He was discharged after confirming two consecutive negative SARS-CoV-2 PCR tests. Three months after COVID-19 treatment, a SARS-CoV-2 PCR test was negative and he underwent a deceased donor kidney transplantation. Basiliximab induction with triple drug immunosuppression consisting of extended-release tacrolimus, mycophenolate mofetil and prednisolone, which is our regular immunosuppression protocol, was used. He was discharged on postoperative day 18 without the need for postoperative hemodialysis or any complications. The serum creatinine level was 1.72 mg/dL 95 days postoperatively and he had a favorable clinical course that was similar to deceased donor kidney recipients without a history of SARS-CoV-2 infection. CONCLUSION: We report the first case of a kidney transplantation after COVID-19 treatment in Japan and the fourth case globally. We would like to provide information about our successful case due to the anticipated increase in similar candidates in the near future.

    DOI: 10.1016/j.jiac.2021.03.018

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  • A Cace of Metastatic Fumarate Hydratase-Deficient-like Renal Cell Carcinoma Successfully Managed by Ipilimumab plus Nivolumab (Ipi/Nivo)

    Sekito T, Takamoto A, Kobayashi Y, Mitsui M, Watari S, Kubota R, Sadahira T, Iwata T, Nishimura S, Edamura K, Sako T, Araki M, Watanabe M, Watanabe T, Shibata R, Ennishi D, Nasu Y

    Acta Med. Okayama   75 ( 3 )   397 - 402   2021.6

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  • A second opinion pathology review improves the diagnostic concordance between prostate cancer biopsy and radical prostatectomy specimens

    Maehara T, Sadahira T, Maruyama Y, Wada K, Araki M, Watanabe M, Watanabe T, Yanai H, Nasu Y

    UROLOGY ANNALS   13 ( 2 )   119 - 124   2021.6

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  • ABO Blood Incompatibility Positively Affects Early Graft Function: Single-Center Retrospective Cohort Study. International journal

    Shogo Watari, Motoo Araki, Koichiro Wada, Kasumi Yoshinaga, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Transplantation proceedings   53 ( 5 )   1494 - 1500   2021.6

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    BACKGROUND: We investigated the association between ABO-incompatible (ABO-I) kidney transplantation and early graft function. METHODS: We retrospectively analyzed 95 patients who underwent living donor kidney transplantation between May 2009 and July 2019. It included 61 ABO-compatible (ABO-C) and 34 ABO-I transplantations. We extracted data on immunologic profile, sex, age, cold ischemic time, type of immunosuppression, and graft function. Two definitions were used for slow graft function (SGF) as follows: postoperative day (POD) 3 serum creatinine level >3 mg/dL and estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m2. Logistic regression analysis was performed to analyze the effect of ABO-I on the incidence of SGF. RESULTS: The characteristics between the ABO-C and ABO-I were not different. ABO-I received rituximab and plasma exchange. Patients also received tacrolimus and mycophenolate mofetil for 2 weeks and prednisolone for 1 week before transplantation as preconditioning. Of the 95 study patients, 19 (20%) and 21 (22%) were identified with SGF according to POD 3 serum creatinine level or eGFR, respectively. Multivariable analysis revealed that ABO-I significantly reduced the incidence of SGF (odds ratio, 0.15; 95% confidence interval, 0.03-0.7; P = .02), and cold ischemic time >150 min increased the incidence of SGF (odds ratio, 6.5; 95% confidence interval, 1.7-25; P = .006). Similar results were identified in POD 3 eGFR. Inferior graft function in patients with SGF was identified up to 6 months after transplantation. CONCLUSION: ABO-I reduces the incidence of SGF, which is associated with an inferior graft function up to 6 months.

    DOI: 10.1016/j.transproceed.2021.03.043

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  • "Intracorporeal versus extracorporeal urinary diversion in robot‑assisted radical cystectomy: a systematic review and meta‑analysis"

    Katayama S, Mori K, Pradere B, Mostafaei H, Schuettfort VM, Quhal F, Motlagh RS, Laukhtina E, Moschini M, Grossmann NC, Nasu Y, Shariat SF, Fajkovic H

    Int J Clin Oncol   26 ( 9 )   1587 - 1599   2021.6

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  • Efficacy of holmium laser enucleation in patients with a small (less than 30 mL) prostate volume. International journal

    Ichiro Tsuboi, Yuki Maruyama, Takuya Sadahira, Nobuyoshi Ando, Yasuhiro Nishiyama, Motoo Araki, Takushi Kurashige, Takaharu Ichikawa, Ryoji Arata, Noriaki Ono, Toyohiko Watanabe, Syunji Hayata, Hiroaki Shiina, Yasutomo Nasu

    Investigative and clinical urology   62 ( 3 )   298 - 304   2021.5

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    PURPOSE: To evaluate the efficacy of holmium laser enucleation of the prostate (HoLEP) in patients with a small prostate volume (≤30 mL). MATERIALS AND METHODS: We retrospectively evaluated 1,135 patients who underwent HoLEP at two institutions between July 2007 and March 2020. Patients who were not evaluated for the International Prostate Symptom Score (IPSS) before or after HoLEP were excluded. We divided patients into two groups according to estimated prostate volume (ePV): ≤30 (n=198) and >30 mL (n=539). The patient characteristics, IPSS, peak urinary flow rate (Qmax), postvoid residual urine volume (PVR), and other data were compared before and after surgery in each group and between the two groups. Multivariate analysis was performed to identify the factors associated with the efficacy of HoLEP in the group with ePV ≤30 mL. RESULTS: A total of 737 patients were included in this retrospective study. ePV (23.4 mL vs. 50 mL; p<0.001) and PVR differed significantly between the two groups. The IPSS, IPSS-quality of life, PVR, and Qmax significantly improved after HoLEP in both groups. Improvements in the IPSS, IPSS-quality of life, Qmax, and PVR were greater in the >30 mL group (p<0.001), whereas operation time and morcellation time were significantly shorter in the ≤30 mL group. In the multivariate analysis, age <70 years was independently associated with improvement by HoLEP. CONCLUSIONS: HoLEP is an effective treatment for patients with a small prostate, even though the extent of improvement after HoLEP was greater in those with a larger prostate.

    DOI: 10.4111/icu.20200450

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  • Relevance of CYP3A5 Expression on the Clinical Outcome of Patients With Renal Cell Carcinoma

    MatsumotoJ, Kotera Y, Watari S, Takeuchi K, Ueki H, Koyama T, Wada K, Fujiyoshi M, Nasu Y, Ariyoshi N

    ANTICANCER RESEARCH   41 ( 5 )   2511 - 2521   2021.5

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  • Evaluation of Neutrophil Dynamics Change by Protective Effect of Tadalafil After Renal Ischemia/Reperfusion Using In Vivo Real-time Imaging. International journal

    Yuki Maruyama, Motoo Araki, Kengo Kidokoro, Yuji Sogawa, Kasumi Yoshinaga, Yosuke Mitsui, Takuya Sadahira, Koichiro Wada, Masami Watanabe, Toyohiko Watanabe, Naoki Kashihara, Yasutomo Nasu

    Transplantation   2021.4

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    BACKGROUND: Neutrophils play a major role in ischemia/reperfusion injury (IRI) in renal transplantation and acute kidney injury. However, it has been difficult to observe changes in neutrophil dynamics over time in living mice kidney. We investigate neutrophil dynamics in IRI in living mice using novel in vivo multiphoton microscope imaging techniques and characterize the renoprotective effects of a selective phosphodiesterase (PDE) 5 inhibitor, tadalafil. METHODS: Wild-type (WT) and eNOS knockout (eNOS-KO) mice, a model of endothelial dysfunction, were used to establish in vivo real-time imaging in living mouse kidneys. Neutrophils were labeled green with Ly-6G monoclonal antibody, and plasma flow was labeled red with bovine serum albumin. Tadalafil was administered orally 1 h before surgery. Both kidney pedicles were reperfused after 37° warm ischemia for 45 min. RESULTS: Our novel approach revealed that neutrophils were trapped in glomerulus within a few minutes after reperfusion. They gradually increased over time and Infiltrated neutrophils were observed in the tubular lumen and peritubular capillary. The neutrophils were clearly visualized rolling on peritubular capillary plexus at 3 μm/min. The administration of tadalafil significantly reduced neutrophil influx into the glomerulus in both WT and eNOS-KO mice. Reduced neutrophil infiltration in tadalafil groups, which was confirmed by flow cytometry, resulted in histopathologically decreased tubular injury. The expression of VCAM-1 and KIM-1 was partially prevented by tadalafil. CONCLUSIONS: Use of a novel technique contributed to elucidation of neutrophil dynamics after reperfusion. Tadalafil has a potential for inhibiting neutrophil infiltration in renal IRI.Supplemental Visual Abstract; http://links.lww.com/TP/C223.

    DOI: 10.1097/TP.0000000000003803

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  • Robot-assisted partial nephrectomy versus standard laparoscopic partial nephrectomy for renal hilar tumor: A prospective multi-institutional study. International journal

    Nobuyuki Hinata, Ryoichi Shiroki, Kazunari Tanabe, Masatoshi Eto, Atsushi Takenaka, Mutsushi Kawakita, Isao Hara, Fumiya Hongo, Naokazu Ibuki, Yasutomo Nasu, Jun Teishima, Noriyasu Kawai, Akihiro Kawauchi, Tsunenori Kondo, Naoki Kawamorita, Chikara Oyama, Shigeo Horie, Masaki Shimbo, Masashi Kato, Hiroomi Kanayama, Yuya Koito, Masato Fujisawa

    International journal of urology : official journal of the Japanese Urological Association   28 ( 4 )   382 - 389   2021.4

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    OBJECTIVE: To investigate whether robot-assisted partial nephrectomy compared with laparoscopic partial nephrectomy is effective for renal hilar tumor removal. METHODS: This was a prospective, multicenter, single-arm, open-label trial with a 2-year enrollment period. A total of 22 academic hospitals in Japan participated in the present study. Comparison with historical control values from reported studies of laparoscopic partial nephrectomy was carried out. The warm ischemia time and positive surgical margin rate were set as primary perioperative and oncological outcomes. In the historical control group, these were 27.7 min and 13%, respectively. RESULTS: The analysis population included 105 participants. The mean warm ischemia time was 20.2 (95% confidence interval 16.7-21.8; P < 0.0001 vs 27.7). Two of 103 participants (1.9%) had a positive surgical margin (95% confidence interval 0.5-6.8%). Both results satisfy the prespecified decision criteria for the superiority of robot-assisted partial nephrectomy over the historical control of laparoscopic partial nephrectomy. Resected weight and preoperative estimated glomerular filtration rate were predictive factors of functional loss of the partially nephrectomized kidney after robot-assisted partial nephrectomy. CONCLUSION: Robot-assisted partial nephrectomy for clinical T1 renal hilar tumors results in shorter warm ischemia time than and comparable positive surgical margin rate to those reported for laparoscopic partial nephrectomy.

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  • Dual-Functional PLGA Nanoparticles Co-Loaded with Indocyanine Green and Resiquimod for Prostate Cancer Treatment. International journal

    Wenfeng Lin, Chaoming Li, Naijin Xu, Masami Watanabe, Ruizhi Xue, Abai Xu, Motoo Araki, Ruifen Sun, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    International journal of nanomedicine   16   2775 - 2787   2021.4

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    Purpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men's health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment. Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation. Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9±1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96±1.88)% compared with (0.99±0.10)% in PBS group, revealing the enhanced immune response against PCa. Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy.

    DOI: 10.2147/IJN.S301552

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  • Photodynamic diagnostic ureteroscopy using the VISERA ELITE video system for diagnosis of upper-urinary tract urothelial carcinoma: a prospective cohort pilot study. International journal

    Koichiro Wada, Motoo Araki, Ryuta Tanimoto, Takuya Sadahira, Shogo Watari, Yuki Maruyama, Yosuke Mitsui, Hirochika Nakajima, Herik Acosta, Satoshi Katayama, Takehiro Iwata, Shingo Nishimura, Atsushi Takamoto, Tomoko Sako, Kohei Edamura, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    BMC urology   21 ( 1 )   45 - 45   2021.3

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    BACKGROUND: The advantages of photodynamic diagnostic technology using 5-aminolevulinic acid (ALA-PDD) have been established. The aim of this prospective cohort study was to evaluate the usefulness of ALA-PDD to diagnose upper tract urothelial carcinoma (UT-UC) using the Olympus VISERA ELITE video system. METHODS: We carried out a prospective, interventional, non-randomized, non-contrast and open label cohort pilot study that involved patients who underwent ureterorenoscopy (URS) to detect UT-UC. 5-aminolevulinic acid hydrochloride was orally administered before URS. The observational results and pathological diagnosis with ALA-PDD and traditional white light methods were compared, and the proportion of positive subjects and specimens were calculated. RESULTS: A total of 20 patients were enrolled and one patient who had multiple bladder tumors did not undergo URS. Fifteen of 19 patients were pathologically diagnosed with UT-UC and of these 11 (73.3%) were ALA-PDD positive. Fourteen of 19 patients were ALA-PDD positive and of these 11 were pathologically diagnosed with UC. For the 92 biopsy specimens that were malignant or benign, the sensitivity for both traditional white light observation and ALA-PDD was the same at 62.5%, whereas the specificities were 73.1% and 67.3%, respectively. Of the 38 specimens that were randomly biopsied without any abnormality under examination by both white light and ALA-PDD, 11 specimens (28.9%) from 5 patients were diagnosed with high grade UC. In contrast, four specimens from 4 patients, which were negative in traditional white light observation but positive in ALA-PDD, were diagnosed with carcinoma in situ (CIS). CONCLUSIONS: Our results suggest that ALA-PDD using VISERA ELITE is not sufficiently applicable for UT-UC. Nevertheless, it might be better particularly for CIS than white light and superior results would be obtained using VISERA ELITE II video system. TRIAL REGISTRATION: The present clinical study was approved by the Okayama University Institutional Review Board prior to study initiation (Application no.: RIN 1803-002) and was registered with the UMIN Clinical Trials Registry (UMIN-CTR), Japan (Accession no.: UMIN000031205).

    DOI: 10.1186/s12894-021-00819-2

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  • Long-term ureteroscopic management of upper tract urothelial carcinoma: 28-year single-centre experience. International journal

    Yuki Maruyama, Motoo Araki, Koichiro Wada, Kasumi Yoshinaga, Yosuke Mitsui, Takuya Sadahira, Shingo Nishimura, Kohei Edamura, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Manoj Monga, Yasutomo Nasu, Hiromi Kumon

    Japanese journal of clinical oncology   51 ( 1 )   130 - 137   2021.1

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    BACKGROUND: Long-term survival outcomes of patients who undergo endoscopic management of non-invasive upper tract urothelial carcinoma remain uncertain. The longest mean follow-up period in previous studies was 6.1 years. This study reports the long-term outcomes of patients with upper tract urothelial carcinoma who underwent ureteroscopic ablation at a single institution over a 28-year period. METHODS: We identified all patients who underwent ureteroscopic management of upper tract urothelial carcinoma as their primary treatment at our institution between January 1991 and April 2011. Survival outcomes, including overall survival, cancer-specific survival, upper-tract recurrence-free survival and renal unit survival, were estimated using Kaplan-Meier methodology. RESULTS: A total of 15 patients underwent endoscopic management, with a mean age at diagnosis of 66 years. All patients underwent ureteroscopy, and biopsy-confirmed pathology was obtained. Median (range; mean) follow-up was 11.7 (2.3-20.9, 11.9) years. Upper tract recurrence occurred in 87% (n = 13) of patients. Twenty percent (n = 3) of patients proceeded to nephroureterectomy. The estimated cancer-specific survival rate was 93% at 5, 10, 15 and 20 years. Estimated overall survival rates were 86, 80, 54 and 20% at 5, 10, 15 and 20 years. Only one patient experienced cancer-specific mortality. The estimated mean and median overall survival times were 14.5 and 16.6 years, respectively. The estimated mean cancer-specific survival time was not reached. CONCLUSIONS: Although upper tract recurrence is common, endoscopic management of non-invasive upper tract urothelial carcinoma provides a 90% cancer-specific survival rate at 20 years in selected patients.

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  • The role of Wnt signaling in male reproductive physiology and pathology

    Xue R, Lin W, Sun J, Watanabe M, Xu A, Araki M, Nasu Y, Tang Z, Huang P

    molecular human reproduction   27 ( 1 )   2021

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  • Feasible kidney donation with living marginal donors, including diabetes mellitus

    Yoshinaga K, Araki M, Wada K, Sekito T, Watari S, Maruyama Y, Mitsui Y, Sadahira T, Kubota R, Nishimura S, Edamura K, Kobayashi Y, Tanabe K, Takeuchi H, Kitagawa M, Kitamura S, Wada J, Watanabe M, Watanabe T, Nasu Y

    lmmun lnflamm Dis   9 ( 3 )   1061 - 1068   2021

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  • Prognostic value of the systemic immune‑infammation index in non‑muscle invasive bladder cance

    Katayama S, Mori K, Pradere B, Laukhtina E, SchuettfortQuhal F, Motlagh RS, Mostafaei H, Grossmann NC, Rajwa P, Moschini M, Mathieu R, Abufaraj M, D'Andrea D, Comperat E, Haydter M, Egawa S, Nasu Y, Shariat SF

    World Journal of Urology   2021

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  • Discovery and Validation of Nitroxoline as a Novel STAT3 Inhibitor in Drug-resistant Urothelial Bladder Cancer

    Lin W, Sun J, Sadahira T, Xu N, Wada K, Liu C, Araki M, Xu A, Watanabe M, Nasu Y, Huang P

    Int. J. Biol. Sci   17 ( 12 )   3255 - 3267   2021

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  • Efficacy of Lactobacillus vaginal suppositories for the prevention of recurrent cystitis: A phase II clinical trial

    Sadahira T, Wada K, Araki M, Mitsuhata R, Yamamoto M, Maruyama Y, Iwata T, Watanabe M, Watanabe T, Kariyama R, Nasu Y, Ishii A

    INTERNATIONAL JOURNAL OF UROLOGY   2021

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  • Comparison of intracorporeal versus extracorporeal urinary diversion after robot-assisted radical cystectomy at a medium-sized facility

    Iwata T, Kobayashi Y, Maruyama Y, Kawad T, Sadahira T, Oiwa Y, Katayama S, Nishimura S, Takamoto A, SakoT, Wada K, Edamura K, Araki M, Watanabe M, Watanabe T, Nasu Y

    Int J Clin Oncol   2021

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  • Management of Groin Pain Using an Iliohypogastric Nerve Block in a Patient with Inguinal Hernia due to Persistent Müllerian Duct Syndrome. International journal

    Takanori Sekito, Takuya Sadahira, Masahiro Sugihara, Kohei Edamura, Motoo Araki, Yasutomo Nasu

    Case reports in urology   2021   7577632 - 7577632   2021

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    Persistent Müllerian duct syndrome can cause an inguinal hernia, although this is a rare occurrence; recurrent inguinal hernias can, in turn, cause ongoing groin pain. Management of groin pain plays an important role in patients' quality of life. We present our experience with a 43-year-old man who had a 2-week history of left-sided groin pain. The patient underwent laparoscopic surgery for a left inguinal hernia via the transabdominal preperitoneal approach. Right-sided cryptorchidism was noted during surgery, with a solid structure-thought to be a uterus-extending into the left inguinal canal. The diagnosis was persistent Müllerian duct syndrome, and the groin pain was relieved after a laparoscopic right orchiectomy with a bilateral preperitoneal hernia repair using a mesh. Four years later, magnetic resonance imaging performed for new-onset left groin pain showed a left inguinal hernia caused by the uterine structure. We diagnosed the recurrent hernia as the cause of his pain. Prior to performing any invasive surgical procedures, an iliohypogastric nerve block was performed using 1% lidocaine. Short-term analgesia was provided by the block, improving his quality of life. He has been followed since then and has declined surgical neurectomy. An iliohypogastric nerve block can be an effective method of controlling groin pain caused by an inguinal hernia resulting from persistent Müllerian duct syndrome; the effectiveness of the nerve block will help determine whether surgical neurectomy is indicated for permanent pain control.

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  • Combined Laparoscopic and CT Monitoring of the Ice-Ball Margin during Cryoablation for Renal Cell Carcinoma Associated with von Hippel-Lindau Disease: First Case.

    Takanori Sekito, Motoo Araki, Takao Hiraki, Mayu Uka, Toshiyuki Komaki, Yusuke Matsui, Toshihiro Iguchi, Satoshi Katayama, Kasumi Yoshinaga, Shogo Watari, Yuki Maruyama, Yosuke Mitsui, Risa Kubota, Takuya Sadahira, Shingo Nishimura, Koichiro Wada, Atsushi Takamoto, Kohei Edamura, Tomoko Sako, Yasuyuki Kobayashi, Toyohiko Watanabe, Susumu Kanazawa, Yasutomo Nasu

    Acta medica Okayama   74 ( 5 )   443 - 448   2020.10

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    We report a 47-year-old Japanese female with 10 previous treatments for multiple bilateral renal cell carcinoma (RCC) associated with von Hippel-Lindau disease. The 14-mm right lower pole renal tumor was in contact with the right ureter. Laparoscopic cryoablation was performed to protect the ureter wrapped with gauze. Computed tomography (CT) monitoring was used to confirm the precise ≥ 6 mm ice-ball margin. There was no local progression at 6-months post-surgery. The serum creatinine has been stable. This is apparently the first report of combined laparoscopic and CT monitoring of an ice-ball formation and its margin during cryoablation for RCC.

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  • Low-dose rituximab induction therapy is effective in immunological high-risk renal transplantation without increasing cytomegalovirus infection. International journal

    Kasumi Yoshinaga, Motoo Araki, Koichiro Wada, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Haruhito Adam Uchida, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    International journal of urology : official journal of the Japanese Urological Association   27 ( 12 )   1136 - 1142   2020.10

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    OBJECTIVES: To analyze the effect and impact of low-dose rituximab induction therapy on cytomegalovirus infection in living-donor renal transplantation. METHODS: A total of 92 recipients undergoing living-donor renal transplantation at Okayama University Hospital from May 2009 to August 2018 were evaluated retrospectively. Indications for preoperative rituximab (200 mg/body) were the following: (i) ABO major mismatch; (ii) ABO minor mismatch; (iii) donor-specific anti-human leukocyte antigen antibody-positive; and (iv) focal segmental glomerulosclerosis. We excluded four recipients who were followed <3 months, five who received >200 mg/body rituximab and seven who received prophylactic therapy for cytomegalovirus. RESULTS: There were 59 patients in the rituximab group and 17 in the non-rituximab group. Groups differed significantly in age (median age 53 vs 37 years, respectively; P = 0.04), but not in sex (male 64% vs 65%, P = 1.00), focal segmental glomerulosclerosis (3% vs 0%, P = 1.00) or percentage of cytomegalovirus-seronegative recipients of renal allografts from cytomegalovirus-seropositive donors (12% vs 18%, P = 0.68). The estimated glomerular filtration rate did not differ significantly between groups until 24 months after transplantation. Cytomegalovirus clinical symptoms (10% vs 24%, P = 0.22), including fever ≥38°C (5% vs 12%, P = 0.31) and gastrointestinal symptoms (5% vs 12%, P = 0.31), and the 5-year survival rates of death-censored graft loss (90% vs 83%, P = 0.43) did not differ significantly between groups. CONCLUSIONS: Low-dose rituximab induction therapy is effective in immunological high-risk recipients without increasing cytomegalovirus infection in the absence of valganciclovir prophylaxis.

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  • Aspects of Gene Therapy Products Using Current Genome-Editing Technology in Japan. International journal

    Teruhide Yamaguchi, Eriko Uchida, Takashi Okada, Keiya Ozawa, Masafumi Onodera, Akihiro Kume, Takashi Shimada, Satoru Takahashi, Kenzaburo Tani, Yasutomo Nasu, Tomoji Mashimo, Hiroyuki Mizuguchi, Kohnosuke Mitani, Kazushige Maki

    Human gene therapy   31 ( 19and20 )   1043 - 1053   2020.10

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    The development of genome-editing technology could lead to breakthrough gene therapy. Genome editing has made it possible to easily knock out or modify a target gene, while current gene therapy using a virus vector or plasmid hampering modification with respect to gene replacement therapies. Clinical development using these genome-editing tools is progressing rapidly. However, it is also becoming clear that there is a possibility of unintended gene sequence modification or deletion, or the insertion of undesired genes, or the selection of cells with abnormalities in the cancer suppressor gene p53; these unwanted actions are not possible with current gene therapy. The Science Board of the Pharmaceuticals and Medical Devices Agency of Japan has compiled a report on the expected aspects of such genome-editing technology and the risks associated with it. This article summarizes the history of that discussion and compares the key concepts with information provided by other regulatory authorities.

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  • Correlation between lumbar skeletal muscle size and urinary incontinence after radical prostatectomy. International journal

    Yosuke Mitsui, Takuya Sadahira, Toyohiko Watanabe, Motoo Araki, Yuki Maruyama, Ryota Sato, Acosta Gonzalez Herik Rodrigo, Koichiro Wada, Masami Watanabe, Michael B Chancellor, Yasutomo Nasu

    Lower urinary tract symptoms   12 ( 3 )   245 - 252   2020.9

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    OBJECTIVES: Urinary incontinence is a major concern after radical prostatectomy because it can decrease quality of life. The aim of the present study was to explore the effect of preoperative skeletal muscle on urinary quality of life after robot-assisted radical prostatectomy. METHODS: A total of 762 patients underwent robot-assisted radical prostatectomy. Longitudinal health-related quality of life was evaluated using the Expanded Prostate Cancer Index Composite instrument. The skeletal muscle area at the level of the third lumbar vertebra was assessed preoperatively by computed tomography and was standardized to height to obtain the skeletal muscle index. Reduced skeletal muscle size (RSMS) was defined as a skeletal muscle index ≤ 53 or ≤ 43 cm2 /m2 in patients with a body mass index (BMI) ≥25 or < 25, respectively. RESULTS: A total of 301 patients were included in this study, of whom 91 were classified as having RSMS (30.2%). Non-RSMS patients exhibited better urinary function at 12 months (P = .012) and better urinary continence recovery at 2 weeks and 12 months (P = .033 and P = .014, respectively) after prostatectomy compared with RSMS patients. Univariate and multivariate analyses identified preoperative RSMS as a significant and independent predictor of urinary incontinence (odds ratio = 1.77, P = .028). CONCLUSIONS: Patients with RSMS had a lower urinary quality of life compared with non-RSMS patients after robot-assisted radical prostatectomy, and RSMS, independent of age or BMI, was predictive of postoperative urinary incontinence.

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  • Tumor suppressor REIC/Dkk-3 and its interacting protein SGTA inhibit glucocorticoid receptor to nuclear transport

    Iwata T, Sadahira T, Ochiai K, Ueki H, Sasaki T, Haung P, Araki M, Watanabe T, Nasu Y, Watanabe M

    20 ( 2 )   1739 - 1745   2020.8

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  • Nitroxoline inhibits bladder cancer progression by reversing EMT process and enhancing anti-tumor immunity. International journal

    Naijin Xu, Wenfeng Lin, Jingkai Sun, Takuya Sadahira, Abai Xu, Masami Watanabe, Kai Guo, Motoo Araki, Gonghui Li, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    Journal of Cancer   11 ( 22 )   6633 - 6641   2020.7

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    Nitroxoline is considered to be an effective treatment for the urinary tract infections. Recently, it has been found to be effective against several cancers. However, few studies have examined the anti-tumor activity of nitroxoline in bladder cancer. The purpose of the study was to reveal the possible mechanisms how nitroxoline inhibited bladder cancer progression. In vitro assay, we demonstrated that nitroxoline inhibited bladder cancer cell growth and migration in a concentration-related manner. Western blot analysis demonstrated that nitroxoline downregulated the expressions of epithelial mesenchymal transition (EMT)-related proteins. Furthermore, treatment with nitroxoline in the C3H/He mice bladder cancer subcutaneous model resulted in significant inhibition of tumor growth. Moreover, the percentage of myeloid-derived suppressor cells (MDSC) in peripheral blood cells significantly decreased after treatment of nitroxoline. Taken together, our results suggested that nitroxoline may be used as a potential drug for bladder cancer.

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  • Impact of sarcopenia on longitudinal erectile functional outcomes after nerve-sparing robot assisted radical prostatectomy

    Mitsui Y, Sadahira T, Maruyama Y, Araki M, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    Eur Urol Open Sci   19 ( Suppl 2 )   e1112   2020.7

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  • The second opinion pathology review improves concordance between prostate biopsy and radical prostatectomy specimens

    Maruyama Y, Sadahira T, Araki M, Mitsui Y, Wada K, Edamura K, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    Eur Urol Open Sci   19 ( Suppl 2 )   e1556   2020.7

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  • Preventive efficacy and safety of lactobacillus vaginal suppositories in women with recurrent cystitis: A phase 2 study

    Sadahira T, Wada K, Ishii A, Maruyama Y, Iwata T, Araki M, Watanabe M, Watanabe T, Nasu Y

    Eur Urol Open Sci   19 ( Suppl 2 )   e2036   2020.7

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  • Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: a randomized phase II trial. International journal

    Masanori Noguchi, Gaku Arai, Shin Egawa, Chikara Ohyama, Seiji Naito, Kazumasa Matsumoto, Hirotsugu Uemura, Masayuki Nakagawa, Yasutomo Nasu, Masatoshi Eto, Shigetaka Suekane, Tetsuro Sasada, Shigeki Shichijo, Akira Yamada, Tatsuyuki Kakuma, Kyogo Itoh

    Cancer immunology, immunotherapy : CII   69 ( 5 )   847 - 857   2020.5

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    A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase II trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances the antitumor effects in patients with castration-resistant prostate cancer (CRPC). In this double-blind, placebo-controlled, randomized phase II study, we enrolled chemotherapy-naïve patients with CRPC from ten medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to receive either KRM-20 combined with docetaxel and dexamethasone (n = 25) or placebo with docetaxel and dexamethasone (n = 26). The primary endpoint was the difference in prostate-specific antigen (PSA) decline between each treatment. The rates of > 50% PSA decline in the two arms were similar (56.5% versus 53.8%; P = 0.851). Human leukocyte antigen (HLA)-matched peptide-specific immunoglobulin G (P = 0.018) and CTL (P = 0.007) responses in the KRM-20 arm significantly increased after treatment. The addition of KRM-20 did not increase toxicity. There were no between-group differences in progression-free or overall survival (OS). The addition of KRM-20 was safe, and similar PSA decline and HLA-matched peptide-specific CTL and IgG responses increased in combination with docetaxel and dexamethasone in CRPC patients. Subgroup analysis suggested that this treatment is favorable for CRPC patients with ≥ 26% lymphocytes or PSA levels of < 11.2 ng/ml, but further clinical trials comparing OS are required.

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  • Clinical Practice Guidelines for Bladder Cancer 2019 edition by the Japanese Urological Association: Revision working position paper

    Hiroaki Matsumoto, Koji Shiraishi, Haruhito Azuma, Keiji Inoue, Hirotsugu Uemura, Masatoshi Eto, Chikara Ohyama, Osamu Ogawa, Eiji Kikuchi, Hiroshi Kitamura, Nobuo Shinohara, Satoru Takahashi, Toyonori Tsuzuki, Masayuki Nakagawa, Yoshifumi Narumi, Hiroyuki Nishiyama, Tomonori Habuchi, Shiro Hinotsu, Yasuhisa Fujii, Kiyohide Fujimoto, Hiroyuki Fujimoto, Takashi Mizowaki, Hideyasu Matsuyama, Nobuyuki Sekita, Hiroshi Juri, Yuki Inada, Takashige Abe, Hideo Fukuhara, Yukio Naya, Satoshi Mutoh, Shigehisa Kitano, Takashi Kobayashi, Teruo Inamoto, Makito Miyake, Junichi Inokuchi, Tetsutaro Hayashi, Takahiro Kojima, Katsuyoshi Hashine, Toshiki Kijima, Yoshiyuki Matsui, Tomohiko Hara, Shingo Hatakeyama, Yoshiaki Yamamoto, Shintaro Narita, Tomoyasu Tsushima, Takafumi Miura, Takeru Shiroiwa, Mototsugu Oya, Momokazu Gotoh, Haruki Kume, Yasutomo Nasu, Katsuyuki Tsunemune

    International Journal of Urology   27 ( 5 )   362 - 368   2020.5

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    DOI: 10.1111/iju.14210

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  • Factors predicting pathological upgrading after prostatectomy in patients with Gleason grade group 1 prostate cancer based on opinion-matched biopsy specimens. Reviewed International journal

    Yuki Maruyama, Takuya Sadahira, Motoo Araki, Yosuke Mitsui, Koichiro Wada, Acosta Gonzalez Herik Rodrigo, Kazuaki Munetomo, Yasuyuki Kobayashi, Masami Watanabe, Hiroyuki Yanai, Toyohiko Watanabe, Yasutomo Nasu

    Molecular and clinical oncology   12 ( 4 )   384 - 389   2020.4

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    The present study investigated the concordance between Gleason scores assigned to prostate biopsy specimens by outside pathologists and a urological pathology expert, and determined the risk of upgrading between opinion-matched Gleason grade group (GGG) 1 biopsy specimens and radical prostatectomy specimens. Between January 2012 and May 2018, 733 patients underwent robot-assisted radical prostatectomy. Patients whose original biopsy specimens from outside hospitals were reviewed by a urological pathology expert Okayama University Hospital were included. Patients who had received neoadjuvant hormonal therapy were excluded. Logistic regression analysis was used to identify predictors of upgrading among GGG 1 diagnoses. A total of 403 patients were included in the present study. Agreement in GGG between initial and second-opinion diagnoses was present in 256 cases (63.5%). Although opinion-matched cases improved concordance between biopsy and prostatectomy specimen GGG compared with single-opinion cases (initial, 35.2%; second-opinion, 36.5%; matched, 41.4%), 71% (56/79) of cases classified as GGG 1 were upgraded after prostatectomy. Multivariate analysis revealed that prostate-specific antigen density and Prostate Imaging Reporting and Data System version 2 score were significant predictors of upgrading (odds ratio, 1.10; P=0.01; and odds ratio, 1.88; P=0.03, respectively). In conclusion, the GGG concordance rate between needle-core biopsy and radical prostatectomy specimens was higher in opinion-matched cases; however, 71% of opinion-matched GGG1 cases were upgraded after robot-assisted radical prostatectomy. Urologists should propose treatment strategies or further biopsy rather than active surveillance for patients with GGG1 and a high PSAD and/or PI-RADS score.

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  • Quality of Life and Mental Satisfaction Improve Slowly in Preemptive Kidney Transplantation Compared With Nonpreemptive Kidney Transplantation. Reviewed International journal

    Yosuke Mitsui, Motoo Araki, Yuki Maruyama, Kasumi Yoshinaga, Takuya Sadahira, Koichiro Wada, Katsuyuki Tanabe, Masashi Kitagawa, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Transplantation proceedings   52 ( 3 )   740 - 747   2020.3

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    BACKGROUND AND AIMS: Preemptive kidney transplantation (PEKT) is recognized as the best therapy to avoid dialysis. However, it is not clear whether PEKT recipients experience an improvement in quality of life (QoL) after kidney transplantation (KT) that exceeds that of non-PEKT recipients, since PEKT recipients have not experienced the heavy burden of dialysis. The aim of this study was to compare the changes in QoL for PEKT and non-PEKT recipients following transplantation. METHODS: Patients included in this study underwent living donor KT in our hospital. We excluded patients with incomplete SF-36 scores and with factors that could affect QoL, such as complications or rejection. QoL was assessed by the Short Form 36-Item Health Survey version 2.0 preoperatively and 3 and 12 months postoperatively. RESULTS: Eighty-eight patients underwent living donor KT in our hospital. Twelve PEKT and 20 non-PEKT recipients were enrolled in this retrospective study. In the non-PEKT group, both the physical and mental domain scores dramatically improved from baseline at 3 months, and remained at a similar level at 12 months. In contrast, in the PEKT group, only 1 domain of the physical and mental score improved at 3 months, and the social functioning score gradually improved at 12 months. Although the mental component score showed significant improvement in the non-PEKT group, it did not change in the PEKT group. CONCLUSIONS: The improvement of QoL after transplantation is more evident in the non-PEKT group. PEKT recipients have less mental satisfaction than non-PEKT recipients.

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  • Differentiation of Small (≤ 4 cm) Renal Masses on Multiphase Contrast-Enhanced CT by Deep Learning. International journal

    Takashi Tanaka, Yong Huang, Yohei Marukawa, Yuka Tsuboi, Yoshihisa Masaoka, Katsuhide Kojima, Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyuki Yanai, Yasutomo Nasu, Susumu Kanazawa

    AJR. American journal of roentgenology   214 ( 3 )   605 - 612   2020.3

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    OBJECTIVE. This study evaluated the utility of a deep learning method for determining whether a small (≤ 4 cm) solid renal mass was benign or malignant on multiphase contrast-enhanced CT. MATERIALS AND METHODS. This retrospective study included 1807 image sets from 168 pathologically diagnosed small (≤ 4 cm) solid renal masses with four CT phases (unenhanced, corticomedullary, nephrogenic, and excretory) in 159 patients between 2012 and 2016. Masses were classified as malignant (n = 136) or benign (n = 32). The dataset was randomly divided into five subsets: four were used for augmentation and supervised training (48,832 images), and one was used for testing (281 images). The Inception-v3 architecture convolutional neural network (CNN) model was used. The AUC for malignancy and accuracy at optimal cutoff values of output data were evaluated in six different CNN models. Multivariate logistic regression analysis was also performed. RESULTS. Malignant and benign lesions showed no significant difference of size. The AUC value of corticomedullary phase was higher than that of other phases (corticomedullary vs excretory, p = 0.022). The highest accuracy (88%) was achieved in corticomedullary phase images. Multivariate analysis revealed that the CNN model of corticomedullary phase was a significant predictor for malignancy compared with other CNN models, age, sex, and lesion size. CONCLUSION. A deep learning method with a CNN allowed acceptable differentiation of small (≤ 4 cm) solid renal masses in dynamic CT images, especially in the corticomedullary image model.

    DOI: 10.2214/AJR.19.22074

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  • Robotic Renal Autotransplantation: A Feasibility Study in a Porcine Model. Reviewed

    Risa Kubota, Motoo Araki, Koichiro Wada, Kasumi Kawamura, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Yuichi Ariyoshi, Takehiro Iwata, Shingo Nishimura, Atsushi Takamoto, Tomoko Sako, Kohei Edamura, Yasuyuki Kobayashi, Yuzuki Kano, Masashi Kitagawa, Katsuyuki Tanabe, Hitoshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Acta medica Okayama   74 ( 1 )   53 - 58   2020.2

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    We investigated the feasibility of robotic renal autotransplantation (RAT) in a porcine model to reduce invasiveness of RAT. Five pigs underwent robotic RAT using the da Vinci® robotic system. A robotic left nephrectomy was performed in all cases. Robotic RAT was performed on the left side in all but one case. Four ports were used. In 3 cases, the kidney was taken out through the GelPort® and irrigated on ice with Ringer's solution. In 2 cases, a complete intracorporeal robotic RAT was performed. An end-to-side anastomosis was performed between the renal vein and the external iliac vein and between the renal artery and the external iliac artery. Ureteroneocystostomy was also performed in 2 cases. All cases were performed robotically without open conversion. The median (IQR) console time was 3.1 (0.7) h, and the operative time was 3.8 (1.1) h. The estimated blood loss was 30 (0) ml. The warm ischemia time was 4.0 (0.2) min, and the cold ischemia time was 97 (17) min. Intracorporeal transarterial hypothermic renal perfusion was feasible in the 2 complete intracorporeal robotic RAT cases by using a perfusion catheter through a laparoscopic port. Robotic RAT has the potential to be a new minimally invasive substitute for conventional open surgery.

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  • Post-ablation syndrome after percutaneous cryoablation of small renal tumors: A prospective study of incidence, severity, duration, and effect on lifestyle

    Kawabata T, Hiraki T, Iguchi T, Matsui Y. Uka M, Masaoka Y, Komaki T, Sakurai J, Gobara H, Araki M, Nasu Y, Kanazawa S

    Eur J Radiol   2020

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  • Comparison of longitudinal health-related quality-of-life outcomes between anterior and posterior surgical approaches to robot-assisted radical prostatectomy. International journal

    Yuki Maruyama, Takuya Sadahira, Motoo Araki, Yosuke Mitsui, Koichiro Wada, Ryuta Tanimoto, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Journal of robotic surgery   14 ( 2 )   255 - 260   2020

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    Increasingly, studies have explored health-related quality-of-life (HRQOL) outcomes after robot-assisted radical prostatectomy (RARP). Nevertheless, no study has compared differences between anterior and posterior surgical approaches. The aim of this study is to assess differences of HRQOL following these two surgical approaches. From January 2012 to September 2017, 653 patients underwent RARP at our institution. We included patients who underwent operations by three experienced surgeons with interchangeability of role as console operator, and who could evaluate preoperatively the Expanded Prostate Cancer Index Composite (EPIC) score. Patients treated with neoadjuvant hormonal therapy were excluded. HRQOL was assessed using the EPIC score, and the questionnaire was administered at 6 timepoints: the baseline survey was conducted within 3 months before the surgery, and follow-up surveys were conducted at 2 weeks, 1, 3, 6, and 12 months after surgery. We defined the minimal clinically important difference (MCID) as half the standard deviation of the baseline score for each domain. A total of 201 patients were included in this retrospective study. Of these, 146 patients underwent RARP using an anterior surgical approach and 55 patients underwent a posterior approach. The clinical characteristics had no significant differences except for median prostate volume between the anterior and posterior groups (27 ml vs 29 ml, p = 0.049). There were no significant differences between the two groups in score decline beyond the MCID in any domain at any timepoint. Our study demonstrates no significant differences in HRQOL between anterior and posterior surgical approaches to RARP.

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  • Percutaneous thermal ablation for renal cell carcinoma in patients with Birt–Hogg–Dubé syndrome

    Y. Matsui, T. Hiraki, H. Gobara, T. Iguchi, K. Tomita, M. Uka, M. Araki, Y. Nasu, M. Furuya, S. Kanazawa

    Diagnostic and Interventional Imaging   100 ( 11 )   671 - 677   2019.11

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    Purpose: The purpose of this study was to analyze the outcome of patients with Birt–Hogg–Dubé (BHD) syndrome who underwent percutaneous thermal ablation of renal cell carcinoma (RCC). Materials and methods: Six patients with genetically proven BHD syndrome who underwent one or more sessions of percutaneous thermal ablation for the treatment of RCC were included. There were 4 men and 2 women, with a mean age of 57.3 ± 7.5 [SD] years (range: 44–67 years). A total of 29 RCCs (1–16 tumors per patient) were treated during 20 thermal ablation sessions (7 with radiofrequency ablation and 13 with cryoablation). Outcomes of thermal ablation therapy were assessed, including technical success, adverse events, local tumor progression, development of metastases, survival after thermal ablation, and changes in renal function. Results: Technical success was achieved in all ablation sessions (success rate, 100%). No grade 4 or 5 adverse events were observed. All patients were alive with no distant metastasis during a median follow-up period of 54 months (range: 6–173 months). No local tumor progression was found. The mean decrease in estimated glomerular filtration rate during follow-up was 10.7 mL/min/1.73 m2. No patients required dialysis or renal transplantation. Conclusion: Radiofrequency ablation and cryoablation show promising results for the treatment of RCCs associated with BHD syndrome. Percutaneous thermal ablation may be a useful treatment option for this rare hereditary condition.

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  • Prognostic role of the urokinase plasminogen activator (uPA) system in patients with nonmuscle invasive bladder cancer

    Iwata T, Kimura S, Abufarai M, Janisch F, Parizi M.K, Haitel A, Rink M, Roupret M, Fajkovic H, Seebacher V, Nyirady P, Karakiewicz P.I, Enikeev D, Rapoport L.M, Nasu Y, Shariat S.F

    Urol Oncol   37 ( 10 )   774 - 783   2019.10

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  • Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts. Reviewed International journal

    Yosuke Mitsui, Nahoko Tomonobu, Masami Watanabe, Rie Kinoshita, I Wayan Sumardika, Chen Youyi, Hitoshi Murata, Ken-Ichi Yamamoto, Takuya Sadahira, Acosta Gonzalez Herik Rodrigo, Hitoshi Takamatsu, Kota Araki, Akira Yamauchi, Masahiro Yamamura, Hideyo Fujiwara, Yusuke Inoue, Junichiro Futami, Ken Saito, Hidekazu Iioka, Eisaku Kondo, Masahiro Nishibori, Shinichi Toyooka, Yasuhiko Yamamoto, Yasutomo Nasu, Masakiyo Sakaguchi

    Oncology research   27 ( 8 )   945 - 956   2019.8

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    S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

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  • Oncologic outcomes after robot‑assisted versus open radical cystectomy: a systematic review and meta‑analysis

    Iwata T, Kimura S, Foerster B, Fossati N, Briganti A, Karakiewicz P.I, Gust K.M, Egawa S, Nasu Y, Abufaraj M, Shariat S.F

    World J Urol   37 ( 8 )   1557 - 1570   2019.8

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  • Comparison of the predictive value among inflammation-based scoring systems for bleomycin pulmonary toxicity in patients with germ cell tumors. International journal

    Yuki Maruyama, Takuya Sadahira, Motoo Araki, Yosuke Mitsui, Koichiro Wada, Kohei Edamura, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    International journal of urology : official journal of the Japanese Urological Association   26 ( 8 )   813 - 819   2019.8

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    OBJECTIVE: To compare the predictive value of pretreatment inflammation-based scoring systems in patients with germ cell tumors receiving first-line bleomycin-based chemotherapy. METHODS: Retrospectively, we evaluated 57 patients with germ cell tumors. Bleomycin pulmonary toxicity was defined as the presence of asymptomatic decline in pulmonary function tests, pulmonary symptoms or interstitial pneumonia on computed tomography in the absence of infection. The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, albumin-to-globulin ratio, Prognostic Nutritional Index, Glasgow Prognostic Score and C-reactive protein were measured in all patients. To assess the predictive ability of each scoring system, the area under the receiver operating characteristic curve was calculated, and multivariate analysis was carried out to identify the predictive scores associated with bleomycin pulmonary toxicity. RESULTS: Of the 57 patients, 15 patients developed bleomycin pulmonary toxicity. The neutrophil-to-lymphocyte ratio had the highest area under the curve value (0.763) of all inflammation-based scoring systems, followed by the Prognostic Nutritional Index (0.749). In multivariate analysis, the neutrophil-to-lymphocyte ratio (odds ratio 11.5; P = 0.009) and Prognostic Nutritional Index (odds ratio 9.07; P = 0.013) were independently associated with development of bleomycin pulmonary toxicity. As these two independent markers were combined, the area under the curve achieved the highest value (0.822). CONCLUSIONS: The present study shows that the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index are independent risk factors for development of bleomycin pulmonary toxicity. The combination of the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index seems to have superior predictive value compared with other inflammation-based scoring systems.

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  • Comparison of perioperative complications and health-related quality of life between robot-assisted and open radical cystectomy:A systematic review and meta-anasis

    Kimura S, Iwata T, Foerster B, Fossati N, Briganti A, Nasu Y, Egawa S, Abufaraj M, Shariat S.F

    Int J Urol   26 ( 8 )   760 - 774   2019.8

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  • Interobserver variability of 3.0-tesla and 1.5-tesla magnetic resonance imaging/computed tomography fusion image-based post -implant dosimetry of prostate brachytherapy

    Watanabe K, Katayama N, Katsui K, Matsushita T, Takamoto A, Ihara H, Nasu Y, Takemoto M, Kuroda M, Kanazawa S

    J Radiat Res   60 ( 4 )   483 - 489   2019.7

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  • Inflammatory myofibroblastic bladder tumor with divergent behavior in a patient with spinal cord injury. International journal

    Ichiro Tsuboi, Yuki Maruyama, Takuya Sadahira, Koichiro Wada, Nobuyoshi Ando, Yosuke Mitsui, Yasuhiro Nishiyama, Ryoji Arata, Motoo Araki, Yasutomo Nasu, Noriaki Ono

    IJU case reports   2 ( 4 )   212 - 214   2019.7

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    Introduction: An inflammatory myofibroblastic tumor of the bladder is rare. Some urothelial carcinoma with sarcomatoid changes may mimic an inflammatory myofibroblastic tumor. Case presentation: A 76-year-old man with indwelling urinary catheters because of a spinal cord injury presented with gross hematuria. Transurethral electrocoagulation and a resection were performed. A T2-weighted magnetic resonance imaging showed a tumor and hematoma in the bladder diverticulum that pathologically resembled an inflammatory myofibroblastic tumor. This lesion was then removed en bloc by partial cystectomy. Histology showed a squamous cell carcinoma with sarcomatoid changes. After 4 months, a computed tomography showed the lesion had expanded outside the skin adjacent to the bladder. Conclusion: Some cases of inflammatory myofibroblastic tumors have a malignant course. Urologists therefore need to be aware of the possibility of rare cases of malignant bladder myofibroblasts.

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  • The role of adjuvant radiotherapy after surgery for upper and lower urinary tract urothelialcarcinoma: A systematic review

    Iwata T, Kimura S, Abufaraj M, Janisch F, Karakiewicz P.I, Seebacher V, Roupre't M, Nasu Y, Shariat S.F

    Urol Oncol   37 ( 10 )   659 - 671   2019.6

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  • Clinical phamacokinetics of oral azithromycin in epididymal tissue

    Sadahira T, Wada K, Ikawa K, Morikawa N, Mitsui M, Araki M, Fujiyoshi M, Ishii A, Watanabe M, Watanabe T, Nasu Y

    J Infect Chemother   25 ( 10 )   832 - 834   2019.6

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  • Rituximab induction therapy is effective without increasing adverse events in immunological high risk recipients

    Kawamura K, Araki M, Maruyama Y, Mitsui Y, Sadahira T, Kubota T, Nishimura S, Wada K, Kobayashi Y, Watanabe T, Nasu Y

    The Journal of Urology   201(Supplement 4) ( 4S )   e1124 - e1125   2019.5

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  • Pelvic magnetic resonance imaging parameters predict urinary incontinence after robot-assisted radical prostatectomy. International journal

    Takuya Sadahira, Yosuke Mitsui, Motoo Araki, Yuki Maruyama, Koichiro Wada, Kohei Edamura, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Lower urinary tract symptoms   11 ( 3 )   122 - 126   2019.5

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    OBJECTIVE: Urinary incontinence (UI) is a major prostate cancer (PCa) treatment-related morbidity. It has been reported that post-prostatectomy UI is related to the width of the pelvic floor muscles (PFM) and the length of the urethra. However, the details of these anatomical parameters are unknown. The aim of this study was to investigate whether preoperative pelvic parameters or anatomical parameters of the urethra, as measured by magnetic resonance imaging (MRI), are correlated with UI. METHODS: Between 2010 and 2017, 571 patients with localized PCa underwent robot-assisted radical prostatectomy (RARP) at Okayama University Hospital. Patients treated by a single experienced surgeon were included in the study. Preoperative prostate volume, obturator internal muscle, anal sphincter muscle, levator ani muscle (LAM), urethra wall thickness (UWT), and membranous urethral length (MUL) were measured by MRI. Patients were divided into two groups depending on leakage status 1 year after RARP using Expanded Prostate Index Composite Item 1. RESULTS: Seventy patients were included in this retrospective study. Based on leakage status, 37 and 33 patients were allocated to the no-leakage and leakage groups, respectively. There were significant differences between the two groups in age (P = 0.03), MUL (P < 0.001), UWT (P = 0.03), and LAM (P = 0.001). Multivariate logistic regression analyses revealed that MUL and LAM predicted UI 1 year after RARP. CONCLUSIONS: Pelvic parameters measured by MRI before RARP may be useful in the prediction of UI. In particular, MUL and LAM can predict postoperative UI by strict definition.

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  • Three-year follow-up of a phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer and bone metastases

    Hirotsugu Uemura, Hiroji Uemura, Satsohi Nagamori, Yoshiaki Wakumoto, Go Kimura, Hiroaki Kikukawa, Akira Yokomizo, Atsushi Mizokami, Takeo Kosaka, Naoya Masumori, Yoshihide Kawasaki, Junji Yonese, Yasutomo Nasu, Satoshi Fukasawa, Takayuki Sugiyama, Seigo Kinuya, Makoto Hosono, Iku Yamaguchi, Takashi Akagawa, Nobuaki Matsubara

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   24 ( 5 )   557 - 566   2019.5

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    Background Radium-223 is a first-in-class targeted alpha therapy to prolong overall survival (OS) in castration-resistant prostate cancer with bone metastases (mCRPC). The aim of the present analysis was to assess the long-term safety with radium-223 in Japanese patients with mCRPC.Methods Patients with symptomatic mCRPC, >= 2 bone metastases and no known visceral metastases received up to 6 injections of radium-223 (55 kBq/kg), one every 4 weeks. Adverse events (AEs) considered to be related to radium-223 were reported until 3 years after the first injection. Pre-specified conditions, such as acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer, or other primary malignancies, were reported regardless of causality.Results Of the 49 patients enrolled in the study, 44 (89.8%) entered the survival follow-up period and 33 (67.3%) died. Throughout the entire study, there were no reports of second primary malignancy or other pre-specified conditions. Eight patients (16.3%) experienced post-treatment drug-related AEs, which were all hematological (anemia and decreased lymphocyte, platelet, and white blood cell counts). No serious post-treatment drug-related AEs were reported. Updated median OS was 19.3 months (95% CI: 14.2, 28.5).Conclusions In Japanese patients with symptomatic mCRPC and bone metastases, radium-223 had a favorable long-term safety profile with no second primary malignancies reported. Taken together with median OS, which was comparable to that in the pivotal phase III ALSYMPCA study, these results support continued benefit from radium-223 in Japanese patients with mCRPC.

    DOI: 10.1007/s10147-018-01389-4

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  • Perioperative blood transfusion affects oncologic outcomes after nephrectomy for renal cellcarcinoma: A systematic review and meta-analysis

    Iwata T, Kimura S, Foerster B, Abufaraj M, Karakiewicz P, Preisse F, Nasu Y, Shariat S.F

    Urol Oncol   37 ( 4 )   273 - 281   2019.4

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  • Use of single-dose perioperative antimicrobial therapy is acceptable in recipients of living-donor renal transplants in the rituximab era. International journal

    Shingo Nishimura, Koichiro Wada, Motoo Araki, Takuya Sadahira, Yuki Maruyama, Yosuke Mitsui, Ryuta Tanimoto, Yasuyuki Kobayashi, Toyohiko Watanabe, Yasutomo Nasu

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   25 ( 4 )   247 - 252   2019.4

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    OBJECTIVE: The aim of this study was to evaluate the efficacy of single-dose perioperative antimicrobial therapy as infection prophylaxis in recipients of living-donor renal transplants in the rituximab era. PATIENTS AND METHODS: Between 2009 and 2017, 84 recipients underwent living-donor renal transplantation (LDRT) at Okayama University Hospital; 3 with vascular/urinary complications requiring additional surgery were excluded from this analysis. Data including recipient characteristics, antimicrobial prophylaxis and administration of rituximab were retrospectively examined for an association with perioperative infections. Prophylactic antimicrobial agents, selected according to the Results of preoperative urine cultures, were administered just before incision. Perioperative infections, which consisted of surgical site infections, remote infections, and urinary tract infections, were defined as a positive culture indicating required administration of additional antimicrobial agents. RESULTS: Among the 81 recipients, prophylactic cefazolin, ampicillin/sulbactam, and others were administered to 66 (82%), 13 (16%), and 2 (3%) recipients, respectively. Twenty-one (26%) received single-dose antimicrobial prophylaxis, while 60 (74%) received multiple doses up to 7 days. Rituximab was used in 59 (72.8%) recipients. The incidence of urinary tract infection, surgical site infection and remote infection was 13 (16%), 1 (1%), and 0, respectively. Univariate analysis could not demonstrate any significant risk factors for postoperative urinary tract infections, including a single dose vs multiple doses of antimicrobial therapy (P = 0.069) and administration of rituximab (P = 0.717). CONCLUSIONS: Our data suggest that the use of single-dose perioperative antimicrobial therapy is acceptable for prophylaxis of infections in patients undergoing LDRT, even in the rituximab era.

    DOI: 10.1016/j.jiac.2018.11.013

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  • Contrast-enhanced computed tomography-guided percutaneous cryoablation of renal cell carcinoma in a renal allograft:First case in Asia

    Tsuboi I, Araki M, Fujiwara H, Iguchi T, Hiraki T, Arichi N, Kawamura K, Maruyama Y, Mitsui Y, Sadahira T, Kubota R, Nishimura S, Sako T, Takamoto A, Wada K, Kobayashi Y, Watanabe T, Yanai H, Kitagawa M, Tanabe K, Sugiyama H, Wada J, Shiina H, Kanazawa S, Nasu Y

    Acta Med. Okayama   73 ( 3 )   269 - 272   2019.4

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  • Comparison of longitudinal health-related quality of life outcomes between the anterior and posterior surgical approach to robot-assisted radical prostatectomy.

    Maruyama Y, Sadahira T, Araki M, Tanimoto R, Kawamura K, Mitsui Y, Wada K, Edamura K, Kobayashi Y, Watanabe M, Nasu Y

    European Urology Supplements   18 ( 1 )   e1186 - e1187   2019.3

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  • Editorial Comment from Dr Sadahira et al. to Use of fosfomycin as targeted antibiotic prophylaxis before prostate biopsy: A prospective randomized study. International journal

    Takuya Sadahira, Koichiro Wada, Yasutomo Nasu

    International journal of urology : official journal of the Japanese Urological Association   26 ( 3 )   399 - 399   2019.3

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  • Clinical impact of abdominal fat distribution measured by 3-D computed tomography volumetry on post-transplant renal function in recipients after living kidney transplantation: a retrospective study.

    Yosuke Mitsui, Takuya Sadahira, Motoo Araki, Yuki Maruyama, Koichiro Wada, Ryuta Tanimoto, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Clinical and experimental nephrology   23 ( 3 )   415 - 424   2019.3

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    BACKGROUND: Excessive visceral fat may decrease renal function because of metabolic derangements. The aim of this study was to evaluate the impact of abdominal fat distribution on renal function of recipients after kidney transplantation using the visceral adipose tissue (VAT)/subcutaneous adipose tissue (SAT) ratio. METHODS: Seventy-nine patients underwent living kidney transplantation from 2009 to 2017. Patients without a correct measurement of VAT and SAT, follow-up of < 6 months, or with kidney transplant rejection or a virus infection were excluded. VAT and SAT were calculated automatically by 3-D volume analyzer software in recipients prior to living kidney transplantation. Our primary aim was to identify abdominal fat distribution measured by CT associated with renal dysfunction (estimate glomerular filtration rate; eGFR < 45) at 6 month post renal transplantation in recipient. RESULTS: Fifty-eight living kidney recipients were included in this retrospective study: 30 for the high VAT/SAT ratio group; 28 for the VAT/SAT low group. Multiple logistic regression analysis showed the VAT/SAT ratio and pre-donor eGFR were associated with eGFR < 45 ml/min/1.73 m2. An increase in VAT/SAT ratio was associated independently with the incidence of decreased renal function. CONCLUSION: This finding indicates that adipose tissue distribution is an important predictor of the outcome of living kidney transplantation in recipients.

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  • The 3-D Volumetric Measurement Including Resected Specimen for Predicting Renal Function AfterRobot-assisted Partial Nephrectomy. International journal

    Yosuke Mitsui, Takuya Sadahira, Motoo Araki, Yuki Maruyama, Shingo Nishimura, Koichiro Wada, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Urology   125   104 - 110   2019.3

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    OBJECTIVE: To investigate the relationship between postoperative renal function and resected cortex margin volume calculated by a 3-dimensional reconstruction technique based on the resected specimen, and to determine predictors of renal function after robot-assisted partial nephrectomy. METHODS: A total of 114 patients underwent robot-assisted partial nephrectomy from 2014 to 2018. Patients without a 1 mm slice computed tomography or renal scintigraphy were excluded. We identified the margins of the tumor from each resected specimen with 2 mm margin being added as the ischemic margin. The volume of the renal cortex was calculated automatically using 3-dimensional volume analyzer software. The total margin volume was excluded from the ipsilateral cortex volume to calculate the cortex volume split. Predicted estimated glomerular filtration rate (eGFR) was calculated using the change in cortex volume and then compared with the actual eGFR. RESULTS: Eighty-two patients were included in this retrospective study. Sixty-six patients (80%) were cT1a. A strong correlation was observed between renal scintigraphy split and pre- and postoperative cortex volume split (Pearson correlation coefficient r = 0.9330 and 0.8742, respectively). The predicted eGFR correlated strongly with post 1, 3, 6, and 12 months eGFR (r = 0.8929, 0.9294, 0.9320, and 0.8952, respectively). Preoperative relative renal function and total cortex margin volume were independent risk factors for decreasing postoperative renal function. CONCLUSION: This precise volumetric assessment that includes the resected margin is an alternative to renal scintigraphy for predicting postoperative relative renal function. The healthy cortex margin volume calculated by the reconstruction technique is an independent risk factor of decreasing postoperative renal function.

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  • Sarcopenia patients are clinically dissatisfied with postoperative urinary function compared with non-sarcopenia patients in robot-assisted radical prostatectomy

    Mitsui Y, Araki M, Maruyama Y, Sadahira T, Wada K, Edamura K, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    European Urology Supplements   18 ( 1 )   e1194 - e1195   2019.3

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  • The level of QOL improves slower in preemptive kidney transplantation than the one in non-preemptive kidney transplantation

    Mitsui Y, Araki M, Maruyama Y, Sadahira T, Wada K, Edamura K, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    European Urology Supplements   18 ( 1 )   e1651 - e1652   2019.3

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  • Tumor suppressor REIC/Dkk-3 and its co-chaperone SGTA: Their interaction and role to control castration-resistant prostate cancer by the release from androgen independence and malignancy

    Sadahira T, Maruyama Y, Mitsui Y, Wada K, Edamura K, Kobayashi Y, Araki M, Watanabe M, Nasu Y

    European Urology Supplements   18 ( 1 )   e68   2019.3

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  • Loss of psoas major muscle volume during systemic chemotherapy is related to worse prognosis in testicular cancer. International journal

    Yosuke Mitsui, Takuya Sadahira, Motoo Araki, Yuki Maruyama, Koichiro Wada, Ryuta Tanimoto, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Japanese journal of clinical oncology   49 ( 2 )   183 - 189   2019.2

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    Objective: In several cancers, the loss of skeletal muscle is well associated with oncological outcome. However, its effect is unknown in testicular cancer. This study evaluated the prognostic impact of psoas major muscle volume loss during systemic chemotherapy. Methods: This was a retrospective study of patients who underwent chemotherapy from 2008 to 2017. Psoas major muscle volume was calculated by volume analyzer software, and its loss was calculated during systemic chemotherapy. The patients were divided according to muscle volume loss: Group 1 (<20%) and Group 2 (≥20%). The losses were compared with Kaplan-Meier curves, and a Cox proportional hazard model was applied to test predictors of poor prognosis. Results: Fifty patients were included. Seventeen were classified into Group 1, and 33 into Group 2. The Kaplan-Meier curves revealed that the progression-free and the overall survival of Group 1 were significantly better than those of Group 2 (P = 0.002, P = 0.03, respectively). A multivariate analysis identified psoas major muscle volume loss as a significant and independent predictor of poor prognosis. Conclusions: Patients with psoas major muscle volume loss during chemotherapy had a significantly worse prognosis than those without loss.

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  • Clitoral Blood Flow Changes after Surgery with Tension-Free Vaginal Mesh for Pelvic Organ Prolapse.

    Yuko Oiwa, Toyohiko Watanabe, Takuya Sadahira, Ayano Ishii, Tomoko Sako, Miyabi Inoue, Koichiro Wada, Yasuyuki Kobayashi, Motoo Araki, Yasutomo Nasu

    Acta medica Okayama   73 ( 1 )   21 - 27   2019.2

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    We measured basal clitoral blood flow by Doppler sonography to determine whether tension-free vaginal mesh(TVM) affects the clitoral blood flow and sexual function in women with pelvic organ prolapse (POP). We performed a prospective study of 22 patients who underwent TVM for POP. Clitoral blood flow was measured by Doppler ultrasound. The resistance index (RI), pulsatility index (PI), peak systolic velocity (PSV), and end-diastolic velocity (EDV) of the clitoral arteries were measured preoperatively and at 1, 3, and 6 months postoperatively. Female sexual function was also investigated with the Female Sexual Function Index (FSFI). The mean PI and RI were increased at 1 month and significantly decreased at 6 months postoperatively (p<0.05). In contrast, the mean PSV and EDV decreased at 1 month postoperatively and increased at 6 months postoperatively. These four parameters recovered to baseline levels at 6 months following surgery. Total FSFI scores improved significantly from 10.2±7.9 at baseline to 18.2±8.9 at 6 months postoperatively. Color Doppler ultrasonography is potentially useful in measuring clitoral blood flow in patients treated with TVM for POP. Prospective long-term studies are needed to evaluate the utility of this modality as a diagnostic and prognostic tool for female sexual dysfunction.

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  • The Novel Combination of Nitroxoline and PD-1 Blockade, Exerts a Potent Antitumor Effect in a Mouse Model of Prostate Cancer. Reviewed International journal

    Naijin Xu, Linglong Huang, Xiezhao Li, Masami Watanabe, Chaoming Li, Abai Xu, Chunxiao Liu, Qiang Li, Motoo Araki, Koichiro Wada, Yasutomo Nasu, Peng Huang

    International journal of biological sciences   15 ( 5 )   919 - 928   2019

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    Programmed cell death protein 1 (PD-1) blockade is a promising therapeutic strategy against prostate cancer. Nitroxoline has been found to have effective anticancer properties in several cancer types. We investigated the efficacy of a combination therapy involving nitroxoline and PD-1 blockade in a prostate cancer mouse model. In our in vitro analysis, we found that nitroxoline inhibited the viability and proliferation of the mouse prostate cancer cell line RM9-Luc-PSA. Additionally, nitroxoline downregulated the expressions of phospho-PI3 kinase, phospho-Akt (Thr308), phospho-Akt (Ser473), phospho-GSK-3β, Bcl-2, and Bcl-xL. Nitroxoline also downregulated programmed death-ligand 1 (PD-L1) expression levels in prostate cancer cell line and tumor tissue. In our murine prostate cancer orthotopic model, nitroxoline plus PD-1 blockade synergistically suppressed tumor growth when compared with nitroxoline or PD-1 blockade alone, leading to reductions in tumor weight, bioluminescence tumor signals, and serum prostate-specific antigen levels. Furthermore, fluorescence-activated cell sorting analysis showed that the combination strategy significantly enhanced antitumor immunity by increasing CD44+CD62L+CD8+ memory T cell numbers and reducing myeloid-derived suppressor cell numbers in peripheral blood. In conclusion, our findings suggest that nitroxoline plus PD-1 blockade may be a promising treatment strategy in patients with prostate cancer.

    DOI: 10.7150/ijbs.32259

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  • Favorable long-term oncological and urinary outcomes of incidental prostate cancer following holmium laser enucleation of the prostate. International journal

    Yusuke Tominaga, Takuya Sadahira, Yosuke Mitsui, Yuki Maruyama, Ryuta Tanimoto, Koichiro Wada, Shuhei Munemasa, Nobuyuki Kusaka, Yasuhiro Nishiyama, Takushi Kurashige, Yasutomo Nasu, Shunji Hayata

    Molecular and clinical oncology   10 ( 6 )   605 - 609   2019

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    The aim of the present study was to investigate the impact of incidental prostate cancer (IPCa), which was diagnosed by holmium laser enucleation of the prostate (HoLEP), on long-term oncological and functional outcomes. A total of 482 patients who underwent HoLEP for benign prostatic hyperplasia (BPH) between 2008 and 2016 at our institution were retrospectively reviewed. We defined IPCa as prostate cancer (PCa) according to the enucleated tissue of transitional zone. Therefore, 64 patients were excluded for the following reasons: Prostate-specific antigen (PSA) ≥4.0 ng/ml and no prostate biopsy (n=46); and PSA ≥4.0 ng/ml and diagnosed with PCa by prostate biopsy performed during HoLEP (n=18). Notably, 418 patients were included in the study and divided into two groups: The BPH group and the IPCa group. For 5 years, postoperative PSA and functional outcomes were evaluated. Of 418 patients, 25 (6%) were diagnosed with IPCa by HoLEP, 21 patients (84%) had a Gleason score ≤6 and 5 patients (20%) received adjuvant therapy for PCa following HoLEP. No significant differences were observed between groups for preoperative PSA, PSA density, or urinary and sexual function outcomes; however, age at the time of HoLEP significantly differed between groups (71.7 vs. 75.5 years, P=0.026). Long-term (5-year) urinary outcomes demonstrated sustained improvement. Postoperative PSA increased gradually in the IPCa group (3-year, P=0.033; 4-year, P=0.037); International Index of Erectile Function 5 conversely decreased (5-year, P=0.068). According to the present results, if standard PSA screening and prostate biopsy are performed, watchful waiting for IPCa is feasible, and IPCa does not impact on 5-year urinary outcomes.

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  • Burned-out Prostate Cancer ? Primary Metastatic Cancer Not Detected on Repeat Biopsy. Reviewed

    Mitsui Y, Sadahira T, Maruyama Y, Wada K, Tanimoto R, Sugimoto M, Araki M, Watanabe M, Yanai H, Watanabe T, Nasu Y

    Acta medica Okayama   72 ( 6 )   605 - 609   2018.12

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    Metastatic prostate cancer (PCa) cases that cannot be detected on repeat prostate biopsy are extremely rare. Our patient was a 51-year-old Japanese man diagnosed as metastatic PCa by histopathological examination of lesions obtained bone biopsy and lymph node dissection. The primary tumor was not detected after repeated prostate biopsy. Metastatic PCa was diagnosed based on immunohistochemical staining: PSA, AR, P504S, and NKX3.1 of bone and lymph node with metastasis. We speculate that the primary PCa was "burned-out," demonstrating remote metastases with no apparent primary tumor in the prostate. Burned-out PCa may be difficult to diagnose and treat due to its rarity.

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  • Prospective randomized controlled trial of postoperative early intravesical chemotherapy with pirarubicin (THP) for solitary non-muscle invasive bladder cancer comparing single and two-time instillation Reviewed

    Ryuta Tanimoto, Takashi Saika, Shin Ebara, Yasuyuki Kobayashi, Ryoji Nasu, Daisuke Yamada, Hitoshi Takamoto, Yoshiyuki Miyaji, Yasutomo Nasu, Tomoyasu Tsushima, Hiromi Kumon

    World Journal of Urology   36 ( 6 )   889 - 895   2018.6

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    Purpose: Single immediate intravesical instillation of chemotherapy after transurethral resection of bladder tumor (TURBT) has been the gold standard treatment for patients with low- and intermediate-risk non-muscle invasive bladder cancer (NMIBC). Herein, we conducted a multicenter prospective randomized controlled trial in Japan, comparing recurrence-free survival between single and two-time instillation of pirarubicin (THP) for solitary NMIBC. Methods: Between 2005 and 2009, 257 patients with solitary NMIBC were enrolled and randomized to single instillation of THP (30 mg/50 mL) immediately after TURBT (Group A) or two-time instillation of THP immediately after and 1 day after TURBT (Group B). The primary endpoint was recurrence-free survival. Secondary endpoints included rates of recurrence and adverse effects, including hematuria, micturition pain, difficult urination, pollakiuria, systemic symptoms, and other complications. This study was registered as UMIN C000000266. Results: Of 257 patients, 99 in Group A and 102 in Group B could be evaluated for recurrence. Median follow-up was 71 months. The overall recurrence rate was 39 and 31%, respectively (p = 0.2704). Although the 5-year recurrence-free survival rates were 55.9% and 67.7% in groups A and B, respectively, the difference between groups was not significant (p = 0.2031). No significant differences in adverse effects were observed between groups, except for pollakiuria (7 vs 22%, p = 0.0031). Multivariate analyses did not show that the treatment group was a significant risk factor for bladder cancer recurrence. Conclusions: Postoperative two-time intravesical instillation of THP was not superior to single immediate instillation for preventing recurrence after complete resection of a solitary NMIBC.

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  • Renal Function after Nephrectomy Influences the Risk of Cardiovascular Events.

    Taiki Kambara, Ryuta Tanimoto, Motoo Araki, Takashi Saika, Hideaki Hashimoto, Tadashi Oeda, Tomoyasu Tsushima, Shunji Hayata, Yasutomo Nasu, Yasuyuki Kobayashi

    Acta medica Okayama   72 ( 3 )   241 - 247   2018.6

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    We retrospectively analyzed the factors related to postoperative cardiovascular (CV) events in patients undergoing partial nephrectomy (PN) or radical nephrectomy (RN) for clinical T1 renal cell carcinoma (RCC). We identified 570 patients who underwent PN or RN for T1 renal cell carcinoma between January 1998 and December 2009 at our institution and related hospitals. We determined the cumulative incidence rate of CV events and overall survival (OS) using Kaplan-Meier survival curves with a log-rank test, and we evaluated the risk for an increase in CV events and OS using Cox proportional hazard regression. Of the 570 patients, 171 underwent PN and 399 underwent RN. The type of surgery was not significantly related with CV events. The only factor that significantly increased the risk of CV events in both the univariate (HR 2.67, p=0.006) and multivariate analyses (HR 2.14, p=0.044) was a postoperative estimated glomerular filtration rate (eGFR) <45 ml/min/1.73 m2. Postoperative eGFR was also a significant risk factor for OS in the univariate analysis (HR 2.38, p=0.0104), but not in the multivariate model. Postoperative renal function was a significant independent predictor of the incidence of subsequent CV events.

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  • Prognostic impact of bleomycin pulmonary toxicity on the outcomes of patients with testicular cancer

    Maruyama Y, Sadahira T, Mitsui Y, Takamoto A, Wada K, Tanimoto R, Kobayashi Y, Araki M, Watanabe M, Watanabe T, Nasu Y

    The Journal of Urology   199 ( 4S )   e1131 - e1132   2018.5

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  • Oncological impact of neoadjuvant hormonal therapy on permanent iodine-125 seed brachytherapy in patients with low- and intermediate-risk prostate cancer. International journal

    Atsushi Takamoto, Ryuta Tanimoto, Kensuke Bekku, Motoo Araki, Takuya Sadahira, Koichiro Wada, Shin Ebara, Norihisa Katayama, Hiroyuki Yanai, Yasutomo Nasu

    International journal of urology : official journal of the Japanese Urological Association   25 ( 5 )   507 - 512   2018.5

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    OBJECTIVES: To determine whether neoadjuvant hormonal therapy improves oncological outcomes of patients with localized prostate cancer treated with permanent brachytherapy. METHODS: Between January 2004 and November 2014, 564 patients underwent transperineal ultrasonography-guided permanent iodine-125 seed brachytherapy. We retrospectively analyzed low- or intermediate-risk prostate cancer based on the National Comprehensive Cancer Network guidelines. The clinical variables were evaluated for influence on biochemical recurrence-free survival, progression-free survival, cancer-specific survival and overall survival. RESULTS: A total of 484 patients with low-risk (259 patients) or intermediate-risk disease (225 patients) were evaluated. Of these, 188 received neoadjuvant hormonal therapy. With a median follow up of 71 months, the 5-year actuarial biochemical recurrence-free survival rates of patients who did and did not receive neoadjuvant hormonal therapy were 92.9% and 93.6%, respectively (P = 0.2843). When patients were stratified by risk group, neoadjuvant hormonal therapy did not improve biochemical recurrence-free survival outcomes in low- (P = 0.8949) or intermediate-risk (P = 0.1989) patients. The duration or type of hormonal therapy was not significant in predicting biochemical recurrence. In a multivariate analysis, Gleason score, pretreatment prostate-specific antigen, clinical T stage, and prostate dosimetry, primary Gleason score and positive core rate were significant predictive factors of biochemical recurrence-free survival, whereas neoadjuvant hormonal therapy was insignificant. Furthermore, neoadjuvant hormonal therapy did not significantly influence progression-free survival, cancer-specific survival or overall survival. CONCLUSIONS: In patients with low- or intermediate-risk disease treated with permanent prostate brachytherapy, neoadjuvant hormonal therapy does not improve oncological outcomes. Its use should be restricted to patients who require prostate volume reduction.

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  • Clinical impact of abdominal fat distribution using 3-D computed tomography volumetry on renal function after renal transplantation

    Mitsui Y, Sadahira T, Maruyama Y, Takamoto A, Wada K, Tanimoto R, Kobayashi Y, Araki M, Watanabe M, Watanabe T, Nasu Y

    The Journal of Urology   199 ( 4S )   e831   2018.4

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  • Acute Inflammatory Syndrome Paradoxically Induced by de novo Purine Inhibitors Synthesis before Renal Transplantation: A Case Report and Review of the Literature

    Maruyama Y, Sadahira T, Mitsui Y, Wada K, Tanimoto R, Nishimura S, Kobayashi Y, Watanabe T, Nasu Y, Araki M

    Transplant Proc   50 ( 3 )   895 - 897   2018.4

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  • Prognostic impact of bleomycin pulmonary toxicity on the outcomes of patients with germ cell tumors

    Maruyama Y, Sadahira T, Mitsui Y, Araki M, Wada K, Tanimoto R, Kobayashi Y, Watanabe M, Watanabe T, Nasu Y

    Med Oncol   35 ( 6 )   453 - 458   2018.4

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  • Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer

    Nobuaki Matsubara, Satsohi Nagamori, Yoshiaki Wakumoto, Hirotsugu Uemura, Go Kimura, Akira Yokomizo, Hiroaki Kikukawa, Atsushi Mizokami, Takeo Kosaka, Naoya Masumori, Yoshihide Kawasaki, Junji Yonese, Yasutomo Nasu, Satoshi Fukasawa, Takayuki Sugiyama, Seigo Kinuya, Makoto Hosono, Iku Yamaguchi, Hirokazu Tsutsui, Hiroji Uemura

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   23 ( 1 )   173 - 180   2018.2

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    Radium-223 dichloride (radium-223) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with bone metastases. This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases.In this open-label, multicenter, phase II study, patients with progressive, symptomatic CRPC and bone metastases were treated with radium-223 (55 kBq/kg, intravenously) in a 4-week cycle for six cycles. The primary endpoint was the percent change in total alkaline phosphatase (ALP) from baseline at 12 weeks. Secondary endpoints included the percent ALP change from baseline to end of treatment (EOT), ALP response rates, percent change in prostate-specific antigen (PSA) from baseline to 12 weeks and EOT, PSA response rates, overall survival (OS), and time to symptomatic skeletal events (SSEs). Adverse events were monitored throughout the study period.Of the 49 Japanese patients (median age 74 years), 28 completed all infusions. Mean percent change in total ALP and PSA from baseline to 12 weeks was -19.3 and +97.4%, respectively. One-year OS and SSE-free rate at the end of active follow-up were 78 and 89%, respectively. The ALP response rate was 31%, while the PSA response rate was 6%. Grade 3/4 treatment-emergent adverse events observed in >= 10% of patients included decreased lymphocyte count (14%), anemia (14%), anorexia (10%), and bone pain (10%).Radium-223 is effective and well tolerated in Japanese patients with CRPC and bone metastases. Results were comparable with the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial.ClinicalTrials.gov NCT01929655.

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  • Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: A randomized, double-blind, placebo-controlled, phase 2 trial.

    Masanori Noguchi, Gaku Arai, Shin Egawa, Chikara Ohyama, Seiji Naito, Kazumasa Matsumoto, Hirotsugu Uemura, Masayuki Nakagawa, Yasutomo Nasu, Masatoshi Eto, Shigetaka Suekane, Tetsuro Sasada, Shigeki Shichijo, Akira Yamada, Tatsuyuki Kakuma, Kyogo Itoh

    JOURNAL OF CLINICAL ONCOLOGY   36 ( 6 )   2018.2

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    DOI: 10.1200/JCO.2018.36.6_suppl.214

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  • Induction of cells with prostate cancer stem-like properties from mouse induced pluripotent stem cells via conditioned medium. Reviewed International journal

    Naijin Xu, Xiezhao Li, Masami Watanabe, Hideo Ueki, Hao Hu, Na Li, Motoo Araki, Koichiro Wada, Abai Xu, Chunxiao Liu, Yasutomo Nasu, Peng Huang

    American journal of cancer research   8 ( 8 )   1624 - 1632   2018

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    Cancer stem cells (CSCs) that closely correlated with tumor growth, metastasis, provide a plausible explanation for chemoresistance and cancer relapse. CSCs are usually isolated and enriched from carcinoma cells, which is inconvenient, low-efficient, and even unreliable. Here, we converted mouse induced pluripotent stem cells (miPSCs) into prostate cancer stem-like cells with carcinoma microenvironment following exposure to conditioned medium (CM) derived from RM9, a mouse prostate cancer cell line. These transformed cells, termed as miPS-RM9CM, displayed CSCs properties, including spheroids morphology and expression of both stemness genes and cancer stem cells surface markers, such as Oct3/4, Sox2, Nanog, Klf-4, c-Myc, CD44, and CD133. In addition, in vivo transplantation experiment was performed to confirm the tumorigenicity. Furthermore, we used the model to assess conventional chemotherapeutic agent, docetaxel. The results showed that miPS-RM9CM cells exhibited increased resistance to docetaxel, however, high susceptibility to the cancer cell stemness inhibitor I (BBI-608). Our current study demonstrates that CM from cultured RM9 cells play a crucial role in the determination of cell fate from miPSCs to cancer stem-like cells and provide a potentially valuable system for the study of CSCs.

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  • Sarcopenia in patients with testicular cancer undergoing chemotherapy :Prognostic impact of psoas major muscle loss

    Mitsui Y, Sadahira T, Maruyama Y, Takanoto A, Wada K, Tanimoto R, Kobayashi Y, Araki M, Watanabe M, Watanabe T, Nasu Y

    European Urology Supplements   17 ( 2 )   e1137 - e1138   2018

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  • Red nodular melanoma of the penile foreskin: A case report and literature review. International journal

    Yuki Maruyama, Takuya Sadahira, Yosuke Mitsui, Koichiro Wada, Ryuta Tanimoto, Yasuyuki Kobayashi, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Molecular and clinical oncology   9 ( 4 )   449 - 452   2018

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    The penis is an extremely rare primary site for malignant melanomas, and the clinical presentation may vary greatly. We herein present the case of a 71-year-old male patient who presented with a 6-year history of two slow growing, asymptomatic red macules on the penile foreskin. On physical examination, the mobility of the foreskin was good, and there was no metastasis on computed tomography and magnetic resonance imaging. The patient underwent segmental circumcision for treatment and histological diagnosis, and the histological examination revealed a malignant melanoma. As cancer cells were identified at the edge of the tissue specimen and computed tomography-positron emission tomography revealed increased uptake of 18F-fluorodeoxyglucose in the penis, wider resection and a right sentinel lymph node biopsy were performed; both specimens came back negative. Two years after the surgery, there has been no evidence of locoregional recurrence or distant metastases. The aim of this report is to alert physicians to include melanoma in the differential diagnosis of red-pigmented lesions of the penile foreskin.

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  • Impact of selective media for detecting fluoroquinolone-insusceptible/extended-spectrum beta-lactamase-producing Escherichia coli before transrectal prostate biopsy Reviewed

    Takuya Sadahira, Koichiro Wada, Motoo Araki, Ayano Ishii, Toyohiko Watanabe, Yoshitsugu Nasu, Masaya Tsugawa, Tadasu Takenaka, Yasutomo Nasu, Hiromi Kumon

    INTERNATIONAL JOURNAL OF UROLOGY   24 ( 12 )   842 - 847   2017.12

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    ObjectivesTo investigate the prevalence of fluoroquinolone-insusceptible and/or extended-spectrum beta-lactamase-producing Escherichia coli colonizing in the male rectum before transrectal prostate biopsy.
    MethodsWe carried out a prospective cohort study of men undergoing transrectal prostate biopsy. CHROMagar Orientation originally supplemented with levofloxacin and CHROMagar Orientation/extended-spectrum beta-lactamase were used for detecting fluoroquinolone-insusceptible and extended-spectrum beta-lactamase-producing Escherichia coli. Rectal specimens were collected before prostate biopsy, and the results of cultures in the selective medium were compared with drug susceptibility measured by standard methods. Targeted prophylactic antimicrobials were administered to patients with drug-resistant Escherichia coli and the incidence of postoperative prostatitis was investigated. In the case of prostatitis, pathogens preoperatively isolated from the rectum and those from urine were compared using pulsed-field gel electrophoresis.
    ResultsRectal colonization of fluoroquinolone-insusceptible or extended-spectrum beta-lactamase-producing Escherichia coli was detected in 217 of 694 (31.3%) and 85 of 640 (13.3%) participants, respectively. The sensitivity and specificity of fluoroquinolone-insusceptible selective media were 96.8% and 88.2%, respectively. A total of 618 participants underwent transrectal prostate biopsy, and postoperative acute prostatitis was observed in four of 618 (0.6%) participants. Escherichia coli strains isolated preoperatively from the rectum and postoperatively from urine were found to be identical.
    ConclusionsThe present findings showed accuracy and performance of the selective media. Screening cultures before transrectal prostate biopsy using selective media seems to be helpful for guiding antibiotic prophylaxis and thus decreasing the rate of post-biopsy acute prostatitis.

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  • Exogenous DKK-3/REIC inhibits Wnt/beta-catenin signaling and cell proliferation in human kidney cancer KPK1 Reviewed

    Jiaqi Xu, Takuya Sadahira, Rie Kinoshita, Shun-Ai Li, Peng Huang, Koichiro Wada, Motoo Araki, Kazuhiko Ochiai, Hirofumi Noguchi, Masakiyo Sakaguchi, Yasutomo Nasu, Masami Watanabe

    ONCOLOGY LETTERS   14 ( 5 )   5638 - 5642   2017.11

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    The third member of the Dickkopf family (DKK-3), also known as reduced expression in immortalized cells (REIC), is a tumor suppressor present in a variety of tumor cells. Regarding the regulation of the Wnt/beta-catenin signaling pathway, exogenous DKK-1 and DKK-2 are reported to inhibit Wnt signaling by binding the associated effectors. However, whether exogenous DKK-3 inhibits Wnt signaling remains unclear. A recombinant protein of human full-length DKK-3 was used to investigate the exogenous effects of the protein in vitro in KPK1 human renal cell carcinoma cells. It was demonstrated that the expression of phosphorylated (p-)beta-catenin (inactive form as the transcriptional factor) was increased in KPK1 cells treated with the exogenous DKK-3 protein. The levels of non-p-beta-catenin (activated form of beta- catenin) were consistently decreased. It was revealed that the expression of transcription factor (TCF) 1 and c-Myc, the downstream transcription factors of the Wnt/beta-catenin signaling pathway, was inhibited following treatment with DKK-3. A cancer cell viability assay confirmed the anti-proliferative effects of exogenous DKK-3 protein, which was consistent with a suppressed Wnt/beta-catenin signaling cascade. In addition, as low-density lipoprotein receptor-related protein 6 (LRP6) is a receptor of DKK-1 and DKK-2 and their interaction on the cell surface inhibits Wnt/beta-catenin signaling, it was examined whether the exogenous DKK-3 protein affects LRP6-mediated Wnt/beta-catenin signaling. The LRP6 gene was silenced and the effects of DKK-3 on the time course of the upregulation of p-beta-catenin expression were subsequently analyzed. Notably, LRP6 depletion elevated the base level of p-beta-catenin; however, there was no significant effect on its upregulation course or expression pattern. These findings indicate that exogenous DKK-3 upregulates p-beta-catenin and inhibits Wnt/beta-catenin signaling in an LRP6-independent manner. Therefore, exogenous DKK-3 protein may inhibit the proliferation of KPK1 cells via inactivating Wnt/beta-catenin signaling.

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  • Ureterolithotripsy for a Ureteral Calculus at the Ureteroureterostomy of a Renal-transplant Recipient Reviewed

    Yosuke Mitsui, Koichiro Wada, Motoo Araki, Takashi Yoshioka, Yuichi Ariyoshi, Shingo Nishimura, Yasuyuki Kobayashi, Katsumi Sasaki, Toyohiko Watanabe, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   71 ( 5 )   449 - 452   2017.10

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    We describe a 40-year-old living-donor renal-transplant recipient who underwent successful ureterolithotripsy. He had been on hemodialysis for &gt;15 years pre-transplant and underwent ureteroureterostomy along with the surgery. One year post-transplant, ultrasound examination demonstrated hydronephrosis, and CT showed a 6-mm ureteral calculus at the ureteroureterostomy site. No pain and no elevated serum creatinine were present. As the ureter was easily accessed, we performed a ureterolithotripsy, which would confirm whether a suture caused the calculus. Despite ureteral tortuosity, laser stone fragmentation succeeded. The calculus was completely removed with an antegrade guidewire. Mild postoperative ureteral stenosis resolved with a temporary ureteral stent without balloon dilation. Ureterolithotripsy is effective even in renal transplant recipients with ureteroureterostomy.

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  • Promising therapeutic efficacy of a novel reduced expression in immortalized cells/dickkopf-3 expressing adenoviral vector for hepatocellular carcinoma Reviewed

    Hiroaki Sawahara, Hidenori Shiraha, Daisuke Uchida, Hironari Kato, Ryo Kato, Atsushi Oyama, Teruya Nagahara, Masaya Iwamuro, Shigeru Horiguchi, Koichiro Tsutsumi, Mari Mandai, Tetsushige Mimura, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Masami Watanabe, Masakiyo Sakaguchi, Akinobu Takaki, Kazuhiro Nouso, Takahito Yagi, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Okada

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   32 ( 10 )   1769 - 1777   2017.10

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    Background and Aim: Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed.
    Methods: Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice.
    Results: REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6).
    Conclusions: Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.

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  • Effects of Cold Ischemia on RNA Stability and Quality of Lung Tissues Based on Standard PREanalytical Code Categorization. International journal

    Takehiro Matsubara, Shuta Tomida, Junichi Soh, Takahiro Uwabo, Yoshiko Mori, Mizuki Morita, Yasutomo Nasu, Susumu Kanazawa, Shinichi Toyooka

    Biopreservation and biobanking   15 ( 5 )   484 - 486   2017.10

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    DOI: 10.1089/bio.2017.0076

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  • Overexpression of REIC/Dkk-3 suppresses the expression of CD147 and inhibits the proliferation of human bladder cancer cells Reviewed

    Yuhei Horikawa, Masami Watanabe, Takuya Sadahirai, Yuichi Ariyoshi, Yasuyuki Kobayashi, Motoo Araki, Koichiro Wada, Kazuhiko Ochiai, Shun-Ai Li, Yasutomo Nasu

    ONCOLOGY LETTERS   14 ( 3 )   3223 - 3228   2017.9

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    Our group previously developed an adenoviral vector encoding the REIC/Dkk-3 gene (Ad-REIC), a tumor suppressor, for cancer gene therapy. The Ad-REIC agent induces apoptosis and inhibits invasion in a number of cancer cell lines; however, the molecular mechanisms underlying its effects remain unclear. Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a key molecule that promotes cancer proliferation and invasion. In order to elucidate the therapeutic mechanism of Ad-REIC, its effect on the expression of CD147 in human bladder cancer KK47 cells was investigated. Treatment with Ad-REIC markedly downregulated the expression of CD147 and significantly inhibited cellular proliferation. Since the expression of CD147 is reported to be under the positive control of mitogen-activated protein kinase (MAPK) signaling and the c-Myc protein, the correlations between the expression of CD147 and the activation of MAPKs or the expression of c-Myc were examined. Unexpectedly, no positive correlation was observed between the level of CD147 and the potential regulators that were assessed, indicating that another signaling pathway is responsible for the downregulation of CD147. The results from the present study demonstrate that Ad-REIC treatment can significantly downregulate the expression of CD147 in bladder cancer cells. Downregulation of the cancer-progression factor CD147 may be a novel mechanism that underlies the therapeutic effects of Ad-REIC treatment.

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  • Robotic Renal Autotransplantation: First Case Outside of North America Reviewed

    Motoo Araki, Koichiro Wada, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Takashi Yoshioka, Yuichi Ariyoshi, Kei Fujio, Atsushi Takamoto, Morito Sugimoto, Katsumi Sasaki, Yasuyuki Kobayashi, Shin Ebara, Hideki Taninishi, Hiroyuki Amano, Masashi Inui, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   71 ( 4 )   351 - 355   2017.8

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    A 38-year-old woman with a 2.7-cm left ureteral stenosis requiring chronic ureteral stent exchange elected to undergo robotic renal autotransplantation. Left ureteropelvic junction obstruction (UPJO) was also suspected. Robotic donor nephrectomy contributed to the fine dissection for desmoplastic changes. The kidney was removed through a Gelport and examined on ice. UPJO was not seen. An end-to-side robotic anastomosis was created between the renal and external iliac vessels. The console time was 507 min, and the warm ischemia time was 4 min 5 sec. She became stent-free. Robotic renal autotransplantation is a new, minimally invasive approach to renal preservation.

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  • Robust cancer-specific gene expression by a novel cassette with hTERT and CMV promoter elements Reviewed

    Masakiyo Sakaguchi, Takuya Sadahira, Hideo Ueki, Rie Kinoshita, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Yasutomo Nasu, Kazuhiko Ochiai, Hiromi Kumon, Nam-Ho Huh, Masami Watanabe

    ONCOLOGY REPORTS   38 ( 2 )   1108 - 1114   2017.8

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    We developed and validated a novel hTERT/CMV promoter element-driven gene expression cassette that can robustly enhance cancer-specific gene expression. The following gene expressional elements were located in tandem within the plasmid construct: [hTERT core promoter, cytomegalovirus (CMV) minimized promoter, RU5' sequence, an inserted gene, BGH polyA, hTERT enhancer]; this is hereafter referred to as the hT/Cm-R-hT construct. Using various human cancer cell lines and normal cells, the cancer-specific transcription of the green fluorescent protein (GFP) gene was examined by western blotting and fluorescence microscopy. Cancer-specific gene expression was robustly achieved in the hT/Cm-R-hT plasmid in comparison to the other control hT/Cm-driven construct. Notably, the expression level of GFP observed in the hT/Cm-RhT-driven construct was superior to that of the control plasmid with the conventional CMV promoter in HEK293 cells, which are known to possess higher hTERT activity than normal cells. We next examined the availability of hT/Cm-R-hT in detecting the target GFP expressing cancer cells from human peripheral blood mononuclear cells (PBMCs). The hT/Cm-R-hT plasmid successfully induced cancer-specific gene expression; the robust expression of GFP was observed in target HeLa cancer cells, whereas GFP was not visibly expressed in normal PBMCs. The plasmid allowed for the selective visualization of viable HeLa cancer cells in mixed cell cultures containing up to 10000-fold more PBMCs. These findings indicate that the hT/Cm-R-hT expressional system is a valuable tool for detecting viable cancer cells mixed with normal cells. The current system can therefore be applied to the in vitro detection of cancer cells that are disseminated in the blood and other types of body fluid in vivo. Since the current system can also be applied to other types of vectors, including virus vectors, this approach using the hTERT promoter-based construct is expected to become a valuable tool for enhancing cancer specific gene expression.

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  • Antimicrobial susceptibilities of Chlamydia trachomatis isolated from the urethra and pharynx of Japanese males Reviewed

    Seiji Kai, Koichiro Wada, Takuya Sadahira, Motoo Araki, Ayano Ishii, Toyohiko Watanabe, Koichi Monden, Satoshi Uno, Tohru Araki, Yasutomo Nasu

    JOURNAL OF INFECTION AND CHEMOTHERAPY   23 ( 8 )   512 - 516   2017.8

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    Objectives: Sexually transmitted infections due to Chlamydia trachomatis (C. trachomatis) are a worldwide public health problem. The aim of this study was to investigate the drug susceptibilities of C. trachomatis strains isolated from the urethra and pharynx of Japanese males.
    Methods: Urethral and pharyngeal swabs were collected between 2013 and 2014 from Japanese males with urethritis. Using a McCoy cell line, 18 chlamydial strains were isolated from urethra in 18 patients and 7 from the pharynx in 7 of the 18 patients. The minimum inhibitory concentrations (MICs) of levofloxacin (LVFX) and azithromycin (AZM) were measured using the standard method of the Japanese Society of Chemotherapy.
    Results: The MICs of LVFX and AZM against urethral chlamydial strains were 0.125-0.5 mu g/mL and 0.125-0.25 mu g/mL, respectively. In pharyngeal strains, the MICs of LVFX and AZM were 0.125-0.25 mu g/mL and 0.125-0.25 mu g/mL, respectively. In 7 patients with chlamydial strains isolated from both the urethra and pharynx, the MICs of LVFX between these strains were identical in 3 of 6 patients (no growth was observed for one pharyngeal strain), while the MICs of AZM between these strains were identical in all 6 patients (not performed for one patient).
    Conclusions: Our data suggest that C. trachomatis strains isolated from the urethra and pharynx of Japanese males are susceptible to LVFX and AZM. Although measuring the MICs of chlamydial strains is labor intensive, it is a significant surveillance tool for treating chlamydial infections and preventing the spread of STIs. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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  • Expression of tumor suppressor REIC/Dkk-3 by a newly improved adenovirus vector with insertion of a hTERT promoter at the 3'-side of the transgene Reviewed

    Endy Widya Putranto, Rie Kinoshita, Masami Watanabe, Takuya Sadahira, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Ken Kataoka, Yusuke Inoue, I. Made Winarsa Ruma, I. Wayan Sumardika, Chen Youyi, Miyoko Kubo, Yoshihiko Sakaguchi, Kenji Saito, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh, Masakiyo Sakaguchi

    ONCOLOGY LETTERS   14 ( 1 )   1041 - 1048   2017.7

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    Reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3) overexpression, induced using an adenovirus (Ad)-REIC, has been revealed to have a dramatic therapeutic effect on multiple types of cancer. To achieve an improved therapeutic effect from Ad-REIC on cancer, our group previously developed an enhanced gene expression system, the C-TSC cassette [cytomegalovirus (CMV)-RU5' located upstream (C); another promoter unit composed of triple tandem promoters, human telomerase reverse transcriptase (hTERT), simian virus 40 and CMV, located downstream of the cDNA (TSC); plus a polyadenylation (polyA) signal]. When applied to the conventional Ad-REIC, this novel system induced the development of an enhanced product, Ad-C-TSC-REIC, which exhibited a noticeable anticancer effect. However, there were difficulties in terms of Ad-C-TSC-REIC productivity in HEK293 cells, which are a widely used donor cell line for viral production. Productivity of Ad-C-TSC-REIC was significantly reduced compared with the conventional Ad-REIC, as the Ad-C-TSC-REIC had a significantly higher ability to induce apoptotic cell death of not only various types of cancer cell, but also HEK293 cells. The present study aimed to overcome this problem by modifying the C-TSC structure, resulting in an improved candidate: A C-T cassette (C: CMV-RU5' located upstream; T: another promoter unit composed of a single hTERT promoter, located downstream of the cDNA plus a polyA signal), which demonstrated gene expression comparable to that of the C-TSC system. The improved adenovirus REIC/Dkk-3 product with the C-T cassette, named Ad-C-T-REIC, exhibited a higher expression level of REIC/Dkk3, similar to that of Ad-C-TSC-REIC. Notably, the vector mitigated the cell death of donor HEK293 cells, resulting in a higher rate of production of its adenovirus. These results indicated that Ad-C-T-REIC has the potential to be a useful tool for application in cancer gene therapy.

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  • Successful microscopic renal autotransplantation for left renal aneurysm associated with segmental arterial mediolysis. International journal

    Takashi Yoshioka, Motoo Araki, Yuichi Ariyoshi, Koichiro Wada, Noriyuki Tanaka, Yasutomo Nasu

    Journal of vascular surgery   66 ( 1 )   261 - 264   2017.7

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    Segmental arterial mediolysis (SAM) is an uncommon, nonarteriosclerotic vascular disease. SAM is characterized by lysis of arterial media and can lead to aneurysm formation. The renal arteries are the third most common arteries associated with SAM. We report the case of a 32-year-old man with left renal artery aneurysm associated with SAM. We successfully performed left renal autotransplantation using microscopic vascular reconstruction. SAM is characterized by vascular fragility; therefore, microscopic surgery is favorable for treating aneurysms associated with SAM.

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  • The Downregulation of the Expression of CD147 by Tumor Suppressor REIC/Dkk-3, and Its Implication in Human Prostate Cancer Cell Growth Inhibition Reviewed

    Akihiro Mori, Masami Watanabe, Takuya Sadahira, Yasuyuki Kobayashi, Yuichi Ariyoshi, Hideo Ueki, Koichiro Wada, Kazuhiko Ochiai, Shun-Ai Li, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   71 ( 2 )   135 - 142   2017.4

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    The cluster of differentiation 147 (CD147), also known as EMMPRIN, is a key molecule that promotes cancer progression. We previously developed an adenoviral vector encoding a tumor suppressor REIC/Dkk-3 gene (Ad-REIC) for cancer gene therapy. The therapeutic effects are based on suppressing the growth of cancer cells, but, the underlying molecular mechanism has not been fully clarified. To elucidate this mechanism, we investigated the effects of Ad-REIC on the expression of CD147 in LNCaP prostate cancer cells. Western blotting revealed that the expression of CD147 was significantly suppressed by Ad-REIC. Ad-REIC also suppressed the cell growth of LNCaP cells. Since other researchers have demonstrated that phosphorylated mitogen-activated protein kinases (MAPKs) and c-Myc protein positively regulate the expression of CD147, we investigated the correlation between the CD147 level and the activation of MAPK and c-Myc expression. Unexpectedly, no positive correlation was observed between CD147 and its possible regulators, suggesting that another signaling pathway was involved in the downregulation of CD147. This is the first study to show the downregulation of CD147 by Ad-REIC in prostate cancer cells. At least some of the therapeutic effects of Ad-REIC may be due to the downregulation of the cancer-progression factor, CD147.

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  • Clinical pharmacokinetics of oral levofloxacin and sitafloxacin in epididymal tissue Reviewed

    Takuya Sadahira, Koichiro Wada, Kazuro Ikawa, Norifumi Morikawa, Hiroaki Kurahashi, Takashi Yoshioka, Yuichi Ariyoshi, Yasuyuki Kobayashi, Motoo Araki, Ayano Ishii, Masami Watanabe, Shinya Uehara, Toyohiko Watanabe, Yasutomo Nasu

    JOURNAL OF INFECTION AND CHEMOTHERAPY   23 ( 4 )   214 - 217   2017.4

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    Objectives: This study aimed to investigate the penetration of fluoroquinolones into human epididymal tissue.
    Methods: The penetration of levofloxacin (LVFX) 500 mg or sitafloxacin (STFX) 100 mg into epididymal tissue was examined. Patients with prostate cancer who were referred for orchiectomy were included. LVFX 500 mg (n = 9) or STFX 100 mg (n = 9) was administered orally 1 h before orchiectomy, and 0.5 g of epididymal tissue and blood samples were collected simultaneously during surgery. Drug concentrations were measured by high-performance liquid chromatography, and patient characteristics and adverse events were analyzed.
    Results: The mean ratio of the epididymal concentration to the serum concentration was 1.48 +/- 0.45 for LVFX and 1.54 +/- 0.81 for STFX. For LVFX, the simulated curves estimated the following: maximum concentrations (Cmax) of 8.84 mu g/ml in serum and 14.1 mu g/g in epididymal tissue and area under the concentration-time curve for 24 h (AUC(24)) of 68.5 mu g h/ml in serum and 108.9 mu g h/g in epididymal tissue. For STFX, the Cmax was 1.22 mu g/ml in serum and 1.66 mu g/g in epididymal tissue, and the AUC24 was 9.58 mu g h/ml in serum and 13.1 mu g h/g in epididymal tissue. Neither treatment-related adverse events nor postoperative urogenital infections were observed.
    Conclusions: The results of this study suggest that oral administration of LVFX 500 mg or STFX 100 mg achieves effective epididymal concentrations for treatment of epididymitis. (C) 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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  • A Combination Therapy of Partial Nephrectomy and Cryoablation Achieved Good Cancer Control and Renal Function in Bilateral Synchronous Renal Cell Carcinoma Reviewed

    Atsushi Takamoto, Motoo Araki, Koichiro Wada, Morito Sugimoto, Yasuyuki Kobayashi, Katsumi Sasaki, Toyohiko Watanabe, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   71 ( 2 )   187 - 190   2017.4

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    We report the case of a 58-year-old Japanese man with bilateral synchronous renal cell carcinoma (RCC). The diameters of the right and left tumors were 56 and 69 mm, respectively. Both tumors were endophytic. Cryoablation with prophylactic embolization was performed for the left tumor, and 1 month later, a right open partial nephrectomy was performed. No recurrence was observed during a 16-month follow-up, and the serum creatinine level has been stable. The prognosis of bilateral synchronous RCC is better than that of dialysis patients. The novel approach of combining cryoablation and partial nephrectomy can achieve good cancer control and renal function in bilateral RCC.

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  • Evaluation of Urinary Stone Composition and Differentiation between Urinary Stones and Phleboliths Using Single-source Dual-energy Computed Tomography.

    Nanako Ogawa, Shuhei Sato, Kentaro Ida, Katsuya Kato, Yuichi Ariyoshi, Koichiro Wada, Yasutomo Nasu, Susumu Kanazawa

    Acta medica Okayama   71 ( 2 )   91 - 96   2017.4

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    The aim of this study was to investigate the utility of single-source dual-energy computed tomography (SS-DECT) composition analysis in characterizing different types of urinary stones and differentiating them from phleboliths. This study included 29 patients with urinary stones who were scheduled for surgery. All patients were scanned, first using single-energy computed tomography acquisition and then DECT acquisition on SS-DECT. Dual-energy data were archived to a Gemstone spectral imaging (GSI) viewer (GE Healthcare, Milwaukee, WI, USA). Hounsfield units (HU) and effective atomic numbers (Zeff) were estimated using the GSI viewer. The results of dual-energy analysis were compared with the biochemical constitution of the stones. The chemical analysis determined that the stones included 32 calcium-based, 6 cystine and 1 struvite stone. Both HU and Zeff values were helpful in differentiating calcium-based stones from cystine and struvite stones and phleboliths. The Zeff values of phleboliths were significantly higher than those for struvite and cystine stones, whereas it was difficult to distinguish phleboliths from struvite and cystine stones using the HU values. Composition analysis using SS-DECT is helpful for distinguishing urinary stone types and discriminating phleboliths from urinary stones. Zeff values may be more useful than HU values for differentiating urinary stones from phleboliths.

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  • Impact of Surgeon and Hospital Volume on the Safety of Robot-Assisted Radical Prostatectomy: A Multi-Institutional Study Based on a National Database

    Yosuke Hirasawa, Kunihiko Yoshioka, Yasutomo Nasu, Masumi Yamamoto, Shiro Hinotsu, Atsushi Takenaka, Masato Fujisawa, Ryoichi Shiroki, Keiichi Tozawa, Satoshi Fukasawa, Akira Kashiwagi, Katsunori Tatsugami, Masaaki Tachibana, Toshiro Terachi, Momokazu Gotoh

    Urologia Internationalis   98 ( 3 )   334 - 342   2017.4

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    © 2017 S. Karger AG, Basel. Introduction: We aimed to perform a multi-institutional study using a national database led by the Japanese Society of Endourology to investigate the effect of surgeon or hospital volume on the safety of robot-assisted radical prostatectomy (RARP). Materials and Methods: Clinical data of 3,214 patients who underwent RARP for the treatment of clinically localized prostate cancer between April 2012 and March 2013 in Japan were evaluated. Surgical outcomes and all intra-A nd perioperative complications were collected. Results: The intraoperative complication rate was 0.56%. In a total number of 241 patients, 261 perioperative complications were observed. The following percentages of patients presented the Clavien-graded complications: 7.2%, grades 1-2; 0.84%, grade 3; and 0.093%, grade 4a. No cases of multiple organ dysfunction or death (grades 4b and 5) were found. Multivariable logistic regression analysis showed that the hospital volume (OR 3.6; p = 0.010) for intraoperative complications and surgeon volume (OR 0.19; p < 0.0001) and extended lymph node discectomy (OR 3.9; p < 0.0001) for perioperative complications were significant independent risk factors. Conclusions: Hospital volume for intraoperative complications and surgeon volume and extended lymph node dissection for perioperative complications were significantly associated with increased risk of each complication in RARP.

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  • Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma Reviewed

    Xiezhao Li, Peng Xu, Chongshan Wang, Naijin Xu, Abai Xu, Yawen Xu, Takuya Sadahira, Motoo Araki, Koichiro Wada, Eiji Matsuura, Masami Watanabe, Junxia Zheng, Pinghua Sun, Peng Huang, Yasutomo Nasu, Chunxiao Liu

    ONCOTARGET   8 ( 13 )   21177 - 21186   2017.3

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    Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.

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  • Reality of nerve sparing and surgical margins in surgeons’ early experience with robot-assisted radical prostatectomy in Japan

    Katsunori Tatsugami, Kunihiko Yoshioka, Ryoichi Shiroki, Masatoshi Eto, Yasushi Yoshino, Keiichi Tozawa, Satoshi Fukasawa, Masato Fujisawa, Atsushi Takenaka, Yasutomo Nasu, Akira Kashiwagi, Momokazu Gotoh, Toshiro Terachi

    International Journal of Urology   24 ( 3 )   191 - 196   2017.3

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    © 2017 The Japanese Urological Association Objective: To analyze nerve sparing performance at an early stage of robot-assisted radical prostatectomy, and the correlation between the surgeons’ experience and the risk of a positive surgical margin in patients treated with robot-assisted radical prostatectomy. Methods: Patients’ records from January 2009 to March 2013 were retrospectively reviewed, and 3469 patients with localized prostate cancer were identified at 45 institutions. Individual surgeon's experience with nerve sparing was recorded as the number of nerve sparing cases among total robot-assisted radical prostatectomies beginning with the first case during which nerve sparing was carried out. Patients were selected by propensity score matching for nerve sparing, and predictive factors of positive surgical margins were analyzed in patients with and without positive surgical margins. Results: A total of 152 surgeons were studied, and the median number of robot-assisted radical prostatectomy cases for all surgeons was 21 (range 1–511). In all, 54 surgeons (35.5%) undertook nerve sparing during their first robot-assisted radical prostatectomy case. For 2388 patients selected with (1194) and without (1194) nerve sparing, predictive factors for positive surgical margin were high initial prostate-specific antigen level (P < 0.0001), high biopsy Gleason score (P = 0.0379), presence of neoadjuvant hormone therapy (P = 0.0002) and surgeon's experience with >100 cases (P = 0.0058). Thus, nerve sparing was not associated with positive surgical margins. Conclusion: The surgeon's experience influences the occurrence of positive surgical margins, although a considerable number of surgeons carried out nerve sparing during their early robot-assisted radical prostatectomy cases. Surgeons should consider their own experience and prostate cancer characteristics before carrying out a nerve sparing robot-assisted radical prostatectomy.

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  • Interfractional Seminal Vesicle Motion Relative to the Prostate Gland for Image-guided Radiotherapy for Prostate Cancer with/without Androgen Deprivation Therapy: A Retrospective Cohort Study Reviewed

    Takahiro Waki, Kuniaki Katsui, Toshiharu Mitsuhashi, Takeshi Ogata, Norihisa Katayama, Mitsuhiro Takemoto, Yasutomo Nasu, Hiromi Kumon, Susumu Kanazawa

    ACTA MEDICA OKAYAMA   71 ( 1 )   31 - 39   2017.2

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    We investigated differences in seminal vesicle (SV) length and interfractional SV motion relative to the prostate gland in prostate cancer patients. We compared 32 patients who received androgen deprivation therapy (ADT) before radiotherapy with 12 patients receiving radiotherapy alone at Okayama University Hospital in August 2008-July 2011. We examined the right and left SVs' length and motion by computed tomography (CT) to determine the ADT's effects and analyzed 347 CT scans in a multiple linear regression model. The ADT patients' SV length was significantly shorter than the non-ADT patients'. The differences in right and left SV lengths between the ADT and non-ADT patients were 6.8 mm (95% CI 2.0-11.7 mm) and 7.2 mm (95% CI 3.111.3 mm) respectively in an adjusted regression model. SV motion did not differ between the ADT and nonADT patients in terms of interfractional motion of the SV tips and the SVs' center relative to the prostate gland. The ADT patients had significantly shorter SVs compared to the non-ADT patients, but no difference in SV motion was observed. SV interfractional motion should thus be compensated using the same planning margins, regardless of whether ADT is used.

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  • Efficacy and safety of 3 day versus 7 day cefditoren pivoxil regimens for acute uncomplicated cystitis: multicentre, randomized, open-label trial Reviewed

    Takuya Sadahira, Koichiro Wada, Motoo Araki, Ayano Ishii, Atsushi Takamoto, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

    JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY   72 ( 2 )   529 - 534   2017.2

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    Background: Fluoroquinolone-non-susceptible Escherichia coli isolated from patients with acute uncomplicated cystitis are a matter of increasing concern. Cefditoren pivoxil is an oral, beta-lactamase-stable, extended-spectrum cephalosporin that is effective against fluoroquinolone-non-susceptible bacteria.
    Objectives: To evaluate the clinical and microbiological efficacies of cefditoren pivoxil against acute uncomplicated cystitis and to determine the optimal duration of cefditoren pivoxil treatment.
    Methods: We compared 3 and 7 day regimens of cefditoren pivoxil in a multicentre, randomized, open-label study.
    Results: A total of 104 female patients with acute uncomplicated cystitis were enrolled and randomized into 3 day (n = 51) or 7 day (n = 53) treatment groups. At first visit, 94 bacterial strains were isolated from the 104 participants of which 81.7% (85/104) were E. coli. Clinical and microbiological efficacies were evaluated 59 days following administration of the final dose of cefditoren pivoxil. The clinical efficacies of the 3 and 7 day groups were 90.9% (40/44) and 93.2% (41/44), respectively (P = 1.000). The microbiological efficacies of the 3 and 7 day groups were 82.5% (33/40) and 90.2% (37/41), respectively (P = 0.349). There were no adverse events due to cefditoren pivoxil treatment, with the exception of a mild allergic reaction in one patient, after which the cefditoren pivoxil was exchanged for another antimicrobial.
    Conclusions: Cefditoren pivoxil is safe and effective for uncomplicated cystitis, with no significant differences in clinical and microbiological efficacies between 3 and 7 day regimens.

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  • The Prostate in Female? Clear Cell Adenocarcinoma in a Female Urethral Diverticulum Reviewed

    Takuya Sadahira, Yuuki Maruyama, Motoo Araki, Yasuyuki Kobayashi, Toyohiko Watanabe, Yasutomo Nasu

    UROLOGY   99   E25 - E26   2017.1

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    Urethral diverticular clear cell adenocarcinoma in a female patient is extremely rare. This tumor sometimes displays a characteristic image on magnetic resonance imaging, surrounding the urethra like the prostate does in men. We report a patient with this tumor who underwent cystourethrectomy and ileal conduit diversion. We think that imaging studies could be useful to make the appropriate diagnosis. UROLOGY 99: e25-e26, 2017. (C) 2016 Elsevier Inc.

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  • Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies Reviewed

    Ken Suzawa, Kazuhiko Shien, Huang Peng, Masakiyo Sakaguchi, Masami Watanabe, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Shuta Tomida, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Hiromi Kumon, Shinichiro Miyoshi, Shinichi Toyooka

    ANTICANCER RESEARCH   37 ( 1 )   301 - 307   2017.1

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    Background: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress. Materials and Methods: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors. Results: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors. Conclusion: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.

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  • Diagnostic Ureteroscopy for Cases Clinically Suspected of Carcinoma in Situ of the Upper Urinary Tract Reviewed

    Katsumi Sasaki, Koichiro Wada, Motoo Araki, Yasuyuki Kobayashi, Morito Sugimoto, Shin Ebara, Toyohiko Watanabe, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   71 ( 3 )   227 - 232   2017

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    We elucidate the fate of cases clinically suspected of carcinoma in situ (Cis) of the upper tract with serial ureteroscopy. Of 143 patients who underwent ureteroscopy for suspected upper tract urothelial carcinoma (UTUC) between January 2008 and February 2016, 12 cases with consistently positive urine cytology and poorly detectable upper-tract malignancies by imaging were reviewed. In these 12 patients, 19 ureteroscopy procedures (25 renal units) were performed. Vesical random biopsy was performed before the 1st ureteroscopy to exclude malignancy of the bladder in all 12 cases. Median follow-up was 42 (13-67) months. Positive biopsy results at the 1st ureteroscopy were obtained in 3 (25%) patients and all were diagnosed wth Cis of the upper tract. Two (17%) of 9 patients who were negative or inconclusive at the 1st ureteroscopy were finally diagnosed as UTUC, but plural ureteroscopy procedures were needed for the diagnoses in both. Carcinoma of the bladder appeared in 5 (42%) patients during follow-up, despite the earlier ruling out of vesical malignancy. Four (33%) of those 5 patients never developed upper-tract urothelial carcinoma during follow-up. Caution is required before undertaking radical surgery for cases clinically suspected of Cis of the upper tract. In our experience, only 42% of such patients developed UTUC; another 33% eventually developed carcinoma of the bladder without UTUC.

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  • Value of percutaneous needle biopsy of small renal tumors in patients referred for cryoablation Reviewed

    Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Jun Sakurai, Yusuke Matsui, Motoo Araki, Yasutomo Nasu, Susumu Kanazawa

    MINIMALLY INVASIVE THERAPY & ALLIED TECHNOLOGIES   26 ( 2 )   86 - 91   2017

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    Purpose: To retrospectively evaluate the safety and diagnostic yield of needle biopsy of small renal tumors, and the clinical consequences of performing needle biopsy in patients referred for percutaneous cryoablation before their treatment.
    Material and methods: Biopsy was performed for 120 tumors (mean diameter, 2.2 cm) in 119 patients. All procedures were divided into diagnostic and non-diagnostic biopsies. Various variables were compared between the two groups. All cryoablation procedures were divided into two groups: procedures with or without simultaneous biopsy. The rates of benign or non-diagnostic tumors in each group were compared.
    Results: After performing 120 initial and eight repeat biopsies, Grade 1 bleedings occurred in 44 cases. Six tumors were non-diagnostic and 114 were pathologically diagnosed. There were no significant variables between the diagnostic and non-diagnostic biopsies. Unnecessary cryoablation was avoided in nine benign lesions by performing biopsy in advance. Cryoablation performed simultaneously with biopsy included significantly more benign or non-diagnostic tumors than cryoablation performed after biopsy (15.2% vs. 1.4%; p =.01).
    Conclusions: Percutaneous biopsy of small renal tumors referred for cryoablation was a safe procedure with high diagnostic yield. The confirmation of pathological diagnosis prior to cryoablation is necessary because patients with benign tumors can avoid unnecessary treatment.

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  • Development of a Novel “Optical Pu+C2:F23ncture Needle” Using Ultrathin High-Definition Image Guide System for Percutaneous Nephrolithotomy

    Tanimoto R, Wada K, Sasaki K, Sadahira T, Takamoto A, Araki M, Kobayashi K, Watanabe T, Nasu Y, Kumon H

    Videourology   31 ( 5 )   2017

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  • The assessment of renal cortex and parenchymal volume using automated CT volumetry for predicting renal function after donor nephrectomy.

    Yosuke Mitsui, Takuya Sadahira, Motoo Araki, Koichiro Wada, Ryuta Tanimoto, Yuichi Ariyoshi, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Clinical and experimental nephrology   22 ( 2 )   1 - 6   2017

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    BACKGROUND: Contrast-enhanced CT is necessary before donor nephrectomy and is usually combined with a Tc-99m-mercapto-acetyltriglycine (MAG3) scan to check split renal function (SRF). However, all transplant programs do not use MAG3 because of its high cost and exposure to radiation. We examined whether CT volumetry of the kidney can be a new tool for evaluating SRF. METHODS: Sixty-three patients underwent live donor nephrectomy. Patients without a 1.0 mm slice CT or follow-up for <12 months were excluded leaving 34 patients' data being analyzed. SRF was measured by MAG3. Split renal volume (SRV) was calculated automatically using volume analyzer software. The correlation between SRF and SRV was examined. The association between the donor's postoperative estimated glomerular filtration rate (eGFR) and predicted eGFR calculated by MAG3 or CT volumetry was analyzed at 1, 3, and 12 months post nephrectomy. RESULTS: Strong correlations were observed preoperatively in a Bland-Altman plot between SRF measured by MAG3 and either CT cortex or parenchymal volumetry. In addition, eGFR after donation correlated with SRF measured by MAG3 or CT volumetry. The correlation coefficients (R) for eGFR Mag3 split were 0.755, 0.615, and 0.763 at 1, 3 and 12 months, respectively. The corresponding R values for cortex volume split were 0.679, 0.638, and 0.747. Those for parenchymal volume split were 0.806, 0.592, and 0.764. CONCLUSION: Measuring kidney by CT volumetry is a cost-effective alternative to MAG3 for evaluating SRF and predicting postoperative donor renal function. Both cortex and parenchymal volumetry were similarly effective.

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  • Ureterolysis with omental wrap for bilateral hydronephrosis secondary to retroperitoneal fibrosis

    Hironori Kojima, Motoo Araki, Kei Fujio, Takashi Yoshioka, Akihiro Mori, Atsushi Takamoto, Yuhei Horikawa, Morito Sugimoto, Koichiro Wada, Katsumi Sasaki, Yasuyuki Kobayashi, Shin Ebara, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    Nishinihon Journal of Urology   79 ( 1 )   12 - 15   2017

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  • Impact of a robotic surgical system on treatment choice for men with clinically organ-confined prostate cancer.

    Takashi Kobayashi, Kent Kanao, Motoo Araki, Naoki Terada, Yasuyuki Kobayashi, Atsuro Sawada, Takahiro Inoue, Shin Ebara, Toyohiko Watanabe, Tomomi Kamba, Makoto Sumitomo, Yasutomo Nasu, Osamu Ogawa

    International journal of clinical oncology   23 ( 2 )   1 - 6   2017

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    BACKGROUND: Introducing a new surgical technology may affect behaviors and attitudes of patients and surgeons about clinical practice. Robot-assisted laparoscopic radical prostatectomy (RALP) was approved in 2012 in Japan. We investigated whether the introduction of this system affected the treatment of organ-confined prostate cancer (PCa) and the use of radical prostatectomy (RP). METHODS: We conducted a retrospective multicenter study on 718 patients with clinically determined organ-confined PCa treated at one of three Japanese academic institutions in 2011 (n = 338) or 2013 (n = 380). Two patient groups formed according to the treatment year were compared regarding the clinical characteristics of PCa, whether referred or screened at our hospital, comorbidities and surgical risk, and choice of primary treatment. RESULTS: Distribution of PCa risk was not changed by the introduction of RALP. Use of RP increased by 70% (from 127 to 221 cases, p < 0.0001), whereas the number of those undergoing radiotherapy or androgen deprivation therapy decreased irrespective of the disease risk of PCa. Increased use of RP (from 34 to 100 cases) for intermediate- or high-risk PCa patients with mild perioperative risk (American Society of Anesthesiologists score 2) accounted for 70% of the total RP increase, whereas the number of low- or very low-risk PCa patients with high comorbidity scores (Charlson Index ≥ 4) increased from 8 to 25 cases, accounting for 18%. Use of expectant management (active surveillance, watchful waiting) in very low-risk PCa patients was 15% in 2011 and 12% in 2013 (p = 0.791). CONCLUSIONS: Introduction of a robotic surgical system had little effect on the risk distribution of PCa. Use of RP increased, apparently due to increased indications in patients who are candidates for RP but have mild perioperative risk. Although small, there was an increase in the number of RPs performed on patients with severe comorbidities but with low-risk or very low-risk PCa.

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  • Dynamin2 GTPase contributes to invadopodia formation in invasive bladder cancer cells Reviewed

    Yubai Zhang, Maya Nolan, Hiroshi Yamada, Masami Watanabe, Yasutomo Nasu, Kohji Takei, Tetsuya Takeda

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   480 ( 3 )   409 - 414   2016.11

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    Cancer cell invasion is mediated by actin-based membrane protrusions termed invadopodia. Invadopodia consist of "core" F-actin bundles associated with adhesive and proteolytic machineries promoting cell invasion by degrading extracellular matrix (ECM). Formation of the F-actin core in invadopodia is regulated by various actin-binding proteins including Arp2/3 complex and cortactin. Dynamin GTPase localizes to the invadopodia and is implicated in cancer cell invasion, but its precise role at the invadopodia remained elusive.
    In this study, we examined the roles of dynamin at the invadopodia of bladder cancer cells. Although all three dynamin isoforms (dynamin1, 2 and 3) are expressed in human bladder cancer cell line T24, only dynamin2 localizes to the invadopodia. Inhibition of dynamin2 function, using either RNA interference (RNAi) or the dynamin specific inhibitor Dynasore, caused defects in invadopodia formation and suppressed invasive activity of 124 bladder cancer cells. Structure-function analysis using dynamin2 deletion fragments identified the proline/arginine-rich domain (PRD) of dynamin2 as indispensable for invadopodia formation and invasiveness of 124 cells. Thus, dynamin2 contributes to bladder cancer invasion by controlling invadopodia formation in bladder cancer cells and may prove a valuable therapeutic target. (C) 2016 Elsevier Inc. All rights reserved.

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  • Adenovirus vector carrying REICIDKK-3 gene: neoadjuvant intraprostatic injection for high-risk localized prostate cancer undergoing radical prostatectomy Reviewed

    H. Kumon, Y. Ariyoshi, K. Sasaki, T. Sadahira, M. Araki, S. Ebara, H. Yanai, M. Watanabe, Y. Nasu

    CANCER GENE THERAPY   23 ( 11 )   400 - 409   2016.11

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    As the First-In-Human study of in situ gene therapy using an adenovirus vector carrying the human REIC (reduced expression in immortalized cell)/Dkk-3 gene (Ad-REIC), we conducted neoadjuvant intraprostatic injections in patients with high-risk localized prostate cancer undergoing radical prostatectomy (RP). Patients with recurrence probability of 35% or more within 5 years following RP, as calculated by Kaftan's nomogram, were enrolled. Patients received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. After confirming the safety of the therapeutic interventions with initially planned three escalating doses of 1.0 x 10(10), 1.0 x 10(11) and 1.0 x 10(12) viral particles (vp) in 1.0-1.2 ml (n=3, 3 and 6), an additional higher dose of 3.0 x 10(12) vp in 3.6 ml (n=6) Was further studied. All four DLs including the additional dose level-4 (DL-4) were feasible with no adverse events, except for grade 1 or 2 transient fever. Laboratory toxicities were grade 1 or 2 elevated aspartate transaminase/alanine transaminase (n=4). Regarding antitumor activities, cytopathic effects (tumor degeneration With cytolysis and pyknosis) and remarkable tumor-infiltrating lymphocytes in the targeted tumor areas were detected in a clear dose-dependent manner. Consequently, biochemical recurrence-free survival in DL-4 was significantly more favorable than in patient groups DL-1+2+2:

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  • A Phase II Clinical Trial Evaluating the Preventive Effectiveness of Lactobacillus Vaginal Suppositories in Patients with Recurrent Cystitis Reviewed

    Koichiro Wada, Shinya Uehara, Ayano Ishii, Takuya Sadahira, Masumi Yamamoto, Ritsuko Mitsuhata, Atsushi Takamoto, Motoo Araki, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Katsuyuki Hotta, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   70 ( 4 )   299 - 302   2016.8

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    Urinary tract infections (UTIs) are the most common bacterial infections in women, and many patients experience frequent recurrence. The aim of this report is to introduce an on-going prospective phase II clinical trial performed to evaluate the preventive effectiveness of Lactobacillus vaginal suppositories for prevention of recurrent cystitis. Patients enrolled in this study are administered vaginal suppositories containing the GAI 98322 strain of Lactobacillus crispatus every 2 days or 3 times a week for one year. The primary endpoint is recurrence of cystitis and the secondary endpoints are adverse events. Recruitment began in December 2013 and target sample size is 20 participants.

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  • The Efficacy of Rituximab in High-risk Renal Transplant Recipients Reviewed

    Motoo Araki, Koichiro Wada, Yosuke Mitsui, Risa Kubota, Takashi Yoshioka, Yuichi Ariyoshi, Yasuyuki Kobayashi, Masashi Kitagawa, Katsuyuki Tanabe, Hiroshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Katsuyuki Hotta, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   70 ( 4 )   295 - 297   2016.8

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    Although graft survival following renal transplantation (RTx) has improved, outcomes following highrisk RTx are variable. Preexisting antibodies, including donor-specific antibodies (DSA), play an important role in graft dysfunction and survival. We have designed a study to investigate the safety and efficacy of anti-CD20 monoclonal antibodies (rituximab) in high-risk RTx recipients. Major eligibility criteria include: 1) major and minor ABO blood group mismatch, 2) positive DSA. Thirty-five patients will receive 200 mg/body of rituximab. The primary endpoint is the incidence of B cell depletion. This study will clarify whether rituximab is efficacious in improving graft survival in high-risk RTx recipients.

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  • Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer Reviewed

    H. Sawahara, H. Shiraha, D. Uchida, H. Kato, T. Nagahara, M. Iwamuro, J. Kataoka, S. Horiguchi, M. Watanabe, M. Sakaguchi, A. Takaki, K. Nouso, Y. Nasu, H. Kumon, H. Okada

    CANCER GENE THERAPY   23 ( 8 )   278 - 283   2016.8

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    Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3), a tumor suppressor gene, is downregulated in various cancers. We previously reported the tumor-inhibitory effects of the REIC/Dkk-3 gene, delivered by a conventional adenoviral vector (Ad-CAG-REIC) in pancreatic cancer. Here, we developed an Ad-REIC vector with a novel gene expression system, termed the super gene expression (SGE) system, and assessed its therapeutic effects relative to those of Ad-CAG-REIC in pantreatic cancer cells. Human pancreatic cancer cell lines ASPC1 and MIAPaCa2 were used. REIC/Dkk-3 expression was assessed by western blot analysis. Relative cell viability and apoptotic effects were examined in vitro. The anti-tumor effects of Ad-REIC treatment were assessed in the mouse xenograft model. Compared with Ad-CAG-REIC, Ad-SGE-REIC elicited a significant increase in REIC protein expression in the cells studied, Relative to Ad-CAG-REIC, Ad-SGE-REIC reduced cell viability and induced apoptosis in the ASPC1 and MIAPaCa2 cell lines in vitro, and achieved superior tumor growth inhibition in the mouse xenograft model. Compared with conventional Ad-REIC agents, Ad-SGE-REIC provided enhanced inhibitory effects against tumor growth. Our results indicate that Ad-SGE-REIC is an innovative therapeutic tool for pancreatic cancer.

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  • Multi-institutional retrospective analysis of learning curves on dosimetry and operation time befor and after introduction of intraoperatively built custom-linked seeds in prostate brachytherapy

    Ishiyama H, Satoh T, Yorozu A, Saito S, Kataoka M, Hashine K, Nakamura R, Tanji S, Masui K, Okihara K, Ohashi T, Momma T, Aoki M, Miki K, Kato M, Morita M, Katayama N, Nasu Y, Kawanaka T, Fukumori T, Ito F, Shiroki R, Baba Y, Inadome A, Yoshioka Y, Takayama H, Hayakawa K

    J Radiat Res   57 ( 1 )   68 - 74   2016.8

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  • MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-kappa B and ROS formation upon ligand binding Reviewed

    I. Made Winarsa Ruma, Endy Widya Putranto, Eisaku Kondo, Hitoshi Murata, Masami Watanabe, Peng Huang, Rie Kinoshita, Junichiro Futami, Yusuke Inoue, Akira Yamauchi, I. Wayan Sumardika, Chen Youyi, Ken-Ichi Yamamoto, Yasutomo Nasu, Masahiro Nishibori, Toshihiko Hibino, Masakiyo Sakaguchi

    CLINICAL & EXPERIMENTAL METASTASIS   33 ( 6 )   609 - 627   2016.8

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    The dynamic interaction between tumor cells and their microenvironment induces a proinflammatory milieu that drives cancer development and progression. The S100A8/A9 complex has been implicated in chronic inflammation, tumor development, and progression. The cancer microenvironment contributes to the up-regulation of this protein complex in many invasive tumors, which is associated with the formation of pre-metastatic niches and poor prognosis. Changing adhesive preference of cancer cells is at the core of the metastatic process that governs the reciprocal interactions of cancer cells with the extracellular matrices and neighboring stromal cells. Cell adhesion molecules (CAMs) have been confirmed to have high-level expression in various highly invasive tumors. The expression and function of CAMs are profoundly influenced by the extracellular milieu. S100A8/A9 mediates its effects by binding to cell surface receptors, such as heparan sulfate, TLR4 and RAGE on immune and tumor cells. RAGE has recently been identified as an adhesion molecule and has considerably high identity and similarity to ALCAM and MCAM, which are frequently over-expressed on metastatic malignant melanoma cells. In this study, we demonstrated that ALCAM and MCAM also function as S100A8/A9 receptors as does RAGE and induce malignant melanoma progression by NF-kappa B activation and ROS formation. Notably, MCAM not only activated NF-kappa B more prominently than ALCAM and RAGE did but also mediated intracellular signaling for the formation of lung metastasis. MCAM is known to be involved in malignant melanoma development and progression through several mechanisms. Therefore, MCAM is a potential effective target in malignant melanoma treatment.

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  • Clinical analysis of bacterial strain profiles isolated from urinary tract infections: A 30-year study. International journal

    Koichiro Wada, Shinya Uehara, Masumi Yamamoto, Takuya Sadahira, Ritsuko Mitsuhata, Motoo Araki, Yasuyuki Kobayashi, Ayano Ishii, Reiko Kariyama, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   22 ( 7 )   478 - 482   2016.7

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    OBJECTIVES: We analyzed bacterial strains isolated from urine samples of patients with urinary tract infections (UTI) at Okayama University Hospital over a 30-year period to characterize trends in species and antimicrobial susceptibilities. METHODS: Clinical isolates were collected from in- and out-patients with pyuria and bacteriuria who were treated between 1984 and 2014 (one episode per patient and plural isolates were counted in polymicrobial infection). We examined these isolates to identify pathogens and tested for antimicrobial susceptibility. RESULTS: Isolates from complicated UTI over a 30-year period revealed Pseudomonas aeruginosa (P. aeruginosa) was the most frequently isolated in the first decade (1984-1994), MRSA in the second decade (1995-2004), and Escherichia coli (E. coli) in the latest decade (2005-2014). In uncomplicated UTI examined over 20 years, E. coli was the most frequently isolated species accounting for 47-94% of isolates. Fluoroquinolone (FQs)-insusceptible E. coli were first isolated in 1994 and increased to about 35% in 2013 in patients with complicated UTI. CONCLUSIONS: Complicated UTI involving P. aeruginosa and MRSA decreased over the last 10 years. Our data suggest that several factors such as shorter hospitalizations, shorter indwelling catheter use, and appropriate antimicrobial use has decreased colonization of P. aeruginosa and MRSA with relative increases in isolation of E. coli including FQs-insusceptible strains. We must continue our surveillance of antimicrobial-resistant bacteria isolated from urine samples and evaluate antibiograms, since their persistence in the urinary tract would be problematic.

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  • Synergistic anti-pancreatic cancer immunological effects by treatment with reduced expression in immortalized cells/dickkopf-3 protein and peripheral blood mononuclear cells Reviewed

    Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Hiroaki Sawahara, Teruya Nagahara, Masaya Iwamuro, Junro Kataoka, Shigeru Horiguchi, Masami Watanabe, Akinobu Takaki, Kazuhiro Nouso, Yasutomo Nasu, Hiromi Kumon, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   31 ( 6 )   1154 - 1159   2016.6

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    Background and AimReduced expression in immortalized cells/dickkopf-3 (REIC/DKK3) is a reported tumor suppressor gene and has potential to become an innovative therapy for various cancers. We examined the antitumor immunological effects of human REIC/DKK3 protein against pancreatic cancer.
    MethodsActivation of extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 by REIC/DKK3 protein was assessed in human peripheral blood mononuclear cells using immunoblotting. Pancreatic cancer cell lines (AsPC-1 and MIA Paca-2) were cocultured with peripheral blood mononuclear cells, and the anticancer effects of REIC/DKK3 protein were assessed using the methyl thiazole tetrazolium, cytotoxicity, and enzyme-linked immunospot assays. The antitumor immunological effects of the combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells were also assessed in a pancreatic cancer model using non-obese diabetic/severe combined immunodeficiency mice.
    ResultsThe REIC/DKK3 protein activated extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 in peripheral blood mononuclear cells. REIC/DKK3 protein inhibited in vitro cancer cell viability and enhanced cytotoxicity when incubated with peripheral blood mononuclear cells. REIC/DKK3 protein induced significant production of interferon gamma from lymphocytes incubated with pancreatic cancer cells, indicating that CD8+ T cells were activated in the peripheral blood mononuclear cells when cocultured with AsPC-1 and MIA Paca-2 in the presence of REIC/DKK3 protein. Combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells produced in vivo anticancer immunostimulatory effects on pancreatic cancer cells.
    ConclusionsThe REIC/DKK3 protein and peripheral blood mononuclear cells synergistically enhanced anticancer immunological effects against pancreatic cancer cells. The observed immunomodulatory effect of combined treatment likely occurs in adenovirus-mediated REIC/DKK3 gene therapy and provides important clues to the therapeutic mechanisms involving immune cells.

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  • Effectiveness and Safety of Ureteroscopic Holmium Laser Lithotripsy for Upper Urinary Tract Calculi in Elderly Patients Reviewed

    Takashi Yoshioka, Hideo Otsuki, Shinya Uehara, Toshihiro Shimizu, Wataru Murao, Koji Fujio, Kei Fujio, Koichiro Wada, Motoo Araki, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   70 ( 3 )   159 - 166   2016.6

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    Upper urinary tract calculi are common; however, there is no recommended treatment selection for elderly patients. Ureteroscopic holmium laser lithotripsy (URS lithotripsy) is minimally invasive, and it provides a high stone-free rate (SFR) treatment for upper urinary tract calculi. Here, we retrospectively evaluated the surgical outcomes of URS lithotripsy after dividing the 189 cases into 3 groups by patient age: the '&lt; 65 group' (&lt; 65 years old, n=108), the '65-74 group' (65-74 years old, n=42), and the '&gt;= 75 group' (&gt;= 75 years old, n=39). The patients 'characteristics, stone status, and perioperative outcomes were assessed. The 65-74 group and the &gt;= 75 group had a significantly higher prevalence of hypertension compared to the &lt; 65 group. Compared to the &lt; 65 group, the 65-74 group had a significantly higher prevalence of hyperlipidemia, and the &gt;= 75 group had significantly higher the American Society of Anesthesiologists (ASA) scores. Despite these preoperative risk factors, SFR and postoperative pyelonephritis in the 65-74 group and the &gt;= 75 group were similar to those of the &lt; 65 group. In conclusion, URS lithotripsy is the preferred treatment for upper urinary tract calculi, even for elderly patients who have multiple preoperative risk factors.

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  • A Case of Metastatic Urachal Cancer Including a Neuroendocrine Component Treated with Gemcitabine, Cisplatin and Paclitaxel Combination Chemotherapy Reviewed

    Shin Ebara, Yasuyuki Kobayashi, Katsumi Sasaki, Motoo Araki, Morito Sugimoto, Koichirou Wada, Kei Fujio, Atsushi Takamoto, Toyohiko Watanabe, Hiroyuki Yanai, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   70 ( 3 )   223 - 227   2016.6

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    The present case report describes a case of recurrent and advanced urachal carcinoma including neuroendocrine features with iliac bone metastasis after partial cystectomy and adjuvant chemotherapy consisting of irinotecan and cisplatin in a 32-year-old man. He received gemcitabine/cisplatin/paclitaxel (GCP) combination chemotherapy, consisting of gemcitabin (1,000mg/m(2)) on day 1, 8, cisplatin (70mg/m(2)) on day 1, and paclitaxel (80mg/m(2)) on day 1 and 8. After three cycles of chemotherapy, PET-CT showed complete regression of the disease. So the patient underwent total cystoure-threctomy, and histological examination showed an almost complete pathological response. External beam radiation therapy was also given to the ileac bone metastasis regions. However, PET-CT taken 17 months after the external beam radiation showed multiple lung metastases. He received GCP chemotherapy again, which resulted in a complete response again after three cycles of chemotherapy. This is the first report on GCP chemotherapy used not only as a salvage chemotherapy but also as a rechallenge regimen for metastatic urachal cancer including a neuroendocrine component.

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  • The induction of antigen-specific CTL by in situ Ad-REIC gene therapy Reviewed

    Y. Ariyoshi, M. Watanabe, S. Eikawa, C. Yamazaki, T. Sadahira, T. Hirata, M. Araki, S. Ebara, Y. Nasu, H. Udono, H. Kumon

    GENE THERAPY   23 ( 5 )   408 - 414   2016.5

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    An adenovirus vector carrying the human Reduced Expression in Immortalized Cell (REIC)/Dkk-3 gene (Ad-REIC) mediates simultaneous induction of cancer-selective apoptosis and augmentation of anticancer immunity. In our preclinical and clinical studies, in situ Ad-REIC gene therapy showed remarkable direct and indirect antitumor effects to realize therapeutic cancer vaccines. We herein aimed to confirm the induction of tumor-associated antigen-specific cytotoxic T lymphocytes (CTLs) by Ad-REIC. Using an ovalbumin (OVA), a tumor-associated antigen, expressing E.G7 tumor-bearing mouse model, we investigated the induction and expansion of OVA-specific CTLs responsible for indirect, systemic effects of Ad-REIC. The intratumoral administration of Ad-REIC mediated clear antitumor effects with the accumulation of OVA-specific CTLs in the tumor tissues and spleen. The CD86-positive dendritic cells (DCs) were upregulated in the tumor draining lymph nodes of Ad-REIC-treated mice. In a dual tumor-bearing mouse model in the left and right back, Ad-REIC injection in one side significantly suppressed the tumor growth on both sides and significant infiltration of OVA-specific CTLs into non-injected tumor was also detected. Consequently, in situ Ad-REIC gene therapy is expected to realize a new-generation cancer vaccine via anticancer immune activation with DC and tumor antigen-specific CTL expansion.

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  • Factors Predicting Adhesion between Renal Capsule and Perinephric Adipose Tissue in Partial Nephrectomy Reviewed

    Yasuyuki Kobayashi, Hiroaki Kurahashi, Yuko Matsumoto, Koichiro Wada, Katsumi Sasaki, Motoo Araki, Shin Ebara, Toyohiko Watanabe, Yasutomo Nasu

    ACTA MEDICA OKAYAMA   70 ( 2 )   69 - 74   2016.4

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    In minimally invasive partial nephrectomy (MIPN), it is important to preoperatively predict the degree of difficulty of tumor resection. When severe adhesions occur between the renal capsule and perinephric adipose tissue, detachment can be difficult. Preoperative prediction of adhesion is thought to be useful in the selection of surgical procedure. Subjects were 63 patients of a single surgeon who had received MIPN between April 2008 and August 2013 at Okayama University Hospital. Of these patients, this study followed 47 in whom the presence or absence of adhesions between the renal capsule and perinephric adipose tissue was confirmed using intraoperative videos. Data collected included: sex, BMI, CT finding (presence of fibroids in perinephric adipose tissue), comorbidities and lifestyle. Adhesion was observed in 7 patients (14.9). The mean operative time was 291.6min in the adhesion group, and 226.3min in the group without. The increased time in the adhesions group was significant (p&lt;0.05). Predictive factors were a positive CT finding for fibroid structure and comorbidity of hypertension (p&lt;0.05). In MIPN, difficulty of surgery can be affected by the presence of adhesion of the perinephric adipose tissue. Predicting such adhesion from preoperative CT is thus important.

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  • Development of a Novel REIC/DKK-3-Encoding Adenoviral Agent: Its Robust and Promising Therapeutic Effects in Pancreatic Cancer Reviewed

    Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Sawahara Hiroaki, Masakiyo Sakaguchi, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Okada

    GASTROENTEROLOGY   150 ( 4 )   S294 - S294   2016.4

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  • Promising Therapeutic Efficacy of a Novel REIC/Dkk-3 Expressing Adenoviral Vector for Hepatocellular Carcinoma Reviewed

    Sawahara Hiroaki, Hidenori Shiraha, Daisuke Uchida, Masakiyo Sakaguchi, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Okada

    GASTROENTEROLOGY   150 ( 4 )   S1153 - S1153   2016.4

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  • Comparison of implant quality between intraoperatively built custom-linked seeds and loose seeds in permanent prostate brachytherapy using sector analysis

    Katayama N, Takemoto M, Takamoto A, Ihara H, Katsui K, Ebara S, Nasu Y, Kanazawa S

    J Radiat Res   57 ( 4 )   393 - 399   2016.3

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  • The gender specific risk factors for prolonged hospitalization due to acute pyelonephritis in a Japanese tertiary emergency center Reviewed

    Risa Muneishi, Ryuta Tanimoto, Koichiro Wada, Philip Hsiao, Jun Eguchi, Motoo Araki, Toyohiko Watanabe, Yasutomo Nasu, Naoki Akebi

    JOURNAL OF INFECTION AND CHEMOTHERAPY   22 ( 1-2 )   108 - 111   2016.1

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    Objectives: The aim of this study is to characterize the potential differences between male and female patients with acute pyelonephritis (AP) and to predict the severity of AP based on the length of hospital stay.
    Methods: We conducted a retrospective medical chart review of 172 consecutive adult patients who were hospitalized in Tsuyama Central Hospital due to AP from January 2007 through June 2012. We analyzed the length of hospital stay by the proportional hazard model.
    Results: A total of 172 patients were identified who were admitted to our hospital with a diagnosis of AP. Of them, 62% (106/172) were female. Except for urological malignancy, there was no significant difference between men and women in underlying disease. Out of 26 variables, univariate analysis in male showed that only urolithiasis (OR 1.75, p = 0.0294) was significantly associated with longer hospital stay, while septic shock (OR 3.18, P = 0.003), urological malignancy (OR 2.94, P = 0.002), age over 65 (OR 1.66, p = 0.018) and neurogenic bladder (OR 1.92, p = 0.014) were all associated with longer hospital stay in female patients.
    Conclusions: This is the first report to identify the risk factors for prolonged hospital stay for the patients who were admitted with AP in the Japanese population. The risk factors causing prolonged hospital stay were totally different between males and females. Reviewing the medical history based on sex gender might enable a clinician to predict the severity of acute pyelonephritis during the initial evaluation. (C) 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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  • An Open-Label, Randomized Phase II Trial of Personalized Peptide Vaccination in Patients with Bladder Cancer that Progressed after Platinum-Based Chemotherapy Reviewed

    Masanori Noguchi, Kazumasa Matsumoto, Hirotsugu Uemura, Gaku Arai, Masatoshi Eto, Seiji Naito, Chikara Ohyama, Yasutomo Nasu, Masatoshi Tanaka, Fukuko Moriya, Shigetaka Suekane, Satoko Matsueda, Nobukazu Komatsu, Tetsuro Sasada, Akira Yamada, Tatsuyuki Kakuma, Kyogo Itoh

    CLINICAL CANCER RESEARCH   22 ( 1 )   54 - 60   2016.1

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    Purpose: The prognosis of platinum-based chemotherapy-resistant metastatic urothelial cancer of the bladder remains poor. Personalized selection of the right peptides for each patient could be a novel approach for a cancer vaccine to boost anticancer immunity.
    Experimental Design: In this randomized, open-label, phase II study, patients ages &gt;= 18 years with progressive bladder cancer after first-line platinum-based chemotherapy were randomly assigned (1: 1) to receive personalized peptide vaccination (PPV) plus best supportive care (BSC) or BSC. PPV treatment used a maximum of four peptides chosen from 31 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for 12 s.c. injections (8 injections, weekly; 4 injections, bi-weekly). The primary endpoint was progression-free survival (PFS). Secondary end-points were overall survival (OS), immune response, and toxicity.
    Results: Eighty patients were randomly assigned to receive either PPV plus BSC (n = 39) or BSC (n = 41). No significant improvement in PFS was noted [HR, 0.7; 95% confidence interval (CI), 0.4-1.2, P = 0.17]. For the secondary endpoints, PPV plus BSC significantly prolonged OS compared with BSC (HR, 0.58; 95% CI, 0.34-0.99, P = 0.049), with median OS of 7.9 months (95% CI, 3.5-12.0) in the PPV plus BSC and 4.1 months (95% CI, 2.8-6.9) in the BSC. PPV treatment was well tolerated, without serious adverse drug reactions.
    Conclusions: PPV could not prolong PFS, but OS appeared to be improved with low toxicity and immune responses. Further large-scale, randomized trials are needed to confirm these results. (C) 2015 AACR.

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  • Tumor suppressor REIC/DKK-3 and co-chaperone SGTA: Their interaction and roles in the androgen sensitivity Reviewed

    Kazuhiko Ochiai, Masami Morimatsu, Yuiko Kato, Toshina Ishiguro-Oonuma, Chihiro Udagawa, Oumaporn Rungsuriyawiboon, Daigo Azakami, Masaki Michishita, Yuichi Ariyoshi, Hideo Ueki, Yasutomo Nasu, Hiromi Kumon, Masami Watanabe, Toshinori Omi

    ONCOTARGET   7 ( 3 )   3273 - 3286   2016.1

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    REIC/DKK-3 is a tumor suppressor, however, its intracellular physiological functions and interacting molecules have not been fully clarified. Using yeast two-hybrid screening, we found that small glutamine-rich tetratricopeptide repeat-containing protein a (SGTA), known as a negative modulator of cytoplasmic androgen receptor (AR) signaling, is a novel interacting partner of REIC/DKK-3. Mammalian two-hybrid and pull-down assay results indicated that the SGTA-REIC/DKK-3 interaction involved the N-terminal regions of both REIC/DKK-3 and SGTA and that REIC/DKK-3 interfered with the dimerization of SGTA, which is a component of the AR complex and a suppressor of dynein motor-dependent AR transport and signaling. A reporter assay in human prostate cancer cells that displayed suppressed AR signaling by SGTA showed recovery of AR signaling by REIC/DKK-3 expression. Considering these results and our previous data that REIC/DKK-3 interacts with the dynein light chain TCTEX-1, we propose that the REIC/DKK-3 protein interferes with SGTA dimerization, promotes dynein-dependent AR transport and then upregulates AR signaling.

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  • Percutaneous CT-guided Radiofrequency Ablation for Renal Cell Carcinoma in von Hippel-Lindau Disease: Midterm Results

    Hideo Gobara, Takao Hiraki, Toshihiro Iguchi, Hiroyasu Fujiwara, Yasutomo Nasu, Susumu Kanazawa

    Interventional Radiology   1 ( 1 )   1 - 6   2016

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  • Feasibility of Neoadjuvant Ad-REIC Gene Therapy in Patients with High-Risk Localized Prostate Cancer Undergoing Radical Prostatectomy Reviewed

    Hiromi Kumon, Katsumi Sasaki, Yuichi Ariyoshi, Takuya Sadahira, Motoo Araki, Shin Ebara, Hiroyuki Yanai, Masami Watanabe, Yasutomo Nasu

    CTS-CLINICAL AND TRANSLATIONAL SCIENCE   8 ( 6 )   837 - 840   2015.12

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    In a phase I/IIa study of in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC), we assessed the inhibitory effects of cancer recurrence after radical prostatectomy (RP), in patients with high risk localized prostate cancer (PCa). After completing the therapeutic interventions with initially planned three escalating doses of 1.0 x 10(10), 1.0 x 10(11), and 1.0 x 10(12) viral particles (VP) in 1.0-1.2 mL (n = 3, 3, and 6), an additional higher dose of 3.0 x 10(12) VP in 3.6 mL (n = 6) was further studied. Patients with recurrence probability of 35% or more within 5 years after RP as calculated by Kattan's nomogram, were enrolled. They received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. Based on the findings of MRI and biopsy mapping, as a rule, one track injection to the most prominent cancer area was given to initial 12 patients and 3 track injections to multiple cancer areas in additional 6 patients. As compared to the former group, biochemical recurrence-free survival of the latter showed a significantly favorable outcome. Neoadjuvant Ad-REIC, mediating simultaneous induction of cancer selective apoptosis and augmentation of antitumor immunity, is a feasible approach in preventing cancer recurrence after RP. (199)

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  • Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies Reviewed

    Suzawa Ken, Shien Kazuhiko, Huang Peng, Sakaguchi Masakiyo, Watanabe Masami, Hashida Shinsuke, Soh Junichi, Yamamoto Hiromasa, Maki Yuho, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Kumon Hiromi, Miyoshi Shinichiro, Toyooka Shinichi

    JOURNAL OF THORACIC ONCOLOGY   10 ( 9 )   S599   2015.9

  • A vaccine strategy with multiple prostatic acid phosphatase (PAP)-fused cytokines for prostate cancer treatment. Reviewed

    Kei Fujio, Masami Watanabe, Hideo Ueki, Shun-Ai Li, Rie Kinoshita, Kazuhiko Ochiai, Junichiro Futami, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

    Oncology Reports   33 ( 4 )   1585 - 1592   2015.4

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  • Ad-REIC Gene Therapy: Promising Results in a Patient with Metastatic CRPC Following Chemotherapy. Reviewed

    Hiromi Kumon, Katsumi Sasaki, Yuichi Ariyoshi, Takuya Sadahira, Shin Ebara, Takao Hiraki, Susumu Kanazawa, Hiroyuki Yanai, Masami Watanabe, Yasutomo Nasu

    Clinical Medicine Insights: Oncology   9   31 - 38   2015.3

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  • Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma. Reviewed International journal

    Y Shimazu, K Kurozumi, T Ichikawa, K Fujii, M Onishi, J Ishida, T Oka, M Watanabe, Y Nasu, H Kumon, I Date

    Gene therapy   22 ( 2 )   146 - 154   2015.2

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    Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was identified as a gene whose expression is reduced in many human cancers. REIC/Dkk-3 expression is also downregulated in malignant glioma and regulates cell growth through caspase-dependent apoptosis. cRGD (EMD121974), an antagonist of integrins, has demonstrated preclinical efficacy against malignant glioma. In this study, we investigated the antiglioma effect of combination therapy using an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) and cRGD. Quantitative real-time reverse-transcription PCR revealed the reduction of REIC/Dkk-3 mRNA levels in malignant glioma cell lines. The reduction of REIC/Dkk-3 protein expression in malignant glioma cell lines was also confirmed with western blot analysis. After treatment with Ad-REIC and cRGD, the proliferative rate of malignant glioma cells was significantly reduced in a time-dependent manner. In vivo, there was a statistically significant increase in the survival of mice treated with Ad-REIC and cRGD combination therapy compared with Ad-REIC monotherapy. We identified an apoptotic effect following monotherapy with Ad-REIC. Moreover, cRGD augmented the antiglioma efficacy of Ad-REIC. These results may lead to a promising new approach for the treatment of malignant glioma.

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  • Genome-wide association study identified SNP on 15q24 associated with bladder cancer risk in Japanese population

    Matsuda K, Takahashi A, Middlebrooks C.D, Obara W, Nasu Y, Inoue K, Tamura K, Yamasaki I, Naya Y, Tanikawa C, Cui R, Figueroa J.D, Silverman D.T, Rothman N, Namiki M, Tomita Y, Nishiyama H, Kohri K, Deguchi T, Nakagawa M, Yokoyama M, Miki T, Kumon H, Fujioka T, Ludmila P.O, Kubo M, Nakamura Y, Shuin T

    Human Molecular Genetics   24 ( 4 )   1177 - 1184   2014.10

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  • Significant association between the Axin2 rs2240308 single nucleotide polymorphism and the incidence of prostate cancer Reviewed

    Chao Ma, Chunxiao Liu, Peng Huang, Haruki Kaku, Jie Chen, Kai Guo, Hideo Ueki, Akiko Sakai, Yasutomo Nasu, Hiromi Kumon, Kenji Shimizu, Masami Watanabe

    ONCOLOGY LETTERS   8 ( 2 )   789 - 794   2014.8

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    The Wnt signaling pathway plays a crucial role in human cancer development, and axis inhibition protein 2 (Axin2) is a master scaffold protein involved in Wnt signaling. Axin2 negatively regulates Wnt signaling and acts as a tumor suppressor protein. The present study evaluated the association between the Axin2 single nucleotide polymorphism (SNP) rs2240308 [guanine (G)/adenine (A)] and the incidence of prostate cancer. In total, 103 patients with prostate cancer and 100 cancer-free control males were included in this case-control study, and were genotyped using the genomic DNA extracted from peripheral blood samples. The results revealed a higher incidence of prostate cancer in the subjects with the homozygous GG genotype and a reduced cancer incidence in the patients with the GA genotype of the rs2240308 SNP (G/A) in the Axin2 gene. T-he adjusted odds ratio for carriers with the GA genotype was 0.377 (95% CI, 0.206-0.688; P=0.001) and that for the AA genotype was 0.830 (95% CI, 0.309-2.232; P=0.712) compared with the GG genotype. Therefore, the GA genotype was found to exhibit a protective effect that decreased the risk of prostate cancer. To the best of our knowledge, this is the first study to demonstrate the significant association between this SNP (rs2240308, G/A) and the risk of prostate cancer. This association indicates the possibility that the variations in the Axin2 gene in this position may play a significant role in promoting the development of cancer in the prostate. We believe that the Axin2 SNP (rs2240308) could be a useful biomarker for the predisposition and early diagnosis of the disease.

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  • Immunological aspects of REIC/Dkk-3 gene therapy : the mechanism of the robust anti-tumor effects. Reviewed

    Masami Watanabe, Peng Huang, Fernando Abarzua, Haruki Kaku, Katsumi Sasaki, Hideo Ueki, Toyohiko Wananabe, Yasutomo Nasu, Hiromi Kumon

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   226 - 227   2014.7

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  • Dramatic Increase in Expression of a Transgene by Insertion of Promoters Downstream of the Cargo Gene Reviewed

    Masakiyo Sakaguchi, Masami Watanabe, Rie Kinoshita, Haruki Kaku, Hideo Ueki, Junichiro Futami, Hitoshi Murata, Yusuke Inoue, Shun-Ai Li, Peng Huang, Endy Widya Putranto, I. Made Winarsa Ruma, Yasutomo Nasu, Hiromi Kumon, Nam-ho Huh

    MOLECULAR BIOTECHNOLOGY   56 ( 7 )   621 - 630   2014.7

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    For expression of genes in mammalian cells, various vectors have been developed using promoters including CMV, EF-1 alpha, and CAG promoters and have been widely used. However, such expression vectors sometimes fail to attain sufficient expression levels depending on the nature of cargo genes and/or on host cell types. In the present study, we aimed to develop a potent promoter system that enables high expression levels of cargo genes ubiquitously in many different cell types. We found that insertion of an additional promoter downstream of a cargo gene greatly enhanced the expression levels. Among the constructs we tested, C-TSC cassette (C: CMV-RU5' located upstream; TSC: another promoter unit composed of triple tandem promoters, hTERT, SV40, and CMV, located downstream of the cDNA plus a polyadenylation signal) had the most potent capability, showing far higher efficiency than that of potent conventional vector systems. The results indicate that the new expression system is useful for production of recombinant proteins in mammalian cells and for application as a gene therapeutic measure.

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  • Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer Reviewed

    Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Teruya Nagahara, Masaya Iwamuro, Junro Kataoka, Shigeru Horiguchi, Masami Watanabe, Akinobu Takaki, Kazuhiro Nouso, Yasutomo Nasu, Takahito Yagi, Hiromi Kumon, Kazuhide Yamamoto

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   29 ( 5 )   973 - 983   2014.5

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    Background and AimThe reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer.
    MethodsREIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine.
    ResultsThe REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling.
    ConclusionsAd-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.

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  • Adenovirus-mediated REIC/Dkk-3 gene therapy: Development of an autologous cancer vaccination therapy (Review) Reviewed

    Masami Watanabe, Yasutomo Nasu, Hiromi Kumon

    ONCOLOGY LETTERS   7 ( 3 )   595 - 601   2014.3

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    Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor suppressor and therapeutic gene and has been studied with respect to the application of cancer gene therapy. Our previous studies demonstrated that the intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) suppresses tumor growth in mouse models of prostate, breast and testicular cancer and malignant mesothelioma. The mechanisms underlying these antitumor therapeutic effects have only been clarified recently. It has been demonstrated that Ad-REIC treatment inhibits cancer progression via the upregulation of systemic anticancer immunity. Under experimental conditions, autologous cancer vaccination via cancer-specific apoptosis and anticancer immune activation is a possible therapeutic mechanism. The robust anticancer effects observed in previous preclinical studies support the clinical utility of Ad-REIC. At present, a phase I-IIa study of Ad-REIC gene therapy in prostate cancer patients is ongoing. The current study reviews the observations of previous fundamental studies and summarizes the anticancer mechanisms of intratumoral Ad-REIC treatment in terms of cancer vaccination.

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  • A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector Reviewed

    Masami Watanabe, Masakiyo Sakaguchi, Rie Kinoshita, Haruki Kaku, Yuichi Ariyoshi, Hideo Ueki, Ryuta Tanimoto, Shin Ebara, Kazuhiko Ochiai, Junichiro Futami, Shun-Ai Li, Peng Huang, Yasutomo Nasu, Nam-Ho Huh, Hiromi Kumon

    ONCOLOGY REPORTS   31 ( 3 )   1089 - 1095   2014.3

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    Gene expression systems with various promoters, including the cytomegalovirus (CMV) promoter, have been developed to increase the gene expression in a variety of normal and cancer cells. In particular, in the clinical trials of cancer gene therapy, a more efficient and robust gene expression system is required to achieve sufficient therapeutic outcomes. By inserting the triple translational enhancer sequences of human telomerase reverse transcriptase (hTERT), Simian virus 40 (SV40) and CMV downstream of the sequence of the BGH polyA, we were able to develop a novel gene expression system that significantly enhances the expression of the genes of interest. We termed this novel gene expression cassette the super gene expression (SGE) system, and herein verify the utility of the SGE cassette for a replication-deficient adenoviral vector. We newly developed an adenoviral vector expressing the tumor suppressor, reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), based on the CMV promoter-driven SGE system (Ad-SGE-REIC) and compared the therapeutic utility of Ad-SGE-REIC with that of the conventional adenoviral vectors (Ad-CMV-REIC or Ad-CAG-REIC). The results demonstrated that the CMV promoter-SGE system allows for more potent gene expression, and that the Ad-SGE-REIC is superior to conventional adenoviral systems in terms of the REIC protein expression and therapeutic effects. Since the SGE cassette can be applied for the expression of various therapeutic genes using various vector systems, we believe that this novel system will become an innovative tool in the field of gene expression and gene therapy.

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  • Retroperitoneal bronchogenic cyst: a rare incidentaloma discovered in a juvenile hypertensive patient

    Terasaka T, Otsuka F, Ogura-Ochi K, Miyoshi T, Inagaki K, Kobayashi Y, Nasu Y, Makino H

    Hypertens Res   37 ( 6 )   595 - 597   2014.3

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  • A Rare Complication: Misdirection of an Indwelling Urethral Catheter into the Ureter Reviewed

    Tsutomu Ishikawa, Motoo Araki, Takeshi Hirata, Masami Watanabe, Shin Ebara, Toyohiko Watanabe, Yasutomo Nasu, Hiromi Kumon

    ACTA MEDICA OKAYAMA   68 ( 1 )   47 - 51   2014.2

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    We report 3 patients with the rare complication of an indwelling urethral catheter misdirected into the ureter. This is the largest series to date. Patients were referred to us for a variety of reasons following exchange of their chronic indwelling urinary catheters. CT in all cases demonstrated the urinary catheters residing in the left ureter. The ages of the patients were 37, 67 and 81 years old. All patients suffered from neurogenic bladder. Two patients were female, one was male, and 2 of the 3 had a sensory disorder inhibiting their pain response. The catheters were replaced with open-end Foley catheters. Extensive follow-up CT scans were obtained in one case, demonstrating improvement of hydronephrosis and no evidence of ureteral stenosis. Cystoscopy in this patient demonstrated normally positioned and functioning ureteral orifices. Although the placement of an indwelling urethral catheter is a comparatively safe procedure, one must keep in mind that this complication can occur, particularly in female patients with neurogenic bladder. CT without contrast is a noninvasive, definitive diagnostic tool.

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  • Anti-Cancer Effects of REIC/Dkk-3-encoding Adenoviral Vector for the Treatment of Non-small Cell Lung Cancer Reviewed

    Kazuhiko Shien, Norimitsu Tanaka, Masami Watanabe, Junichi Soh, Masakiyo Sakaguchi, Keitaro Matsuo, Hiromasa Yamamoto, Masashi Furukawa, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Nam-Ho Huh, Shinichiro Miyoshi, Hiromi Kumon, Shinichi Toyooka

    PLOS ONE   9 ( 2 )   2014.2

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    Objectives: REIC/Dkk-3 is down-regulated in a broad range of human cancer cells and is considered to function as a tumor suppressor. We previously reported that REIC/Dkk-3-expressing adenovirus vector (Ad-REIC) induced endoplasmic reticulum (ER) stress and cancer-specific apoptosis in human prostate cancer. In this study, we examined the therapeutic impact of Ad-REIC on non-small cell lung cancer (NSCLC).
    Materials and Methods: We examined the anti-tumor effect of Ad-REIC on 25 NSCLC cell lines in vitro and A549 cells in vivo. Two of these cell lines were artificially established as EGFR-tyrosine kinase inhibitor (TKI) resistant sublines.
    Results: Ad-REIC-treatment inhibited the cell viability by 40% or more in 13 (52%) of the 25 cell lines at multiplicity of infection (MOI) of 20 (20 MOI). These cell lines were regarded as being highly sensitive cells. The cell viability of a nonmalignant immortalized cell line, OUMS-24, was not inhibited at 200 MOI of Ad-REIC. The effects of Ad-REIC on EGFR-TKI resistant sublines were equivalent to those in the parental cell lines. Here, we demonstrated that Ad-REIC treatment activated c-Jun N-terminal kinase (JNK) in NSCLC cell lines, indicating the induction of ER stress with GRP78/BiP (GRP78) up-regulation and resulting in apoptosis. A single intratumoral injection of Ad-REIC significantly inhibited the tumorigenic growth of A549 cells in vivo. As predictive factors of sensitivity for Ad-REIC treatment in NSCLC, we examined the expression status of GRP78 and coxsackievirus and adenovirus receptor (CAR). We found that the combination of the GRP78 and CAR expressional statuses may be used as a predictive factor for Ad-REIC sensitivity in NSCLC cells.
    Conclusion: Ad-REIC induced JNK activation and subsequent apoptosis in NSCLC cells. Our study indicated that Ad-REIC has therapeutic potential against NSCLC and that the expression statuses of GRP78 and CAR may predict a potential therapeutic benefit of Ad-REIC.

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  • Robot-Assisted Radical Prostatectomy: Modified Ultradissection Reduces pT2 Positive Surgical Margins on the Bladder Neck Reviewed

    Motoo Araki, Wooju Jeong, Sung Yul Park, Young Hoon Lee, Yasutomo Nasu, Hiromi Kumon, Sung Joon Hong, Koon Ho Rha

    ACTA MEDICA OKAYAMA   68 ( 1 )   35 - 41   2014.2

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    The purpose of this study was to compare the positive surgical margin (PSM) rates of 2 techniques of robot-assisted radical prostatectomy (RARP) for pT2 (localized) prostate cancer. A retrospective analysis was conducted of 361 RARP cases, performed from May 2005 to September 2008 by a single surgeon (KHR) at our institution (Yonsei University College of Medicine). In the conventional technique, the bladder neck was transected first. In the modified ultradissection, the lateral border of the bladder neck was dissected and then the bladder neck was transected while the detrusor muscle of the bladder was well visualized. Perioperative characteristics and outcomes and PSM rates were analyzed retrospectively for pT2 patients (n = 217), focusing on a comparison of those undergoing conventional (n = 113) and modified ultradissection (n = 104) techniques. There was no difference between the conventional and modified ultradissection group in mean age, BMI, PSA, prostate volume, biopsy Gleason score, and D'Amico prognostic criteria distributions. The mean operative time was shorter (p &lt; 0.001) and the estimated blood loss was less (p &lt; 0.01) in the modified ultradissection group. The PSM rate for the bladder neck was significantly reduced by modified ultradissection, from 6.2% to 0% (p &lt; 0.05). In conclusion, modified ultradissection reduces the PSM rate for the bladder neck.

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  • Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder Reviewed

    Hiroaki Kurahashi, Masami Watanabe, Morito Sugimoto, Yuichi Ariyoshi, Sabina Mahmood, Motoo Araki, Kazushi Ishii, Yasutomo Nasu, Atsushi Nagai, Hiromi Kumon

    ENDOCRINE JOURNAL   60 ( 12 )   1321 - 1327   2013.12

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    Gender identity disorder (GID) results from a disagreement between a person's biological sex and the gender to which he or she identifies. With respect to the treatment of female to male GID, testosterone replacement therapy (TRT) is available. The uric acid (UA) level can be influenced by testosterone; however, the early effects and dose-dependency of TRT on the serum UA concentration have not been evaluated in this population. We herein conducted a dose-response analysis of TRT in 160 patients with female to male GID. The TRT consisted of three treatment groups who received intramuscular injections of testosterone enanthate: 125 mg every two weeks, 250 mg every three weeks and 250 mg every two weeks. Consequently, serum UA elevation was observed after three months of TRT and there was a tendency toward testosterone dose-dependency. The onset of hyperuricemia was more prevalent in the group who received the higher dose. We also demonstrated a positive correlation between increased levels of serum UA and serum creatinine. Since the level of serum creatinine represents an individual's muscle volume and the muscle is a major source of purine, which induces UA upregulation, the serum UA elevation observed during TRT is at least partially attributed to an increase in muscle mass. This is the first study showing an association between serum UA elevation and a TRT-induced increase in muscle mass. The current study provides important information regarding TRT for the follow-up and management of the serum UA levels in GID patients.

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  • Predictive factors for acute and late urinary toxicity after permanent interstitial brachytherapy in Japanese patients

    KANIMOTO Ryuta, BEKKU Kensuke, KATAYAMA Norihisa, KOBAYASHI Yasuyuki, EBARA Shin, ARAKI Motoo, TAKEMOTO Mitsuhiro, YANAI Hiroyuki, NASU Yasutomo, KUMON Hiromi

    20 ( 8 )   812 - 817   2013.8

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  • Clinical significance of CD24 as a predictor of bladder cancer recurrence. Reviewed

    Chunxiao Liu, Shaobo Zheng, Haiyan Shen, Kai Xu, Jie Chen, Hulin Li, Yawen Xu, Abai Xu, Binshen Chen, Haruki Kaku, Yasutomo Nasu, Hiromi Kumon, Peng Huang, Masami Watanabe

    Oncology Letters   96 - 100   2013.7

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  • Dose-response analysis of testosterone replacement therapy in patients with female to male gender identity disorder

    Nakamura A, Watanabe M, Sugimoto M, Sako T, Mahmood S, Kaku H, Nasu Y, Ishii K, Nagai A, Kumon H

    Endocrine Journal   60 ( 3 )   275 - 281   2013.3

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  • Could salvage surgery after chemotherapy have clinical impact on cancer survival of patients with metastatic urothelial carcinoma? Reviewed

    Kensuke Bekku, Takashi Saika, Yasuyuki Kobayashi, Ryo Kioshimoto, Taiki Kanbara, Yasutomo Nasu, Hiromi Kumon

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   18 ( 1 )   110 - 115   2013.2

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    The clinical impact of salvage surgery after chemotherapy on cancer survival of patients with metastatic urothelial carcinoma is controversial. We aimed to verify the clinical role of salvage surgery by analyzing the long-term outcome in patients with urothelial carcinoma treated by chemotherapy.
    Between 2003 and 2010 at a single institution, 31 of 47 patients (66%) with metastatic urothelial carcinoma showed objective responses (CR in 4, PR in 27) after multiple courses of cisplatin/gemcitabine/paclitaxel-based chemotherapy, and a cohort of patients with partial response (PR) were retrospectively enrolled. Twelve (10 male and 2 female, median age 64.0 years) of 27 patients with PR underwent salvage surgeries after the chemotherapy: metastatectomy of residual lesions (10 retroperitoneal lymph nodes, 2 lung), and 6 radical surgeries for primary lesions as well. Progression-free survival and overall patient survival rates were analyzed retrospectively and compared with those of patients without salvage surgery.
    All 12 patients achieved surgical CR. Pathological findings of metastatic lesions showed viable cancer cells in 3 patients. In univariate analysis, sole salvage surgery affected overall survival in 27 patients with PR to the chemotherapy (P = 0.0037). Progression-free survival and overall survival rates in patients with salvage surgery were better than those in 15 PR patients without the surgery (39.8 vs. 0%, and 71.6 vs. 12.1% at 3 years, P = 0.01032 and 0.01048; log-rank test).
    Salvage surgery for patients with residual tumor who achieve partial response to chemotherapy could have a possible impact on cancer survival.

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  • Cancer stem cell-like characteristics of a CD133+ subpopulation in the J82 human bladder cancer cell line. Reviewed

    Peng Huang, Masami Watanabe, Haruki Kaku, Hideo Ueki, Hirofumi Noguchi, Morito Sugimoto, Takeshi Hirata, Hiroshi Yamada, Kohji Takei, Shaobo Zheng, Kai Xu, Yasutomo Nasu, Yasuyuki Fujii, Chunxiao Liu, Hiromi Kumon

    Molecular and Clinical Oncology   180 - 184   2013.1

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  • Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy Reviewed

    Morito Sugimoto, Masami Watanabe, Haruki Kaku, Shun-Ai Li, Hirofumi Noguchi, Hideo Ueki, Masakiyo Sakaguchi, Nam-Ho Huh, Yasutomo Nasu, Hiromi Kumon

    ONCOLOGY REPORTS   28 ( 5 )   1645 - 1652   2012.11

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    The biodistribution and safety of adenoviral vectors encoding the human REIC/Dkk-3 tumor suppressor gene (Ad-REIC) were examined in this preclinical study for in situ prostate cancer gene therapy. First, the in vitro apoptotic effects of Ad-REIC in normal and cancer cells derived from the prostate and liver were examined. Significant apoptotic effects were observed at 100 MOI (multiplicity of infection) in prostate cancer cells (LNCaP, PC3) and hepatoma cells (HEP3B and HEPG2); however, no effects were seen in normal cells. To analyze the safety of intraprostatic Ad-REIC administration, the biodistribution and histology after Ad-REIC injection were evaluated in various organs of normal male C57BL6 mice. In a supporting study, vector dissemination following intravenous injection of Ad-REIC into tail veins was determined. To evaluate whether Ad-REIC was present in the collected tissue specimens, human REIC gene detection was performed using DNA-PCR. Intraprostatic treatment administered at lower doses showed vector biodistribution into the colon, urinary bladder and prostate. At higher doses, vector dissemination was observed in tissues more distant from the prostate, including the lung, thymus, heart, liver and adrenal gland. After intravenous injection a: Ad-REIC, dissemination was observed in the liver and spleen. These results indicate that the biodistribution of Ad-REIC is determined by the dose and route of administration. Although acute inflammatory effects were observed in the prostate after intraprostatic administration at higher doses, no abnormal histological findings were noted in the other tissues, including those of intravenously treated mice. Regarding the safety of Ad-REIC administration, no deaths and no signs of toxicity or unusual behavior were observed in the mice in any treatment group. Based on these preclinical experiments, adenovirus-mediated in situ REIC/Dkk-3 gene therapy is considered to be safe for use as a treatment for human prostate cancer.

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  • DIRECT THERAPEUTIC EFFECT OF REIC/DKK-3-ENCODING ADENOVIRAL VECTOR FOR NON-SMALL CELL LUNG CANCER Reviewed

    Yamamoto Hiromasa, Tanaka Norimitsu, Toyooka Shinichi, Watanabe Masami, Sakaguchi Masakiyo, Soh Junichi, Shien Kazuhiko, Furukawa Masashi, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Huh Nam-ho, Kumon Hiromi, Miyoshi Shinichirou

    JOURNAL OF THORACIC ONCOLOGY   7 ( 11 )   S463   2012.11

  • Laparoscopic management of complicated urachal remnants in adults Reviewed

    Motoo Araki, Takashi Saika, Daiji Araki, Yasuyuki Kobayashi, Shinya Uehara, Toyohiko Watanabe, Kiyoshi Yamada, Yasutomo Nasu, Hiromi Kumon

    WORLD JOURNAL OF UROLOGY   30 ( 5 )   647 - 650   2012.10

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    Objectives The traditional surgical approach for removing a urachal remnant is via a large transverse or midline infraumbilical incision. We review our experience with laparoscopic urachal cyst excision and report the efficacy and outcomes of this approach as a less morbid, minimally invasive alternative.
    Methods Between August 2005 and March 2009, eight patients with a mean age of 26 years who had symptomatic urachal cysts underwent laparoscopic radical excision of the urachal remnant. Using three ports, the urachal remnant was dissected from the umbilicus to the bladder dome and then removed intact via the umbilicus. Umbilicoplasty was performed by a plastic surgeon. We retrospectively reviewed the perioperative records to assess morbidity and outcomes.
    Results All eight operations were completed successfully. No intraoperative or postoperative complications were reported at a mean follow-up of 3.2 years. Mean operative time was 147.5 min including umbilicoplasty. Pathological evaluation confirmed a benign urachal remnant in each case. There have been no recurrences of symptoms nor postoperative complications during follow-up. Mean time to full recovery, defined as return to normal life without pain, was 16 days. The patients with bladder cuff resection had a delayed full convalescence (25 vs. 13 days) due to a minimum degree of dysuria.
    Conclusion A laparoscopic approach with the removal of urachal remnants via the umbilicus appears to be a safe and effective alternative with better cosmesis when compared to an open approach.

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  • REIC/Dkk-3-encoding adenoviral vector as a potentially effective therapeutic agent for bladder cancer Reviewed

    Takeshi Hirata, Masami Watanabe, Haruki Kaku, Yasuyuki Kobayashi, Hiroshi Yamada, Masakiyo Sakaguchi, Kohji Takei, Nam-Ho Huh, Yasutomo Nasu, Hiromi Kumon

    INTERNATIONAL JOURNAL OF ONCOLOGY   41 ( 2 )   559 - 564   2012.8

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    Bladder cancer is one of the most common urogenital malignancies. The intravesical instillation of anticancer agents is an attractive strategy to treat a superficial lesion or floating/disseminated cancer cells after transurethral operation. An adenovirus carrying REIC/Dkk-3, a tumor suppressor gene (Ad-REIC), exhibits cancer-specific apoptotic effects in various types of cancer cells. The aim of the present study was to examine the potential of Ad-REIC as a therapeutic agent for bladder cancer. KK47 and RT4 human bladder cancer cells were sensitive to the Ad-REIC treatment for apoptosis induction, but some human bladder cancer cell lines (T24, J82 and TccSup) were resistant. Significant cell growth inhibition was observed when these resistant cancer cell lines were treated with Ad-REIC in a condition of floating cells, which is clinically observed after transurethral operation and becomes a cause of intravesical cancer dissemination. The therapeutic potential of Ad-REIC for the treatment of multidrug-resistant bladder cancer was investigated. The adriamycin-resistant KK47 bladder cancer cells (KK47/ADM), which also present multidrug resistance, showed induction of significant apoptosis following Ad-REIC treatment. The Ad-REIC treatment induced downregulation of P-glycoprotein in KK47/ADM cells and restored the sensitivity to doxorubicin (adriamycin). Ad-REIC suppressed P-glycoprotein expression in a c-Jun-NH2-kinase (JNK)-dependent manner. Therefore, the current study indicated two therapeutic aspects of the Ad-REIC agent against human bladder cancer cells, as an apoptosis inducer/cell growth inhibitor and as a sensitizer of chemotherapeutic agents in multidrug-resistant cancer cells. The intravesical instillation of Ad-REIC could be an attractive therapeutic method in human bladder cancer where the treatment of superficial lesions and floating/disseminated or multidrug-resistant cancer cells is necessary.

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  • A novel gene expression system for detecting viable bladder cancer cells Reviewed

    Hideo Ueki, Masami Watanabe, Haruki Kaku, Peng Huang, Shun-Ai Li, Kazuhiko Ochiai, Takeshi Hirata, Hirofumi Noguchi, Hiroshi Yamada, Kohji Takei, Yasutomo Nasu, Yuji Kashiwakura, Hiromi Kumon

    INTERNATIONAL JOURNAL OF ONCOLOGY   41 ( 1 )   135 - 140   2012.7

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    A novel transcriptional system was developed that can robustly enhance cancer-specific gene expression. In the system, hTERT promoter-driven gene expression was enhanced by an advanced two-step transcriptional amplification (TSTA). This construct was used to develop a novel system for detection of bladder cancer cells. The current study evaluated the advanced TSTA system by examining the cancer-specific gene transcription in various bladder cancer cell lines. The system significantly enhanced cancer-specific luciferase gene expression in the bladder cancer cell lines in comparison to the previous expression system of one-step or conventional TSTA. The fold gain of the enhancement was significantly correlated to the telomerase activity of the cell lines. A green fluorescent protein (GFP) gene encoding plasmid vector was constructed where hTERT promoter-driving transcription is enhanced by the advanced TSTA to utilize the system for the imaging and detection of viable bladder cancer cells. The advanced TSTA-hTERT-GFP plasmid successfully induced cancer-specific gene expression, showing robust GFP expression in human bladder cancer cell lines, but no visible GFP expression in normal bladder urothelial cells. The control GFP plasm id with a CMV promoter yielded GFP expression in both normal bladder cells and cancer cells. The advanced TSTA-hTERT-GFP plasmid allowed selective visualization of viable human bladder cancer cells in mixed cell culture containing 10- and 100-fold more normal bladder urothelial cells. These findings indicate that the advanced TSTA-hTERT expressional system is a valuable tool for detecting viable bladder cancer cells. The current system can be applied for in vitro detection of bladder cancer cells in urine and other types of cancer cells disseminated in vivo.

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  • The clinical impact of pathological review on selection the treatment modality for localized prostate cancer in candidates for brachytherapy monotherapy Reviewed

    Ryo Kishimoto, Takashi Saika, Kensuke Bekku, Hiroyuki Nose, Fernando Abarzua, Yasuyuki Kobayashi, Motoo Araki, Hiroyuki Yanai, Yasutomo Nasu, Hiromi Kumon

    WORLD JOURNAL OF UROLOGY   30 ( 3 )   375 - 378   2012.6

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    To evaluate the impact of pathological review by pathologist with genitourinary expertise (PGU) on treatment modality of localized prostate cancer, we analyzed Gleason grade (GG) migration and the final treatment decision in a cohort of patients designated for permanent prostate brachytherapy (PPB).
    From February 2005 to July 2010, a total of 247 patients with localized prostate cancer diagnosed by local community hospitals were referred to our hospital for PPB monotheray. All pathologic slides of prostate biopsies were reviewed by a single PGU. Patients ultimately selected their treatment modality from our recommendations based on the review. Indication for PPB monotherapy was the NCCN classification of patients as good or intermediate risk. In addition, patient with Primary GG 4 was regarded as unadapted case.
    Six cases were reinterpreted as no cancer (2.4%). GG change occurred in 94 cases (38.1%) of which 77 (81.9%) were upgraded and 17 (18.1%) downgraded. Of the total 247 patients, 86 (34.8%) changed therapies and 30 (12.1%) did so based on the pathologic slide review.
    Pathological review of biopsy specimens is mandatory for the determination of treatment modality especially in candidates for monotherapy of permanent prostate brachytherapy.

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  • Implications of transcriptional factor, OCT-4, in human bladder malignancy and tumor recurrence Reviewed

    Peng Huang, Jie Chen, Lei Wang, Yanqun Na, Haruki Kaku, Hideo Ueki, Katsumi Sasaki, Ken Yamaguchi, Kai Zhang, Takashi Saika, Yasutomo Nasu, Masami Watanabe, Hiromi Kumon

    MEDICAL ONCOLOGY   29 ( 2 )   829 - 834   2012.6

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    OCT-4, which is also known as POU5f1, is a key regulator of self-renewal in embryonic stem cells. The new cancer stem cell concept proposes that the expression of such genes is potentially correlated with tumorigenesis and can affect some aspects of the cancer behavior, such as recurrence or metastasis. This study investigated the association between OCT-4 expression in cancer tissues obtained by transurethral surgery and the clinical data to clarify the involvement of OCT-4 in human bladder malignancy. Immunohistochemical analysis demonstrated that a positive rate of OCT-4 expression was significantly associated with the higher-grade cancer (G2 and G3) in comparison with that of the lower grade (G1). In addition, positive OCT-4 expression was significantly associated with the intra-bladder tumor recurrence after the operation. The staining intensity of OCT-4 expression was also correlated with tumor recurrence. These data indicate that positive OCT-4 expression may be involved in the development of high-grade bladder cancer and with the bladder cancer recurrence. This is the first study showing a correlation between the expression of OCT-4 and bladder cancer recurrence. OCT-4 may be a valuable clinical marker for the progression of bladder cancer and may be an attractive therapeutic target for the development of new medicines for the treatment of malignancy.

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  • Ureteroscopic Management of Chronic Unilateral Hematuria: A Single-Center Experience over 22 Years Reviewed

    Motoo Araki, Shinya Uehara, Katsumi Sasaki, Koichi Monden, Masaya Tsugawa, Toyohiko Watanabe, Manoji Monga, Yasutomo Nasu, Hiromi Kumon

    PLOS ONE   7 ( 6 )   e36729   2012.6

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    Objective: To analyze the short and long term safety and efficacy of ureteroscopic evaluation and management of chronic unilateral hematuria.
    Methods: We retrospectively reviewed patients with chronic unilateral hematuria from 1987 to 2008. The distal to middle ureter was evaluated with a semi-rigid ureteroscope without a guidewire. Subsequently, the flexible ureteroscope was advanced into the upper ureter to the renal pelvis using a low-pressure automated irrigant system (Uromat (TM)). Lesions identified ureteroscopically were treated with diathermy fulguration.
    Results: One hundred and four (56 male, 48 female) patients were identified, with a median age of 37 (14-80) years and median follow-up of 139 (34-277) months. The median preoperative duration of gross hematuria was 5 (1-144) months. Endoscopic findings included 61 (56%) minute venous rupture (MVR; a venous bleeding without clear abnormalities), 21 (20%) hemangioma (vascular tumor-like structure), 3 (3%) varix (tortuous vein), 1 (1%) calculus and 18 (17%) no lesions. The incidence of "no lesions" was less in the recent 12 years (9%) than the first 10 years (27%), while the incidence of MVR increased from 40 to 66% (p&lt;0.05). All patients were treated endoscopically. Immediate success rate was 96% (100% in the recent 12 years). Long-term recurrent gross hematuria rate was 7%. Six resolved spontaneously and only 1 required ureteroscopy, revealing a different bleeding site.
    Conclusion: Ureteroscopy and diathermy fulguration is highly useful for evaluation and treatment of chronic unilateral hematuria. Sophisticated technique and improved instrumentation contributes to a better outcome.

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  • DNA methylation status of REIC/Dkk-3 gene in human malignancies Reviewed

    Tatsuro Hayashi, Hiroaki Asano, Shinichi Toyooka, Kazunori Tsukuda, Junichi Soh, Tadahiko Shien, Naruto Taira, Yuho Maki, Norimitsu Tanaka, Hiroyoshi Doihara, Yasutomo Nasu, Nam-ho Huh, Shinichiro Miyoshi

    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY   138 ( 5 )   799 - 809   2012.5

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    The REIC (reduced expression in immortalized cells)/Dkk-3 is down-regulated in various cancers and considered to be a tumor suppressor gene. REIC/Dkk-3 mRNA has two isoforms (type-a,b). REIC type-a mRNA has shown to be a major transcript in various cancer cells, and its promoter activity was much stronger than that of type-b. In this study, we examined the methylation status of REIC/Dkk-3 type-a in a broad range of human malignancies.
    We examined REIC/Dkk-3 type-a methylation in breast cancers, non-small-cell lung cancers, gastric cancers, colorectal cancers, and malignant pleural mesotheliomas using a quantitative combined bisulfite restriction analysis assay and bisulfate sequencing. REIC/Dkk-3 type-a and type-b expression was examined using reverse transcriptional PCR. The relationships between the methylation and clinicopathological factors were analyzed.
    The rate of REIC/Dkk-3 type-a methylation ranged from 26.2 to 50.0% in the various primary tumors that were examined. REIC/Dkk-3 type-a methylation in breast cancer cells was significantly heavier than that in the other cell lines that we tested. REIC/Dkk-3 type-a methylation was inversely correlated with REIC/Dkk-3 type-a expression. There was a correlation between REIC/Dkk-3 type-a and type-b mRNA expression. REIC/Dkk-3 type-a expression was restored in MDA-MB-231 cells using 5-aza-2'-deoxycytidine treatment. We found that estrogen receptor-positive breast cancers were significantly more common among the methylated group than among the non-methylated group.
    REIC/Dkk-3 type-a methylation was frequently detected in a broad range of cancers and appeared to play a key role in silencing REIC/Dkk-3 type-a expression in these malignancies.

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  • Preoperative positive urine cytology is a risk factor for subsequent development of bladder cancer after nephroureterectomy in patients with upper urinary tract urothelial carcinoma Reviewed

    Yasuyuki Kobayashi, Takashi Saika, Yoshiyuki Miyaji, Michinao Saegusa, Ryoji Arata, Naoki Akebi, Tadasu Takenaka, Daisuke Manabe, Yasutomo Nasu, Hiromi Kumon

    WORLD JOURNAL OF UROLOGY   30 ( 2 )   271 - 275   2012.4

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    To determine the independent risk factors of bladder recurrence in patients with upper urinary tract urothelial carcinoma (UUT-UC).
    A total of 364 patients underwent nephroureterectomy (NUx) for UUT-UC between January 2005 and April 2009 in Okayama University and 17 affiliated hospitals. Patients with concomitant bladder cancer were excluded from the analysis. The clinicopathologic data for the remaining 288 patients with UUT-UC were retrospectively reviewed. Median follow-up after NUx was 20.2 months. The following variables were evaluated for any association with bladder recurrence: sex, age, tumor stage, tumor grade, venous invasion, lymphatic invasion, tumor location, multifocality, surgical modalities, time of ligation of the ureter, and preoperative urine cytology. The significance of each variable was tested univariately using the log-rank test. The simultaneous effects of multiple risk factors were estimated by multiple regression analysis using the Cox proportional hazards model.
    Bladder recurrence occurred in 103 patients (35.8%). Median time to first bladder recurrence was 6.9 months. Significant risk factors for bladder recurrences on univariate analysis were tumor location (P = 0.046) and preoperative positive urine cytology (P &lt; 0.001). Multivariate analysis revealed that preoperative urine cytology positive was significant for bladder recurrence (HR: 1.977; 95% CI: 1.310-2.983, P = 0.001).
    Risk factor for subsequent development of bladder cancer after NUx was preoperative positive urine cytology.

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  • Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1 Reviewed

    Yu Jin, Hitoshi Murata, Masakiyo Sakaguchi, Ken Kataoka, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

    ONCOLOGY REPORTS   27 ( 3 )   695 - 699   2012.3

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    REIC/Dkk-3 is a tumor suppressor gene that was first identified as a gene downregulated in association with immortalization of normal human fibroblasts. We have demonstrated that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) showed a tumor-specific killing effect on a wide range of cancers. However, some human cancers, bladder cancers in particular, are resistant to Ad-REIC. In this study, we investigated the combination effect of downregulation of BRPK/PINK1 (PINK1) and Ad-REIC on bladder cancer cells. Five bladder cancer cell lines among six cell lines examined were resistant to Ad-REIC. Among the cell lines, the resistance of two cell lines was probably due to low infection efficiency of the adenovirus. PINK1-specific siRNA remarkably downregulated Bcl-x(L) and TRAP1 proteins and upregulated BAX protein expression. Finally, downregulation of PINK1 partially sensitized the other three cell lines that were resistant to Ad-REIC. This sensitization was associated with increasing production of reactive oxygen species (ROS). These results indicate that PINK1 is one of the key molecules for the mitochondrial protection system and that PINK1 can be a new target molecule to sensitize bladder cancer cells that are resistant to Ad-REIC.

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  • Preclinical Safety and Efficacy of in Situ REIC/Dkk-3 Gene Therapy for Prostate Cancer Reviewed

    Keiichiro Kawauchi, Masami Watanabe, Haruki Kaku, Peng Huang, Kasumi Sasaki, Masakiyo Sakaguchi, Kazuhiko Ochiai, Nam-ho Huh, Yasutomo Nasu, Hiromi Kumon

    ACTA MEDICA OKAYAMA   66 ( 1 )   7 - 16   2012.2

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    The preclinical safety and therapeutic efficacy of adenoviral vectors that express the REIC/Dkk-3 tumor suppressor gene (Ad-REIC) was examined for use in prostate cancer gene therapy. The Ad-human (h) and mouse (m) REIC were previously demonstrated to induce strong anti-cancer effects in vitro and in vivo, and we herein report the results of two in vivo studies. First, intra-tumor Ad-hREIC administration was examined for toxicity and therapeutic effects in a subcutaneous tumor model using the PC3 prostate cancer cell line. Second, intra-prostatic Ad-mREIC administration was tested for toxicity in normal mice. The whole-body and spleen weights, hematological and serum chemistry parameters, and histological evaluation of tissues from throughout the body were analyzed. Both experiments indicated that there was no significant difference in the examined parameters between the Ad-REIC-treated group and the control (PBS- or Ad-LacZ-treated) group. In the in vitro analysis using PC3 cells, a significant apoptotic effect was observed after Ad-hREIC treatment. Confirming this observation, the robust anti-tumor efficacy of Ad-hREIC was demonstrated in the in vivo subcutaneous prostate cancer model. Based on the results of these preclinical experiments, we consider the adenovirus-mediated REIC/Dkk-3 in situ gene therapy to be safe and useful for the clinical treatment of prostate cancer.

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  • Primary Gleason grade 4 impact on biochemical recurrence after permanent interstitial brachytherapy in Japanese patients with low- or intermediate-risk prostate cancer. Reviewed International journal

    Uesugi T, Saika T, Edamura K, Nose H, Kobuke M, Ebara S, Abarzua F, Katayama N, Yanai H, Nasu Y, Kumon H

    International journal of radiation oncology, biology, physics   82 ( 2 )   e219 - 23   2012.2

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    PURPOSE: To reveal a predictive factor for biochemical recurrence (BCR) after permanent prostate brachytherapy (PPB) using iodine-125 seed implantation in patients with localized prostate cancer classified as low or intermediate risk based on National Comprehensive Cancer Network (NCCN) guidelines. METHODS AND MATERIALS: From January 2004 to December 2009, 414 consecutive Japanese patients with clinically localized prostate cancer classified as low or intermediate risk based on the NCCN guidelines were treated with PPB. The clinical factors including pathological data reviewed by a central pathologist and follow-up data were prospectively collected. Kaplan-Meier and Cox regression analyses were used to assess the factors associated with BCR. RESULTS: Median follow-up was 36.5 months. The 2-, 3-, 4-, and 5-year BCR-free rates using the Phoenix definition were 98.3%, 96.0%, 91.6%, and 87.0%, respectively. On univariate analysis, the Gleason score, especially primary Gleason grade 4 in biopsy specimens, was a strong predicting factor (p < 0.0001), while age, initial prostate-specific antigen (PSA) level, T stage, and minimal dose delivered to 90% of the prostate volume (D90) were insignificant. Multivariate analysis indicated that a primary Gleason grade 4 was the most powerful prognostic factor associated with BCR (hazard ratio = 6.576, 95% confidence interval, 2.597-16.468, p < 0.0001). CONCLUSIONS: A primary Gleason grade 4 carried a worse BCR prognosis than the primary grade 3 in patients treated with PPB. Therefore, the indication for PPB in patients with a Gleason sum of 4 + 3 deserves careful and thoughtful consideration.

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  • URETEROSCOPIC MANAGEMENT FOR UPPER TRACT UROTHELIAL CARCINOMA: LONG-TERM SINGLE INSTITUTION EXPERIENCE Reviewed

    Araki Motoo, Uehara Shinya, Watanabe Toyohiko, Koichi Monden, Masaya Tsugawa, Yasuyuki Kobayashi, Shin Ebara, Saika Takashi, Yasutomo Nasu, Hiromi Kumon

    JOURNAL OF ENDOUROLOGY   25   A177 - A177   2011.11

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  • Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging Reviewed

    Masami Watanabe, Hideo Ueki, Kazuhiko Ochiai, Peng Huang, Yasuyuki Kobayashi, Yasutomo Nasu, Katsumi Sasaki, Haruki Kaku, Yuji Kashiwakura, Hiromi Kumon

    ONCOLOGY REPORTS   26 ( 4 )   769 - 775   2011.10

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    The two-step transcriptional amplification (TSTA) system was previously reported to enhance the tissue-specific gene expression driven by weak promoters, but the enhancement of the gene expression is limited to use in in vitro and in vivo experimental situations. To achieve robust tissue-specific gene expression using the TSTA system, we developed an advanced TSTA system which includes polyglutamines and rat glucocorticoid receptor sequences between the GAL4 and VP16 sequences in the region of the first step of transcription. We evaluated the advanced TSTA system as a method to enhance the human telomerase reverse transcriptase (hTERT) promoter-driving cancer-specific transcription in various cancer cell lines. As a result, the advanced TSTA enhanced cancer-specific luciferase gene expression in all of the examined cancer cell lines, when compared with both the one-step and conventional TSTA systems (an similar to 6- and similar to 17-fold enhancement, respectively). Notably, the enhancement of the hTERT driven expression by the conventional TSTA system was modest and even inferior to the one-step system in several cancer cell lines. We then constructed a luciferase gene encoding the adeno-associated virus vector in which the hTERT promoter-mediated expression was driven by the advanced TSTA or control systems. In an orthotopic liver tumor model, mice were treated with the vector via tail vein injection. An optical imaging device was used to visualize the in vivo luciferase expression in the orthotopic tumor. The advanced TSTA system significantly enhanced the luciferase expression compared with the one-step and conventional TSTA systems (18.0+/-1.0- and 15.9+/-0.85-fold gain, respectively). Therefore, the advanced TSTA system significantly improves hTERT-dependent cancer-specific gene expression both in vitro and in vivo when compared with the previous systems. Since the advanced TSTA method can also be applied to other site-specific gene expression systems using tissue-specific promoters, this approach is expected to become a valuable tool enabling in vivo site-specific targeting in the field of gene therapy and molecular imaging.

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  • Single Nucleotide Polymorphism WRN Leu1074Phe Is Associated with Prostate Cancer Susceptibility in Chinese Subjects Reviewed

    Lei Wang, Haruki Kaku, Peng Huang, Kexin Xu, Kai Yang, Jiheng Zhang, Ming Li, Liping Xie, Xiaofeng Wang, Akiko Sakai, Masami Watanabe, Yasutomo Nasu, Kenji Shimizu, Hiromi Kumon, Yanqun Na

    ACTA MEDICA OKAYAMA   65 ( 5 )   315 - 323   2011.10

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    Deficiencies in the human DNA repair gene WRN are the cause of Werner syndrome, a rare autosomal recessive disorder characterized by premature aging and a predisposition to cancer. This study evaluated the association of WRN Leu1074Phe (rs1801195), a common missense single nucleotide polymorphism in WRN, with prostate cancer susceptibility in Chinese subjects. One hundred and forty-seven prostate cancer patients and 111 male cancer-free control subjects from 3 university hospitals in China were included. Blood samples were obtained from each subject, and the single nucleotide polymorphism WRN Leu1074Phe was genotyped by using a Snapshot assay. The results showed that WRN Leu1074Phe was associated with the risk of prostate cancer in Chinese men and that the TG/GG genotype displayed a decreased prevalence of prostate cancer compared with the TT genotype (OR = 0.58, 95% CI: 0.35-0.97, p = 0.039). Through stratified analysis, more significant associations were revealed for the TG/GG genotype in the subgroup with diagnosis age &lt;= 72 yr (OR = 0.27, 95% CI: 0.12-0.61, p = 0.002) and in patients with localized diseases (OR = 0.36, 95% CI: 0.19-0.70, p = 0.003). However, no statistically significant difference was found in the subgroup with age &gt; 72 yr or in patients with advanced diseases. We concluded that the genetic variant Leu1074Phe in the DNA repair gene WRN might play a role in the risk of prostate cancer in Chinese subjects.

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  • T2*-weighted image/T2-weighted image fusion in postimplant dosimetry of prostate brachytherapy

    Katayama N, Takemoto M, Yoshio K, Katsui K, Uesugi T, Nasu Y, Matsushita T, Kaji M, Kumon H, Kanazawa S

    J Radiat Res   52 ( 5 )   680 - 684   2011.9

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  • Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1 Reviewed

    Kazuhiko Ochiai, Masami Watanabe, Hideo Ueki, Peng Huang, Yasuyuki Fujii, Yasutomo Nasu, Hirofumi Noguchi, Takeshi Hirata, Masakiyo Sakaguchi, Nam-ho Huh, Yuji Kashiwakura, Haruki Kaku, Hiromi Kumon

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   412 ( 2 )   391 - 395   2011.8

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    REIC/Dkk-3 is a member of the Dickkopf family proteins known as Wnt-antagonists, and REIC/Dkk-3 expression is downregulated in a broad range of cancer types. REIC/Dkk-3 acts as a tumor suppressor in multiple cancer cell lines by inducing apoptosis through endoplasmic reticulum (ER) stress signaling. However, the intracellular interaction partners of REIC/Dkk-3 have not been fully elucidated. By employing yeast two-hybrid screening, we identified the human dynein light chain, Tctex-1, as a novel interaction partner of REIC/Dkk-3. We further disclosed that the interaction involves the 136-157 amino acid region of REIC/Dkk-3 by using the mammalian two-hybrid system. Interestingly, this binding region of REIC/Dkk-3 with Tctex-1 contains an amino acid sequence motif [-(E) under bar -X-(G) under bar-(R) under bar-(R) under bar -X-(H) under bar-] which was previously reported as the Tctex-1 binding domain of dynein intermediate chain (DIC). Immunocytochemistry demonstrated that both REIC/Dkk-3 and Tctex-1 were localized around the ER of human fibroblasts, and the similar distribution pattern of the proteins suggests that their interaction occurs around the ER. This is the first study showing the interaction of a Dickkopf family protein with a dynein motor complex protein. The link between REIC/Dkk-3 and Tctex-1 may be of significance for understanding the molecular functions of the proteins in ER stress signaling and intracellular dynein motor dynamics, respectively. (C) 2011 Elsevier Inc. All rights reserved.

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  • Epigenetic Silencing of MicroRNA-34b/c Plays an Important Role in the Pathogenesis of Malignant Pleural Mesothelioma Reviewed

    Takafumi Kubo, Shinichi Toyooka, Kazunori Tsukuda, Masakiyo Sakaguchi, Takuya Fukazawa, Junichi Soh, Hiroaki Asano, Tsuyoshi Ueno, Takayuki Muraoka, Hiromasa Yamamoto, Yasutomo Nasu, Takumi Kishimoto, Harvey I. Pass, Hideki Matsui, Nam-ho Huh, Shinichiro Miyoshi

    CLINICAL CANCER RESEARCH   17 ( 15 )   4965 - 4974   2011.8

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    Purpose: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM.
    Experimental Design: Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle.
    Results: Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2&apos;-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c-transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G(1) cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells.
    Conclusions: We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM. Clin Cancer Res; 17(15); 4965-74. (C)2011 AACR.

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  • Nerve growth factor level in the prostatic fluid of patients with chronic prostatitis/chronic pelvic pain syndrome is correlated with symptom severity and response to treatment Reviewed

    Toyohiko Watanabe, Miayabi Inoue, Katsumi Sasaki, Motoo Araki, Shinya Uehara, Koichi Monden, Takashi Saika, Yasutomo Nasu, Hiromi Kumon, Michael B. Chancellor

    BJU INTERNATIONAL   108 ( 2 )   248 - 251   2011.7

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    OBJECTIVE
    To explore whether levels of nerve growth factor (NGF) in expressed prostatic secretions (EPS) are correlated with symptom severity in chronic prostatitis (CP) and chronic pelvic pain syndrome (CPPS).
    PATIENTS AND METHODS
    All patients with CP/CPPS underwent a complete history and physical examination, and were scored according to the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI).
    Expressed prostatic secretion samples from 20 patients with CP/CPPS and from four asymptomatic control patients were collected and frozen, and NGF levels in EPS were measured by enzyme-linked immunosorbent assay.
    Patients were asked to complete NIH-CPSI questionnaires at baseline and 8 weeks after treatment and patients with at least a 25% decrease in total NIH-CPSI score from the baseline values were classified as responders to treatment.
    RESULTS
    The mean (+/-SD) NGF levels in EPS of patients with CP/CPPS and asymptomatic control patients were 7409 (+/-3788) pg/mL and 4174 (+/-1349) pg/mL, respectively. The NGF level in patients with CP/CPPS correlated directly with pain severity (P = 0.014, r = 0.541).
    There were no significant differences between NGF levels in EPS before and after treatment. However, successful treatment significantly decreased NGF levels in responders (P = 0.001).
    CONCLUSION
    Nerve growth factor might contribute to the pathophysiology of CP/CPPS as changes in NGF level in EPS occurred in proportion to pain severity. Therefore, these results suggest that NGF could be used as a new biomarker to evaluate the symptoms of CP/CPPS and the effects of treatment.

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  • Maintenance therapy with bacillus Calmette-Guerin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer

    Shiro Hinotsu, Hideyuki Akaza, Seiji Naito, Seiichiro Ozono, Yoshiteru Sumiyoshi, Sumio Noguchi, Akito Yamaguchi, Satoshi Nagamori, Akito Terai, Yasutomo Nasu, Haruki Kume, Yoshihiko Tomita, Yoshinori Tanaka, Shoji Samma, Hirotsugu Uemura, Hirofumi Koga, Tomoyasu Tsushima

    BJU INTERNATIONAL   108 ( 2 )   187 - 195   2011.7

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    OBJECTIVETo confirm the recurrence-preventing efficacy and safety of 18-month bacillus Calmette-Guerin (BCG) maintenance therapy for non-muscle-invasive bladder cancer.PATIENTS AND METHODSThe enrolled patients had been diagnosed with recurrent or multiple non-muscle-invasive bladder cancer (stage Ta or T1) after complete transurethral resection of bladder tumours (TURBT).The patients were randomized into three treatment groups: a maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks as induction therapy, followed by three once-weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy), a non-maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks) and an epirubicin group (epirubicin, 40 mg, intravesically instilled nine times). The primary endpoint was recurrence-free survival (RFS).RESULTSEfficacy analysis was performed for 115 of the full-analysis-set population of 116 eligible patients, including 41 maintenance group patients, 42 non-maintenance group patients and 32 epirubicin group patients.At the 2-year median point of the overall actual follow-up period, the final cumulative RFS rates in the maintenance, non-maintenance and epirubicin groups were 84.6%, 65.4% and 27.7%, respectively.The RFS following TURBT was significantly prolonged in the maintenance group compared with the non-maintenance group (generalized Wilcoxon test, P = 0.0190).CONCLUSIONBCG maintenance therapy significantly prolonged the post-TURBT RFS compared with BCG induction therapy alone or epirubicin intravesical therapy.

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  • Nerve growth factor level in the prostatic fluid of patients with chronic prostatitis/chronic pelvic pain syndrome is correlated with symptom severity and response to treatment

    Watanabe T, Inoue M, Sasaki K, Araki M, Uehara S, Monden K, Saika T, Nasu Y, Kumon H, Chancellor MB

    JU   185 ( 4 )   1301 - 1302   2011.7

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  • [REIC/Dkk-3 gene therapy]. Reviewed

    Masami Watanabe, Haruki Kaku, Peng Huang, Hiromi Kumon, Yasutomo Nasu

    Nihon rinsho. Japanese journal of clinical medicine   69 Suppl 5   559 - 63   2011.6

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  • Unexpected occurrence of adrenal Cushing&apos;s syndrome in a patient with systemic lupus erythematosus Reviewed

    Akihiro Katayama, Fumio Otsuka, Katsuyuki Tanabe, Naoko Tsukamoto, Ryutaro Yamanaka, Yoshinori Matsumoto, Yasutomo Nasu, Hirofumi Makino

    HYPERTENSION RESEARCH   34 ( 5 )   662 - 663   2011.5

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  • Intraperitoneal administration of an adenovirus vector carrying REIC/Dkk-3 suppresses peritoneal dissemination of scirrhous gastric carcinoma Reviewed

    Swe Swe Than, Ken Kataoka, Masakiyo Sakaguchi, Hitoshi Murata, Fernando Abarzua, Chika Taketa, Gang Du, Masakazu Yashiro, Kazuyoshi Yanagihara, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

    ONCOLOGY REPORTS   25 ( 4 )   989 - 995   2011.4

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    Expression levels of the novel tumor suppressor gene REIC/Dkk-3 are reduced in many human cancers. We have previously showed that an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) induced apoptosis of cancer cells selectively and exerted bystander antitumor effects via ER stress. We examined possible effects of Ad-REIC in a peritoneal dissemination model of scirrhous gastric carcinoma (SGC). Among various types of gastric cancer, SGC continues to be associated with the worst prognosis due to a high incidence of metastases in the peritoneal cavity. We found that a single intraperitoneal injection of Ad-REIC suppressed tumor dissemination and disease progression. Immunomodulation by Ad-REIC led to recruitment of natural killer cells inside tumor nodules. We conclude that Ad-REIC gene therapy may be a potential tool in combinatorial approaches to achieve curative effects in SGC.

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  • CHANGES IN CLITORIAL BLOOD FLOW FOLLOWING SURGERY WITH TENSION-FREE VAGINAL MESH FOR PELVIC ORGAN PROLAPSE Reviewed

    Toyohiko Watanabe, Miyabi Inoue, Ayano Ishii, Toyoko Yamato, Motoo Araki, Shinya Uehara, Takashi Saika, Yasutomo Nasu, Hiromi Kumon

    JOURNAL OF UROLOGY   185 ( 4 )   E685 - E685   2011.4

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  • PRIMARY GLEASON GRADE 4 IMPACTS ON BIOCHEMICAL RECURRENCE AFTER PERMANENT INTERSTITIAL BRACHYTHERAPY IN JAPANESE PATIENTS WITH LOW- OR INTERMEDIATE-RISK PROSTATE CANCER Reviewed

    Takashi Saika, Tatsuya Uesugi, Kohei Edamura, Hiroyuki Nose, Makoto Kobuke, Shin Ebara, Norihisa Katayama, Hiroyuki Yanai, Yasutomo Nasu, Hiromi Kumon

    JOURNAL OF UROLOGY   185 ( 4 )   E523 - E523   2011.4

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  • Prognostic Factors Influencing Survival after Nephroureterectomy for Transitional Cell Carcinoma of the Upper Urinary Tract Reviewed

    Yasuyuki Kobayashi, Takashi Saika, Daisuke Manabe, Yasutomo Nasu, Hiromi Kumon

    ACTA MEDICA OKAYAMA   65 ( 2 )   A27 - A31   2011.4

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    We analyzed the prognostic factors influencing survival after surgeries for upper urinary tract urothelial carcinoma (UUT-UC) with longer follow-up periods than in previous studies. Between January 2000 and December 2004, 386 patients underwent nephroureterectomy for UUT-UC. The data for the 221 patients with UUT-UC were retrospectively reviewed. Nine variables were evaluated for association with the survival outcomes of disease-specific survival. The prognostic significance was tested univariately with the log-rank test. The simultaneous effects of multiple prognostic factors were estimated by multiple regression analysis using the Cox proportional hazards model. The median follow-up was 38.4 months. The 5-year over all survival was 62.3%. Significant prognostic factors for disease-specific survival rate on univariate analysis were pathological stage (p &lt; 0.0001), tumor grade (p = 0.0324), and venous invasion (p &lt; 0.0001). Multivariate analysis revealed that only venous invasion was significant for disease-specific survival rate (p = 0.0205). Venous invasion was the only independent prognostic factor in pathologically localized UUT-UC.

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  • URETEROSCOPIC EVALUATION AND TREATMENT OF CHRONIC UNILATERAL HEMATURIA: A 24-YEAR EXPERIENCE Reviewed

    Motoo Araki, Shinya Uehara, Koichi Monden, Toyohiko Watanabe, Takashi Saika, Yasutomo Nasu, Hiromi Kumon

    JOURNAL OF UROLOGY   185 ( 4 )   E556 - E557   2011.4

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  • Expression pattern of REIC/Dkk-3 in various cell types and the implications of the soluble form in prostatic acinar development

    Kai Zhang, Masami Watanabe, Yuji Kashiwakura, Shun-Al Li, Kohei Edamura, Peng Huang, Ken Yamaguchi, Yasutomo Nasu, Yasuyuki Kobayashi, Masakiyo Sakaguchi, Kazuhiko Ochiai, Hiroshi Yamada, Kohji Takei, Hideo Ueki, Nam-Ho Huh, Ming Li, Haruki Kaku, Yanqun Na, Hiromi Kumon

    INTERNATIONAL JOURNAL OF ONCOLOGY   37 ( 6 )   1495 - 1501   2010.12

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    The tumor suppressor REIC/Dkk-3 is a secretory protein which was originally identified to be downregulated in human immortalized cells In the present study, we investigated the expression pattern of REIC/Dkk-3 in various cell types to characterize its physiological functions We first examined the expression level of REIC/Dkk-3 in a broad range of cancer cell types and confirmed that it was significantly downregulated in all of the cell types We also examined the tissue distribution pattern in a variety of normal mouse organs Ubiquitous REIC/Dkk-3 protein expression was observed in the organs The expression was abundant in the liver, heart and brain tissue, but was absent in the spleen and peripheral blood mononuclear cells The immunohistochemical analyses revealed that the subcellular localization of REIC/Dkk-3 had a punctate pattern around the nucleus, indicating its association with secretory vesicles In cancer cells stably transfected with REIC/Dkk-3 the protein was predominantly localized to the endoplasmic reticulum (ER) under observation with confocal microscopy Because REIC/ Dkk-3 was found to be abundantly expressed in the acinar epithelial cells of the mouse prostate, we analyzed the effects of recombinant REIC/Dkk-3 protein on the acinar morphogenesis of RWPE-1 cells, which are derived from human normal prostate epithelium Statistically significant acinar growth was observed in the culture condition with 10 mu g/m1 REIC/Dkk-3 protein, implicating the soluble form m prostatic acinar development Current results suggest that REIC/Dkk-3 may play a role in regulating the morphological process of normal tissue architecture through an autocrine and/or paracrine manner

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  • Indications for Ureteropyeloscopy Based on Radiographic Findings and Urine Cytology in Detection of Upper Urinary Tract Carcinoma Reviewed

    Akira Takao, Takashi Saika, Shinya Uehara, Koichi Monden, Fernando Abarzua, Yasutomo Nasu, Hiromi Kumon

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   40 ( 11 )   1087 - 1091   2010.11

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    To verify the indication of diagnostic ureteropyeloscopy based on clinical features for upper urinary tract urothelial cancer with over 100 patients and over a 10-year series.
    From January 1997 to December 2008, consecutive 129 units in 124 patients underwent ureteropyeloscopy to obtain a definitive diagnosis of upper urinary tract cancer or to rule out a malignancy. Patients were divided into four subgroups based on voided urine cytology and preoperative radiographic findings: group A (n = 8), positive urine cytology and positive radiographic findings; group B (n = 4), positive cytology and negative radiographic findings; group C (n = 55), negative cytology and positive radiographic findings and group D (n = 62), gross hematuria originating from the upper urinary tract with negative cytology and negative radiographic findings. Ureteropyeloscopic findings were compared with radiographic and cytological results. Adverse effects were also investigated.
    In group A, all patients had confirmed cancer. In group B, one revealed small cancer and the remaining three confirmed carcinoma in situ by biopsy with ureteropyeloscopy. In groups C and D, 33 patients (60%) and four (6.5%) revealed cancer. Seventy-eight patients out of 80 (97.5%) in groups C and D were confirmed to have benign disease. No patient was found with malignancy during follow up after negative finding of ureteropyeloscopy.
    Ureteropyeloscopy can help in detecting upper urinary tract cancer or to rule out malignancy for patients with negative voiding cytology. However, ureteropyeloscopy is redundant for patients with positive radiographic findings and positive voiding cytology.

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  • Bladder cancer working group report

    Kakehi Y, Hirao Y, Kim W-J, Ozono S, Masumori N, Miyanaga N, Nasu Y, Yokomizo A

    Jpn J Clin Oncol   40 ( Suppl1 )   57 - 64   2010.9

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  • Hepatocyte growth factor activator inhibitors(HAI-1 and HAI-2) are potential targets in uterine leiomyosarcoma

    Nakamura K, Abarzua F, Hongo A, Kodama J, Nasu Y, Kumon H, Hiramatsu Y

    Int J Oncol   37 ( 3 )   605 - 614   2010.9

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  • Two instillations of epirubicin as prophylaxis for recurrence after transurethral resection of Ta and T1 transitional cell bladder cancer: a prospective, randomized controlled study Reviewed

    Takashi Saika, Tomoyasu Tsushima, Yasutomo Nasu, Yoshiyuki Miyaji, Michihisa Saegusa, Katsuji Takeda, Hiromi Kumon

    WORLD JOURNAL OF UROLOGY   28 ( 4 )   413 - 418   2010.8

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    Although transurethral resection (TUR) is the standard treatment for non-muscle-invasive bladder tumors, 40-80% of tumors recur in spite of complete resection.
    To evaluate the efficacy, dose effectiveness and safety of early short-duration intravesical instillation therapy using epirubicin (EPI) administered immediately after TUR and on the next day following TUR.
    Between 1995 and 2001, 303 patients with Ta and T1 non-muscle-invasive bladder carcinoma were enrolled in this study. Patients were randomized into three groups. Group A patients were treated with two intravesical infusions of EPI 20 mg/40 ml saline immediately after TUR and within 24 h. Group B patients were treated with EPI 50 mg/100 ml on the same schedule as group A. Group C patients were treated by TUR alone as a control group. The primary endpoint was a duration to the first recurrence.
    Of the 303 patients, 79 in Group A, 84 in Group B, and 77 in Group C could be evaluated for recurrence. Median follow-up was 44 months. Median recurrence-free survival durations for Groups A, B, and C were 24, 38, and 13 months, respectively. The difference between Groups B and C was statistically significant (p = 0.04). Adverse reactions related to instillation were observed in about 30% of the patients. These reactions included micturition pain and frequency. These toxicities were mild and transient.
    Intravesical instillation of EPI 50 mg twice within 24 h after TUR was effective as prophylactic therapy for non-muscle-invasive bladder cancer with tolerable toxicity problems.

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  • 5alphaDH-DOC (5alpha-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer. International journal

    Motohide Uemura, Seijiro Honma, Suyoun Chung, Ryo Takata, Mutsuo Furihata, Kazuo Nishimura, Norio Nonomura, Yasutomo Nasu, Tsuneharu Miki, Taro Shuin, Tomoaki Fujioka, Akihiko Okuyama, Yusuke Nakamura, Hidewaki Nakagawa

    Cancer science   101 ( 8 )   1897 - 1904   2010.8

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    Prostate cancer often relapses during androgen-depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration-resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5alpha-dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and steroid metabolism, such as 5alpha-steroid reductases, are activated in CRPCs. In this report, we screened eight natural 5alphaDH-steroids to search for novel products of 5alpha-steroid reductases, and identified 11-deoxycorticosterone (DOC) as a novel substrate for 5alpha-steroid reductases in CRPCs. 11-Deoxycorticosterone (DOC) and 5alpha-dihydro-deoxycorticosterone (5alphaDH-DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5alpha-steroid reductase (SRD5A1) could convert from DOC to 5alphaDH-DOC. Sensitive liquid chromatography-tandem mass spectrometric analysis detected 5alphaDH-DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5alphaDH-DOC and other products of 5alpha-steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration.

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  • Potent antitumor effects of combined therapy with a telomerase-specific, replication-competent adenovirus (OBP-301) and IL-2 in a mouse model of renal cell carcinoma Reviewed

    P. Huang, H. Kaku, J. Chen, Y. Kashiwakura, T. Saika, Y. Nasu, Y. Urata, T. Fujiwara, M. Watanabe, H. Kumon

    CANCER GENE THERAPY   17 ( 7 )   484 - 491   2010.7

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    OBP-301 (a telomerase-specific, replication-competent adenovirus with hTERT promoter) was constructed in a previous study and it showed a strong anticancer effect by inducing cell lysis in human lung and prostate cancer cells. This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell-killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells. In in vivo experiment, luciferase-expressing RENCA cells were implanted in the left kidney and lung of BALB/c mice to prepare the RCC metastatic model. The animals were randomly divided into four treatment groups: PBS, IL-2 alone, OBP-301 alone and the combination. The analyses of orthotopic tumor weight, lung metastasis and luciferin-stained tumor images 14 days after each treatment showed significant tumor growth inhibition in the combination group in comparison with that in the OBP-301- or IL-2-treated groups. In addition, the percentage of regulatory T-cells (Tregs) in the combination group was significantly suppressed in comparison with that in the PBS and single-agent treatment groups. The outcomes of this study suggest that tumor-specific oncolytic immunovirotherapy may become an attractive strategy for the treatment of human RCC. Cancer Gene Therapy (2010) 17, 484-491; doi:10.1038/cgt.2010.5; published online 19 February 2010

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  • A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer

    Masanori Noguchi, Tatsuyuki Kakuma, Hirotsugu Uemura, Yasutomo Nasu, Hiromi Kumon, Yasuhiko Hirao, Fukuko Moriya, Shigetaka Suekane, Kei Matsuoka, Nobukazu Komatsu, Shigeki Shichijo, Akira Yamada, Kyogo Itoh

    CANCER IMMUNOLOGY IMMUNOTHERAPY   59 ( 7 )   1001 - 1009   2010.7

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    Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.

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  • Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3 Reviewed

    Ryuta Tanimoto, Masakiyo Sakaguchi, Fernando Abarzua, Ken Kataoka, Kaoru Kurose, Hitoshi Murata, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

    INTERNATIONAL JOURNAL OF CANCER   126 ( 7 )   1562 - 1569   2010.4

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    We have recently shown that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) exhibits a potent tumor-specific cell-killing function for various human cancers. It has also become evident that some human cancers are resistant to Ad-REIC-induced apoptosis. The aim of the present study was to determine the molecular mechanisms of resistance to Ad-REIC. First, we isolated resistant clones from a human prostate cancer cell line, PC3, after repeated exposure to Ad-REIC. Infection efficiency of the adenovirus vector and expression level of REIC/Dkk-3 in the resistant clones were similar to those in the parental PC3 cells. By screening for alteration in levels and functional status of proteins involved in Ad-REIC-induced apoptosis, we found that BiP/GRP78, an ER-residing chaperone protein, was expressed at higher levels consistently among resistant cells. Expression levels of BiP and rates of apoptosis induced by Ad-REIC were inversely correlated. Down-regulation of BiP with siRNA sensitized the resistant cells to Ad-REIC in vivo as well as in culture. These results indicate that BiP is a major determinant of resistance to Ad-REIC-induced apoptosis. Thus BiP is useful for diagnosis of inherent and acquired resistance of cancers and also as a target molecule to overcome resistance to the gene therapeutic Ad-REIC.

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  • Frequent silencing of tumor suppressive MicroRNA-34b/c by aberrant methylation in malignant mesothelioma Reviewed

    Takafumi Kubo, Shinichi Toyooka, Kazunori Tsukuda, Hiroaki Asano, Masakiyo Sakaguchi, Junichi Soh, Tsuyoshi Ueno, Hiromasa Yamamoto, Masaomi Yamane, Takahiro Oto, Yasutomo Nasu, Hideki Matsui, Nam Ho Huh, Shinichro Miyoshi

    CANCER RESEARCH   70   2010.4

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  • CLITORIAL BLOOD FLOW CHANGES AFTER SURGERY WITH TENSION-FREE VAGINAL MESH FOR PELVIC ORGAN PROLAPSE Reviewed

    Watanabe Toyohiko, Inoue Miyabi, Ishii Ayano, Yamato Toyoko, Nose Hiroyuki, Uematsu Katsutoshi, Sasaki Katsumi, Araki Motoo, Uehara Shinya, Saika Takashi, Nasu Yasutomo, Kumon Hiromi

    JOURNAL OF UROLOGY   183 ( 4 )   E583   2010.4

  • Prognostic Factors Influencing Survival after Nephroureterectomy for Transitional Cell Carcinoma of the Upper Urinary Tract Reviewed

    Yasuyuki Kobayashi, Takashi Saika, Daisuke Manabe, Yasutomo Nasu, Hiromi Kumon

    ACTA MEDICA OKAYAMA   64 ( 1 )   27 - 31   2010.2

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    We analyzed the prognostic factors influencing survival after surgeries for upper urinary tract urothelial carcinoma (UUT-UC) with longer follow-up periods than in previous studies. Between January 2000 and December 2004, 386 patients underwent nephroureterectomy for UUT-UC. The data for the 221 patients with UUT-UC were retrospectively reviewed. Nine variables were evaluated for association with the survival outcomes of cause-specific survival. The prognostic significance wits tested univariately with the log-rank test. The simultaneous effects of multiple prognostic factors were estimated by multiple regression analysis using the Cox proportional hazards model. The median follow-up was 38.4 months. The 5-year over all survival was 62.3%. Significant prognostic factors for disease-specific survival rate on univariate analysis were pathological stage (p &lt; 0.0001), tumor grade (p = 0.0324), and venous invasion (p &lt; 0.0001). Multivariate analysis revealed that only venous invasion was significant for disease-specific survival rate (p = 0.0205). Venous invasion wits the only independent prognostic factor in pathologrically localized UUT-UC.

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  • REIC/Dkk-3 stable transfection reduces the malignant phenotype of mouse prostate cancer RM9 cells

    Jie Chen, Masami Watanabe, Peng Huang, Masakiyo Sakaguchi, Kazuhiko Ochiai, Yasutomo Nasu, Mamoru Ouchida, Nam-Ho Huh, Kenji Shimizu, Yuji Kashiwakura, Haruki Kaku, Hiromi Kumon

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE   24 ( 6 )   789 - 794   2009.12

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    The reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3. a member of the Dkk gene family, is a tumor suppressor in a broad range of cancers. REIC/Dkk-3 transfected stable clones of mouse prostate cancer RM9 cells (RM9-REIC) and the empty vector-transfected control clone cells (RM9-EV) were established. Clones were used to evaluate the anti-cancer effects and a proteomics analysis of REIC/Dkk-3 continuous expression was performed. The RM9-REIC cells show a feeble appearance and the cell membrane shows irregular buds known as blebs. In vitro cell proliferation was significantly suppressed in RM9-REIC clones in comparison to the control. The apoptosis assay was done under standard culture conditions and RM9-REIC showed a higher incidence of apoptosis. The RM9-EV and RM9-REIC cells were orthotopically implanted into a C57BL/6 mouse prostate. After 2 weeks, the tumor growth was significantly inhibited in RM9-REIC cells in comparison to the control. Two-dimensional gel electrophoresis was used to examine the modification of protein expression by the gene transfection. The analysis with mass spectrometry disclosed that expression of peroxiredoxin-l, GST-P1. transgelin-2, MRP-L12, ARD, GRP78 and Sorcin were increased and eEF1A-1 and cyclophilin-40 protein were decreased in RM9-REIC cells. Therefore, REIC/Dkk-3 stable transfectants show a reduction of malignancy in mouse prostate cancer RM9 cells in vitro and in vivo. The result of the proteomics analysis might provide important clues to clarify the anti-cancer molecular mechanism of REIC/Dkk-3 gene transfer.

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  • Dynasore, a dynamin inhibitor, suppresses lamellipodia formation and cancer cell invasion by destabilizing actin filaments Reviewed

    Hiroshi Yamada, Tadashi Abe, Shun-Ai Li, Yuki Masuoka, Mihoko Isoda, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Akira Asai, Kohji Takei

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   390 ( 4 )   1142 - 1148   2009.12

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    Dynamic remodeling of actin filaments are bases for a variety of cellular events including cell motility and cancer invasion, and the regulation of actin dynamics implies dynamin, well characterized endocytotic protein. Here we report that dynasore, a inhibitor of dynamin GTPase, potently destabilizes F-actin in vitro, and it severely inhibits the formation of pseudopodia and cancer cell invasion, both of which are supported by active F-actin formation. Dynasore rapidly disrupted F-actin formed in brain cytosol in vitro, and the dynasore&apos;s effect on F-actin was indirect. Dynasore significantly suppressed serum-induced lamellipodia formation in U2OS cell. Dynasore also destabilized F-actin in resting cells, which caused the retraction of the plasma membrane. A certain amount of dynamin 2 in U2OS cells localized along F-actin, and co-localized with cortactin, a physiological binding partner of dynamin and F-actin. However. these associations of dynamin were partially disrupted by dynasore treatment. Furthermore, invasion activity of H1080 cell, a lung cancer cell line, was suppressed by approximately 40% with dynasore treatment. These results strongly suggest that dynasore potently destabilizes F-actin, and the effect implies dynamin. Dynasore or its derivative would be suitable candidates as potent anti-cancer drugs. (C) 2009 Elsevier Inc. All rights reserved.

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  • A comparison of proteomic profiles changes during 17beta-estradiol treatment in human prostate cancer PC-3 cell line. Reviewed

    Chen J,Huang P, Kaku H, Zhang K, Watanabe M, Saika T, Nasu Y, Kumon H

    Cancer Genomics Proteomics   2009.11

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  • Overexpression of the potential kinase serine/ threonine/tyrosine kinase 1 (STYK 1) in castration-resistant prostate cancer

    Chung S, Tamura K, Furihata M, Uemura M, Daigo Y, Nasu Y, Miki T, Shuin T, Fujioka T, Nakamura Y, Nakagawa H

    Cancer Sci   100 ( 11 )   2109 - 2114   2009.11

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  • The role of hepatocyte growth factor activator inhibitor-1(HAI-1)as a prognostic indicator in cervical cancer

    Nakamura K, Abarzua F, Hongo A, Kodama J, Nasu Y, Kumon H, Hiramatsu Y

    Int J Oncol   35 ( 2 )   239 - 248   2009.8

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  • Overexpressing PKIB in prostate cancer promotes its aggressiveness by linking between PKA and Akt pathways

    Chung S, Furihata M, Tamura K, Uemura M, Daigo Y, Nasu Y, Miki T, Shuin T, Fujioka T, Nakamura Y, Nakagawa H

    Oncogene   28 ( 32 )   2849 - 2859   2009.8

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  • Prospective Longitudinal Comparative Study of Health-Related Quality of Life in Patients Treated with Radical Prostatectomy or Permanent Brachytherapy for Prostate Cancer Reviewed

    Makoto Kobuke, Takashi Saika, Yoshiko Nakanishi, Shin Ebara, Daisuke Manabe, Tatsuya Uesugi, Hiroyuki Nose, Ryoji Arata, Tomoyasu Tsushima, Yasutomo Nasu, Hiromi Kumon

    ACTA MEDICA OKAYAMA   63 ( 3 )   129 - 135   2009.6

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    To determine health-related quality of life (HRQOL) after radical retropubic prostatectomy (RRP) or permanent prostate brachytherapy (BT), third party-conducted QOL surveys were prospectively compared. Between 2004 and 2005, 37 patients underwent RRP and 36 were treated with BT. A QOL survey consisting of the Medical Outcomes Study 36-Item Short Form (SF-36), the University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) and the International Prostate Symptoms Score (IPSS) was completed prospectively by a research coordinator at baseline, and at 1, 3, 6 and 12 months after treatment. The RRP patients scored well in general QOL except at I month after surgery, with their mental health better than at baseline by 6 months after surgery. Disease-specific QOL in RRP patients received a low score at I month for both urinary and sexual function, though urinary function rapidly recovered to baseline levels. BT patient QOL was not affected by the therapy except in the IPSS score. However, general and mental health scores in BT patients were inferior to those in RRP patients. This prospective study revealed differences in QOL after RRP and BT. These results will be helpful in making treatment decisions.

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  • Overexpression of REIC/Dkk-3 in Normal Fibroblasts Suppresses Tumor Growth via Induction of Interleukin-7

    Masakiyo Sakaguchi, Ken Kataoka, Fernando Abarzua, Ryuta Tanimoto, Masami Watanabe, Hitoshi Murata, Swe Swe Than, Kaoru Kurose, Yuji Kashiwakura, Kazuhiko Ochiai, Yasutomo Nasu, Hiromi Kumon, Nam-ho Huh

    JOURNAL OF BIOLOGICAL CHEMISTRY   284 ( 21 )   14236 - 14244   2009.5

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    We previously showed that the tumor suppressor gene REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through a mechanism triggered by endoplasmic reticulum stress. Adenovirus vectors show no target cell specificity and thus may elicit unfavorable side effects through infection of normal cells even upon intra-tumoral injection. In this study, we examined possible effects of Ad-REIC on normal cells. We found that infection of normal human fibroblasts (NHF) did not cause apoptosis but induced production of interleukin (IL)-7. The induction was triggered by endoplasmic reticulum stress and mediated through IRE1 alpha, ASK1, p38, and IRF-1. When Ad-REIC-infected NHF were transplanted in a mixture with untreated human prostate cancer cells, the growth of the cancer cells was significantly suppressed. Injection of an IL-7 antibody partially abrogated the suppressive effect of Ad-REIC-infected NHF. These results indicate that Ad-REIC has another arm against human cancer, an indirect host-mediated effect because of overproduction of IL-7 by mis-targeted NHF, in addition to its direct effect on cancer cells.

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  • Expression of Matriptase and Clinical Outcome of Human Endometrial Cancer Reviewed

    Keiichiro Nakamura, Atsushi Hongo, Junichi Kodama, Fernando Abarzua, Yasutomo Nasu, Hiromi Kumon, Yuji Hiramatsu

    ANTICANCER RESEARCH   29 ( 5 )   1685 - 1690   2009.5

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    Background: Matriptase, a type II transmembrane serine protease is involved in angiogenesis, degradation of extracellular matrix and in progression of some epithelial cancers. The purpose of the present study was to examine matriptase expression and evaluate its clinicopathological significance in endometrial cancer. Patients and Methods: Matriptase expression was examined in normal endometrium (n=20), endometrial hyperplasia (n=11) and endometrial cancer (n=65) samples. The distribution of cases that scored positive for each of the biological parameters examined was correlated with matriptase expression status obtained by immunohistochemistry. Results: Matriptase was found to be significantly overexpressed in endometrial cancer as compared with normal endometrium and endometrial hyperplasia. Interestingly, matriptase expression is associated with stage (p=0.010), grade (p=0.021), depth of myometrial invasion (p=0.004), cervical involvement (p=0.021), lymph node metastasis (p=0.009), LVS involvement (p=0.041) and peritoneal cytology (p=0.045). The high matriptase expression was a significant predictor for poor prognosis when compared with low matriptase expression (Disease-free survival rate; p=0.032, Overall survival rate; p=0.011). Conclusion: High matriptase expression in endometrial cancer may be associated with poor prognosis.

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  • Stanniocalcin 2 overexpression in castration-resistant prostate cancer and aggressive prostate cancer

    Tamura K, Furihata M, Chung S.Y, Uemura M, Yoshioka H, Iiyama T, Ashida S, Nasu Y, Fujioka T, Shuin T, Nakamura Y, Nakagawa H

    Cancer Sci   100 ( 5 )   914 - 919   2009.5

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  • Prostate-specific antigen 'bounce' after permanent 125I -implant brachytherapy in Japanese men:a multi-institutional pooled analysis

    Satoh T, Ishiyama H, Matsumoto K, Tsumura H, Kitano M, Hayakawa K, Ebara S, Nasu Y, Kumon H, Kanazawa S, Miki K, Egawa S, Aoki M, Toya K, Yorozu A, Nagata H, Saito S, Baba S

    BJU International   103 ( 8 )   1064 - 1068   2009.4

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  • Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression

    Masami Watanabe, Yuji Kashiwakura, Peng Huang, Kazuhiko Ochiai, Junichiro Futami, Shun-Ai Li, Munenori Takaoka, Yasutomo Nasu, Masakiyo Sakaguchi, Nam-Ho Huh, Hiromi Kumon

    INTERNATIONAL JOURNAL OF ONCOLOGY   34 ( 3 )   657 - 663   2009.3

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    The REIC/Dkk-3 gene has been reported to be a tumor suppressor and the expression is significantly down-regulated in a broad range of cancer cell types. The protein is secretory, but the physiological function remains unclear. This study demonstrated that recombinant REIC/Dkk-3 protein induced the differentiation of human CD14(+) monocytes into a novel cell type ((REIC/Dkx-3)Mo). (REIC/Dkk-3)Mo resembles immature dendritic cells generated with IL-4 and GM-CSF. Both these cell populations exhibit similar proportions of CD11c(+), CD40(+), CD86(+) and HLA-DR(+) cells and endocytic capacity, but (REIC/Dkk-3)Mo is negative for CD1a antigen. An analysis of the signal transducers and activators of transcription (STAT) pathways revealed that REIC/Dkk-3 induces phosphorylation of STAT 1 and STAT 3. Furthermore, intratumoral administration of REIC/Dkk-3 protein significantly suppressed tumor growth with CD11c(+) and CD8(+) (dendritic and killer T cell marker, respectively) cell accumulation and enhanced anticancer cytolytic activity of splenocytes. These data indicated a cytokine-like role of REIC/Dkk-3 protein in monocyte differentiation that might be exploited therapeutically.

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  • Expression of hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) in ovarian cancer

    Nakamura K, Abarzua F, Kodama J, Hongo A, Nasu Y, Kumon H, Hiramatsu Y

    Int J Oncol   34 ( 2 )   345 - 353   2009.2

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  • Hepatocyte growth factor activator inhibitor-2(HAI-2)is a favorable prognosis marker and inhibits cell growth through the apoptotic pathway in cervical cancer

    Nakamura K, Abarzua F, Hongo A, Kodama J, Nasu Y, Kumon H, Hiramatsu Y

    Annals of Oncology   20 ( 1 )   63 - 70   2009.1

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  • Initial report of hybrid radical prostatectomy for prostate cancer: reduced bleeding, clear vision, and secure surgical margins. Reviewed

    Saika T, Kobayashi Y, Watanabe T, Manabe D, Ebara S, Uehara S, Nasu Y, Kumon H

    Acta medica Okayama   62 ( 6 )   379 - 384   2008.12

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    To evaluate morbidity in Hybrid Radical Prostatectomy (HRP, hybridized laparoscopic and open retropubic radical prostatectomy). The operative and pathological outcomes obtained in 25 consecutive patients who underwent HRP were reviewed. The median operating time was 220 min, median blood loss was 550 ml, and no patient required an allogenic blood transfusion. No severe postoperative complications were observed. The surgical margin was positive in 12% of all patients, and in 1 patient with pT2 or less (4.5%). These results indicate that HRP is safe and may be able to combine the benefits of both laparoscopic and open procedures.

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  • Mechanistic analysis of resistance to REIC/Dkk-3-induced apoptosis in human bladder cancer cells. Reviewed

    Kobayashi T, Sakaguchi M, Tanimoto R, Abarzua F, Takaishi M, Kaku H, Kataoka K, Saika T, Nasu Y, Miyazaki M, Kumon H, Huh NH

    Acta medica Okayama   62 ( 6 )   393 - 401   2008.12

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    We have recently shown that a new therapeutic modality using the REIC/Dkk-3 gene (Ad-REIC) is effective against various human cancers, including those of prostate, testis and breast origins. The aim of the present study was to examine the sensitivity of bladder cancers to Ad-REIC and to clarify the molecular mechanisms that determine sensitivity/resistance. We found that 2 human bladder cancer cell lines, T24 and J82, are resistant to Ad-REIC. In T24 and J82 cells, the ER stress response and activation of JNK were observed in a manner similar to that in the sensitive PC3 cells. Translocation of Bax to mitochondria occurred in PC3 cells but not in T24 and J82 cells. Bcl-2 was remarkably overexpressed in T24 and J82 compared with the expression levels in sensitive cell lines. Treatment of T24 and J82 cells with a Bcl-2 inhibitor sensitized the cells to Ad-REIC-induced apoptosis. The results indicate that some human bladder cancers are resistant to apoptosis induced by overexpression of REIC/Dkk-3, which is at least in part due to up-regulation of Bcl-2. These results provide a basis for possible use of Bcl-2 as a marker of sensitive cancers and to try to sensitize resistant cancers to Ad-REIC by down-regulation of Bcl-2.

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  • An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis

    Fernando Abarzua, Yuji Kashiwakura, Munenori Takaoka, Masami Watanabe, Kazuhiko Ochiai, Masakiyo Sakaguchi, Takao Iwawaki, Ryuta Tanimoto, Yasutomo Nasu, Nam-ho Huh, Hiromi Kumon

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   375 ( 4 )   614 - 618   2008.10

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    Overexpression of REIC/Dkk-3 (a tumor suppressor gene) induces cancer cell apoptosis through endoplasmic reticulum (ER) stress. Therefore, the identification of the portion of REIC/Dkk-3 that causes ER stress may be essential for the development of cancer treatment based on REIC/Dkk-3. Here, we made several truncated forms of REIC/Dkk-3 and investigated their therapeutic potentials against prostate cancer. Among three truncated forms, a variant comprising the N-terminal 78 amino acid region of REIC/Dkk-3 ((1-78) REIC/Dkk-3) most strongly induced ER stress and apoptosis in human prostate cancer cells (PC3). For in vivo gene expression, we coupled a biodegradable polymer with naked DNA, which attained robust trans-gene expression in PC3-derived subcutaneous tumor. In therapeutic experiments, we demonstrated that multiple direct injections of polymer-conjugated (1-78)REIC/Dkk-3 plasmid provoke ER stress and significantly reduced the subcutaneous tumor volume compared with the control group. We suggest this non-viral strategy may be an effective alternative to viral gene therapy. (C) 2008 Elsevier Inc. All rights reserved.

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  • Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3-Induced Apoptosis

    Yuji Kashiwakura, Kazuhiko Ochiai, Masami Watanabe, Fernando Abarzua, Masakiyo Sakaguchi, Munenori Takaoka, Ryuta Tanimoto, Yasutomo Nasu, Nam-ho Hub, Hiromi Kumon

    CANCER RESEARCH   68 ( 20 )   8333 - 8341   2008.10

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    REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, has been investigated in gene therapy studies. Our previous study suggested that REIC/Dkk-3-induced apoptosis mainly resulted from phosphorylation of c-Jun-NH2 kinase (JNK) in prostate cancer cells. However, the precise mechanisms, especially the molecular mechanisms regulating JNK phosphorylation, remain unclear. In this study, we investigated the mechanisms participating in JNK phosphorylation in the context of a refractory cancer disease, malignant mesothelioma (MM). Adenovirus-mediated overexpression of REIC/Dkk-3 induced apoptosis mainly through JNK activation in immortalized MM cells (211H cells). Interestingly, transcriptional down-regulation of inhibition of differentiation-1 (Id-1) was detected in REIC/Dkk-3-overexpressed 211H cells. Moreover, restoration of Id-1 expression antagonized REIC/Dkk-3-induced JNK phosphorylation and apoptosis. Mutagenesis experiments with the 2.1-kb human Id-1 promoter revealed that activating transcription factor 3 (ATF3) and Smad interaction, with their respective binding motifs, was essential for REIC/Dkk-3-mediated suppression of Id-1 promoter activity. ATF3 activation was probably induced by endoplasmic reticulum stress. Finally, we showed strong antitumor effects from REIC/Dkk-3 gene transfer into the pleural cavity in an orthotopic MM mouse model. Relative to control tumor tissue, REIC/Dkk-3-treated tumor tissue showed down-regulated expression of Id-1 mRNA, enhanced expression of phosphorylated JNK, and an increased number of apoptotic cells. In summary, we first showed that both ATF3 and Smad were crucially and synergistically involved in down-regulation of Id-1, which regulated JNK phosphorylation in REIC/Dkk-3-induced apoptosis. Thus, gene therapy with REIC/Dkk-3 may be a promising therapeutic tool for MM. [Cancer Res 2008;68(20):8333-41]

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  • The benefits of clamping the renal artery in laparoscopic partial nephrectomy Reviewed

    Yasuyuki Kobayashi, Takashi Saika, Daisuke Manabe, Yasutomo Nasu, Hiromi Kumon

    ACTA MEDICA OKAYAMA   62 ( 4 )   269 - 273   2008.8

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    The purpose of this study is to compare the performance of laparoscopic partial nephrectomy (LPN) with and without clamping of the renal artery and to evaluate the impact of clamping on postoperative renal function. A total of 20 patients underwent LPN, 13 without and 7 with clamping of the renal artery. The 2 groups were compared with respect to complications, blood loss, operative time, mean tumor size, and incidence of positive margins. Renal function was evaluated by pre- and postoperative renal scintigraphy using (99m)Technetium-mercaptoacetyltriglycine (Tc-99m-MAG3). Intraoperative blood loss was significantly higher in the group without clamping than in the group with clamping (p = 0.04). In the group with clamping, the median warm ischemic time was 35 min (range 25-40 min). The serum creatinine values and the renal scintigraphy showed no influence on postoperative renal function with or without clamping. In the group without clamping, 2 cases were showed positive surgical margins. The procedure performed with clamping of the renal artery is superior to the procedure performed without clamping as it provides the advantages of controlling hemorrhaging without injury to renal function and prolonging the surgical time and allowing for more accurate resection of renal tumors.

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  • Adenovirus-mediated REIC/DKK-3 gene transfer prevented mesothelioma tumor progressions in orthotopic mice model Reviewed

    Kashiwakura Yuji, Watanabe Masami, Abarzua Fernando, Sakaguchi Masakiyo, Takaoka Munenori, Tanimoto Ryuta, Nasu Yasutomo, Huh Nam-ho, Kumon Hiromi

    JOURNAL OF GENE MEDICINE   10 ( 4 )   469 - 470   2008.4

  • REIC/DKK-3 as a potential gene therapeutic agent against human testicular cancer Reviewed

    Tanimoto Ryuta, Abarzua Fernando, Sakaguchi Masakiyo, Nasu Yasutomo, Kumon Hiromi, Huh Nam-Ho

    JOURNAL OF GENE MEDICINE   10 ( 4 )   454   2008.4

  • A comparative study of the oncological long-term outcome of laparoscopic nephroureterectomy and standard nephroureterectomy for upper urinary tract transitional cell carcinoma Reviewed

    Kobayashi Yasuyuki, Manabe Daisuke, Uehara Shinya, Watanabe Toyohiko, Saika Takashi, Nasu Yasutomo, Kumon Hiromi

    JOURNAL OF UROLOGY   179 ( 4 )   291   2008.4

  • A rare tumor in the adrenal region: Neuron-specific enolase (NSE)-producing leiomyosarcoma in an elderly hypertensive patient Reviewed

    Junko Goto, Fumio Otsuka, Ryo Kodera, Tomoko Miyoshi, Masaru Kinomura, Hiroyuki Otani, Yukari Mimura, Toshio Ogura, Hiroyuki Yanai, Yasutomo Nasu, Hirofumi Makino

    ENDOCRINE JOURNAL   55 ( 1 )   175 - 181   2008.2

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    A 73-year-old Japanese woman was referred for examination of right flank pain and progressive hypertension. Abdominal CT incidentally detected a right adrenal mass 8 cm in size. The tumor exhibited isodensity by CT and contained high-intense lesion by T2-weighted MRI. Scintigraphy with I-131-metaiodobenzylguanidine and I-131-adosterol showed no abnormal uptake by whole body scan. Positron emission tomography scan with F-18-2-fluoro-D-deoxyglucose demonstrated an exclusive uptake in the right adrenal mass. Adrenocortical hormone levels and catecholamine secretion were within normal range; however, the level of serum neuron-specific enolase (NSE) was found to be markedly high. After controlling systemic blood pressure with an alpha 1-blocker, the right adrenal tumor was surgically removed, along with the right kidney and inferior vena cava which adhered to it. The tumor was pathologically proven to be leiomyosarcoma, which was immunohistochemically positive with a-smooth muscle actin and negative with CD57, S-100 and c-kit proteins. Notably, NSE protein was massively expressed in the resected tumor. After surgery blood pressure was controlled with regular medication and serum NSE levels have since normalized. The possibility of leiomyosarcoma should be kept in mind in adrenal incidentalomas with rapid growth and atypical radiological images. Our findings suggest that circulating NSE levels may be clinically useful for early detection of recurrence.

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  • Iodine-125 seed implantation (permanent brachytherapy) for clinically localized prostate cancer Reviewed

    Shin Ebara, Yoshihisa Katayama, Ryuta Tanimoto, Kohei Edamura, Hiroyuki Nose, Daisuke Manabe, Tomoko Kobayashi, Yasuyuki Kobayashi, Makoto Kobuke, Mitsuhiro Takemoto, Takashi Saika, Yasutomo Nasu, Susumu Kanazawa, Hiromi Kumon

    ACTA MEDICA OKAYAMA   62 ( 1 )   9 - 13   2008.2

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    From January 2004 to March 2007, 308 patients with clinically localized prostate cancer were treated using iodine-125 (I-125) seed implantation (permanent brachytherapy) at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. We evaluated the treatiment's efficacy and morbidity in 300 prostate cancer patients who were followed up for more than I month after brachytherapy. Based on the National Comprehensive Cancer Network (NCCN) guidelines, patients with a prostate volume of less than 40 ml in transrectal ultrasound imaging were classified as low or intermediate risk. The median patient age was 67 years (range 50 to 79 years), the median prostate-specific antigen (PSA) value before biopsy was 6.95 ng/ml (range 1.13 to 24.7 ng/ml), and the median prostate volume was 24.33 ml (range 9.3 to 41.76 ml). The median follow-up was 18 months (range 1 to 36 months) and the PSA levels decreased in almost all patients after brachytherapy. Although 194 of 300 patients (64.7%) complained of difficulty in urination, pollakisuria/urgency, miction pain, and/or urinary incontinence, all of which might be associated with radiation prostatitis during the first month after brachytherapy, these symptoms gradually improved. I-125 seed implantation brachytherapy is safe and effective for localized prostate cancer within short-term follow up.

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  • Expression of the serine protease hepsin and clinical outcome of human endometrial cancer

    Matsuo T, Nakamura K, Takamoto N, Kodama J, Hongo A, Abrzua F, Nasu Y, Kumon H, Hiramatsu Y

    Anticancer Research   28   159 - 164   2008

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  • New highly potent and specific E6 and E7 siRNAs for treatment of HPV16 positive cervical cancer

    Yamato K, Yamada T, Kizaki M, Ui-Tei K, Natori Y, Fujino M, Nishihara T, Ikeda Y, Nasu Y, Saigo K, Yoshinouchi M

    Cancer Gene Therapy   15   140 - 153   2008

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  • Secretory leukoprotease inhibitor inhibits cell growth through apoptotic pathway on ovarian cancer

    Nakamura K, Takamoto N, Hongo A, Kodama J, Abrzua F, Nasu Y, Kumon H, Hiramatsu Y

    Oncol Rep   19 ( 5 )   1085 - 1091   2008

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  • Hepsin inhibits the cell growth of endometrial cancer

    Nakamura K, Takamoto N, Abarzua F, Hongo A, Kodama J, Nasu Y, Kumon H, Hiramatsu Y

    Int J Mol Med   22 ( 3 )   389 - 397   2008

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  • REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer

    K. Kawasaki, M. Watanabe, M. Watanabe, M. Sakaguchi, Y. Ogasawara, K. Ochiai, Y. Nasu, H. Doihara, H. Doihara, Y. Kashiwakura, N. H. Huh, H. Kumon, H. Kumon, H. Date

    Cancer Gene Therapy   16 ( 1 )   65 - 72   2008

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    The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH2-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents. © 2009 Nature Publishing Group All rights reserved.

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  • Routine transurethral biopsy of the bladder is not necessary to evaluate the response to bacillus Calmette-Guerin therapy Reviewed

    Takanori Murakami, Shin Ebara, Takashi Saika, Shin Irie, Katsuji Takeda, Yoshio Maki, Sadayuki Miyaji, Daisuke Manabe, Haruki Kaku, Yasutomo Nasu, Tomoyasu Tsushima, Hiromi Kumon

    ACTA MEDICA OKAYAMA   61 ( 6 )   341 - 344   2007.12

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    We evaluated the need for transurethral biopsy at first follow-up after intravesical. bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer. The records of 84 patients with superficial bladder cancer who received a 6- or 8-week course of BCG were reviewed. Pathological results before BCG, cystoscopic findings, urinary cytology, and biopsy results for evaluation of BCG therapy were reviewed. All 19 patients with positive urinary cytology had evidence of positive bladder biopsy results. Fifty-three of 54 patients (98.1 %) with no visible recurrent tumor and negative urinary cytology demonstrated negative pathological results on bladder biopsy. When not found in conjunction with positive urinary cytology, erythematous mucosa on cystoscopy was not an indicator of tumor recurrence or residual cancer. In conclusion, routine transurethral biopsy of the bladder for evaluating the response to BCG intravesical therapy is not necessary in patients who have no visible tumor on cystoscopy and negative urinary cytology.

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  • The efficacy of neoadjuvant androgen deprivation therapy as a prostate volume reduction before brachytherapy for clinically localized prostate cancer Reviewed

    Shin Ebara, Daisuke Manabe, Yasuyuki Kobayashi, Ryuta Tanimoto, Takashi Saika, Yasutomo Nasu, Shirou Saito, Takefumi Satoh, Kenta Miki, Katsuyoshi Hashine, Hiromi Kumon

    ACTA MEDICA OKAYAMA   61 ( 6 )   335 - 340   2007.12

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    From September 2003 to December 2005, 188 patients who visited our hospital and allied institutions for the purpose of prostate brachytherapy were administrated hormonal therapy for volume reductions before brachytherapy. The pretreatment and posttreatment of prostate volume using a transrectal ultrasound volumetric study and the types and duration of hormonal therapy were analyzed. We administered 91 patients with Luteinizing hormone-releasing hormone (LH-RH) agonis, 49 patients with anti-androgen (bicaltamide/flutamide), and 48 patients with maximum androgen blockade (MAB). The duration of the hormonal therapy was 1-3 months for 49 patients, 4-6 months for 59 patients, 7-9 months for 40 patients, 10-12 months for 32 patients, and over 13 months for 8 patients. Before the initiation of hormonal therapy, the mean prostate volume was 35.12 ml (11.04-78.71 ml), and the average of prostate volume before and after hormonal therapy was 36.79 ml and 24.79 ml, respectively (a 32.4 % reduction). The prostate volume reduction rate was 32.0 % for the LH-RH agonist only, 18.1 % for the anti-androgen only and 41.2 % for the NUB. No statistically significant difference was observed for the duration of hormonal therapy between 3 groups. A three-month course of the neoadjuvant LH-RH agonist indicated a sufficient volume reduction effectiveness for a large prostate volume.

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  • Adenovirus-mediated REIC/Dkk-3 gene transfer inhibits tumor growth and metastasis in an orthotopic prostate cancer model Reviewed

    K. Edamura, Y. Nasu, M. Takaishi, T. Kobayashi, F. Abarzua, M. Sakaguchi, Y. Kashiwakura, S. Ebara, T. Saika, M. Watanabe, N-H Huh, H. Kumon

    CANCER GENE THERAPY   14 ( 9 )   765 - 772   2007.9

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    We had previously reported that REIC/Dkk-3, a member of the Dickkopf ( Dkk) gene family, works as a tumor suppressor. In this study, we evaluated the therapeutic effects of an intratumoral injection with adenoviral vector encoding REIC/Dkk-3 gene ( Ad-REIC) using an orthotopic mouse prostate cancer model of RM-9 cells. We also investigated the in vivo anti-metastatic effect and in vitro anti-invasion effect of Ad-REIC gene delivery. We demonstrated that the Ad-REIC treatment inhibited prostate cancer growth and lymph node metastasis, and prolonged mice survival in the model. These therapeutic responses were consistent with the intratumoral apoptosis induction and in vitro suppression of cell invasion/migration with reduced matrix metalloprotease-2 activity. We thus concluded that in situ Ad-REIC/Dkk-3 gene transfer may be a promising therapeutic intervention modality for the treatment of prostate cancer.

    DOI: 10.1038/sj.cgt.7701071

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  • Health-related quality of life after radical cystectomy for bladder cancer in elderly patients with an ileal conduit, ureterocutaneostomy, or orthotopic urinary reservoir: A comparative questionnaire survey Reviewed

    Takashi Saika, Ryoji Arata, Tomoyasu Tsushima, Yasutomo Nasu, Bunzo Suyama, Katsuji Takeda, Shin Ebara, Daisuke Manabe, Tomoko Kobayashi, Ryuta Tanimoto, Hiromi Kumon

    ACTA MEDICA OKAYAMA   61 ( 4 )   199 - 203   2007.8

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    To compare the health-related quality of life of elderly patients after radical cystectomy for bladder cancer in urinary diversion groups: ileal conduit, ureterocutaneostomy, or orthotopic urinary reservoir. The 109 participating elderly patients aged 75 or older completed self-reporting questionnaires: the QNQ-C30, and on satisfaction with urinary diversion methods. Fifty-six patients had undergone constructions for ileal conduit diversion, 31 for ureterocutaneostomy, and 22 for orthotopic urinary reservoir (OUR). The median follow-up period for each group was 4.0 years (range 0.3-11.2), 4.5 years (range 0.3-18.0), and 3.3 years (range 0.3-6.7), respectively. Regardless of the type of urinary diversion, the majority of patients reported having good overall quality of life, although with some problem of pain. No significant differences among urinary diversion subgroups were found in any quality of life area in the QLQ-C30 questionnaire. More patients in the OUR sub-group felt disappointment than those in the ileal conduit or cutaneostomy sub-groups. However, a questionnaire which asked which diversion method would be preferable showed a trend that more patients in the OUR subgroup would have chosen the same one. Health-related quality of life appeared relatively good in these 3 groups. Patient demands and expectations may be so different from the results that the details of each urinary diversion method should be explained thoroughly. OUR construction could be a candidate even for elderly patients.

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  • Orthotopic ileal neobladder versus sigmoidal neobladder: A "Quality of life" (QOL) survey Reviewed

    Ryoji Arata, Takashi Saika, Tomoyasu Tsushima, Fernando Abarzua, Yasutomo Nasu, Hiromi Kumon

    ACTA MEDICA OKAYAMA   61 ( 4 )   229 - 234   2007.8

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    To compare the quality of life (QOL) in patients with ileal neobladder and sigmoidal neobladder, a retrospective survey was conducted using a formulated questionnaire. Between January and March 1999, a QOL survey was conducted using self-administered questionnaires (EORTC QLQ-C30, IPSS, supplemented with detailed questionnaires about continence, sexual function, and patient's satisfaction with the selected urinary diversion method) for 78 patients with orthotopic urinary reservoir (OUR) who were followed-up for more than 3 months after cystectomy. Among 78 patients, 63 had OUR using an ileal segment (male/female 59/4, median age: 70.8 years old, median follow-up: 1.7 years). Fifteen patients had OUR using a sigmoidal segment (male/female = 13/2, median age: 71.9, median follow-up: 3.9). The QLQ-C30 functional evaluation and the items in relation to sexual function showed no differences between the 2 groups. Concerning the voiding condition, bladder emptying, frequency, and urgency, scores in the sigmoidal OUR group were significantly higher. The QOL score concerning voiding conditions, daytime, and nighttime continence and quantity of pad showed a better score in the ileal OUR group. Concerning the satisfaction with methods of urinary diversion, patients in the sigmoidal OUR group expressed less satisfaction than their preoperative expectations. Considering several postoperative voiding conditions, ileal OUR seems superior to sigmoidal OUR.

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  • Natural course of lower urinary tract symptoms following discontinuation of alpha-1-adrenergic blockers in patients with benign prostatic hyperplasia Reviewed

    Teruhiko Yokoyama, Toyohiko Watanabe, Takashi Saika, Yasutomo Nasu, Hiromi Kumon, Yoshiyuki Miyaji, Atsushi Nagai

    INTERNATIONAL JOURNAL OF UROLOGY   14 ( 7 )   598 - 601   2007.7

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    Objectives: alpha 1-adrenergic blockers (alpha b) remain the first-line therapy in men with lower urinary tract symptoms (LUTS). The current published work advocates continued use of alpha b for their effect to be maintained. However, some patients decide to discontinue use of the medication after their symptoms are relieved and can keep good conditions. In this study, we investigated the natural course of LUTS after the discontinuation of successful treatment of alpha b.
    Methods: Among 75 patients with LUTS who stopped alpha b medication once their symptoms improved, 60 patients (age, 50-87 years; median, 70) who could be followed for at least 12 months after discontinuation of alpha b were analyzed in this study. Evaluations included a clinical determination of the International Prostate Symptom Score (IPSS), peak flow rate (Qmax) and postvoid residual urine volume (PVR). Upon patient request or in cases of PVR more than 100 mL, administration of alpha b was resumed.
    Results: Eighteen out of the 60 patients (30%) asked for re-treatment within 12 months after discontinuation (re-treatment group). The other 42 patents were able to maintain good condition without medication (discontinuation group). The IPSS was 15.9, 8.7, 10.1, 10.2, 9.7, 8.8 and 9.0, on the first visit, just before discontinuation, and 1, 3, 6, 9 and 12 months after stopping treatment among the discontinuation group, respectively. Similarly, Qmax was 10.6, 14.8, 14.2, 14.3, 14.7, 13.2 and 13.6 mL/ s, respectively. Treatment periods, prostatic volume and peak flow rates just before discontinuation of medication differed significantly between the re-treatment and discontinuation group.
    Conclusions: In spite of the short follow-up periods, these results suggest that selected patients with relatively small prostatic volume and good flow rates after therapy can discontinue alpha b medication after their symptoms improve.

    DOI: 10.1111/j.1442-2042.2007.01784.x

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  • Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3 Reviewed

    Fernando Abarzua, Masakiyo Sakaguchi, Ryuta Tanimoto, Hiroyuki Sonegawa, Dai-Wei L, Kohei Edamura, Tomoko Kobayashi, Masami Watanabe, Yuji Kashiwakura, Haruki Kaku, Takashi Saika, Keiichiro Nakamura, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE   20 ( 1 )   37 - 43   2007.7

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    We recently showed that overexpression of REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in a tumor cell-specific manner. The aim of the present study was to determine the mechanisms underlying the selective induction of apoptosis. At first, we found a mouse renal carcinoma cell line, RENCA, to be extremely sensitive to an adenovirus carrying REIC/Dkk-3 (Ad-REIC), and we showed that activation of c-Jun N-terminal kinase (JNK) was a critical step in cell death, i.e. a process similar to that in human prostate and testicular cancer observed in our previous studies. Among the proteins interfering with the activation of JNK, heat shock protein (Hsp)70/72 was reduced in expression in RENCA cells compared with that in NIH3T3 cells. An Hsp70/72 inducer protected RENCA cells from Ad-REIC-induced apoptosis, while an Hsp70/72 inhibitor sensitized NIH3T3 cells for apoptosis induction. These results indicate that functionally active Hsp70/72 is a key factor in tumor cell-specific induction of apoptotic cell death and that analyses of the expression levels of Hsp70/72 may be essential in determining the significance of Ad-REIC-based gene therapy against human cancer.

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  • Molecular features of hormone-refractory prostate cancer cells by genome-wide gene expression profiles Reviewed

    Kenji Tamura, Mutsuo Furihata, Tatsuhiko Tsunoda, Shingo Ashida, Ryo Takata, Wataru Mara, Hiroki Yoshioka, Yataro Daigo, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Konaka, Mikio Namiki, Keiichi Tozawa, Kenjiro Kohri, Nozomu Tanji, Masayoshi Yokoyama, Toru Shimazui, Hideyuki Akaza, Yoichi Mizutani, Tsuneharu Miki, Tomoaki Fujioka, Taro Shuin, Yusuke Nakamura, Hidewaki Nakagawa

    CANCER RESEARCH   67 ( 11 )   5117 - 5125   2007.6

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    One of the most critical issues in prostate cancer clinic is emerging hormone-refractory prostate cancers (HRPCs) and their management. Prostate cancer is usually androgen dependent and responds well to androgen ablation therapy. However, at a certain stage, they eventually acquire androgen-independent and more aggressive phenotype and show poor response to any anticancer therapies. To characterize the molecular features of clinical HRPCs, we analyzed gene expression profiles of 25 clinical HRPCs and 10 hormone-sensitive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdissection. An unsupervised hierarchical clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from three patients were closely clustered regardless of metastatic organs. A supervised analysis and permutation test identified 36 up-regulated genes and 70 down-regulated genes in HRPCs compared with HSPCs (average fold difference &gt; 1.5; P &lt; 0.0001). We observed overexpression of AR, ANLN, and SNWPE and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. AR overexpression is likely to play a central role of hormone-refractory phenotype, and other genes we identified were considered to be related to more aggressive phenotype of clinical HRPCs, and in fact, knockdown of these overexpressing genes by small interfering RNA resulted in drastic attenuation of prostate cancer cell viability. Our microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression and to identify molecular targets for development of HRPC treatment.

    DOI: 10.1158/0008-5472.CAN-06-4040

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  • Suicide gene therapy with adenoviral delivery of HSV-tK gene for patients with local recurrence of prostate cancer after hormonal therapy Reviewed International journal

    Nasu Yasutomo, Saika Takashi, Ebara Shin, Kusaka Nobuyuki, Kaku Haruki, Abarzua Fernando, Manabe Daisuke, Thompson Timothy C, Kumon Hiromi

    MOLECULAR THERAPY   15 ( 4 )   834 - 840   2007.4

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    We conducted a Phase I study of in situ herpes simplex virus thymidine kinase (HSV-tk) plus ganciclovir (GCV) gene therapy, which was approved by the Japanese government as the first prostate cancer gene therapy trial. Major inclusion criteria were local recurrence of prostate cancer after hormonal therapy and no metastasis. Adv.HSV-tk was injected directly into the prostate in escalating doses from 10(9) to 10(10) infection units, followed by intravenous administration of GCV for 14 days. Eight patients received nine courses of this gene therapy. The detection of vector DNA in blood/urine was only transient and no remarkable adverse events were observed in any patient. With regard to clinical response, significant prolongation of the median serum prostate-specific antigen (PSA) doubling time from 2.9 to 6.2 months (P = 0.041) was detected. In five patients (six injections), a clear decrease of PSA values was observed. One patient showed repeated clinical response after repeated injections. Serum cytokine analysis showed no notable changes after treatment. Fluorescence-activated cell sorting analysis also showed no influence on phenotypic distribution in peripheral blood samples, except for an increasing trend of CD8(+)/HLA-DR(+) after therapy. This study confirmed the safety profile and possibility of clinical response at the surrogate marker level in a clinical trial of HSV-tk gene therapy for hormone-refractory prostate cancer.

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  • Comparative study of oncologic outcome of laparoscopic nephroureterectomy and standard nephroureterectomy for upper urinary tract transitional cell carcinoma Reviewed

    Daisuke Manabe, Takashi Saika, Shin Ebara, Shinya Uehara, Atsushi Nagai, Ryuji Fujita, Shin Irie, Daisuke Yamada, Tomoyasu Tsushima, Yasutomo Nasu, Hiromi Kumon

    UROLOGY   69 ( 3 )   457 - 461   2007.3

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    OBJECTIVES To determine the oncologic safety of laparoscopic nephroureterectomy (LNU), we compared the long-term oncologic outcome of LNU versus open nephroureterectomy (ONU) in patients with upper tract transitional cell carcinoma.
    METHODS A total of 367 nephroureterectomy procedures were performed at our institutes for upper tract transitional cell carcinoma without distant metastases. Of 224 patients without concomitant or previous bladder cancer, 58 underwent LNU with open intact specimen retrieval plus open distal ureter and bladder cuff removal and 166 underwent ONU. Their data were reviewed and analyzed retrospectively. The mean follow-up was 13.6 months (range 14 to 34) for the LNU group and 28.0 months (range 14 to 36) for the ONU group.
    RESULTS Bladder recurrence was recognized in 19 patients (32.8%) after LNU at a median follow-up of 5.6 months compared with 63 patients (38.0%) after ONU. Local recurrence only developed in 2 patients (1.1%) after ONU. One port site metastasis occurred in a patient who had undergone LNU. Distant metastases developed in 10 patients (17.2%) after LNU and 33 patients (19.9%) after ONU. The frequency of bladder recurrence, local recurrence, and distant metastases did not differ significantly between the two groups. The actual disease-free 2-year survival rates were similar (75.6% versus 81.7%). In all patients, the risk of metastases and death increased with advanced tumor stage and grade, but not by surgical procedure.
    CONCLUSIONS In the surgical management of upper tract transitional cell carcinoma, LNU does not negatively affect long-term oncologic control and can be considered an alternative modality. Tumor stage and grade are, however, important prognostic factors in the incidence of metastases and cancer-specific mortality.

    DOI: 10.1016/j.urology.2006.11.005

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  • REIC/Dkk-3 as a potential gene therapeutic agent against human testicular cancer Reviewed

    Ryuta Tanimoto, Fernando Abarzua, Masakiyo Sakaguchi, Mikiro Takaishi, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE   19 ( 3 )   363 - 368   2007.3

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    Human testicular cancer is very sensitive to chemotherapy and radiation therapy and is regarded as a curable cancer. The cancer prevails in the young reproductive generation and testicular dysfunction is often observed as a side effect, remaining a serious challenge. In the present study, we examined the potential utility of REIC/Dkk-3-based gene therapy against human testicular cancer. Expression of REIC/Dkk-3 was reduced in all of the human seminoma and non-seminomatous germ cell tumor tissues. Overexpression of REIC/Dkk-3 using an adenovirus vector (Ad-REIC) induced apoptosis in a testicular germ cell cancer cell line NCCIT but not in normal human fibroblasts. c-Jun terminal kinase (JNK) was activated by Ad-REIC and the induction of apoptosis was abrogated by a JNK inhibitor. A single intratumoral injection of Ad-REIC markedly inhibited the tumorigenic growth of NCCIT cells in nude mice. These results indicate that Ad-REIC may lead to developing less insulting and non-genotoxic therapeutic measures against human testicular cancer.

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  • Primary aldosteronism caused by a unilateral adrenal adenoma accompanied by autonomous cortisol secretion

    Suzuki J, Otsuka F, Inagaki K, Otani H, Miyoshi T, Terasaka T, Ogura T, Omori M, Nasu Y, Makino H

    Hypertens Res   30 ( 4 )   367 - 373   2007

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  • Implication of amphiphysin 1 and dynamin 2 in tubulobulbar complex formation and spermatid release

    Kusumi N, Watanabe M, Yamada H, Li S, Kashiwakura Y, Matsukawa T, Nagai A, Nasu Y, Kumon H, Takei K

    Cell Structure and Function   32   101 - 113   2007

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  • Phase study of adenoviral vector delivery of HSV-tk gene and the intravenous administration of ganciclovir in men with local recurrence of prostate cancer after hormonal therapy Reviewed

    Nasu Yasutomo, Kaku Haruki, Ebara Shin, Saika Takashi, Thompson Timothy C, Kumon Hiromi

    JOURNAL OF GENE MEDICINE   8 ( 12 )   1443   2006.12

  • Telomerase-specific replication-selective virotherapy for prostate cancer Reviewed

    Kaku Haruki, Nasu Yasutomo, Huang Peng, Saika Takashi, Kagawa Shunsuke, Fujiwara Toshiyoshi, Kumon Hiromi, Urata Yasuo

    JOURNAL OF GENE MEDICINE   8 ( 12 )   1454   2006.12

  • Phase I/II Study of Adenoviral Vector Delivery of HSV-tk Gene and the Intravenous Administration of Ganciclovir in Men with Local Recurrence of Prostate Cancer after Hormonal Therapy Reviewed

    Nasu Yasutomo, Kaku Haruki, Ebara Shin, Saika Takashi, Kumon Hiromi, Thompson Timothy C

    MOLECULAR THERAPY   13   S19 - S20   2006.5

  • Effects of radiofrequency ablation on individual renal function: Assessment by technetium-99m mercaptoacetyltriglycine renal scintigraphy Reviewed

    T Mukai, S Sato, T Iguchi, H Mimura, K Yasui, H Gobara, T Saika, Y Nasu, H Kumon, S Kanazawa

    ACTA MEDICA OKAYAMA   60 ( 2 )   85 - 91   2006.4

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    We quantitatively evaluated total and individual renal function by technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) renal scintigraphy before and after radiofrequency ablation (RFA) of renal tumors. Eleven patients who underwent Tc-99m MAG3 renal scintigraphy I week before and after RFA were evaluated (7 men and 4 women; age range: 23-83 years; mean age: 60.6 years). Five patients had solitary kidneys, and five had normally or minimally functioning contralateral kidneys. One patient had a renal cell carcinoma in the contralateral. kidney. One patient with a solitary kidney underwent RFA a second time for a residual tumor. In patients with a solitary kidney, MAG3 clearance decreased after 5 of 6 RFAs, and in patients with a normally functioning contralateral kidney, MAG3 clearance decreased after 4 of 5 RFAs, but no significant differences were observed between before and after treatments. In addition to the total MAG3 clearance, the split MAG3 clearance was evaluated in patients with a normally functioning contralateral. kidney. MAG3 clearance decreased in 4 of 5 treated kidneys, while it adversely increased in the contralateral kidneys after 4 of 5 RFAs. No significant differences, however, were observed between before and after treatments. The results of our study revealed no significant differences in sCr, BUN, CCr, or MAG3 clearance between pre- and post-RFA values. These results support data regarding the functional impact and safety of renal RFA in published reports. We evaluated total and individual renal function quantitatively using Tc-99m MAG3 renal scintigraphy before and after treatment. This scintigraphy was very useful in assessing the effects of RFA on renal function.

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  • Time course of serum testosterone and luteinizing hormone levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer Reviewed

    H Kaku, T Saika, T Tsushima, S Ebara, T Senoh, T Yamato, Y Nasu, H Kumon

    PROSTATE   66 ( 4 )   439 - 444   2006.3

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    INTRODUCTION. In order to elucidate the influence of hormone-releasing hormone (LHRH) agonist therapy cessation on pituitary/testicular function and its clinical implications, we investigated prospectively hormonal (luteinizing hormone: LH; testosterone: T) responses in patients with prostate cancer who received long-term LH-RH 10 agonist therapy.
    PATIENTS AND METHODS. A consecutive 32 patients who had received LH-RH agonist therapy over 24 months were enrolled. As a baseline, T and LH were measured at the time of LHRH agonist therapy cessation, monthly for 3 months, and subsequently, every 3 months.
    RESULTS. The median duration of LH-RH agonist therapy was 30 months (24-87 months) with median follow-up duration of 24 months following cessation. All patients had castrated T levels and suppressed LH levels at baseline. Median duration of castrated T levels following cessation was 6 months. Median time to normalization of T levels was 24 months. LH levels returned to normal within 3 months in all cases. Patients who received androgen deprivation therapy for 30 months or longer required a longer time for recovery of T levels. Patients over 65 years of age showed a statistically significant longer time for recovery of T levels (P = 0.0167).
    CONCLUSIONS. Long-term LH-RH agonist therapy has remarkable effects on serum T level that last for a significant time after cessation, a fact that should be applied to the interpretation of both PSA and serum T levels after cessation of androgen deprivation therapy.

    DOI: 10.1002/pros.20341

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  • Combination chemotherapy with estramustine phosphate, ifosfamide and cisplatin for hormone-refractory prostate cancer Reviewed

    H Kaku, T Saika, T Tsushima, A Nagai, T Yokoyama, F Abarzua, S Ebara, D Manabe, Y Nasu, H Kumon

    ACTA MEDICA OKAYAMA   60 ( 1 )   43 - 49   2006.2

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    We evaluated the efficiency and toxicity of estramustine phosphate (ECT), ifosfamide (IFM) and cisplatin (CDDP) combination chemotherapy in twenty-one patients with hormone-refractory prostate cancer (HRPC), for which there is currently no effective treatment. Patients received a daily dose of 560 mg ECT in combination with 1.2 g/m(2) IFM on days 1 to 5 and 70 mg/m(2) CDDP on day 1. This combination therapy was given every 3 to 4 weeks. An objective response of more than 50% reduction in prostate-specific antigen was observed in 9 of 18 patients (50% and a more than 50% reduction in bi-dimensionally measurable soft-tissue lesions was observed in 2 of 7 patients (29%). The median duration of response among the cases showing partial response was 40 weeks, while the median duration of response of overall partial-response plus stable cases was 30 weeks. The median survival duration of all cases was 47 weeks. Toxicity was modest and acceptable. In conclusion, the ECT, IFM and CDDP combination chemotherapy regimen is a viable treatment option for HRPC. However, in comparison with our previous chemotherapy regimen of IFM and CDDP, no additional long-lasting effects resulting from the inclusion of ECT could be affirmed.

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  • Induction of cell death in human papillomavirus 18-positive cervical cancer cells by E6 siRNA

    Yamato K, Fen J, Kobuchi H, Nasu Y, Yamada T, Nishihara T, Ikeda Y, Kizaki M, Yoshinouchi M

    Cancer Gene Therapy   13   234 - 241   2006

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  • Comparison of 25 and 75 mg/day naftopidil for lower urinary tract symptoms associated with benign prostatic hyperplasia: a prospective, randomized controlled study.

    Yokoyama T, Kumon H, Nasu Y, Takamoto H, Watanabe T

    Int J Urol   13 ( 7 )   932 - 938   2006

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  • The Jounal of gene medicine Japanese society of gene therapy young investigator award 2006

    Nasu Y

    The Journal of Gene Medicine   8   1363 - 1364   2006

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  • Hepsin shows inhibitory effects through apoptotic pathway on ovarian cancer cell lines

    Nakamura K, Nasu Y, Hongo A, Matsuo T, Kodama J, Ebara S, Nagai A, Abrzua F, Kumon H, Hiramatsu Y

    International Journal of Oncology   28   393 - 398   2006

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  • Intracavernous injection of prostaglandin E-1 is effective in patients with erectile dysfunction not responding to phosphodiesterase 5 inhibitors Reviewed

    A Nagai, N Kusumi, H Tsuboi, K Ishii, T Saika, Y Nasu, H Kumon

    ACTA MEDICA OKAYAMA   59 ( 6 )   279 - 280   2005.12

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    We report on 64 patients who did not achieve erections adequate for satisfactory sexual intercourse from among a total of 243 patients who were prescribed PDE5 inhibitors for erectile dysfunction (ED). Intracavernous injection (ICI) of PGE(1), was performed in this non-responder group. An ICI of 20 or 40 mcg of PGE(1) in 1 ml saline was performed and the responses evaluated. Forty-nine out of 64 (77%) cases responded to 20 mcg of PGE(1). Forty mcg of PGE(1) was injected into the 15 non-responding cases, and 9 patients responded favorably. The overall effective rate was 58/64 (91 %). No major adverse effects were observed.

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  • Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase Reviewed

    F Abarzua, M Sakaguchi, M Takaishi, Y Nasu, K Kurose, S Ebara, M Miyazaki, M Namba, H Kumon, N Huh

    CANCER RESEARCH   65 ( 21 )   9617 - 9622   2005.11

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    Alteration in genes which takes place during malignant conversion and progression could be potential targets for gene therapy. We previously identified REIC/Dkk-3 as a gene whose expression is reduced in many human cancers. Here, we showed that expression of REIC/Dkk-3 was consistently reduced in human prostate cancer tissues in a stage-dependent manner. Forced expression of REIC/Dkk-3 induced apoptosis in human prostate cancer cell lines lacking endogenous REIC/Dkk-3 expression but not in REIC/Dkk3-proficient normal prostate epithelial and stromal cells. The apoptosis involved c-jun-NH2-kinase activation, mitochondrial translocation of Bax, and reduction of Bcl-2. A single injection of an adenovirus vector carrying REIC/Dkk-3 showed a dramatic antitumor effect on a xenotransplanted human prostate cancer. Thus, REIC/Dkk-3 could be a novel target for gene-based therapy of prostate cancer.

    DOI: 10.1158/0008-5472.CAN-05-0829

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  • Long-term clinical outcomes of 420 consecutive prostate cancer patients in a single institute Reviewed

    K Edamura, T Saika, T Senoh, F Koizumi, D Manabe, S Ebara, H Kaku, T Yokoyama, F Abarzua, A Nagai, Y Nasu, T Tsushima, H Kumon

    ACTA MEDICA OKAYAMA   59 ( 5 )   195 - 199   2005.10

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    This study was undertaken to reveal the trends of prostate cancer and the outcome of treatment modalities for each disease stage in patients in a single institute over a 10-year period. From January 1994 through December 2003, 420 consecutive patients with previously untreated and histologically confirmed prostate cancer were analyzed for annual distributions of disease stages and treatment modalities and for long-term clinical progression-free survival, prostate cancer-specific survival, and prostate-specific antigen (PSA) failure-free survival rates for each stage and treatment modality. Annual trends showed that the number of patients, especially those with clinically localized cancer, increased dramatically. The 5-year disease-specific survival rates for patients with clinically localized disease were 100% for all treatment modalities, including hormonal therapy alone. Patients with PSA levels less than 10 ng/ml showed an 81% 5-year PSA failure-free survival rate with radical prostatectomy. Stage C patients treated by surgery or radiation-based therapy with concomitant hormonal therapy obtained 93% and 100% cause-specific survival rates, respectively, and those treated by hormonal therapy alone showed a 79% rate. The number of patients with localized prostate cancer was increasing in this decade. While long-term hormonal therapy alone was highly efficient in controlling localized prostate cancer, radical therapies in conjunction with neo-adjuvant hormonal therapy produced better survival rates in cases of locally advanced disease.

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  • Clinical results of one-stage urethroplasty with parameatal foreskin flap for hypospadias Reviewed

    A Nagai, Y Nasu, M Watanabe, N Kusumi, H Tsuboi, H Kumon

    ACTA MEDICA OKAYAMA   59 ( 2 )   45 - 48   2005.4

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    We investigated the usefulness of one-stage urethroplasty by the parameatal foreskin flap method (OUPF procedure), which is useful for repairing all types of hypospadias. Between June 1992 and March 2001, the OUPF procedure was performed on 18 patients with hypospadias: 10 patients with distal and 8 with proximal hypospadias. The follow-up periods ranged from 33-75 months, with an average of 52 months. The duration of surgery, the catheter indwelling period, and the postoperative complications of each patient were analyzed. The median age of the patients at the time of surgery was 3 years and 8 months. The length of surgery for OUPF II ranged from 150-230 min (average 186 min), and from 190-365 min (average 267 min) for OUPF IV. Postoperative complications were confirmed in 3 of the 18 patients (16.6%). Two patients had fistulas, and one had a meatal regression. The fistulas were successfully closed by the simple multilayered closure method. After adopting DuoDerm dressings instead of elastic bandages for protection of the wound, no fistulization occurred. DuoDerm dressings are useful in the healing of wounds without complications. To date, the longest follow-up period has been 75 months, and during that time there have been no late complications such as urethral stenosis or penile curvature. OUPF is a useful method in the treatment of hypospadias with a low incidence of early and late complications.

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  • Predicting postoperative renal insufficiency in patients undergoing nephrectomy for renal malignancy: Assessment by renal scintigraphy using (99m)Technetium-mercaptoacetyltriglycine Reviewed

    Y Shirasaki, T Saika, T Tsushima, Y Nasu, R Arata, H Kumon

    JOURNAL OF UROLOGY   173 ( 2 )   388 - 390   2005.2

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    Purpose: We performed 99(m)Tc-mercaptoacetyltriglycine (MAG3) renal scintigraphy in patients with renal malignancy to evaluate the function of each renal unit before and after nephrectomy to see if postoperative functional deterioration could be predicted based on scintigraphy results and creatinine clearance.
    Materials and Methods: A total of 22 men and 13 women with renal malignancy, including 32 with renal cell carcinoma and 3 with urothelial cancer, were prospectively enrolled in this study. Average patient age was 64.3 years (median 65, range 43 to 88). All patients underwent MAG3 renal scintigraphy before and after unilateral nephrectomy. At the same time serum creatinine and endogenous creatinine clearance were determined.
    Results: Mean serum creatinine was 0.93 mg/dl before and 1.31 after nephrectomy (p &lt;0.0001). Preoperative endogenous creatinine clearance was 70.8 ml per minute per 1.73 m(2), which decreased to 49.0 ml per minute per 1.73 m(2) after nephrectomy (p &lt;0.0001). Mean MAG3 clearance of the remaining kidney increased 35.1% above baseline from 156.5 to 211.5 ml per minute per 1.73 m(2) following nephrectomy. Spearman rank core analysis revealed that preoperative MAG3 clearance of the remaining kidney significantly correlated with postoperative creatinine clearance (r = 0.596, p = 0.0005). Preoperative MAG3 clearance of the remaining kidney more than 130 ml per minute per 1.73 M-2 coincided with postoperative creatinine clearance above 40 ml per minute per 1.73 m(2).
    Conclusions: MAG3 renal scintigraphy may be useful for predicting renal insufficiency after nephrectomy. The findings in this study suggest that preoperative MAG3 clearance of the remaining kidney less than 130 ml per minute per 1.73 m(2) is a risk factor for postoperative renal insufficiency.

    DOI: 10.1097/01.ju.0000149980.61593.5f

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  • Varicocele rupture due to sexual intercourse

    Nishiyama Y, Nagai A, Nasu Y, Watanabe M, Kusumi N, Monden K, Kumon H

    Int J Urol   12   585 - 587   2005

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  • Sex reassignment surgery for male to female transsexuals: initial experience in Okayama university hospital.

    Atsushi Nagai, Eijirou Tokuyama, Yuzaburo Nanba, Tetsuya Tsutsui, Yoshihiro Kimata, Mikiya Nakatsuka, Isao Koshima, Takashi Saika, Yasutomo Nasu, Hiromi Kumon

    Acta medica Okayama   59 ( 5 )   231 - 233   2005

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    The first case of sex reassignment surgery (SRS) in our hospital was performed in January 2001; as of February, 2005, 4 cases of MTF-SRS had been performed. In the 2 most recent cases, we used penile and scrotal skin flaps to avoid complications. The depth and width of the new vagina was made to be adequate for sexual intercourse. Future attention should be focused on devising a surgical technique that will help prevent the complications of partial necrosis of the epidermal skin and wound dehiscence. Although ours is only an initial experience, we describe our surgical technique herein.

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  • Adeno-associated virus-mediated human IL-10 gene transfer suppresses the development of experimental autoimmune orchitis

    Watanabe M, Kashiwakura Y, Kusumi N, Tamayose K, Nasu Y, Nagai A, Shimada T, Daida H, Kumon H

    Gene Therapy   12   1126 - 1132   2005

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  • Minimal invasiveness and effectivity of subinguinal microscopic varicocelectomy:A comparative study with retroperitoneal high and laparoscopic approaches

    Watanabe M, Nagai A, Kusumi N, Tsuboi H, Nasu Y, Kumon H

    Int J Urol   12   892 - 898   2005

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  • Transrectal high-intensity focused ultrasound in the treatment of localized prostate cancer: a multicenter study.

    Toyoaki Uchida, Shiro Baba, Akira Irie, Shigehiro Soh, Naoya Masumori, Taiji Tsukamoto, Hiroomi Nakatsu, Hiroyuki Fujimoto, Tadao Kakizoe, Takeshi Ueda, Tomohiko Ichikawa, Nobutaka Ohta, Tadaichi Kitamura, Makoto Sumitomo, Masamichi Hayakawa, Teiichiro Aoyagi, Masaaki Tachibana, Ryusuke Ikeda, Kohji Suzuki, Nobuo Tsuru, Kazuo Suzuki, Seiichiro Ozono, Kiyohide Fujimoto, Yoshihiko Hirao, Kohichi Monden, Yasutomo Nasu, Hiromi Kumon, Kazuhiko Nishi, Shoichi Ueda, Hirofumi Koga, Seiji Naitoh

    Hinyokika kiyo. Acta urologica Japonica   51 ( 10 )   651 - 658   2005

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    We report a multicenter trial with transrectal high-intensity focused ultrasound (HIFU) in the treatment of localized prostate cancer. A total of 72 consecutive patients with stage T1c-2NOM0 prostate cancer were treated using the Sonablate 500TM HIFU device (Focus Surgery, Indianapolis, USA). Biochemical recurrence was defined according to the criteria recommended by the American Society for Therapeutic Radiology and Oncology Consensus Panel. The median age and prostate specific antigen (PSA) level were 72 years and 8.10 ng/ml, respectively. The median follow-up period for all patients was 14.0 months. Biochemical disease-free survival rates in all patients at 1 and 2 years were 78% and 76%, respectively. Biochemical disease-free survival rates in patients with stage T1c, T2a and T2b groups at 2 years were 89, 67% and 40% (p = 0.0817). Biochemical disease-free survival rates in patients with Gleason scores of 2-4, 5-7 and 8-10 at 2 years were 88, 72% and 80% (p = 0.6539). Biochemical disease-free survival rates in patients with serum PSA of less than 10 ng/ml and 10-20 ng/ml were 75% and 78% (p = 0.6152). No viable tumor cells were noted in 68% of patients by postoperative prostate needle biopsy. Prostatic volume was decreased from 24.2 ml to 14.0 ml at 6 months after HIFU (p < 0.01). No statistically significant differences were noted in International Prostate Symptom Score, maximum urinary flow rate and quality of life analysis with Functional Assessment of Cancer Therapy. HIFU therapy appears to be minimally invasive, efficacious and safe for patients with localized prostate cancer with pretreatment PSA levels less than 20 ng/ml.

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  • Analysis of human ejaculation using color doppler ultrasonography:A comparison between antegrade and retrograde ejaculation

    Nagai A, Watanabe M, Nasu Y, Iguchi H, Kusumi N, Kumon H

    Urology   65 ( 2 )   365 - 368   2005

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  • Adeno-associated virus 2-mediated intratumoral prostate cancer gene therapy: long-term maspin expression efficiently suppresses tumor growth. International journal

    Masami Watanabe, Yasutomo Nasu, Yuji Kashiwakura, Norihiro Kusumi, Kenji Tamayose, Atsushi Nagai, Tetsuo Sasano, Takashi Shimada, Hiroyuki Daida, Hiromi Kumon

    Human gene therapy   16 ( 6 )   699 - 710   2005

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    Maspin is a member of the serine protease inhibitors and the maspin gene, a tumor suppressor gene, is down-regulated in a large fraction of prostate cancers. We evaluated the use of adeno-associated virus (AAV, serotype 2) vector encoding maspin as a means for in vivo gene therapy for human prostate cancer. TUNEL assay of subcutaneously formed LNCaP or DU145 tumors in nude mice showed that intratumoral AAV-mediated maspin expression significantly upregulated the number of apoptotic cells compared with AAV-LacZ treatment. Immunofluorescence double staining for maspin protein and apoptosis in LNCaP tumors showed that the percentage of apoptotic cells in AAV-maspin-mediated maspin-expressing cells was significantly high compared with that in AAV-GFP-mediated GFP-expressing cells. Moreover, significantly fewer CD31-positive microvessels were observed in AAV-maspin-treated tumors compared with the control tumors. These therapeutic responses were highly correlated to persistent maspin expression in tumors, confirmed by Western blot analysis until at least day 56 after treatment. Finally, intratumoral delivery of AAV-maspin significantly suppressed growth of LNCaP and DU145 tumors and improved survival of mice. We conclude that AAV-mediated prolonged maspin expression efficiently suppresses human prostate tumor growth in vivo by apoptosis induction and inhibition of angiogenesis.

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  • XAGE-1 rnRNA expression in prostate cancer and antibody response in patients Reviewed

    F Koizumi, Y Noguchi, T Saika, K Nakagawa, S Sato, AMA Eldib, Y Nasu, H Kumon, E Nakayama

    MICROBIOLOGY AND IMMUNOLOGY   49 ( 5 )   471 - 476   2005

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    To evaluate the feasibility of cancer vaccine targeting XAGE-1, we investigated the expression of 4 XAGE-1 transcript variants and the humoral immune response to XAGE-1 in prostate cancer patients. XAGE-1a, b, c, d mRNA expression was analyzed in 54 prostate cancer specimens and 8 specimens of benign prostate hypertrophy (BPH) by reverse transcription-polymerase chain reaction (RT-PCR). The Immoral response to XAGE-1 was investigated in sera obtained from 278 patients with prostate cancer and 40 healthy volunteers by enzyme-linked immunosorbent assay (ELISA) using recombinant protein. XAGE-1b mRNA expression was observed in 14 of 54 (26%) prostate cancer specimens, while XAGE-1a, c, and d mRNA expressions were observed in 1, 1, and 3, respectively. None of the 4 XAGE-1 transcript variants was observed in the 8 BPH specimens. Antibody against XAGE-1 was detected in sera from 2 of 129 stage D2 patients, whereas none of sera from 149 patients with localized prostate cancer or lymph node metastasis had detectable XAGE-1 antibody. No reactivity to XAGE-1 was found in sera from the 40 healthy individuals.

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  • Long-term consequence of renal function following nephrectomy for renal cell cancer Reviewed

    Y Shirasaki, T Tsushima, Y Nasu, H Kumon

    INTERNATIONAL JOURNAL OF UROLOGY   11 ( 9 )   704 - 708   2004.9

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    Aim: A retrospective analysis was performed involving patients who had undergone radical nephrectomy for renal cell cancer to determine the long-term outcome of this surgery on renal status.
    Materials and Methods Between 1977 and 2001, 172 patients having undergone radical nephrectomy for renal cell cancer were followed for a period of more than one year at the Department of Urology Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. The preoperative and postoperative serum creatinine values of these individuals were reviewed. Long-term effects of radical nephrectomy on renal function and factors influencing postoperative renal dysfunction were analyzed.
    Results: Six (3.5%) of the 172 individuals progressed to hemodialysis. Eleven (6.4%) patients displayed serum creatinine values of greater than or equal to1.6 mg/dL. The remaining 155 patients (90.1%) demonstrated postoperative serum creatinine values of &lt;1.6 mg/dL. The present study suggests that aging, a high degree of proteinuria, hypertension and diabetes mellitus were the predominant risk factors for renal deterioration following nephrectomy.
    Conclusions: We have primarily selected radical nephrectomy for cases exhibiting smaller renal tumors with a normal contralateral kidney. We encourage nephron-sparing surgery where possible in patients displaying risk factors, including a high degree of proteinuria, hypertension, or diabetes mellitus.

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  • Positive correlation between allelic loss at chromosome 14q24-31 and poor prognosis of patients with renal cell carcinoma Reviewed

    H Kaku, S Ito, S Ebara, M Ouchida, Y Nasu, T Tsushima, H Kumon, K Shimizu

    UROLOGY   64 ( 1 )   176 - 181   2004.7

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    Objectives. To report our development of a new application of the inter-AN long polymerase chain reaction (PCR) for genomic scanning to screen for tumor-specific alterations in tumor DNA. Using this method, we detected a rearranged chromosomal region in renal cell carcinomas (RCCs). We then examined tumor-specific allelic loss in this region using microsatellite markers and determined whether a relationship was present between this allelic loss and the clinicopathologic features of the patients.
    Methods. The inter-Alu long PCR genomic scan method was performed using RCC DNA samples and primers specific for a minor subset of the human repeat sequence Alu. We analyzed DNA samples from 42 pairs of matched normal and nonpapillary RCC tissues with seven microsatellite markers.
    Results. The inter-Alu long PCR genomic scan method revealed an altered DNA region on chromosome 14q24-31, which is the location of several putative tumor suppressor genes. At least one of seven microsatellite markers on chromosome 14q24-31 showed loss of heterozygosity in 23 (54.8%) of 42 informative cases of RCC. The prevalent loss region was confined to a 2-Mb region around D14S67. We found a positive correlation between the presence of the loss of heterozygosity on 14q24-31 and tumor stage (P &lt; 0.05). We also found that cases with allelic loss at 14q24-31 had a poor prognosis (P = 0.045).
    Conclusions. Our inter-Alu long PCR genomic scan method is a powerful method for the screening of DNA alterations, and our data suggest that the chromosome 14q24-31 region contains likely tumor suppressor genes associated with the progression of RCC. (C) 2004 Elsevier Inc.

    DOI: 10.1016/j.urology.2004.03.015

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  • Effects of conadotropin-releasing hormone agonists on bone metabolism markers and bone mineral density in patients with prostate cancer Reviewed

    Y Miyaji, T Saika, Y Yamamoto, N Kusaka, R Arata, S Ebara, Y Nasu, T Tsushima, H Kumon

    UROLOGY   64 ( 1 )   128 - 131   2004.7

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    Objectives. To better understand bone metabolism and predict bone loss in treatment using gonadotropin-releasing hormone agonist for patients with prostate cancer.
    Methods. The changes in bone mineral density and blood levels of bone metabolism markers and the level of pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen, a specific marker of bone resorption, and carboxy-terminal pro-peptide of human type I procollagen, a specific marker of bone formation, were examined in 27 consecutive patients with prostate cancer without bone metastasis.
    Results. After 2 years of gonadotropin-releasing hormone treatment, the bone mineral density was significantly lower (median 0.937 g/cm(2)) than before treatment. Pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen began to increase significantly 6 months after the start of treatment (3.0 to 8.3 ng/mL, median 4.6, at baseline versus 3.4 to 8.2 ng/mL, median 5.2, after 6 months). Carboxy-terminal pro-peptide of human type I procollagen began to show a significant rise I year after the start of treatment (from 72.8 to 221.5 ng/mL, median 102.0, at baseline to 82.7 to 293.4 ng/mL, median 132.0, at I year).
    Conclusions. Functional coupling between bone resorption and formation was noted, and a decrease in bone mass, even in men, owing to androgen deficiency, was biochemically demonstrated. Fluctuations in these two bone metabolism markers preceded the decrease of bone mineral density. Therefore, these markers might be a predictor of bone loss. (C) 2004 Elsevier Inc.

    DOI: 10.1016/j.urology.2004.03.012

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  • Kidney function after nephrectomy for renal cell carcinoma Reviewed

    Y Shirasaki, T Tsushima, T Saika, Y Nasu, H Kumon

    UROLOGY   64 ( 1 )   43 - 47   2004.7

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    Objectives. To evaluate the function of the remaining kidney after nephrectomy for renal cell cancer by technetium-99m-mercaptoacetyltriglycine (Tc-99m-MAG3) renal scintigraphy.
    Methods. We evaluated 30 consecutive patients who were undergoing unilateral radical nephrectomy by Tc-99m-MAG3 scintigraphy. All patients underwent three consecutive 99mTc-MAG3 scintigraphy studies. The first study was performed before nephrectomy, the second 1 month after surgery, and the third 1 year after surgery. At these times, the serum creatinine levels were also evaluated.
    Results. The mean preoperative MAG3 clearance of the remaining kidney of the 30 patients was 155.4 mL/min/1.73 m(2). The mean MAG3 clearance of the remaining kidney had increased to 209.2 mL/min/1.73 m(2) by I month after nephrectomy, and the average percentage increase was 39.5%. After 1 year, it had increased to 211.3 mL/min/1.73 m(2), with a 40.5% average percentage increase. The preoperative MAG3 clearance of the remaining kidney was inversely correlated with the percentage of increase in MAG3 clearance of the remaining kidney. Abnormal serum creatinine levels (greater than 1.3 mg/dL) were more common after nephrectomy, occurring in 6 patients at 1 month and in 5 patients at 1 year postoperatively. In all 6 patients with elevated creatinine levels, the preoperative MAG3 clearance of the remaining kidney was less than 150 mL/min/1.73 m(2).
    Conclusions. Adaptive hyperfunction occurs soon after nephrectomy that is not associated with age or sex and continues for at least 1 year. A greater compensatory response is produced in patients with more severe renal deterioration. Using (99)mTc-MAG3 scintigraphy, we may be able to predict postoperative renal function. (C) 2004 Elsevier Inc.

    DOI: 10.1016/j.urology.2004.02.039

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  • Comparative study of ureteral stripping versus open ureterectomy for nephroureterectomy in patients with transitional carcinoma of the renal pelvis Reviewed

    T Saika, J Nishiguchi, T Tsushima, Y Nasu, A Nagai, Y Miyaji, Y Maki, T Akaeda, M Saegusa, H Kumon

    UROLOGY   63 ( 5 )   848 - 852   2004.5

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    Objectives. To evaluate the clinical outcome of nephroureterectomy with endoscopically assisted transurethral ureteral stripping for transitional cell carcinoma of the renal pelvis in a comparative study.
    Methods. Sixty patients with localized renal pelvic cancer were enrolled in a prospective comparative nonrandomized study. Of these, 28 patients underwent nephroureterectomy with endoscopically assisted transurethral ureteral stripping and 32 underwent conventional nephroureterectomy with a bladder cuff. Both short-term and long-term results were analyzed in this series.
    Results. The operating time for patients with ureteral stripping was significantly shorter than for those with a standard two-incision nephroureterectomy (median 183 versus 250 minutes, P = 0.0231), and the amount of blood loss was significantly less (median 150 versus 390 mL, P = 0.0002). Intravesical recurrence was detected in 10 (35.7%) of the 28 patients with ureteral stripping, and the 1-year and 3-year recurrence-free rate was 68.0% and 57.7%, respectively. Seven patients treated by the standard two-incision nephroureterectomy (21.9%) experienced intravesical recurrence, with a 1-year and 3-year recurrence-free rate of 96.8% and 75.0%, respectively. The recurrence rate was significantly greater in the group with ureteral stripping (P = 0.0287).
    Conclusions. Compared with conventional nephroureterectomy with a bladder cuff, nephroureterectomy with transurethral stripping is a minimally invasive procedure with a shorter operating time and less blood loss, but a statistically significantly greater intravesical recurrence rate. Greater consideration should be taken before selecting this procedure. (C) 2004 Elsevier Inc.

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  • Decreased expression of REIC/Dkk-3 in human renal clear cell carcinoma

    Kurose K, Sakaguchi M, Nasu Y, Ebara S, Kaku H, Kariyama R, Arao Y, Miyazaki M, Tsushima T, Namba M, Kumon H, Huh N

    J Urol   171   1314 - 1318   2004

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  • Analysis of retrograde ejaculation using color Doppler ultrasonography before and after transurethral collagen injection

    Nagai A, Nasu Y, Watanabe M, Tsugawa M, Iguchi H, Kumon H

    International Journal of Impotence Research   16   456 - 458   2004

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  • Ureteroscopy using a detachable access sheath

    Abarazua F, Monden K, Nagai A, Nasu Y, Kumon H

    Acta Med. Okayama   58 ( 4 )   215 - 216   2004

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  • Dynamin-2 regulates oxidized low-density lipoprotein-induced apoptosis of vascular smooth muscle cell.

    Kashiwakura Y, Watanabe M, Kusumi N, Sumiyoshi K, Nasu Y, Yamada H, Sawamura T, Kumon H, Takei K, Daida H

    Circulation   110 ( 21 )   3329 - 3334   2004

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  • Anterior urethral recurrence of superficial bladder cancer: Its clinical significance Reviewed

    T Saika, T Tsushima, Y Nasu, R Arata, H Kaku, N Akebi, N Kusaka, H Kumon

    ACTA MEDICA OKAYAMA   57 ( 6 )   293 - 297   2003.12

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    The aim of this study was to reveal the clinical features of anterior urethral recurrence in patients with superficial bladder cancer, and to determine the appropriate treatment. Three hundred and three patients with superficial bladder cancer, who were newly diagnosed and initially treated conservatively in our hospital between 1965 and 1990, were followed for at least 5 years and their clinical outcomes were analyzed. Clinical factors, including anterior urethral recurrence, were evaluated statistically regarding tumor progression. Eight patients (2.6%) had anterior urethral recurrence following superficial bladder cancer. Twenty-four patients (7.9%) had tumor progression and 149 (49.2%) had tumor recurrence. In a multivariate analysis using a logistic model, anterior urethral recurrence was the most important factor, followed by histological grade. Four of 5 patients who were treated for anterior urethral recurrent tumors by transurethral resection showed progression and died of the cancer within one year. Two of the remaining three patients who underwent radical cysto-urethrectomy at the time of anterior urethral recurrence survived. Anterior urethral recurrence following superficial bladder cancer is a predictor for rapid subsequent malignant progression. Once there is anterior urethral recurrence, radical intensive therapy, including radical cysto-urethrectomy, should be carried out immediately.

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  • NY-ESO-1 mRNA expression and immunogenicity in advanced prostate cancer Reviewed

    Tetsuya Nakada, Yuji Noguchi, Shuichiro Satoh, Toshiro Ono, Takashi Saika, Takushi Kurashige, Sacha Gnjatic, Gerd Ritter, Yao-Tseng Chen, Elisabeth Stockert, Yasutomo Nasu, Tomoyasu Tsushima, Hiromi Kumon, Lloyd J. Old, Eiichi Nakayama

    Cancer Immunity   3   1 - 12   2003.7

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    NY-ESO-1 mRNA expression was investigated in advanced prostate cancer by conventional and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). NY-ESO-1 mRNA was detected in 20 of 53 (38%) tumor specimens. Four of 15 (27%) stage C, 1 of 3 stage D1 (33%) and 15 of 35 (43%) stage D2 prostate cancers were positive. The presence of NY-ESO-1 antibodies was evaluated in sera from a panel of 218 patients with prostate cancer, including the 53 patients whose tumors were examined for NY-ESO-1 mRNA expression. NY-ESO-1 antibodies were detected in 1 of 30 (3.3%) stage D1 and 9 of 110 (8.2%) stage D2 patients, whereas none of the 78 patients with localized prostate cancer (stages A, B and C) had detectable NY-ESO-1 antibodies. Of the 53 patients whose tumors were examined for NY-ESO-1 mRNA expression, 2 of 20 patients with NY-ESO-1 mRNA-positive tumors had NY-ESO-1 antibodies. No antibody was found in the sera of 32 patients with NY-ESO-1 mRNA-negative tumors, with the exception of one patient with regional lymph node metastasis (stage D1). CD8 T cell responses specific to NY-ESO-1 were detected in two of three patients with NY-ESO-1 antibodies.

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  • Laparoscopic removal of mullerian structures and orchiopexy for persistent mullerian duct syndrom

    Shirasaki Y, Nagai A, Nasu Y, Iguchi H, Kumon H

    Urology   62 ( 6 )   1121   2003

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  • Clinical study of G3 superficial bladder cancer without concomitant CIS treated with conservative therapy Reviewed

    T Saika, T Tsushima, Y Nasu, R Arata, H Kaku, N Kusaka, H Kumon

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   32 ( 11 )   461 - 465   2002.11

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    Objective: The treatment for superficial G3 transitional cell carcinoma (TCC) of the urinary bladder remains controversial. It is important to reveal the clinical features of superficial G3 bladder cancer that can be treated conservatively.
    Patients and Methods: A total of 39 patients with primary superficial bladder cancer (Ta, T1) with G3 components but without concomitant carcinoma in situ (CIS), who had been treated initially with transurethral resection (TUR), were retrospectively analyzed for factors related to tumor recurrence, progression and survival. The patients were 34 males and five females who,se age ranged from 49 to 85 years (average, 68 years). Initial tumor stages were Ta in one patient and T1 in 38. Initial treatments were TUR alone in 18 patients and TUR with adjuvant therapy (intravesical chemotherapy or BCG therapy) in 21. Factors examined included age, gender, morphology, size and number of tumors and adjuvant therapies.
    Results: Follow-up periods were 3-138 months (median, 37 months). Tumor recurrence, progression and cancer death were observed in 23, seven and four cases, respectively. The 5-year progression-free rate (75%) and survival rate (83%) in 39 patients with G3 did not show a statistically significant difference from those of the 109 patients with G1 or the 187 patients with G2-superficial bladder cancer who were treated with TUR initially. Only the rate of recurrence of patients with G3 was significantly higher than that of patients with G2 or G1. Adjuvant therapies reduced the recurrence rate of the patients with G3. Only tumor morphology, papillary or non-papillary, affected both the progression-free rate and the survival rate of patients with G3. There were no statistically significant differences associated with other factors.
    Conclusion: The results suggest that superficial G3 bladder cancer could be treated with TUR initially, especially for papillary tumors.

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  • Prostate specific antigen complexed to alpha-1-antichymotrypsin in patients with intermediate prostate specific antigen levels Reviewed

    T Saika, T Tsushima, Y Nasu, N Kusaka, Y Miyaji, H Takamoto, K Takeda, S Uno, H Kumon

    CANCER   94 ( 6 )   1685 - 1691   2002.3

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    BACKGROUND. The authors attempted to evaluate prospectively the usefulness of serum prostate specific antigen (PSA) complexed to alpha-1-antichymotrypsin (PSA-ACT) in the early detection of prostate carcinoma and its ability to discriminate between prostate carcinoma and benign prostatic hyperplasia (BPH), especially among patients with intermediate PSA levels.
    METHODS. Between December 1999 and August 2000, systematic sextant biopsies were performed on 281 prospective patients with prostate carcinoma who had serum PSA levels between 4.1 ng/mL and 20.0 ng/mL. The serum samples were assayed by using kits that were designed specifically for measuring serum PSA, PSA-ACT, and free PSA levels. The clinical values of PSA, PSA-ACT, the free PSA to total PSA ratio (F/T ratio), the free PSA to PSA-ACT ratio, PSA density (PSAD), and PSA-ACT density (ACTD) were compared by using receiver operating characteristic (ROC) curve analysis.
    RESULTS. Biopsy yielded no evidence of malignancy in 198 patients, and prostate carcinoma was confirmed in 83 patients. ROC analysis demonstrated that the area under the curve (AUC) for PSA-ACT was greater than that for total PSA and was equivalent to that for the F/T ratio in both groups of patients (PSA ranges of 4.1-20.0 ng/mL and 4.1-10.0 ng/mL, respectively). The AUC for the ACTD was greater than the AUC for the PSAD and had the highest value of all parameters.
    CONCLUSIONS. The measurement of PSA-ACT represents an alternative to the use of total and free PSA. The ACTD value is the most useful for discriminating between BPH and prostate carcinoma. (C) 2002 American Cancer Society

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  • Validation of transrectal ultrasonographic volumetry for orthotopic prostate tumours in mice

    Kraaji R, van Weerden W.M, de Ridder C.M, Gussenhoven E.J, Honkoop J, Nasu Y, Bangma C.H

    Lab Anim   36 ( 2 )   165 - 172   2002

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  • Laparoscopic radical prostatectomy:Initial cases at Okayama University Hospital

    Nagai A, Nasu Y, Shirasaki Y, Iguchi H, Arata R, Tsugawa M, Tsushima T, Kumon H

    Acta Med. Okayama   56 ( 1 )   51 - 52   2002

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  • Gene therapy for prostate cancer: toxicological profile of four HSV-tk transducing adenoviral vectors regulated by different promoters Reviewed

    S Ebara, S Shimura, Y Nasu, H Kaku, H Kumon, G Yang, J Wang, TL Timme, E Aguilar-Cordova, TC Thompson

    PROSTATE CANCER AND PROSTATIC DISEASES   5 ( 4 )   316 - 325   2002

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    Adenoviral vector delivery of the Herpes simplex virus thymidine kinase (HSV-tk) gene in combination with the prodrug ganciclovir (GCV) has been tested in phase I clinical trials for prostate cancer and found to exhibit a satisfactory toxicity profile. We have developed additional adenoviral vectors with differing promoters to optimize the expression profile and in the present study evaluate the potential systemic toxicity of these vectors. Four recombinant adenoviral vectors that express the HSV-tk gene were generated using three different promoters: CMV (leftward orientation); RSV (both rightward and leftward orientation); and the mouse caveolin-1 (cav-1) promoter (leftward orientation). Efficacy was determined in vitro by cytotoxicity assays in a mouse prostate cancer cell line, RM-9, and in vivo by treating orthotopic tumors. Potential toxicity was evaluated from liver histology and apoptotic cell counts and enzyme levels in the serum following intravenous adenoviral vector injection. Although there were differences in HSV-tk expression at the protein level among the four vectors there were no significant differences in in-vitro cytotoxicity studies with GCV or in vivo in tumor growth suppression of an orthotopic mouse prostate cancer model in GCV treated mice. Intravenous delivery of high doses of all adenoviral vectors lead to abnormalities in liver function as measured by specific serum markers and histological evaluation of liver tissue and increased levels of apoptosis in the liver. These abnormalities were most prevalent with the vector containing the CMV promoter and the rightward oriented RSV promoter. They were least prevalent in the vector regulated by the cav-1 promoter. Upregulation of specific chemokines, MIP-2 and MIP-1beta was correlated with apoptotic counts. Our results demonstrate that comprehensive toxicological analysis of adenoviral vectors provides internally consistent information that can differentiate vectors with comparable efficacy based on toxicity. In these studies vectors with the cav-1 promoter-driven and leftward RSV-driven HSV-tk gene demonstrated minimal toxicities with cytotoxic effectiveness comparable to more toxic vectors. Our studies further suggest that promoter selection can influence the toxic effects of an adenoviral gene therapy vector.

    DOI: 10.1038/sj.pcan.4500610

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  • Orthotopic neobladder reconstruction in elderly bladder cancer patients Reviewed

    T Saika, B Suyama, T Murata, D Manabe, T Kurashige, Y Nasu, T Tsushima, H Kumon

    INTERNATIONAL JOURNAL OF UROLOGY   8 ( 10 )   533 - 538   2001.10

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    Background: We compared the clinical results of orthotopic neobladder reconstruction in elderly patients and those in younger patients retrospectively in order to verify whether age is a critical factor in selecting a method of urinary diversion.
    Methods: Following radical cystectomy for bladder cancer, 12 patients aged 75 or older and 17 patients under 75 who underwent orthotopic neobladder reconstruction between January 1992 and May 1999 were investigated in this study. The authors TS and BS were among the surgeons who performed operations for all cases. Of the 12 elderly patients, orthotopic neobladders were constructed according to Hautmann's method in nine cases, Studer's method in one case and Reddy's method in two cases. Of the 17 younger patients, these methods were employed in 12, one and four cases, respectively. Operative procedure, early and late complications, prognosis, continence and voiding pattern were investigated in these patients.
    Results: The follow-up periods for elderly and younger groups ranged from 21.3 to 82.7 months and from 8.8 to 94.2 months, respectively. No difference in operation time, amount of bleeding or postoperative length of hospitalization was observed between elderly and younger patients. The rates of early complications in elderly and younger patients were 41.7% and 35.3%, respectively. Late complication rates were 33.3% and 47.1%, respectively The difference in these complication rates was not statistically significant. One of the elderly and two of the younger patients had local recurrence and metastasis postoperatively. Those three patients had died of their bladder cancer. No statistically significant difference between groups was recognized in either cause-specific survival or overall survival, nor was there such a difference in relation to micturition/continence.
    Conclusion: Based on these results, we believe that because age is not a critical factor in the selection of urinary diversion method, neobladder reconstruction following cystectomy for bladder cancer is indicated in elderly patients. As stoma management is difficult for the patients, we consider orthotopic neobladder reconstruction to be the method of choice if the patients' general physical condition allows.

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  • Retroperitoneoscopic pyelotomy combined with the transposition of crossing vessels for ureteropelvic junction obstruction

    Nagai A, Nasu Y, Hashimoto H, Tsugawa M, Yasui K, Kumon H

    The Journal of Urology   165   23 - 26   2001

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  • Optimal starting time for flutamide to prevent disease flare in prostate cancer patients treated with a gonadotropin-releasing hormone agonist Reviewed

    T Tsushima, Y Nasu, T Saika, Y Maki, M Noda, B Suyama, T Yamato, H Kumon

    UROLOGIA INTERNATIONALIS   66 ( 3 )   135 - 139   2001

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    Objective: Flare-up phenomena, such as an increase in prostate-specific antigen (PSA) and/or deterioration of symptoms, are observed in some patients undergoing gonadotropin-releasing hormone (GnRH) agonist therapy. This study was carried out to determine the optimal time for starting the administration of flutamide to prevent flare-up phenomena. Patients and Methods: Twenty-six patients with prostate cancer and elevated serum levels of PSA were randomly assigned to 5 groups. Group A patients (n = 6) were treated with a subcutaneous injection of 3.75 mg leuprorelin acetate depot alone. Group B, C, D and E patients (5 patients in each group) were treated with 375 mg/day of orally administered flutamide combined with leuprorelin. Flutamide was initiated on the day of leuprorelin injection in group B, and at 1, 2 and 4 weeks before leuprorelin injection in groups C, D and E, respectively. Serum PSA and testosterone levels were measured in each patient. Results: Pretreatment with flutamide increased the serum testosterone level, but the testosterone surge after leuprorelin administration was almost the same in all 5 treatment groups. In patients who had been treated with flutamide in combination with leuprorelin, the mean PSA level did not exceed the pretreatment levels after leuprorelin administration. The rate of decrease in PSA in the group receiving simultaneous administration of flutamide with leuprorelin showed a decline comparable to that during the period before leuprorelin administration in the flutamide pretreatment groups. Conclusion: Simultaneous administration of flutamide with a GnRH agonist is sufficient to prevent flare-up phenomena. Copyright (C) 2001 S. Karger AG, Basel.

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  • Treatment of androgen-independent prostate cancer with dexamethasone: A prospective study in stage D2 patients Reviewed

    T Saika, N Kusaka, T Tsushima, T Yamato, T Ohashi, B Suyama, R Arata, Y Nasu, H Kumon

    INTERNATIONAL JOURNAL OF UROLOGY   8 ( 6 )   290 - 294   2001

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    Purpose: In order to evaluate the efficacy of dexamethasone in the treatment of Japanese men with androgen-independent prostate cancer, a prospective study was conducted using prostate-specific antigen (PSA) as a primary end-point.
    Methods: Nineteen Japanese men with stage D2 androgen-independent prostate cancer were registered and treatment was started. After ruling out anti-androgen withdrawal syndrome, they were treated with dexamethasone (1.5 mg daily). Patients were monitored for PSA, symptoms, radiologic response, survival rate, time to disease progression, time to treatment failure and complications.
    Results: Prostate-specific antigen levels decreased in nine patients (50.0%); five (27.8%) showed a 50% or greater decrease and two (11.1%) showed an 80% or greater decrease. For the nine patients, the mean duration of PSA response was 7.3 months and the median duration was 2.1 months (range, 1.2-27.5+). Bone pain, which was noted in 13 patients at study entry, improved in seven patients (53.8%). Of nine patients who had serial radiographic examinations with bone scan, three (33%) showed partial response, two (22%) were stable and four (44%) showed disease progression. Treatment was well tolerated, except for one patient who suffered a severe pulmonary infection.
    Conclusion: Dexamethasone decreased PSA levels and produced subjective symptomatic improvement in the patients with stage D2 androgen-independent prostate cancer.

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  • Noninvasive urodynamic evaluation of bladder outlet obstruction using doppler ultrasonography

    Ozawa H, Chancellor M.B, Ding Y.Y, Nasu Y, Yokoyama T, Kumon H

    Urology   56 ( 3 )   408 - 412   2000

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  • Reliability of color doppler ultrasound urodynamics in the evaluation of bladder outlet obstruction

    Yew Yoong Ding, Ozawa H, Yokoyama T, Nasu Y, Chancellor M.B, Kumon H

    Urology   56 ( 6 )   967 - 971   2000

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  • The clinical value of contrast-enhanced color doppler ultrasound : is it really useful in the diagnosis of prostate cancer?

    Nasu Y, Saika T, Arata R, Tsugawa M, Tsushima T, Kumon H, Seno T

    J Urol   163 ( 4 )   280   2000

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  • Primary non-Hodgkin lymphoma of the ureter Reviewed

    H Hashimoto, M Tsugawa, Y Nasu, T Tsushima, H Kumon

    BJU INTERNATIONAL   83 ( 1 )   148 - 149   1999.1

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  • Clinical evaluation of serum prostate-specific antigen-alpha1-antichymotrypsin complex values in diagnosis of prostate cancer:A cooperative study

    Kuriyama M, Ueno K, Uno H, Kawada Y, Akimoto S, Noda M, Nasu Y, Tsushima T, Ohmori H, Sakai H, Saito Y, Meguro N, Usami M, Kotake T, Suzuki Y, Arai Y, Shimazaki J

    Int J Urol   5 ( 1 )   48 - 54   1998

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  • Gene therapy for prostate cancer

    Bangma C.H, Thompson T.C, Timme T.L, Scardino P.T, Yang G, Wang J, Nasu Y, Park S.H, Hull J.W

    Prostate Cancer and Prostatic Diseases   1 ( S-1 )   33   1998

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  • Prospective randomized comparative study of antibiotic prophylaxis in urethrocystoscopy and urethrocystography

    Tsugawa M, Monden K, Nasu Y, Kumon H, Ohmori H

    Int J Urol   5 ( 5 )   441 - 443   1998

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  • Absorption of epirubicin instilled intravesically immediately after transurethral resection of superficial bladder cancer Reviewed

    T Tsushima, Y Miyaji, M Noda, Y Nasu, H Kumon, H Ohmori

    UROLOGIA INTERNATIONALIS   60 ( 3 )   161 - 164   1998

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    As postoperative adjuvant therapy for superficial bladder cancer, intravesical instillation therapy is commonly conducted. In this case, from the view point of prevention of intraoperative dissemination, commencement of instillation therapy at an early postoperative period is preferred. However, increased drug permeability is suspected because of damage to the bladder mucosa during operation. Therefore, this study was conducted to investigate the plasma level of epirubicin (EPI) instilled immediately after transurethral operation. EPI (20 mg/40 ml or 50 mg/100 ml) was instilled immediately after a transurethral operation, and retained in the bladder for 1 h. Blood samples were obtained before instillation, as well as 30, 60, 120 and 240 min after instillation, and EPI levels were assayed. The mean EPI concentrations (ng/ml) among the 20-mg/40 ml group (n = 5) were &lt;2.5 and &lt;2.0 at 30 and 60 min, respectively, after which they were undetectable. The 50-mg/100 ml group (n = 5) recorded 5.0, 4.4 and &lt;3.0 after 30, 60 and 120 min, respectively, and after 240 min it was undetectable. Intravesical instillation of EPI immediately after a transurethral operation causes a small increase in the plasma level and it is thought to cause small systemic side effects.

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  • INHIBITION OF A PRIMARY MOUSE PROSTATE TUMOR WITH ADENOVIRAL MEDIATED HERPES SIMPLEX VIRUS THYMIDINE KINASE GENE TRANSDUCTION & GANCICLOVIR THERAPY

    Hall S.J, Yang G, Mutchnik S.E, Adier H.L, Nasu Y, Timme T.L, Woo S.L.C, Thompson T.C

    The Journal of Urology   157 ( S-4 )   368   1997

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  • THE EFFECT OF A GONADOTROPIN-RELEASING HORMONE AGONIST ON BONE MINERAL DENSITY OF PROSTATIC CANCER PATIENTS

    Noda M, Tsushima T, Nasu Y, Ohmori H

    The Journal of Urology   157 ( S-4 )   232   1997

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  • Study of the Nephrotoxicity of Iron Oxide Fumes Released by Welding in an Experimental Model

    Noda M, Tsushima T, Nasu Y, Kumon H, Ohmori H, Okada S

    Pathophysiology   4   221 - 226   1997

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  • Clinical Studies on Advantages and Safety of Visual Laser Ablation for Patients with Benign Prostatic Hyperplasia

    Nasu Y, Watanabe T, Kumon H, Ohmori H

    Int J Urol   3 ( S-1 )   S53 - S54   1996

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  • New Technological Methods of Managing BPH -Visual Laser Ablation of Prostate(VLAP):Non-contact-

    Nasu Y, Kumon H, Ohmori H

    Japanese Journal of Endourology and ESWL   9 ( 2 )   137 - 139   1996

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  • Relationship of intracellular concentration and duration of contamination of pirarubicin and adriamycin in human bladder cancer cell lines and human bladder normal mucosa cell line Reviewed

    T. Saika, T. Tsushima, Y. Nasu, N. Akebi, H. Ohmori

    Japanese Journal of Cancer and Chemotherapy   23 ( 7 )   905 - 909   1996

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    To establish a method for reasonable clinical use of adriamycin (ADM) and pirarubicin (THP) in the intravesical chemotherapy for superficial bladder cancer, intracellular concentrations of these drugs were examined in culture cell lines (T-24, T-24/ADM and FHS736b1) with variable durations of contamination. The intracellular concentration of THP showed a plateau at 15- 30 min. contamination in T-24, and in T-24/ADM, and showed the time dependence of contamination in FHS736b1, human normal bladder mucosa cell line. The intracellular concentration of ADM showed the time dependence of contamination in T-24, T-24/ADM and FHS736b1. And these concentrations of THP were 20 times higher than those of ADM. In conclusion, it seems better that THP was retained for 5-15 min. in the bladder in the intravesical chemotherapy, from the point of view of drug efficacy and preventing side effects. And it seems good that ADM was retained for more than 30 min. in the case with drug sensitive tumors.

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  • EPIDERMAL GROWTH FACTOR AS A MARKER FOR RECURRENCE OF THE BLADDER CANCER Reviewed

    T SAIKA, T TSUSHIMA, Y NASU, M NODA, Y MORIYA, H OHMORI

    PROCEEDINGS OF THE XVI INTERNATIONAL CANCER CONGRESS - FREE PAPERS AND POSTERS, TOMES 1-4   2145 - 2149   1994

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  • THERAPEUTIC OUTCOME OF G-CSF THERAPY ON ADVANCED TESTICULAR TUMORS Reviewed

    T TSUSHIMA, M TAKAMATSU, T SAIKA, Y MAKI, N AKEBI, Y NASU, H OHMORI

    PROCEEDINGS OF THE XVI INTERNATIONAL CANCER CONGRESS - FREE PAPERS AND POSTERS, TOMES 1-4   2225 - 2229   1994

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  • OVER‐EXPRESSION OF METALLOTHIONEIN AND DRUG‐RESISTANCE IN BLADDER CANCER Reviewed

    Takashi Saika, Tomoyasu Tsushima, Jyunzo Och, Naoki Akebi, Yasutomo Nasu, Yosuke Matsumura, Hiroyuki Ohmori

    International Journal of Urology   1 ( 2 )   135 - 139   1994

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    Metallothionein (MT) in tumor cells has been implicated as one of the factors involved in mechanisms of resistance to anti‐cancer drugs, including cis‐diaminedichroloplatinum (CDDP) and adriamycin (ADM). The relationship between the expression of MT and chemotherapy with anti‐cancer drugs was studied in CDDP‐ and ADM‐resistant human bladder cancer cell lines and tissue samples from clinical cases. In drug‐resistant cell lines (T‐24/ADM, CI‐7/CDDP) established in our laboratory, MT expression was studied by immunohistochemistry using the avidin‐biotin peroxidase complex (ABC) method and radioimmunoassay (RIA), using anti‐MT antibody. In addition, other potentfal mechanisms of drug resistance, such as P‐glycoprotein expression were examined and the levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione‐S‐transferase (GST) determined in these cell lines. The results of these investigations demonstrate that the expression of MT in resistant cell lines increased 2.1‐ and 2.5‐fold when compared with parent cell lines (CI‐7, T‐24). GSH, GSSG and GST levels were unchanged and P‐glycoprotein was not over‐expressed. A total of 120 tissue samples from 35 clinical cases of bladder cancer, before and after chemotherapy, were stained for MT which was detected in 10 of the 35 cases before chemotherapy. The incidence of MT expression was significantly higher (p less than 0.05) in cases with lower pathological tumor grades. By analyzing the MT staining after chemotherapy in the cases whose MT staining was negative before chemotherapy, it was found that cases receiving continuous administration (intravesical chemotherapy or peroral chemotherapy) showed a higher incidence (9/13) of positive staining for MT, than patients receiving intermittent administration (intravenous chemotherapy) (1/8), (p less than 0.05). These results demonstrate that: 1) a correlation exists between MT expression and tumor differentiation and 2) repetitive and continuous administration of anti‐cancer drugs results in increased MT expression in bladder cancer cells. MT expression may therefore be one of the mechanisms by which urothelial tumors acquire resistance to anti‐cancer drugs. Copyright © 1994, Wiley Blackwell. All rights reserved

    DOI: 10.1111/j.1442-2042.1994.tb00022.x

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  • Clinical study of urethral recurrence of superficial bladder cancer : its clinical significance as a prognostic implication

    Nasu Y, Tsushima T, Akebi N, Maki Y, Takamatsu M, Inoue T, Ohmori H

    J Urol   151 ( 5 )   232A   1994

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  • Hyperthermotherapy Added to the Multidisciplinary Therpay for Penile Cancer

    Kuroda M, Tsushima T, Nasu Y, Asaumi J, Nishikawa K, Gao X.S, Joja I, Takeda Y, Togami I, Makihata E, Kawasaki S, Ohmor H, Hiraki Y

    Acta Med. Okayama   47 ( 3 )   169 - 174   1993

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  • Endopyeloplasty for Ureteropelvic Junction Obstruction with a New, Multifunction Surgical Endoscope in Children

    Kumon H, Nasu Y, Ono N, Hayashi T, Ohmori H

    Japanese Journal of Endourology and ESWL   6 ( 1 )   35 - 38   1993

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  • Tissue concentration of intravesically instilled (2″R)-4′-0-tetrahydropyranyl-adriamycin or adriamycin in superficial bladder cancer Reviewed

    Takashi Saika, Tomoyasu Tsushima, Yasutomo Nasu, Masatoshi Noda, Naoki Akebi, Syunko Kaku, Masatake Takamatsu, Hiroyuki Ohmori, Satoru Uno, Taiichiro Johsen

    Japanese Journal of Urology   84 ( 7 )   1206 - 1210   1993

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    Twenty-one patients with superficial bladder cancer entered an analysis of single dose (2′R)-4′-0-tetrahydropyranyladriamycin (THP) or adriamycin (ADM) administration. The patients in each group that have been or not have been treated previously with anti-cancer drugs were randomized into two groups, one was given THP and the other ADM. Thirty-mg of THP or ADM dissolved in 30 ml of physiologic saline was instilled into the bladder, and retained for 1 hour. After 1 hour retention of the drugs, tumor tissues and normal mucosas were removed by punch biopsy forceps transurethrally. The tissue concentrations of THP and ADM were estimated by high performance liquid chromatography. The tissue concentrations of THP and ADM in the tumors were significantly greater (p&lt
    0.05) than those in the normal bladder mucosas. The tissue concentration of THP in the tumors were greater than that of ADM. The tissue concentrations of THP and ADM in the tumor of patients who have been treated with anti-cancer drugs priviously were less than those of patients who have not. This results demonstrated that prior therapy with anti-cancer drug may cause a resistance for intravesical instillation chemotherapy. However in patients with prior therapy, the tissue concentration of THP in the tumors were greater than that of ADM. Based on these findings, THP has been shown to be were effective as an intravesical instillating agent expecially, in cases with prior chemotherapy. © 1993, THE JAPANESE UROLOGICAL ASSOCIATION. All rights reserved.

    DOI: 10.5980/jpnjurol1989.84.1206

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  • Phase 2 study of 5'-DFUR for bladder and prostatic cancer Reviewed

    H. Ohmori, Y. Matsumura, J. Ochi, K. Kobashi, N. Akebi, T. Saika, K. Nanba, T. Tanahashi, T. Josen, Y. Nasu, M. Saegusa, Y. Ozaki, M. Hara, T. Asahi, N. Ike, T. Tsushima, N. Mitsuhata, T. Akagi, T. Kaeda

    Japanese Journal of Cancer and Chemotherapy   18 ( 13 )   2307 - 2314   1991

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    Phase 2 study of 5'-DFUR in bladder and prostatic cancer was conducted at 15 collaborative institutions including Okayama University. 5'-DFUR was orally administered to patients at a daily dose of 800-1200 mg for more than 4 weeks. Forty-one patients with bladder cancer and 12 patients with prostatic cancer were evaluated. The response rate for bladder cancer was 31.7% (CFR, 1 case: PR, 12 cases), against no response with prostatic cancer. Moreover, the concentration of 5-FU in bladder tumors was confirmed to be high. Adverse reactions such as diarrhea, anorexia, and nausea were observed. Thus, 5'-DFUR seems to be useful for the treatment of bladder cancer.

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  • A COMBINED LIGHT AND SCANNING ELECTRON-MICROSCOPY ON HUMAN URINARY CYTOLOGY Reviewed

    H KUMON, Y NASU, Y MATSUMURA, H OHMORI, T TANAKA

    JOURNAL OF ELECTRON MICROSCOPY   32 ( 1 )   27 - 32   1983

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  • 5.4.2遺伝子医療(治療)

    那須保友, 一般社団法人日本医療情報学会医療情報技師育成部会( Role: Contributor ,  医療情報第5版 医学・医療編)

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    医学書院,東京  2014.1 

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  • 遺伝子治療の最先端

    賀来春紀, 那須保友, 公文裕巳, 村井, 勝, 奥山明彦, 内藤誠二編( Role: Contributor ,  泌尿器疾患治療の新しいストラテジー)

    メジカルビュー社,東京  2007 

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  • 中皮腫に対する遺伝子治療

    柏倉祐司, 那須保友, 公文裕巳( Role: Contributor ,  胸膜中皮腫診療ハンドブック)

    中外医学社,東京  2007 

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  • Chapter 10 Committee 13 New therapeutic targets and treatments for metastatic prostate cancer:New therapeutic targets and treatments for metastatic prostate cancer

    Nelson W.G, Saad F, Debruyne F.M.J, Eisenberger M.A, Fourcade R, Frenkel E.P, Kantoff P.W, Kumon H, Nasu Y, Oudard S, Wirth M.(editors. Mcconnell J, Denis L, Akaza H, Khoury S, Schalken J( Role: Contributor ,  Prostate Cancer)

    Health Publications,Paris  2006 

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  • Indications for ureteroscopy

    Kumon H, Abarzua F, Nasu Y, Smith A.D, Badlani G.H, Bagley D.H, Clayman R.V, Docimo S.G, Jordan G.H, Kavoussi L.R, Lee B.R, Lingeman J.E, Preminger G.M, Segura J( Role: Contributor ,  Smith's Textbook of Endourology Second Edition)

    BC Decker Inc,London  2006 

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  • Targeting energy-assisted gene delivery in urooncology

    Nasu Y, Abarzua F, Kumon H, Kumon H, Murai M, Baba S. E( Role: Contributor ,  Recent Advances in Endourology 6 Endourooncology New Horizons in Endourology)

    Springer  2005 

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  • 泌尿器科領域 3.前立腺癌の遺伝子治療

    那須保友, 伊藤克己, 浅野 泰, 遠藤 仁, 御手洗哲也, 東原英二( Role: Contributor ,  Annual Review 腎臓)

    中外医学社,東京  2003 

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  • 泌尿器科癌に対する遺伝子治療

    那須保友, 勝岡洋治, 赤座英之( Role: Contributor ,  泌尿器科悪性腫瘍治療ハンドブック)

    新興医学出版社,東京  2001 

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  • 腎機能検査

    那須保友, 日下信行( Role: Contributor ,  看護のための最新医学講座22泌尿・生殖器疾患)

    中山書店,東京  2001 

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  • Bone metastasis of urogenital cancer

    Bone metastasis and related disease  1995 

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  • IV骨転移診療の実際 5章 泌尿器科領域悪性腫瘍の骨転移

    骨転移 病態・診断・治療 金芳堂  1995 

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MISC

  • 腎門部に発生した粘液囊胞腺癌の 1 例

    三宅修司, 岩田健宏, 長尾賢太郎, 河田達志, 富永悠介, 定平卓也, 西村慎吾, 高本 篤, 佐古智子, 和田耕一郎, 枝村康平, 小林康之, 荒木元朗, 渡部昌実, 渡辺豊彦, 柳井広之, 那須保友

    西日本泌尿器科   83 ( 2 )   100 - 105   2021.6

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  • 腎癌-最新の診断-局所療法(凍結療法,ラジオ波焼却術を含む)

    高本 篤, 荒木元朗, 那須保友

    日本臨牀   79 ( 5 )   753 - 758   2021.5

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  • 遠隔治療 泌尿器科編

    富永悠介, 荒木元朗, 那須保友

    岡山医学会雑誌   133 ( 1 )   73 - 75   2021.4

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  • 第34回日本泌尿器内視鏡学会総会開催報告

    那須保友

    岡山医学会雑誌   133 ( 1 )   83 - 84   2021.4

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  • 若年発症の前立腺炎症性偽腫瘍の 1 例

    佐久間貴文, 丸山雄樹, 定平卓也, 高本 篤, 和田耕一郎, 小林泰之, 荒木元朗, 渡部昌実, 渡辺豊彦, 那須保友

    西日本泌尿器科   83 ( 1 )   54 - 58   2021.4

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  • 遺伝性平滑筋腫症-腎細胞癌症候群関連腎細胞癌の術後骨転移に対してイピリムマブ・ニボルマブ併用療法が有効であった1例

    渡部智文, 榮枝一磨, 津川昌也, 関戸崇了, 富永悠介, 高本 篤, 定平卓也, 小林泰之, 荒木元朗, 渡辺豊彦, 小田和歌子, 黒田直人, 十川麗美, 山本英喜, 平沢 晃, 那須保友

    西日本泌尿器科   83 ( 1 )   31 - 36   2021.4

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  • 抗 TFE3 抗体による免疫染色陽性所見からXp11.2 転座型腎癌と考えられた 3 例

    井上陽介, 関戸崇了, 定平卓也, 高本 篤, 杉本盛人, 和田耕一郎, 荒木元朗, 那須保友

    西日本泌尿器科   83 ( 1 )   42 - 47   2021.4

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  • 当科における尿中分離Extended Spectrum Beta Lactamase(ESBL)産生大腸菌株の薬剤感受性年次推移と分子生物学的解析

    和田里 章悟, 定平 卓也, 和田 耕一郎, 山本 満寿美, 岩田 健宏, 石井 亜矢乃, 渡邉 豊彦, 那須 保友

    日本化学療法学会雑誌   69 ( Suppl.A )   277 - 277   2021.4

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  • 乳酸菌腟坐剤の反復性膀胱炎再発予防効果に関する臨床的検討

    石井 亜矢乃, 定平 卓也, 和田 耕一郎, 岩田 健宏, 狩山 玲子, 和田里 章悟, 山本 満寿美, 渡邉 豊彦, 那須 保友

    日本化学療法学会雑誌   69 ( Suppl.A )   216 - 216   2021.4

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  • ロボット支援腹腔鏡下膀胱全摘除術〜現状の課題と今後の方向性〜 岡山大学病院におけるRARC ICUD(回腸導管)

    小林 泰之, 西村 慎吾, 岩田 健宏, 枝村 康平, 和田 耕一郎, 荒木 元朗, 渡辺 豊彦, 那須 保友

    日本内視鏡外科学会雑誌   25 ( 7 )   SY16 - 2   2021.3

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  • 第323回日本泌尿器科学会岡山地方会演題抄録 岡山大学病院における去勢抵抗性前立腺癌に対するドセタキセルの長期治療成績

    河田達志, 高本 篤, 横山周平, 宗田大二郎, 坪井一馬, 長尾賢太郎, 富永悠介, 岩田健宏, 西村慎吾, 佐古智子, 枝村康平, 小林泰之, 荒木元朗, 渡辺豊彦, 那須保友

    西日本泌尿器科   82 ( 6 )   605 - 605   2021.2

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  • 高血圧・糖尿病に焦点を当てたマージナルドナーからの生体腎移植

    吉永 香澄, 荒木 元朗, 関戸 崇了, 和田里 章悟, 丸山 雄樹, 定平 卓也, 窪田 理沙, 西村 慎吾, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 竹内 英実, 田邉 克幸, 森永 裕士, 杉山 斉, 和田 淳, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本臨床腎移植学会プログラム・抄録集   54回   193 - 193   2021.2

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  • 尿路バイオフィルム感染症に対する乳酸菌の有用性に関する基礎的検討

    狩山 玲子, 光畑 律子, 山本 満寿美, 定平 卓也, 和田 耕一郎, 石井 亜矢乃, 渡邉 豊彦, 那須 保友

    日本細菌学雑誌   76 ( 1 )   93 - 93   2021.2

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  • 神経線維腫症1型に合併した後腹膜悪性末梢神経鞘腫瘍の1例

    宗田大二郎, 岩田健宏, 定平卓也, 富永悠介, 片山 聡, 西村慎吾, 高本 篤, 佐古智子, 枝村康平, 小林泰之, 荒木元朗, 渡部昌実, 渡辺豊彦, 那須保友, 中田英二, 柳井広之

    西日本泌尿器科   82 ( 6 )   596 - 600   2021

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  • 排尿障害を伴う全周性尿道憩室に対して外科的治療を行った1例

    松尾聡子, 谷本竜太, 杉本盛人, 津島知靖, 中村あや, 定平卓也, 和田里章悟, 小林泰之, 荒木元朗, 渡辺豊彦, 那須保友

    西日本泌尿器科   82 ( 5 )   514 - 517   2020.12

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  • 当院における開腹膀胱全摘術(ORC)と腹腔鏡下膀胱全摘術(LRC)の治療成績の比較

    和田里 章悟, 小林 泰之, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 高本 篤, 佐古 智子, 枝村 康平, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本泌尿器科学会総会   108回   1138 - 1138   2020.12

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  • 保険委員会:Future vision 病院経営におけるこれからの泌尿器科医の役割

    渡邉 豊彦, 那須 保友

    日本泌尿器科学会総会   108回   381 - 381   2020.12

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  • 膀胱癌に対する革新的アブレーション技術の確立と新展開

    定平 卓也, 那須 保友

    日本泌尿器科学会総会   108回   483 - 483   2020.12

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  • Lynch症候群に発症した上部尿路上皮癌の1例

    本郷智拡, 神原太樹, 野田 岳, 森 聰博, 中田哲也, 田中屋宏爾, 赤木 究, 定平卓也, 荒木元朗, 那須保友

    西日本泌尿器科   82 ( 4 )   477 - 482   2020.10

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  • ニボルマブ・イピリムマブ併用療法による血球貧食症候群を発症した1例

    笹岡丈人, 平田武志, 倉繁拓志, 早田俊司, 富永悠介, 光井洋介, 定平卓也, 高本 篤, 小林泰之, 荒木元朗, 渡辺豊彦, 那須保友

    西日本泌尿器科   82 ( 4 )   449 - 452   2020.10

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  • 腎摘除術を要した多房性気腫性腎盂腎炎の1例

    小林宏州, 高本 篤, 定平卓也, 和田耕一郎, 前原貴典, 大岩裕子, 岩田健宏, 西村慎吾, 杉本盛人, 小林泰之, 荒木元朗, 渡部昌実, 渡辺豊彦, 那須保友

    西日本泌尿器科   82 ( 4 )   465 - 469   2020.10

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  • 新たなin vivoイメージング技術から明らかになった、タダラフィルによる腎虚血/再灌流後好中球浸潤低下(The novel in vivo imaging techniques for visualizing neutrophil infiltration following renal ischemia/reperfusion which was reduced by tadalafil)

    丸山 雄樹, 荒木 元朗, 城所 研吾, 十川 裕史, 吉永 香澄, 光井 洋介, 定平 卓也, 和田 耕一郎, 渡部 昌実, 渡邉 豊彦, 柏原 直樹, 那須 保友

    西日本泌尿器科   82 ( 増刊 )   136 - 136   2020.10

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  • 生体腎移植において低用量リツキシマブはウイルス感染症を増加させない

    吉永 香澄, 荒木 元朗, 関戸 崇了, 和田里 章悟, 丸山 雄樹, 光井 洋介, 定平 卓也, 窪田 理沙, 西村 慎吾, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 渡邉 豊彦, 那須 保友

    移植   55 ( 総会臨時 )   384 - 384   2020.10

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  • 尿路変向術:私の工夫 RARC ICUD失敗から学んだこと

    小林 泰之, 枝村 康平, 西村 慎吾, 岩田 健宏, 定平 卓也, 高本 篤, 佐古 智子, 荒木 元朗, 渡邊 豊彦, 那須 保友

    西日本泌尿器科   82 ( 増刊 )   111 - 111   2020.10

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  • 腎移植後の尿細胞診におけるSV40染色はBKウイルス腎症の発症予測に有効である

    関戸 崇了, 荒木 元朗, 吉永 香澄, 和田里 章悟, 丸山 雄樹, 光井 洋介, 定平 卓也, 窪田 理沙, 西村 慎吾, 佐古 智子, 枝村 康平, 小林 泰之, 渡邉 豊彦, 柳井 広之, 那須 保友

    移植   55 ( 総会臨時 )   384 - 384   2020.10

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  • 生体腎移植において好中球・リンパ球比の高値の継続は腎機能低下の予後予測因子となる

    丸山 雄樹, 荒木 元朗, 関戸 崇了, 和田里 章悟, 吉永 香澄, 光井 洋介, 窪田 理沙, 西村 慎吾, 山下 里美, 枝村 康平, 小林 泰之, 渡邉 豊彦, 田邊 克幸, 杉山 斉, 和田 淳, 那須 保友

    移植   55 ( 総会臨時 )   355 - 355   2020.10

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  • 後腹膜SFT(Solitary fibrous tumor)の一例

    坪井 一馬, 高本 篤, 関戸 崇了, 富永 悠介, 岩田 健宏, 佐古 智子, 枝村 康平, 小林 泰之, 石井 亜矢乃, 荒木 元朗, 渡部 昌美, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   82 ( 増刊 )   191 - 191   2020.10

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  • 進行腎癌に対してipilimumb、nivolumab併用療法が奏功するも重度肝機能障害を来たし死亡の転機をたどった1例

    宗田 大二郎, 岩田 健宏, 横山 周平, 大岩 裕子, 窪田 理沙, 西村 慎吾, 高本 篤, 佐古 智子, 枝村 康平, 小林 泰之, 荒木 元朗, 渡邊 豊彦, 那須 保友

    西日本泌尿器科   82 ( 増刊 )   165 - 165   2020.10

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  • Pembrolizumabが著効した進行性尿膜管癌の一例

    横山 周平, 長尾 賢太郎, 河田 達志, 富永 悠介, 岩田 健宏, 西村 慎吾, 高本 篤, 佐古 智子, 枝村 康平, 小林 泰之, 荒木 元朗, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   82 ( 増刊 )   184 - 184   2020.10

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  • 生体腎移植後に急性浸潤性の再燃を呈した副鼻腔真菌症の1例

    西村 慎吾, 荒木 元朗, 関戸 崇了, 吉永 香澄, 和田里 章悟, 丸山 雄樹, 光井 洋介, 窪田 理沙, 山下 美里, 和田 耕一郎, 小林 泰之, 渡邉 豊彦, 村井 綾, 檜垣 貴哉, 那須 保友

    移植   55 ( 総会臨時 )   387 - 387   2020.10

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  • ハイリスク腎移植game changers DSA陽性ハイリスク腎移植

    西村 慎吾, 荒木 元朗, 関戸 崇了, 吉永 香澄, 和田里 章悟, 丸山 雄樹, 光井 洋介, 窪田 理沙, 定平 卓也, 岩田 健宏, 高本 篤, 佐古 智子, 枝村 康平, 和田 耕一郎, 小林 泰之, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   82 ( 増刊 )   90 - 90   2020.10

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  • Education of robotic surgery in the Department of Urology, Okayama University Hospital

    Kobayashi Yasuyuki, Nasu Yasutomo, Iwata Takehiro, Nishimura Shingo, Takamoto Atsushi, Sako Tomoko, Sadahira Takuya, Edamura Kohei, Araki Motoo, Watanabe Toyohiko

    Japanese Journal of Endourology   33 ( 2 )   221 - 224   2020.9

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    <p>  Since robot-assisted laparoscopic radical prostatectomy in 2012 was covered by insurance, robotic surgery has rapidly spread. At the Okayama University Hospital-related facilities, da Vinci has spread rapidly over the past few years, and 13 da Vinci (including Okayama University Hospital) are in operation and 45 surgeons are operating. However, the surgical methods and instruction methods at each facility are not the same. Due to personnel changes in related facilities, surgeons with various backgrounds have become enrolled at Okayama University Hospital, and multiple surgical methods have been disrupted even within the same facility. The robot surgery education of our facility could not cope well with this situation, and the perioperative results tended to deteriorate from around 2015. In order to solve this problem, we tried to overcome this situation by applying the concept of "unifying the surgery contents, improving the reproducibility of the surgery contents and aiming for a short learning curve" cultivated in laparoscopic education.</p>

    DOI: 10.11302/jsejje.33.221

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  • 術後感染予防抗菌薬(口腔外科、泌尿器科、脳外科、整形外科、大腸) 泌尿器科における術後感染予防抗菌薬の適正使用

    和田 耕一郎, 定平 卓也, 山本 満寿美, 石井 亜矢乃, 狩山 玲子, 渡邉 豊彦, 那須 保友, 光畑 律子

    日本化学療法学会雑誌   68 ( Suppl.A )   157 - 157   2020.9

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  • 特集 人工知能(AI)を活用した医療の展開 序説 人工知能(AI)への期待:Development of artificial intelligence (AI) in medical field

    那須保友

    岡山医学会雑誌   132   91   2020.8

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  • 【腎盂・尿管癌の治療を考える】腎盂・尿管癌における腹腔鏡下腎尿管全摘除術の適応

    吉永香澄, 荒木元朗, 和田里章悟, 丸山雄樹, 光井洋介, 窪田理沙, 定平卓也, 岩田健宏, 西村慎吾, 高本 篤, 和田耕一郎, 佐古智子, 枝村康平, 小林泰之, 渡部昌実, 渡辺豊彦, 那須保友

    泌尿器外科   33 ( 5 )   455 - 461   2020.5

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  • 尿路感染症・性感染症における多剤耐性菌の迅速診断 前立腺生検前の直腸内におけるキノロン耐性菌の迅速スクリーニング

    和田 耕一郎, 定平 卓也, 石井 亜矢乃, 山本 満寿美, 狩山 玲子, 渡邉 豊彦, 那須 保友, 光畑 律子

    日本化学療法学会雑誌   68 ( 3 )   399 - 399   2020.5

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  • 乳酸菌タブレットの直腸および腟内細菌叢に及ぼす影響に関する検討

    和田 耕一郎, 定平 卓也, 石井 亜矢乃, 山本 満寿美, 三井 將雄, 狩山 玲子, 渡邉 豊彦, 那須 保友, 光畑 律子, 岩田 健宏, 佐久間 貴文, 和田里 章悟

    日本化学療法学会雑誌   68 ( 3 )   449 - 449   2020.5

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  • 尿路感染症・性感染症における多剤耐性菌の迅速診断 前立腺生検前の直腸内におけるキノロン耐性菌の迅速スクリーニング

    和田 耕一郎, 定平 卓也, 石井 亜矢乃, 山本 満寿美, 狩山 玲子, 渡邉 豊彦, 那須 保友, 光畑 律子

    感染症学雑誌   94 ( 3 )   361 - 361   2020.5

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  • 岡山大学病院における進行性尿路上皮癌に対するpembrolizumabの治療経験

    富永悠介, 高本 篤, 関戸崇了, 和田里章悟, 大岩裕子, 窪田理沙, 片山 聡, 岩田健宏, 西村慎吾, 佐古智子, 和田耕一郎, 枝村康平, 小林泰之, 荒木元朗, 渡辺豊彦, 那須保友

    西日本泌尿器科   82 ( 1 )   106 - 110   2020.4

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  • 第321回日本泌尿器科学会岡山地方会演題抄録 後腹膜悪性末梢神経鞘腫の1例

    宗田大二郎, 高本 篤, 荒木元朗, 角南亮輔, 関戸崇了, 佐久間貴文, 和田里章悟, 吉永香澄, 丸山雄樹, 光井洋介, 富永悠介, 大岩裕子, 窪田理沙, 定平卓也, 片山 聰, 岩田健宏, 西村慎吾, 佐古智子, 和田耕一郎, 枝村康平, 小林泰之, 石井亜矢乃, 渡部昌実, 渡辺豊彦, 那須保友

    西日本泌尿器科   82 ( 1 )   173   2020.4

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  • 学会好事:第7回泌尿器画像診断・治療技術研究会(JSURT)

    那須保友

    Urology Today   27 ( 1 )   41   2020.3

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  • 非淋菌性尿道炎に対する 1 日 200 mg sitafloxacin 投与法

    和田耕一郎, 定平卓也, 荒木元朗, 渡辺豊彦, 那須保友

    日本化学療法学会雑誌   68 ( 2 )   181 - 185   2020.3

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    臨床的に遭遇する頻度の高い尿道炎は、初診時に淋菌性か非淋菌性か鑑別してマネジメントを行う。非淋菌性尿道炎(Non-gonococcal urethritis、NGU)の場合にはクラミジア性尿道炎をまず想定するが、保険収載の関係から淋菌(Neisseria gonorrhoeae)、クラミジア(Chlamydia trachomatis)以外の病原微生物に関する検査は行うことができない。検査の性格上、一次治療を開始したあとにC.trachomatisの有無が判明する。治療失敗例では、Mycoplasma genitaliumなど、C.trachomatis以外の病原体の存在を考慮して二次治療を開始する。その際、M.genitaliumの薬剤感受性が低下していることや治療失敗例が報告されており、薬剤の選択には十分な注意が必要である。わが国のガイドラインでは、NGUに対してsitafloxacin(STFX)が推奨薬の一つとして挙げられており、良好な治療効果も報告されている。現時点ではNGUに対してazithromycin(AZM)を第一選択、STFXを第二選択として使用されることが一般的であるが、AZMによる治療失敗例だけでなく、症例によっては初期からSTFXが採用されるべきである。(著者抄録)

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  • 尿路性器感染症POCT"外来で求められる迅速検査" 尿路感染症領域のPOCTと課題

    和田 耕一郎, 定平 卓也, 山本 満寿美, 光畑 律子, 石井 亜矢乃, 渡邉 豊彦, 那須 保友

    感染症学雑誌   94 ( 臨増 )   195 - 195   2020.3

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  • 生体腎移植後slow graft functionのリスク因子の検討

    和田里 章悟, 荒木 元朗, 河村 香澄, 関戸 崇了, 丸山 雄樹, 光井 洋介, 窪田 理沙, 西村 慎吾, 和田 耕一郎, 小林 泰之, 渡邉 豊彦, 北川 正史, 田邊 克幸, 杉山 斉, 和田 淳, 那須 保友

    日本臨床腎移植学会プログラム・抄録集   53回   242 - 242   2020.2

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  • 生体腎移植レシピエントにおけるCT値と骨密度の関係と推移

    丸山 雄樹, 荒木 元朗, 関戸 崇了, 和田里 章悟, 河村 香澄, 光井 洋介, 窪田 理沙, 西村 慎吾, 枝村 康平, 小林 泰之, 渡邉 豊彦, 北川 正史, 田邊 克幸, 那須 保友

    日本臨床腎移植学会プログラム・抄録集   53回   200 - 200   2020.2

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  • 生体ドナー腎採取術における後腹膜鏡下手術の有用性

    西村 慎吾, 荒木 元朗, 小林 泰之, 山下 里美, 関戸 崇了, 坪井 一朗, 河村 香澄, 和田里 章悟, 丸山 雄樹, 光井 洋介, 窪田 理沙, 和田 耕一郎, 渡邉 豊彦, 那須 保友

    日本臨床腎移植学会プログラム・抄録集   53回   209 - 209   2020.2

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  • 生体腎移植後に発症したBKウイルス腎症の2例

    関戸 崇了, 荒木 元朗, 河村 香澄, 和田里 章悟, 丸山 雄樹, 光井 洋介, 窪田 理沙, 西村 慎吾, 和田 耕一郎, 山下 里美, 佐古 智子, 枝村 康平, 小林 泰之, 渡邉 豊彦, 加納 弓月, 北川 正史, 田邊 克幸, 杉山 斉, 和田 淳, 那須 保友

    日本臨床腎移植学会プログラム・抄録集   53回   213 - 213   2020.2

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  • CMV初感染の腎移植レシピエントへのリツキシマブ投与の検討

    河村 香澄, 荒木 元朗, 関戸 崇了, 和田里 章悟, 丸山 雄樹, 光井 洋介, 窪田 理沙, 西村 慎吾, 和田 耕一郎, 小林 泰之, 渡辺 豊彦, 加納 弓月, 北川 正史, 田邉 克幸, 杉山 斉, 和田 淳, 那須 保友

    日本臨床腎移植学会プログラム・抄録集   53回   207 - 207   2020.2

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  • 第65回日本化学療法学会総会シンポジウム12:性感染症の治療におけるUp to date 非淋菌性尿道炎に対するSTFX 200 mg/day

    和田耕一郎, 定平卓也, 荒木元朗, 渡辺豊彦, 那須保友

    日化療会誌   68 ( 2 )   181 - 185   2020

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  • 経皮的腎凍結療法の困難症例における術中CTと腹腔鏡の併用の有用性

    荒木元朗, 関戸崇了, 平木隆夫, 宇賀麻由, 片山聡, 高本篤史, 枝村康平, 小林泰之, 渡邉豊彦, 那須保友

    日本泌尿器内視鏡学会(Web)   34th   2020

  • 岡山大学病院における進行性尿路上皮癌に対するpembrolizumabの治療経験

    富永 悠介, 高本 篤, 角南 亮輔, 関戸 崇了, 和田里 章悟, 河村 香澄, 丸山 雄樹, 光井 洋介, 大岩 裕子, 窪田 理沙, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 荒木 元朗, 石井 亜矢乃, 渡部 昌実, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   81 ( 6 )   656 - 656   2019.12

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  • Fumarate hydratase(FH)欠損腎細胞癌によるリンパ節転移に対して、イピリムマブ+ニボルマブ併用療法が奏功した一例

    関戸 崇了, 高本 篤, 小林 泰之, 三井 將雄, 和田里 章吾, 窪田 理沙, 岩田 健宏, 枝村 康平, 佐古 智子, 荒木 元朗, 渡邉 豊彦, 柳井 広之, 那須 保友

    西日本泌尿器科   81 ( 増刊 )   151 - 151   2019.10

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  • セカンドルック前立腺生検標本を含めた病理標本の一致率の検討

    定平 卓也, 丸山 雄樹, 光井 洋介, 荒木 元朗, 小林 泰之, 渡辺 豊彦, 那須 保友

    西日本泌尿器科   81 ( 増刊 )   199 - 199   2019.10

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  • S100A11は筋浸潤性膀胱癌細胞と線維芽細胞のクロストークに関与し腫瘍進行に寄与する(S100A11 contributes to tumor progression with cross talking between muscle invasive bladder cancer cells and fibroblasts)

    光井 洋介, 定平 卓也, 渡部 昌実, 丸山 雄樹, 荒木 元朗, 渡邉 豊彦, 阪口 政清, 那須 保友

    西日本泌尿器科   81 ( 増刊 )   138 - 138   2019.10

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  • 症例から学ぶ 治療変遷から読み解く腎癌治療 何を、どこまで、どのように? 下大静脈腫瘍塞栓を伴う腎腫瘍の新しい手術アプローチ

    荒木 元朗, 小林 泰之, 枝村 康平, 角南 亮輔, 関戸 崇了, 和田里 章悟, 河村 香澄, 丸山 雄樹, 光井 洋介, 大岩 裕子, 窪田 理沙, 定平 卓也, 片山 聡, 岩田 健宏, 西村 慎吾, 高本 篤, 佐古 智子, 和田 耕一郎, 渡辺 豊彦, 渡部 昌実, 那須 保友, 楳田 佑三, 八木 孝仁

    西日本泌尿器科   81 ( 増刊 )   113 - 113   2019.10

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  • 岡山大学病院における進行性尿路上皮腫瘍に対するpembrolizumabの治療経験

    高本 篤, 小林 泰之, 大岩 裕子, 片山 聡, 枝村 康平, 窪田 理沙, 岩田 健宏, 西村 慎吾, 佐古 智子, 和田 耕一郎, 荒木 元朗, 渡邉 豊彦, 那須 保友

    西日本泌尿器科   81 ( 増刊 )   183 - 183   2019.10

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  • 糖尿病患者は腎部分切除術後一年で腎機能が低下する Propensity Score-Matched Analysis

    河村 香澄, 荒木 元朗, 丸山 雄樹, 光井 洋介, 定平 卓也, 佐古 智子, 和田 耕一郎, 枝村 康平, 小林 泰之, 渡辺 豊彦, 那須 保友

    西日本泌尿器科   81 ( 増刊 )   177 - 177   2019.10

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  • 反復性膀胱炎に対する乳酸菌腟坐剤の再発予防効果に関する臨床的検討

    石井 亜矢乃, 和田 耕一郎, 光畑 律子, 山本 満寿美, 定平 卓也, 岩田 健宏, 狩山 玲子, 小林 泰之, 荒木 元朗, 渡辺 豊彦, 那須 保友

    西日本泌尿器科   81 ( 増刊 )   154 - 154   2019.10

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  • サルコペニアが前立腺全摘除後の排尿関連QoLに与える影響 Expanded Prostate Cancer Index Compositeを用いた経時的変化

    光井 洋介, 渡邉 豊彦, 定平 卓也, 丸山 雄樹, 和田 耕一郎, 枝村 康平, 小林 泰之, 荒木 元朗, 渡部 昌実, 那須 保友

    日本排尿機能学会誌   30 ( 1 )   255 - 255   2019.9

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  • ロボット補助腹腔鏡下前立腺全摘術後尿失禁の予測因子としての骨盤MRIパラメーターの有用性

    定平 卓也, 河村 香澄, 丸山 雄樹, 光井 洋介, 和田 耕一郎, 小林 泰之, 荒木 元朗, 渡部 昌実, 渡邉 豊彦, 那須 保友

    日本排尿機能学会誌   30 ( 1 )   321 - 321   2019.9

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  • 腎虚血再灌流障害における好中球動態の2光子励起顕微鏡を用いた解析

    丸山 雄樹, 荒木 元朗, 城所 研吾, 和田 耕一郎, 河村 香澄, 光井 洋介, 定平 卓也, 窪田 理沙, 西村 慎吾, 渡部 昌実, 渡邉 豊彦, 田邊 克幸, 和田 淳, 柏原 直樹, 那須 保友

    移植   54 ( 総会臨時 )   241 - 241   2019.9

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  • 生体腎移植におけるドナー・レシピエントのQoL変化の相違の検討

    光井 洋介, 荒木 元朗, 山下 里美, 丸山 雄樹, 河村 香澄, 窪田 理沙, 西村 慎吾, 和田 耕一郎, 小林 泰之, 渡邉 豊彦, 北川 正史, 田邊 克幸, 杉山 斉, 和田 淳, 那須 保友

    移植   54 ( 総会臨時 )   253 - 253   2019.9

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  • 生体腎移植8年後に回腸末端に発生したPTLDの一例

    和田里 章悟, 荒木 元朗, 河村 香澄, 丸山 雄樹, 光井 洋介, 窪田 理沙, 定平 卓也, 西村 慎吾, 和田 耕一郎, 枝村 康平, 小林 泰之, 渡邉 豊彦, 北川 正史, 田邊 克幸, 那須 保友

    移植   54 ( 総会臨時 )   278 - 278   2019.9

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  • マージナルドナーからの生体腎移植の検討

    河村 香澄, 荒木 元朗, 関戸 崇了, 丸山 雄樹, 光井 洋介, 窪田 理沙, 西村 慎吾, 和田 耕一郎, 山下 里美, 小林 泰之, 渡邉 豊彦, 那須 保友

    移植   54 ( 総会臨時 )   324 - 324   2019.9

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    Language:Japanese   Publisher:(一社)日本移植学会  

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  • 岡山大学病院における腹腔鏡下と後腹膜鏡下ドナー腎採取術の比較検討

    西村 慎吾, 荒木 元朗, 小林 泰之, 山下 里美, 坪井 一朗, 河村 香澄, 和田里 章悟, 丸山 雄樹, 光井 洋介, 窪田 理沙, 和田 耕一郎, 渡辺 豊彦, 那須 保友

    移植   54 ( 総会臨時 )   201 - 201   2019.9

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    Language:Japanese   Publisher:(一社)日本移植学会  

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  • 腎移植後に発生し治療により完治したリンパ嚢腫の2例

    窪田 理沙, 荒木 元朗, 和田 耕一郎, 河村 香澄, 丸山 雄樹, 光井 洋介, 西村 慎吾, 山下 里美, 小林 泰之, 渡邉 豊彦, 那須 保友, 加納 弓月, 北川 正史, 田邊 克幸, 和田 淳

    移植   54 ( 総会臨時 )   278 - 278   2019.9

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    Language:Japanese   Publisher:(一社)日本移植学会  

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  • 岡山大学病院泌尿器科における腹腔鏡教育プログラムの有用性 腹腔鏡下副腎摘除術

    和田里 章悟, 小林 泰之, 定平 卓也, 岩田 健宏, 西村 慎吾, 高本 篤, 佐古 智子, 枝村 康平, 和田 耕一郎, 荒木 元朗, 渡