Think different in metastatic RCC treatment 免疫チェックポイント阻害薬時代におけるCytoreductive nephrectomy(CN)の意義
大澤 崇宏, 菊地 央, 山田 修平, 宮田 遥, 松本 隆児, 安部 崇重, 篠原 信雄
泌尿器外科, 36, 臨増, 788, 789, 医学図書出版(株), Aug. 2023
Japanese

Cisplatin resistance driver claspin is a target for immunotherapy in urothelial carcinoma.
Shuhei Yamada, Haruka Miyata, Makoto Isono, Kanta Hori, Junko Yanagawa, Aiko Murai, Tomoyuki Minowa, Yuka Mizue, Kenta Sasaki, Kenji Murata, Serina Tokita, Munehide Nakatsugawa, Sadahiro Iwabuchi, Shinichi Hashimoto, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Takashige Abe, Nobuo Shinohara, Yoshihiko Hirohashi, Toshihiko Torigoe
Cancer immunology, immunotherapy : CII, 16 Feb. 2023, [International Magazine]
English, Scientific journal, Bladder cancer is a major and fatal urological disease. Cisplatin is a key drug for the treatment of bladder cancer, especially in muscle-invasive cases. In most cases of bladder cancer, cisplatin is effective; however, resistance to cisplatin has a significant negative impact on prognosis. Thus, a treatment strategy for cisplatin-resistant bladder cancer is essential to improve the prognosis. In this study, we established a cisplatin-resistant (CR) bladder cancer cell line using an urothelial carcinoma cell lines (UM-UC-3 and J82). We screened for potential targets in CR cells and found that claspin (CLSPN) was overexpressed. CLSPN mRNA knockdown revealed that CLSPN had a role in cisplatin resistance in CR cells. In our previous study, we identified human leukocyte antigen (HLA)-A*02:01-restricted CLSPN peptide by HLA ligandome analysis. Thus, we generated a CLSPN peptide-specific cytotoxic T lymphocyte clone that recognized CR cells at a higher level than wild-type UM-UC-3 cells. These findings indicate that CLSPN is a driver of cisplatin resistance and CLSPN peptide-specific immunotherapy may be effective for cisplatin-resistant cases.

GRIK2 is a target for bladder cancer stem-like cell-targeting immunotherapy.
Haruka Miyata, Yoshihiko Hirohashi, Shuhei Yamada, Junko Yanagawa, Aiko Murai, Shinichi Hashimoto, Serina Tokita, Kanta Hori, Takashige Abe, Terufumi Kubo, Tomohide Tsukahara, Takayuki Kanaseki, Nobuo Shinohara, Toshihiko Torigoe
Cancer immunology, immunotherapy : CII, 71, 4, 795, 806, Apr. 2022, [International Magazine]
English, Scientific journal, Recent studies have revealed that treatment-resistant cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be targeted by cytotoxic T lymphocytes (CTLs). CTLs recognize antigenic peptides derived from tumor-associated antigens; thus, the identification of tumor-associated antigens expressed by CSCs/CICs is essential. Human leucocyte antigen (HLA) ligandome analysis using mass spectrometry enables the analysis of naturally expressed antigenic peptides; however, HLA ligandome analysis requires a large number of cells and is challenging for CSCs/CICs. In this study, we established a novel bladder CSC/CIC model from a bladder cancer cell line (UM-UC-3 cells) using an ALDEFLUOR assay. CSCs/CICs were isolated as aldehyde dehydrogenase (ALDH)-high cells and several ALDHhigh clone cells were established. ALDHhigh clone cells were enriched with CSCs/CICs by sphere formation and tumorigenicity in immunodeficient mice. HLA ligandome analysis and cap analysis of gene expression using ALDHhigh clone cells revealed a distinctive antigenic peptide repertoire in bladder CSCs/CICs, and we found that a glutamate receptor, ionotropic, kainite 2 (GRIK2)-derived antigenic peptide (LMYDAVHVV) was specifically expressed by CSCs/CICs. A GRIK2 peptide-specific CTL clone recognized GRIK2-overexpressing UM-UC-3 cells and ALDHhigh clone cells, indicating that GRIK2 peptide can be a novel target for bladder CSC/CIC-targeting immunotherapy.

Development and validation of a porcine organ model for training in essential laparoscopic surgical skills.
Madoka Higuchi, Takashige Abe, Kiyohiko Hotta, Ken Morita, Haruka Miyata, Jun Furumido, Naoya Iwahara, Masafumi Kon, Takahiro Osawa, Ryuji Matsumoto, Hiroshi Kikuchi, Yo Kurashima, Sachiyo Murai, Abdullatif Aydin, Nicholas Raison, Kamran Ahmed, Muhammad Shamim Khan, Prokar Dasgupta, Nobuo Shinohara
International journal of urology : official journal of the Japanese Urological Association, 03 Aug. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, OBJECTIVES: To develop a wet laboratory training model for learning core laparoscopic surgical skills and evaluating learners' competency level outside the operating room. METHODS: Participants completed three tasks (task 1: tissue dissection around the aorta; task 2: tissue dissection and division of the renal artery; task 3: renal parenchymal closure). Each performance was video recorded and subsequently evaluated by two experts, according to the Global Operative Assessment of Laparoscopic Skills and task-specific metrics that we developed (Assessment Sheet of Laparoscopic Skills in Wet Lab score). Mean scores were used for analyses. The subjective mental workload was also assessed (NASA Task Load Index). RESULTS: The 54 participants included 32 urologists, eight young trainees and 14 medical students. A total of 13 participants were categorized as experts (≥50 laparoscopic surgeries), eight as intermediates (10-49) and 33 as novices (0-9). There were significant differences in the Global Operative Assessment of Laparoscopic Skills and Assessment Sheet of Laparoscopic Skills in Wet Lab scores among the three groups in all three tasks. Higher NASA Task Load Index scores were observed in novices, and there were significant differences in tasks 1 (Kruskal-Wallis test, P = 0.0004) and 2 (P = 0.0002), and marginal differences in task 3 (P = 0.0745) among the three groups. CONCLUSIONS: Our training model has good construct validity, and differences in the NASA Task Load Index score reflect previous laparoscopic surgical experiences. Our findings show the ability to assess both laparoscopic surgical skills and mental workloads, which could help educators comprehend trainees' level outside the operating room. Given the decreasing opportunity to carry out pure laparoscopic surgeries because of the dissemination of robotic surgery, especially in urology, our model can offer practical training opportunities.

Abscopal effect following nivolumab induction in a patient with metastatic renal cell carcinoma-unique pathological features of the primary specimen: A case report.
Kanta Hori, Yoshihiko Hirohashi, Toshiki Aoyagi, Narumi Taniguchi, Masashi Murakumo, Haruka Miyata, Toshihiko Torigoe, Takashige Abe, Nobuo Shinohara, Ken Morita
Experimental and therapeutic medicine, 19, 3, 1903, 1907, Mar. 2020, [International Magazine]
English, Scientific journal, The case of a patient with metastatic renal cell carcinoma who exhibited the abscopal effect following treatment by anti-programmed death-1 (PD-1) antibody is presented. A 40-year-old woman was diagnosed with an 8.2-cm renal tumor without distant metastases, and radical nephrectomy was subsequently performed. Pathological examination revealed a clear cell renal cell carcinoma. At 3 months after surgery, the patient developed one lung metastasis. Following treatment with interferon and three types of tyrosine kinase inhibitors, anti-PD1 antibody (nivolumab) was started. During the treatment, para-aortic/supraclavicular lymph nodes and several lung lesions remained, although other lesions decreased markedly. The patient was subsequently treated by palliative radiotherapy to the para-aortic and supraclavicular lymph nodes for pain control. After the radiotherapy, the lung lesions previously refractory to nivolumab started to decrease, probably due to an abscopal effect. Additionally, the laboratory data and Karnofsky Performance Status improved. Histological re-examination of the primary lesion revealed heterogeneity of the immunological microenvironment, which may be associated with the heterogeneity of treatment sensitivity.

Prognostic impact of local radiotherapy on metastatic urothelial carcinoma patients receiving systemic chemotherapy.
Takashige Abe, Keita Minami, Toru Harabayashi, Ataru Sazawa, Hiroki Chiba, Hiroshi Kikuchi, Haruka Miyata, Jun Frumido, Ryuji Matsumoto, Takahiro Osawa, Ishizaki Junji, Mochizuki Tango, Chiba Satoshi, Akino Tomoshige, Murakumo Masashi, Miyajima Naoto, Tsuchiya Kunihiko, Maruyama Satoru, Sachiyo Murai, Nobuo Shinohara
Japanese journal of clinical oncology, 50, 2, 206, 213, 17 Feb. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, OBJECTIVE: To clarify the prognostic impact of local radiotherapy on metastatic urothelial carcinoma patients treated by systemic chemotherapy. METHODS: Of the 228 metastatic urothelial carcinoma patients treated with systemic chemotherapy, 97 received radiotherapy mainly to metastatic sites. In patients for whom the purpose of radiotherapy was not specified, more than 50 Gy irradiation was considered to be for disease consolidation for survival analysis, while less than 50 Gy was categorized as palliation. According to the Kaplan-Meier method, we analysed overall survival from the initiation of treatment for metastatic urothelial carcinoma until death or the last follow-up, using the log-rank test to assess the significance of differences. The Cox model was applied for prognostic factor analysis. RESULTS: Overall, there was no significant difference in survival between patients with and those without radiotherapy (P = 0.1532). When analysing the patients undergoing consolidative radiotherapy separately, these 25 patients showed significantly longer survival than the 72 patients with palliative radiotherapy (P = 0.0047), with a 3-year overall survival of 43.3%. Of the present cohort, 22 underwent metastasectomy for disease consolidation, and there was no overlapping case between the metastasectomy cohort and cohort receiving consolidative radiotherapy. After controlling for four independent prognostic factors (sex, performance status, haemoglobin level and number of organs with metastasis) in our previous study, radiotherapy for disease consolidation showed a marginal value (hazard ratio = 0.666, P = 0.0966), while metastasectomy remained significant (hazard ratio = 0.358, P = 0.0006). CONCLUSIONS: In the selected patients, long-term disease control could be achieved after consolidative radiotherapy for metastatic urothelial carcinoma disease. Our observations suggest that local ablative therapy (surgery or radiotherapy) could facilitate long-term disease control. However, the treatment decision should be individualized because of the lack of randomized control trials.

Validity assessment of the laparoscopic radical nephrectomy module of the LapVision virtual reality simulator.
Haruka Miyata, Takashige Abe, Kiyohiko Hotta, Madoka Higuchi, Takahiro Osawa, Ryuji Matsumoto, Hiroshi Kikuchi, Yo Kurashima, Sachiyo Murai, Nobuo Shinohara
Surgery open science, 2, 1, 51, 56, Jan. 2020, [International Magazine]
English, Scientific journal, Background: Virtual reality simulators allow trainees to perform repeated practice and provide objective dexterity metrics regarding their performance, which means that virtual reality-based surgical training is becoming a vital part of initial learning of basic laparoscopic surgical skills. However, its educational role in learning advanced procedures remains undetermined. We evaluated the validity of the laparoscopic radical nephrectomy module of the LapVision virtual reality simulator. Methods: Urologists, medical students, and a junior resident voluntarily participated in the present study, and they performed training with a laparoscopic left radical nephrectomy module. For construct validation, dexterity metrics calculated in the simulator and the mean score of Global Operative Assessment of Laparoscopic Skills evaluated by 2 experts' video review were compared according to the certification of Japanese Endoscopic Surgical Skill Qualification or previous surgical experience. Results: Ten experts (≥ 50 laparoscopic surgeries), 9 intermediates (11-49), and 14 novices (0-10) voluntarily participated in the present study. Regarding the construct validity, there was a significant difference in the total number of errors, blood loss, and Global Operative Assessment of Laparoscopic Skills score among the groups for both the Endoscopic Surgical Skill Qualification status and previous surgical experience. Conclusion: The present study demonstrated good construct validity for the LapVision nephrectomy module. Furthermore, global skill assessment was possible by experts' reviews, which indicates the usefulness of the virtual reality procedural module as a skill assessment tool. Virtual reality-based procedural simulation has marked potential to become a vital part of integrated laparoscopic training programs.

[Treatment Outcome of Axitinib for Metastatic Renal-Cell Carcinoma Patients].
Naohisa Kusakabe, Takahiro Osawa, Haruka Miyata, Hiroshi Kikuchi, Ryuji Matsumoto, Satoru Maruyama, Takashige Abe, Nobuo Shinohara
Hinyokika kiyo. Acta urologica Japonica, 64, 9, 353, 358, Sep. 2018, [Peer-reviewed], [Domestic magazines]
Japanese, Scientific journal, Axitinib was approved for use in Japan as a salvage therapy for patients with metastatic renal cell carcinoma (RCC) in 2012. We retrospectively evaluated the cases of 32 RCC patients that were treated with Axitinib as a 2nd- or further-line therapy between November 2012 and March 2017. Overall survival (OS), progression-free survival (PFS), and adverse events were assessed. The median OS and PFS from the initiation of Axitinib were 29 and 11 months, respectively. Nineteen patients received Axitinib as a 2nd-line treatment, in whom the median OS and median PFS were 22 and 10 months, respectively, while the median OS and PFS were 29 and 15.5 months, respectively, amongthe 13 patients who received Axitinib as a 3rd- or further-line treatment, which suggested that Axitinib is effective in the 3rd-line and further-line settings. A Cox multivariate model revealed that bone metastasis was a significant adverse factor for OS. Common grade 3 or higher adverse events included hypertension (28%), diarrhea (7%), and proteinuria (7%). Although the present study demonstrated the efficacy and safety of salvage Axitinib treatment in patients who had recurrent disease after the initial systemic therapy, further large-scale studies should be warranted to make clear its clinical effectiveness in these patients.

The significance of metastasectomy in patients with metastatic renal cell carcinoma
Haruka Miyata, Nobuo Shinohara, Norihiro Murahashi, Kunihiko Tsuchiya, Naoto Miyajima, Satoru Maruyama, Takashige Abe, Kichizo Kaga, Satoshi Hirano, Katsuya Nonomura
Acta Urologica Japonica, 61, 2, 49, 54, Editorial Board of Acta Urologica Japonica, 01 Feb. 2015, [Peer-reviewed]
Japanese, Scientific journal

前立腺癌との鑑別を要した前立腺Xanthomaの1例
山田 修平, 松野 吉宏, 大澤 崇宏, 古御堂 純, 宮田 遥, 菊池 央, 松本 隆児, 安部 崇重, 篠原 信雄, 泌尿器外科, 34, 3, 315, 315, Mar. 2021
医学図書出版(株), Japanese

Health-related quality of life in Japanese patients with bladder cancer according to a newly developed Japanese version of the Bladder Cancer Index
Takahiro Osawa, John Wei, Takashige Abe, Shuhei Yamada, Jun Frumido, Haruka Miyata, Hiroshi Kikuchi, Ryuji Matsumoto, Yasuyuki Sato, Kazushi Hirakawa, Yoshihiro Sasaki, Hiroshi Tanaka, Akira Kashiwagi, Ken Morita, Norikata Takada, Keita Minami, Toru Harabayashi, Sachiyo Murai, Nobuo Shinohara, JOURNAL OF CLINICAL ONCOLOGY, 38, 6, Feb. 2020
English, Summary international conference

The role of tumor endothelial cell in urological cancer
菊地央, 菊地央, 山田修平, 古御堂純, 古御堂純, 宮田遥, 松本隆児, 大澤崇宏, 大澤崇宏, 秋野文臣, 秋野文臣, 秋野文臣, 土屋邦彦, 土屋邦彦, 土屋邦彦, 安部祟重, 間石奈湖, 樋田京子, 篠原信雄, 日本泌尿器科学会総会(Web), 108th, 500, 500, 2020
(一社)日本泌尿器科学会総会事務局, Japanese

complications after radical cystectomy: multicenter retrospective study
山田修平, 安部祟重, 松本隆児, 古御堂純, 宮田遥, 菊地央, 大澤崇宏, 篠原信雄, 日本泌尿器科学会総会(Web), 108th, 1751, 1751, 2020
(一社)日本泌尿器科学会総会事務局, Japanese

Bladder Cancer Index(BCI)日本語版の開発におけるPilot Study
大澤 崇宏, Wei John T, 伊藤 陽一, 成田 学, 賀古 勇輝, 宮田 遙, 菊地 央, 松本 隆児, 宮島 直人, 丸山 覚, 安部 崇重, 村井 祥代, 篠原 信雄, 泌尿器外科, 32, 5, 518, 518, May 2019
医学図書出版(株), Japanese

前立腺癌監視療法におけるゲノムアッセイの有用性　　　　　　　　　　　　　　　
丸山 覚, 宮田 遥, 菊地 央, 松本 隆児, 大澤 崇宏, 安部 崇重, 篠原 信雄, 泌尿器外科, 32, 5, 520, 520, May 2019
医学図書出版(株), Japanese

RENAL NEPHROMETRY SCORE CORRELATED WITH TUMOR PROLIFERATIVE ACTIVITY OF T1 CLEAR CELL RENAL CELL CARCINOMA
Hiroshi Kikuchi, Takashige Abe, Ryuji Matsumoto, Jun Furumido, Haruka Miyata, Takahiro Osawa, Sachiyo Murai, Nobuo Shinohara, JOURNAL OF UROLOGY, 201, 4, E274, E275, Apr. 2019
English, Summary international conference

COMPARISON OF LONG-TERM OUTCOMES BETWEEN RADICAL PROSTATECTOMY AND INTENSITY-MODULATED RADIATION THERAPY FOR HIGH-RISK LOCALIZED PROSTATE CANCER: A SINGLE-CENTER PROPENSITY SCORE-MATCHED ANALYSIS
Ryuji Matsumoto, Satoru Maruyama, Jun Furumido, Haruka Miyata, Hiroshi Kikuchi, Takahiro Osawa, Takashige Abe, Nobuo Shinohara, JOURNAL OF UROLOGY, 201, 4, E1059, E1060, Apr. 2019
English, Summary international conference

尿路上皮癌における抗癌剤治療後の腫瘍血管ABCB1発現亢進と薬剤耐性　　　　　　　　　　　　　　　
菊地 央, 間石 奈湖, 宮田 遥, 松本 隆児, 大澤 孝宏, 安部 崇重, 樋田 泰浩, 丸山 覚, 原林 透, 飴田 要, 柏木 明, 松野 吉宏, 篠原 信雄, 樋田 京子, 日本癌治療学会学術集会抄録集, 56回, O22, 3, Oct. 2018
(一社)日本癌治療学会, English

前立腺癌監視療法におけるゲノムアッセイの有用性(第1報)　　　　　　　　　　　　　　　
丸山 覚, 宮田 遥, 菊地 央, 松本 隆児, 大澤 崇宏, 安部 崇重, 篠原 信雄, 日本泌尿器科学会総会, 106回, OP, 247, Apr. 2018
(一社)日本泌尿器科学会総会事務局, Japanese

Bladder Cancer Index(BCI)日本語版の開発におけるPilot Study　　　　　　　　　　　　　　　
大澤 崇宏, ウェイ・ジョン, 伊藤 陽一, 成田 学, 賀古 勇輝, 宮田 遙, 菊地 央, 松本 隆児, 宮島 直人, 丸山 覚, 安部 崇重, 村井 祥代, 篠原 信雄, 日本泌尿器科学会総会, 106回, PP1, 201, Apr. 2018
(一社)日本泌尿器科学会総会事務局, Japanese

Studies on effect of combination therapy with immunotherapy targeting bladder cancer stem cell-like cells and chemotherapy/radiotherapy
Grants-in-Aid for Scientific Research
01 Apr. 2023 - 31 Mar. 2026
宮田 遥
本研究の目的は膀胱癌組織において化学療法・放射線療法の前後で、1)免疫学的に重要な役割を示す分子(具体的にはHLA, PD-L1など)の発現の変化、2)CSCsの含有割合の変化（ALDH1, GRIK2をマーカーとする）、3)CSCsを標的とした免疫療法に対する感受性の変化を調べ、化学療法・放射線療法とCSCsを標的とした免疫療法の有効性との関連を証明することである。そのための研究計画として1)放射線療法・化学療法前後での膀胱癌組織の採取、2)放射線療法・化学療法前後でのHLA, PD-L1, ALDH1, GRIK2の発現量の解析、3）放射線療法・化学療法前後でのGRIK2特異的細胞障害性T細胞の反応性の解析、4)In vitroでの化学療法・放射線療法によるCSCs濃度変化とGRIK2特異的の確認, 5)In vivoでの化学療法・放射線療法と免疫療法との併用療法の効果の解析, として研究計画を立てていた。
令和5年度は①放射線療法前後、術前補助化学療法前後の手術検体から膀胱癌組織を採取しHLA、PD-L1,癌幹細胞様細胞のマーカー発現の解析、②膀胱癌cell lineへの抗癌剤投与・放射線照射前後における癌幹細胞様細胞のマーカー発現の解析を計画していたが、研究代表者の妊娠に伴う体調不良、令和6年1月より産前産後休暇、育児休業を取得していることにより研究を進められていない状況である。
Japan Society for the Promotion of Science, Grant-in-Aid for Early-Career Scientists, Hokkaido University, 23K14555