Updated on 2023/11/14

写真a

 
AKAMATSU Shusuke
 
Organization
Graduate School of Medicine Program in Integrated Medicine Musculoskeletal and Cutaneous Medicine Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Professor

Degree 1

  1. Doctor of Medicine ( 2013.3   Kyoto University ) 

 

Papers 191

  1. This Issue 30-10

    Akamatsu S.

    International journal of urology : official journal of the Japanese Urological Association   Vol. 30 ( 10 ) page: 807   2023.10

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    Language:English   Publisher:International journal of urology : official journal of the Japanese Urological Association  

    DOI: 10.1111/iju.15297

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  2. Recent insights on the clinical, pathological, and molecular features of intraductal carcinoma of the prostate

    Naito, Y; Kato, M; Nagayama, J; Sano, Y; Matsuo, K; Inoue, S; Sano, T; Ishida, S; Matsukawa, Y; Tsuzuki, T; Akamatsu, S

    INTERNATIONAL JOURNAL OF UROLOGY     2023.9

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    Language:English   Publisher:International Journal of Urology  

    Intraductal carcinoma of the prostate, a unique histopathologic entity that is often observed (especially in advanced prostate cancer), is characterized by the proliferation of malignant cells within normal acini or ducts surrounded by a basement membrane. Intraductal carcinoma of the prostate is almost invariably associated with an adjacent high-grade carcinoma and is occasionally observed as an isolated subtype. Intraductal carcinoma of the prostate has been demonstrated to be an independent poor prognostic factor for all stages of cancer, whether localized, de novo metastatic, or castration-resistant. It also has a characteristic genetic profile, including high genomic instability. Recognizing and differentiating it from other pathologies is therefore important in patient management, and morphological diagnostic criteria for intraductal carcinoma of the prostate have been established. This review summarizes and outlines the clinical and pathological features, differential diagnosis, molecular aspects, and management of intraductal carcinoma of the prostate, as described in previous studies. We also present a discussion and future perspectives regarding intraductal carcinoma of the prostate.

    DOI: 10.1111/iju.15299

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  3. Development and validation of a nomogram (APGRC) to predict the presence of germline DNA damage repair pathogenic variants in Asian patients with prostate cancer

    Zhang, TW; Wei, Y; Hong, BH; Sumiyoshi, T; Ong, EHW; Zeng, H; Li, YH; Ng, CF; Pan, J; Fang, BW; Wang, BH; Wu, JL; Wang, HK; Akamatsu, S; Chua, MLK; Ye, DW; Zhu, Y

    CLINICAL AND TRANSLATIONAL MEDICINE   Vol. 13 ( 9 ) page: e1411   2023.9

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  4. Clinical factors for tumor response, progression, and survival in nivolumab for advanced renal cell carcinoma in the SNiP-RCC study

    Blas, L; Shiota, M; Miyake, H; Takahashi, M; Oya, M; Tsuchiya, N; Masumori, N; Matsuyama, H; Obara, W; Shinohara, N; Fujimoto, K; Nozawa, M; Ohba, K; Ohyama, C; Hashine, K; Akamatsu, S; Kamba, T; Mita, K; Gotoh, M; Tatarano, S; Fujisawa, M; Tomita, Y; Mukai, S; Ito, K; Tanegashima, T; Tokunaga, S; Eto, M

    INTERNATIONAL JOURNAL OF UROLOGY   Vol. 30 ( 9 ) page: 788 - 796   2023.8

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    Language:English   Publisher:International Journal of Urology  

    Background: This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. Methods: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). Results: We included 222 patients. The median age was 69 years (interquartile range 62–74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. Conclusion: The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.

    DOI: 10.1111/iju.15265

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  5. Impact of Long-term Adjuvant Hormonal Therapy in High-dose IMRT for Unfavorable Locally Advanced Prostate Cancer

    Ogata, T; Aizawa, R; Nakamura, K; Kobayashi, T; Akamatsu, S; Nakamura, E; Ogawa, O; Mizowaki, T

    ANTICANCER RESEARCH   Vol. 43 ( 8 ) page: 3589 - 3596   2023.8

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    Language:English   Publisher:Anticancer Research  

    Background/Aim: The aim of this study was to evaluate the benefit of adding long-term adjuvant hormonal therapy to high-dose intensity-modulated radiation therapy for locally advanced prostate cancer patients with multiple unfavorable risks. Patients and Methods: All cT3-4N0M0 prostate cancer patients with Gleason score 8-10 and prostate-specific antigen ≥30 ng/ml who received intensity-modulated radiation therapy to the prostate and seminal vesicle alone (78 Gy in 39 fractions) between September 2000 and June 2017 at our institution were analyzed retrospectively. All patients received short-term neoadjuvant hormonal therapy. Before May 2011, salvage hormonal therapy was initiated when prostate-specific antigen levels exceeded 4.0 ng/ml (early salvage hormonal therapy cohort). In June 2011, 2-year adjuvant hormonal therapy was added (adjuvant hormonal therapy cohort). Clinical outcomes were retrospectively compared using the log-rank test. Results: In total, 88 patients (44 in both cohorts) were analyzed. Median follow-up periods were 10.9 and 6.1 years in early salvage hormonal therapy and adjuvant hormonal therapy cohorts, respectively. No significant difference in overall survival rates was observed (p=0.58). Disease controls were significantly better in the adjuvant hormonal therapy cohort: 95.5 versus 73.6% for castration-resistant prostate cancer-free rate (p=0.04), and 73.6 versus 34.1% for biochemical failure-free rate (p<0.001), both at 8 years, respectively. Conclusion: Among locally advanced prostate cancer patients with multiple unfavorable risks, adding long-term adjuvant hormonal therapy to high-dose intensity-modulated radiation therapy resulted in significantly better disease control than short-term hormonal therapy, even when salvaged early after biochemical failure.

    DOI: 10.21873/anticanres.16538

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  6. Dual inhibition of PARP and ATR induces homologous recombination repair deficiency and leads to synthetic lethality in prostate cancer with CDK12 alteration

    Akamatsu, S; Kamiyama, Y; Sunada, T; Hikami, K; Fukui, T; Mizuno, K; Sumiyoshi, T; Goto, T; Kobayashi, T; Sasanuma, H

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 41 ( 16 )   2023.6

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  7. Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial

    Shiota, M; Miyake, H; Takahashi, M; Oya, M; Tsuchiya, N; Masumori, N; Matsuyama, H; Obara, W; Shinohara, N; Fujimoto, K; Nozawa, M; Ohba, K; Ohyama, C; Hashine, K; Akamatsu, S; Kamba, T; Mita, K; Gotoh, M; Tatarano, S; Fujisawa, M; Tomita, Y; Mukai, S; Ito, K; Tanegashima, T; Tokunaga, S; Eto, M

    CANCER IMMUNOLOGY IMMUNOTHERAPY   Vol. 72 ( 6 ) page: 1903 - 1915   2023.6

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    Language:English   Publisher:Cancer Immunology, Immunotherapy  

    Background: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. Methods: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. Results: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. Conclusion: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

    DOI: 10.1007/s00262-023-03367-w

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  8. The Roles of Extracellular Vesicles in the Progression of Renal Cell Carcinoma and Their Potential for Future Clinical Application

    Takeda, M; Akamatsu, S; Kita, Y; Goto, T; Kobayashi, T

    NANOMATERIALS   Vol. 13 ( 10 )   2023.5

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    Language:English   Publisher:Nanomaterials  

    Renal cell carcinoma (RCC) is the most common type of kidney cancer and is thought to originate from renal tubular epithelial cells. Extracellular vesicles (EVs) are nanosized lipid bilayer vesicles that are secreted into extracellular spaces by nearly all cell types, including cancer cells and non-cancerous cells. EVs are involved in multiple steps of RCC progression, such as local invasion, host immune modulation, drug resistance, and metastasis. Therefore, EVs secreted from RCC are attracting rapidly increasing attention from researchers. In this review, we highlight the mechanism by which RCC-derived EVs lead to disease progression as well as the potential and challenges related to the clinical implications of EV-based diagnostics and therapeutics.

    DOI: 10.3390/nano13101611

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  9. qShot MALDI analysis: A rapid, simple, convenient, and reliable quantitative phospholipidomics approach using MALDI-TOF/MS

    Nakayama K., Li X., Shimizu K., Akamatsu S., Inoue T., Kobayashi T., Ogawa O., Goto T.

    Talanta   Vol. 254   page: 124099   2023.3

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    Matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS) has potential applications in the qualitative analysis of phospholipids (PLs). However, its capability for quantitative analysis is limited by the unavailability and/or high cost of isotope-labeled internal standards (interSTDs, e.g., 1-oleoyl (d7)-2-hydroxy-sn-glycero-3-phosphocholine, 1-pentadecanoyl-2-oleoyl (d7)-sn-glycero-3-phosphocholine). This study investigated and validated whether only two PL interSTDs could be used to normalize the entire PL species in a complex bio-lipid background (i.e., urinary lipid extracts). The normalized intensities of PL ionization standards (ionSTDs) were found to have better linear regressions (R2 > 0.984 for all PL subcategories) than those of traditional methods, such as total ion current and matrix-peak normalization methods. Furthermore, the intra-day precision of all the analyte concentrations after normalizing using our ionSTD method was superior to those of traditional methods. The inter-day precision of all the negatively charged analytes also differed statistically between our ionSTD and the two traditional methods. Meanwhile, a comparison of the three normalization methods revealed that the precision of all the positive analytes using the ionSTD method was comparable. Consequently, a cost-effective, fast, simple, convenient, and reliable quantitative method, defined as “qShot MALDI analysis,” was developed to analyze PLs that could potentially be applied in clinical biomarker screening, especially in a negative mode.

    DOI: 10.1016/j.talanta.2022.124099

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  10. ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen

    Najnin R.A., Al Mahmud M.R., Rahman M.M., Takeda S., Sasanuma H., Tanaka H., Murakawa Y., Shimizu N., Akter S., Takagi M., Sunada T., Akamatsu S., He G., Itou J., Toi M., Miyaji M., Tsutsui K.M., Keeney S., Yamada S.

    Cell Reports   Vol. 42 ( 1 ) page: 111909   2023.1

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    ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis after ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. After estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes, including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis.

    DOI: 10.1016/j.celrep.2022.111909

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  11. Genetic variations predicting progression with docetaxel and novel androgen-receptor pathway inhibitors

    Shiota Masaki, Akamatsu Shusuke, Sekine Yuya, Kimura Hiroko, Narita Shintaro, Fujimoto Naohiro, Terada Naoki, Blas Leandro, Habuchi Tomonori, Kamoto Toshiyuki, Momozawa Yukihide, Eto Masatoshi

    CANCER SCIENCE     2023.1

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    Language:English   Publisher:Cancer Science  

    Genetic variations represented by single-nucleotide polymorphisms (SNPs) could be helpful for choosing an effective treatment for patients with prostate cancer. This study investigated the prognostic and predictive values of SNPs associated with the prognoses of pharmacotherapy for prostate cancer through their pharmacological mechanisms. Patients treated with docetaxel or androgen receptor pathway inhibitors (ARPIs), such as abiraterone and enzalutamide, for castration-resistant prostate cancer were included. The SNPs of interest were genotyped for target regions. The prognostic and predictive values of the SNPs for time to progression (TTP) were examined using the Cox hazard proportional model and interaction test, respectively. Rs1045642 in ABCB1, rs1047303 in HSD3B1, rs1856888 in HSD3B1, rs523349 in SRD5A2, and rs34550074 in SLCO2A1 were differentially associated with TTP between docetaxel chemotherapy and ARPI treatment. In addition to rs4775936 in CYP19A1, rs1128503 in ABCB1 and rs1077858 in SLCO2B1 might be differentially associated with TTP between abiraterone and enzalutamide treatments. Genetic predictive models using these SNPs showed a differential prognosis for treatments. This study identified SNPs that could predict progression as well as genetic models that could predict progression when patients were treated with docetaxel versus ARPI and abiraterone versus enzalutamide. The use of genetic predictive models is expected to be beneficial in selecting the appropriate treatment for the individual patient.

    DOI: 10.1111/cas.15718

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  12. [Ⅰ. Medical Treatment of Advanced Prostate Cancer-Update 2022].

    Akamatsu S, Sumiyoshi T, Goto T, Kobayashi T

    Gan to kagaku ryoho. Cancer & chemotherapy   Vol. 50 ( 1 ) page: 40 - 44   2023.1

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  13. Ten-year outcomes of whole-pelvic intensity-modulated radiation therapy for prostate cancer with regional lymph node metastasis

    Nakamura Kiyonao, Norihisa Yoshiki, Ikeda Itaru, Inokuchi Haruo, Aizawa Rihito, Kamoto Toshiyuki, Kamba Tomomi, Inoue Takahiro, Yamasaki Toshinari, Akamatsu Shusuke, Kobayashi Takashi, Ogawa Osamu, Mizowaki Takashi

    CANCER MEDICINE     2022.12

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    Background: Management of pelvic node-positive prostate cancer has been challenging and controversial. We conducted a study to evaluate the outcomes of whole-pelvic (WP) simultaneous integrated boost (SIB) intensity-modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT). Methods: A total of 67 consecutive patients with cT1c-4N1M0 prostate cancer were definitively treated by WP SIB-IMRT. Neoadjuvant ADT (median: 8.3 months) was administered in all cases. WP SIB-IMRT was designed to simultaneously deliver 78, 66.3, and 58.5 Gy in 39 fractions to the prostate plus seminal vesicles, metastatic lymph nodes (LNs), and the pelvic LN region, respectively. Adjuvant ADT (median: 24.7 months) was administered in 66 patients. Results: The median follow-up period was 81.6 months (range: 30.5–160.7). Biochemical relapse-free, overall, and prostate cancer-specific survival rates at 10 years were 59.8%, 79.6%, and 86.3%, respectively. Loco-regional recurrence was not observed. Being in International Society of Urological Pathology grade group 5 and having a posttreatment detectable nadir prostate-specific antigen (PSA) level (≥0.010 ng/ml) were significantly associated with worse prostate cancer-specific survival and progression of castration resistance. The 10-year cumulative incidence rates of grade 2 and 3 late toxicities were, respectively, 1.5% and 0% for genitourinary, 0% and 1.5% for gastrointestinal events. No grade 4 acute or late toxicities were observed. Conclusions: WP SIB-IMRT can be safely administered to patients with pelvic node-positive prostate cancer. Since grade group 5 and detectable nadir PSA levels are risks for castration resistance, we may need to increase the intensity of treatment for such cases.

    DOI: 10.1002/cam4.5554

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  14. Prevalence and risk estimation of cancer-predisposing genes for upper urinary tract urothelial carcinoma in Japanese

    Sekine Yuya, Iwasaki Yusuke, Hakozaki Nozomi, Endo Mikiko, Kamatani Yoichiro, Matsuda Koichi, Murakami Yoshinori, Sano Takeshi, Akamatsu Shusuke, Kobayashi Takashi, Nakagawa Hidewaki, Numakura Kazuyuki, Narita Shintaro, Habuchi Tomonori, Momozawa Yukihide

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   Vol. 52 ( 12 ) page: 1441 - 1445   2022.12

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    Language:English   Publisher:Japanese journal of clinical oncology  

    Upper urinary tract urothelial carcinoma is a rare cancer that has been associated with mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2. In addition, patients with pathogenic variants of cancer-predisposing genes such as BRCA1 and BRCA2 have been reported. However, how cancer-predisposing genes affect the risk of upper urinary tract urothelial carcinoma in the Japanese population remains unclear. Thus, we performed a case-control sequencing study of 27 cancer-predisposing genes in 208 upper urinary tract urothelial carcinoma patients and 37 727 controls. Only MSH6 and MSH2 were observed with a value of P < 0.05. However, there was no difference in the prevalence of pathogenic variants of BRCA1/2, which does not support the use of a poly adenosine diphosphate-ribose polymerase inhibitor in patients with upper urinary tract urothelial carcinoma. Only mismatch repair genes were associated with patients with upper urinary tract urothelial carcinoma, but the prevalence of pathogenic variants in mismatch repair genes was lower than that reported in previous studies from other populations.

    DOI: 10.1093/jjco/hyac141

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  15. Limited predictive impact of tumor size dynamics on further tumor shrinkage after 4 cycles of first-line chemotherapy in patients with advanced urothelial carcinoma

    Hamada Akihiro, Sano Takeshi, Kita Yuki, Takada Hideaki, Sakatani Toru, Nakamura Kenji, Ito Katsuhiro, Goto Takayuki, Sawada Atsuro, Akamatsu Shusuke, Kobayashi Takashi

    UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS   Vol. 40 ( 12 ) page: 540.e1 - 540.e10   2022.12

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    Language:English   Publisher:Urologic Oncology: Seminars and Original Investigations  

    Purpose: To investigate the correlation between tumor size changes during the initial 4 cycles of first-line chemotherapy and tumor shrinkage following 2 additional cycles of chemotherapy in patients with advanced urothelial carcinoma (aUC) who experienced disease control after initial chemotherapy. Methods: We retrospectively reviewed 128 patients with aUC who received first-line chemotherapy. We analyzed 51 patients with disease control (stable disease or better) at the end of the fourth cycle. Of these, 47 patients received 1 to 2 additional cycles of chemotherapy, whereas the remaining patients underwent observation. For patients who received additional chemotherapy, the change in tumor size after additional chemotherapy (cycles 5–6) was defined as “no shrinkage” (tumor growth), “minor shrinkage” (no tumor growth or ≤10% reduction in tumor size), or “shrinkage” (>10% reduction in tumor size). Then, we investigated the relationship between the rate of tumor size change during the initial 4 cycles and that after additional chemotherapy. Results: Of the patients who received additional chemotherapy, the change in tumor size was categorized as no shrinkage in 21 patients (44.7%), minor shrinkage in 18 patients (38.3%), and shrinkage in 8 patients (17%). Regarding predictors of tumor shrinkage after additional chemotherapy, the rate of tumor size change between the cycles 3 and 4 (area under the receiver operating characteristics curve = 0.642) was correlated with the trend of the tumor shrinkage (P = 0.009) and the likelihood of beneficial tumor shrinkage after additional chemotherapy (minor shrinkage + shrinkage; P = 0.02). However, the change in tumor size between cycles 1 and 2, cycles 1 and 4, or cycles 3 and 4 was not satisfactorily predictive of further tumor shrinkage because of substantial overlaps of the tumor size changes. Conclusions: Only a small subset of patients would have substantial tumor shrinkage by additional cycles after successful induction of 4 cycle chemotherapy. Tumor size dynamics during the initial 4 cycles of chemotherapy displayed limited ability to predict the subset of patients with further tumor shrinkage after additional chemotherapy. Therefore, it might be better to consider switch maintenance immunotherapy for patients who experience disease control after the fourth cycle of first-line chemotherapy.

    DOI: 10.1016/j.urolonc.2022.07.008

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  16. Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer

    Kimura Hiroko, Mizuno Kei, Shiota Masaki, Narita Shintaro, Terada Naoki, Fujimoto Naohiro, Ogura Keiji, Hatano Shotaro, Iwasaki Yusuke, Hakozaki Nozomi, Ishitoya Satoshi, Sumiyoshi Takayuki, Goto Takayuki, Kobayashi Takashi, Nakagawa Hidewaki, Kamoto Toshiyuki, Eto Masatoshi, Habuchi Tomonori, Ogawa Osamu, Momozawa Yukihide, Akamatsu Shusuke

    BRITISH JOURNAL OF CANCER   Vol. 127 ( 9 ) page: 1680 - 1690   2022.11

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    Background: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. Methods: Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed. Results: Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15–3.44 and 1.23–4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations. Conclusions: Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.

    DOI: 10.1038/s41416-022-01915-2

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  17. 特集 限局性前立腺癌診療バイブル-このへんでキッチリと前立腺癌診療の"あたりまえ"を整理しよう! 〈診断〉 限局性前立腺癌における遺伝子診断の意義と将来性

    赤松 秀輔

    臨床泌尿器科   Vol. 76 ( 11 ) page: 792 - 796   2022.10

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    Publisher:株式会社医学書院  

    DOI: 10.11477/mf.1413207667

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  18. Androgen receptor mutations for precision medicine in prostate cancer

    Shiota Masaki, Akamatsu Shusuke, Tsukahara Shigehiro, Nagakawa Shohei, Matsumoto Takashi, Eto Masatoshi

    ENDOCRINE-RELATED CANCER   Vol. 29 ( 10 ) page: R143 - R155   2022.10

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    Language:English   Publisher:Endocrine-Related Cancer  

    Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. However, treatment resistance emerges after hormonal manipulation in most prostate cancers, and it is attributable to a number of mechanisms, including AR amplification and overexpression, AR mutations, the expression of constitutively active AR variants, intra-tumor androgen synthesis, and promiscuous AR activation by other factors. Although various AR mutations have been reported in prostate cancer, specific AR mutations (L702H, W742L/C, H875Y, F877L, and T878A/S) were frequently identified after treatment resistance emerged. Intriguingly, these hot spot mutations were also revealed to change the binding affinity of ligands including steroids and antiandrogens and potentially result in altered responses to AR pathway inhibitors. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Since clinical data between AR mutations and the efficacy of AR pathway inhibitors are accumulating, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy. However, there are few reviews on clinical significance of AR hot spot mutations in prostate cancer. Then, this review summarized the clinical landscape of AR mutations and discussed their potential implication for clinical utilization.

    DOI: 10.1530/ERC-22-0140

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  19. Combined laparoscopic and transperineal total pelvic exenteration for recurrent rectal cancer-a video vignette

    Kawada Kenji, Hanada Keita, Yokoyama Daiju, Akamatsu Shusuke, Goto Takayuki, Obama Kazutaka

    COLORECTAL DISEASE     2022.9

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    Language:English   Publisher:Colorectal Disease  

    DOI: 10.1111/codi.16308

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  20. Paraurachal paraganglioma

    Tsuruta M., Goto T., Kono J., Kita Y., Masui K., Sano T., Fujimoto M., Sawada A., Akamatsu S., Kobayashi T.

    IJU Case Reports   Vol. 5 ( 5 ) page: 358 - 361   2022.9

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    Introduction: Paragangliomas (PGLs) are frequently reported around the abdominal aorta; however, are extremely rare near the urachus. Case presentation: A 78-year-old woman was referred to the urology department of our hospital for further examination and treatment of a 1.2-cm tumor in the lower abdominal wall, a tumor excision was then performed. On immunohistochemical staining, the tumor and supporting cells were positive for chromogranin A and the S 100 protein, respectively, and were diagnosed as PGL. The PGL was thought to be derived from chromaffin cells that migrated to the wall of the urachus during embryonic life and remained even after the wall regressed. Conclusion: We report a case of PGL near the urachus that can be explained by the distribution of the sympathetic network around the midline of the lower abdominal wall during embryonic development. Therefore, PGL should be considered in the differential diagnosis of periurachal tumors.

    DOI: 10.1002/iju5.12488

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  21. Up-regulation of secretory leukocyte protease inhibitor in human samples might have a potential role of predicting prostate cancer recurrence and progression after surgery and hormonal therapy

    Miyazaki Yu, Goto Takayuki, Li Xin, Nakayama Kenji, Okasho Kosuke, Takeda Masashi, Mizuno Kei, Kimura Hiroko, Uegaki Masayuki, Sumiyoshi Takayuki, Teramoto Yuki, Akamatsu Shusuke, Kobayashi Takashi, Ogawa Osamu, Inoue Takahiro

    CANCER MEDICINE     2022.8

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    Using new castration-resistant prostate cancer (CRPC) cell lines developed from LNCaP cells as a model for CRPC, we searched for novel biomarkers by analyzing the proteins secreted in culture supernatants. The results showed that the levels of secretory leukocyte protease inhibitor (SLPI) in these cell lines were 4.7–6.7 times higher than those secreted in parental LNCaP. Patients with localized prostate cancer (PC) and who expressed SLPI had a significantly lower prostate-specific antigen (PSA) progression-free survival rate than those who did not. Multivariate analysis revealed that SLPI expression was an independent risk factor for PSA recurrence. By contrast, when immunostaining of SLPI was performed on consecutive prostate tissue samples obtained from 11 patients, both in hormone naive (HN) and castration resistant (CR) conditions, only one patient expressed SLPI in the HNPC state; however, four of the 11 patients expressed SLPI in the CRPC state. In addition, two of these four patients were resistant to enzalutamide, and there was a discrepancy between their serum PSA levels and radiographic progression of the disease. These results suggest that SLPI can be a predictor of prognosis in patients with localized PC and disease progression in CRPC patients.

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  22. Identification of the alpha 2 chain of interleukin-13 receptor as a potential biomarker for predicting castration resistance of prostate cancer using patient-derived xenograft models

    Nagai Takahiro, Terada Naoki, Fujii Masato, Nagata Yasuhisa, Nakahara Kozue, Mukai Shoichiro, Okasho Kosuke, Kamiyama Yuki, Akamatsu Shusuke, Kobayashi Takashi, Iida Kei, Denawa Masatsugu, Hagiwara Masatoshi, Inoue Takahiro, Ogawa Osamu, Kamoto Toshiyuki

    CANCER REPORTS     2022.8

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    Background: Several treatment strategies use upfront chemotherapy or androgen receptor axis-targeting therapies for metastatic prostate cancer. However, there are no useful biomarkers for selecting appropriate patients who urgently require these treatments. Methods: Novel patient-derived xenograft (PDX) castration-sensitive and -resistant models were established and gene expression patterns were comprehensively compared. The function of a gene highly expressed in the castration-resistant models was evaluated by its overexpression in LNCaP prostate cancer cells. Protein expression in the tumors and serum of patients was examined by immunohistochemistry and ELISA, and correlations with castration resistance were analyzed. Results: Expression of the α2 chain of interleukin-13 receptor (IL13Rα2) was higher in castration-resistant PDX tumors. LNCaP cells overexpressing IL13Rα2 acquired castration resistance in vitro and in vivo. In tissue samples, IL13Rα2 expression levels were significantly associated with castration-resistant progression (p < 0.05). In serum samples, IL13Rα2 levels could be measured in 5 of 28 (18%) castration-resistant prostate cancer patients. Conclusion: IL13Rα2 was highly expressed in castration-resistant prostate cancer PDX models and was associated with the castration resistance of prostate cancer cells. It might be a potential tissue and serum biomarker for predicting castration resistance in prostate cancer patients.

    DOI: 10.1002/cnr2.1701

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  23. A novel missense mutation in the folliculin gene associated with the renal tumor-only phenotype of Birt-Hogg-Dubé syndrome

    Sano T., Fukui T., Makita N., Shimizu K., Kono J., Masui K., Sato T., Goto T., Sawada A., Fujimoto M., Kojima F., Torishima M., Wada T., Furuya M., Ogawa O., Kobayashi T., Akamatsu S.

    Cancer Genetics   Vol. 266-267   page: 28 - 32   2022.8

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    Birt-Hogg-Dubé syndrome is an autosomal dominant disease caused by germline mutations in the folliculin gene (FLCN), characterized by skin fibrofolliculomas, pulmonary cysts, and multiple renal tumors. We report the case of a 51-year-old woman with multiple bilateral renal tumors resected by bilateral open partial nephrectomy. Following pathological diagnosis of hybrid oncocytic/chromophobe tumors, targeted next-generation sequencing of FLCN of the patient's blood revealed a novel missense mutation (c.602A>C, p.Gln201Pro) in exon 6. Sanger sequencing revealed that this mutation was heterozygous. In silico prediction programs consistently indicated the mutation as pathogenic. Western blot analysis and immunohistochemistry revealed suppressed FLCN expression and the upregulation of glycoprotein nonmetastatic B, a downstream target negatively regulated by FLCN, in the tumor tissue, suggesting that the mutation resulted in reduction of functional FLCN expression. Whole-genome sequencing of one of the tumors identified another frameshift mutation in exon 4, suggesting a “second hit” leading to tumorigenesis. We recommend that gene sequencing should be considered in patients with multiple renal tumors to identify their genetic predisposition to renal tumors.

    DOI: 10.1016/j.cancergen.2022.06.001

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  24. Erratum: Author Correction: Comprehensive genomics in androgen receptor-dependent castration-resistant prostate cancer identifies an adaptation pathway mediated by opioid receptor kappa 1 (Communications biology (2022) 5 1 (299))

    Makino Y., Kamiyama Y., Brown J.B., Tanaka T., Murakami R., Teramoto Y., Goto T., Akamatsu S., Terada N., Inoue T., Kodama T., Ogawa O., Kobayashi T.

    Communications biology   Vol. 5 ( 1 ) page: 718   2022.7

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    DOI: 10.1038/s42003-022-03707-z

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  25. Case Report: A Case of Renal Cell Carcinoma Unclassified With Medullary Phenotype Exhibiting a Favorable Response to Combined Immune Checkpoint Blockade

    Takeda Masashi, Kashima Soki, Fuchigami Yasushi, Yoshino Takayuki, Kataoka Tatsuki R., Yamasaki Toshinari, Kagamu Hiroshi, Kobayashi Takashi, Akamatsu Shusuke

    FRONTIERS IN IMMUNOLOGY   Vol. 13   page: 934991   2022.7

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    Renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) is an extremely rare variant of kidney cancer with poor prognosis. Recently, immune checkpoint inhibitors (ICIs) have been the mainstay of treatment for advanced clear cell renal cell carcinoma (RCC). However, the efficacy of ICI in the treatment of RCCU-MP remains unclear. Here, we report about a 63-year-old Japanese man who was referred to our hospital with a diagnosis of RCC of the left kidney with multiple–lymph node involvement (cT3aN1M1). The patient underwent nephrectomy with lymph node biopsy, which was histopathologically diagnosed as RCCU-MP. Thereafter, he received combined immune checkpoint blockade with nivolumab and ipilimumab. After induction therapy, follow-up computed tomography revealed shrinkage of the metastatic lymph nodes. Moreover, the patient was relieved of his subjective symptoms and his performance status improved. However, after 15 months, maintenance ICI therapy was discontinued because of disease progression, and the patient died 28 months after diagnosis. Longitudinal analysis of peripheral blood mononuclear cells revealed increased stem cell memory and central memory CD8+ T-cell subsets during response to therapy and enhanced expression of exhaustion markers on CD8+ T cells upon treatment resistance. Combined immune checkpoint blockade could be effective in the treatment of metastatic RCCU-MP.

    DOI: 10.3389/fimmu.2022.934991

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  26. Radiotherapy plus androgen deprivation therapy for prostate-specific antigen persistence in lymph node-positive prostate cancer

    Shiota Masaki, Takamatsu Dai, Kimura Takahiro, Tashiro Kojiro, Matsui Yoshiyuki, Tomida Ryotaro, Saito Ryoichi, Tsutsumi Masakazu, Yokomizo Akira, Yamamoto Yoshiyuki, Edamura Kohei, Miyake Makito, Morizane Shuichi, Yoshino Takayuki, Matsukawa Akihiro, Narita Shintaro, Matsumoto Ryuji, Kasahara Takashi, Hashimoto Kohei, Matsumoto Hiroaki, Kato Masashi, Akamatsu Shusuke, Joraku Akira, Kato Manabu, Yamaguchi Takahiro, Saito Toshihiro, Kaneko Tomoyuki, Takahashi Atsushi, Kato Takuma, Sakamoto Shinichi, Enokida Hideki, Kanno Hidenori, Terada Naoki, Suekane Shigetaka, Nishiyama Naotaka, Eto Masatoshi, Kitamura Hiroshi

    CANCER SCIENCE   Vol. 113 ( 7 ) page: 2386 - 2396   2022.7

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    The treatment for lymph node involvement (LNI) after radical prostatectomy (RP) has not been established. This study aimed to reveal the outcomes of various management strategies among patients with LNI after RP. Retrospectively, 561 patients with LNI after pelvic lymph node dissection (PLND) with RP treated between 2006 and 2019 at 33 institutions participating in the Japanese Urological Oncology Group were investigated. Metastasis-free survival (MFS) was the primary outcome. Patients were stratified by prostate-specific antigen (PSA) persistence after RP. Cox regression models were used to analyze the relationships between clinicopathological characteristics and survival. Survival analyses were conducted using the Kaplan-Meier method and log-rank test with or without propensity score matching. Prognoses, including MFS and overall survival, were prominently inferior among patients with persistent PSA compared with those without persistent PSA. In multivariate analysis, androgen deprivation therapy (ADT) plus radiotherapy (RT) was associated with better MFS than ADT alone among patients with persistent PSA (hazard ratio = 0.37; 95% confidence interval = 0.15-0.93; p = 0.034). Similarly, MFS and overall survival were significantly better for ADT plus RT than for ADT alone among patients with persistent PSA after propensity score matching. This study indicated that PSA persistence in LNI prostate cancer increased the risk of poor prognoses, and intensive treatment featuring the addition of RT to ADT might improve survival.

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  27. Clinical significance of IDC-P as predictive factor after intensity-modulated radiation therapy

    Aizawa Rihito, Tsuzuki Toyonori, Haga Hironori, Nakamura Kiyonao, Ogata Takashi, Inoue Takahiro, Kobayashi Takashi, Akamatsu Shusuke, Goto Takayuki, Ogawa Osamu, Mizowaki Takashi

    CANCER SCIENCE   Vol. 113 ( 7 ) page: 2425 - 2433   2022.7

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    The clinical significance of intraductal carcinoma of the prostate (IDC-P) in men with nonmetastatic prostate cancer (PCa) treated with high-dose external-beam radiation therapy remains unclear. The aim of this study was to evaluate the impact of IDC-P in men who received intensity-modulated radiation therapy (IMRT) for nonmetastatic PCa. All patients with high-risk (H-R) and very high–risk (VH-R) PCa who received IMRT between September 2000 and December 2013 at our institution were analyzed retrospectively. We re-reviewed biopsy cores for the presence of IDC-P. Treatment consisted of IMRT (median: 78 Gy at 2 Gy per fraction) plus 6-month neoadjuvant hormonal therapy (HT). In total, 154 consecutive patients with H-R and VH-R PCa were analyzed. Intraductal carcinoma of the prostate was present in 27.9% (n = 43). The median follow-up period was 8.4 years. The 10-year PCa-specific survival, biochemical failure (BF), clinical failure, and castration-resistant PCa rates were 90.0%, 47.8%, 27.5%, and 24.5% in patients with IDC-P, and 96.6%, 32.6%, 10.8%, and 7.0% in those without IDC-P, respectively (p = 0.12, 0.04, 0.0031, and 0.012, respectively). In multivariable analysis, IDC-P was not identified as an independent predictive factor for BF (p = 0.26). The presence of IDC-P was correlated with a significantly higher incidence of disease progression in men with H-R and VH-R PCa who received IMRT, although it was not identified as an independent predictive factor for BF. Further investigations are needed to determine the significance of IDC-P as an independent predictive factor for survival outcomes.

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  28. Incomplete sagittal septum of the bladder with cystolithiasis

    Fujimoto T., Goto T., Kanematsu A., Nishimatsu H., Fujimoto M., Matsuoka T., Kono J., Kita Y., Masui K., Sano T., Sawada A., Akamatsu S., Kobayashi T.

    IJU Case Reports   Vol. 5 ( 4 ) page: 264 - 267   2022.7

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    Introduction: Incomplete sagittal septum of the urinary bladder is an extremely rare congenital anomaly and one of the variations in bladder duplication. Herein, we report a case of incomplete sagittal septum of the bladder with cystolithiasis. Case presentation: A 20-year-old man was referred to our department for examination and treatment of symptomatic cystolithiasis and a suspected giant ureterocele on the left side. Cystoscopy and urography performed under general anesthesia revealed anatomical structures suggestive of the sagittal septum of the bladder. Subsequently, transurethral septostomy and cystolithotripsy were performed. The detrusor muscle was microscopically identified, leading to the diagnosis of an incomplete sagittal septum of the bladder. Conclusion: Although extremely rare, an incomplete sagittal septum of the bladder may be difficult to differentiate from a ureterocele, and should be considered when a large cystic lesion is found in the bladder.

    DOI: 10.1002/iju5.12451

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  29. Development and validation of prediction model for incident overactive bladder: The Nagahama study

    Funada Satoshi, Luo Yan, Yoshioka Takashi, Setoh Kazuya, Tabara Yasuharu, Negoro Hiromitsu, Yoshimura Koji, Matsuda Fumihiko, Efthimiou Orestis, Ogawa Osamu, Furukawa Toshi A., Kobayashi Takashi, Akamatsu Shusuke

    INTERNATIONAL JOURNAL OF UROLOGY   Vol. 29 ( 7 ) page: 748 - 756   2022.7

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    Objectives: We aimed to develop models to predict new-onset overactive bladder in 5 years using a large prospective cohort of the general population. Methods: This is a secondary analysis of a longitudinal cohort study in Japan. The baseline characteristics were measured between 2008 and 2010, with follow-ups every 5 years. We included subjects without overactive bladder at baseline and with follow-up data 5 years later. Overactive bladder was assessed using the overactive bladder symptom score. Baseline characteristics (demographics, health behaviors, comorbidities, and overactive bladder symptom scores) and blood test data were included as predictors. We developed two competing prediction models for each sex based on logistic regression with penalized likelihood (LASSO). We chose the best model separately for men and women after evaluating models' performance in terms of discrimination and calibration using an internal validation via 200 bootstrap resamples and a temporal validation. Results: We analyzed 7218 participants (male: 2238, female: 4980). The median age was 60 and 55 years, and the number of new-onset overactive bladder was 223 (10.0%) and 288 (5.8%) per 5 years in males and females, respectively. The in-sample estimates for C-statistic, calibration intercept, and slope for the best performing models were 0.77 (95% confidence interval 0.74–0.80), 0.28 and 1.15 for males, and 0.77 (95% confidence interval 0.74–0.80), 0.20 and 1.08 for females. Internal and temporal validation gave broadly similar estimates of performance, indicating low optimism. Conclusion: We developed risk prediction models for new-onset overactive bladder among men and women with good predictive ability.

    DOI: 10.1111/iju.14887

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  30. Machine learning diagnosis by immunoglobulin N-glycan signatures for precision diagnosis of urological diseases

    Iwamura Hiromichi, Mizuno Kei, Akamatsu Shusuke, Hatakeyama Shingo, Tobisawa Yuki, Narita Shintaro, Narita Takuma, Yamashita Shinichi, Kawamura Sadafumi, Sakurai Toshihiko, Fujita Naoki, Kodama Hirotake, Noro Daisuke, Kakizaki Ikuko, Nakaji Shigeyuki, Itoh Ken, Tsuchiya Norihiko, Ito Akihiro, Habuchi Tomonori, Ohyama Chikara, Yoneyama Tohru

    CANCER SCIENCE   Vol. 113 ( 7 ) page: 2434 - 2445   2022.7

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    Early diagnosis of urological diseases is often difficult due to the lack of specific biomarkers. More powerful and less invasive biomarkers that can be used simultaneously to identify urological diseases could improve patient outcomes. The aim of this study was to evaluate a urological disease-specific scoring system established with a machine learning (ML) approach using Ig N-glycan signatures. Immunoglobulin N-glycan signatures were analyzed by capillary electrophoresis from 1312 serum subjects with hormone-sensitive prostate cancer (n = 234), castration-resistant prostate cancer (n = 94), renal cell carcinoma (n = 100), upper urinary tract urothelial cancer (n = 105), bladder cancer (n = 176), germ cell tumors (n = 73), benign prostatic hyperplasia (n = 95), urosepsis (n = 145), and urinary tract infection (n = 21) as well as healthy volunteers (n = 269). Immunoglobulin N-glycan signature data were used in a supervised-ML model to establish a scoring system that gave the probability of the presence of a urological disease. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC). The supervised-ML urologic disease-specific scores clearly discriminated the urological diseases (AUC 0.78–1.00) and found a distinct N-glycan pattern that contributed to detect each disease. Limitations included the retrospective and limited pathological information regarding urological diseases. The supervised-ML urological disease-specific scoring system based on Ig N-glycan signatures showed excellent diagnostic ability for nine urological diseases using a one-time serum collection and could be a promising approach for the diagnosis of urological diseases.

    DOI: 10.1111/cas.15395

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  31. Robot-assisted partial nephrectomy for renal cell carcinoma in the isthmus of horseshoe kidney

    Sawada Atsuro, Kono Jin, Hattori Yuto, Goto Takayuki, Akamatsu Shusuke, Kobayashi Takashi

    UROLOGY CASE REPORTS   Vol. 43   page: 102076   2022.7

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    The anatomic features of a horseshoe kidney are unique—the kidney is fixed and poorly mobile, with many arterial and venous blood supplies, thereby complicating minimally invasive surgery for renal cancer in this setting. Several reports have described robot-assisted partial nephrectomy (RAPN) to treat renal cancer in a horseshoe kidney, but no reports of RAPN for renal cancer in the isthmus of a horseshoe kidney have been published to date. This case report describes the technique and usefulness of RAPN for treatment of renal cancer located in the isthmus of a horseshoe kidney.

    DOI: 10.1016/j.eucr.2022.102076

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  32. A Retrospective Study of Lymph Node Dissection for Renal Cell Carcinoma

    SUZUKI Ryosuke, GOTO Takayuki, YOSHINO Takayuki, SAWADA Atsuro, AKAMATSU Shusuke, SAITO Ryoichi, KOBAYASHI Takashi, YAMASAKI Toshinari, INOUE Takahiro, KAMBA Tomomi, OGAWA Osamu

      Vol. 68 ( 6 ) page: 165 - 170   2022.6

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    We retrospectively analyzed the effect of lymph node dissection (LND) in patients with renal cell carcinoma (RCC). Of 151 patients who underwent nephrectomy for RCC, 86 underwent LND. No distant metastasis (M0) was present in 71 patients, although distant metastasis (M1) was present in 15. Three (4.2%) and eight (53%) patients in the M0 and M1 groups, respectively, were clinical N-stage positive. Two (2.8%) and three (20%) patients in the M0 and M1 groups, respectively, were pathological N-stage positive. Both pathological N stage-positive patients in the M0 group were pathologically diagnosed with microphthalmia transcription family translocation RCC. The clinical and pathological positive node areas exhibited concordance in all three pathological N stage-positive patients in the M1 group. Chylous leakage occurred in 16 (19%) patients in the LND group (p<0.05). Extended LND was a statistically significant risk factor for chylous leakage in the multivariate analysis. Only limited cases should undergo LND, owing to the low frequency of positive pathological lymph node metastasis, and high complication rate.

    DOI: 10.14989/actauroljap_68_6_165

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  33. Tumor Lysis Syndrome in a Patient with Germ Cell Tumor : A Case Report

    KOTERAZAWA Shigeki, MASUI Kimihiko, HAMA Yusuke, TAKAHASHI Yudai, SAWADA Atsuro, AKAMATSU Shusuke, KOBAYASHI Takashi

      Vol. 68 ( 6 ) page: 201 - 205   2022.6

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    A 36-year-old man presented to our hospital with right scrotal swelling. A computed tomographic scan revealed a mass in the right scrotum, multiple masses in the lung and liver, and enlarged cervical, mediastinal, and retroperitoneal lymph nodes. After right high orchiectomy, he was diagnosed with nonseminomatous germ cell tumor (pT3N3M1b), with poor risk prediction according to the International Germ Cell Consensus classification. We started chemotherapy with bleomycin, etoposide, and cisplatin. Since serum alphafetoprotein (AFP) and human chorionic gonadotropin (HCG) levels did not decrease to normal levels, second-line chemotherapy with paclitaxel, ifosfamide, and cisplatin was administered. Six days after the start of treatment, the patient became unconscious, and his blood pressure decreased. Seven days later, blood tests revealed high uric acid levels, hyperphosphatemia, and increased creatinine. This was diagnosed as tumor lysis syndrome. Following diagnosis, continuous hemodiafiltration was started, and his condition gradually improved.

    DOI: 10.14989/actauroljap_68_6_201

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  34. Different risk genes contribute to clear cell and non-clear cell renal cell carcinoma in 1532 Japanese patients and 5996 controls

    Sekine Yuya, Iwasaki Yusuke, Aoi Tomomi, Endo Mikiko, Hirata Makoto, Kamatani Yoichiro, Matsuda Koichi, Sugano Kokichi, Yoshida Teruhiko, Murakami Yoshinori, Fukui Tomohiro, Akamatsu Shusuke, Ogawa Osamu, Nakagawa Hidewaki, Numakura Kazuyuki, Narita Shintaro, Habuchi Tomonori, Momozawa Yukihide

    HUMAN MOLECULAR GENETICS   Vol. 31 ( 12 ) page: 1962 - 1969   2022.6

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    Identifying causative genes via genetic testing is useful for screening, preventing and treating cancer. Several hereditary syndromes occur in patients with renal cell carcinoma (RCC). However, the evidence is from the European population; it remains unclear how the RCC-related genes and other cancer-predisposing genes contribute to RCC development in the Japanese population. A case-control study of 14 RCC-related genes and 26 cancer-predisposing genes was performed in 1563 Japanese patients with RCC and 6016 controls. The patients were stratified into clear cell RCC (ccRCC) or non-ccRCC (nccRCC). Gene-based analysis of germline pathogenic variants in patients with each subtype and cancer-free subjects was performed. Following quality control, 1532 patients with RCC and 5996 controls were analyzed. For ccRCC, 52 of 1283 (4.05%) patients carried pathogenic variants mainly in the cancer-predisposing genes such as TP53 (P = 1.73 × 10-4; OR, 5.8; 95% CI, 2.2-15.7). Approximately 80% of patients with pathogenic variants in TP53 had p.Ala189Val that was specific in East Asian population. For nccRCC, 14 of 249 (5.62%) patients carried pathogenic variants mainly in the RCC-related genes such as BAP1 and FH (P = 6.27 × 10-5; OR, Inf; 95% CI, 10.0-Inf). The patients with the pathogenic variants in the associated genes were diagnosed 15.8 years earlier and had a higher proportion of patients with a family history of RCC (OR, 20.0; 95% CI, 1.3-237.4) than the non-carriers. We showed different and population-specific contributions of risk genes between ccRCC and nccRCC in Japanese for improved personalized medicine.

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  35. A case of microsatellite instability-high clinically advanced castration-resistant prostate cancer showing a remarkable response to pembrolizumab sustained over at least 18 months

    Shimizu K., Sano T., Mizuno K., Sunada T., Makita N., Hagimoto H., Goto T., Sawada A., Fujimoto M., Ichioka K., Ogawa O., Kobayashi T., Akamatsu S.

    Cold Spring Harbor Molecular Case Studies   Vol. 8 ( 4 )   2022.6

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    Defective DNA mismatch repair genes can lead to microsatellite instability (MSI)- high status in prostate cancer (PC). Accumulation of replication errors in DNA leads to the production of abundant neoantigens, which could be targets for immune checkpoint inhibitors (CPIs). However, the incidence of MSI-high PC is low, and not all patients show a satisfactory therapeutic response to CPIs. Here, we present the case of a patient with MSI-high castration-resistant PC who showed a remarkable and durable response to pembrolizumab. The patient was resistant to abiraterone, docetaxel, and cabazitaxel and was suffering from multiple tumor-associated or treatment-related complications, such as urinary tract infection, infective endocarditis, and uncontrollable prostatic hemorrhage. Soon after the start of pembrolizumab therapy, the patient showed a dramatic decrease in prostate-specific antigen from35.67 ng/mL to an undetectable level and a remarkable reduction in the size of a massive prostate mass and lymph node metastases, with an absence of treatment-related complications. Specimens from the transurethral resection of prostate cancer during cabazitaxel treatment for control of prostate bleeding and also that from the prostate biopsy at initial diagnosis revealed MSI-high status. Immunohistochemistry showed loss of MSH2 and MSH6, and whole-exome sequencing revealed an approximate tumor mutation burden of 61 mutations/Mb as well as biallelic loss of MSH2. Pembrolizumab could show a significant effect even in a heavily treated patient with MSI-high advanced PC. Accumulation of detailed clinical and genomic information of cases of MSI-high PC treated with pembrolizumab is necessary for optimal patient selection.

    DOI: 10.1101/mcs.a006194

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  36. A Retrospective Study of Lymph Node Dissection for Renal Cell Carcinoma

    Suzuki R., Goto T., Yoshino T., Sawada A., Akamatsu S., Saito R., Kobayashi T., Yamasaki T., Inoue T., Kamba T., Ogawa O.

    Acta Urologica Japonica   Vol. 68 ( 6 ) page: 165 - 170   2022.6

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    We retrospectively analyzed the effect of lymph node dissection (LND) in patients with renal cell carcinoma (RCC). Of 151 patients who underwent nephrectomy for RCC, 86 underwent LND. No distant metastasis (M0) was present in 71 patients, although distant metastasis (M1) was present in 15. Three (4.2%) and eight (53%) patients in the M0 and M1 groups, respectively, were clinical N-stage positive. Two (2.8%) and three (20%) patients in the M0 and M1 groups, respectively, were pathological N-stage positive. Both pathological N stage-positive patients in the M0 group were pathologically diagnosed with microphthalmia transcription family translocation RCC. The clinical and pathological positive node areas exhibited concordance in all three pathological N stage-positive patients in the M1 group. Chylous leakage occurred in 16 (19%) patients in the LND group (p<0.05). Extended LND was a statistically significant risk factor for chylous leakage in the multivariate analysis. Only limited cases should undergo LND, owing to the low frequency of positive pathological lymph node metastasis, and high complication rate.

    DOI: 10.14989/ActaUroIJap_68_6_165

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  37. Tumor Lysis Syndrome in a Partient with Germ Cell Tumor : A Case Report

    Koterazawa S., Masui K., Hama Y., Takahashi Y., Sawada A., Akamatsu S., Kobayashi T.

    Acta Urologica Japonica   Vol. 68 ( 6 ) page: 201 - 205   2022.6

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    A 36-year-old man presented to our hospital with right scrotal swelling. A computed tomographic scan revealed a mass in the right scrotum, multiple masses in the lung and liver, and enlarged cervical, mediastinal, and retroperitoneal lymph nodes. After right high orchiectomy, he was diagnosed with nonseminomatous germ cell tumor (pT3N3M1b), with poor risk prediction according to the International Germ Cell Consensus classification. We started chemotherapy with bleomycin, etoposide, and cisplatin. Since serum alphafetoprotein (AFP) and human chorionic gonadotropin (HCG) levels did not decrease to normal levels, second-line chemotherapy with paclitaxel, ifosfamide, and cisplatin was administered. Six days after the start of treatment, the patient became unconscious, and his blood pressure decreased. Seven days later, blood tests revealed high uric acid levels, hyperphosphatemia, and increased creatinine. This was diagnosed as tumor lysis syndrome. Following diagnosis, continuous hemodiafiltration was started, and his condition gradually improved.

    DOI: 10.14989/ActaUroIJap_68_6_201

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  38. Cell Lines of Circulating Tumor Cells: What Is Known and What Needs to Be Resolved

    Shimada Yutaka, Sudo Tetsuo, Akamatsu Shusuke, Sunada Takuro, Myomoto Akira, Okano Kiyoshi, Shimizu Kazuharu

    JOURNAL OF PERSONALIZED MEDICINE   Vol. 12 ( 5 )   2022.5

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    The importance of circulating tumor cells (CTC) is well recognized. However, the biological characteristics of CTC in the bloodstream have not yet been examined in detail, due to the limited number of CTC cell lines currently available. Thirty-nine CTC cell lines were reported by 2021. For successful cell culturing, these CTC cell lines were reviewed. Previous studies on short-term cultures of CTC also analyzed approaches for establishing the long-term culture of CTC. Negative selection, hypoxic conditions, three-dimensional conditions, and careful management are preferable for the long-term culture of CTC. However, the establishment of CTC cell lines is dependent on the specific characteristics of each cell type. Therefore, a method to establish CTC cell lines has not yet been developed. Further efforts are needed to resolve this issue.

    DOI: 10.3390/jpm12050666

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  39. Detection efficacy of PET/CT with F-18-FSU-880 in patients with suspected recurrent prostate cancer: a prospective single-center study (vol 36, pg 302, 2022)

    Otani Tomoaki, Saga Tsuneo, Ishimori Takayoshi, Kidera Eitaro, Shimizu Yoichi, Aizawa Rihito, Nakamura Kiyonao, Goto Takayuki, Akamatsu Shusuke, Mizowaki Takashi, Nakamoto Yuji

    ANNALS OF NUCLEAR MEDICINE   Vol. 36 ( 5 ) page: 504 - 505   2022.5

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    The authors would like to correct the errors in the original article. The correction details are given below: The contents of Tables 2, 4 were incorrect. The correct Tables 2 and 4 are given below. The last sentence under the “Results”, under the subheading “Patient‑based analysis” in page 3 should be “When patients were divided into two groups according to GS, the detection rate in patients with GS of 8 and 9 tended to be higher than that in patients with GS of 6 and 7 [79% (33/42) vs. 60% (18/30)], although this difference was not statistically significant (p = 0.087).”. The p values were corrected in the subheading “Diagnostic performance according to initial treatment methods” under the “Results” section as given below: The overall detection rate of recurrence tended to be higher in patients who received RT than those underwent RP (81% (30/37) vs. 60% (21/35), p = 0.049). In patients with PSA levels greater than 0.5 ng/ml, no significant difference in the detection rate was observed between patients who underwent RP and those who received RT (73% (19/26) vs. 81% (30/37), p = 0.452). The second sentence under the heading “Conclusion” should be deleted.

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  40. Intensity-modulated radiation therapy for prostate cancer after rectal surgery: a single hospital long-term safety analysis

    Zhang Shuang, Nakamura Kiyonao, Aizawa Rihito, Akamatsu Shusuke, Mizowaki Takashi

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 27 ( 5 ) page: 977 - 982   2022.5

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    Background: Radiotherapy is a treatment option for prostate cancer patients after rectal surgery; however, the toxicity profile of radiotherapy for such patients has not been elucidated. This study aimed to evaluate the long-term toxicities and efficacy of intensity-modulated radiotherapy (IMRT) in patients with prostate cancer who had undergone rectal surgery. Methods: We retrospectively analyzed patients with prostate cancer after rectal surgery, who were definitively treated with IMRT between January 2000 and December 2019 at our institution. The planned total dose was 70–78 Gy in 2-Gy fraction, and the dose to the rectal anastomosis was limited to 70 Gy. The acute and late toxicities and survival outcomes were evaluated. Results: Twenty patients were included in the analysis. The median age was 71 years, with a median follow-up of 86 months. The median time from surgery to IMRT was 93.5 months. The median prostate-specific antigen value was 13.17 ng/ml. The median total dose was 74 Gy, and the median maximum dose to rectal anastomosis was 66.97 Gy. The 8-year biochemical recurrence-free and overall survival rates were 70.2% and 90.0%, respectively. The incidence rates of grade 2 acute genitourinary and gastrointestinal toxicities were 14.3% and 0%, respectively. No grade ≥ 3 acute or late toxicities were observed when the rectal anastomosis dose was limited to 70 Gy. Conclusions: This retrospective analysis suggested that IMRT for patients with prostate cancer after rectal surgery may be safe and effective with rectal dose constraint of Dmax < 70 Gy if more than 5 years have passed after surgery.

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  41. Diagnostic Accuracy of Transperineal MRI-Ultrasound Fusion Biopsy at the Introduction Period

    HATTORI Yuto, KONO Jin, YOSHINO Takayuki, MASUI Kimihiko, SATO Takuma, KASHIMA Soki, SANO Takeshi, GOTO Takayuki, SAWADA Atsuro, AKAMATSU Shusuke, KOBAYASHI Takashi, INOUE Takahiro, OGAWA Osamu

      Vol. 68 ( 4 ) page: 99 - 105   2022.4

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    Magnetic resonance imaging (MRI) ultrasound fusion biopsy is becoming popular owing to the better detection rate of clinically significant prostate cancer (csPCa). We retrospectively evaluated the accuracy of MRI-targeted biopsy during the period of introduction at a single academic center by comparing findings of its specimen and whole-mount histopathology. Between June 2018 and January 2021, 106 transperineal MRI-ultrasound fusion biopsies using BioJet software were performed. Among the cases, 15 subsequently underwent robotic-assisted laparoscopic radical prostatectomy and were eligible for analysis. This study included all regions of interest (ROIs) with a Prostate Imaging Reporting and Data System v2 category of 3 or greater on pre-biopsy MRI.For each lesion, grade group of MRI-targeted biopsy specimens and prostatectomy specimens were compared. From a total of 25 ROIs identified among 15 males, csPCa was found in 21 (84%) of the concordant locations of prostatectomy specimens. However, MRI-targeted biopsy could diagnose csPCa in only 12 (48%) of them. In the csPCa undetected group, the ROI volume was significantly smaller (median volume 0.23 ml vs 0.40 ml, p=0.03). We also found that in cases where PCa was not detected through MRI-targeted biopsy, the biopsy sample length was significantly shorter (median length 9 mm vs 17 mm, p=0.01). Our data suggest that failure of detecting PCa in MRI-targeted biopsy could be due to technical errors at the introduction period of the technique. A sufficient sampling length of 10 mm or more is desirable, especially for small lesions.

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  42. Clinical characteristics of renal transplant recipients who developed de novo donor-specific antigen in Kyoto University Hospital: a case series

    Nakamura Kenji, Sawada Atsuro, Kita Yuki, Kono Jin, Masui Kimihiko, Sato Takuma, Sano Takeshi, Goto Takayuki, Akamatsu Shusuke, Ogawa Osamu, Kobayashi Takashi

    RENAL REPLACEMENT THERAPY   Vol. 8 ( 1 )   2022.4

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    Background: The clinical significance of de novo donor-specific antigen (DSA) in renal transplant recipients is not yet fully understood. This study aimed to report the prevalence of de novo DSA detected in antihuman leukocyte antigen (HLA) antibody testing and to evaluate the association between de novo DSA and renal transplant prognosis in living-donor renal transplant recipients at our hospital. Methods: Of the 110 patients who underwent living-donor renal transplantation from 1980 to 2019, 80 patients who underwent anti-HLA antibody screening tests were retrospectively reviewed for the development of de novo DSA and outcomes regarding graft function. Results: The mean age at transplantation was 43.2 ± 14.6 years. Of the 80 patients, 43 (53.8%) were men and 68 (85.0%) underwent ABO-compatible transplantation. Anti-HLA antibody was detected in 14 patients (17.5%), including eight (10.0%) with de novo DSA. Graft loss occurred in two (25%) of the eight patients with de novo DSA, none of the six patients with non-DSA anti-HLA antibody and no anti-HLA antibody (P = 0.0419, log-rank test). The mean estimated glomerular filtration rate at the time of the anti-HLA antibody test was 45.1 ± 14.4 mL/min/1.73m2 in the 66 patients with no anti-HLA antibody, while it was 35.0 ± 11.5 mL/min/1.73m2 in the eight patients with de novo DSA (P = 0.0702) and 39.3 ± 15.3 mL/min/1.73m2 in the six patients with non-DSA anti-HLA antibody (P = 0.3921). The mean monthly cyclosporin A trough concentration for the past year from the anti-HLA antibody test was 59.2 ± 24.8 ng/ml in the seven patients with no anti-HLA antibody, while it was 61.9 ± 12.5 ng/ml in the five patients with de novo DSA (P = 0.5670) and 36.3 ± 9.0 ng/ml in a patient with non-DSA anti-HLA antibody (P = 0.3921). The mean monthly tacrolimus trough concentration for the past year from the anti-HLA antibody test was 4.62 ± 1.20 ng/ml in the 55 patients with no anti-HLA antibody, while it was 4.09 ± 1.10 ng/ml in the three patients with de novo DSA (P = 0.0027) and 4.21 ± 1.14 ng/ml in the four patients with non-DSA anti-HLA antibody (P = 0.0722). Conclusions: The optimal treatment for patients with de novo DSA has not been established, and immunosuppressive management that suppresses the development of de novo DSA is essential.

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  43. Comprehensive genomics in androgen receptor-dependent castration-resistant prostate cancer identifies an adaptation pathway mediated by opioid receptor kappa 1

    Makino Yuki, Kamiyama Yuki, Brown J. B., Tanaka Toshiya, Murakami Ryusuke, Teramoto Yuki, Goto Takayuki, Akamatsu Shusuke, Terada Naoki, Inoue Takahiro, Kodama Tatsuhiko, Ogawa Osamu, Kobayashi Takashi

    COMMUNICATIONS BIOLOGY   Vol. 5 ( 1 ) page: 299   2022.4

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    Castration resistance is a lethal form of treatment failure of prostate cancer (PCa) and is associated with ligand-independent activation of the androgen receptor (AR). It is only partially understood how the AR mediates survival and castration-resistant growth of PCa upon androgen deprivation. We investigated integrative genomics using a patient-derived xenograft model recapitulating acquired, AR-dependent castration-resistant PCa (CRPC). Sequencing of chromatin immunoprecipitation using an anti-AR antibody (AR-ChIP seq) revealed distinct profiles of AR binding site (ARBS) in androgen-dependent and castration-resistant xenograft tumors compared with those previously reported based on human PCa cells or tumor tissues. An integrative genetic analysis identified several AR-target genes associated with CRPC progression including OPRK1, which harbors ARBS and was upregulated upon androgen deprivation. Loss of function of OPRK1 retarded the acquisition of castration resistance and inhibited castration-resistant growth of PCa both in vitro and in vivo. Immunohistochemical analysis showed that expression of OPRK1, a G protein-coupled receptor, was upregulated in human prostate cancer tissues after preoperative androgen derivation or CRPC progression. These data suggest that OPRK1 is involved in post-castration survival and cellular adaptation process toward castration-resistant progression of PCa, accelerating the clinical implementation of ORPK1-targeting therapy in the management of this lethal disease.

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  44. Proteolysis of a histone acetyl reader, ATAD2, induces chemoresistance of cancer cells under severe hypoxia by inhibiting cell cycle progression in S phase

    Haitani Takao, Kobayashi Minoru, Koyasu Sho, Akamatsu Shusuke, Suwa Tatsuya, Onodera Yasuhito, Nam Jin-Min, Phuong Thi Lien Nguyen, Menju Toshi, Date Hiroshi, Ogawa Osamu, Harada Hiroshi

    CANCER LETTERS   Vol. 528   page: 76 - 84   2022.3

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    Cancer cells acquire chemoresistance in hypoxic regions of solid tumors, which is suggested to be at least partly due to reduction of their proliferative activity. However, molecular mechanisms behind it have not been fully elucidated. Here, we revealed the importance of active proteolysis of a histone acetylation reader, ATPase family AAA domain containing 2 (ATAD2), under hypoxia. We found that inactivation of an O2/Fe2+/α-ketoglutarate-dependent dioxygenase triggered ATAD2 proteolysis by the proteasome system upon severe hypoxia in a hypoxia-inducible factors (HIFs)-independent manner. Consistently, ATAD2 expression levels were markedly lower in perinecrotic hypoxic regions in both xenografted and clinical tumor tissues. The ATAD2 proteolysis was accompanied by a decrease in the amount of acetylated histone H3 lysine 27 and inhibited cell cycle progression from the early to late S phase under severe hypoxia. The retardation of S phase progression induced chemoresistance, which was blocked by overexpression of ATAD2. Together, these results indicate that ATAD2 proteolysis upon severe hypoxia induces chemoresistance of cancer cells through heterochromatinization and the subsequent retardation of S phase progression; therefore, inhibition of ATAD2 proteolysis is expected to be a strategy to overcome chemoresistance of hypoxic tumor cells.

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  45. Detection efficacy of PET/CT with F-18-FSU-880 in patients with suspected recurrent prostate cancer: a prospective single-center study

    Otani Tomoaki, Saga Tsuneo, Ishimori Takayoshi, Kidera Eitaro, Shimizu Yoichi, Aizawa Rihito, Nakamura Kiyonao, Goto Takayuki, Akamatsu Shusuke, Mizowaki Takashi, Nakamoto Yuji

    ANNALS OF NUCLEAR MEDICINE   Vol. 36 ( 3 ) page: 302 - 309   2022.3

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    Purpose: Our objective was to investigate the efficacy of PET/CT with a novel prostate-specific membrane antigen (PSMA)-targeted PET probe, 18F-FSU-880, for detection and localization of recurrent disease in prostate cancer patients in whom recurrence was suspected based on an increase in plasma prostate-specific antigen (PSA) levels after initial treatment. Methods: This study was a prospective institutional review board-approved study of 72 patients (age 56–84 years, PSA level 0.22–40.00 ng/ml) with suspected relapse of prostate cancer after primary therapy, including radical prostatectomy (RP) (n = 35) or radiation therapy (RT) (n = 37). Patients underwent PET/CT approximately 1 h and 3 h after injection of 18F-FSU-880 (101.8–380 MBq). The correlation between patient-based detection rate and Gleason score (GS) of the primary tumor and plasma PSA levels at the time of PET/CT was evaluated. Maximum standardized uptake values (SUVmax) of the positive uptakes at 1 h post-injection were compared with those at 3 h post-injection. Results: In total, 51 patients (71%) showed at least one positive PSMA PET result. The PSA-stratified detection rates were 22% (2/9), 36% (4/11), 89% (16/18) and 85% (29/34) for PSA levels of 0.2 to < 0.5, 0.5 to < 1.0, 1.0 to < 2.0 and ≥ 2.0 ng/ml, respectively. The GS-stratified detection rates were 33% (2/6), 67% (16/24), 70% (16/23) and 89% (17/19) for GS 6, 7, 8 and 9, respectively. In lesion-based analysis, 157 positive lesions were detected at 3 h post-injection, 18 in the prostate or prostate bed, 65 in lymph nodes, 71 in the bone and 3 in the lung. Two local recurrences, eight pelvic lymph nodes and one distant lymph node were depicted only at 3 h post-injection. SUV max at 3 h post-injection was significantly higher than SUVmax at 1 h post-injection (p < 0.001). Conclusion: Our preliminary data suggest that 18F-FSU-880 might be a promising new PSMA-targeting tracer for detecting recurrence after initial treatment in patients with prostate cancer.

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  46. Evaluation of tumor genomic variants in Japanese patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide: Protocol of a phase 4 study (CUARTET).

    Uemura Hirotsugu, Kamoto Toshiyuki, Uemura Hiroji, Masumori Naoya, Terada Naoki, Akamatsu Shusuke, Koroki Yosuke, Ono Shintaro, Ito Miku, Matsuyama Hideyasu

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 40 ( 6 )   2022.2

  47. Long-term outcomes of a pilot study on highly hypofractionated intensity-modulated radiation therapy over three weeks for localized prostate cancer.

    Nakamura Kiyonao, Ikeda Itaru, Inokuchi Haruo, Aizawa Rihito, Akamatsu Shusuke, Kobayashi Takashi, Mizowaki Takashi

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 40 ( 6 )   2022.2

  48. Large-scale genomic analysis of renal cell carcinoma using 1,532 Japanese patients and 5,996 controls

    Sekine Y., Iwasaki Y., Aoi T., Mikiko E., Hirata M., Kamatani Y., Matsuda K., Kokichi S., Yoshida T., Murakami Y., Fukui T., Akamatsu S., Ogawa O., Nakagawa H., Numakura K., Narita S., Momozawa Y., Habuchi T.

    EUROPEAN UROLOGY   Vol. 81   page: S1648 - S1649   2022.2

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  49. The combination of CDK12 KO and TP53 KD may not mimic aggressive phenotype seen in clinical CDK12 LOF prostate cancer.

    Kamiyama Yuki, Fukui Tomohiro, Sunada Takuro, Kimura Hiroko, Goto Takayuki, Kobayashi Takashi, Akamatsu Shusuke

    CANCER SCIENCE   Vol. 113   page: 1594 - 1594   2022.2

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  50. Clinical Utility of Germline Genetic Testing in Japanese Men Undergoing Prostate Biopsy

    Akamatsu Shusuke, Terada Naoki, Takata Ryo, Kinoshita Hidefumi, Shimatani Kimihiro, Momozawa Yukihide, Yamamoto Michio, Tada Harue, Kawamorita Naoki, Narita Shintaro, Kato Takuma, Nitta Masahiro, Kandori Shuya, Koike Yusuke, Inazawa Johji, Kimura Takahiro, Kimura Hiroko, Kojima Takahiro, Terachi Toshiro, Sugimoto Mikio, Habuchi Tomonori, Arai Yoichi, Yamamoto Shingo, Matsuda Tadashi, Obara Wataru, Kamoto Toshiyuki, Inoue Takahiro, Nakagawa Hidewaki, Ogawa Osamu

    JNCI CANCER SPECTRUM   Vol. 6 ( 1 )   2022.1

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    Background: Multiple common variants and also rare variants in monogenic risk genes such as BRCA2 and HOXB13 have been reported to be associated with risk of prostate cancer (PCa); however, the clinical setting in which germline genetic testing could be used for PCa diagnosis remains obscure. Herein, we tested the clinical utility of a 16 common variant–based polygenic risk score (PRS) that has been developed previously for Japanese men and also evaluated the frequency of PCa-associated rare variants in a prospective cohort of Japanese men undergoing prostate biopsy. Methods: A total of 1336 patients undergoing first prostate biopsy were included. PRS was calculated based on the genotype of 16 common variants, and sequencing of 8 prostate cancer–associated genes was performed by multiplex polymerase chain reaction based target sequencing. PRS was combined with clinical factors in logistic regression models to assess whether addition of PRS improves the prediction of biopsy positivity. Results: The top PRS decile was associated with an odds ratio of 4.10 (95% confidence interval ¼ 2.46 to 6.86) with reference to the patients at average risk, and the estimated lifetime absolute risk approached 20%. Among the patients with prostate specific antigen 2-10 ng/mL who had prebiopsy magnetic resonance imaging, high PRS had an equivalent impact on biopsy positivity as a positive magnetic resonance imaging finding. Rare variants were detected in 19 (2.37%) and 7 (1.31%) patients with positive and negative biopsies, respectively, with BRCA2 variants being the most prevalent. There was no association between PRS and high-risk rare variants. Conclusions: Germline genetic testing could be clinically useful in both pre- and post-PSA screening settings.

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  51. A rare case of intestinal lymphangiectasia induced by pazopanib

    Masui Kimihiko, Hama Yusuke, Sawada Atsuro, Akamatsu Shusuke, Sakaue Junya, Okabe Makoto, Kobayashi Takashi

    INTERNATIONAL CANCER CONFERENCE JOURNAL   Vol. 11 ( 1 ) page: 87 - 90   2022.1

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  52. IFN-Gamma Expression in the Tumor Microenvironment and CD8-Positive Tumor-Infiltrating Lymphocytes as Prognostic Markers in Urothelial Cancer Patients Receiving Pembrolizumab

    Sakatani Toru, Kita Yuki, Fujimoto Masakazu, Sano Takeshi, Hamada Akihiro, Nakamura Kenji, Takada Hideaki, Goto Takayuki, Sawada Atsuro, Akamatsu Shusuke, Kobayashi Takashi

    CANCERS   Vol. 14 ( 2 )   2022.1

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    Although immune checkpoint inhibitors have shown benefit for advanced urothelial carcinoma (aUC) patients, prognostication of treatment efficacy and response duration remains a clinical challenge. We evaluated the expression of immune markers in the tumor microenvironment and assessed their associations with response to and survival after pembrolizumab treatment in 26 aUC patients. High levels of CD8+ tumor-infiltrating lymphocytes (TILs) were associated with favorable objective responses (23.0% vs. 15.3%, p = 0.0425), progression-free survival (median, 8.8 vs 2.1 months; hazard ratio (HR), 0.24; 95% confidence interval (CI), 0.07–0.66, p = 0.0060), and overall survival (median, >24.0 vs. 5.3 months; HR, 0.17; 95% CI, 0.04–0.56, p = 0.0034) compared with low levels. High interferon-gamma (IFNγ) expression levels were associated with longer post-progression survival (median, 4.9 vs. 1.0 months; HR, 0.18; 95% CI, 0.04–0.59, p = 0.0027) compared with low expression. Multivariate analysis incorporating clinical prognosticators demonstrated that the coincidence of low CD8+ T cells/IFNγ was an independent factor for unfavorable overall survival after pembrolizumab treatment (HR, 4.07; 95% CI, 1.36–12.73; p = 0.0125). The combination of low CD8+ TILs and IFNγ expression was an independent prognostic factor with predictive ability equivalent to previously reported clinical prognosticators.

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  53. Rapidly Progressive Bladder Cancer Diagnosed because of Spontaneous Bladder Rupture.

    Hagimoto H, Sano T, Kashima S, Yoshino T, Goto T, Sawada A, Akamatsu S, Yamasaki T, Fujimoto M, Kajita Y, Kobayashi T, Ogawa O

    Case reports in urology   Vol. 2022   page: 4586199   2022

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  54. SPINK1 as a plasma marker for tumor hypoxia and a therapeutic target for radiosensitization

    Suwa Tatsuya, Kobayashi Minoru, Shirai Yukari, Nam Jin-Min, Tabuchi Yoshiaki, Takeda Norihiko, Akamatsu Shusuke, Ogawa Osamu, Mizowaki Takashi, Hammond Ester M., Harada Hiroshi

    JCI INSIGHT   Vol. 6 ( 21 )   2021.11

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    Hypoxia is associated with tumor radioresistance; therefore, a predictive marker for tumor hypoxia and a rational target to overcome it have been sought to realize personalized radiotherapy. Here, we show that serine protease inhibitor Kazal type I (SPINK1) meets these 2 criteria. SPINK1 expression was induced upon hypoxia (O2 < 0.1%) at the transcription initiation level in a HIF-dependent manner, causing an increase in secreted SPINK1 levels. SPINK1 proteins were detected both within and around hypoxic regions of xenografted and clinical tumor tissues, and their plasma levels increased in response to decreased oxygen supply to xenografts. Secreted SPINK1 proteins enhanced radioresistance of cancer cells even under normoxic conditions in EGFR-dependent and nuclear factor erythroid 2–related factor 2–dependent (Nrf2-dependent) manners and accelerated tumor growth after radiotherapy. An anti-SPINK1 neutralizing antibody exhibited a radiosensitizing effect. These results suggest that SPINK1 secreted from hypoxic cells protects the surrounding and relatively oxygenated cancer cells from radiation in a paracrine manner, justifying the use of SPINK1 as a target for radiosensitization and a plasma marker for predicting tumor hypoxia.

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  55. Clinical Impact of Detecting Low-Frequency Variants in Cell-Free DNA on Treatment of Castration-Resistant Prostate Cancer

    Mizuno Kei, Sumiyoshi Takayuki, Okegawa Takatsugu, Terada Naoki, Ishitoya Satoshi, Miyazaki Yu, Kojima Takahiro, Katayama Hiromichi, Fujimoto Naohiro, Hatakeyama Shingo, Shiota Masaki, Yoshimura Koji, Matsui Yoshiyuki, Narita Shintaro, Matsumoto Hiroaki, Kurahashi Ryoma, Kanno Hidenori, Ito Katsuhiro, Kimura Hiroko, Kamiyama Yuki, Sunada Takuro, Goto Takayuki, Kobayashi Takashi, Yamada Hitoshi, Tsuchiya Norihiko, Kamba Tomomi, Matsuyama Hideyasu, Habuchi Tomonori, Eto Masatoshi, Ohyama Chikara, Ito Akihiro, Nishiyama Hiroyuki, Okuno Hiroshi, Kamoto Toshiyuki, Fujimoto Akihiro, Ogawa Osamu, Akamatsu Shusuke

    CLINICAL CANCER RESEARCH   Vol. 27 ( 22 ) page: 6164 - 6173   2021.11

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    Purpose: Although cell-free DNA (cfDNA) testing is expected to drive cancer precision medicine, little is known about the significance of detecting low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castrationresistant prostate cancer (CRPC). We aimed to identify genomic profile including low-frequency variants in ctDNA from patients with CRPC and investigate the clinical utility of detecting variants with variant allele frequency (VAF) below 1%. Experimental Design: This prospective, multicenter cohort study enrolled patients with CRPC eligible for treatment with abiraterone or enzalutamide. We performed targeted sequencing of pretreatment cfDNA and paired leukocyte DNA with molecular barcodes, and ctDNA variants with a VAF ≥0.1% were detected using an in-house pipeline. We investigated progression-free survival (PFS) and overall survival (OS) after different ctDNA fraction cutoffs were applied. Results: One hundred patients were analyzed (median follow-up 10.7 months). We detected deleterious ATM, BRCA2, and TP53 variants even in samples with ctDNA fraction below 2%. When the ctDNA fraction cutoff value of 0.4% was applied, significant differences in PFS and OS were found between patients with and without defects in ATM or BRCA2 [HR, 2.52; 95% confidence interval (CI), 1.24-5.11; P = 0.0091] and TP53 (HR, 3.74; 95% CI, 1.60-8.71; P = 0.0014). However, these differences were no longer observed when the ctDNA fraction cutoff value of 2% was applied, and approximately 50% of the samples were classified as ctDNA unquantifiable. Conclusions: Detecting low-frequency ctDNA variants with a VAF <1% is important to identify clinically informative genomic alterations in CRPC.

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  56. Long-term safety of high-dose whole pelvic IMRT for high-risk localized prostate cancer through 10-year follow-up

    Aizawa Rihito, Nakamura Kiyonao, Norihisa Yoshiki, Ogata Takashi, Inoue Takahiro, Yamasaki Toshinari, Kobayashi Takashi, Akamatsu Shusuke, Ogawa Osamu, Mizowaki Takashi

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 26 ( 11 ) page: 2113 - 2122   2021.11

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    Background: The aim of this study was to evaluate the long-term efficacy and safety of whole pelvic intensity-modulated radiation therapy with a simultaneous-integrated boost (WP-SIB-IMRT) for locally advanced prostate cancer (LAPCa). Methods: All patients with cT3–4N0M0 prostate cancer treated with WP-SIB-IMRT between February 2006 and September 2009 at our institution were analyzed retrospectively. The prescribed dose was 78 Gy to the prostate and 58.5 Gy to the prophylactic pelvic lymph nodal area in 39 fractions delivered using the simultaneous-integrated boost technique. All patients received short-term neoadjuvant androgen-deprivation therapy alone (median 8.3 months). Propensity-score matching (PSM) analysis was performed to evaluate the additional benefit of prophylactic whole pelvic radiation therapy (WPRT), using the cohort of 203 LAPCa patients treated with prostate-only IMRT (PO-IMRT). Results: In total, 47 consecutive patients were analyzed. The median estimated risk of pelvic lymph node involvement was 57.5%. The median follow-up period was 10.5 years. The 10 year prostate cancer-specific survival and biochemical failure (BF) rates were 92.2 and 54.8%, respectively. The 10 year cumulative incidence rates of ≥ grade 2 late genitourinary and gastrointestinal toxicities were 21.6 and 17.2%, respectively. From a total of 250 patients, PSM analysis identified 76 patients with similar characteristics, and no significant difference in BF rates was observed between WP-SIB-IMRT and PO-IMRT cohorts (p = 0.261). Conclusions: WP-SIB-IMRT for LAPCa was safe over long-term observation, although no clear benefit of WPRT was observed among our small and highly selected cohort. Regarding the additional efficacy of WPRT, further investigations are needed.

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  57. The Clinical Utility of Liquid Biopsies as Biomarkers in Metastatic Prostate Cancer

    Sumiyoshi T., Akamatsu S.

    Japanese Journal of Cancer and Chemotherapy   Vol. 48 ( 10 ) page: 1203 - 1208   2021.10

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    With increasing treatment options for metastatic prostate cancer (mPC), there is a growing attention to circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) as minimally invasive biomarkers to facilitate precision medicine. CTC count and ctDNA abundance have been reported to be prognostic factors. In addition, on-treatment changes in these values might also be associated with the treatment response. Androgen receptor gene alterations, including ligand-binding domain mutations, copy number amplification, or structural rearrangements, are identified in most metastatic castration-resistant prostate cancer (mCRPC) and associated with treatment response to androgen receptor pathway inhibitors. Alterations in different DNA damage repair genes, including BRCA2, ATM, CDK12, or mismatch repair genes, are linked to favorable response to targeted therapies such as poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or immune checkpoint inhibitors. Overactivation of the PI3K signaling pathway is mainly caused by PTEN loss, and several clinical trials are underway to assess the treatment effect of the targeted therapies such as Akt inhibitors. To disseminate treatment strategies using CTC and ctDNA in clinical practice, we will require prospective biomarker-driven clinical trials, development of novel targeted therapies, and exploration of other molecular characteristics such as epigenome.

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  58. [The Clinical Utility of Liquid Biopsies as Biomarkers in Metastatic Prostate Cancer].

    Sumiyoshi T, Akamatsu S

    Gan to kagaku ryoho. Cancer & chemotherapy   Vol. 48 ( 10 ) page: 1203 - 1208   2021.10

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  59. High level of phosphatidylcholines/lysophosphatidylcholine ratio in urine is associated with prostate cancer

    Li Xin, Nakayama Kenji, Goto Takayuki, Kimura Hiroko, Akamatsu Shusuke, Hayashi Yujiro, Fujita Kazutoshi, Kobayashi Takashi, Shimizu Koji, Nonomura Norio, Ogawa Osamu, Inoue Takahiro

    CANCER SCIENCE   Vol. 112 ( 10 ) page: 4292 - 4302   2021.10

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    The altered levels of phospholipids (PLs) and lysophospholipids (LPLs) in prostate cancer (CaP) and benign tissues in our previous findings prompted us to explore PLs and LPLs as potential biomarkers for CaP. Urinary lipidomics has attracted increasing attention in clinical diagnostics and prognostics for CaP. In this study, 31 prostate tissues obtained from radical prostatectomy were assessed using high-resolution matrix-assisted laser desorption/ionization imaging mass spectrometry (HR-MALDI-IMS). Urine samples were collected after digital rectal examination (DRE), and urinary lipids were extracted using the acidified Bligh-Dyer method. The discovery set comprised 75 patients with CaP and 44 with benign prostatic hyperplasia (BPH) at Kyoto University Hospital; the validation set comprised 74 patients with CaP and 59 with BPH at Osaka University Hospital. Urinary lipidomic screening was performed using MALDI time-of-flight MS (MALDI-TOF/MS). The levels of urinary lysophosphatidylcholine (LPC) and phosphatidylcholines (PCs) were compared between the CaP and BPH groups. The (PC [34:2] + PC [34:1])/LPC (16:0) ratio was significantly higher (P <.001) in CaP tissues than in benign epithelial tissues. The urinary PCs/LPC ratio was significantly higher (P <.001) in the CaP group than in the BPH group in the discovery and validation sets.

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  60. Narrative review of challenges in the management of advanced neuroendocrine prostate cancer

    Okasho Kosuke, Ogawa Osamu, Akamatsu Shusuke

    TRANSLATIONAL ANDROLOGY AND UROLOGY   Vol. 10 ( 10 ) page: 3953 - 3962   2021.10

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    With wide availability of potent androgen receptor targeted agents (ARTAs), the incidence of treatment-related neuroendocrine prostate cancer (t-NEPC) has been dramatically increasing. However, there is no standard effective treatment for this disease state. Recent advances in genomic and molecular medicine have identified some critical features of NEPC that would help in understanding the biology of the disease. Furthermore, invaluable pre-clinical in vivo and in vitro research models that represent NEPC have been developed. These advances in research have revealed a large heterogeneity of t-NEPC with varying degree of androgen receptor (AR), neuroendocrine (NE) marker, and cell cycle associated gene expressions, which may have clinical implication in terms of prognosis and treatment selection. Based on these studies, some potential drug targets have been identified, and early clinical trials are ongoing. In the future, more precise disease classification and biomarker-driven selection of patients will be critical for optimization of treatment for patients with NEPC. In the present review, we describe up-to-date findings of recent research on this topic and introduce ongoing therapeutic developments that are expected to lead to novel treatment strategies for NEPC in the future.

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  61. Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer

    Murakami Kaoru, Kita Yuki, Sakatani Toru, Hamada Akihiro, Mizuno Kei, Nakamura Kenji, Takada Hideaki, Matsumoto Keiyu, Sano Takeshi, Goto Takayuki, Akamatsu Shusuke, Saito Ryoichi, Tsuruyama Tatsuaki, Ogawa Osamu, Kobayashi Takashi

    CANCER SCIENCE   Vol. 112 ( 9 ) page: 3669 - 3681   2021.9

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    Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP-based chemotherapy is the first-line treatment. WEE1, a G2/M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK-1775, a WEE1 inhibitor also known as AZD-1775, blocked proliferation of UC cell lines in a dose-dependent manner irrespective of TP53 status. MK-1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53-mutant UC cells but not in TP53-WT cells. Knocking down TP53 in TP53-WT cells induced synergism of MK-1775 and CDDP. In UMUC3 cell xenografts and two patient-derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD-1775 combined with CDDP suppressed tumor growth inducing both M-phase entry and apoptosis, whereas AZD-1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue-originated spheroid system showed correlations with the in vivo efficacy of AZD-1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system.

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  62. Detection of von Hippel-Lindau gene mutation in circulating cell-free DNA for clear cell renal cell carcinoma

    Sumiyoshi Takayuki, Yamasaki Toshinari, Takeda Masashi, Mizuno Kei, Utsunomiya Noriaki, Sakamoto Hiromasa, Nakamura Eijiro, Ogawa Osamu, Akamatsu Shusuke

    CANCER SCIENCE   Vol. 112 ( 8 ) page: 3363 - 3374   2021.8

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    The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel-Lindau gene (VHL) using a combination of digital PCR and multiplex PCR–based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell-free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%-4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%-2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.

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  63. The association between missense polymorphisms in SRD5A2 and HSD3B1 and treatment failure with abiraterone for castration-resistant prostate cancer

    Shiota Masaki, Akamatsu Shusuke, Narita Shintaro, Sumiyoshi Takayuki, Fujiwara Maki, Uchiumi Takeshi, Ogawa Osamu, Habuchi Tomonori, Eto Masatoshi

    PHARMACOGENOMICS JOURNAL   Vol. 21 ( 4 ) page: 440 - 445   2021.8

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    Missense polymorphism in HSD3B1, encoding 3β-hydroxysteroid dehydrogenase-1, was associated with outcome after abiraterone treatment. Other androgen-metabolizing enzymes may be involved in therapeutic effect in abiraterone. In this study, we investigated the significance of polymorphisms in genes involved in androgen and abiraterone metabolisms in prostate cancer patients treated with abiraterone. A total of 99 Japanese male castration-resistant prostate cancer patients treated with abiraterone between 2014 and 2018 were included. Genomic DNA was obtained from whole blood samples, and genotyping on SRD5A2 (rs523349), CYP17A1 (rs743572), CYP17A1 (rs2486758), and AKR1C3 (rs12529) was performed by PCR-based technique. Among the 99 patients, 32 (32.3%), 49 (49.5%), and 18 patients (18.2%) carried GG, GC, and CC alleles in SRD5A2, respectively. CC allele was associated with lower risk of treatment failure (hazard ratio, 0.43; 95% confidence interval, 0.20–0.87; P = 0.017) on multivariate analyses, compared with GG/GC alleles. In the combination model using HSD3B1 and SRD5A2 polymorphisms, compared with the combination of AA in HSD3B1 and GG/GC in SRD5A2, other combinations were associated with lower risk of treatment failure (hazard ratio, 0.34; 95% confidence interval, 0.17–0.62; P = 0.0003) on multivariate analyses. This study showed that SRD5A2 genetic variation was associated with the risk of treatment failure in abiraterone. Combinational use of genetic variation in HSD3B1 with SRD5A2 genetic variation augmented the ability of prognostic stratification.

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  64. A multilocular thymic cyst associated with mediastinal seminoma: evidence for its medullary epithelial origin highlighted by POU2F3-positive thymic tuft cells and concomitant myoid cell proliferation

    Sugimoto Akihiko, Yamada Yosuke, Fujimoto Masakazu, Minamiguchi Sachiko, Sato Takuma, Akamatsu Shusuke, Marx Alexander, Haga Hironori

    VIRCHOWS ARCHIV   Vol. 479 ( 1 ) page: 215 - 220   2021.7

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    Multilocular thymic cyst (MTC) and germ cell tumors are common diseases that impact the mediastinum. Correctly diagnosing these diseases can be difficult because several other conditions can mimic them. We report a male patient with MTC associated with mediastinal seminoma. A needle biopsy of the mediastinal tumor revealed numerous epithelioid cell granulomas that mimicked sarcoidosis or mycobacterial infection. However, large atypical cells positive for Oct3/4 and KIT were noted between the granulomas; thus, we diagnosed the patient with mediastinal seminoma. The resected tumor, after chemotherapy, consisted of multiple cystic lesions, and a residual germ cell tumor was first considered. However, thymic medulla-specific elements, namely, POU2F3-positive thymic tuft cells and rhabdomyomatous myoid cells accompanying the epithelium, led to the correct diagnosis of MTC. Our case underscores the importance of recognizing the histological features associated with mediastinal seminoma and provides novel findings for MTC pathogenesis, namely, the presence of thymic tuft cells.

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  65. ctDNA&beyond in urological tumors

    Akamatsu Shusuke

    ANNALS OF ONCOLOGY   Vol. 32   page: S230 - S230   2021.7

  66. Establishment and characterization of a novel treatment-related neuroendocrine prostate cancer cell line KUCaP13

    Okasho Kosuke, Mizuno Kei, Fukui Tomohiro, Lin Yen-Yi, Kamiyama Yuki, Sunada Takuro, Li Xin, Kimura Hiroko, Sumiyoshi Takayuki, Goto Takayuki, Kobayashi Takashi, Lin Dong, Wang Yuzhuo, Collins Colin C., Inoue Takahiro, Ogawa Osamu, Akamatsu Shusuke

    CANCER SCIENCE   Vol. 112 ( 7 ) page: 2781 - 2791   2021.7

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    The prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC-associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient-derived, treatment-related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC.

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  67. Long-term clinical outcomes of external beam radiation therapy for oligometastatic prostate cancer: A combination of prostate-targeted treatment and metastasis-directed therapy

    Aizawa Rihito, Takayama Kenji, Nakamura Kiyonao, Ogata Takashi, Inoue Takahiro, Yamasaki Toshinari, Kobayashi Takashi, Akamatsu Shusuke, Tashiro Yu, Ota Hideto, Ogawa Osamu, Mizowaki Takashi

    INTERNATIONAL JOURNAL OF UROLOGY   Vol. 28 ( 7 ) page: 749 - 755   2021.7

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    Objective: To assess the efficacy of combination of prostate-targeted treatment and metastasis-directed therapy for oligometastatic prostate cancer. Methods: We retrospectively evaluated the clinical outcomes of synchronously diagnosed oligometastatic prostate cancer patients treated with external beam radiation therapy for the prostate and all metastatic lesions (≤3 lesions) at Kyoto University Hospital between January 2004 and April 2019. The prescribed dose was basically ≥70 Gy for the prostate with or without whole pelvic irradiation, and ≥45 Gy for the metastatic lesions. Clinical outcomes were compared with a contemporary cohort of 55 synchronous oligometastatic prostate cancer patients treated with the standard of care. Results: In total, 16 consecutive patients with synchronous oligometastatic prostate cancer were analyzed. The median follow-up period was 7.4 years. The 8-year overall survival, prostate cancer-specific survival, biochemical failure-free, clinical failure-free and castration-resistant prostate cancer-free rates were 64.8%, 71.3%, 38.5%, 47.3% and 67.3%, respectively. No grade 3 or higher radiation-induced late toxicities occurred. Patients with prostate-targeted treatment plus metastasis-directed therapy had a significantly higher castration-resistant prostate cancer-free rate than those without prostate-targeted treatment plus metastasis-directed therapy (P = 0.00741). Conclusions: Prostate-targeted treatment plus metastasis-directed therapy through external beam radiation therapy can result in favorable long-term disease-free and survival outcomes with acceptable morbidities among synchronous oligometastatic prostate cancer patients. Therefore, this approach may represent a promising treatment strategy for this population. Further investigation is required.

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  68. Complete Remission of Metastatic Renal Cell Carcinoma with Invasion of the Duodenum and Pancreas after Treatment with Nivolumab Plus Ipilimumab Followed by Axitinib and Surgery : A Case Report

    HAGIMOTO Hiroki, YAMAZAKI Toshinari, KASHIMA Soki, YOSHINO Takayuki, GOTO Takayuki, SANO Takeshi, SAWADA Atsuro, AKAMATSU Shusuke, KOBAYASHI Takashi, NAKANO Kenzo, YAGI Shintaro, MATSUOKA Yui, FUJIMOTO Masakazu, KITAMURA Takaaki, OGAWA Osamu

      Vol. 67 ( 5 ) page: 197 - 203   2021.5

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    A man in his 60s was diagnosed with clear cell carcinoma of the right kidney with multiple lung metastases, tumor thrombus of the inferior vena cava (IVC), and invasion of the duodenum and pancreas. Ipilimumab plus nivolumab was administered as first-line therapy. After 3 treatment courses, computed tomography (CT) demonstrated a slight decrease in the size of the primary tumor and lung metastases. However, the patient became hemodynamically unstable due to persistent duodenal bleeding during treatment despite frequent blood transfusions. Axitinib was then initiated as second-line therapy. The duodenal bleeding ceased 10 days after starting axitinib and his anemia remissed. Subsequent CT showed further decrease in the size of the primary tumor and lung metastases. The patient underwent right nephrectomy after improvement of nutrition. IVC thrombectomy, and pancreaticoduodenectomy. The lung metastases disappeared on postoperative imaging and no additional treatment was provided. Twelve months after surgery, he was in good health and showed no signs of recurrence.

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  69. Protocol for development and validation of a prediction model for 5-year risk of incident overactive bladder in the general population: the Nagahama study

    Funada Satoshi, Luo Yan, Yoshioka Takashi, Setoh Kazuya, Tabara Yasuharu, Negoro Hiromitsu, Akamatsu Shusuke, Yoshimura Koji, Matsuda Fumihiko, Furukawa Toshi A., Efthimiou Orestis, Ogawa Osamu

    BMC UROLOGY   Vol. 21 ( 1 ) page: 78   2021.5

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    Background: An accurate prediction model could identify high-risk subjects of incident Overactive bladder (OAB) among the general population and enable early prevention which may save on the related medical costs. However, no efficient model has been developed for predicting incident OAB. In this study, we will develop a model for predicting the onset of OAB at 5-year in the general population setting. Methods: Data will be obtained from the Nagahama Cohort Project, a longitudinal, general population cohort study. The baseline characteristics were measured between Nov 28, 2008 and Nov 28, 2010, and follow-up was performed every 5 years. From the total of 9,764 participants (male: 3,208, female: 6,556) at baseline, we will exclude participants who could not attend the follow-up assessment and those who were defined as having OAB at baseline. The outcome will be incident OAB defined using the Overactive Bladder Symptom Score (OABSS) at follow-up assessment. Baseline questionnaires (demographic, health behavior, comorbidities and OABSS) and blood test data will be included as predictors. We will develop a logistic regression model utilizing shrinkage methods (LASSO penalization method). Model performance will be evaluated by discrimination and calibration. Net benefit will be evaluated by decision curve analysis. We will perform an internal validation and a temporal validation of the model. We will develop a web-based application to visualize the prediction model and facilitate its use in clinical practice. Discussion: This will be the first study to develop a model to predict the incidence of OAB.

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  70. A Case of Pelvic Unicentric Castleman Disease Treated by Preoperative Transcatheter Arterial Embolization and Tumor Complete Resection with Combined Lower Abdominal and Posterior Approach

    SUZUKI Ryosuke, GOTO Takayuki, BANNO Haruka, FUCHIGAMI Yasushi, HIDA Takuya, FUJIWARA Maki, YOSHINO Takayuki, KITA Yuki, SAWADA Atsuro, AKAMATSU Shusuke, SAITO Ryoichi, KOBAYASHI Takashi, YAMAZAKI Toshinari, INOUE Takahiro, SHIMIZU Hironori, KURATA Mariyo, MAEDA Hirona, OKAMOTO Takeshi, TOGUCHIDA Junya, OGAWA Osamu

      Vol. 67 ( 4 ) page: 157 - 162   2021.4

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    A 22-year-old woman was referred to our hospital for further examination of an incidentally discovered hypervascular pelvic tumor with a maximum diameter of 10 cm. Although Castleman disease was suspected based on the imaging findings and pathologic findings of the needle biopsy, a definitive diagnosis was not made. Preoperative transcatheter arterial embolization was performed to decrease intraoperative bleeding, and tumor resection was performed on the following day. As for posterior approach prior to anterior approach, the patient was placed in a prone position, and the dorsal aspect of tumor was approached through the dissection of gluteal muscles. Then, dilated branches of the internal iliac vein was found on the tumor capsule, which were safely ligated under direct vision with favorable visual field. Then, the patient was placed in a supine position, the tumor was completely resected by anterior approach without transfusion. Histopathological diagnosis was Castleman disease hyaline vascular type. The patient was discharged without complication and has been free from recurrence for 6 months after surgery.

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  71. 特集 前立腺癌のバイオロジーと最新の治療-いま起こりつつあるパラダイムシフト 〈基礎〉 難治性前立腺癌の分子メカニズム

    赤松 秀輔

    臨床泌尿器科   Vol. 75 ( 5 ) page: 280 - 282   2021.4

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    DOI: 10.11477/mf.1413207218

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  72. Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer

    Shiota Masaki, Akamatsu Shusuke, Narita Shintaro, Terada Naoki, Fujimoto Naohiro, Eto Masatoshi

    JMA Journal   Vol. 4 ( 2 ) page: 99 - 111   2021.4

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    <p>The therapeutic landscape of pharmacotherapy for prostate cancer has dramatically evolved, and multiple therapeutic options have become available for prostate cancer patients. Therefore, useful biomarkers to identify suitable candidates for treatment are required to maximize the efficacy of pharmacotherapy. Genetic polymorphisms such as single-nucleotide polymorphisms (SNPs) and tandem repeats have been shown to influence the therapeutic effects of pharmacotherapy for prostate cancer patients. For example, genetic polymorphisms in the genes involved in androgen receptor signaling are reported to be associated with the therapeutic outcome of androgen-deprivation therapy as well as androgen receptor-pathway inhibitors. In addition, SNPs in genes involved in drug metabolism and efflux pumps are associated with therapeutic effects of taxane chemotherapy. Thus, genetic polymorphisms such as SNPs are promising biomarkers to realize personalized medicine. Here, we overview the current findings on the influence of genetic polymorphisms on the outcome of pharmacotherapy for prostate cancer and discuss current issues as well as future visions in this field.</p>

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  73. A CASE of PELVIC UNICENTRIC CASTLEMAN DISEASE TREATED by PREOPERATIVE TRANSCATHETER ARTERIAL EMBOLIZATION and TUMOR COMPLETE RESECTION with COMBINED LOWER ABDOMINAL and POSTERIOR APPROACH

    Suzuki R., Goto T., Banno H., Fuchigami Y., Hattahara K., Hida T., Fuziwara M., Yoshino T., Kjta Y., Sawada A., Akamatsu S., Saito R., Kobayashi T., Yamasaki T., Inoue T., Shimizu H., Maeda H., Kurata M., Okamoto T., Toguchida J., Ogawa O.

    Acta Urologica Japonica   Vol. 67 ( 4 ) page: 157 - 162   2021.4

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    A 22-year-old woman was referred to our hospital for further examination of an incidentally discovered hypervascular pelvic tumor with a maximum diameter of 10 cm. Although Casdeman disease was suspected based on the imaging findings and padiologic findings of the needle biopsy, a definitive diagnosis was not made. Preoperative transcatheter arterial embolization was performed to decrease intraoperative bleeding, and tumor resection was performed on the following day. As for posterior approach prior to anterior approach, the patient was placed in a prone position, and the dorsal aspect of tumor was approached through the dissection of gluteal muscles. Then, dilated branches of the internal iliac vein was found on die tumor capsule, which were safely ligated under direct vision widi favorable visual field. Then, the patient was placed in a supine position, the tumor was completely resected by anterior approach without transfusion. Histopathological diagnosis was Casdeman disease hyaline vascular type. The patient was discharged without complication and has been free from recurrence for 6 months after surgery.

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  74. A narrative review of urinary phospholipids: from biochemical aspect towards clinical application

    Li Xin, Nakayama Kenji, Goto Takayuki, Akamatsu Shusuke, Kobayashi Takashi, Shimizu Koji, Ogawa Osamu, Inoue Takahiro

    TRANSLATIONAL ANDROLOGY AND UROLOGY   Vol. 10 ( 4 ) page: 1829 - 1849   2021.4

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    As a newly emerged discipline, lipidomic studies have focused on the comprehensive characterization and quantification of lipids in a given biological system, which has remarkably advanced in recent years owing to the rapid development of analytical techniques, especially mass spectrometry. Among diverse lipid classes, phospholipids, which have fundamental roles in the formation of cellular membranes, signaling processes, and bioenergetics have gained momentum in several fields of research. The altered composition, concentration, spatial distribution, and metabolism of phospholipids in cells, tissues, and body fluids have been elucidated in various human diseases such as cancer, inflammation, as well as cardiovascular and metabolic disorders. Among the different kinds of phospholipid sources in the human body, urine has not been extensively investigated in recent years owing to the extremely low concentrations of phospholipids and high levels of salts and other contaminants, which can interfere with precise detection. However, with profound advances and rapid expansion in analytical methods, urinary phospholipids have attracted increasing attention in current biomedical research as urine is an easily available source for the discovery of noninvasive biomarkers. In this review, we provide an overview of urinary phospholipids, including their biochemical aspects and clinical applications, aimed at promoting this field of research.

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  75. p2PSA-associated parameters are significant predictors of reclassification of first-year protocol biopsy on active surveillance for early-stage prostate cancer patients: From the PRIAS-JAPAN study.

    Kato Takuma, Sugimoto Mikio, Kakehi Yoshiyuki, Shinohara Nobuo, Egawa Shin, Sasaki Hiroshi, Saito Toshihiro, Tanikawa Toshiki, Matsumura Masafumi, Hashine Katsuyoshi, Akamatsu Shusuke, Ogawa Osamu, Hara Isao

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 39 ( 6 )   2021.2

  76. Analysis of genetic rare variants in Japanese advanced prostate cancer patients.

    Kimura Hiroko, Mizuno Kei, Narita Shintaro, Shiota Masaki, Fujimoto Naohiro, Terada Naoki, Goto Takayuki, Kobayashi Takashi, Kamoto Toshiyuki, Eto Masatoshi, Habuchi Tomonori, Nakagawa Hidewaki, Ogawa Osamu, Akamatsu Shusuke

    CANCER SCIENCE   Vol. 112   page: 657 - 657   2021.2

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  77. CDK12 null prostate cancer cell line LNCaP shows reduced growth potential

    Kamiyama Yuki, Akamatsu Shusuke, Sunada Takuro, Kouno Yuka, Kimura Hiroko, Lee Xin, Mizuno Kei, Matsuoka Takashi, Goto Takayuki, Kobayashi Takashi, Ogawa Osamu

    CANCER SCIENCE   Vol. 112   page: 846 - 846   2021.2

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  78. Identification of twelve new susceptibility loci and polygenic risk for prostate cancer in Japanese population

    Takata Ryo, Akamatsu Shusuke, Nakagawa Hidewaki, Takahashi Atsushi, Egawa Shin, Kamatani Yoichiro, Inazawa Johji, Ogawa Osamu, Obara Wataru

    CANCER SCIENCE   Vol. 112   page: 321 - 321   2021.2

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  79. Genomic landscape of metastatic hormone-naive prostate cancer

    Mizuno Kei, Akamatsu Shusuke, Goto Takayuki, Kobayashi Takashi, Ogawa Osamu

    CANCER SCIENCE   Vol. 112   page: 656 - 656   2021.2

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  80. Establishment of organoids from patients-derived xenografts (PDX) of castration resistant prostate cancer(CRPC)

    Sunada Takuro, Fukui Tomohiro, Kohno Yuka, Kamiyama Yuki, Kimura Hiroko, Li Xin, Matsuoka Takashi, Mizuno Kei, Nakayama Kenji, Goto Takayuki, Akamatsu Shusuke, Kobayashi Takashi, Ogawa Osamu

    CANCER SCIENCE   Vol. 112   page: 613 - 613   2021.2

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  81. Differential effects of WEE1 blockade in urothelial carcinoma in the context of TP53 status

    Sakatani Toru, Murakami Kaoru, Nakamura Kenji, Hamada Akihiro, Mizuno Kei, Matsumoto Keiyu, Sano Takeshi, Goto Takayuki, Akamatsu Shusuke, Saito Ryoichi, Kobayashi Takashi, Tsuruyama Tatsuaki, Inoue Takahiro, Ogawa Osamu

    CANCER SCIENCE   Vol. 112   page: 898 - 898   2021.2

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  82. Increased risk of disease progression in younger men: Analysis of factors predicting biochemical failure and castration-resistant prostate cancer after high-dose intensity-modulated radiation therapy for nonmetastatic prostate cancer

    Aizawa Rihito, Takayama Kenji, Nakamura Kiyonao, Inoue Takahiro, Yamasaki Toshinari, Kobayashi Takashi, Akamatsu Shusuke, Ogawa Osamu, Mizowaki Takashi

    UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS   Vol. 39 ( 2 ) page: 131.e9 - 131.e15   2021.2

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    Background: The aim of this study was to investigate the clinical significance of the effect of age on disease control in men who received high-dose intensity-modulated radiation therapy (IMRT) for nonmetastatic prostate cancer (NMPCa). Methods: NMPCa patients with favorable intermediate to very high-risk features (National Comprehensive Cancer Network risk classification) treated with IMRT at our institution between September 2000 and May 2011 were analyzed retrospectively. Treatment consisted of high-dose IMRT (74–78 Gy/37–39 fractions) combined with 6 months of neoadjuvant hormonal therapy. Multivariable analysis using Fine and Gray's regression model was performed to evaluate whether age at initiation of IMRT was associated with biochemical failure (BF) and castration-resistant prostate cancer (CRPC) progression. Results: A total of 367 patients were analyzed. The median follow-up period was 8.8 years after IMRT. The 5- and 10-year BF rates were 22.1 and 31.7%, and those of CRPC rates were 4.5 and 12.6%, respectively. Multivariable analysis revealed that a younger age (cut-off: 70 years old) at the initiation of IMRT was significantly correlated with both a higher BF rate (hazard ratio: 1.691, P= 0.0064) and higher CRPC rate (hazard ratio: 2.579, P = 0.0079). Conclusions: Younger men with NMPCa had increased risks of BF and CRPC after high-dose IMRT, and may benefit from more intensive treatments. Our findings should be further tested in prospective studies.

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  83. The Urinary Phosphatidylcholine/Lysophosphatidylcholine Ratio as a Novel Diagnostic Index for Prostate Cancer

    Li Xin, Nakayama Kenji, Goto Takayuki, Kimura Hiroko, Akamatsu Shusuke, Hayashi Yujiro, Fujita Kazutoshi, Kobayashi Takashi, Nonomura Norio, Ogawa Osamu, Inoue Takahiro

    CANCER SCIENCE   Vol. 112   page: 772 - 772   2021.2

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  84. Tumor exosomes derived from bone-tropic renal cell carcinoma cell lines induce blood vessel formation in bone marrow.

    Takeda Masashi, Akamatsu Shusuke, Yamasaki Toshinari, Fukui Tomohiro, Haitani Takao, Goto Takayuki, Sakamoto Hiromasa, Kobayashi Takashi, Ueda Koji, Ogawa Osamu

    CANCER SCIENCE   Vol. 112   page: 713 - 713   2021.2

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  85. Clinical feasibility and acceptability of adding cognitive behavioral therapy to pharmacotherapy for drug-resistant overactive bladder in women: A single-arm pilot study

    Funada Satoshi, Watanabe Norio, Goto Takayuki, Negoro Hiromitsu, Akamatsu Shusuke, Uozumi Ryuji, Kishimoto Sanae, Ichioka Kentaro, Segawa Takehiko, Furukawa Toshi A., Ogawa Osamu

    LUTS-LOWER URINARY TRACT SYMPTOMS   Vol. 13 ( 1 ) page: 69 - 78   2021.1

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    Objectives: Drug-resistant overactive bladder (OAB) represents an unmet medical need in that treatment options are limited. We developed a treatment model based on cognitive behavioral therapy and evaluated its feasibility and acceptability for drug-resistant OAB in women. Methods: This was an open-label, single-arm, multicenter pilot study. We defined drug-resistant OAB as OAB with moderate to severe symptoms despite pharmacotherapy for more than 12 weeks. A face-to-face intervention was prescribed as six sessions (30 minutes each) over 6 to 12 weeks according to a treatment manual. The effects were assessed by self-reported questionnaires and frequency voiding charts (FVC) at baseline, during intervention, immediately after intervention, and at follow-up. Results: Ten patients participated in this study. Median age was 72 years, median OAB Symptom Score was nine points, and median duration of prior treatment for OAB was 5.5 years at baseline. Two participants dropped out of the study. Among the remaining patients, the scores of the OAB Questionnaire subscales improved (effect size: 0.75-1.73), and the mean urinary frequency in the FVC also improved from baseline (9.0 times, SD: 2.1) to follow-up (6.2 times, SD: 1.2). All participants were satisfied with the intervention. There were no adverse events during this study. Conclusions: The new treatment based on cognitive behavioral therapy was well tolerated and feasible in women with drug-resistant OAB. Further randomized research is needed to rigorously evaluate the efficacy of the treatment.

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  86. Functional and genomic characterization of patient-derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma

    Sakamoto Hiromasa, Yamasaki Toshinari, Sumiyoshi Takayuki, Takeda Masashi, Shibasaki Noboru, Utsunomiya Noriaki, Arakaki Ryuichiro, Akamatsu Shusuke, Kobayashi Takashi, Inoue Takahiro, Kamba Tomomi, Nakamura Eijiro, Ogawa Osamu

    CANCER MEDICINE   Vol. 10 ( 1 ) page: 119 - 134   2021.1

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    Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus-resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.

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  87. Modification of Platinum-based Systemic Chemotherapy for Advanced Urothelial Carcinoma in Patients With Suboptimal Renal Function

    Hamada Akihiro, Sano Takeshi, Matsumoto Keiyu, Sakatani Toru, Nakamura Kenji, Sawada Atsuro, Akamatsu Shusuke, Matsui Yoshiyuki, Ogawa Osamu, Kobayashi Takashi

    IN VIVO   Vol. 35 ( 5 ) page: 2821 - 2829   2021

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    Background/Aim: Standard chemotherapy for advanced urothelial carcinoma (UC) patients with moderate renal dysfunction has not yet been established. Patients and Methods: We retrospectively assessed outcomes of patients with advanced UC who underwent first-line chemotherapy with full-/reduced-dose gemcitabine plus cisplatin (GC-f/GCr) or full-/reduced-dose gemcitabine plus carboplatin (GCar- f/G-Car-r) according to renal function. Results: Seventyeight patients were included in this study. The objective response rate was 42%, 30%, 42%, and 27% for the GC-f, GC-r, G-Car-f, and G-Car-r groups, respectively. For the GC-r and G-Car-f groups, the median progression-free survival and the median overall survival was 4.5 vs. 7.0 months (p=0.07) and 7.5 months vs. 12.0 months (p=0.124), respectively. Grade 3/4 thrombocytopenia occurred more frequently in the GC-r group than the G-Car-f group (80% vs. 38%, p=0.021). Conclusion: G-Car-f could be more beneficial than GC-r for patients with advanced UC who have moderate renal dysfunction.

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  88. Reply by Authors

    Funada S., Tabara Y., Setoh K., Negoro H., Akamatsu S., Yoshino T., Yoshimura K., Watanabe N., Furukawa T.A., Matsuda F., Ogawa O.

    The Journal of urology   Vol. 204 ( 5 ) page: 1002   2020.11

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  89. Impact of Nocturia on Mortality: The Nagahama Study

    Funada Satoshi, Tabara Yasuharu, Setoh Kazuya, Negoro Hiromitsu, Akamatsu Shusuke, Yoshino Takayuki, Yoshimura Koji, Watanabe Norio, Furukawa Toshi A., Matsuda Fumihiko, Ogawa Osamu

    JOURNAL OF UROLOGY   Vol. 204 ( 5 ) page: 996 - 1001   2020.11

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    PURPOSE: Nocturia has been reported as a risk factor for mortality. However, evidence is limited and has a high risk of bias. We evaluated the association between nocturia and mortality using longitudinal data from the general Japanese population. MATERIALS AND METHODS: Data were obtained from the Nagahama Cohort Project, a longitudinal, general population cohort study. Nocturia was measured using the International Prostate Symptom Score. Mortality data were obtained from the Basic Resident Register in Nagahama City. We used Cox proportional hazard models and time-varying covariates at baseline and 5-year followup to analyze the association between nocturia and mortality. RESULTS: We analyzed 9,762 participants (median age 56.8 years, male 32.8%). The prevalence rates of nocturnal voiding at 0, 1, 2 and 3 or more times were 44.3%, 39.1%, 11.7% and 4.9%, respectively. A total of 263 participants died. Followup assessment was performed 3,224 (SD 537) days after baseline. According to multivariable Cox proportional hazard regressions, mortality increased dose dependently with the nocturnal voiding frequency as HR 1.46 for 1 time (95% CI 1.02-2.09), HR 1.85 for 2 times (95% CI 1.23-2.77) and HR 2.06 (95% CI 1.28-3.32) for 3 or more times in comparison with 0 times (p for trend=0.00084). In the time varying Cox proportional hazard regression the association was still significant (p for trend=0.0017). CONCLUSIONS: According to this longitudinal study with a low incidence of missing data and high representation of the general population, nocturia is associated with mortality.

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  90. Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion, and Survival of Bladder Cancer

    Kawai Yoshihisa, Imada Kenjiro, Akamatsu Shusuke, Zhang Fan, Seiler Roland, Hayashi Tetsutaro, Leong Jeffrey, Beraldi Eliana, Saxena Neetu, Kretschmer Alexander, Oo Htoo Zarni, Contreras-Sanz Alberto, Matsuyama Hideyasu, Lin Dong, Fazli Ladan, Collins Colin C., Wyatt Alexander W., Black Peter C., Gleave Martin E.

    MOLECULAR CANCER THERAPEUTICS   Vol. 19 ( 10 ) page: 2210 - 2220   2020.10

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    Paternally expressed gene 10 (PEG10) has been associated with neuroendocrine muscle-invasive bladder cancer (MIBC), a subtype of the disease with the poorest survival. In this work, we further characterized the expression pattern of PEG10 in The Cancer Genome Atlas database of 412 patients with MIBC, and found that, compared with other subtypes, PEG10 mRNA level was enhanced in neuroendocrine-like MIBC and highly correlated with other neuroendocrine markers. PEG10 protein level also associated with neuroendocrine markers in a tissue microarray of 82 cases. In bladder cancer cell lines, PEG10 expression was induced in drug-resistant compared with parental cells, and knocking down of PEG10 resensitized cells to chemotherapy. Loss of PEG10 increased protein levels of cell-cycle regulators p21 and p27 and delayed G1–S-phase transition, while overexpression of PEG10 enhanced cancer cell proliferation. PEG10 silencing also lowered levels of SLUG and SNAIL, leading to reduced invasion and migration. In an orthotopic bladder cancer model, systemic treatment with PEG10 antisense oligonucleotide delayed progression of T24 xenografts. In summary, elevated expression of PEG10 in MIBC may contribute to the disease progression by promoting survival, proliferation, and metastasis. Targeting PEG10 is a novel potential therapeutic approach for a subset of bladder cancers.

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  91. Bone tropic renal cell carcinoma cell lines-derived exosomes induce blood vessel formation in bone marrow

    Takeda Masashi, Akamatsu Shusuke, Yamasaki Toshinari, Fukui Tomohiro, Haitani Takao, Goto Takayuki, Sakamoto Hiromasa, Kobayashi Takashi, Ueda Koji, Ogawa Osamu

    INTERNATIONAL JOURNAL OF UROLOGY   Vol. 27   page: 75 - 75   2020.10

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  92. Solitary recurrence of prostate cancer surrounded by seminal vesicle/vas deferens-like epithelium.

    Takamori H, Kamba T, Sumiyoshi S, Tsuzuki T, Kashima S, Yoshino T, Sano T, Goto T, Sawada A, Akamatsu S, Kobayashi T, Yamasaki T, Mizowaki T, Ogawa O, Inoue T

    IJU case reports   Vol. 3 ( 5 ) page: 171 - 173   2020.9

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  93. Cognitive behavioral therapy for overactive bladder in women: study protocol for a randomized controlled trial

    Funada Satoshi, Watanabe Norio, Goto Takayuki, Negoro Hiromitsu, Akamatsu Shusuke, Ueno Kentaro, Uozumi Ryuji, Ichioka Kentaro, Segawa Takehiko, Akechi Tatsuo, Furukawa Toshiaki A., Ogawa Osamu

    BMC UROLOGY   Vol. 20 ( 1 ) page: 129   2020.8

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    Background: Overactive bladder (OAB) symptoms affect daily life by decreasing health-related quality of life (HRQol). However, there remain no very effective treatment for OAB. Pharmacotherapy is one of the best treatments, but it is not always efficient and may incur adverse events. Although behavioral therapy is another effective treatment, there are very few structured treatment manuals on how to prescribe behavioral therapy to treat OAB for whom. Cognitive behavioral therapy (CBT) is a psychotherapy consisting of structured sessions to solve problems with the collaborative empiricism between therapists and patients. OAB symptoms are supposed to worsen with cognitive distortion, and CBT is expected to be effective in treating OAB by modifying such cognitive processes. In this trial, we will evaluate the efficacy of CBT for OAB. Methods: A randomized, controlled, open-label, multicenter parallel-group superiority trial will be conducted. Participants with moderate to severe OAB symptoms with or without pharmacotherapy will be recruited and will be randomly allocated 1:1 to two different groups by minimization (age, baseline OAB severity, treatment status, types of intervention, and treating institutions). The intervention group will be prescribed an individual CBT program covering six techniques in 4 sessions (30 min each), with or without pharmacotherapy. The primary outcome is the change scores in an OAB-questionnaire (OAB-q) from baseline to the end of the trial (week 13). Secondary outcomes will include other patient reported outcome measures and the frequency volume chart. All analyses will be conducted on an intention-to-treat principle. Discussion: This trial will determine the efficacy of CBT to treat OAB using a rigorous methodology. The effectiveness of CBT with a structured manual may not only lead to a new treatment option for patients suffering from OAB symptoms, but may also reduce the social burden by OAB. Trial registration: UMIN-CTR Clinical Trial, CTR-UMIN000038513. Registered on November 7, 2019.

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  94. A case of renal cell carcinoma unclassified with medullary phenotype without detectable gene deletion (vol 69, pg 710, 2019)

    Tsuzuki Sadatoshi, Kataoka Tatsuki R., Ito Hiroaki, Ueshima Chiyuki, Asai Satsuki, Akamatsu Shunsuke, Ogawa Osamu, Yokoo Hideaki, Haga Hironori

    PATHOLOGY INTERNATIONAL   Vol. 70 ( 7 ) page: 479 - 479   2020.7

  95. Long-term clinical outcomes of salvage pelvic radiation therapy for oligo-recurrent pelvic lymph nodes after definitive external-beam radiation therapy for non-metastatic prostate cancer

    Sato Genki Edward, Aizawa Rihito, Nakamura Kiyonao, Takayama Kenji, Inoue Takahiro, Yamasaki Toshinari, Kobayashi Takashi, Akamatsu Shusuke, Ogawa Osamu, Mizowaki Takashi

    JOURNAL OF RADIATION RESEARCH   Vol. 61 ( 4 ) page: 622 - 628   2020.7

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    Although salvage external-beam radiation therapy (EBRT) is an attractive treatment option for pelvic lymph nodal recurrence (PeNR) in patients with prostate cancer (PCA), limited data are available regarding its long-term efficacy. This study examined the long-term clinical outcomes of patients who underwent salvage pelvic radiation therapy (sPRT) for oligo-recurrent pelvic lymph nodes after definitive EBRTfor non-metastatic PCA. Patientswho developed PeNRafter definitive EBRTandwere subsequently treatedwith sPRTat our institution betweenNovember 2007 and December 2015 were retrospectively analyzed. The prescribed dose was 45-50.4 Gy (1.8-2 Gy per fraction) to the upper pelvis, with up to 54-66 Gy (1.8-2 Gy per fraction) for recurrent nodes. Long-term hormonal therapy was used as neoadjuvant and/or adjuvant therapy. The study population consisted of 12 consecutive patients with PeNR after definitive EBRT (median age: 73 years). The median follow-up period was 58.9 months. The 5-year overall survival, PCA-specific survival, biochemical failure-free, clinical failure-free, and castration-resistant PCA-free rates were 82.5, 100.0, 62.3, 81.8, and 81.8%, respectively. No grade 2 or higher sPRT-related late toxicities occurred. In conclusion,more than half of the study patients treated with sPRT had a long-termdisease-free status with acceptable morbidities. Moreover, most of the patients maintained hormonal sensitivity. Therefore, this approach may be a promising treatment method for oligo-recurrent pelvic lymph nodes.

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  96. TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands

    Al Mahmud Md. Rasel, Ishii Kenichiro, Bernal-Lozano Cristina, Delgado-Sainz Irene, Toi Masakazu, Akamatsu Shusuke, Fukumoto Manabu, Watanabe Masatoshi, Takeda Shunichi, Cortes-Ledesma Felipe, Sasanuma Hiroyuki

    GENES TO CELLS   Vol. 25 ( 7 ) page: 450 - 465   2020.7

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    Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double-strand breaks (DSBs), where TOP2 homodimers covalently bind to 5′ DSB ends, called TOP2-DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase-2 (TDP2) removes 5′ TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G0/G1 phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G0/G1 phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G1 phase, and loss of TDP2 causes a five times higher number of androgen-induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2-deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs.

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  97. Longitudinal Analysis of Bidirectional Relationships between Nocturia and Depressive Symptoms: The Nagahama Study

    Funada Satoshi, Tabara Yasuharu, Negoro Hiromitsu, Akamatsu Shusuke, Yoshino Takayuki, Yoshimura Koji, Watanabe Norio, Furukawa Toshiaki A., Matsuda Fumihiko, Ogawa Osamu

    JOURNAL OF UROLOGY   Vol. 203 ( 5 ) page: 984 - 990   2020.5

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    Purpose:Although the association between nocturia and depressive symptoms has been demonstrated, the causal direction remains unclear. We investigated the directional association between nocturia and depressive symptoms using longitudinal data from the general population.Materials and Methods:This longitudinal analysis was conducted as part of the Nagahama Cohort Project, a population based cohort study, with baseline and 5-year followup investigations. Nocturnal voiding frequency and mental health were measured with self-report questionnaires, the International Prostate Symptom Score and the 5-item Mental Health Inventory. Logistic regression analyses and a cross-lagged panel analysis were performed to analyze the bidirectional association between nocturia and depressive symptoms.Results:With 9,764 participants at baseline, data from 8,285 were used in this analysis. Median age at baseline was 57.3 years and the proportion of men was 32.0%. New onset depressive symptoms and nocturia were observed among 369 and 793 participants, respectively. In adjusted logistic regression analyses we observed a clear dose-relationship between baseline nocturnal voiding frequency and new onset depressive symptoms (p for trend <0.001) and a weak association between baseline 5-item Mental Health Inventory and new onset nocturia (p for trend=0.0087). In a cross-lagged panel analysis the path coefficient from nocturnal voiding frequency to 5-item Mental Health Inventory (β=-0.06, p <0.001) was stronger than that from 5-item Mental Health Inventory to nocturnal voiding frequency (β=-0.02, p=0.047).Conclusions:This longitudinal study demonstrated a bidirectional association between nocturia and depressive symptoms. The cross-lagged path coefficient suggested that nocturia could more likely be a cause than a result of depressive symptoms.

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  98. Bladder training for treating overactive bladder in adults

    Funada S., Yoshioka T., Luo Y., Sato A., Akamatsu S., Watanabe N.

    Cochrane Database of Systematic Reviews   Vol. 2020 ( 4 )   2020.4

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    This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:. To assess the effects of bladder training for treating adults with OAB; and summarise the principal findings of relevant economic evaluations of this intervention.

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  99. Detectability of prostate cancer in different parts of the gland with 3-Tesla multiparametric magnetic resonance imaging: correlation with whole-mount histopathology

    Ito Katsuhiro, Furuta Akihiro, Kido Akira, Teramoto Yuki, Akamatsu Shusuke, Terada Naoki, Yamasaki Toshinari, Inoue Takahiro, Ogawa Osamu, Kobayashi Takashi

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 25 ( 4 ) page: 732 - 740   2020.4

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    Background: We investigated whether the detectability of prostate cancer with 3-Tesla (3T) multiparametric magnetic resonance imaging (mpMRI) differs by tumor location. Methods: We identified 136 patients with prostate cancer who underwent 3-T mpMRI before prostatectomy at a single academic center. Two uroradiologists scored all MRIs with Prostate Imaging–Reporting and Data System version 2 (PI-RADS v2). A genitourinary pathologist mapped tumor foci from serial whole-mount radical prostatectomy sections. We assessed concordance of images with cancer sites. Tumor foci with Gleason score ≥ 3 + 4 or volume ≥ 0.5 mL were considered significant. Results: A total of 122 foci in 106 cases were identified with mpMRI. Twenty-four were PI-RADS 3, 52 were 4, and 46 were 5. A total of 274 tumor foci were identified with whole-mount pathology. The sensitivity stratified by location to detect significant cancer with a PI-RADS cutoff value of 3 was 56.0% overall, 50.0% in the peripheral zone (PZ), 71.2% in the transitional zone (TZ), 62.4% anterior, 49.5% posterior, 42.0% apical, 63.6% in the midgland, and 43.8% in the gland base. In multivariate analysis, tumor location was not a significant predictor of identification by mpMRI. Tumor volume, Gleason score, and index tumor status were significantly associated with identification by mpMRI. Conclusions: mpMRI detected the majority of high-grade and large cancers, but had low sensitivity in the PZ, posterior, and apex and base of the gland. The high prevalence of low-volume, low-Gleason score index tumors, as well as satellite tumors in those areas, accounted for the difference.

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  100. Low incidence of late recurrence in patients with intermediate-risk prostate cancer treated by intensity-modulated radiation therapy plus short-term androgen deprivation therapy

    Aizawa Rihito, Takayama Kenji, Nakamura Kiyonao, Inoue Takahiro, Yamasaki Toshinari, Kobayashi Takashi, Akamatsu Shusuke, Ogawa Osamu, Mizowaki Takashi

      Vol. 25   page: 713 - 719   2020.4

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    Objectives: This study evaluated the long-term outcomes of intensity-modulated radiation therapy (IMRT) combined with short-term neoadjuvant androgen deprivation therapy (ADT) in patients with intermediate-risk (IR) prostate cancer (PCa). Materials and methods: Patients with IR PCa treated with IMRT at our institution between September 2000 and November 2010 were analyzed retrospectively. The treatment consisted of IMRT (70–78 Gy in 35–39 fractions) combined with 6 months of neoadjuvant ADT. Salvage ADT was initiated when the prostate-specific antigen level was > 4.0 ng/mL Results: In total, 106 consecutive patients with IR PCa (median age: 70 years old) were analyzed. The median follow-up period was 8.0 years. The overall survival, PCa-specific survival, biochemical failure, and clinical failure rates were 99.0%, 100.0%, 6.8%, and 1.9% at 5 years and 89.1%, 100.0%, 11.3%, and 2.9% at 10 years, respectively. Late recurrence (> 5 years) was observed in three cases (2.8%). The cumulative incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicities (grade 2/3) were 10.5% and 5.8% at 5 years, and 14.7% and 5.8% at 10 years, respectively. No patient developed grade 4/5 GU toxicities or grade 3–5 GI toxicities. Conclusion: IMRT at a dose up to 78 Gy combined with short-term neoadjuvant ADT resulted in excellent long-term disease-free outcomes with acceptable morbidities among patients with IR PCa. In addition, the incidence of late recurrence was very low. Further investigation is warranted to confirm our findings.

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  101. Low incidence of late recurrence in patients with intermediate-risk prostate cancer treated by intensity-modulated radiation therapy plus short-term androgen deprivation therapy

    Aizawa Rihito, Takayama Kenji, Nakamura Kiyonao, Inoue Takahiro, Yamasaki Toshinari, Kobayashi Takashi, Akamatsu Shusuke, Ogawa Osamu, Mizowaki Takashi

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 25 ( 4 ) page: 713 - 719   2020.4

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    Objectives: This study evaluated the long-term outcomes of intensity-modulated radiation therapy (IMRT) combined with short-term neoadjuvant androgen deprivation therapy (ADT) in patients with intermediate-risk (IR) prostate cancer (PCa). Materials and methods: Patients with IR PCa treated with IMRT at our institution between September 2000 and November 2010 were analyzed retrospectively. The treatment consisted of IMRT (70–78 Gy in 35–39 fractions) combined with 6 months of neoadjuvant ADT. Salvage ADT was initiated when the prostate-specific antigen level was > 4.0 ng/mL Results: In total, 106 consecutive patients with IR PCa (median age: 70 years old) were analyzed. The median follow-up period was 8.0 years. The overall survival, PCa-specific survival, biochemical failure, and clinical failure rates were 99.0%, 100.0%, 6.8%, and 1.9% at 5 years and 89.1%, 100.0%, 11.3%, and 2.9% at 10 years, respectively. Late recurrence (> 5 years) was observed in three cases (2.8%). The cumulative incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicities (grade 2/3) were 10.5% and 5.8% at 5 years, and 14.7% and 5.8% at 10 years, respectively. No patient developed grade 4/5 GU toxicities or grade 3–5 GI toxicities. Conclusion: IMRT at a dose up to 78 Gy combined with short-term neoadjuvant ADT resulted in excellent long-term disease-free outcomes with acceptable morbidities among patients with IR PCa. In addition, the incidence of late recurrence was very low. Further investigation is warranted to confirm our findings.

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  102. LacdiNAc-Glycosylated Prostate-specific Antigen Density is a Potential Biomarker of Prostate Cancer

    Inoue Takahiro, Kaneko Tomonori, Muramatsu Shinichi, Kimura Hiroko, Yoshino Takayuki, Goto Takayuki, Sawada Atsuro, Akamatsu Shusuke, Kobayashi Takashi, Yamasaki Toshinari, Kaya Takatoshi, Ogawa Osamu

    CLINICAL GENITOURINARY CANCER   Vol. 18 ( 1 ) page: E28 - E36   2020.2

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    Background: Serum LacdiNAc-glycosylated prostate-specific antigen (LDN-PSA) and LDN-PSA density together with PSA and PSA density (PSAD) were measured as a diagnostic tool for prostate cancer (PCa). Patients and Methods: We included 150 patients with PCa without hormonal therapy and 41 patients without PCa obtained from the Kyoto University Hospital between 2012 and 2017. LDN-PSA levels were measured through a WFA–anti-PSA antibody sandwich immunoassay using a highly sensitive surface plasmon field-enhanced fluorescence spectroscopy (SPFS) system. Diagnostic performance of serum LDN-PSA and LDN-PSAD was evaluated by measuring the area under the receiver-operating characteristic curve (AUC). Results: The AUCs of LDN-PSA, LDN-PSAD, and PSAD levels (0.780, 0.848, and 0.835, respectively) detected in patients with PCa were significantly higher (P = .0001, P < .0001, and P < .0001, respectively) than that of PSA (0.590). Moreover, among 143 patients with PCa who received radical prostatectomy (RP), the AUCs of LDN-PSA, LDN-PSAD, and PSAD levels (0.750, 0.812, and 0.769, respectively) detected in patients with a pathologic Gleason grade group ≥ 2 were significantly higher (P = .0170, P = .0028, and P = .0003, respectively) than that of PSA (0.578). In the group comprising 35 patients who received RP with a Gleason grade group 1-graded biopsy, the LDN-PSA, LDN-PSAD, and PSAD levels were significantly different (P = .0097, P = .0024, and P = .0312, respectively). However, PSA alone could not discriminate cases with adverse features (P = .454). Conclusions: LDN-PSAD is a potential marker for detecting PCa and selecting candidates for RP.

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  103. Sequential Use of Androgen Receptor Axis-targeted Agents in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Retrospective Analysis With 3-Year Follow-up

    Kobayashi Takashi, Terada Naoki, Kimura Takahiro, Matsubara Nobuaki, Murakami Kaoru, Mori Keiichiro, Fujimoto Yumi, Akamatsu Shusuke, Inoue Takahiro, Ogawa Osamu

    CLINICAL GENITOURINARY CANCER   Vol. 18 ( 1 ) page: E46 - E54   2020.2

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    We performed a multicenter retrospective study on patients with chemotherapy-naive castration-resistant prostate cancer who underwent sequential treatment with androgen receptor axis-targeted agents, namely abiraterone and enzalutamide. At 3-year median follow-up, there were no significant differences in overall survival and combined progression-free survival between the 2 sequential treatments.

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  104. Add-on effects of tadalafil in tamsulosin-treated patients with small benign prostatic enlargement: A randomized, placebo-controlled, double-blind, crossover study

    Negoro Hiromitsu, Goto Takayuki, Akamatsu Shusuke, Terada Naoki, Kobayashi Takashi, Matsui Yoshiyuki, Yamamoto Takashi, Omura Tomohiro, Yonezawa Atsushi, Matsubara Kazuo, Ogawa Osamu

    NEUROUROLOGY AND URODYNAMICS   Vol. 39 ( 1 ) page: 237 - 242   2020.1

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    Aim: To assess the add-on effects of tadalafil in patients with a relatively small benign prostatic enlargement (BPE) treated with tamsulosin. Methods: From September 2014 to July 2018, we prospectively studied patients (aged 50 years or more) attending our hospital who had received tamsulosin for small BPE (20–40 mL) for 4 weeks at least and still had residual lower urinary tract symptoms (LUTS) with total International Prostate Symptom Scores (IPSS) of at least 8 and IPSS-quality of life scores at least 3. We randomized eligible patients into two groups: one of which received tadalafil 5 mg once daily for 6 weeks, followed by placebo for 6 weeks, and the other of which received placebo followed by tadalafil in the same manner. The patients were reviewed at our outpatient clinic after 2, 6, 8, and 12 weeks. Results: There were 13 patients in the tadalafil-placebo and 13 in the placebo-tadalafil group. Their median ages (range) were 70 (65-85) and 73 (50-80) years, prostatic volumes (median) 30.0 (22.0-39.7) and 32.0 (20.1-39.5) mL, and total IPSS (median) 17 (10-27) and 16 (10-24), respectively. The primary endpoints, namely mean changes of total IPSS from baseline, were 1.85 on placebo and −3.42 on tadalafil; this difference is statistically significant (difference: −1.57; 95% confidence interval: −3.00, −0.69; P =.032). We encountered no adverse effects. Conclusions: Add-on of tadalafil for symptomatic patients with small BPE treated with tamsulosin appears to be effective and safe.

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  105. Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies

    Kita Yuki, Hamada Akihiro, Saito Ryoichi, Teramoto Yuki, Tanaka Ryusuke, Takano Keishi, Nakayama Kenji, Murakami Kaoru, Matsumoto Keiyu, Akamatsu Shusuke, Yamasaki Toshinari, Inoue Takahiro, Tabata Yasuhiko, Okuno Yasushi, Ogawa Osamu, Kobayashi Takashi

    BRITISH JOURNAL OF CANCER   Vol. 121 ( 12 ) page: 1027 - 1038   2019.12

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    Background: Since the standard gemcitabine and cisplatin (GC) chemotherapy for advanced bladder cancer yields limited therapeutic effect due to chemoresistance, it is a clinical challenge to enhance sensitivity to GC. Methods: We performed high-throughput screening by using a library of known chemicals and repositionable drugs. A total of 2098 compounds were administered alone or with GC to human bladder cancer cells, and chemicals that enhanced GC effects were screened. Results: Disulfiram (DSF), an anti-alcoholism drug, was identified as a candidate showing synergistic effects with cisplatin but not with gemcitabine in multiple cell lines. Co-administration of DSF with GC affected cellular localisation of a cisplatin efflux transporter ATP7A, increased DNA–platinum adducts and promoted apoptosis. Micellar DSF nanoparticles (DSF-NP) that stabilised DSF in vivo, enhanced the inhibitory effect of cisplatin in patient-derived and cell-based xenograft models without severe adverse effects. A drug susceptibility evaluation system by using cancer tissue-originated spheroid culture showed promise in identifying cases who would benefit from DSF with cisplatin. Conclusions: The present study highlighted the advantage of drug repurposing to enhance the efficacy of anticancer chemotherapy. Repurposing of DSF to a chemotherapy sensitiser may provide additional efficacy with less expense by using an available drug with a well-characterised safety profile.

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  106. Downregulation of RalGTPase-activating protein promotes invasion of prostatic epithelial cells and progression from intraepithelial neoplasia to cancer during prostate carcinogenesis

    Uegaki Masayuki, Kita Yuki, Shirakawa Ryutaro, Teramoto Yuki, Kamiyama Yuki, Saito Ryoichi, Yoshikawa Takeshi, Sakamoto Hiromasa, Goto Takayuki, Akamatsu Shusuke, Yamasaki Toshinari, Inoue Takahiro, Suzuki Akira, Horiuchi Hisanori, Ogawa Osamu, Kobayashi Takashi

    CARCINOGENESIS   Vol. 40 ( 12 ) page: 1535 - 1544   2019.12

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    RalGTPase-activating protein (RalGAP) is an important negative regulator of small GTPases RalA/B that mediates various oncogenic signaling pathways in various cancers. Although the Ral pathway has been implicated in prostate cancer (PCa) development and progression, the significance of RalGAP in PCa has been largely unknown. We examined RalGAPα2 expression using immunohistochemistry on two independent tissue microarray sets. Both datasets demonstrated that the expression of RalGAPα2 was significantly downregulated in PCa tissues compared to adjacent benign prostatic epithelia. Silencing of RalGAPα2 by short hairpin RNA enhanced migration and invasion abilities of benign and malignant prostate epithelial cell lines without affecting cell proliferation. Exogenous expression of wild-type RalGAP, but not the GTPase-activating protein activity-deficient mutant of RalGAP, suppressed migration and invasion of multiple PCa cell lines and was phenocopied by pharmacological inhibition of RalA/B. Loss of Ralgapa2 promoted local microscopic invasion of prostatic intraepithelial neoplasia without affecting tumor growth in a Pten-deficient mouse model for prostate tumorigenesis. Our findings demonstrate the functional significance of RalGAP downregulation to promote invasion ability, which is a property necessary for prostate carcinogenesis. Thus, loss of RalGAP function has a distinct role in promoting progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma.

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  107. Kidney Auto-Transplantation for Intraoperative Right Renal Artery Injury in a Single Kidney Patient : A Case Report

    Magaribuchi Toshihiro, Kobayashi Takashi, Kamo Naoko, Kaido Toshimi, Sakai Kaoru, Teramoto Yuki, Ito Katsuhiro, Kubota Masashi, Takada Hideaki, Sawada Atsuro, Akamatsu Shusuke, Yamasaki Toshinari, Inoue Takahiro, Yanagita Motoko, Uemoto Shinji, Ogawa Osamu

      Vol. 65 ( 11 ) page: 455 - 458   2019.11

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    A man in his 70's who had undergone left radical nephrectomy for kidney cancer had the right renal artery ablated unexpectedly during pancreatoduodenectomy for a huge duodenal tumor. For this intraoperative emergency, an autologous kidney transplantation was performed with the right kidney being removed, perfused, and transplanted into the right iliac fossa. Warm ischemic time was over 2 hours. The patient developed postoperative hemorrhagic infarction of a renal artery branch, which was successfully treated with intravascular intervention. The patient was weaned off hemodialysis and was discharged in 16 weeks postoperatively.

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  108. Post-Operative Urethral Stricture after Holmium Laser Enucleation of the Prostate

    Imai Kazuto, Negoro Hiromitsu, Takashima Yasushi, Goto Takayuki, Sawada Atsuro, Akamatsu Shusuke, Saito Ryoichi, Kobayashi Takashi, Yamasaki Toshinari, Inoue Takahiro, Ogawa Osamu

      Vol. 65 ( 11 ) page: 445 - 449   2019.11

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    Holmium laser enucleation of the prostate (HoLEP) is a safe and effective surgical procedure for patients suffering from comparatively larger benign prostatic hyperplasia. However, the rate of postoperative urethral stricture (POUS) is relatively high, which can render further invasive intervention. Here we assessed the POUS rate, riskfactors and outcomes in 206 patients with benign prostatic hyperplasia who underwent HoLEP at our hospital between January 2006 and December 2015. POUS was observed in 24 patients (11.7%). The rate of intraoperative urethral stricture was significantly higher in the patients with POUS (8 out of 24 patients, 33.3%) than in those without POUS (12 out of 186 patients, 6.6%). The odds ratio was 7.08, 95% and combination index (CI) was 2.53-19.9, p<0.001). The relative riskfor POUS based on intraoperative urethral stricture was 4.65 (95% CI : 2.28-9.48). The most common POUS site was external urethral orifice (12 out of 24 cases). The POUS onset was significantly earlier in patients with external urethral orifice than the other sites (p=0.0389). The site of postoperative stricture concurred with that of intraoperative stricture at a high rate (7 out of 8 patients). Significant differences were observed between patients with and without POUS within one month in international prostate symptom score, quality of life score and in Qmax after the operation, while they were improved by simple interventions such as bougie. In conclusion, we should consider the possibility of POUS when the patient had an intraoperative stricture in HoLEP.

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  109. Kidney auto-transplantation for intraoperative right renal artery injury in a single kidney patient: A case report

    Magaribuchi T., Kobayashi T., Kamo N., Kaido T., Sakai K., Teramoto Y., Ito K., Kubota M., Takada H., Sawada A., Akamatsu S., Yamasaki T., Inoue T., Yanagita M., Uemoto S., Ogawa O.

    Acta Urologica Japonica   Vol. 65 ( 11 ) page: 455 - 458   2019.11

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    A man in his 70's who had undergone left radical nephrectomy for kidney cancer had the right renal artery ablated unexpectedly during pancreatoduodenectomy for a huge duodenal tumor. For this intraoperative emergency, an autologous kidney transplantation was performed with the right kidney being removed, perfused, and transplanted into the right iliac fossa. Warm ischemic time was over 2 hours. The patient developed postoperative hemorrhagic infarction of a renal artery branch, which was successfully treated with intravascular intervention. The patient was weaned off hemodialysis and was discharged in 16 weeks postoperatively.

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  110. Post-operative urethral stricture after holmium laser enucleation of the prostate

    Imai K., N'Egoro H., Takashima Y., Goto T., Sawada A., Akamatsu S., Saito R., Kobayashi T., Yamasaki T., Inoue T., Ogawa O.

    Acta Urologica Japonica   Vol. 65 ( 11 ) page: 445 - 449   2019.11

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    Holmium laser enucleation of the prostate (HoLEP) is a safe and effective surgical procedure for patients suffering from comparatively larger benign prostatic hyperplasia. However, the rate of postoperative urethral stricture (POUS) is relatively high, which can render further invasive intervention. Here we assessed the POUS rate, risk factors and outcomes in 206 patients with benign prostatic hyperplasia who underwent HoLEP at our hospital between January 2006 and December 2015. POUS was observed in 24 patients (11.7%). The rate of intraoperative urethral stricture was significandy higher in the patients with POUS (8 out of 24 pauents, 33.3%) than in those without POUS (12 out of 186 patients, 6.6%). The odds ratio was 7.08, 95% and combination index (CI) was 2.53-19.9, p< 0.001). The relative risk for POUS based on intraoperative urethral stricture was 4.65 (95% CI: 2.28-9.48). The most common POUS site was external urethral orifice (12 out of 24 cases). The POUS onset was significantly earlier in patients with external urethral orifice than the other sites (p = 0.0389). The site of postoperative stricture concurred with that of intraoperative stricture at a high rate (7 out of 8 patients). Significant differences were observed between patients with and without POUS within one month in international prostate symptom score, quality of life score and in Qmax after the operation, while they were improved by simple interventions such as bougie. In conclusion, we should consider the possibility of POUS when the patient had an intraoperative stricture in HoLEP.

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  111. Clinical Effect of Nivolumab on Advanced Renal Cell Carcinoma with Peritoneal Metastasis

    Hida Takuya, Yamasaki Toshinari, Banno Haruka, Fuchigami Yasushi, Hattahara Kodai, Fujiwara Maki, Suzuki Ryosuke, Kita Yuki, Yoshino Takayuki, Goto Takayuki, Sawada Atsuro, Akamatsu Shusuke, Saito Ryoichi, Kobayashi Takashi, Inoue Takahiro, Ogawa Osamu

      Vol. 65 ( 10 ) page: 413 - 419   2019.10

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    Peritoneal dissemination or metastasis is a relatively rare presentation of renal cell carcinoma. We report four cases of advanced renal cell carcinoma with peritoneal metastases treated with nivolumab. Three cases showed an objective response in the metastatic lesions including peritoneal sites. After nivolumab administration, the computed tomography scan showed a transient enlargement of peritoneal lesions in two cases, which could be considered as pseudoprogression. Temporal changes of neutrophil-tolymphocyte ratio, C-reactive protein, and eosinophil ratio during the clinical course reflected the treatment effect of nivolumab in these patients, indicating that these could be potential biomarkers of the response. To our knowledge, this is the first case series showing therapeutic activity of nivolumab against peritoneal metastases in patients with renal cell carcinoma.

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  112. eVIDENCE: a practical variant filtering for low-frequency variants detection in cell-free DNA

    Mizuno Kei, Akamatsu Shusuke, Sumiyoshi Takayuki, Wong Jing Hao, Fujita Masashi, Maejima Kazuaki, Nakano Kaoru, Ono Atushi, Aikata Hiroshi, Ueno Masaki, Hayami Shinya, Yamaue Hiroki, Chayama Kazuaki, Inoue Takahiro, Ogawa Osamu, Nakagawa Hidewaki, Fujimoto Akihiro

    SCIENTIFIC REPORTS   Vol. 9 ( 1 ) page: 15017   2019.10

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    Plasma cell-free DNA (cfDNA) testing plays an increasingly important role in precision medicine for cancer. However, circulating cell-free tumor DNA (ctDNA) is highly diluted by cfDNA from non-cancer cells, complicating ctDNA detection and analysis. To identify low-frequency variants, we developed a program, eVIDENCE, which is a workflow for filtering candidate variants detected by using the ThruPLEX tag-seq (Takara Bio), a commercially-available molecular barcoding kit. We analyzed 27 cfDNA samples from hepatocellular carcinoma patients. Sequencing libraries were constructed and hybridized to our custom panel targeting about 80 genes. An initial variant calling identified 36,500 single nucleotide variants (SNVs) and 9,300 insertions and deletions (indels) across the 27 samples, but the number was much greater than expected when compared with previous cancer genome studies. eVIDENCE was applied to the candidate variants and finally 70 SNVs and 7 indels remained. Of the 77 variants, 49 (63.6%) showed VAF of < 1% (0.20–0.98%). Twenty-five variants were selected in an unbiased manner and all were successfully validated, suggesting that eVIDENCE can identify variants with VAF of ≥ 0.2%. Additionally, this study is the first to detect hepatitis B virus integration sites and genomic rearrangements in the TERT region from cfDNA of HCC patients. We consider that our method can be applied in the examination of cfDNA from other types of malignancies using specific custom gene panels and will contribute to comprehensive ctDNA analysis.

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  113. Efficacy and Safety of Carboplatin Plus Paclitaxel as the First-, Second-, and Third-line Chemotherapy in Men With Castration-resistant Prostate Cancer

    Fujiwara Maki, Akamatsu Shusuke, Sumiyoshi Takayuki, Segawa Takehiko, Mizuno Kei, Yoshino Takayuki, Goto Takayuki, Sawada Atsuro, Saito Ryoichi, Kobayashi Takashi, Yamasaki Toshinari, Inoue Takahiro, Ogawa Osamu

    CLINICAL GENITOURINARY CANCER   Vol. 17 ( 5 ) page: E923 - E929   2019.10

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    Introduction: Carboplatin and paclitaxel (CP) had shown moderate efficacy in treating castration-resistant prostate cancer (CRPC) before standard first-line docetaxel chemotherapy became available. Currently, for patients with homology-directed repair gene defects as well as for unselected patients, platinum chemotherapy is administered after all standard treatments have been ineffective. Here, we retrospectively studied the efficacy and safety of CP administered as the first-, second-, and third-line chemotherapy in patients with CRPC. Patients and Methods: A retrospective chart review was performed for 58 patients with CRPC who received CP between 2001 and 2018 in a single institution. Twenty-seven patients received CP as the first-line chemotherapy, 21 as the second-line after docetaxel, and 10 as the third-line after docetaxel and cabazitaxel. Prostate-specific antigen (PSA) responses (> 50% decline of PSA from baseline), progression-free survival, overall survival, and adverse events were examined. Results: PSA responses at any time were 55.6%, 19.0%, and 10.0%; PSA responses at 12 weeks were 48.1%, 14.3%, and 10.0%; the median progression-free survival was 3, 1, and 1 month; and the median overall survival was 19, 11, and 6 months, respectively, for the first-, second-, and third-line settings. The only patient who achieved exceptional and durable PSA response in the third-line setting had a deleterious germline BRCA2 mutation (5645C>A). The adverse event profile was favorable. Conclusion: CP shows moderate efficacy against CRPC in the first-line setting, but shows little effect in the third-line setting. CP after docetaxel and cabazitaxel may be recommended in selected patients with CRPC with homology-directed repair gene defects.

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  114. Laparoscopic excision of an acquired ureteral diverticulum: A case report

    Negoro Hiromitsu, Inoue Takahiro, Imai Kazuto, Goto Takayuki, Sawada Atsuro, Akamatsu Shusuke, Saito Ryoichi, Kobayashi Takashi, Yamasaki Toshinari, Ogawa Osamu

    ASIAN JOURNAL OF ENDOSCOPIC SURGERY   Vol. 12 ( 4 ) page: 478 - 481   2019.10

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    Ureteral diverticula, especially acquired diverticula, are rare. Surgery is indicated when a diverticulum is accompanied by complications such as stones, pyelonephritis, stenosis, and signs of malignancy. A 59-year-old woman visited our urology department with asymptomatic macrohematuria. Enhanced CT scan revealed a right ureteral diverticulum with a 16-mm diameter that contained two tiny stones inside. After 8 months, the size of these stones increased; therefore, the patient underwent laparoscopic resection of the ureteral diverticulum and end-to-end anastomosis of the ureter. Subsequent histopathology of the excised specimen revealed an acquired diverticulum. Follow-up intravenous pyelography showed adequate urine passage with only minor dilatation of the pelvis at 3 months after the operation. The laparoscopic approach is believed to be feasible for ureteral diverticula cases that require ureteral end-to-end anastomosis.

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  115. Ten-year outcomes of high-dose intensity-modulated radiation therapy for nonmetastatic prostate cancer with unfavorable risk: early initiation of salvage therapy may replace long-term adjuvant androgen deprivation

    Aizawa Rihito, Takayama Kenji, Nakamura Kiyonao, Inoue Takahiro, Yamasaki Toshinari, Kobayashi Takashi, Akamatsu Shusuke, Ogawa Osamu, Mizowaki Takashi

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 24 ( 10 ) page: 1247 - 1255   2019.10

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    Background: The optimal timing of salvage androgen deprivation therapy (ADT) following definitive radiation therapy for prostate cancer (PCa) is unknown. This study evaluated the efficacy of early initiation of salvage-ADT (S-ADT) based on predetermined timing among patients with unfavorable PCa treated with high-dose intensity-modulated radiation therapy (IMRT). Materials and methods: High-risk (HR) and very-high-risk (VHR) PCa patients treated with IMRT at our institution between September 2000 and December 2010 were analyzed retrospectively. Treatment consisted of high-dose IMRT (78 Gy/39 fractions) combined with 6 months of neoadjuvant-ADT (NA-ADT). S-ADT was initiated when prostate-specific antigen levels exceeded 4.0 ng/mL. Results: In total, 268 (184 HR and 84 VHR) patients were analyzed. The median follow-up period was 114.4 months. The 10-year overall survival (OS), PCa-specific survival (PCSS), biochemical failure (BF), and clinical failure (CF) rates were 82.8%, 97.1%, 27.3%, and 12.8% among the HR PCa patients and 79.4%, 87.9%, 56.2%, and 26.7% among the VHR PCa patients (p = 0.839, = 0.0377, < 0.001, and < 0.001), respectively. The 10-year cumulative incidence rates of urinary and rectal (grades 2–3) toxicities were 22.6% and 5.8%, respectively. No grade 4 or higher toxicities were observed. Conclusion: High-dose IMRT combined with short-term NA-ADT resulted in long-term disease-free status, with acceptable morbidity among approximately three-fourths of the HR PCa patients and nearly half of the VHR PCa patients. Moreover, excellent survival outcomes were achieved by the early S-ADT initiation. This approach may be a promising alternative to uniform provision of long-term ADT.

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  116. 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population

    Takata Ryo, Takahashi Atsushi, Fujitat Masashi, Momozawa Yukihide, Saunders Edward J., Yamada Hiroki, Maejima Kazuhiro, Nakano Kaoru, Nishida Yuichiro, Hishida Asahi, Matsuo Keitaro, Wakai Kenji, Yamaji Taiki, Sawada Norie, Iwasaki Motoki, Tsugane Shoichiro, Sasaki Makoto, Shimizu Atsushi, Tanno Kozo, Minegishi Naoko, Suzuki Kichiya, Matsuda Koichi, Kubo Michiaki, Inazawa Johji, Egawa Shin, Haiman Christopher A., Ogawa Osamu, Obara Wataru, Kamatani Yoichiro, Akamatsu Shusuke, Nakagawa Hidewaki

    NATURE COMMUNICATIONS   Vol. 10 ( 1 ) page: 4422   2019.9

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    Genome-wide association studies (GWAS) have identified ~170 genetic loci associated with prostate cancer (PCa) risk, but most of them were identified in European populations. We here performed a GWAS and replication study using a large Japanese cohort (9,906 cases and 83,943 male controls) to identify novel susceptibility loci associated with PCa risk. We found 12 novel loci for PCa including rs1125927 (TMEM17, P = 3.95 × 10−16), rs73862213 (GATA2, P = 5.87 × 10−23), rs77911174 (ZMIZ1, P = 5.28 × 10−20), and rs138708 (SUN2, P = 1.13 × 10−15), seven of which had crucially low minor allele frequency in European population. Furthermore, we stratified the polygenic risk for Japanese PCa patients by using 82 SNPs, which were significantly associated with Japanese PCa risk in our study, and found that early onset cases and cases with family history of PCa were enriched in the genetically high-risk population. Our study provides important insight into genetic mechanisms of PCa and facilitates PCa risk stratification in Japanese population.

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  117. Comparative evaluation of the extraction and analysis of urinary phospholipids and lysophospholipids using MALDI-TOF/MS

    Li Xin, Nakayama Kenji, Goto Takayuki, Akamatsu Shusuke, Shimizu Koji, Ogawa Osamu, Inoue Takahiro

    CHEMISTRY AND PHYSICS OF LIPIDS   Vol. 223   page: 104787   2019.9

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    Lipids, particularly phospholipids (PLs) and lysophospholipids (LPLs), are attracting increasing scientific interest for their biological functions in cells and their potential as disease biomarkers for Alzheimer's disease and several types of cancer. Urinary PLs and LPLs could be ideal clinical biomarkers, because urine can be collected easily and noninvasively. However, due to their very low concentrations in urine compared with the relatively large quantity of contaminants in this matrix, efficient extraction and sensitive detection are required for analyzing urinary PLs and LPLs. In this study, various methods for analyzing PLs and LPLs in urine were compared and optimized from a clinical perspective. An optimized lipid extraction method and a matrix for matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) were established using two external ionization standards and an internal standard mix containing 13 human urinary lipids. 9-Aminoacridine (9-AA) was a useful and effective matrix for the MALDI-TOF/MS analysis of all the internal standard lipids in both positive and negative ion modes. However, it was necessary to determine the proportional lipid concentrations from the balance between the extracted lipid and the matrix. The extraction efficiency and reproducibility of the acidified Bligh and Dyer method were excellent for both positively and negatively charged lipids. Analysis of small volumes of urine was the most efficient with the 9-AA MALDI matrix at concentrations of or below 5 mM. The combined analytical procedures allowed rapid and comprehensive screening of low concentrations of PLs and LPLs in clinical samples.

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  118. ADD-ON EFFECTS OF TADALAFIL FOR TAMSULOSIN-TREATED PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA SUFFERING FROM RESIDUAL LOWER URINARY TRACT SYMPTOMS: A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, CROSSOVER STUDY

    Negoro H., Goto T., Akamatsu S., Terada N., Kobayashi T., Matsui T., Yamamoto T., Yonezawa A., Omura T., Matsubara K., Ogawa O.

    NEUROUROLOGY AND URODYNAMICS   Vol. 38   page: S170 - S171   2019.8

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  119. Data processing on a comparative evaluation of the extraction and analysis procedures for urinary phospholipid and lysophospholipid using MALDI-TOF/MS

    Li Xin, Nakayama Kenji, Goto Takayuki, Akamatsu Shusuke, Shimizu Koji, Ogawa Osamu, Inoue Takahiro

    DATA IN BRIEF   Vol. 25   page: 104275   2019.8

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  120. Urinary phospholipids by Maldi-Tof/Ms analyses are potential biomarkers for prostate cancer

    Li X., Nakayama K., Goto T., Akamatsu S., Shimizu K., Ogawa O., Inoue T.

    INTERNATIONAL JOURNAL OF UROLOGY   Vol. 26   page: 186 - 186   2019.8

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  121. A Case of Late Onset Nivolumab-Induced Interstitial Nephritis in a Patient with Metastatic Renal Cell Carcinoma

    Hattahara Kodai, Yamasaki Toshinari, Sawada Atsuro, Tanigaki Katsuya, Endo Syuichiro, Teramoto Yuki, Banno Haruka, Fuchigami Yasushi, Suzuki Ryosuke, Fujiwara Maki, Hida Takuya, Yoshino Takayuki, Kita Yuki, Goto Takayuki, Akamatsu Shusuke, Saito Ryoichi, Kobayashi Takashi, Inoue Takahiro, Ogawa Osamu

      Vol. 65 ( 5 ) page: 157 - 161   2019.5

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    A 43-year-old man underwent nephrectomy for right renal cell carcinoma (cT3aN0M1 (PUL), clear cell carcinoma). Thereafter, he was treated with sunitinib for lung metastases as the first-line therapy for three months. Because lung metastases progressed and new bone metastases appeared, nivolumab was started for the second-line treatment. Although the cancer progression was suppressed by multidisciplinary treatment combined with systemic immunotherapy and local radiation therapy, he developed severe acute kidney injury with cortical swelling after eighteen months of nivolumab treatment. A diagnosis of acute interstitial nephritis induced by nivolumab was made based on biopsy findings. Treatment with prednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function. We must consider the possibility of immunerelated adverse events, especially nivolumab-induced acute kidney injury, even after long-term treatment.

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  122. A case of late onset nivolumab-induced interstitial nephritis in a patient with metastatic renal cell carcinoma

    Hattahara K., Yamasaki T., Sawada A., Tanigaki K., Endo S., Teramoto Y., Banno H., Fuchigami Y., Suzuki R., Fujiwara M., Hida T., Yoshino T., Kita Y., Goto T., Akamatsu S., Saito R., Kobayashi T., Inoue T., Ogawa O.

    Acta Urologica Japonica   Vol. 65 ( 5 ) page: 157 - 161   2019.5

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    A 43-ycar-old man underwent nephrectomy for right renal cell carcinoma (cT3aN0M 1 (PUL), clear cell carcinoma). Thereafter, he was treated with sunitinib for lung metastases as the first-line therapy for three months. Because lung metastases progressed and new bone metastases appeared, nivolumab was started for the second-line treatment. Although the cancer progression was suppressed by multidisciplinary treatment combined with systemic immunotherapy and local radiation therapy, he developed severe acute kidney injury with cortical swelling after eighteen months of nivolumab treatment. A diagnosis of acute interstitial nephritis induced by nivolumab was made based on biopsy findings. Treatment with prednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function. We must consider the possibility of immune-related adverse events, especially nivolumab-induccd acute kidney injury, even after long-term treatment.

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  123. Consecutive Prostate Cancer Specimens Revealed Increased Aldo-Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer

    Miyazaki Yu, Teramoto Yuki, Shibuya Shinsuke, Goto Takayuki, Okasho Kosuke, Mizuno Kei, Uegaki Masayuki, Yoshikawa Takeshi, Akamatsu Shusuke, Kobayashi Takashi, Ogawa Osamu, Inoue Takahiro

    JOURNAL OF CLINICAL MEDICINE   Vol. 8 ( 5 )   2019.5

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    Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poorPSAPFS (p=0.032). Moreover, AKR1C3immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

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  124. Development and Validation of a Novel Prognostic Model for Predicting Overall Survival in Treatment-naive Castration-sensitive Metastatic Prostate Cancer

    Akamatsu Shusuke, Kubota Masashi, Uozumi Ryuji, Narita Shintaro, Takahashi Masahiro, Mitsuzuka Koji, Hatakeyama Shingo, Sakurai Toshihiko, Kawamura Sadafumi, Ishidoya Shigeto, Hoshi Senji, Ishida Masanori, Mizuno Kei, Ogura Keiji, Goto Takayuki, Terada Naoki, Kobayashi Takashi, Yamasaki Toshinari, Inoue Takahiro, Tsuchiya Norihiko, Ohyama Chikara, Arai Yoichi, Habuchi Tomonori, Morita Satoshi, Ogawa Osamu

    EUROPEAN UROLOGY ONCOLOGY   Vol. 2 ( 3 ) page: 320 - 328   2019.5

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    Background: There has been growth in the treatment options for castration-sensitive metastatic prostate cancer (mPCa), but without clear guidance for risk stratification. Objective: To identify clinical parameters associated with overall survival (OS) and establish a prognostic model for use with treatment-naïve castration-sensitive mPCa. Design, setting, and participants: A retrospective review of 304 patients treated at Kyoto University Hospital was performed. A prognostic model was created using clinical parameters associated with OS. The model was externally validated in an independent cohort of 520 patients. Outcome measurements and statistical analysis: Multivariable analysis was performed to identify the clinical parameters associated with OS. Risk scores were calculated using Cox proportional hazards analysis for each combination of risk factors, and patients were grouped into categories based on those scores. Results and limitations: Over 80% of the cohort had a Gleason sum score ≥8. The median OS was 53 mo among patients with CHAARTED high-volume PCa (n = 172) and 131 mo among those with low-volume PCa (n = 100). Independent factors associated with OS were extent of disease score ≥2 or the presence of liver metastasis; lactate dehydrogenase >250 U/L; and a primary Gleason score of 5. The median OS for the high-, intermediate-, and low-risk groups according to the new model were 28 mo, 59 mo, and not reached, respectively; the corresponding values in the validation cohort were 41 mo, 63 mo, and not reached. Harrell's C-index was 0.649. Conclusions: Our simple and reproducible prognostic model for treatment-naïve castration-sensitive mPCa could aid in risk stratification and treatment selection. Patient summary: We identified clinical parameters associated with prognosis in castration-sensitive metastatic prostate cancer and established a reproducible prognostic model that could be used to guide treatment decisions. We identified three readily available clinical parameters significantly associated with prognosis in castration-sensitive metastatic prostate cancer and established a highly reproducible prognostic model. The model could be used to guide treatment decisions or stratify patients in future clinical trials.

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  125. How and when to use novel androgen receptor target drugs for castration-resistant prostate cancer

    Terada N., Fujii M., Mukai S., Kamoto T., Akamatsu S., Kobayashi T., Inoue T., Ogawa O.

    Nishinihon Journal of Urology   Vol. 81 ( 2 ) page: 143 - 147   2019.4

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    Since the development of novel effective systemic agents, the treatment strategy for castrationresistant prostate cancer (CRPC) has been changing dramatically. Two novel androgen receptor target drugs, enzalutamide and abiraterone, have improved the survival rate of metastatic CRPC with similar effectiveness 1)2) . At present, we have no guidelines for the appropriate timing of using these drugs. We performed a multi-institutional retrospective study of patients who were treated with enzalutamide or abiraterone, and reported their efficacy and adverse effects 3)4) . Based on the results of our study and previously reported studies, we present some discussion and suggestions as to how and when to use enzalutamide and abiraterone.

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  126. Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer

    Sumiyoshi Takayuki, Mizuno Kei, Yamasaki Toshinari, Miyazaki Yu, Makino Yuki, Okasho Kosuke, Li Xin, Utsunomiya Noriaki, Goto Takayuki, Kobayashi Takashi, Terada Naoki, Inoue Takahiro, Kamba Tomomi, Fujimoto Akihiro, Ogawa Osamu, Akamatsu Shusuke

    SCIENTIFIC REPORTS   Vol. 9 ( 1 ) page: 4030   2019.3

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    The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma circulating cell-free DNA (cfDNA) and evaluated the AR statuses of patients with CRPC. AR amplification was detectable in VCaP cell line (AR amplified) genomic DNA (gDNA) diluted to 1.0% by digital PCR (dPCR). AR mutation were detectable in LNCaP cell line (AR T878A mutated) gDNA diluted to 0.1% and 1.0% by dPCR and target sequencing, respectively. Next, we analyzed AR status in cfDNA from 102 patients. AR amplification and mutations were detected in 47 and 25 patients, respectively. As a biomarker, AR aberrations in pretreatment cfDNA were associated with poor response to abiraterone, but not enzalutamide. In serial cfDNA analysis from 41 patients, most AR aberrations at baseline diminished with effective treatments, whereas in some patients with disease progression, AR amplification or mutations emerged. The analysis of AR in cfDNA is feasible and informative procedure for treating patients with CRPC. cfDNA may become a useful biomarker for precision medicine in CRPC.

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  127. Outcomes of high-dose whole pelvic simultaneous integrated boost IMRT in patients with pelvic lymph node-positive prostate cancer.

    Mizowaki Takashi, Takayama Kenji, Nakamura Kiyonao, Aizawa Rihito, Inoue Takahiro, Yamasaki Toshinari, Kobayashi Takashi, Akamatsu Shusuke, Ogawa Osamu

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 37 ( 7 )   2019.3

  128. The efficacy and toxicity of cabazitaxel for treatment of docetaxel-resistant prostate cancer correlating with the initial doses in Japanese patients

    Terada Naoki, Kamoto Toshiyuki, Tsukino Hiromasa, Mukai Shoichiro, Akamatsu Shusuke, Inoue Takahiro, Ogawa Osamu, Narita Shintaro, Habuchi Tomonori, Yamashita Shinichi, Mitsuzuka Koji, Arai Yoichi, Kandori Shuya, Kojima Takahiro, Nishiyama Hiroyuki, Kawamura Yoshiaki, Shimizu Yuki, Terachi Toshiro, Sugi Motohiko, Kinoshita Hidefumi, Matsuda Tadashi, Yamada Yusuke, Yamamoto Shingo, Hirama Hiromi, Sugimoto Mikio, Kakehi Yoshiyuki, Sakurai Toshihiko, Tsuchiya Norihiko

    BMC CANCER   Vol. 19 ( 1 ) page: 156   2019.2

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    Background: We analyzed the efficacy and toxicity of cabazitaxel (CBZ) at high and low initial doses in Japanese patients with docetaxel-resistant castration-resistant prostate cancer (CRPC). Methods: We retrospectively evaluated 118 patients who received CBZ for docetaxel-resistant CRPC in 10 university hospitals in Japan between 2014 and 2016. The rate of decrease of prostate-specific antigen (PSA), adverse events, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving initially high (≥22.5 mg/m2, n = 36) and low (≤20 mg/m2, n = 80) CBZ doses. Factors associated with survival and grade 4 neutropenia were evaluated. Results: PSA values decreased by > 50% in 22 patients (19%), with a higher frequency in the high-dose group than in the low-dose group (29 and 14%, P = 0.073). The median PFS time for the all-patient, high- and low-dose groups was 2.8 months (95% confidence interval [CI] 1.9-4.4), 2.1 months (1.2-5.5), and 3.0 months (2.0-4.4), respectively (P = 0.904). The median OS times were 16.3 months (95% CI 9.7-30.9), 30.9 months (11.8-47.4), and 10.2 months (8.6-20), respectively (P = 0.020). In multivariate analyses, PFS was significantly associated with existing bone metastasis at diagnosis (P = 0.005) and OS with PSA > 100 ng/ml (P = 0.007), hemoglobin < 12 g/dl (P = 0.030), and low initial CBZ dose (P = 0.030). Grade 4 neutropenia occurred in 53 patients (45%) and was associated with a low CBZ dose (hazard ratio 0.21, 95% CI 0.08-0.59, P = 0.002). Conclusions: CBZ at a higher initial dose may have similar response rate and response duration, but longer survival duration after treatment with higher toxicity than a lower initial dose for docetaxel-resistant CRPC in Japanese patients.

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  129. Association of Missense Polymorphism in HSD3B1 With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone

    Shiota Masaki, Narita Shintaro, Akamatsu Shusuke, Fujimoto Naohiro, Sumiyoshi Takayuki, Fujiwara Maki, Uchiumi Takeshi, Habuchi Tomonori, Ogawa Osamu, Eto Masatoshi

    JAMA NETWORK OPEN   Vol. 2 ( 2 ) page: e190115   2019.2

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    Importance: Recently, genetic polymorphism in HSD3B1 encoding 3β-hydroxysteroid dehydrogenase-1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer. Upfront abiraterone combined with ADT has proved survival benefit. However, its effect on oncological outcome among different ethnicities and in abiraterone treatment remain unclear. Objective: To investigate the significance of missense polymorphism in HSD3B1 gene among men treated with primary ADT or abiraterone. Design, Setting, and Participants: This prognostic study included Japanese patients with metastatic hormone-sensitive prostate cancer between June 1993 and July 2005 and with castration-resistant prostate cancer between September 2014 and February 2018. Genome DNA was obtained from patient whole blood samples, and genotyping on HSD3B1 (rs1047303, 1245C) was performed by Sanger sequencing. Exposures: Primary ADT for metastatic hormone-sensitive prostate cancer and abiraterone for castration-resistant prostate cancer. Main Outcomes and Measures: The association of genotype in HSD3B1 with clinicopathological parameters and oncological outcome, including prostate-specific antigen response, progression-free survival, treatment failure-free survival, and overall survival was examined. Results: Of 203 men, 104 were in the primary ADT cohort (median [interquartile range] age, 72 [67-76] years) and 99 men were in the abiraterone group (median [interquartile range] age, 74 [67-80] years). Most patients carried metastatic lesions in each cohort. Among the cohort of primary ADT, men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk (hazard ratio [HR], 2.34; 95% CI, 1.08-4.49; P = .03) but not any-caused death risk (HR, 1.36; 95% CI, 0.52-2.92; P = .50), compared with men carrying homozygous wild type. In contrast, among the abiraterone cohort, men carrying variant type in HSD3B1 gene showed lower progression risk (HR, 0.32; 95% CI, 0.12-0.69; P = .006) and lower all-cause mortality risk (HR, 0.40; 95% CI, 0.13-0.94; P = .04) compared with men carrying homozygous wild type. Conclusions and Relevance: This study showed that HSD3B1 genetic variant is distinctly associated with oncological outcome between primary ADT and abiraterone in Japanese men, suggesting universal significance among different ethnicities in primary ADT, as well as promise as a predictive biomarker of ADT and abiraterone.

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  130. Initial evaluation of PET/CT with F-18-FSU-880 targeting prostate-specific membrane antigen in prostate cancer patients

    Saga Tsuneo, Nakamoto Yuji, Ishimori Takayoshi, Inoue Takahiro, Shimizu Yoichi, Kimura Hiroyuki, Akamatsu Shusuke, Goto Takayuki, Watanabe Hiroyuki, Kitaguchi Kosuke, Watanabe Masao, Ono Masahiro, Saji Hideo, Ogawa Osamu, Togashi Kaori

    CANCER SCIENCE   Vol. 110 ( 2 ) page: 742 - 750   2019.2

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    This first-in-man study was carried out to evaluate the safety, whole-body distribution, dose estimation, and lesion accumulation of 18F-FSU-880, a newly developed probe targeting prostate-specific membrane antigen. Six prostate cancer patients with known metastatic lesions underwent serial whole-body PET/computed tomography (CT) with 18F-FSU-880. Blood and urine were analyzed before and after PET/CT. Accumulation of 18F-FSU-880 in organs and metastatic lesions in serial PET images were evaluated by measuring the standardized uptake values. From the biodistribution data, the organ doses and whole-body effective dose were calculated using OLINDA/EXM software was developed by Dr. Michael Stabin of Vanderbilt University, Nashville, Tennessee, USA. 18F-FSU-880 PET/CT could be carried out without significant adverse effects. High physiological uptake was observed in the salivary/lachrymal glands and kidneys. The effective dose was calculated to be 0.921 × 10−2 mSv/MBq. Known metastatic lesions were clearly visualized with high image contrast that increased with time, except in 1 patient, whose bone metastases were well-controlled and inactive. The PET/CT with 18F-FSU-880 could be carried out safely and could clearly visualize active metastatic lesions. The present results warrant further clinical studies with a larger number of cases to verify the clinical utility of 18F-FSU-880 PET/CT in the management of prostate cancer patients.

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  131. A Case of Advanced Right Renal Pelvic Cancer with Left Supraclavicular Lymph Node Metastasis that Attained Long-Term Survival by Multidisciplinary Treatments

    Imai Kazuto, Inoue Takahiro, Saito Ryoichi, Goto Takayuki, Sawada Atsuro, Akamatsu Shusuke, Negoro Hiromitsu, Kobayashi Takashi, Terada Naoki, Yamasaki Toshinari, Okubo Kazutoshi, Yoshimura Koji, Kanematsu Akihiro, Ogawa Osamu

      Vol. 65 ( 1 ) page: 13 - 17   2019.1

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    A man in his 70s was referred to our hospital for further examination of a positive occult blood finding. Imaging studies showed that the patient had right renal pelvic cancer with interaortocaval, multiple paracaval and left supraclavicular lymph node metastases (cT3N2Ml). Induction chemotherapy was performed with 5 cycles of MEC (methotrexate/epirubicin/cisplatin) followed by 2 cycles of GT (gemcitabine/paclitaxel). After the combined chemotherapies, the residual lesions were the primary tumor in the right renal pelvis and the left supraclavicular lymph node. Right total nephroureterectomy combined with lymph node dissection of paraaortic, paracaval, and interaortocaval area and left cervical area were performed. Histopathologically the postoperative T stage of the primary tumor was determined as ypT3. As for lymph nodes dissected, an interaortocaval lymph node alone, but not the other nodes, contained viable cancer cells. Adjuvant chemotherapy was performed with 7 courses of GT therapy. The patient had intravesical recurrence once and received transurethral resection of bladder tumor followed by intravesical instillations of Bacillus Calmette-Guerin (BCG). Finally, the patient has been free from recurrence for 10 years after the final treatment.

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  132. A case of advanced right renal pelvic cancer with left supraclavicular lymph node metastasis that attained long-term survival by multidisciplinary treatments

    Imai K., Inoue T., Saito R., Goto T., Sawada A., Akamatsu S., Negoro H., Kobayashi T., Terada N., Yamasaki T., Okubo K., Yoshimura K., Kanematsu A., Ogawa O.

    Acta Urologica Japonica   Vol. 65 ( 1 ) page: 13 - 17   2019.1

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    A man in his 70s was referred to our hospital for further examination of a positive occult blood finding. Imaging studies showed that the patient had right renal pelvic cancer with interaortocaval, multiple paracaval and left supraclavicular lymph node metastases (cT3N2Ml). Induction chemotherapy was performed with 5 cycles of MEG (methotrexate/epirubicin/cisplatin) followed by 2 cycles of GT (gemcitabine/paclitaxel). After the combined chemotherapies, the residual lesions were the primary tumor in the right renal pelvis and the left supraclavicular lymph node. Right total nephroureterectomy combined with lymph node dissection of paraaortic, paracaval, and interaortocaval area and left cervical area were performed. Histopath-ologically the postoperative T stage of the primary tumor was determined as ypT3. As for the lymph nodes dissected, an interaortocaval lymph node alone, but not the other nodes, contained viable cancer cells. Adjuvant chemotherapy was performed with 7 courses of GT therapy. The patient had intravesical recurrence once and received transurethral resection of bladder tumor followed by intravesical instillations of Bacillus Galmette-Guerin (BCG). Finally, the patient has been free from recurrence for 10 years after the final treatment.

    DOI: 10.14989/ActaUroiJap_65_l_13

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  133. Evaluation of phospholipids expression in prostate cancer cell lines in LCMS

    Okasho Kosuke, Inoue Takahiro, Kimura Hiroko, Kamiyama Yuki, Li Xin, Mizuno Kei, Sumiyoshi Takayuki, Goto Takayuki, Akamatsu Shusuke, Kobayashi Takashi, Ogawa Osamu

    CANCER SCIENCE   Vol. 109   page: 930 - 930   2018.12

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  134. Identification of fourteen new susceptibility loci for prostate cancer in the Japanese population

    Takata Ryo, Akamatsu Shusuke, Nakagawa Hidewaki, Takahashi Atsushi, Terada Naoki, Kato Yoichiro, Kanehira Mitsugu, Sugimura Jun, Inazawa Johji, Ogawa Osamu, Obara Wataru

    CANCER SCIENCE   Vol. 109   page: 1142 - 1142   2018.12

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  135. Genomics and lipidomics analysis of blood and urine toward prostate cancer precision medicine

    Inoue Takahiro, Li Xin, Sumiyoshi Takayuki, Nakayama Kenji, Mizuno Kei, Okasho Kosuke, Goto Takayuki, Akamatsu Shusuke, Ogawa Osamu

    CANCER SCIENCE   Vol. 109   page: 1221 - 1221   2018.12

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  136. The impact of p53 point mutation on the characteristics of BBN-induced mouse bladder cancer

    Murakami Kaoru, Masuda Norihiko, Matsumoto Keiyu, Kita Yuki, Akamatsu Shusuke, Saito Ryoichi, Kobayashi Takashi, Yamasaki Toshinari, Inoue Takahiro, Ogawa Osamu

    CANCER SCIENCE   Vol. 109   page: 966 - 966   2018.12

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  137. Initial Clinical Experience of Nivolumab for Metastatic Renal Cell Carcinoma

    Fukunaga Arinobu, Yamasaki Toshinari, Okuno Tomoya, Imai Kazuto, Ikeuchi Ryosuke, Hishiki Kosuke, Goto Takayuki, Sawada Atsuro, Negoro Hiromitsu, Akamatsu Syusuke, Saito Ryoichi, Kobayashi Takashi, Inoue Takahiro, Ogawa Osamu

      Vol. 64 ( 10 ) page: 383 - 389   2018.10

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    Nivolumab was approved as a new agent for advanced renal cell carcinoma (RCC) in Japan on September 2016. Nivolumab is an immune checkpoint inhibitor that activates the cytotoxic immune response and has exerted antitumor effects in a mechanism different from other available molecular targeted agents. Therefore, its response pattern, efficacy and adverse events are different from those of the molecular targeted agents for RCC. Here, we report our initial clinical experience with nivolumab. From December 2016 to September 2017, we applied nivolumab to 7 patients with metastatic RCC. The most common metastatic site was the lungs, followed by lymph nodes, bones and brain. According to the immune-related response criteria, the efficacy was stable disease in 2 patients and progressive disease in 5 patients. In 5 cases with multiple metastases, responses differed with the site of metastasis. The response was best in lung metastasis and worst in brain metastasis. Six cases had minor adverse events. In two cases, we discontinued administration of nivolumab temporarily. The patients recovered completely and we considered nivolumab effective and safe for treatment of metastatic RCC.

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  138. Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents: Opportunities and Challenges

    Kita Yuki, Goto Takayuki, Akamatsu Shusuke, Yamasaki Toshinari, Inoue Takahiro, Ogawa Osamu, Kobayashi Takashi

    CANCERS   Vol. 10 ( 10 )   2018.10

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    Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone and enzalutamide, enable stronger blockade of the androgen receptor (AR) axis and longer survival of men with castration-resistant prostate cancer (CRPC). However, the extent of the improved survival remains insufficient and the majority of patients eventually develop resistance to these novel agents. Some patients develop resistance against ARAT treatment through mechanisms termed “complete AR independence” or “AR indifference”, and no longer require activation of the AR axis. However, a considerable proportion of CRPC patients remain persistently dependent on AR or its downstream signaling pathways. Ligand-independent activation of the AR, an AR axis-dependent mechanism, is mediated by truncated forms of ARs that lack the ligand-binding domain (LBD), arising as products of AR splicing variants or nonsense mutations of AR. Post-translational modifications of ARs can also contribute to ligand-independent transactivation of the AR. Other mechanisms for AR axis activation are mediated by pathways that bypass the AR. Recent studies revealed that the glucocorticoid receptor can upregulate a similar transcription program to that of the AR, thus bypassing the AR. ARAT agents are essentially ineffective for CRPC driven by these AR-independent mechanisms. This review article describes recent efforts to overcome these refractory machineries for the development of next-generation AR axis blockade in CRPC.

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  139. Initial clinical experience of nivolumab for metastatic renal cell carcinoma

    Fukunaga A., Yamasaki T., Okuno T., Imai K., Ikeuchi R., Hishiki K., Goto T., Sawada A., Negoro H., Akamatsu S., Saito R., Kobayashi T., Inoue T., Ogawa O.

    Acta Urologica Japonica   Vol. 64 ( 10 ) page: 383 - 389   2018.10

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    Nivolumab was approved as a new agent for advanced renal cell carcinoma (RCG) in Japan on September 2016. Nivolumab is an immune checkpoint inhibitor that activates the cytotoxic immune response and has exerted antitumor effects in a mechanism different from other available molecular targeted agents. Therefore, its response pattern, efficacy and adverse events are different from those of the molecular targeted agents for RCG. Here, we report our initial clinical experience with nivolumab. From December 2016 to September 2017, we applied nivolumab to 7 patients with metastatic RCG. The most common metastatic site was the lungs, followed by lymph nodes, bones and brain. According to the immune-related response criteria, the efficacy was stable disease in 2 patients and progressive disease in 5 patients. In 5 cases with multiple metastases, responses differed with the site of metastasis. The response was best in lung metastasis and worst in brain metastasis. Six cases had minor adverse events. In two cases, we discontinued administration of nivolumab temporarily. The patients recovered completely and we considered nivolumab effective and safe for treatment of metastatic RCG.

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  140. Investigation of novel therapeutic targets for CRPC based on androgen receptor (AR) chromatin immunoprecipitation (ChIP) using a patient-derived xenograft

    Makino Yuki, Kobayashi Takashi, Brown J. B., Mizuno Kei, Okasho Kosuke, Sumiyoshi Takayuki, Goto Takayuki, Akamatsu Shusuke, Terada Naoki, Inoue Takahiro, Tanaka Toshiya, Kodama Tatsuhiko, Ogawa Osamu

    INTERNATIONAL JOURNAL OF UROLOGY   Vol. 25   page: 348 - 348   2018.10

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  141. Intravesical prostatic protrusion is not always the same shape: Evaluation by preoperative cystoscopy and outcome in HoLEP

    Ito Katsuhiro, Takashima Yasushi, Akamatsu Shusuke, Terada Naoki, Kobayashi Takashi, Yamasaki Toshinari, Inoue Takahiro, Kamba Tomomi, Ogawa Osamu, Negoro Hiromitsu

    NEUROUROLOGY AND URODYNAMICS   Vol. 37 ( 7 ) page: 2160 - 2166   2018.9

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    Aims: To examine how morphological differences in intravesical prostatic protrusion (IPP) predict outcome of Holmium laser enucleation of prostate (HoLEP) treatment. Methods: We analyzed 173 patients who had undergone HoLEP in our hospital. The protrusion shape was evaluated by outpatient preoperative flexible cystoscopy and classified into five groups: A, no protrusion; B, middle lobe only; C, unilateral lobe only; D, bilateral lobes; and E, B + C or B + D. Paired-match analysis that adjusted for preoperative International Prostate Symptom Score (IPSS) voiding/storage subscores and IPP was performed between the group with middle lobe protrusion (B + E) and the group without it (C + D). Results: Type A prostate shape was found in 23 patients, type B in 14, type C in 31, type D in 71, and type E in 34. Groups with middle lobe protrusion (B and E) had better changes in the total IPSS (P < 0.05) and the IPSS storage subscore (P < 0.01). Pair matching identified 37 patients each with or without middle lobe protrusion. The group with middle lobe protrusion had significantly more improved total IPSS (−17.5 ± 7.5 vs −13.5 ± 8.3, P < 0.05) and IPSS storage subscore (−6.9 ± 3.4 vs −4.8 ± 3.3, P < 0.05) than did those without middle lobe protrusion. Conclusions: Patients with middle lobe protrusion had greater IPSS improvement after HoLEP than those having comparable-length IPP but without middle lobe protrusion. IPP is not always the same shape and should be clinically divided into at least two groups.

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  142. Long-term outcomes of definitive external-beam radiotherapy for non-metastatic castration-resistant prostate cancer

    Aizawa Rihito, Takayama Kenji, Nakamura Kiyonao, Inoue Takahiro, Kobayashi Takashi, Akamatsu Shusuke, Yamasaki Toshinari, Ogawa Osamu, Mizowaki Takashi

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 23 ( 4 ) page: 749 - 756   2018.8

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    Background: Although definitive external-beam radiotherapy (EBRT) is one of the treatment options for non-metastatic castration-resistant prostate cancer (NM-CRPC), there are limited data on the long-term outcomes of this treatment. Methods: We retrospectively evaluated 31 NM-CRPC patients consecutively treated with definitive EBRT. The median age was 74 years upon EBRT initiation. The initial T stage distribution was as follows: T1c in 3, T2 in 11, T3 in 14, and T4 in 3 cases, respectively. The median prostate dose was 70.4 Gy. A castration-resistant status was defined as continuously increasing serum prostate-specific antigen levels despite ongoing hormonal therapy (HT). Results: The median follow-up duration after EBRT was 66.6 months. The median period of primary HT was 18.0 months. The 5- and 8-year overall survival rates were 74.6 and 49.8%, respectively. The 5- and 8-year prostate cancer-specific survival rates were 77.4 and 51.7%, respectively. Fourteen patients died, and prostate cancer was the cause of death in 12 of these patients. The 5- and 8-year relapse-free survival rates were 32.3 and 25.8%, respectively. Among 23 patients who experienced biochemical or clinical failure, the median duration to recurrence after EBRT was 19.3 months. The 5- and 8-year clinical failure-free survival rates were 56.0 and 51.4%, respectively. Among the 14 patients who experienced clinical failure, the median duration after EBRT was 16.0 months. The local relapse-free rates at 5 and 8 years were 91.0 and 91.0%, respectively. Grade 3 or higher adverse events were observed in four patients. Conclusion: Definitive EBRT achieved a long-term disease-free and clinical failure-free status in approximately one-third of and half of the treated NM-CRPC patients, respectively. This approach was also associated with favorable local relapse-free rates and overall survival outcomes. Definitive EBRT is a promising approach for NM-CRPC patients.

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  143. Clinical and molecular features of treatment-related neuroendocrine prostate cancer

    Akamatsu Shusuke, Inoue Takahiro, Ogawa Osamu, Gleave Martin E.

    INTERNATIONAL JOURNAL OF UROLOGY   Vol. 25 ( 4 ) page: 345 - 351   2018.4

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    Treatment-related neuroendocrine prostate cancer is a lethal form of prostate cancer that emerges in the later stages of castration-resistant prostate cancer treatment. Treatment-related neuroendocrine prostate cancer transdifferentiates from adenocarcinoma as an adaptive response to androgen receptor pathway inhibition. The incidence of treatment-related neuroendocrine prostate cancer has been rising due to the increasing use of potent androgen receptor pathway inhibitors. Typically, treatment-related neuroendocrine prostate cancer is characterized by either low or absent androgen receptor expression, small cell carcinoma morphology and expression of neuroendocrine markers. Clinically, it manifests with predominantly visceral or lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels or a short response duration to androgen deprivation therapy. Furthermore, although the tumor initially responds to platinum-based chemotherapy, the duration of the response is short. Based on the poor prognosis, it is imperative to identify novel molecular targets for treatment-related neuroendocrine prostate cancer. Recent advances in genomic and molecular research, supported by novel in vivo models, have identified some of the key molecular characteristics of treatment-related neuroendocrine prostate cancer. The gain of MYCN and AURKA oncogenes, along with the loss of tumor suppressor genes TP53 and RB1 are key genomic alterations associated with treatment-related neuroendocrine prostate cancer. Androgen receptor repressed genes, such as BRN2 and PEG10, are also necessary for treatment-related neuroendocrine prostate cancer. These genetic changes converge on pathways upregulating genes, such as SOX2 and EZH2, that facilitate lineage plasticity and neuroendocrine differentiation. As a result, on potent androgen receptor pathway inhibition, castration-resistant prostate cancer transdifferentiates to treatment-related neuroendocrine prostate cancer in a clonally divergent manner. Further understanding of the disease biology is required to develop novel drugs and biomarkers that would help treat this aggressive prostate cancer variant.

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  144. Two Cases of Metastatic and Recurrent Non-Clear Cell Renal Cell Carcinoma Re-Diagnosed as Renal Mucinous Tubular and Spindle Cell Carcinoma during Long-Term Follow-Up

    Kubota Masashi, Yamasaki Toshinari, Teramoto Yuki, Ito Katsuhiro, Takada Hideaki, Magaribuchi Toshihiro, Sawada Atsuro, Akamatsu Shusuke, Negoro Hiromitsu, Saito Ryoichi, Kobayashi Takashi, Terada Naoki, Inoue Takahiro, Kamba Tomomi, Ogawa Osamu

      Vol. 64 ( 3 ) page: 111 - 115   2018.3

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    Renal mucinous tubular and spindle cell carcinoma (MTSCC) is a rare, low-grade renal epithelial neoplasm. MTSCC has a lower malignant potential and shows relatively good prognosis, but can be difficult to distinguish from other renal cell carcinoma (RCC) subtypes. Here, we report two cases of metastatic and recurrent renal MTSCC diagnosed after long-term follow-up. Case 1 was a 79-year-old man with a history of macroscopic hematuria in whom a right kidney mass was detected and diagnosed as RCC (cT3bN0M0). After a radical nephrectomy, microscopic findings showed that the tumor consisted of spindle cells arranged in tubular patterns embedded in sarcomatoid tissues ; we diagnosed it as unclassified RCC with sarcomatoid differentiations (pT3aN0M0). Thereafter, metastases were twice detected and resected completely. The patient had no evidence of disease at his most recent follow-up, 10 years 1 month after the initial surgery. Case 2 was in a 72-year-old man in whom a right kidney mass, swollen lymph nodes, and a lung node were incidentally detected. This tumor was diagnosed as RCC (cT4N2M1), and radical nephrectomy and lymph node dissections were carried out. From the microscopic findings, we diagnosed papillary RCC type-2 (pT3aN2M1). After the surgery, pleural and bone metastases was detected. Despite sequential treatments with IFN-α and sunitinib, the patient suffered indolent-growing metastases and died at 5 years 6 months after operation. As these patients had relatively good prognoses despite assumed aggressive RCC subtypes, we reviewed their pathological findings. In both cases, tumor samples showed tubules lined by short cuboidal cells that were set within myxoid stromata and spindle cells ; we finally diagnosed these cases as renal MTSCC.

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  145. Clinical Utility of Upper Urinary Tract Reconstruction by Ileal-Ureter Substitution

    Okumura Yoshinaga, Akamatsu Shusuke, Okada Yoshiyuki, Negoro Hiromitsu, Kobayashi Takashi, Terada Naoki, Yamasaki Toshinari, Matsui Yoshiyuki, Inoue Takahiro, Kamba Tomomi, Ogawa Osamu

      Vol. 64 ( 3 ) page: 87 - 94   2018.3

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    We retrospectively reviewed the indications and outcomes of ileal-ureter substitution cases for complex ureteral reconstruction. We analyzed the patient clinical characteristics, outcomes, and complications of eight patients who had ileal ureter substitution surgery at Kyoto University Hospital between 2009 and 2016. The median patient age was 55.5 years (36-79), and the median follow up period was 25.5 months (7-85). Seven patients had unilateral ureteral obstruction (right:left=4:3), and one had bilateral ureteral obstruction. The etiologies of the ureteral defects were ureteral stricture due to non-urologic malignant tumorinvasion (n=2), benign ureteral stricture (n=2), anastomotic stricture after cystectomy (n=2), and iatrogenic ureteral injury (n=2). The mean length of operation time was 384.7 minutes (median 323 minutes, 242-397), and the mean hospital stay was 32.9 days (median 31 days, 19-41). Simple anastomosis of an untailored ileal segment to ureter and bladder was performed in 5 cases, bilateral ureteral anastomosis to a single ileal segment in one case, and in the remaining two cases, the ileal ureter was anastomosed to ileal conduit or neobladder. A nipple valve was used as the antireflux mechanism, in 2 cases but not in the remaining 6 cases. The outcome was favourable in all cases with no stricture and no requirement for further intervention. There was no significant deterioration of renal function in any patient, and no metabolic abnormality was detected. The ileal-ureter substitution appears to be a reasonable option, allowing nephron sparing in complex ureteral reconstruction cases.

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  146. Clinical utility of upper urinary tract reconstruction by ileal-ureter substitution

    Okumura Y., Akamatsu S., Okada Y., Negoro H., Kobayashi T., Terada N., Yamasaki T., Matsui Y., Inoue T., Kamba T., Ogawa O.

    Acta Urologica Japonica   Vol. 64 ( 3 ) page: 87 - 94   2018.3

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    We retrospectively reviewed the indications and outcomes of ileal-ureter substitution cases for complex ureteral reconstruction. We analyzed the patient clinical characteristics, outcomes, and complications of eight patients who had ileal ureter substitution surgery at Kyoto University Hospital between 2009 and 2016. The median patient age was 55.5 years (36-79), and the median follow up period was 25.5 months (7-85). Seven patients had unilateral ureteral obstruction (right: left = 4:3), and one had bilateral ureteral obstruction. The etiologies of the ureteral defects were ureteral stricture due to non-urologic malignant tumor invasion (n = 2), benign ureteral stricture (n = 2), anastomotic stricture after cystectomy (n = 2), and iatrogenic ureteral injury (n = 2). The mean length of operation time was 384.7 minutes (median 323 minutes, 242-397), and the mean hospital stay was 32.9 days (median 31 days, 19-41). Simple anastomosis of an untailored ileal segment to ureter and bladder was performed in 5 cases, bilateral ureteral anastomosis to a single ileal segment in one case, and in the remaining two cases, the ileal ureter was anastomosed to ileal conduit or neobladder. A nipple valve was used as the antireflux mechanism, in 2 cases but not in the remaining 6 cases. The outcome was favourable in all cases with no stricture and no requirement for further intervention. There was no significant deterioration of renal function in any patient, and no metabolic abnormality was detected. The ileal-ureter substitution appears to be a reasonable option, allowing nephron sparing in complex ureteral reconstruction cases.

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  147. Cross-Sectional Epidemiological Analysis of the Nagahama Study for Correlates of Overactive Bladder: Genetic and Environmental Considerations

    Funada Satoshi, Kawaguchi Takahisa, Terada Naoki, Negoro Hiromitsu, Tabara Yasuharu, Kosugi Shinji, Yamada Ryo, Nakayama Takeo, Akamatsu Shusuke, Yoshimura Koji, Matsuda Fumihiko, Ogawa Osamu

    JOURNAL OF UROLOGY   Vol. 199 ( 3 ) page: 774 - 778   2018.3

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    Purpose: The prevalence of overactive bladder is increasing globally. It has a substantial impact on quality of life and represents a heavy economic burden. We evaluated the prevalence of overactive bladder in a Japanese population and analyzed whether genetic and environmental factors influence overactive bladder. Materials and Methods: This cross-sectional study was performed as part of the Nagahama cohort project. It comprised a questionnaire survey as well as anthropometric, physiological and biochemical measures, and genomic information on participants 30 to 74 years old in Nagahama, Japan. A genome-wide association study was performed in 4,645 participants, including 1,521 men and 3,124 women, using 99,059 single nucleotide polymorphisms. Univariate and multivariable logistic regression was done to analyze environmental factors associated with overactive bladder. Results: The prevalence of overactive bladder was 11.8%, including 15.3% in men and 10.1% in women, and it increased with age. We found no significant association between overactive bladder and any single nucleotide polymorphism in the genome-wide association study. However, in the multivariable logistic regression model overactive bladder was positively associated with environmental factors, including age, depression and the consumption of cake or Japanese confection. Conclusions: The prevalence of overactive bladder was greater in men than in women, especially among the elderly. Environmental factors rather than genetic variants more likely contribute to overactive bladder.

    DOI: 10.1016/j.juro.2017.09.146

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  148. Two cases of metastatic and recurrent non-clear cell renal cell carcinoma re-diagnosed as renal mucinous tubular and spindle cell carcinoma during long-term follow-up

    Kubota M., Yamasaki T., Teramoto Y., Ito K., Takada H., Magaribuchi T., Sawada A., Akamatsu S., Negoro H., Saito R., Kobayashi T., Terada N., Inoue T., Kamba T., Ogawa O.

    Acta Urologica Japonica   Vol. 64 ( 3 ) page: 111 - 115   2018.3

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    Renal mucinous tubular and spindle cell carcinoma (MTSCG) is a rare, low-grade renal epithelial neoplasm. MTSCC has a lower malignant potential and shows relatively good prognosis, but can be difficult to distinguish from other renal cell carcinoma (RCG) subtypes. Here, we report two cases of metastatic and recurrent renal MTSCC diagnosed after long-term follow-up. Case 1 was a 79-year-old man with a history of macroscopic hematuria in whom a right kidney mass was detected and diagnosed as RCC (cT3bN0M0). After a radical nephrectomy, microscopic findings showed mat the tumor consisted of spindle cells arranged in tubular patterns embedded in sarcomatoid tissues; we diagnosed it as unclassified RCC with sarcomatoid differentiations (pT3aN0M0). Thereafter, metastases were twice detected and resected completely. The patient had no evidence of disease at his most recent follow-up, 10 years 1 month after the initial surgery. Case 2 was in a 72-year-old man in whom a right kidney mass, swollen lymph nodes, and a lung node were incidentally detected. This tumor was diagnosed as RCC (cT4N2M1), and radical nephrectomy and lymph node dissections were carried out. From the microscopic findings, we diagnosed papillary RCC type-2 (pT3aN2M 1). After the surgery, pleural and bone metastases was detected. Despite sequential treatments with IFN-α and sunitinib, the patient suffered indolent-growing metastases and died at 5 years 6 months after operation. As these patients had relatively good prognoses despite assumed aggressive RCC subtypes, we reviewed their pathological findings. In both cases, tumor samples showed tubules lined by short cuboidal cells that were set within myxoid stromata and spindle cells; we finally diagnosed these cases as renal MTSCC.

    DOI: 10.14989/ActaUrolJap-64-3-111

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  149. Long-term outcomes of intensity-modulated radiation therapy combined with neoadjuvant hormonal therapy for Japanese patients with non-metastatic prostate cancer.

    Aizawa Rihito, Takayama Kenji, Nakamura Kiyonao, Inoue Takahiro, Kobayashi Takashi, Akamatsu Shusuke, Yamasaki Toshinari, Ogawa Osamu, Mizowaki Takashi

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 36 ( 6 )   2018.2

  150. An analysis of phosphatidic acid for clear cell renal cell carcinoma

    Utsunomiya Noriaki, Yamasaki Toshinari, Takeda Masashi, Sumiyoshi Takayuki, Goto Takayuki, Akamatsu Shusuke, Kobayashi Takashi, Inoue Takahiro, Kamba Tomomi, Ogawa Osamu

    CANCER SCIENCE   Vol. 109   page: 328 - 328   2018.1

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  151. Analysis of copy number variations of androgen receptor gene in cell-free DNA from castration-resistant prostate cancer

    Sumiyoshi Takayuki, Akamatsu Shusuke, Yamasaki Toshinari, Mizuno Kei, Okasho Kosuke, Makino Yuki, Utsunomiya Noriaki, Goto Takayuki, Terada Naoki, Kobayashi Takashi, Inoue Takahiro, Kamba Tomomi, Ogawa Osamu

    CANCER SCIENCE   Vol. 109   page: 726 - 726   2018.1

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  152. Development of Subtype-specific Models of Bladder Cancer

    Saito Ryoichi, Matsumoto Keiyu, Murakami Kaoru, Kita Yuki, Akamatsu Shusuke, Kobayashi Takashi, Yamasaki Toshinari, Inoue Takahiro, Ogawa Osamu

    CANCER SCIENCE   Vol. 109   page: 166 - 166   2018.1

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  153. Retrotransposon-derived protein PEG10 affect PTEN ubiquitination by WWP2 in neuroendocrine prostate cancer

    Okasho Kosuke, Akamatsu Shusuke, Kawai Yoshihisa, Mizuno Kei, Li Xin, Sumiyoshi Takayuki, Makino Yuki, Goto Takayuki, Kobayashi Takashi, Inoue Takahiro, Ogawa Osamu

    CANCER SCIENCE   Vol. 109   page: 1071 - 1071   2018.1

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  154. The usefulness of testosterone administration in identifying false-positive elevation of serum human chorionic gonadotropin in patients with germ cell tumor

    Takizawa Akitoshi, Kawai Koji, Kawahara Takashi, Kojima Takahiro, Maruyama Satoru, Shinohara Nobuo, Akamatsu Shusuke, Kamba Tomomi, Nakamura Terukazu, Ukimura Osamu, Jikuya Ryosuke, Kishida Takeshi, Kakimoto Kenichi, Nishimura Kazuo, Harabayashi Toru, Nagamori Satoshi, Yamashita Shinichi, Arai Yoichi, Sawada Yoshitomo, Sekido Noritoshi, Kinoshita Hidefumi, Matsuda Tadashi, Nakagawa Tohru, Homma Yukio, Nishiyama Hiroyuki

    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY   Vol. 144 ( 1 ) page: 109 - 115   2018.1

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    Objective: The pituitary production of human chorionic gonadotropin (hCG) can cause false-positive results during or after germ cell tumor (GCT) treatment. Because hypogonadism leads to pituitary hCG production, testosterone administration test (TAT) has been recommended for pituitary hCG diagnosis. However, little is known about its efficacy for the discrimination of pituitary hCG as detected by currently used hCG assays in treatment of GCT. We conducted a retrospective multicenter study to determine the usefulness of TAT. Materials and methods: The study included 60 patients who underwent TAT for the discrimination of pituitary hCG. In principle, serum hCG levels were measured 1 week after testosterone enanthate administration (250 mg). When the serum hCG levels decreased below the normal upper range, the results of TAT were determined positive. In this case, the elevated hCG was considered to be derived from pituitary and not from GCT. Results: Serum hCG levels were normalized after TAT in 36 of 60 patients (60%). Before TAT, the hCG levels were below 1.0 IU/L in 13 patients (36%), 1.0–1.9 IU/L in 11 (31%), 2.0–2.9 IU/L in 7 (19%), and >3.0 IU/L in 5 (14%) of TAT-positive patients. Of them, 28 (78%) patients were successfully managed without further treatment with chemotherapy after TAT. Pituitary hCG was associated with higher levels of LH and not necessarily associated with low levels of testosterone. Conclusion: Determining the TAT status of patients was effective in discriminating pituitary hCG production.

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  155. Safe and effective administration of BCG for bladder carcinoma in situ after umbilical cord blood stem cell transplantation

    Magaribuchi Toshihiro, Akamatsu Shusuke, Kobayashi Takashi, Kawabata Hiroshi, Yamasaki Toshinari, Inoue Takahiro, Ogawa Osamu

    TRANSPLANT INFECTIOUS DISEASE   Vol. 19 ( 6 )   2017.12

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    Although intravesical Bacillus Calmette-Guérin (BCG) instillation is the standard treatment for carcinoma in situ of the bladder, it is generally contraindicated in immunocompromised patients. Here we report the first case, to our knowledge, of BCG treatment for a bladder cancer patient who had received umbilical cord blood stem cell transplantation (UCBSCT). BCG can be given safely and effectively in select cases where reconstitution of the immune system has been achieved at least 2 years after UCBSCT.

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  156. Simultaneous Hepatorenal Transplantation from a Brain-Dead Donor for Graft Dysfunction and Renal Insufficiency in a Liver Transplant Recipient : A Case Report

    Takada Hideaki, Kobayashi Takashi, Ogawa Kohei, Miyata Hitomi, Sawada Atsuro, Akamatsu Shusuke, Negoro Hiromitsu, Saito Ryoichi, Terada Naoki, Yamasaki Toshinari, Inoue Takahiro, Teramoto Yuki, Shibuya Shinsuke, Haga Hironori, Kaido Toshimi, Uemoto Shinji, Ogawa Osamu

      Vol. 63 ( 8 ) page: 313 - 318   2017.8

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    We report a case of lethal hepatorenal insufficiency in a 52-year-old man who received successful simultaneous hepatorenal transplantation from a deceased donor. The patient had undergone live-donor liver transplantation for type-C hepatitis and liver cirrhosis 11 years before he developed graft liver dysfunction due to recurrent viral hepatitis and cirrhosis. At that instance, he also developed end-stage renal dysfunction due to calcineurin inhibitor nephropathy and hepatorenal syndrome. Although he needed three open hemostases and abundant blood transfusion, he was withdrawn from continuous hemodiafiltration on the 55th day and discharged from the hospital on the 272nd day postoperatively. Simultaneous hepatorenal transplantation was reported to be associated with more favorable outcomes of graft function, lower rejection rates, but higher perioperative complication rates compared with liver transplantation alone in patients on hemodialysis. Particularly, close attention should be paid for hemostasis since patients have a hemorrhagic tendency until the recovery of graft liver function.

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  157. Prognostic and predictive biomarkers in prostate cancer: latest evidence and clinical implications

    Terada Naoki, Akamatsu Shusuke, Kobayashi Takashi, Inoue Takahiro, Ogawa Osamu, Antonarakis Emmanuel S.

    THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY   Vol. 9 ( 8 ) page: 565 - 573   2017.8

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    Advances in our understanding of the mechanisms driving castration-resistant prostate cancer have promoted the development of several new drugs including androgen receptor-directed therapy and chemotherapy. Concomitant docetaxel treatment at the beginning of hormonal therapy for metastatic prostate cancer has resulted in longer overall survival than with hormonal therapy alone. Elucidating an appropriate treatment sequence using these therapies is important for maximizing clinical benefit in castration-sensitive and castration-resistant prostate cancer patients. The development of advanced high-throughput 'omics' technology has enabled the use of novel markers to guide prognosis and treatment of this disease. In this review, we outline the genomic landscape of prostate cancer and the molecular mechanisms of castration-resistant progression, and how these affect the development of new drugs, and their clinical implications for selecting treatment sequence. We also discuss many of the potential tissue-based or liquid biomarkers that may soon enter clinical use, with the hope that several of these prognostic or predictive markers will guide precision medicine for prostate cancer patients in the near future.

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  158. A 45,X/46,XY Male with Orchidopexy Diagnosed with Mixed Germ Cell Tumor After 21-year Follow-up

    Kubota M., Terada N., Ito K., Takada H., Magaribuchi T., Sawada A., Akamatsu S., Negoro H., Saito R., Kobayashi T., Yamasaki T., Inoue T., Ogawa O.

    Urology Case Reports   Vol. 13   page: 120 - 122   2017.7

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    A case of a 45,X/46,XY boy with gonadal dysgenesis is presented. The patient showed hypospadias and right undescended testis. He underwent underwent repair surgery for hypospadias, right orchidopexy, and bilateral testicular biopsy. Testicular biopsy revealed no malignant finding. He was followed-up annually by scrotum palpation. When the patient grew up to 24 years old, he was diagnosed to have right testicular tumor. High orchiectomy revealed pT1 seminoma. The management of undescended testis in men with gonadal dysgenesis and disordered sexual development is discussed.

    DOI: 10.1016/j.eucr.2017.04.001

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  159. Exploring the optimal sequence of abiraterone and enzalutamide in patients with chemotherapy-naive castration-resistant prostate cancer: The Kyoto-Baltimore collaboration

    Terada Naoki, Maughan Benjamin L., Akamatsu Shusuke, Kobayashi Takashi, Yamasaki Toshinari, Inoue Takahiro, Kamba Tomomi, Ogawa Osamu, Antonarakis Emmanuel S.

    INTERNATIONAL JOURNAL OF UROLOGY   Vol. 24 ( 6 ) page: 441 - 448   2017.6

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    Objectives: To evaluate and compare the efficacy of sequential treatment with abiraterone followed by enzalutamide or vice versa for castration-resistant prostate cancer. Methods: We retrospectively evaluated data on 198 consecutive chemotherapy-naïve patients who had received both abiraterone and enzalutamide for castration-resistant prostate cancer at Kyoto University Hospital (including satellite hospitals) and at Johns Hopkins Cancer Center. Prostate-specific antigen progression-free survival and overall survival in patients treated with sequential abiraterone-to-enzalutamide versus enzalutamide-to-abiraterone without intervening therapies were compared. Results: Overall, 113 patients were treated with the abiraterone-to-enzalutamide sequence and 85 with the enzalutamide-to-abiraterone sequence. Median prostate-specific antigen progression-free survival was not significantly different between abiraterone and enzalutamide in the first-line setting (hazard ratio 0.88, 95% confidence interval 0.66–1.19, P = 0.412), but there was an advantage favoring enzalutamide compared with abiraterone in the second-line setting (hazard ratio 0.67, 95% confidence interval 0.49–0.91, P = 0.009). Furthermore, the combined prostate-specific antigen progression-free survival was significantly longer in the abiraterone-to-enzalutamide sequence than in the enzalutamide-to-abiraterone sequence (hazard ratio 0.56, 95% confidence interval 0.41–0.76, P < 0.001). The difference was significant even in multivariate analyses (hazard ratio 0.65, 95% confidence interval 0.42–0.99, P = 0.044). There was no statistical difference in overall survival between the two sequences in univariate (hazard ratio 0.88, 95% confidence interval 0.53–1.43, P = 0.599) and multivariate analyses (hazard ratio 0.81, 95% confidence interval 0.49–1.35, P = 0.427). Conclusions: The abiraterone-to-enzalutamide sequence might have more favorable efficacy in terms of combined prostate-specific antigen progression-free survival than the enzalutamide-to-abiraterone sequence, although no differences in overall survival were observed. This could possibly be attributable to longer prostate-specific antigen progression-free survival with second-line enzalutamide compared with abiraterone.

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  160. A Case of Thyroid-Like Follicular Carcinoma of the Kidney

    Ito Katsuhiro, Negoro Hiromitsu, Kubota Masashi, Takada Hideaki, Magaribuchi Toshihiro, Sawada Atsuro, Akamatsu Shusuke, Kobayashi Takashi, Terada Naoki, Yamasaki Toshinari, Inoue Takahiro, Kamba Tomomi, Teramoto Yuki, Ogawa Osamu

      Vol. 63 ( 4 ) page: 145 - 149   2017.4

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    A 51-year-oldwoman with a right renal mass was referredto our hospital. Computedtomographic (CT) scan demonstrated a 30 mm-diameter renal mass with delayed enhancement. She underwent a robotassistedlaparoscopic right partial nephrectomy. The pathological examination showedthat tumor cells with eosinophilic, clear cytoplasm formedtubules of various sizes containing colloid-like material, which resembled the findings of thyroidfollicular carcinoma. The tumor was immunoreactive for vimentin andcytokeratin (CK) 7, whereas it lackedreactivity for thyroidtranscription factor-1 (TTF-1) or thyroglobulin. No tumors were detectedin the thyroidglandor other organs of the patient. Subsequently, the diagnosis of thyroidlike follicular carcinoma of the kidney (TLFCK) was determined. At 4 months postoperatively, the patient is alive with no evidence of disease recurrence. TLFCK is an extremely rare subtype of renal cancer, and only 26 cases have been reportedpreviously. We provide a brief literature review on this cancer.

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  161. A case of thyroid-like follicular carcinoma of the Kidney

    Ito K., Negoro H., Kubota M., Takada H., Magaribuchi T., Sawada A., Akamatsu S., Kobayashi T., Terada N., Yamasaki T., Inoue T., Kamba T., Teramoto Y., Ogawa O.

    Acta Urologica Japonica   Vol. 63 ( 4 ) page: 145 - 149   2017.4

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    A 51-year-old woman with a right renal mass was referred to our hospital. Computed tomographic (CT) scan demonstrated a 30 mm-diameter renal mass with delayed enhancement. She underwent a robot-assisted laparoscopic right partial nephrectomy. The pathological examination showed that tumor cells with eosinophilic, clear cytoplasm formed tubules of various sizes containing colloid-like material, which resembled the findings of thyroid follicular carcinoma. The tumor was immunoreactive for vimentin and cytokeratin (CK) 7, whereas it lacked reactivity for thyroid transcription factor-1 (TTF-1) or thyroglobulin. No tumors were detected in the thyroid gland or other organs of the patient. Subsequently, the diagnosis of thyroidlike follicular carcinoma of the kidney (TLFCK) was determined. At 4 months postoperatively, the patient is alive with no evidence of disease recurrence. TLFCK is an extremely rare subtype of renal cancer, and only 26 cases have been reported previously. We provide a brief literature review on this cancer.

    DOI: 10.14989/ActaUrolJap-63-4-145

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  162. Factors predicting efficacy and adverse effects of enzalutamide in Japanese patients with castration-resistant prostate cancer: results of retrospective multi-institutional study

    Terada Naoki, Akamatsu Shusuke, Okada Yoshiyuki, Negoro Hiromitsu, Kobayashi Takashi, Yamasaki Toshinari, Matsui Yoshiyuki, Inoue Takahiro, Kamba Tomomi, Ogawa Osamu

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 21 ( 6 ) page: 1155 - 1161   2016.12

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    Background: We aimed to evaluate the factors predicting efficacy and adverse effects of enzalutamide in patients with castration-resistant prostate cancer. Methods: We retrospectively evaluated data on 345 patients who had received enzalutamide for castration-resistant prostate cancer in 20 hospitals (Kyoto University Hospital and other satellite hospitals). Cox proportional hazards regression analysis was performed to identify factors predicting prostate-specific antigen (PSA) progression after enzalutamide treatment and logistic regression analysis for those associated with development of adverse effects. Results: PSA titers decreased by >50 % in 197 patients (57 %). The median PSA progression free survival was 163 days. Gleason score >8 (HR 2.078, 95 % CI 1.37–3.153, P = 0.00058), performance status ≥1 (HR 2.292, 95 % CI 1.463–3.592, P = 0.000296), presence of bone metastasis (HR 1.774, 95 % CI 1.019–3.090, P = 0.0429), visceral metastasis (HR 2.127, 95 % CI 1.215–3.722, P = 0.00823), previous steroid treatment (HR 1.780, 95 % CI 1.207–2.626, P = 0.00361) and docetaxel treatment (HR 1.602, 95 % CI 1.051–2.442, P = 0.0284) significantly predicted the efficacy of enzalutamide. Adverse effects, including fatigue or appetite loss, occurred in 169 patients (49 %), 48 (18 %) of whom stopped enzalutamide. Age >75 years (HR 1.980, 95 % CI 1.270–3.09, P = 0.00246) and lower enzalutamide dose (HR 0.437, 95 % CI 0.255–1.270, P = 0.00249) were significantly associated with development of adverse effects. Conclusions: Enzalutamide treatment is effective in patients with castration-resistant prostate cancer with low Gleason scores, good performance status, without bone or visceral metastasis and no prior steroid or docetaxel treatment. Lower doses of enzalutamide decrease the incidence of adverse effects, especially in older patients.

    DOI: 10.1007/s10147-016-1004-y

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  163. Deceased Donor Kidney Transplantation from a Liver Transplantation Recipient

    Koike Shuhei, Kobayashi Takashi, Okada Yoshiyuki, Shibuya Shinsuke, Sakai Kaoru, Tanaka Yukari, Akamatsu Shusuke, Negoro Hiromitsu, Terada Naoki, Yamasaki Toshinari, Matsui Yoshiyuki, Inoue Takahiro, Kamba Tomomi, Umeya Yumi, Kaido Toshimi, Ogawa Osamu

      Vol. 62 ( 10 ) page: 529 - 534   2016.10

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    We report a 40-year-old man with end-stage renal disease due to IgA nephropathy who underwent deceased donor kidney transplantation. The donor was diagnosed to be brain-dead due to cerebral hemorrhage after her second liver transplantation for non-viral liver cirrhosis. Intraoperative 1-hour biopsy of the graft kidney revealed moderate global glomerular sclerosis (22%) and interstitial fibrosis (40%) consistent with underlying nephrosclerosis or calcineurin inhibitor nephrotoxicity. Although hemodialysis was needed until the graft began functioning several days after the kidney transplantation, the postoperative clinical course thereafter was uneventful and the graft functioned well with stable serum creatinine levels around 2.4 mg/dl at 6 monthspos toperatively.

    DOI: 10.14989/actauroljap_62_10_529

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  164. Deceased donor kidney transplantation from a liver transplantation recipient

    Koike S., Kobayashi T., Okada Y., Shibuya S., Sakai K., Tanaka Y., Akamatsu S., Negoro H., Terada N., Yamasaki T., Matsui Y., Inoue T., Kamba T., Umeya Y., Kaido T., Ogawa O.

    Acta Urologica Japonica   Vol. 62 ( 10 ) page: 529 - 534   2016.10

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    We report a 40-year-old man with end-stage renal disease due to IgA nephropathy who underwent deceased donor kidney transplantation. The donor was diagnosed to be brain-dead due to cerebral hemorrhage after her second liver transplantation for non-viral liver cirrhosis. Intraoperative 1-hour biopsy of the graft kidney revealed moderate global glomerular sclerosis (22%) and interstitial fibrosis (40%) consistent with underlying nephrosclerosis or calcineurin inhibitor nephrotoxicity. Although hemodialysis was needed until the graft began functioning several days after the kidney transplantation, the postoperative clinical course thereafter was uneventful and the graft functioned well with stable serum creatinine levels around 2.4 mg/dl at 6 months postoperatively.

    DOI: 10.14989/ActaUrolJap_62_10_52)

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  165. An original patient-derived xenograft of prostate cancer with cyst formation

    Yoshikawa Takeshi, Kobori Go, Goto Takayuki, Akamatsu Shusuke, Terada Naoki, Kobayashi Takashi, Tanaka Yoshinori, Jung Giman, Kamba Tomomi, Ogawa Osamu, Inoue Takahiro

    PROSTATE   Vol. 76 ( 11 ) page: 994 - 1003   2016.8

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    BACKGROUND: The high rate of failure of new agents in oncology clinical trials indicates a weak understanding of the complexity of human cancer. Recent understanding of the mechanisms underlying castration resistance in prostate cancer led to the development of new agents targeting the androgen receptor pathway; however, their effectiveness is limited. Hence, there is a need for experimental systems that are able to better reproduce the biological diversity of prostate cancer in preclinical settings. In this study, we established a unique patient-derived xenograft (PDX) model to identify biomarkers for treatment efficacy and resistance and better understand prostate cancer biology. METHODS: A prostate cancer tissue sample from a Japanese patient was transplanted subcutaneously into male, severe combined immune-deficient (SCID) mice and this PDX mouse model was named KUCaP3. Sequential tumor volume changes were observed before and after castration. Androgen receptor (AR), prostate-specific antigen (PSA), and other molecular markers were examined immunohistochemically. Sequence analysis of AR was also performed to detect mutations. Proteomic analysis of cyst fluid and sera samples of KUCaP3 mice were analyzed by mass spectrometry (MS). RESULTS: KUCaP3 cell line, derived from human tissue, was successfully and serially passaged in vivo with approximately 60% take rate. KUCaP3 exhibited cyst formation, showed androgen-dependent growth initially, and developed castration-resistant growth several months after castration of the mice. Immunohistochemical analysis showed that KUCaP3 was positive for AR, PSA, CK18, and α-methyl acyl-coenzyme A racemase, but negative for CK5/6 and ERG. The AR gene in KUCaP3 cells contained a substitution from CAT (histidine) to TAT (tyrosine) at the nucleotide positions corresponding to codon 875 (H875Y) in the ligand-binding domain. Chemiluminescent immunoassay revealed higher levels of PSA in cystic fluid and the serum of KUCaP3-bearing mice. MS analysis detected 23 proteins of human origin in cystic fluids of KUCaP3. CONCLUSIONS: We developed KUCaP3, an androgen-dependent PDX model with cyst formation. Several proteins including PSA were detected in the cystic fluid and sera of tumor-bearing mice. This original PDX model has the potential to be used as a clinically relevant model to evaluate molecular markers for prostate cancer diagnosis and treatment. Prostate 76:994–1003, 2016. © 2016 Wiley Periodicals, Inc.

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  166. POPULATION-BASED SURVEY OF OVERACTIVE BLADDER IN JAPAN: A CROSS-SECTIONAL ANALYSIS OF THE NAGAHAMA STUDY

    Funada S., Kawaguchi T., Terada N., Negoro H., Akamatsu S., Kobayashi T., Yamasaki T., Inoue T., Kamba T., Yoshimura K., Matsuda F., Ogawa O.

    NEUROUROLOGY AND URODYNAMICS   Vol. 35   page: S288 - S289   2016.8

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  167. A Prospective Randomized Trial Comparing a Combined Regimen of Amikacin and Levofloxacin to Levofloxacin Alone as Prophylaxis in Transrectal Prostate Needle Biopsy.

    Miyazaki Y, Akamatsu S, Kanamaru S, Kamiyama Y, Sengiku A, Iguchi R, Sano T, Takahashi A, Ito M, Takenawa J, Ito N, Ogura K

    Urology journal   Vol. 13 ( 1 ) page: 2533 - 40   2016.3

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  168. Effective and Safe Administration of Low-Dose Estramustine Phosphate for Castration-Resistant Prostate Cancer

    Inoue Takahiro, Ogura Keiji, Kawakita Mutushi, Tsukino Hiromasa, Akamatsu Shusuke, Yamasaki Toshinari, Matsui Yoshiyuki, Segawa Takehiko, Sugino Yoshio, Kamoto Toshiyuki, Kamba Tomomi, Tanaka Shiro, Ogawa Osamu

    CLINICAL GENITOURINARY CANCER   Vol. 14 ( 1 ) page: E9 - E17   2016.2

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    Background We evaluated the efficacy and safety of low-dose estramustine phosphate (EMP) in Japanese patients with castration-resistant prostate cancer (CRPC). Patients and Methods The present study was a single-arm, nonrandomized prospective study in which all patients received EMP orally twice daily for a total dose of 280 mg/day. A total of 31 patients with CRPC were enrolled from December 2009 to December 2012 at 5 institutions in Japan. The primary endpoint was the prostate-specific antigen (PSA) response, defined as a 50% decline in the serum PSA level, confirmed ≥ 3 weeks later. The secondary endpoints included the objective response rate, interval to PSA progression, PSA response duration, progression-free survival, disease-specific survival, overall survival, safety, and quality-of-life assessment using the Functional Assessment of Cancer Therapy-Prostate scores. Results Ten patients (32%) had a PSA response, and no patient had an objective response. The treatment was well tolerated, and the most frequent toxicities were grade 1 to 2 nausea/vomiting, anorexia, and gynecomastia. The median interval to PSA progression was 140 days (95% confidence interval [CI], 117-260 days). The PSA response duration was 119 days (95% CI, 49-219 days). The median progression-free survival was 213 days (95% CI, 167-422 days). The 3-year disease-specific survival and overall survival rates were 68.6% (median not reached; 95% CI, 33 months to not available) and 59.9% (median 42 months, 95% CI, 28 months to not available), respectively. Conclusion Low-dose EMP seems to be a safe treatment option with some efficacy in patients with CRPC.

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  169. A prospective randomized trial comparing a combined regimen of amikacin and levofloxacin to levofloxacin alone as prophylaxis in transrectal prostate needle biopsy

    Miyazaki Y., Akamatsu S., Kanamaru S., Kamiyama Y., Sengiku A., Iguchi R., Sano T., Takahashi A., Ito M., Takenawa J., Ito N., Ogura K.

    Urology Journal   Vol. 13 ( 1 ) page: 2533 - 2540   2016.1

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    Purpose: We investigated whether addition of amikacin to levofloxacin-based antimicrobial prophylaxis reduces febrile urinary tract infections after transrectal ultrasound-guided prostate needle biopsy (TRUSB). Materials and Methods: A total of 447 patients undergoing TRUSB were prospectively randomized into two groups. The 230 patients in Group A were given one oral dose of levofloxacin 400 mg prior to TRUSB; the 217 patients in Group B each received the same dose of levofloxacin and one 200 mg intravenous dose of amikacin. Patients' characteristics were assessed prior to TRUSB and their symptoms were checked after the TRUSB. Results: Both regimens were well tolerated with no side effects. No statistically significant difference in patients' characteristics, or in incidence of inflammation- or infection-related symptoms was seen between the two groups; nor any significant difference among those who developed fever and those who did not. Two Group A patients and one Group B patient developed febrile urinary tract infections. Accountable pathogens determined by urine and blood cultures were fluoroquinolone-resistant E.coli and extended-spectrum β-lactamase-producing E.coli. All pathogens isolated were levofloxacin-resistant, amikacin-susceptible species. Conclusion: Although the present study was under-powered by unexpectedly low overall incidence of febrile urinary tract infections, addition of one intravenous administration of amikacin to one oral administration of levofloxacin showed no advantage compared with levofloxacin alone as antimicrobial prophylaxis in TRUSB. Strikingly, all pathogens isolated from febrile patients were sensitive to amikacin in vitro. Therefore, further understanding of amikacin's drug kinetics in the prostate is necessary to develop a more efficient drug delivery system for amikacin.

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  170. A Prospective Randomized Trial Comparing a Combined Regimen of Amikacin and Levofloxacin to Levofloxacin Alone as Prophylaxis in Transrectal Prostate Needle Biopsy

    Miyazaki Yu, Akamatsu Shusuke, Kanamaru Sojun, Kamiyama Yuki, Sengiku Atsushi, Iguchi Ryo, Sano Takeshi, Takahashi Akira, Ito Masaaki, Takenawa Jun, Ito Noriyuki, Ogura Keiji

    UROLOGY JOURNAL   Vol. 13 ( 1 ) page: 2533 - 2540   2016

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  171. Plasma Low-Molecular-Weight Proteome Profiling Identified Neuropeptide-Y as a Prostate Cancer Biomarker Polypeptide

    Ueda Koji, Tatsuguchi Ayako, Saichi Naomi, Toyama Atsuhiko, Tamura Kenji, Furihata Mutsuo, Takata Ryo, Akamatsu Shusuke, Igarashi Masahiro, Nakayama Masato, Sato Taka-Aki, Ogawa Osamu, Fujioka Tomoaki, Shuin Taro, Nakamura Yusuke, Nakagawa Hidewaki

    JOURNAL OF PROTEOME RESEARCH   Vol. 12 ( 10 ) page: 4497 - 4506   2013.10

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    In prostate cancer diagnosis, PSA test has greatly contributed to the early detection of prostate cancer; however, expanding overdiagnosis and unnecessary biopsies have emerged as serious issues. To explore plasma biomarkers complementing the specificity of PSA test, we developed a unique proteomic technology QUEST-MS (Quick Enrichment of Small Targets for Mass Spectrometry). The QUEST-MS method based on 96-well formatted sequential reversed-phase chromatography allowing efficient enrichment of <20 kDa proteins quickly and reproducibly. Plasma from 24 healthy controls, 19 benign prostate hypertrophy patients, and 73 prostate cancer patients were purified with QUEST-MS and analyzed by LC/MS/MS. Among 153 057 nonredundant peptides, 189 peptides showed prostate cancer specific detection pattern, which included a neurotransmitter polypeptide neuropeptide-Y (NPY). We further validated the screening results by targeted multiple reaction monitoring technology using independent sample set (n = 110). The ROC curve analysis revealed that logistic regression-based combination of NPY, and PSA showed 81.5% sensitivity and 82.2% specificity for prostate cancer diagnosis. Thus QUEST-MS technology allowed comprehensive and high-throughput profiling of plasma polypeptides and had potential to effectively uncover very low abundant tumor-derived small molecules, such as neurotransmitters, peptide hormones, or cytokines. © 2013 American Chemical Society.

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  172. Reproducibility, Performance, and Clinical Utility of a Genetic Risk Prediction Model for Prostate Cancer in Japanese

    Akamatsu Shusuke, Takahashi Atsushi, Takata Ryo, Kubo Michiaki, Inoue Takahiro, Morizono Takashi, Tsunoda Tatsuhiko, Kamatani Naoyuki, Haiman Christopher A., Wan Peggy, Chen Gary K., Le Marchand Loic, Kolonel Laurence N., Henderson Brian E., Fujioka Tomoaki, Habuchi Tomonori, Nakamura Yusuke, Ogawa Osamu, Nakagawa Hidewaki

    PLOS ONE   Vol. 7 ( 10 )   2012.10

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    Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1-10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies. © 2012 Akamatsu et al.

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  173. Reproducibility, performance, and clinical utility of a genetic risk prediction model for prostate cancer in Japanese patients.

    Akamatsu Shusuke, Takata Ryo, Takahashi Atsushi, Inoue Takahiro, Kubo Michiaki, Kamatani Naoyuki, Inazawa Johji, Fujioka Tomoaki, Habuchi Tomonori, Ogawa Osamu, Nakamura Yusuke, Nakagawa Hidewaki

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 30 ( 15 )   2012.5

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  174. IRX4 at 5p15 suppresses prostate cancer growth through the interaction with vitamin D receptor, conferring prostate cancer susceptibility

    Hai Ha Nguyen, Takata Ryo, Akamatsu Shusuke, Shigemizu Daichi, Tsunoda Tatsuhiko, Furihata Mutsuo, Takahashi Atsushi, Kubo Michiaki, Kamatani Naoyuki, Ogawa Osamu, Fujioka Tomoaki, Nakamura Yusuke, Nakagawa Hidewaki

    HUMAN MOLECULAR GENETICS   Vol. 21 ( 9 ) page: 2076 - 2085   2012.5

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    Recent genome-wide association studies (GWAS) identified a number of prostate cancer (PC) susceptibility loci, but most of their functional significances are not elucidated. Through our previous GWAS for PC in a Japanese population and subsequent resequencing and fine mapping, we here identified that IRX4 (Iroquois homeobox 4), coding Iroquois homeobox 4, is a causative gene of the PC susceptibility locus (rs12653946) at chromosome 5p15. IRX4 is expressed specifically in the prostate and heart, and quantitative expression analysis revealed a significant association between the genotype of rs12653946 and IRX4 expression in normal prostate tissues. Knockdown of IRX4 in PC cells enhanced their growth and IRX4 overexpression in PC cells suppressed their growth, indicating the functional association of IRX4 with PC and its tumor suppressive effect. Immunoprecipitation confirmed its protein-protein interaction to vitamin D receptor (VDR), and we found a significant interaction between IRX4 and VDR in their reciprocal transcriptional regulation. These findings indicate that the PC-susceptibility locus represented by rs12653946 at 5p15 is likely to regulate IRX4 expression in prostate which could suppress PC growth by interacting with the VDR pathway, conferring to PC susceptibility. © The Author 2012. Published by Oxford University Press. All rights reserved.

    DOI: 10.1093/hmg/dds025

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  175. Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese

    Akamatsu Shusuke, Takata Ryo, Haiman Christopher A., Takahashi Atsushi, Inoue Takahiro, Kubo Michiaki, Furihata Mutsuo, Kamatani Naoyuki, Inazawa Johji, Chen Gary K., Le Marchand Loic, Kolonel Laurence N., Katoh Takahiko, Yamano Yuko, Yamakado Minoru, Takahashi Hiroyuki, Yamada Hiroki, Egawa Shin, Fujioka Tomoaki, Henderson Brian E., Habuchi Tomonori, Ogawa Osamu, Nakamura Yusuke, Nakagawa Hidewaki

    NATURE GENETICS   Vol. 44 ( 4 ) page: 426 - U234   2012.4

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    We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 x 10 -4) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 x 10 -10; FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 x 10 -8) and 3p11.2 (rs2055109; P = 3.94 x 10 -8). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 x 10 -7). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations. © 2012 Nature America, Inc. All rights reserved.

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  176. Prostate cancer genomics, biology, and risk assessment through genome-wide association studies

    Nakagawa Hidewaki, Akamatsu Shusuke, Takata Ryo, Takahashi Atsushi, Kubo Michiaki, Nakamura Yusuke

    CANCER SCIENCE   Vol. 103 ( 4 ) page: 607 - 613   2012.4

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    Prostate cancer (PC) is the most common malignancy observed in men. It is evident that genetic factors play some important roles in PC etiology. Recently, genome-wide association studies in diverse ethnic groups have identified more than 40 germline variants of various genes or chromosomal loci that are significantly associated with PC susceptibility, including multiple 8q24 loci, prostate-specific genes, metabolic and hormone-related genes, and many regions where no coding gene is annotated. However, there are only a few variants or genes for which biological significance or functions have been elucidated so far. The greatest challenge related to genome-wide association studies loci in prostate genomics is to understand the functional consequences of these PC-associated loci and their involvement in PC biology and carcinogenesis. There have been attempts to determine PC risk estimations by combining multiple PC-associated variants for clinical tests, and these can identify a very minor population with high risk of PC. However, they cannot distinguish risk of aggressive PC from that of non-aggressive PC. Further identification of PC-susceptibility loci in larger genome-wide association studies cohorts and biological insights gained from such functional analyses have the potential to translate into clinical benefits, including the development of reliable biomarkers, risk estimation, and effective strategies for screening and prevention of PC. © 2011 Japanese Cancer Association.

    DOI: 10.1111/j.1349-7006.2011.02193.x

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  177. Four loci at 11q12, 10q26, 3p11.2, and 2p11 are associated with prostate cancer susceptibility in the Japanese population

    Akamatsu S., Takata R., Haiman C. A., Inoue T., Takahashi A., Kubo M., Furihata M., Kamatani N., Inazawa J., Chen G. K., Marchand L. L., Kolonel L. N., Yamada H., Egawa S., Fujioka T., Henderson B. E., Habuchi T., Ogawa O., Nakamura Y., Nakagawa H.

    EUROPEAN UROLOGY SUPPLEMENTS   Vol. 11 ( 1 ) page: E434 - U950   2012.2

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  178. APP-033 A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression(総会賞応募ポスター,第99回日本泌尿器科学会総会)

    赤松 秀輔, 高田 亮, 久保 充明, 鎌谷 直之, 藤岡 知昭, 小川 修, 中村 祐輔, 中川 英刀

    日本泌尿器科学会雑誌   Vol. 102 ( 2 ) page: 309   2011

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    Language:Japanese   Publisher:一般社団法人 日本泌尿器科学会  

    DOI: 10.5980/jpnjurol.102.309_1

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  179. PP-276 経直腸的前立腺生検における予防的抗菌剤の検討 : アミノグリコシドの有用性(一般演題ポスター発表・討論,一般演題ポスター,第99回日本泌尿器科学会総会)

    宮崎 有, 赤松 秀輔, 金丸 聰淳, 上山 裕樹, 千菊 敦士, 井口 亮, 高橋 彰, 伊藤 哲之, 小倉 啓司

    日本泌尿器科学会雑誌   Vol. 102 ( 2 ) page: 449   2011

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    DOI: 10.5980/jpnjurol.102.449_5

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  180. PP-511 去勢抵抗性前立腺癌の治療標的探索のための新規xenograftにおけるmicroRNA発現解析(発表・討論,一般演題ポスター,第99回日本泌尿器科学会総会)

    前野 淳, 岡田 能幸, 小堀 豪, 赤松 秀輔, 清木 洋祐, 井上 貴博, 神波 大己, 小川 修

    日本泌尿器科学会雑誌   Vol. 102 ( 2 ) page: 489   2011

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    DOI: 10.5980/jpnjurol.102.489_2

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  181. 医道白寿5-2-1 日本人の前立腺癌に関連する遺伝子多型の同定とその臨床的意義(泌尿器科分野におけるゲノム医療の挑戦,第2部:ワークショップ,5.臨床遺伝学,医道白寿企画,第99回日本泌尿器科学会総会)

    高田 亮, 赤松 秀輔, 中川 英刀, 久保 充明, 小川 修, 稲澤 譲治, 中村 祐輔, 藤岡 知昭

    日本泌尿器科学会雑誌   Vol. 102 ( 2 ) page: 168   2011

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    DOI: 10.5980/jpnjurol.102.168_1

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  182. A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression

    Akamatsu Shusuke, Takata Ryo, Ashikawa Kyota, Hosono Naoya, Kamatani Naoyuki, Fujioka Tomoaki, Ogawa Osamu, Kubo Michiaki, Nakamura Yusuke, Nakagawa Hidewaki

    HUMAN MOLECULAR GENETICS   Vol. 19 ( 21 ) page: 4265 - 4272   2010.11

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    Genome-wide association studies (GWAS) identified multiple susceptible loci for prostate cancer (PC), and recent GWAS implicated that a common variant rs1512268 on chromosome 8p21 is associated with PC susceptibility, which is located at 14 kb downstream of a prostate tumor suppressor gene NKX3.1. To clarify a susceptibility gene and functional variants in this locus, we performed re-sequencing and fine mapping of this region and identified 12 candidates of functional single nucleotide polymorphisms that were absolutely linked with each other. Screening of these variants by RNA stability assay, electrophoretic mobility shift assay (EMSA) and reporter assay indicated that rs11781886 in the 5′-UTR of NKX3.1 displayed different binding affinity to nuclear proteins between the alleles, and that the transcriptional activity of the NKX3.1 promoter was significantly lower in the susceptible allele of this variant. Sp1 was determined to be the transcription factor that binds to the susceptible G allele, but not to the non-susceptible A allele. Allele-specific transcript quantification (ASTQ) and quantitative PCR analyses showed that the expression of NKX3.1 in the prostate was significantly lower in the subjects with the haplotype carrying the susceptible allele. These results suggest that the functional variant rs11781886 in the 5′-UTR of NKX3.1 can affect its transcription by altering the binding affinity of a transcriptional factor Sp1, and might result in PC susceptibility by lowering expression of NKX3.1 in the prostate. © The Author 2010. Published by Oxford University Press. All rights reserved.

    DOI: 10.1093/hmg/ddq350

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  183. Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population

    Takata Ryo, Akamatsu Shusuke, Kubo Michiaki, Takahashi Atsushi, Hosono Naoya, Kawaguchi Takahisa, Tsunoda Tatsuhiko, Inazawa Johji, Kamatani Naoyuki, Ogawa Osamu, Fujioka Tomoaki, Nakamura Yusuke, Nakagawa Hidewaki

    NATURE GENETICS   Vol. 42 ( 9 ) page: 751 - U34   2010.9

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    Prostate cancer is one of the most common malignancies in males throughout the world1, and its incidence is increasing in Asian countries. We carried out a genome-wide association study and replication study using 4,584 Japanese men with prostate cancer and 8,801 control subjects. From the thirty-one associated SNPs reported in previous genome-wide association studies in European populations, we confirmed the association of nine SNPs at P < 1.0 x 10-7 and ten SNPs at P < 0.05 in the Japanese population. The remaining 12 SNPs showed no association (P > 0.05). In addition, we report here five new loci for prostate cancer susceptibility, at 5p15 (λ -corrected probability PGC = 3.9 x 10-18), GPRC6A/RFX6 (PGC = 1.6 x 10-12), 13q22 (PGC = 2.8 x 10-9), C2orf43 (PGC = 7.5 x 10-8) and FOXP4 (PGC = 7.6 x 10-8). These findings advance our understanding of the genetic basis of prostate carcinogenesis and also highlight the genetic heterogeneity of prostate cancer susceptibility among different ethnic populations. © 2010 Nature America, Inc. All rights reserved.

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  184. PP-151 表在性膀胱癌に対するBCG注入療法 : Tokyo株とConnaught株の副作用・再発予防効果についての比較検討(発表・討論,一般演題ポスター,第98回日本泌尿器科学総会)

    伊藤 将彰, 宮崎 有, 高橋 彰, 小倉 啓司, 赤松 秀輔

    日本泌尿器科学会雑誌   Vol. 101 ( 2 ) page: 406   2010

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    DOI: 10.5980/jpnjurol.101.406_3

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  185. PP-270 前立腺生検の癌検出率における免疫組織化学染色法(IHC)およびdynamic MRIの有用性(発表・討論,一般演題ポスター,第98回日本泌尿器科学会総会)

    小倉 啓司, 伊藤 将彰, 高橋 彰, 宮崎 有, 赤松 秀輔, 白瀬 智之, 雑賀 興慶, 小林 久人

    日本泌尿器科学会雑誌   Vol. 101 ( 2 ) page: 436   2010

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  186. Retroperitoneoscopic nephrectomy as a second-line treatment after transarterial embolization for symptomatic autosomal dominant polycystic kidney disease

    Akamatsu S., Kinoshita H., Shimizu Y., Yoshimura K., Ito N., Kamoto T., Ogawa O.

    Acta Urologica Japonica   Vol. 52 ( 12 ) page: 947 - 950   2006.12

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    Publisher:Acta Urologica Japonica  

    Patients with autosomal dominant polycystic kidney disease (ADPKD) often suffer from abdominal symptoms. Although laparoscopic nephrectomy has been reported as a minimally invasive therapy, it is still technically demanding due to the large size of the kidneys. Transarterial embolization (TAE) is one of the alternatives, but there are only limited reports on its application in ADPKD. We describe a case in which bilateral nephrectomy was performed as a second-line treatment after TAE. One kidney was removed because a small feeding arterial branch was not completely embolized. The other kidney was removed due to infection. Retroperitoneoscopic nephrectomy was a good choice as a second-line modality in the case without infection because the volume of the kidney was reduced even with incomplete TAE, and adhesion after TAE was minimal. TAE is an effective choice in ADPKD patients without infection as a first-line treatment even when complete embolization is difficult, since nephrectomy after TAE is technically easier than removal of a fresh ADPKD kidney.

    Scopus

  187. Retroperitoneoscopic nephrectomy as a second-line treatment after transarterial embolization for symptomatic autosomal dominant polycystic kidney disease.

    Akamatsu S, Kinoshita H, Shimizu Y, Yoshimura K, Ito N, Kamoto T, Ogawa O

    Hinyokika kiyo. Acta urologica Japonica   Vol. 52 ( 12 ) page: 947 - 50   2006.12

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    Language:English  

    PubMed

  188. Retroperitoneoscopic nephrectomy as a second-line treatment after transarterial embolization for symptomatic autosomal dominant polycystic kidney disease

    Akamatsu Shusuke, Kinoshita Hidefumi, Shimizu Yousuke, Yoshimura Koji, Ito Noriyuki, Kamoto Toshiyuki, Ogawa Osamu

    Hinyokika Kiyo   Vol. 52 ( 12 ) page: 947 - 950   2006.12

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    Language:English  

    Patients with autosomal dominant polycystic kidney disease (ADPKD) often suffer from abdominal symptoms. Although laparoscopic nephrectomy has been reported as a minimally invasive therapy, it is still technically demanding due to the large size of the kidneys. Transarterial embolization (TAE) is one of the alternatives, but there are only limited reports on its application in ADPKD. We describe a case in which bilateral nephrectomy was performed as a second-line treatment after TAE. One kidney was removed because a small feeding arterial branch was not completely embolized. The other kidney was removed due to infection. Retroperitoneoscopic nephrectomy was a good choice as a second-line modality in the case without infection because the volume of the kidney was reduced even with incomplete TAE, and adhesion after TAE was minimal. TAE is an effective choice in ADPKD patients without infection as a first-line treatment even when complete embolization is difficult, since nephrectomy after TAE is technically easier than removal of a fresh ADPKD kidney.

    CiNii Research

  189. [Primary transitional carcinoma of the remaining ureter after nephrectomy for pyonephrosis: a case report].

    Okada Y, Yamamoto S, Akamatsu S, Kanamaru S, Ito N, Kinoshita H, Kamoto T, Ogawa O

    Hinyokika kiyo. Acta urologica Japonica   Vol. 51 ( 2 ) page: 101 - 3   2005.2

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    Language:Japanese  

    PubMed

  190. Primary transitional carcinoma of the remaining ureter after nephrectomy for pyonephrosis: A case report

    Okada Y., Yamamoto S., Akamatsu S., Kanamaru S., Ito N., Kinoshita H., Kamoto T., Ogawa O.

    Acta Urologica Japonica   Vol. 51 ( 2 ) page: 101 - 103   2005.2

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    Publisher:Acta Urologica Japonica  

    A case of primary carcinoma of the remaining ureter is reported. A 70-year-old man presented with asymptomatic gross hematuria. Three years ago, he had received right nephrectomy for pyonephrosis. Although drip infusion pyelography (DIP) and cystoscopy showed no abnormal findings, computed tomography (CT) and retrograde ureterography demonstrated the irregular thickening of the right remaining ureteral wall. He underwent right ureterectomy with bladder cuff resection. Pathological examination revealed transitional cell carcinoma of the remaining ureter. He has been free of disease for 3 years.

    Scopus

  191. Primary transitional carcinoma of the remaining ureter after nephrectomy for pyonephrosis : a case report

    Okada Yoshiyuki, Yamamoto Shingo, Akamatsu Shusuke, Kanamaru Sojun, Ito Noriyuki, Kinoshita Hidefumi, Kamoto Toshiyuki, Ogawa Osamu

    Hinyokika Kiyo   Vol. 51 ( 2 ) page: 101 - 103   2005.2

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    Language:Japanese  

    CiNii Research

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Books 1

  1. Molecular basis of neuroendocrine prostate cancer

    Akamatsu S.

    Hormone Therapy and Castration Resistance of Prostate Cancer  2018.5  ( ISBN:9789811070129

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    Although de-novo neuroendocrine prostate cancer (NEPC) is rare, with increasing use of potent androgen receptor (AR) pathway inhibitors, the incidence of treatment-related NEPC (t-NEPC) is rapidly rising. Since NEPC is an aggressive disease with poor prognosis, novel therapeutic strategies are urgently needed. Recent genomic and molecular analysis have identified key oncogenes (MYCN, AURKA) and tumor suppressor genes (TP53, RB1) to play key roles in driving NEPC. Novel in vivo and in vitro research models of NEPC were developed to serve as valuable resource to study functional relevance of the key genes in NEPC development. Upon AR pathway inhibition, these genomic alterations seem to facilitate epithelial plasticity by upregulating the genes implicated in maintaining pluripotency (SOX2, EZH2), resulting in development of divergent tumor including NEPC from castration resistant prostate cancer. Further understanding of the molecular biology is required to identify novel molecular targets and biomarkers that would help rescue patients from this lethal variant.

    DOI: 10.1007/978-981-10-7013-6_39

    Scopus

KAKENHI (Grants-in-Aid for Scientific Research) 9

  1. 次世代遺伝子発現解析法に立脚したシーケンスレスながん分子サブタイプ規定法の開発

    Grant number:23H00435  2023.4 - 2027.3

    科学研究費助成事業  基盤研究(A)

    赤松 秀輔, 住吉 崇幸, 藤本 明洋, 村川 泰裕, 小林 恭, 北野 滋久

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    Authorship:Principal investigator 

    Grant amount:\47450000 ( Direct Cost: \36500000 、 Indirect Cost:\10950000 )

    前立腺癌は症例ごとに多様ですが、最近では腫瘍組織の遺伝子発現情報を基にいくつかの群に分類できることがわかっています。しかし従来の分類は症例ごとに煩雑な大規模遺伝子発現解析が必要でした。そこで本研究では最新の遺伝子発現解析手法(ロングリードシーケンス、単一細胞シーケンス)を用いて、ヒト前立腺癌検体を細胞単位で精密な遺伝子発現解析を行い、それを基に新たな分類法を提唱することを目指します。そして最終的に網羅的な遺伝子発現解析を行わなくても同様の分類が容易にできて臨床現場で使えるような方法の開発を目指します。

  2. 患者由来ゼノグラフトを用いたCDK12変異前立腺癌のPARP阻害薬不応性の克服

    Grant number:22K09446  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(C)

    後藤 崇之, 小林 恭, 赤松 秀輔

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    Authorship:Coinvestigator(s) 

    近年、去勢抵抗性前立腺癌の約11%の症例で相同組換え修復関連遺伝子の1つであるCDK12の変異が報告され、難治性であり新規治療の開発が望まれている。CDK12変異前立腺癌においては有用な基礎研究モデルが存在しなかったが、申請者は患者検体由来ゼノグラフトを用いることで、投薬実験と機能解析が可能な実験モデルを確立した。本研究はPARP阻害薬とATR阻害薬の併用投与を治療候補として、その有効性の確認と作用機序の解明を行い、臨床応用を目指す。

  3. 可塑性の制御による固形癌の革新的治療法の開発

    Grant number:21K19568  2021.7 - 2024.3

    科学研究費助成事業  挑戦的研究(萌芽)

    赤松 秀輔, 佐野 剛視, 後藤 崇之

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    Authorship:Principal investigator 

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

    本研究では独自に樹立した新規神経内分泌前立腺癌(NEPC)細胞株KUCaP13を用いて、NEPCにアンドロゲン受容体(AR)を再発現させる化合物をスクリーニングする。可塑性を制御して、ARを発現しないNEPCから発現する前立腺癌に細胞系統を戻し、新規AR経路阻害剤(ARPI)の感受性再獲得を目指す。本研究の成果はNEPCの治療開発に留まらず、可塑性のメカニズム解明や他癌種の新規治療開発につながると期待され、癌腫の垣根を超えた革新的な研究となる。
    今回の研究で用いる独自に樹立した新規神経内分泌前立腺癌(NEPC)細胞株KUCaP13について論文を作成し受理された。
    研究の進捗状況については、まずKUCaP13にARElucをレンチウイルスを用いて導入した。ARElucは、アンドロゲンレセプター(AR)の活性に連動してluciferaseが発現し、luciferase assayで発光を確認することでAR活性を測定できる最も鋭敏かつ簡便な実験系である。続いて陽性コントロールとしてKUCaP13_ARElucにレンチウイルスでAR遺伝子を導入した。ウエスタンブロットでARが発現していることを確認した。このAR強制発現株を用いてluciferase assayを行い、発光を確認することができた。このことから、KUCaP13においてもARElucによりAR発現を感知できることが証明できた。また陰性コントロ-ルの細胞もレンチウイルスを用いて作成済である。
    今後は本学の「創薬拠点コアラボ」が保有している約2500種類の既存薬および機能既知化合物を用いてドラッグスクリーニングを行う。現在、ドラッグスクリーニングにむけて至適条件を検討中である。今回の化合物スクリーニングでは、1stスクリーニングで2500種類から数種類程度まで候補化合物が絞られると予想される。2ndスクリーニングを実施の上、ヒット化合物によりARを標的とした治療が可能となるか検証予定である。
    ドラッグスクリーニングを行うために必要な細胞の作成は終了し、至適条件は検討中であるものの、ARの発現をLuciferase assayで感知できることは確認できているため。
    ①化合物スクリーニングの実施:KUCaP13_AREluc細胞に各化合物および合成アンドロゲンを添加し、ルシフェラーゼアッセイで有意に発光増強を認めた化合物を、ARを再発現させたヒット化合物として選択する。化合物には本学の「創薬拠点コアラボ」が保有している約2500種類の既存薬および機能既知化合物を用いる。今回の化合物スクリーニングでは、1stスクリーニングで2500種類から数種類程度まで候補化合物が絞られると予想される。
    ②2ndスクリーニング:候補化合物をそれぞれ単剤でKUCaP13_AREluc細胞に投与し、ルシフェラーゼ活性だけでなく、mRNA、蛋白質レベルでもARやPSAおよびNSEなどの発現に変化があるか確認する。候補化合物が複数ある場合はそれらの組み合わせの評価も行う。また、各化合物が既存のNEPC細胞株NCI-H660でも効果を示すか確認する。
    ③候補薬剤とARPIの併用投与:②で検証された化合物をin vitro、in vivoでエンザルタミドと併用してKUCaP13に投与し、細胞増殖が抑制されるか評価する。効果が見られた場合、申請者が留学していたバンクーバー前立腺センターが保有する数系統のNEPCの患者検体由来ゼノグラフトでも効果を検証する。
    ④作用機序の解明:AR再発現の機序の解明のため、候補化合物投与前後のKUCaP13を用いてRNAシーケンス、ATACシーケンス解析を行い、候補化合物の投与でどのような遺伝子発現変化やエピゲノムの変化が生じたか検討する。

  4. Identification of the enhancer sequences that are controlled by androgen receptor

    Grant number:20K09539  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Coinvestigator(s) 

  5. 血中遊離DNA解析を応用した前立腺癌のDNA修復遺伝子異常の生物学的特性の解明

    Grant number:20H03814  2020.4 - 2023.3

    科学研究費助成事業  基盤研究(B)

    赤松 秀輔, 澤田 篤郎, 小川 修

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    Authorship:Principal investigator 

    Grant amount:\18070000 ( Direct Cost: \13900000 、 Indirect Cost:\4170000 )

    我々が独自に開発した血中遊離DNA(cfDNA)の高感度捕捉法により前立腺癌の治療中に蓄積する遺伝子異常を経時的に捕捉し、その遺伝子背景を細胞株で反映することで臨床を模倣するモデルを樹立できると考える。本研究では約100例の臨床検体の経時的cfDNA解析と、臨床検体と遺伝子背景が揃ったモデルを樹立・解析することにより、HDR関連遺伝子異常と病態並びに薬剤感受性の関係を調べ、病態解明を目指す共に、薬剤選択、投薬時期に関するエビデンスを患者毎に創出する。
    ①CRPC患者血中遊離DNA(cfDNA)の縦断的遺伝子異常の解析:申請者らが独自に開発したcfDNAにおける変異アレル頻度1%未満の変異を高感度・高特異度に検出する分子バーコード法を用いた解析法eVIDENCEを用いて、すでに収集したcfDNA100症例の解析を行った。その結果、腫瘍由来cfDNA(ctDNA)割合2%未満の症例においてもATM、BRCA2、TP53の病的変異が同定され、これらの遺伝子異常はPFSまたはOSの独立した予測因子であり、DNA修復遺伝子を含めたcfDNAの低頻度変異検出が重要であることを示した。
    ② 臨床における遺伝子異常を再現した細胞株の樹立:BRCA2、ATM、CDK12をそれぞれノックアウト(KO)したLNCaP細胞株をCRISPR/Cas9の手法で作成した (BRCA2単独の両アレルKOは致死的なため存在しない)。CDK12KO細胞株に関してはin vitroおよびin vivoにおいて増殖能の低下を示し、BRCA paradoxを呈した。フローサイトメトリーにより解析からはG2/Mでのcell cycle arrestの可能性が示唆された。さらに細胞周期やDNA修復関連遺伝子のタンパク発現の解析を行った。
    ③臨床検体より樹立したゼノグラフトモデルの作成:我々はCDK12異常のある前立腺癌患者検体から、患者由来ゼノグラフト(PDX)を2系統樹立した。PDXを用いることでBRCA paradoxを克服することができる。今後症例があれば、BRCAやATM変異の症例でもPDX樹立を試みる。
    100症例のCRPC患者cfDNAの解析を行い、DNA修復遺伝子を含めたcfDNAの低頻度変異検出が重要であることを示した。HDR関連遺伝子異常細胞株(ATM KO, CDK12 KO)を樹立し、CDK12KO細胞株については機能解析も進んでいる。
    現在、治療抵抗性となる毎に経時的にcfDNAを収集している。経時的なDNA解析によって判明した遺伝子異常蓄積の情報を解析し、細胞特性変化のキーとなる候補遺伝子を同定する。さらには、樹立した細胞株にそれらの遺伝子異常を加えた表現型の変化を確認する。
    CDK12KO細胞株の機能解析から治療候補となる分子を同定した。CDK12細胞株はBRCA paradoxを呈し臨床像を反映していないので、CDK12異常PDXを用いて薬剤投与実験を行い、治療標的となるか検討予定である。ATM KO細胞株についても機能解析を行う。さらにはATM異常やBRCA異常の患者検体を採取できれば、PDX樹立を目指す。

  6. Development of innovative cancer diagnostic and therapeutic seeds focusing on tissue specific exosomics using xenotransplantation model

    Grant number:18H04064  2018.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

    Ogawa Osamu

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    Authorship:Coinvestigator(s) 

    Intercellular communication between cancer cells and stromal cells is essential for drug resistance and metastasis formation of cancer, exosomes play a important role as messenger. In our study of drug resistance, exosomes secreted from sunitinib-resistant tumor have shown distinct miRNA profiles compared with control. Further study is required to elucidate the mechanism by which exosomes induce drug resistance. In our study of metastasis formation, we established a bone metastatic RCC cell line. Treatment of mice with exosomes collected from culture supernatant of bone metastatic RCC cells promoted angiogenesis in bone in a time-dependent manner and increased bone metastasis. We showed that exosomal CD13 contributed to angiogenesis. In addition, exosomes from bone metastatic RCC contained abundant CD13 and promoted angiogenesis compared with exosomes from RCC without metastasis. Our findings provide a new insight to the role of exosome in cancer metastasis and drug resistance.

  7. Genomic analysis of circulating cell-free DNA to achieve precision medicine for advanced urological cancers

    Grant number:17H04327  2017.4 - 2020.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Yamasaki Toshinari

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    There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers and mutations in plasma circulating cell-free DNA (cfDNA) from castration-resistant prostate cancer (CRPC) patients using next-generation sequencer and digital PCR. We also established a method to detect VHL gene mutations in cfDNA from renal cell carcinoma (RCC) patients.
    AR aberrations in pretreatment cfDNA from CRPC patients were associated with poor response to abiraterone, a novel anti-androgen receptor agent. We also found that the mutation rate of VHL in cfDNA from RCC patients could depend on the tumor volume.
    cfDNA may become a useful predictive biomarker for precision medicine in patients with advanced urological cancers.

  8. Development of retrotransposon gene PEG10 targeting treatment for neuroendocrine prostate cancer

    Grant number:17K11133  2017.4 - 2020.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Shusuke Akamatsu

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    Authorship:Principal investigator 

    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    PEG10 is a unique particle derived from retrotransposon and promotes growth and invasion of neuroendocrine prostate cancer (NEPC). At first, we aimed to elucidate the mechanism of tumor proliferation focused on the particle interacting with PEG10, but enough achievements were not obtained. Next, we tried to culture xenograft model and cell line derived from a NEPC patient. We succeeded in establishing a new NEPC model named KUCaP13. We confirmed that the model was derived from prostate cancer and that it had features of NEPC. Furthermore, we generated the PEG10 knockdown (shPEG10) strain and evaluated its proliferation in vivo. The growth of shPEG10 was suppressed clearly, and this result suggested that PEG10 could be a therapeutic target.

  9. 前立腺癌のゲノムワイド関連解析

    Grant number:10J02102  2010 - 2012

    科学研究費助成事業  特別研究員奨励費

    赤松 秀輔

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    Authorship:Other 

    当該年度においては、まず、GWASにおいて日本人の前立腺癌罹患との関連が確認された16の単塩基多型を用いて日本人の前立腺癌患者689人、対照群749人の情報を基にロジスティック回帰分析による罹患リスクモデルを構築した。次に、モデルの再現性を全く独立した2つの日本人サンプル(前立腺癌患者3,294人、対照群6,281人)を用いて確認した。その結果、リスクモデルを構築したサンプル群におけるモデルの曲線下面積(AUC)は0.679、再現性評価に用いた2群におけるAUCは0.655,0.661であり、高い再現性が確認された。さらに、カルフォルニアおよびハワイに在住する日系人サンプルにおいても高い再現性が認められた。次に、罹患リスクモデルとPSAの関連の有無について検討した。PSA1-10ng/mlのサンプルに限定した場合においてもAUCはほぼ同等であり、リスクスコアとPSAの間にも相関は認められず、リスクモデルがPSAとは独立した指標であることが確認された。最後に、PSAグレーゾーンにおいて罹患リスクモデルを適用した場合の検査後確率についてシミュレーションを行い、罹患リスクモデルの臨床における有用性について検討した。リスクモデルによって24.2%のサンプルが低リスク(オッズ<0.5)、9.7%のサンプルが高リスク(オッズ>2.0)と分類された。PSAグレーゾーンにおける前立腺癌診断率を20%と想定した場合にリスクモデルを適用すると低リスク、高リスク群における検査後確率はそれぞれ10.7%,42.4%であり、臨床において有用な指標になる可能性が示唆された。
    本研究において単塩基多型に基づく前立腺癌罹患リスクモデルは高い再現性を示し、PSAと完全に独立した指標であった。PSAグレーゾーンにおいて適用することで、高リスク群は即時前立腺生検、低リスク群はPSA経過観察するといった臨床判断に影響を与えうる指標であることが確認された。今後、実臨床現場においての精度、再現性、有用性の確認が待たれる。
    当該年度においては、これまでのGWASにおける研究成果を臨床現場に還元すべく、GWASで得られたデータに基づき前立腺癌の罹患リスクモデルを構築し、その再現性や精度、臨床における有用性の評価等に関する研究が行われた。その結果、構築されたリスクモデルが、現在、臨床上課題となっている、PSAグレーゾーンにおいてPSAと独立した指標としてPSAを補完しうることが確認され、研究成果をPlos One誌に報告できたため。
    今後は、今回のデータを基に、先進医療申請を含めて臨床現場での応用を準備していく予定である。

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