| 1. |
Lee K, Takahashi R, Imada K, Okabe A, Kajioka S, Kashiwagi E, Shiota M, Inokuchi J, Eto M:, Initial experience with vibegron for the treatment of neurogenic lower urinary tract storage dysfunction in patients with spinal cord injury., Continence, 4:100516, 2022, 2022.12. |
| 2. |
Kato T, Matsubara N, Shiota M, Eto M, Osawa T, Abe T, Shinohara N, Yasumizu Y, Tanaka N, Oya M, Nishimoto K, Hayashi T, Nakayama M, Kojima T, Namikawa K, Fujisawa T, Okano S, Hida E, Nakamura Y, Bando H, Yoshino T, Nonomura N:, IMAGENE trial: multicenter, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy of niraparib with PD-1 inhibitor in solid cancer patients with homologous recombination repair genes mutation., BMC Cancer, 22 (1):1292, 2022, 2022.12. |
| 3. |
Kudo Y, Endo S, Tanio M, Saka T, Himura R, Abe N, Takeda M, Yamaguchi E, Yoshino Y, Arai Y, Kashiwagi H, Oyama M, Itoh A, Shiota M, Fujimoto N, Ikari A:, Antiandrogenic Effects of a Polyphenol in Carex kobomugi through Inhibition of Androgen Synthetic Pathway and Downregulation of Androgen Receptor in Prostate Cancer Cell Lines., Int J Mol Sci, 23 (22):14356, 2022, 2022.11. |
| 4. |
Kimura H, Mizuno K, Shiota M, Narita S, Terada N, Fujimoto N, Ogura K, Hatano S, Iwasaki Y, Hakozaki N, Ishitoya S, Sumiyoshi T, Goto T, Kobayashi T, Nakagawa H, Kamoto T, Eto M, Habuchi T, Ogawa O, Momozawa Y, Akamatsu S:, Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer., Br J Cancer, 127 (9):1680-1690, 2022, 2022.11. |
| 5. |
Kashiwagi E, Shiota M, Naganuma H, Monji K, Imada K, Lee K, Matsumoto T, Takeuchi A, Inokuchi J, Eto M:, Testosterone level in seminal vesicle fluid is a better indicator of erectile function than serum testosterone in patients with prostate cancer., Int J Urol, 29 (10):1155-1162, 2022, 2022.10. |
| 6. |
Narita S, Terada N, Nomura K, Sakamoto S, Hatakeyama S, Kato T, Matsui Y, Inokuchi J, Yokomizo A, Tabata KI, Shiota M, Kimura T, Kojima T, Inoue T, Mizowaki T, Sugimoto M, Kitamura H, Kamoto T, Nishiyama H, Habuchi T; Japanese Urological Oncology Group:, Cancer-specific and net overall survival in older patients with de novo metastatic prostate cancer initially treated with androgen deprivation therapy., Int J Urol, 29 (10):1147-1154, 2022, 2022.10. |
| 7. |
Kashiwagi E, Shiota M, Lee K, Monji K, Naganuma H, Matsumoto T, Takeuchi A, Inokuchi J, Eto M:, Psoas Muscle Volume Is a Predictive Marker of Fatigue and Anorexia in Prostate Cancer Patients Treated with Enzalutamide., JMA J, 5 (4):491-497, 2022, 2022.10. |
| 8. |
Igami K, Uchiumi T, Shiota M, Ueda S, Tsukahara S, Akimoto M, Eto M, Kang D:, Extracellular vesicles expressing CEACAM proteins in the urine of bladder cancer patients., Cancer Sci, 113 (9):3120-3133, 2022, 2022.09. |
| 9. |
Shiota M, De Moor R, Koroki Y, Yu DY, Wu DB:, Assessing the correlation between second progression-free survival (PFS2) and overall survival (OS) in advanced prostate cancer patients using medical data vision (MDV) claims database in Japan., Curr Med Res Opin, 38 (8):1351-1359, 2022, 2022.08. |
| 10. |
Komori H, Blas L, Shiota M, Takamatsu D, Matsumoto T, Lee K, Monji K, Kashiwagi E, Inokuchi J, Eto M:, Impact of nerve sparing in robot-assisted radical prostatectomy on the risk of positive surgical margin and biochemical recurrence., Int J Urol, 29 (8):824-829, 2022, 2022.08. |
| 11. |
Shiota M, Takamatsu D, Kimura T, Tashiro K, Matsui Y, Tomida R, Saito R, Tsutsumi M, Yokomizo A, Yamamoto Y, Edamura K, Miyake M, Morizane S, Yoshino T, Matsukawa A, Narita S, Matsumoto R, Kasahara T, Hashimoto K, Matsumoto H, Kato M, Akamatsu S, Joraku A, Kato M, Yamaguchi T, Saito T, Kaneko T, Takahashi A, Kato T, Sakamoto S, Enokida H, Kanno H, Terada N, Suekane S, Nishiyama N, Eto M, Kitamura H; Japanese Urological Oncology Group:, Radiotherapy plus androgen deprivation therapy for prostate-specific antigen persistence in lymph node-positive prostate cancer., Cancer Sci, 113(7):2386-2396, 2022, 2022.07. |
| 12. |
Nagumo Y, Onozawa M, Kojima T, Terada N, Shiota M, Mitsuzuka K, Yasumoto H, Matsumoto H, Enokida H, Sugiyama T, Kuroiwa K, Saito T, Yokomizo A, Kohei N, Tabata KI, Takahashi A, Sugimoto M, Kitamura H, Kamoto T, Nishiyama H; Japanese Urological Oncology Group (JUOG):, Efficacy of combined androgen blockade therapy in patients with metastatic hormone-sensitive prostate cancer stratified by tumor burden., Int J Urol, 29 (5):398-405, 2022, 2022.05. |
| 13. |
Ushijima M, Shiota M, Matsumoto T, Kashiwagi E, Inokuchi J, Eto M:, An oral first-in-class small molecule RSK inhibitor suppresses AR variants and tumor growth in prostate cancer., Cancer Sci, 113 (5):1731-1738, 2022, 2022.05. |
| 14. |
Tsukahara S, Shiota M, Takamatsu D, Nagakawa S, Matsumoto T, Kiyokoba R, Yagi M, Setoyama D, Noda N, Matsumoto S, Hayashi T, Contreras-Sanz A, Black PC, Inokuchi J, Kohashi K, Oda Y, Uchiumi T, Eto M, Kang D:, Cancer genomic profiling identified dihydropyrimidine dehydrogenase deficiency in bladder cancer promotes sensitivity to gemcitabine., Sci Rep, 12 (1):8535, 2022, 2022.05. |
| 15. |
Blas L, Shiota M, Nagakawa S, Tsukahara S, Matsumoto T, Monji K, Kashiwagi E, Takeuchi A, Inokuchi J, Eto M:, Validation of models predicting lymph node involvement probability in patients with prostate cancer., Int J Urol, 29 (5):428-434, 2022, 2022.05. |
| 16. |
Blas L, Shiota M, Nakamura M, Yokomizo A, Tomoda T, Sakamoto N, Seki N, Hasegawa S, Yunoki T, Harano M, Kuroiwa K, Eto M:, External Validation of a Prognostic Model Predicting Metastatic Castration-Resistant Prostate Cancer Survival in Patients Receiving Post-Docetaxel Second-Line Chemotherapy., JMA J, 5 (2):224-229, 2022, 2022.04. |
| 17. |
Kobayashi M, Fujiyama N, Tanegashima T, Narita S, Yamamoto Y, Fujimoto N, Ueda S, Takeuchi A, Numakura K, Habuchi T, Matsuyama H, Eto M, Shiota M:, Effect of HLA genotype on intravesical recurrence after bacillus Calmette-Guérin therapy for non-muscle-invasive bladder cancer., Cancer Immunol Immunother, 71 (3):727-736, 2022, 2022.03. |
| 18. |
Chikamatsu S, Shiota M, Yamada S, Blas L, Matsumoto T, Kashiwagi E, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Prognostic significance of risk stratification in CHAARTED and LATITUDE studies among Japanese men with castration-resistant prostate cancer., Prostate Int, 10 (1):7-13, 2022, 2022.03. |
| 19. |
Yamada S, Shiota M, Blas L, Matsumoto T, Kashiwagi E, Takeuchi A, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Prognostic impact of dose reduction in androgen receptor pathway inhibitors for castration-resistant prostate cancer., Prostate Int, 10 (1):50-55, 2022, 2022.03. |
| 20. |
Shiota M, Fujimoto N, Sekino Y, Tsukahara S, Nagakawa S, Takamatsu D, Abe T, Kinoshita F, Ueda S, Ushijima M, Matsumoto T, Kashiwagi E, Inokuchi J, Uchiumi T, Oda Y, Eto M:, Clinical impact of HSD3B1 polymorphism by metastatic volume and somatic HSD3B1 alterations in advanced prostate cancer., Andrologia, 54 (1):e14307, 2022, 2022.02. |
| 21. |
Takahashi Y, Narita S, Shiota M, Miura M, Kagaya H, Kashima S, Yamamoto R, Nara T, Huang M, Numakura K, Saito M, Eto M, Habuchi T:, Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate., Eur J Clin Pharmacol, 79 (1):89-98, 2022, 2022.01. |
| 22. |
Matsumoto T, Shiota M, Yamada S, Blas L, Naganuma H, Lee K, Monji K, Kashiwagi E, Takeuchi A, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Anticancer Effect of Second-line Treatment for Castration-Resistant Prostate Cancer Following First-line Treatment with Androgen Receptor Pathway Inhibitors., JMA J, 5 (1):83-90, 2022, 2022.01. |
| 23. |
Kobayashi H, Shiota M, Sato N, Kobayashi S, Matsumoto T, Monji K, Kashiwagi E, Takeuchi A, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Differential prognostic impact of complete blood count-related parameters by prior use of novel androgen receptor pathway inhibitors in docetaxel-treated castration-resistant prostate cancer patients., Anticancer Drugs, 33 (1):e541-e547, 2022, 2022.01. |
| 24. |
Shiota M, Blas L, Kobayashi S, Matsumoto T, Kashiwagi E, Takeuchi A, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Predictive factors of survival outcomes in first-line therapy for metastatic castration-resistant prostate cancer., Int J Urol, 29 (1):26-32, 2022, 2022.01. |
| 25. |
Tomohiko Murakami, Satoshi Otsubo, Ryo Namitome, Masaki Shiota, Junichi Inokuchi, Ario Takeuchi, Eiji Kashiwagi, Katsunori Tatsugami, Masatoshi Eto, Clinical factors affecting perioperative outcomes in robot-assisted radical prostatectomy., Molecular and clinical oncology, 10.3892/mco.2018.1718, 9, 5, 575-581, 2018.11, The present study investigated clinical factors affecting perioperative outcomes in robot-assisted radical prostatectomy (RARP). The study included 625 Japanese cases treated with RARP between 2009 and 2017. The association between clinical factors (age, overweight status, prostate volume, clinical T-stage, nerve sparing, lympho-node dissection, and the number of experienced cases) and perioperative outcomes (operation time, estimated blood loss, catheterization duration, and perioperative complication) were analyzed. Results revealed that overweight status, prostate volume, lymph-node dissection, and the number of experienced cases were associated with operation time. For estimated blood loss, the identified risk factors were overweight status, prostate volume, nerve sparing, lymph-node dissection, and the number of experienced cases. Lymph-node dissection and the number of experienced cases were also associated with catheterization duration. Additionally, only lymph-node dissection was associated with increased perioperative complication. Taken together, the present study identified several clinical factors affecting perioperative outcomes in RARP. This information may help surgeons to estimate perioperative outcomes as well as to inform patients.. |
| 26. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Therapeutic Outcome of >10 Cycles of Cabazitaxel for Castration-resistant Prostate Cancer: A Multi-institutional Study., Anticancer research, 10.21873/anticanres.13612, 39, 8, 4411-4414, 2019.08, BACKGROUND/AIM: Cabazitaxel use has usually been limited to up to 10 cycles in most countries according to the protocol in the TROPIC trial. Therefore, clinical data on cabazitaxel use beyond 10 cycles is limited. The aim of this study was to report the therapeutic outcome of cabazitaxel chemotherapy administered for >10 cycles. PATIENTS AND METHODS: This study included 74 Japanese patients with prostate cancer between 2014 and 2017. Patients background, and treatment outcomes including PSA decline, progression-free survival, treatment-failure-free survival, overall survival, and adverse events were investigated, comparing patients treated with ≤10 and >10 cycles. RESULTS: Patients characteristics were favorable as indicated by the higher number of cycles of prior docetaxel chemotherapy, absence of pain, and absence of bony and visceral metastases among men who received >10 cycles of cabazitaxel. PSA response, progression-free survival, treatment-failure-free survival and overall survival were better among patients treated with >10 cycles of cabazitaxel compared to those treated with ≤10 cycles. The incidence of severe adverse events was similar between the two groups. CONCLUSION: Taken together, this study suggested that continuous chemotherapy with cabazitaxel beyond 10 cycles may be beneficial.. |
| 27. |
Masaki Shiota, Naohiro Fujimoto, Akira Yokomizo, Ario Takeuchi, Momoe Itsumi, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito, SRD5A gene polymorphism in Japanese men predicts prognosis of metastatic prostate cancer with androgen-deprivation therapy, European Journal of Cancer, 10.1016/j.ejca.2015.06.122, 51, 14, 1962-1969, 2015.09, AIM: De novo androgen synthesis is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). During androgen synthesis, 5α-reductase encoded by SRD5A catalyses testosterone into more active dihydrotestosterone and may be involved in the progression to CRPC. Then, this study aimed to reveal the association between genetic variations in SRD5A and the prognosis in metastatic prostate cancer. METHODS: We studied the polymorphisms rs518673 and rs166050 in SRD5A1, and rs12470143, rs523349, rs676033 and rs2208532 in SRD5A2 as well as the time to CRPC progression and overall survival in 104 patients with metastatic prostate cancer that had undergone primary ADT. The association between the polymorphisms and the progression to CRPC as well as overall survival was examined. RESULTS: Patients carrying the more active GG genotype in SRD5A2 rs523349 exhibited a higher risk of the progression (hazard ration [95% confidence interval], 1.93 [1.14-3.14], p=0.016) and death (hazard ration [95% confidence interval], 2.14 [1.16-3.76], p=0.016), compared with less active GC/CC genotypes in SRD5A2 rs523349. CONCLUSIONS: High 5α-reductase activity due to the polymorphism in SRD5A2 may contribute to resistance to ADT. Furthermore, SRD5A2 rs523349 polymorphism may be a promising biomarker for metastatic prostate cancer patients treated with primary ADT and a molecular target for advanced prostate cancer.. |
| 28. |
Dai Takamatsu, Masaki Shiota, Masaaki Sugimoto, Tomoharu Uozumi, Hiroshi Uchi, Ario Takeuchi, Ryosuke Takahashi, Katsunori Tatsugami, Akira Yokomizo, Yoshinao Oda, Masutaka Furue, Masatoshi Eto, A case report of primary malignant melanoma of male urethra with distinct appearance in multiple regions., International cancer conference journal, 10.1007/s13691-016-0252-z, 5, 4, 174-177, 2016.10, A 66-year-old man presented with macrohematuria. Cystoscope examination found a 5 mm nodular tumor at external urethral orifice and multiple papillary tumors at fossa navicularis of urethra; those are non-black colored. Transurethral resection of the urethra tumor was performed, and pathologically diagnosed as malignant melanoma. Image examinations showed no lymphadenopathy and metastasis. Accordingly, total penectomy was conducted to remove the remaining tumors, resulting in surgically curative resection. After the operation, monthly interferon-β injection into inguinal region has been administered as adjuvant therapy, resulting in no recurrence at 6 months after penectomy.. |
| 29. |
Masaki Shiota, Eiji Kashiwagi, Tomohiko Murakami, Ario Takeuchi, Kenjiro Imada, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Serum testosterone before and during androgen-deprivation therapy, and prognosis between cigarette smokers and nonsmokers with metastatic prostate cancer, Andrologia, 10.1111/and.13119, 50, 10, e13119, 2018.12, Cigarette smoking is suggested to influence androgen milieu, which is closely associated with pathogenesis and prognosis of prostate cancer. In this study, we investigated the association between serum testosterone level before or during androgen-deprivation therapy (ADT) as well as prognoses and cigarette smoking status among men with metastatic prostate cancer. Serum testosterone level before ADT in current smokers (n = 6, median [interquartile range, IQR]; 454 ng/ml [426-478 ng/ml]) was significantly higher than that in nonsmokers (n = 26, median [IQR]; 397 ng/ml [312-435 ng/ml]). Serum testosterone level during ADT in current smokers (n = 7, median [IQR]; 7 ng/ml [3-11 ng/ml]) was comparable with that in nonsmokers (n = 55, median [IQR]; 9 ng/ml [3-20 ng/ml]). Progression-free survival and overall survival were comparable between current smokers and nonsmokers when adjusted with serum testosterone level before ADT or during ADT. These results suggest adequate pharmacological effect of ADT, even in current smokers. However, serum testosterone level before ADT was higher in current smokers. Thus, we need to interpret serum testosterone level in current smokers with caution.. |
| 30. |
Takahiko Hajime, Masaki Shiota, Tatsuro Abe, Ario Takeuchi, Shingo Baba, Junichi Inokuchi, Katsunori Tatsugami, Yoshinao Oda, Hiroshi Honda, Masatoshi Eto, Progression to bone-marrow carcinomatosis and extraosseous legion during treatment with radium-223 for multiple bone metastases, International Cancer Conference Journal, 10.1007/s13691-017-0316-8, 7, 2, 48-51, 2018.04, A 67-year-old man with metastatic prostate cancer presented with progression to castration-resistant prostate cancer. After sequential therapies with flutamide, estramustine phosphate, docetaxel, enzalutamide, and cabazitaxel for castration-resistant prostate cancer, radium-223 was initiated and continued up to 4 cycles. However, concurrently with radiological and clinical progressions, pancytopenia was observed due to bone-marrow carcinomatosis by prostatic adenocarcinoma. This case suggested that radium-223 should be employed at appropriated timing before appearances of extraosseous and bone-marrow lesions in addition to visceral metastasis.. |
| 31. |
Tomohiko Murakami, Hirofumi Obata, Naoko Akitake, Masaki Shiota, Ario Takeuchi, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Prognostic and Predictive Factors for Anti-androgen Withdrawal in Castration-resistant Prostate Cancer., Anticancer research, 10.21873/anticanres.12702, 38, 7, 4115-4121, 2018.07, BACKGROUND/AIM: We aimed to identify prognostic and predictive factors for anti-androgen withdrawal syndrome (AWS) to help guide decisions on anti-androgen withdrawal in castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: This study included 95 patients with prostate cancer which progressed to CRPC despite primary androgen-deprivation therapy (ADT). AWS was defined as >50% prostate-specific antigen decline after anti-androgen withdrawal. Associations between AWS, and clinicopathological factors and prognosis were investigated. RESULTS: Among the 95 patients, 84 (88.4%) underwent anti-androgen withdrawal, among whom AWS was recognized in nine (10.8%). Gleason score and response duration to primary ADT were predictors of AWS. Long duration of response to primary ADT was also associated with better progression-free survival [hazard ratio (HR)=0.021, 95% confidence interval (CI)=0.0025-0.14, p |
| 32. |
Naoko Akitake, Masaki Shiota, Hirofumi Obata, Ario Takeuchi, Eiji Kashiwagi, Kenjiro Imada, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Neoadjuvant androgen-deprivation therapy with radical prostatectomy for prostate cancer in association with age and serum testosterone, Prostate International, 10.1016/j.prnil.2017.10.002, 6, 3, 104-109, 2018.09, BACKGROUND: We aimed to identify the candidate prostate cancer patients suitable for neoadjuvant androgen-deprivation therapy (ADT) with radical prostatectomy (RP). MATERIALS AND METHODS: This study included 711 Japanese patients with clinically localized prostate cancer who were treated with RP between 2000 and 2013. Patients were treated with or without neoadjuvant ADT before RP. The prognostic significance of neoadjuvant ADT on biochemical recurrence (BCR) was analyzed according to various clinicopathological characteristics. RESULTS: BCR occurred in 186 (26.2%) of 711 patients. The group treated with neoadjuvant ADT showed higher levels of prostate-specific antigen at diagnosis and advanced clinical T-stage, but suppressed pathological T-stage. Neoadjuvant ADT was not associated with the risk of BCR. In subgroup analysis, neoadjuvant ADT was significantly associated with increased BCR in patients aged >65 years [hazard ratio (95% confidence interval), 2.04 (1.13-3.43), P = 0.020]. Among the 53 patients with available serum testosterone levels, neoadjuvant ADT was associated with the risk of BCR according to serum testosterone levels. CONCLUSION: This study demonstrated that neoadjuvant ADT showed potential deleterious effects in older patients and patients with lower serum testosterone levels, while a possible improved prognosis in patients with high serum testosterone levels treated with neoadjuvant ADT was suggested, warranting further exploration.. |
| 33. |
Masaki Shiota, Naohiro Fujimoto, Katuyoshi Higashijima, Kenjiro Imada, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto, Mineralocorticoid receptor signaling affects therapeutic effect of enzalutamide, The Prostate, 10.1002/pros.23661, 78, 14, 2018.10, BACKGROUND: Corticosteroids play important roles in prostate cancer therapeutics. However, their role when combined with enzalutamide remains obscure. Then, we aimed to elucidate the functional and clinical impact of corticosteroids on steroid receptors in androgen receptor (AR)-targeting therapy utilizing enzalutamide. METHODS: The therapeutic effect was studied according to concomitant use of corticosteroids in 86 men treated with enzalutamide. The sensitivity to various agents was evaluated using cytotoxicity assays in prostate cancer cells. Gene expression levels were evaluated by quantitative real-time polymerase chain reaction in prostate cancer cells and tissues. RESULTS: The therapeutic effect of enzalutamide was particularly lessened with concomitant treatment with dexamethasone. Consistently, dexamethasone increased cellular resistance to enzalutamide while prednisolone and aldosterone decreased cellular resistance to enzalutamide in prostate cancer cells. Inversely, mineralocorticoid receptor (MR) knockdown augmented the activity of AR signaling and the cellular resistance to enzalutamide. CONCLUSIONS: MR plays a critical role in resistance to AR-targeting therapies, which may be overcome by activation of MR signaling.. |
| 34. |
Masaki Shiota, Takashi Dejima, Yoshiaki Yamamoto, Ario Takeuchi, Kenjiro Imada, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto, Collateral resistance to taxanes in enzalutamide-resistant prostate cancer through aberrant androgen receptor and its variants, Cancer Science, 10.1111/cas.13751, 109, 10, 3224-3234, 2018.10, Currently, the optimal sequential use of androgen receptor (AR) axis-targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide-resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane-resistant cells showed no collateral resistance to enzalutamide; taxane-resistant cells expressed comparable protein levels of full-length AR and AR variants. Knockdown of both full-length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full-length AR rendered cells resistant to taxanes. Consistently, the prostate-specific antigen response and progression-free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance.. |
| 35. |
Masakazu Akitake, Keijiro Kiyoshima, Akira Yokomizo, Kenichiro Shiga, Hirofumi Koga, Ario Takeuchi, Masaki Shiota, Junichi Inokuchi, Katsunori Tatsugami, Akito Yamaguchi, Masatoshi Eto, A rational risk assessment for intravesical recurrence in primary low-grade Ta bladder cancer: A retrospective analysis of 245 cases., Molecular and clinical oncology, 10.3892/mco.2018.1602, 8, 6, 785-790, 2018.06, The aim of the present study was to evaluate the prognostic impact of size and number of tumors in primary low-grade (LG) Ta bladder urothelial carcinoma (UC), and thus allow accurate risk stratification of low-risk non-muscle invasive bladder cancer (NMIBC). This study was a retrospective analysis of 245 patients with primary LG Ta UC of the urinary bladder who were treated with transurethral resection. Differences in intravesical recurrence-free survival (RFS) according to various cutoff values of tumor size and tumor number were calculated using Cox proportional hazards model. Median maximum size of tumor was 1.4 cm, and 153 patients (62.4%) had solitary tumors. Forty-nine patients experienced intravesical recurrence during a median 34 months of follow-up. Patients with solitary tumors had significantly longer RFS times compared with those with ≥8 tumors (P=0.003). Patients with larger tumors had significantly shorter RFS times for each cutoff value (P=0.01 for 1.0 cm, P |
| 36. |
Yohei Sekino, Xiangrui Han, Takafumi Kawaguchi, Takashi Babasaki, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Jun Teishima, Masaki Shiota, Wataru Yasui, Akio Matsubara, TUBB3 Reverses Resistance to Docetaxel and Cabazitaxel in Prostate Cancer, International Journal of Molecular Sciences, 10.3390/ijms20163936, 20, 16, 3936-3936, 2019.08, Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.. |
| 37. |
Masaki Shiota, Eiji Kashiwagi, Tomohiko Murakami, Ario Takeuchi, Kenjiro Imada, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Serum testosterone level as possible predictive marker in androgen receptor axis-targeting agents and taxane chemotherapies for castration-resistant prostate cancer, Urologic Oncology: Seminars and Original Investigations, 10.1016/j.urolonc.2018.10.020, 37, 3, 180.e19-180.e24, 2019.03, PURPOSE: Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC. PATIENTS AND METHODS: The present study included Japanese patients with metastatic prostate cancer whose serum testosterone levels during androgen-deprivation therapy were available. The antitumor outcomes when treated with enzalutamide, abiraterone, docetaxel, and cabazitaxel with clinicopathological parameters including serum testosterone levels during androgen-deprivation therapy, as well as prognoses including progression-free survival and overall survival, were examined. RESULTS: Progression-free survival among men with higher serum testosterone level was superior to that among men with lower serum testosterone level when treated with enzalutamide. On the contrary, progression-free survival and overall survival among men with higher serum testosterone level were significantly inferior to those among men with lower serum testosterone level when treated with docetaxel and cabazitaxel, respectively. CONCLUSIONS: The present study indicated distinct prognostic values of serum testosterone level when treated with androgen receptor axis-targeting agent and taxane chemotherapy for CRPC, suggesting that serum testosterone level may be useful predictive biomarker to navigate the appropriate therapy in patients with CRPC.. |
| 38. |
Takeshi Kobayashi, Ryo Namitome, Y U Hirata, Masaki Shiota, Kenjiro Imada, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Serum Prognostic Factors of Androgen-deprivation Therapy Among Japanese Men With De Novo Metastatic Prostate Cancer., Anticancer research, 10.21873/anticanres.13457, 39, 6, 3191-3195, 2019.06, BACKGROUND/AIM: To date, several serum prognostic factors have been reported in metastatic prostate cancer. In this study, we examined the prognostic value of these serum markers in Japanese men. PATIENTS AND METHODS: This study included 104 patients with metastatic prostate cancer who were treated with primary androgen-deprivation therapy from 2001 to 2013. Clinicopathological factors including several serum markers were investigated for association with progression-free (PFS) and overall (OS) survival. RESULTS: During a median follow-up of 48.1 months, median PFS and OS were 24.0 months and 67.4 months, respectively. When adjusted by age, prostate-specific antigen at diagnosis, Gleason score, and clinical stage, serum lactate dehydrogenase value was significantly associated with PFS [hazard ratio (HR)=1.42, 95% confidence interval (CI)=1.15-1.74; p=0.0004] and OS (HR=1.46, 95% CI=1.13-1.82; p=0.0014), in addition to alkaline phosphatase value for OS (HR=1.04; 95% CI=1.00-1.07; p=0.015). CONCLUSION: This study demonstrates the prognostic significance of alkaline phosphatase and lactate dehydrogenase values in Japanese men with de novo metastatic hormone-sensitive prostate cancer.. |
| 39. |
Eiji Kashiwagi, Kenjiro Imada, Keisuke Monji, Ario Takeuchi, Masaki Shiota, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Psoas muscle volume is correlated with sexual activity and erectile dysfunction among patients with localised prostate cancer, Andrologia, 10.1111/and.13354, 51, 9, e13354, 2019.10, Several endocrinological and physical activities orchestrate men's sexual activities. To determine whether body composition calculated by computed tomography measurements is useful for estimating sexual function, we evaluated sexual function of localised prostate cancer patients using the Sexual Health Inventory for Men score, an original questionnaire, and computed tomography and magnetic resonance imaging. The imaging was performed to determine body composition, particularly the psoas muscle. Univariate and multivariate analyses were performed to identify factors affecting sexual activity. The multivariate analysis showed that the volume of the psoas muscle was significantly correlated with sexual activity (odds ratio [95% confidence interval]) (2.507 [1.029-6.109], p = 0.043) and erectile dysfunction (0.261 [0.098-0.692], p = 0.006). We concluded that the psoas muscle is an important predictor of sexual activity and erectile function.. |
| 40. |
Masaki Shiota, Takeshi Kobayashi, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Prognostic significance of antihypertensive agents in men with castration-resistant prostate cancer, Urologic Oncology: Seminars and Original Investigations, 10.1016/j.urolonc.2019.04.020, 37, 11, 813.e21-813.e26, 2019.11, PURPOSE: Comorbidity with hypertension (HTN) may affect the outcome of castration-resistant prostate cancer (CRPC). In this study, we evaluated the prognostic impact of antihypertensive agents in patients with CRPC treated with androgen receptor axis-targeting (ARAT) agents or docetaxel chemotherapy. PATIENTS AND METHODS: This study included 156 Japanese men with CRPC who were treated with ARAT agents (n = 85) or docetaxel (n = 71) at our hospital between 2008 and 2017. Associations between clinicopathological factors, HTN status, progression-free survival (PFS) and overall survival (OS) were evaluated by univariate and multivariate analysis. RESULTS: When adjusted for age, prostate-specific antigen levels at pretreatment, Gleason score, and clinical M-stage, comorbid HTN was significantly associated with better OS (hazards ratio, 95% confidence interval: 0.41, 0.21-0.77; P = 0.0051), but not with PFS (hazards ratio, 95% confidence interval: 0.64, 0.38-1.11; P = 0.11) in patients treated with ARAT agent. However, HTN was not associated with PFS or OS for patients treated with docetaxel. CONCLUSIONS: Use of antihypertensive agents has prognostic significance for patients with CRPC treated with ARAT agent, but not docetaxel.. |
| 41. |
Yu Hirata, Masaki Shiota, Takeshi Kobayashi, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Prognostic significance of diabetes mellitus and dyslipidemia in men receiving androgen-deprivation therapy for metastatic prostate cancer., Prostate international, 10.1016/j.prnil.2019.10.003, 7, 4, 166-170, 2019.12, Objective: The outcome of the androgen-deprivation therapy (ADT) may be affected by metabolic diseases such as diabetes mellitus (DM) and dyslipidemia and/or by their treatments. We aimed to evaluate the prognostic impact of these disorders and corresponding medications in Japanese men treated with ADT for prostate cancer. Methods: This study retrospectively included 121 patients with metastatic prostate cancer who were treated with primary ADT at our hospital between 2001 and 2013. All patients received primary ADT with castration and/or an antiandrogen agent (bicalutamide or flutamide). Associations between clinicopathological factors, metabolic disease profiles, medication use, and prognosis (progression-free survival [PFS] and overall survival [OS]) were evaluated by univariate and multivariate analysis. Results: The median follow-up time was 54.9 months, and the median PFS and OS were 23.9 months and 73.0 months, respectively. High serum glucose levels at baseline (hazard ratio [HR], 95% confidence interval [CI]: 2.12, 1.16-3.76; P = 0.015), and concurrent DM (HR, 95% CI: 2.07, 1.06-3.94; P = 0.034) were significantly associated with poorer OS after adjustment for age, prostate-specific antigen levels at diagnosis, Gleason score, and clinical stage. Treatment with sulfonylurea drugs was significantly associated with a reduced risk of disease progression in men with DM (HR, 95% CI: 0.36, 0.12-0.90; P = 0.028). Conclusions: Impaired glucose tolerance and treatment with sulfonylureas have prognostic significance in prostate cancer. These findings demonstrate the importance of managing DM during ADT and point to a possible favorable effect of sulfonylureas on prostate cancer.. |
| 42. |
Masaki Shiota, Primary Androgen Deprivation Therapy for Nonmetastatic Prostate Cancer in Asia: Unique or Not?, Journal of the National Comprehensive Cancer Network : JNCCN, 10.6004/jnccn.2019.7302, 17, 5, 523-524, 2019.05. |
| 43. |
Masakazu Akitake, Akito Yamaguchi, Masaki Shiota, Kenjiro Imada, Katsunori Tatsugami, Akira Yokomizo, Seiji Naito, Masatoshi Eto, Predictive Factors for Residual Cancer in Second Transurethral Resection for Non-muscle-invasive Bladder Cancer., Anticancer research, 10.21873/anticanres.13598, 39, 8, 4325-4328, 2019.08, BACKGROUND/AIM: The significance of second transurethral resection (TUR), and identification of predictive factors for residual cancer remain unrevealed. This study aimed to find residual cancer and up-staging rates, as well as predictive factors for residual cancer, in patients who undergo second TUR for non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Patients who underwent second TURs for NMIBC between 2015 and 2017, were included in the study and their clinicopathological characteristics were analyzed for predictors of residual cancer. RESULTS: Among 143 Japanese patients whose tumors were initially diagnosed as high-risk NMIBC, residual cancers detected at second TURs were, Tis: n=22 (15.4%), Ta: n=15 (10.5%) and T1: n=29 (20.3%). No patients showed up-staging from NMIBC to MIBC. The presence of carcinoma-in situ at initial TUR was an independent risk factor for any residual cancer (Tis, Ta and T1), non-flat residual cancer (Ta and T1), and flat residual cancer (Tis). CONCLUSION: The presence of carcinoma-in situ is suggested to be an independent predictor of residual cancer. This may help guide decisions to perform second TUR.. |
| 44. |
Yohei Sekino, Naohide Oue, Yuki Koike, Yoshinori Shigematsu, Naoya Sakamoto, Kazuhiro Sentani, Jun Teishima, Masaki Shiota, Masaki Shiota, Wataru Yasui, KIFC1 Inhibitor CW069 Induces Apoptosis and Reverses Resistance to Docetaxel in Prostate Cancer, Journal of Clinical Medicine, 10.3390/jcm8020225, 8, 2, 2019.02, Kinesin family member C1 (KIFC1) is a minus end-directed motor protein that plays an essential role in centrosome clustering. Previously, we reported that KIFC1 is involved in cancer progression in prostate cancer (PCa). We designed this study to assess the involvement of KIFC1 in docetaxel (DTX) resistance in PCa and examined the effect of KIFC1 on DTX resistance. We also analyzed the possible role of a KIFC1 inhibitor (CW069) in PCa. We used DTX-resistant PCa cell lines in DU145 and C4-2 cells to analyze the effect of KIFC1 on DTX resistance in PCa. Western blotting showed that KIFC1 expression was higher in the DTX-resistant cell lines than in the parental cell lines. Downregulation of KIFC1 re-sensitized the DTX-resistant cell lines to DTX treatment. CW069 treatment suppressed cell viability in both parental and DTX-resistant cell lines. DTX alone had little effect on cell viability in the DTX-resistant cells. However, the combination of DTX and CW069 significantly reduced cell viability in the DTX-resistant cells, indicating that CW069 re-sensitized the DTX-resistant cell lines to DTX treatment. These results suggest that a combination of CW069 and DTX could be a potential strategy to overcome DTX resistance.. |
| 45. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Efficacy and safety of cabazitaxel for castration-resistant prostate cancer in patients with > 10 cycles of docetaxel chemotherapy: a multi-institutional study, Medical Oncology, 10.1007/s12032-019-1257-1, 36, 4, 32-32, 2019.04, This multi-institutional study aimed to investigate the efficacy and safety profiles of cabazitaxel after prior docetaxel chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 63 Japanese patients with CRPC who were treated with cabazitaxel from 2014 to 2017. The oncological outcomes and adverse events (AEs) were documented, and prognostic factors for oncological outcomes and predictive factors for AEs were analysed. PSA decline was observed in 68.3% of patients, including 25.4% who achieved a ≥ 50% decline. The median progression-free survival, treatment failure-free survival, and overall survival were 4.3, 4.1, and 9.0 months, respectively. More cycles of prior docetaxel therapy was identified as common favourable prognostic factors for progression-free survival, treatment failure-free survival, and overall survival. Severe neutropenia, febrile neutropenia, and severe non-haematological AEs were observed in 73.0%, 33.3%, and 23.8% of patients, respectively. However, > 10 cycles of docetaxel was not associated with increased incidence of AEs. In conclusion, cabazitaxel chemotherapy was still active in Japanese CRPC patients treated with > 10 cycles of docetaxel chemotherapy, with an acceptable risk of AE burden. Treatment with cabazitaxel after > 10 cycles of docetaxel may be an appropriate option when it can be administered.. |
| 46. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Efficacy and safety of 4-weekly cabazitaxel for castration-resistant prostate cancer: a multi-institutional study, Cancer Chemotherapy and Pharmacology, 10.1007/s00280-019-03874-7, 84, 3, 561-566, 2019.09, OBJECTIVE: This study aimed to reveal the efficacy and safety profiles of 4-weekly cabazitaxel in patients with castration-resistant prostate cancer (CRPC). METHODS: The study included 62 Japanese patients who were treated for CRPC with ≥ 2 courses of cabazitaxel between 2014 and 2017. The oncological outcomes and adverse events were compared between 16 (25.8%) and 46 (74.2%) men who were treated with standard 3-weekly and alternative 4-weekly regimens, respectively. RESULTS: The prostate-specific antigen (PSA) response was comparable between the 3-weekly and 4-weekly regimens (median [interquartile range]: - 9.9% [- 64.5 to 13.0%] and - 30.7% [- 52.8 to 10.9%], P = 0.89), respectively. For patients on the 4-weekly regimen, the risks of progression (hazard ratio [HR], 95% confidence interval [CI] 1.27, 0.71-2.43, P = 0.44), treatment failure (HR, 95% CI 0.84, 0.48-1.55, P = 0.57) and any-cause mortality (HR, 95% CI 1.09, 0.58-2.17, P = 0.79) were comparable to those for patients on the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. CONCLUSIONS: 3-weekly and 4-weekly regimens of cabazitaxel showed similar efficacy and safety profiles in a real-world clinical setting. These data suggest that a 4-weekly regimen may be acceptable for selected patients.. |
| 47. |
Masaki Shiota, Miho Ushijima, Kenjiro Imada, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Masatoshi Eto, Cigarette smoking augments androgen receptor activity and promotes resistance to antiandrogen therapy, The Prostate, 10.1002/pros.23828, 79, 10, 1147-1155, 2019.07, BACKGROUND: Cigarette smoking is associated with worse outcomes in prostate cancer, whose growth is dependent on androgen receptor (AR) signaling. We aimed to elucidate the biological effect of cigarette smoking on AR signaling and its clinical influence on oncological outcome. METHODS: Gene expression levels after exposure to tobacco smoke condensate (TSC) were evaluated by quantitative real-time polymerase chain reaction and Western blot analysis in prostate cancer cells. Cellular sensitivities to enzalutamide and docetaxel after TSC exposure were evaluated using a prostate cancer cell proliferation assay. Prognosis was compared between current smokers and nonsmokers when treated with AR-axis-targeting (ARAT) agent enzalutamide and docetaxel. RESULTS: Expression of AR variants as well as prostate-specific antigen was augmented after TSC exposure, which occurred after Akt phosphorylation. These inductions were suppressed by Akt inhibitor LY294002 as well as antioxidant N-acetylcysteine. Consistently, TSC exposure augmented cellular resistance to enzalutamide. In clinical data, cigarette smoking was associated with worse progression-free survival and cancer-specific survival when patients with prostate cancer were treated with ARAT agents but not docetaxel. CONCLUSIONS: It was suggested that cigarette smoking leads to detrimental oncological outcome when prostate cancer patients are treated with ARAT agents through induction of aberrant AR signaling. Accordingly, we recommend that patients with advanced prostate cancer should refrain from cigarette smoking.. |
| 48. |
Masaki Shiota, Shintaro Narita, Shusuke Akamatsu, Naohiro Fujimoto, Takayuki Sumiyoshi, Maki Fujiwara, Takeshi Uchiumi, Tomonori Habuchi, Osamu Ogawa, Masatoshi Eto, Association of Missense Polymorphism in HSD3B1 With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone., JAMA network open, 10.1001/jamanetworkopen.2019.0115, 2, 2, e190115, 2019.02, 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.. |
| 49. |
Kosuke Ieiri, Masaki Shiota, Eiji Kashiwagi, Ario Takeuchi, Ryosuke Takahashi, Junichi Inokuchi, Hidenori Iwai, Ken-Ichiro Shiga, Akira Yokomizo, Tadamasa Yoshitake, Yoshiyuki Shioyama, Kousei Ishigami, Hiromi Terashima, Masatoshi Eto, The prognosis and the impact of radiotherapy in clinically regional lymph node-positive prostate cancer: Which patients are candidates for local therapy with radiation?, Urologic oncology, 10.1016/j.urolonc.2020.08.018, 38, 12, 931.e1-931.e7, 2020.12, BACKGROUND: This study aimed to identify the prognostic and predictive factors of local radiotherapy in clinically regional lymph node-positive prostate cancer. PATIENTS AND METHODS: This study includes patients who were newly diagnosed with regional lymph node-positive prostate cancer between 2008 and 2017. We investigated the prognostic value of clinicopathological parameters for progression-free survival (PFS) and overall survival (OS) as well as the differential prognostic impact of radiotherapy by subgroup analysis. RESULTS: Among the 93 men enrolled as patients, 48 (51.6 %) were treated with radiotherapy. The biopsy positive core rate and biopsy Gleason score were associated with PFS, and the number of lymph node metastases was associated with both PFS and OS. Patients who underwent radiotherapy showed better PFS and OS. High-risk features (at least 2 criteria among ≥75% biopsy positive core rate, Gleason score ≥9, and ≥2 positive lymph nodes) were especially associated with improved outcomes after undergoing radiotherapy. CONCLUSION: We identified prognostic factors for clinically regional lymph node-positive prostate cancer and showed the benefits of local radiation therapy. Patients with high-risk features may be especially suitable candidates for radiotherapy.. |
| 50. |
Takashi Matsumoto, Masaki Shiota, The established risk of prostate cancer comorbidity in BRCA1/2 mutation carriers: where is the clinically relevant hotspot for prostate cancer?, Translational andrology and urology, 10.21037/tau-20-866, 9, 5, 2289-2291, 2020.10. |
| 51. |
Eiji Kashiwagi, Masaki Shiota, Hiroyuki Masaoka, Kenjiro Imada, Keisuke Monji, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Relationship between body composition and hormone sensitivity for androgen deprivation therapy in patients with metastatic prostate cancer, Prostate International, 10.1016/j.prnil.2019.11.002, 8, 1, 22-26, 2020.03, Background: To evaluate the relationship between body composition and the oncological outcome of androgen deprivation therapy (ADT), we investigated whether body composition features including the psoas muscle may be predictive factors of ADT. Methods: This study enrolled patients with hormone-naïve metastatic prostate cancer who were treated with primary ADT from April 1996 to November 2013 at Kyushu University Hospital and who underwent a computed tomography scan before primary ADT for calculating body fat percentage, psoas muscle ratio (psoas muscle, cm3/height, cm), and body mass index. Results: Of the 178 patients enrolled, 60 patients died during follow-up. Median follow-up was 32 months, and progression-free survival and overall survival (OS) were 28 and 80 months, respectively. Multivariate analysis revealed that the psoas muscle ratio was correlated with OS (hazard ratio: 0.448; 95% confidence interval = 0.206-0.922; p = 0.028). Conclusions: This study demonstrated that higher psoas muscle ratio predicts longer OS among patients with nonlocalized prostate cancer treated with primary ADT.. |
| 52. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Prognostic significance of lactate dehydrogenase in cabazitaxel chemotherapy for castration-resistant prostate cancer: a multi-institutional study., Anti-cancer drugs, 10.1097/CAD.0000000000000884, 31, 3, 298-303, 2020.03, This multi-institutional study aimed to identify prognostic factors for cabazitaxel treatment of castration-resistant prostate cancer (CRPC). This study included 74 Japanese patients with CRPC who were treated with cabazitaxel between 2014 and 2017. Associations between clinicopathological factors including serum markers and progression-free survival (PFS) and overall survival (OS) were investigated. On multivariate analysis, high Gleason score [≥9 vs. ≤7; hazard ratio (HR), 95% confidence interval (CI): 2.00 (1.01-4.34); P = 0.047], presence of pain [HR, 95% CI: 2.02 (1.14-3.58); P = 0.016], and lactate dehydrogenase (LDH) level [HR, 95% CI: 47.31 (3.79-577.49); P = 0.0019] were significantly associated with PFS. Similarly, number of docetaxel cycles [HR, 95% CI: 0.050 (0.0037-0.45); P = 0.0057], performance status [≥2 vs. 0; HR, 95% CI: 5.07 (1.57-16.24); P |
| 53. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Prognostic Impact of Prior Androgen Receptor Axis-targeting Agents in Cabazitaxel Chemotherapy After Docetaxel., Anticancer research, 10.21873/anticanres.13957, 40, 1, 335-339, 2020.01, BACKGROUND/AIM: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents. PATIENTS AND METHODS: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy. RESULTS: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents. CONCLUSION: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the post-docetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.. |
| 54. |
Naoki Terada, Takashi Mizowaki, Toshihiro Saito, Akira Yokomizo, Naoki Kohei, Ken‐ichi Tabata, Masaki Shiota, Atsushi Takahashi, Toru Shimazui, Takayuki Goto, Yasuhiro Hashimoto, Masato Fujii, Ryotaro Tomida, Toshihiko Sakurai, Kohei Hashimoto, Sadafumi Kawamura, Shogo Teraoka, Shinichi Sakamoto, Takahiro Kimura, Manabu Kamiyama, Shintaro Narita, Nobumichi Tanaka, Takuma Kato, Masashi Kato, Takahiro Osawa, Takahiro Kojima, Takahiro Inoue, Mikio Sugimoto, Hiroyuki Nishiyama, Toshiyuki Kamoto, Potential effectiveness of local radiotherapy for extending survival and reducing symptomatic local events in patients with de novo metastatic prostate cancer, BJUI Compass, 10.1002/bco2.35, 1, 5, 165-173, 2020.11, Objectives: To evaluate the association between the use of local radiotherapy (RT) with the survival of patients with de novo metastatic prostate cancer and symptomatic local events (SLEs). Patients and methods: Patients were initially diagnosed with metastatic prostate cancer between 2008 and 2017 at 30 institutes in Japan. Prostate-specific antigen (PSA) progression-free survival (PSA-PFS) under initial androgen deprivation therapy and overall survival (OS) was compared between patients receiving local RT (RT group) and no RT (no-RT group) by multivariate Cox proportional hazard analyses. The occurrence rate of grade ≥2 SLEs was compared by multivariate logistic regression analyses. Propensity score matching (PSM) analyses were performed to compare PSA-PFS and OS of the groups in the high and low metastatic burden cohort. Results: Two hundred and five (7%) of 2829 patients received RT before PSA progression. Median PSA-PFS and OS were significantly longer in the RT group than in the no-RT group and the difference was significant in multivariate analyses (HR = 0.44, 95% CI = 0.33-0.57 and HR = 0.40, 95% CI = 0.27-0.60, respectively). The occurrence rate of grade ≥2 SLEs was significantly lower in the RT group (2%) than the no-RT group (9%) and the difference was significant in multivariate analyses (HR = 0.28, 95% CI = 0.10-0.76). Using PSM analyses, PSA-PFS and OS remained significantly different (HR = 0.64, 95% CI = 0.46-0.89 and HR = 0.47, 95% CI = 0.30-0.72, respectively), between the RT (n = 182) and the no-RT (n = 182) groups. The difference in OS was significant in the high metastatic burden cohort (HR = 0.55, 95% CI = 0.37-0.81). Conclusions: Addition of local RT to standard treatment for de novo metastatic prostate cancer patients tends to have the potential to extend survival, even in patients with high metastatic burden, and to reduce SLEs.. |
| 55. |
Masaki Shiota, Satoshi Endo, Naohiro Fujimoto, Shigehiro Tsukahara, Miho Ushijima, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Takeshi Uchiumi, Masatoshi Eto, Polymorphisms in androgen metabolism genes with serum testosterone levels and prognosis in androgen-deprivation therapy., Urologic oncology, 10.1016/j.urolonc.2020.06.033, 38, 11, 849.e11-849.e18, 2020.11, OBJECTIVE: Androgen metabolism is a key component in therapeutic resistance to androgen deprivation therapy (ADT). This study aimed to reveal the significance of genetic polymorphisms in genes involved in androgen metabolism, including CYP17A1, AKR1C3, and HSD17B, on serum testosterone levels during ADT, as well as the prognosis of men undergoing ADT for metastatic prostate cancer (CaP). MATERIALS AND METHODS: This study included 104 Japanese patients with metastatic CaP, for whom serum testosterone data during ADT were available for 80 patients. The association of CYP17A1 (rs743572), AKR1C3 (rs12529), HSD17B1 (rs605059), HSD17B3 (rs2066479), and HSD17B4 (rs7737181) with serum testosterone levels during ADT and prognosis (progression-free survival and overall survival) was examined. Enzymatic activity in AKR1C3 H5Q was examined using recombinant protein. RESULTS: Homozygous wild-type (GG allele; median [interquartile range], 12.0 ng/ml [8.0-19.0 ng/ml]) AKR1C3 rs12529 was associated with higher serum testosterone levels during ADT compared with variant-type (GC/CC alleles; median [interquartile range], 9.0 ng/ml [6.4-10.8 ng/ml]). Consistently, variant-type (GC/CC alleles) AKR1C3 rs12529 showed significantly lower risk of progression (hazard ratio [95% confidence interval], 0.47 [0.24-0.96], P = 0.039) compared with homozygous wild-type (GG allele) on multivariate analysis. Meanwhile, other genetic variations were associated with neither serum testosterone during ADT nor prognosis. Enzyme activity of wild-type AKR1C3 was comparable to the H5Q mutant. CONCLUSIONS: Taken together, this study demonstrated that AKR1C3 polymorphism, which was associated with serum testosterone levels during ADT, may be a prognostic factor of the progression to castration-resistant prostate cancer in Japanese men with metastatic CaP.. |
| 56. |
Yohei Sekino, Xiangrui Han, Takashi Babasaki, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Jun Teishima, Masaki Shiota, Yukio Takeshima, Wataru Yasui, Akio Matsubara, Microtubule-associated protein tau (MAPT) promotes bicalutamide resistance and is associated with survival in prostate cancer., Urologic oncology, 10.1016/j.urolonc.2020.04.032, 38, 10, 795.e1-795.e8, 2020.10, INTRODUCTION: Microtubule-associated protein tau (MAPT), facilitates tubulin assembly and microtubule stabilization. Several studies have shown that overexpression of MAPT is linked to poor prognosis and is involved in taxane resistance in cancer. This study aimed to assess the expression and function of MAPT in prostate cancer (CaP). METHODS: The expression of MAPT was determined using immunohistochemistry in CaP. We analyzed the interaction between MAPT, Phosphatase and Tensin Homolog (PTEN), and androgen receptor and investigated the role of MAPT in bicalutamide resistance. RESULTS: Immunohistochemistry in 155 CaP cases showed that 15% of them were positive for MAPT. High MAPT expression was significantly orrelated with high Gleason score and high T stage. Kaplan-Meier analysis showed that the high MAPT expression was significantly associated with poor prostate-specific antigen recurrence survival after radical prostatectomy. There was an inverse correlation between MAPT and PTEN. In the CaP cell lines, knockout of PTEN increased the expression of MAPT, whereas knockdown of MAPT suppressed the expression of androgen receptor and increased the sensitivity to bicalutamide. Furthermore, immunohistochemical staining of MAPT showed that high MAPT expression was significantly associated with poor overall survival in 74 CaP patients who were treated with androgen deprivation therapy. CONCLUSION: These results suggest that MAPT may be a promising predictive biomarker for survival and play an essential role in bicalutamide resistance in CaP.. |
| 57. |
Masaki Shiota, Asako Machidori, Tatsuro Abe, Keisuke Monji, Eiji Kashiwagi, Ario Takeuchi, Ryosuke Takahashi, Junichi Inokuchi, Akira Yokomizo, Seiji Naito, Masatoshi Eto, Impact of antiandrogen withdrawal syndrome in castration-resistant prostate cancer patients treated with abiraterone or enzalutamide., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14366, 27, 12, 1109-1115, 2020.12, OBJECTIVES: To assess the impact of antiandrogen withdrawal syndrome after bicalutamide withdrawal in castration-resistant prostate cancer patients treated with androgen receptor-axis targeted agents. METHODS: The study cohort comprised 94 patients treated with abiraterone (n = 34) or enzalutamide (n = 60) as a first-line androgen receptor-axis targeted agent for castration-resistant prostate cancer despite combined androgen blockade by castration with bicalutamide as the first-line therapy. The association between clinicopathological factors (including antiandrogen withdrawal syndrome) and therapeutic outcome after using abiraterone and enzalutamide was investigated. RESULTS: The decline in the prostate-specific antigen level after use of abiraterone or enzalutamide was comparable between patients with and without antiandrogen withdrawal syndrome. Antiandrogen withdrawal syndrome (hazard ratio 3.84, 95% confidence interval 1.29-11.45; P = 0.016) was associated with a higher risk of progression on multivariate analysis, but not all-cause death after abiraterone use. Progression-free survival and overall survival after enzalutamide use did not differ between patients with and without antiandrogen withdrawal syndrome. CONCLUSIONS: The present data suggest a modest therapeutic efficacy of abiraterone in castration-resistant prostate cancer patients with anti-androgen withdrawal syndrome after bicalutamide withdrawal.. |
| 58. |
Momoe Itsumi, Masaki Shiota, Yohei Sekino, Miho Ushijima, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto, High‐throughput screen identifies 5‐HT receptor as a modulator of AR and a therapeutic target for prostate cancer, The Prostate, 10.1002/pros.24022, 80, 11, 885-894, 2020.08, BACKGROUND: Eradication of persistent androgen receptor (AR) activity in castration-resistant prostate cancer may be a promising strategy to overcome castration resistance. We aimed to identify novel compounds that inhibit AR activity and could be potential therapeutic agents for prostate cancer. METHODS: A high-throughput screening system involving cell lines stably expressing AR protein and AR-responsive luciferase was employed for the 1260 compound library. Molecular and antitumor effects on candidate pathways that interacted with AR signaling were examined in prostate cancer cells expressing AR. RESULTS: The high-throughput screening identified various potential compounds that interfered with AR signaling through known and novel pathways. Among them, a 5-hydroxytryptamine 5A (5-HT5A) receptor antagonist suppressed AR activity through protein kinase A signaling, which was confirmed by 5-HT5A receptor knockdown. Consistently, 5-HT5A receptor inhibitors showed cytotoxic effects toward prostate cancer cells. CONCLUSIONS: Taken together, this study identifies 5-HT5A receptor as a promising therapeutic target for prostate cancer via its interaction with AR signaling.. |
| 59. |
Masaki Shiota, Naohiro Fujimoto, Yoshiaki Yamamoto, Ario Takeuchi, Katsunori Tatsugami, Takeshi Uchiumi, Hideyasu Matsuyama, Masatoshi Eto, Genome-wide association study of genetic variations associated with treatment failure after intravesical bacillus Calmette–Guérin therapy for non-muscle invasive bladder cancer, Cancer Immunology, Immunotherapy, 10.1007/s00262-020-02533-8, 69, 7, 1155-1163, 2020.07, Bacillus Calmette-Guérin (BCG) instillation is a key therapy to manage non-muscle invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in approximately half of the patients, leading to recurrence and progression. We aimed to reveal the genetic variations associated with treatment failure after intravesical BCG therapy for NMIBC. This study included 91 Japanese patients treated with BCG instillation for NMIBC. Genomic DNA was obtained from patient whole-blood samples, and a genome-wide association study and genotyping for target regions were performed. The association between genetic variation and treatment failure was analyzed by genome-wide association in 44 patients as the discovery cohort. As a validation study, candidate single nucleotide polymorphisms (SNPs) were examined among 47 patients in another cohort. The genome-wide association study indicated 19 candidate SNPs (rs1607282, rs7825442, rs1319325, rs3738088, rs4250, rs11894207, rs161448, rs2764326, rs2814707, rs3787194, rs58081719, rs3095966, rs73520681, rs16877113, rs16887173, rs10269584, rs11772249, rs118137814, and rs61094339) associated with BCG failure. Following the cumulative analysis of candidate SNPs, 2-gene (rs73520681 and rs61094339) and 4-gene (rs4250, rs11894207, rs73520681, and rs61094339) models successfully predicted treatment failure after intravesical BCG therapy. This study showed that several SNPs were possibly associated with outcome after intravesical BCG therapy in a Japanese population with NMIBC. The cumulative models of these SNPs may have value in clinical applications, although this should be confirmed in future studies.. |
| 60. |
Masaki Shiota, Mizuki Onozawa, Shiro Hinotsu, Masatoshi Eto, Seiji Naito, Hideyuki Akaza, Family history in primary hormone therapy for prostate cancer: Analysis from a community-based multi-institutional Japan-wide database., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14184, 27, 4, 313-318, 2020.04, OBJECTIVES: To determine the association between hormone therapy and outcomes in a cohort of prostate cancer patients with a family history of prostate cancer. METHODS: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 13 346 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival and overall survival, were compared between men with familial and men with sporadic prostate cancer. RESULTS: A positive family history was identified in 220 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a possible favorable prognostic factor for overall survival among patients with a prostate-specific antigen level at diagnosis |
| 61. |
Nobuaki Sato, Masaki Shiota, Ken-Ichiro Shiga, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Akira Yokomizo, Seiji Naito, Masatoshi Eto, Effect of Smoking on Oncological Outcome among Prostate Cancer Patients after Radical Prostatectomy with Neoadjuvant Hormonal Therapy., Cancer investigation, 10.1080/07357907.2020.1833212, 38, 10, 559-564, 2020.11, We analyzed the association between smoking and oncological outcome after radical prostatectomy with neoadjuvant hormonal therapy. This study included men who had undergone radical prostatectomy with neoadjuvant hormonal therapy between 2003 and 2016. We evaluated the association between clinicopathological factors and smoking status as well as the prognostic significance of smoking status in biochemical recurrence. The patients' backgrounds were comparable between smokers and nonsmokers. Smoking status were identified as significant risk factors of biochemical recurrence. Smoking was a risk factor of biochemical recurrence, suggesting that smoking may promote cancer recurrence after surgical treatment combined with hormonal therapy.. |
| 62. |
Masaki Shiota, Editorial Comment to Validation and development of the CHAARTED criteria in patients with hormone-naïve metastatic prostate cancer: A multi-institutional retrospective study in Japan., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14143, 27, 1, 92-92, 2020.01. |
| 63. |
Ario Takeuchi, Masaki Shiota, Editorial Comment to Resumption of anti‐programmed cell death 1 monotherapy for severe immune‐related adverse events experienced patient with renal cell carcinoma, IJU Case Reports, 10.1002/iju5.12181, 3, 5, 179-180, 2020.09. |
| 64. |
Masaki Shiota, Editorial Comment from Dr Shiota to Magnetic resonance imaging/transrectal ultrasonography fusion targeted prostate biopsy finds more significant prostate cancer in biopsy-naïve Japanese men compared with the standard biopsy., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14156, 27, 2, 147-148, 2020.02. |
| 65. |
Masaki Shiota, Shintaro Narita, Tomonori Habuchi, Masatoshi Eto, Validated prognostic significance of YB-1 genetic variation in metastatic prostate cancer, The Pharmacogenomics Journal, 10.1038/s41397-020-00188-3, 21, 1, 102-105, 2021.02, Genetic polymorphism in YB-1 was previously shown to be associated with the prognosis of advanced prostate cancer patients treated with primary androgen-deprivation therapy. However, the significance of this polymorphism remains invalidated. In this study, we aimed to validate the prognostic significance of the YB-1 genetic polymorphism in metastatic prostate cancer. This study included 79 Japanese patients who were diagnosed as metastatic prostate cancer between 2000 and 2016. Genomic DNA was obtained from patient whole blood samples, and genotyping on YB-1 (rs12030724) was performed by PCR-based technique. The association of genotype in YB-1 with clinicopathological parameters and oncological outcome, including progression-free survival and overall survival, was examined. Homozygous wild-type (AA), heterozygous variant (AT), and homozygous variant (TT) were identified in 47 (59.5%), 26 (32.9%) and 6 patients (7.6%), respectively. Heterozygous/homozygous variant (AT/TT) in YB-1 was significantly associated with lower progression risk compared with homozygous wild-type (AA) (hazard ratio = 0.52; 95% confidence interval = 0.30-0.88, P = 0.015). Consistent with this finding, heterozygous/homozygous variant (AT/TT) in YB-1 was significantly associated with lower risk of any-cause mortality compared with homozygous wild-type (AA) (hazard ratio = 0.46; 95% confidence interval = 0.21-0.93, P = 0.031). Gene polymorphism in YB-1 rs12030724 was validated to be a promising predictive biomarker of androgen-deprivation therapy in metastatic prostate cancer to identify patients requiring more intensive therapeutics.. |
| 66. |
Leandro Blas, Masaki Shiota, Unrecognized Pitfall When Doing Nerve-Sparing Surgery in Radical Prostatectomy, Annals of Surgical Oncology, 10.1245/s10434-021-10282-w, 28, 9, 4775-4776, 2021.09. |
| 67. |
Naohiro Fujimoto, Kenichi Harada, Masaki Shiota, Ikko Tomisaki, Akinori Minato, Yujiro Nagata, Rieko Kimuro, Mirii Harada, Masato Fujisawa, Treatment of Metastatic Castration-resistant Prostate Cancer: Are PARP Inhibitors Shifting the Paradigm?, Anticancer research, 10.21873/anticanres.15282, 41, 10, 4687-4695, 2021.10, Remarkable developments in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have been achieved over the past decade. Although targeting the novel androgen receptor axis and using chemotherapeutic agents have improved survival, mCRPC is still a lethal disease. A better molecular characterization of cancer resulted in the determination of the important role of homologous recombination repair (HRR) genes in cancer development, and poly (ADP-ribose) polymerase (PARP) is one of the most attractive therapeutic targets. Recent clinical studies have demonstrated that PARP inhibitors significantly improve oncological outcomes in patients with mCRPC harboring BRCA mutations, and PARP inhibitors are becoming a standard of care for these patients. However, not only PARP inhibitors, but also chemotherapeutic agents such as platinum agents, taxanes, and radium-223 are active in HRR gene mutation carriers, and platinum sensitivity may predict the efficacy of PARP inhibitors for mCRPC. The combination of PARP inhibitors with other anti-cancer agents may overcome resistance mechanisms against PARP inhibitors and lead to survival benefits. Appropriate treatment sequences and combinations may change the therapeutic landscape of DNA repair deficient mCRPC.. |
| 68. |
Shohei Nagakawa, Masaki Shiota, Naohiro Fujimoto, Yoshiaki Yamamoto, Leandro Blas, Shigehiro Tsukahara, Takashi Matsumoto, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Takeshi Uchiumi, Hideyasu Matsuyama, Masatoshi Eto, The impact of single-nucleotide polymorphisms on intravesical recurrence after bacillus Calmette-Guérin therapy for non-muscle invasive bladder cancer in a genome-wide association study., Urologic oncology, 10.1016/j.urolonc.2021.05.034, 39, 10, 733.e17-733.e24, 2021.10, OBJECTIVE: Bacillus Calmette-Guérin (BCG) instillation therapy is widely used to reduce intravesical recurrence in non-muscle invasive bladder cancer (NMIBC). In this study, we aimed to reveal the genetic variations associated with intravesical recurrence after BCG therapy for NMIBC in a genome-wide association study (GWAS). MATERIALS AND METHODS: This study included Japanese patients with NMIBC, in whom genomic DNA was obtained from whole blood samples. The association between genetic variation and treatment failure was analyzed by GWAS in 44 patients treated with BCG instillation as a discovery cohort. Candidate single-nucleotide polymorphisms (SNPs) were examined separately in 47 patients treated with BCG instillation and in 62 patients treated with chemotherapeutic agent instillation as validation studies. RESULTS: Among the 44 patients in the discovery cohort, 14 cases experienced intravesical recurrent diseases. GWAS identified 12 candidate SNPs (rs9374832, rs35176001, rs363765, rs2127120, rs4277759, rs73664140, rs1607282, rs12141654, rs4541358, rs6986852, rs12373386, and rs17637903). In the validation study, a genetic risk stratification model using the number of risk alleles in rs363765 and rs6986852 discriminated the risk of intravesical recurrence after BCG therapy, but not after non-BCG therapy. CONCLUSION: This study suggested that several SNPs were associated with intravesical recurrence after BCG therapy for NMIBC. A genetic risk model may be useful to predict intravesical recurrence after BCG therapy, warranting further research and development for clinical application.. |
| 69. |
Masaki Shiota, Shusuke Akamatsu, Shintaro Narita, Takayuki Sumiyoshi, Maki Fujiwara, Takeshi Uchiumi, Osamu Ogawa, Tomonori Habuchi, Masatoshi Eto, The association between missense polymorphisms in SRD5A2 and HSD3B1 and treatment failure with abiraterone for castration-resistant prostate cancer, The Pharmacogenomics Journal, 10.1038/s41397-021-00220-0, 21, 4, 440-445, 2021.08, 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.. |
| 70. |
Yohei Sekino, Xiangrui Han, Takashi Babasaki, Shunsuke Miyamoto, Kohei Kobatake, Hiroyuki Kitano, Kenichiro Ikeda, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Jun Teishima, Masaki Shiota, Yukio Takeshima, Wataru Yasui, Akio Matsubara, TUBB3 is associated with PTEN, neuroendocrine differentiation, and castration resistance in prostate cancer., Urologic oncology, 10.1016/j.urolonc.2021.03.001, 39, 6, 368.e1-368.e9, 2021.06, BACKGROUND: Tubulin-β3 encoded by the Tubulin-β3 (TUBB3) gene is a microtubule protein. Previous studies have shown that TUBB3 expression is upregulated in castration-resistant prostate cancer (CaP) and is involved in taxane resistance. However, the biological mechanism of TUBB3 involvement in the progression to castration-resistant CaP is not fully elucidated. This study aimed to analyze the expression and function of TUBB3 in localized and metastatic CaP. METHODS: TUBB3 expression was determined using immunohistochemistry in localized and metastatic CaP. We also investigated the association between TUBB3, phosphatase and tensin homolog (PTEN), and neuroendocrine differentiation and examined the involvement of TUBB3 in new antiandrogen drugs (enzalutamide and apalutamide) resistance in metastatic CaP. RESULTS: In 155 cases of localized CaP, immunohistochemistry showed that 5 (3.2%) of the CaP cases were positive for tubulin-β3. Kaplan-Meier analysis showed that high expression of tubulin-β3 was associated with poor prostate-specific antigen recurrence-free survival after radical prostatectomy. In 57 cases of metastatic CaP, immunohistochemistry showed that 14 (25%) cases were positive for tubulin-β3. Tubulin-β3 expression was higher in metastatic CaP than in localized CaP. High tubulin-β3 expression was correlated with negative PTEN expression. TUBB3 expression was increased in neuroendocrine CaP based on several public databases. PTEN knockout decreased the sensitivity to enzalutamide and apalutamide in 22Rv-1 cells. TUBB3 knockdown reversed the sensitivity to enzalutamide and apalutamide in PTEN-CRISPR 22Rv-1 cells. High expression of tubulin-β3 and negative expression of PTEN were significantly associated with poor overall survival in metastatic CaP treated with androgen deprivation therapy. CONCLUSIONS: These results suggest that TUBB3 may be a useful predictive biomarker for survival and play an essential role in antiandrogen resistance in CaP.. |
| 71. |
Hiroki Kobayashi, Satoshi Kobayashi, Masaki Shiota, Dai Takamatsu, Tatsuro Abe, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Kenichi Kohashi, Yoshiyuki Shioyama, Yoshinao Oda, Masatoshi Eto, Salvage robot-assisted radical prostatectomy after carbon ion radiotherapy: a case report, International Cancer Conference Journal, 10.1007/s13691-020-00464-w, 10, 2, 96-99, 2021.04, Salvage radical prostatectomy is a therapeutic option for the biochemical recurrence of prostate cancer after radiotherapy. However, only one case report of salvage radical prostatectomy after carbon ion radiotherapy has been reported. We report a case of salvage robot-assisted radical prostatectomy for local recurrence of prostate cancer after carbon ion radiotherapy with surgical video. Owing to adhesion and degeneration after radiotherapy, difficulties in surgery and post-operative complications have been anticipated. However, surgery was feasible without severe peri- and post-operative complications. Salvage robot-assisted radical prostatectomy after carbon ion radiotherapy may be a reasonable therapeutic option. Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-020-00464-w.. |
| 72. |
Masaki Shiota, Ryota Sumikawa, Mizuki Onozawa, Shiro Hinotsu, Yasuhide Kitagawa, Shinichi Sakamoto, Taketo Kawai, Masatoshi Eto, Haruki Kume, Hideyuki Akaza, Regional and facility disparities in androgen deprivation therapy for prostate cancer from a multi-institutional Japan-wide database., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14518, 28, 5, 584-591, 2021.05, OBJECTIVES: To examine the differences in prognosis of prostate cancer patients receiving primary androgen deprivation therapy by region and facility type using a Japan-wide database. METHODS: Data on patients treated with primary androgen deprivation therapy between 2001 and 2003 from a nationwide community-based database established by the Japan Study Group of Prostate Cancer were obtained. Clinicopathological characteristics and prognostic variables, including progression, cancer-specific survival and overall survival, were compared according to region and facility type where the patients were treated. RESULTS: Among 19 162 patients, 7102 (37.1%) and 12 060 (62.9%) men were in urban and rural areas, respectively, and 3556 (18.6%), 13 623 (71.1%) and 1983 (10.3%) patients were enrolled from academic centers, non-academic hospitals and urological clinics, respectively. The risks of progression, cancer-specific mortality and all-cause mortality were comparable between urban and rural areas in propensity-score matched analysis. Risks of progression, cancer-specific mortality and all-cause mortality in urological clinics were higher than those in academic centers in propensity-score matched analysis. CONCLUSIONS: Our findings suggest that Japan facility type, but not geographical regions, might affect the prognosis of prostate cancer patients receiving primary androgen deprivation therapy.. |
| 73. |
Asako Machidori, Masaki Shiota, Satoshi Kobayashi, Takashi Matsumoto, Keisuke Monji, Eiji Kashiwagi, Ario Takeuchi, Ryosuke Takahashi, Junichi Inokuchi, Masatoshi Eto, Prognostic significance of complete blood count parameters in castration-resistant prostate cancer patients treated with androgen receptor pathway inhibitors., Urologic oncology, 10.1016/j.urolonc.2020.09.036, 39, 6, 365.e1-365.e7, 2021.06, BACKGROUND: This study investigated the prognostic significance of complete blood count data in castration-resistant prostate cancer patients treated using androgen receptor pathway inhibitors (ARPIs). PATIENTS AND METHODS: Patients treated with an ARPI, abiraterone or enzalutamide, as first-line therapy for castration-resistant prostate cancer from 2014 to 2018 were included. The association between complete blood count data and prognoses including progression-free survival and overall survival (OS) was investigated. RESULTS: High white blood cell counts ( |
| 74. |
Mikifumi Koura, Masaki Shiota, Shohei Ueda, Takashi Matsumoto, Satoshi Kobayashi, Keisuke Monji, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Ken-ichiro Shiga, Akira Yokomizo, Masatoshi Eto, Prognostic impact of prior local therapy in castration-resistant prostate cancer, Japanese Journal of Clinical Oncology, 10.1093/jjco/hyab019, 51, 7, 1142-1148, 2021.07, OBJECTIVE: This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC). METHODS: The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis. RESULTS: In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95% confidence interval, 0.40-0.79; P = 0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis. CONCLUSIONS: This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC.. |
| 75. |
Leandro Blas, Kosuke Ieiri, Masaki Shiota, Shohei Nagakawa, Shigehiro Tsukahara, Takashi Matsumoto, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Ken-Ichiro Shiga, Akira Yokomizo, Masatoshi Eto, Prognostic Value of Lower Tract Urinary Symptoms in Clinically Regional Lymph Node-positive Prostate Cancer., Anticancer research, 10.21873/anticanres.15373, 41, 11, 5593-5598, 2021.11, BACKGROUND/AIM: To explore the prognostic value of lower urinary tract symptoms (LUTS) in patients with newly diagnosed regional lymph node-positive prostate cancer. PATIENTS AND METHODS: The prognostic value of LUTS for progression-free (PFS) and overall (OS) survival, as well as the differential prognostic impact of radiotherapy by LUTS was investigated. RESULTS: Univariate Cox-model analysis showed a statistically significantly increased hazard risk for PFS and OS for men with International Prostate Symptom Score (IPSS)≥19 and Overactive Bladder Symptom Score (OABSS) ≥8 at diagnosis. Patients with lower IPSS had a better PFS at 5 years (70.0% vs. 51.9%, p=0.027) and OS at 5 year (89.3% vs. 73.6%, p=0.016). Similarly, a lower OABSS was associated with greater PFS at 5 years (67.4% vs. 23.4%, p |
| 76. |
Momoe Itsumi, Masaki Shiota, Shunichi Kajioka, Masatoshi Eto, Profile of androgen receptor activators identified using high‐throughput screen, Andrologia, 10.1111/and.13856, 53, 1, e13856, 2021.02. |
| 77. |
Takashi Babasaki, Kazuhiro Sentani, Yohei Sekino, Go Kobayashi, Quoc Thang Pham, Narutaka Katsuya, Shintaro Akabane, Daiki Taniyama, Tetsutaro Hayashi, Masaki Shiota, Naohide Oue, Jun Teishima, Akio Matsubara, Wataru Yasui, Overexpression of claspin promotes docetaxel resistance and is associated with prostate‐specific antigen recurrence in prostate cancer, Cancer Medicine, 10.1002/cam4.4113, 10, 16, 5574-5588, 2021.08, Although docetaxel (DTX) confers significant survival benefits in patients with castration-resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S-phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin-positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan-Meier analysis showed that high claspin expression was related to poor prostate-specific antigen (PSA) relapse-free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse-free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX-resistant DU145 (DU145-DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145-DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.. |
| 78. |
Masaki Shiota, Naoki Terada, Hiroshi Kitamura, Takahiro Kojima, Toshihiro Saito, Akira Yokomizo, Naoki Kohei, Takayuki Goto, Sadafumi Kawamura, Yasuhiro Hashimoto, Atsushi Takahashi, Takahiro Kimura, Ken‐ichi Tabata, Ryotaro Tomida, Kohei Hashimoto, Toshihiko Sakurai, Toru Shimazui, Shinichi Sakamoto, Manabu Kamiyama, Nobumichi Tanaka, Koji Mitsuzuka, Takuma Kato, Shintaro Narita, Hiroaki Yasumoto, Shogo Teraoka, Masashi Kato, Takahiro Osawa, Yoshiyuki Nagumo, Hiroaki Matsumoto, Hideki Enokida, Takayuki Sugiyama, Kentaro Kuroiwa, Takahiro Inoue, Mikio Sugimoto, Takashi Mizowaki, Toshiyuki Kamoto, Hiroyuki Nishiyama, Masatoshi Eto, Novel metastatic burden‐stratified risk model in de novo metastatic hormone‐sensitive prostate cancer, Cancer Science, 10.1111/cas.15038, 112, 9, 3616-3626, 2021.09, The metastatic burden is a critical factor for decision-making in the treatment of metastatic hormone-sensitive prostate cancer (HSPC). This study aimed to develop and validate a novel risk model for survival in patients with de novo low- and high-burden metastatic HSPC. The retrospective observational study included men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We created a risk model for overall survival (OS) in the discovery cohort (n = 1449) stratified by the metastatic burden (low vs high) and validated its predictive ability in a separate cohort (n = 951). Based on multivariate analyses, lower hemoglobin levels, higher Gleason grades, and higher clinical T-stage were associated with poor OS in low-burden disease. Meanwhile, lower hemoglobin levels, higher Gleason grade group, liver metastasis, and higher extent of disease scores in bone were associated with poor OS in patients with high-burden disease. In the discovery and validation cohorts, the risk model using the aforementioned parameters exhibited excellent discriminatory ability for progression-free survival and OS. The predictive ability of this risk model was superior to that of previous risk models. Our novel metastatic burden-stratified risk model exhibited excellent predictive ability for OS, and it is expected to have several clinical uses, such as precise prognostic estimation.. |
| 79. |
Leandro Blas, Mizuki Onozawa, Masaki Shiota, Shiro Hinotsu, Shinichi Sakamoto, Yasuhide Kitagawa, Taketo Kawai, Masatoshi Eto, Haruki Kume, Hideyuki Akaza, Long‐term outcomes of androgen deprivation therapy in prostate cancer among Japanese men over 80 years old, Cancer Science, 10.1111/cas.14974, 112, 8, 3074-3082, 2021.08, This study aimed to analyze the survival rate and to examine the risk of death from prostate cancer when accounting for competing risk of death, in men aged ≥80 y treated with primary androgen deprivation therapy (ADT). Data of patients with prostate cancer who had received ADT were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Prognostic variables, including progression-free survival, cancer-specific survival, overall survival, and death rates were compared between men stratified by prostate cancer risk. Overall, 4760 patients older than 80 y were included. The proportion of low-, intermediate-, high-, or very high-risk, regional, and metastatic prostate cancer among super-elderly men was 9.5%, 14.6%, 48.8%, 9.0%, 3.2%, and 24.9%, respectively. Survival rates decreased with increasing risk stratification. The cumulative 5-y death rate by prostate cancer for low-, intermediate-, high-, or very high-risk, regional, and metastatic prostate cancer, was 0.92% (95% confidence interval [CI]: 0.2%-3.6%), 1.6% (95% CI: 0.8%-3.4%), 5.75% (95% CI: 4.25%-7.75%), 15.6% (95% CI: 11.6%-23.3%), 20.7% (95% CI: 13.1%-31.7%), and 36.9% (95% CI: 32.8%-41.4%), respectively. Our findings support that there is no need for immediate ADT for low- and intermediate-risk groups. Conversely, in high- or very high-risk, regional, and metastatic prostate cancer, more efforts for curative therapy and intensive therapy are needed in selected patients.. |
| 80. |
Leandro Blas, Masaki Shiota, Shigetomo Yamada, Kosuke Ieiri, Shohei Nagakawa, Shigehiro Tsukahara, Takashi Matsumoto, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Ken-Ichiro Shiga, Akira Yokomizo, Masatoshi Eto, Lactate Dehydrogenase Is a Serum Prognostic Factor in Clinically Regional Lymph Node-positive Prostate Cancer., Anticancer research, 10.21873/anticanres.15183, 41, 8, 3885-3889, 2021.08, BACKGROUND/AIM: Currently, there is no established prognostic serum parameter except PSA in clinically regional lymph node-positive prostate cancer. The aim of this study was to identify serum prognostic factors in clinically regional lymph node-positive prostate cancer. PATIENTS AND METHODS: Patients diagnosed with regional lymph node-positive prostate cancer between 2008 and 2017 were included. The prognostic value of serum parameters for progression-free survival (PFS) and overall survival (OS) was investigated. RESULTS: Univariate and multivariate analyses showed a statistically significant increased hazard risk for PFS and OS for men with lactate dehydrogenase (LDH) ≥230 IU/l at diagnosis. PFS at 5 years for patients with high and low LDH levels were 69.9% (95% CI=56.8-79.8%) and 18.9% (95% CI=1.23-53.2%), respectively (p=0.003). OS at 5 years for low and high LDH levels were 89.2% (95% CI=78.6-94.7%) and 46.3 (95% CI=11.2-76.2%), respectively (p=0.006). CONCLUSION: This study shows that LDH is an independent predictor of PFS and OS in patients with regional lymph node metastatic prostate cancer.. |
| 81. |
Yohei Sekino, Quoc Thang Pham, Kohei Kobatake, Hiroyuki Kitano, Kenichiro Ikeda, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Masaki Shiota, Wataru Yasui, Jun Teishima, HOXB5 Overexpression Is Associated with Neuroendocrine Differentiation and Poor Prognosis in Prostate Cancer., Biomedicines, 10.3390/biomedicines9080893, 9, 8, 2021.07, Homeobox genes function as master regulatory transcription factors during embryogenesis. HOXB5 is known to play an important role in several cancers. However, the biological role of HOXB5 in prostate cancer (PCa) is not fully elucidated. This study aimed to analyze the expression and function of HOXB5 and involvement of HOXB5 in neuroendocrine differentiation in PCa. Immunohistochemistry showed that 56 (43.8%) of 128 cases of localized PCa were positive for HOXB5. HOXB5-positive cases were associated with poor prostate-specific antigen recurrence-free survival after prostatectomy. Among 74 cases of metastatic PCa, 43 (58.1%) were positive for HOXB5. HOXB5 expression was higher in metastatic PCa than that in localized PCa. HOXB5 knockdown suppressed cell growth and invasion, but HOXB5 overexpression increased cell growth and invasion in PCa cell lines. Furthermore, HOXB5 regulated RET expression. Gene set enrichment analysis revealed that Nelson androgen response gene set was enriched in low HOXB5 expression group. RB1 knockout increased HOXB5 expression. Of note, additional p53 knockdown further increased HOXB5 expression in RB1 knockout cells. In silico analysis showed that HOXB5 expression was increased in neuroendocrine PCa (NEPC). These results suggest that HOXB5 may be a promising prognostic marker after prostatectomy and is involved in progression to NEPC.. |
| 82. |
Takashi Matsumoto, Masaki Shiota, Takeshi Uchiumi, Shohei Ueda, Shigehiro Tsukahara, Takahiro Toshima, Shinya Matsumoto, Nozomi Noda, Masatoshi Eto, Dongchon Kang, Genomic characteristics revealed by targeted exon sequencing of testicular germ cell tumors in Japanese men., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14396, 28, 1, 40-46, 2021.01, OBJECTIVE: To investigate the somatic mutation profiles of testicular germ cell tumors in Japanese men. METHODS: We analyzed the somatic missense mutation profile of testicular germ cell tumors among 21 Japanese men with seminoma (n = 14), pure embryonic carcinoma (n = 3) and mixed testicular germ cell tumor (n = 4) by targeted next-generation sequencing of 409 cancer-related genes covering 1.23 Mb of the genome. RESULTS: We identified a total of 22 missense mutations in 21 primary testicular germ cell tumor samples (0.89 mutations/Mb), of which seven mutations were confirmed to be absent from the germline. KIT:p.Asn822Tyr, KIT:p.Leu576Pro, PIK3CA:p.Glu542Lys and FBXW7:p.Arg505His were statistically and functionally potential. A total of 18 missense mutations were previously unknown in testicular germ cell tumors. PDGFRA amplification from one patient with seminoma was detected. KIT, BCR,PIK3CG, PIK3CA and PDGFRA mutations involved in aberrant signaling of the KIT-PI3K-AKT pathway was detected in 27.3% of detected mutations. CONCLUSIONS: The present investigation identified a low mutation rate in testicular germ cell tumors among Asian patients, 18 novel mutations and PDGFRA amplification. Limitations of the present study are the small sample and missing normal DNA for some testicular germ cell tumors.. |
| 83. |
Masaki Shiota, Shusuke Akamatsu, Shintaro Narita, Naoki Terada, Naohiro Fujimoto, Masatoshi Eto, Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer., JMA journal, 10.31662/jmaj.2021-0004, 4, 2, 99-111, 2021.04, 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.. |
| 84. |
Masaki Shiota, Yohei Sekino, Shigehiro Tsukahara, Tatsuro Abe, Fumio Kinoshita, Kenjiro Imada, Shohei Ueda, Miho Ushijima, Shohei Nagakawa, Takashi Matsumoto, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Takeshi Uchiumi, Yoshinao Oda, Masatoshi Eto, Gene amplification of YB‐1 in castration‐resistant prostate cancer in association with aberrant androgen receptor expression, Cancer Science, 10.1111/cas.14695, 112, 1, 323-330, 2021.01, Although Y-box binding protein-1 (YB-1) is known to be overexpressed in prostate cancer, especially castration-resistant prostate cancer (CRPC), the mechanism of its overexpression remains unclear. We aimed to elucidate the mechanism of YB-1 overexpression in CRPC. Gene amplification in CRPC cells and tissues was examined by public database analysis, and digital PCR. The significance of YB-1 amplification for the YB-1/androgen receptor (AR) axis and prognosis was examined by public database analysis and immunohistochemistry. YB-1 amplification was mainly observed in CRPC tissues by public database analysis and confirmed in CRPC cells and tissues by digital PCR. Expression of YB-1 was increased in CRPC tissues compared with treatment-naïve tissues. Furthermore, YB-1 and phosphorylated YB-1 levels were associated with AR and AR V7 expression levels. Finally, YB-1 amplification was associated with poor outcomes in CRPC. Taken together, the present findings suggest that YB-1 amplification contributes to progression to CRPC through regulation of AR and AR V7 expressions, and that YB-1 is a promising therapeutic target in CRPC.. |
| 85. |
Kefeng Liu, Yanfang Ma, Yongjie Yang, Jingli Lu, Jie Zhao, Shuzhang Du, Xuepei Zhang, Chunlei Liu, Francesco Del Giudice, Masaki Shiota, Shingo Hatakeyama, Xiaojian Zhang, Jian Kang, Evaluation of the reporting quality of clinical practice guidelines on prostate cancer using the RIGHT checklist., Annals of translational medicine, 10.21037/atm-21-2956, 9, 14, 1173-1173, 2021.07, Background: The International Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement is a set of recommendations for reporting in clinical practice guidelines (CPGs). We aimed to use RIGHT to evaluate the reporting quality of CPGs on prostate cancer. Methods: We systematically searched literature databases and websites from January 1, 2018 to December 1, 2020 to identify CPGs on prostate cancer. Two investigators reviewed the identified articles and assessed the reporting quality independently by using the RIGHT checklist. We reported the proportions of guidelines that complied with each of the 35 RIGHT checklist item and the mean reporting compliance percentages for each of the seven domains of RIGHT. Results: A total of 38 CPGs were included. The mean overall reporting rate over the included CPGs was 51.6%. Eighteen items were reported by more than half of the guidelines four items (1a 3, 7a and 13a) were reported by all guidelines. Items 7b (10.5%), 13b (10.5%), 14c (13.2%), and 18b (7.9%) had the lowest reporting proportions. The mean reporting rates in each RIGHT domain were 74.6% for "Basic Information", 26.3% for "Review and quality assurance", 59.9% for "Background", 43.7% for "Evidence", 43.2% for "Recommendations", 43.4% for "Funding and declaration and management of interests", and 43.0% for "Other information". Conclusions: The overall adherence of CPGs on prostate cancer to RIGHT checklist is poor. Following the RIGHT checklist during the development of the guideline could improve the quality of reporting in the future.. |
| 86. |
Takashi Matsumoto, Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Efficacy and safety of cabazitaxel therapy in elderly (≥75 years) patients with castration-resistant prostate cancer: A multiinstitutional study, Prostate International, 10.1016/j.prnil.2020.12.001, 9, 2, 96-100, 2021.06, Background: There is little data on the outcome of cabazitaxel (CBZ) treatment of elderly patients with castration-resistant prostate cancer (CRPC). This study assessed the efficacy and safety of CBZ chemotherapy in patients with CRPC aged 75 years or older in a multiinstitutional study. Methods: We retrospectively reviewed the 74 patients with CRPC treated with CBZ enrolled in 10 institutions. Clinicopathological backgrounds, prognosis including prostate-specific antigen decline, time to treatment failure, progression-free survival, overall survival, and safety profiles were compared between younger ( |
| 87. |
Takuya Yamashita, Masaki Shiota, Asako Machidori, Satoshi Kobayashi, Takashi Matsumoto, Keisuke Monji, Eiji Kashiwagi, Ario Takeuchi, Ryosuke Takahashi, Junichi Inokuchi, Ken-ichiro Shiga, Akira Yokomizo, Masatoshi Eto, Efficacy and Safety of 4-Weekly Docetaxel for Castration-Resistant Prostate Cancer, Cancer Investigation, 10.1080/07357907.2020.1871486, 39, 3, 251-256, 2021.03, We investigated the efficacy and safety profiles of 4-weekly docetaxel for castration-resistant prostate cancer. Patients treated with ≥2 courses of docetaxel chemotherapy (median, 70 mg/m2) between 2008 and 2018 were included. Among 125 Japanese men, 40 (32.0%) and 85 (68.0%) were treated with 3-weekly and 4-weekly regimens, respectively. In the 4-weekly regimen, the risks of progression, treatment failure, and any-cause mortality were comparable to those in the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. These data suggest that the 4-weekly regimen may be an acceptable option for selected patients.. |
| 88. |
Takashi Matsumoto, Masaki Shiota, Editorial Comment to Prominent response to platinum‐based chemotherapy in a patient with BRCA2 mutant‐neuroendocrine prostate cancer and MDM2 amplification, IJU Case Reports, 10.1002/iju5.12291, 4, 4, 219-220, 2021.07. |
| 89. |
Satoshi Kobayashi, Masaki Shiota, Editorial Comment to Endoscopic laser treatment for urine leakage caused by an isolated calyx after robot‐assisted partial nephrectomy, IJU Case Reports, 10.1002/iju5.12349, 4, 6, 346-346, 2021.11. |
| 90. |
Masaki Shiota, Editorial Comment from Dr Shiota to Stage and cancer-specific mortality differ within specific Asian ethnic groups for upper tract urothelial carcinoma: North American population-based study., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14709, 28, 12, 1253-1253, 2021.12. |
| 91. |
Sotaro Chikamatsu, Masaki Shiota, Mizuki Onozawa, Shiro Hinotsu, Yasuhide Kitagawa, Shinichi Sakamoto, Taketo Kawai, Masatoshi Eto, Haruki Kume, Hideyuki Akaza, Dynamics of conditional survival and risk factors in androgen deprivation therapy for prostate cancer using a multi‐institutional Japan‐wide database, International Journal of Urology, 10.1111/iju.14605, 28, 9, 927-935, 2021.09, OBJECTIVES: The objectives of this study were to analyze the conditional survival and prognostic factors in androgen deprivation therapy for prostate cancer using the Japan Study Group of Prostate Cancer database. METHODS: Data on patients treated with primary androgen deprivation therapy between 2001 and 2003 from a nationwide database of the Japan Study Group of Prostate Cancer were used. The conditional 5-year progression-free rate, cancer-specific survival and overall survival, as well as the conditional mortality owing to prostate cancer and other causes were calculated as per subgroups. Prognostic factors for progression-free rate, cancer-specific survival and overall survival at each time after androgen deprivation therapy initiation were calculated using the Cox proportional hazards model. RESULTS: The conditional 5-year progression-free rate and cancer-specific survival, but not overall survival, gradually increased with time. The prognostic impact of stage IV characteristics (T4, N1 and M1) changed over time; however, the prognostic impact of the Gleason score remained unchanged. In the subgroup analysis, prostate-specific mortality risk reduced over time in patients with stage IV prostate cancer, whereas non-prostate cancer mortality increased over time in elderly patients. CONCLUSIONS: Information regarding conditional survival and mortality obtained in this study would provide a benchmark for physicians and cancer survivors.. |
| 92. |
Masaki Shiota, Naoki Terada, Toshihiro Saito, Akira Yokomizo, Naoki Kohei, Takayuki Goto, Sadafumi Kawamura, Yasuhiro Hashimoto, Atsushi Takahashi, Takahiro Kimura, Ken‐ichi Tabata, Ryotaro Tomida, Kohei Hashimoto, Toshihiko Sakurai, Toru Shimazui, Shinichi Sakamoto, Manabu Kamiyama, Nobumichi Tanaka, Koji Mitsuzuka, Takuma Kato, Shintaro Narita, Hiroaki Yasumoto, Shogo Teraoka, Masashi Kato, Takahiro Osawa, Yoshiyuki Nagumo, Hiroaki Matsumoto, Hideki Enokida, Takayuki Sugiyama, Kentaro Kuroiwa, Takahiro Inoue, Takashi Mizowaki, Toshiyuki Kamoto, Takahiro Kojima, Hiroshi Kitamura, Mikio Sugimoto, Hiroyuki Nishiyama, Masatoshi Eto, Differential prognostic factors in low‐ and high‐burden de novo metastatic hormone‐sensitive prostate cancer patients, Cancer Science, 10.1111/cas.14722, 112, 4, 1524-1533, 2021.04, Metastatic burden is a critical factor for therapy decision-making in metastatic hormone-sensitive prostate cancer. The present study aimed to identify prognostic factors in men with high- or low-metastatic burden treated with primary androgen-deprivation therapy. The study included 2450 men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We investigated the prognostic value of various clinicopathological parameters for progression-free survival (PFS) and overall survival (OS) in patients stratified by low- or high-metastatic burden. Among the 2450 men, 841 (34.3%) and 1609 (65.7%) were classified as having low- and high-metastatic burden, respectively. Median PFS of the low- and high-burden groups were 44.5 and 16.1 months, respectively, and the median OS was 103.2 and 62.7 months, respectively. Percentage of biopsy-positive core, biopsy Gleason grade group, T-stage, and N-stage were identified to be differentially prognostic. M1a was associated with worse PFS than was M1b in the low-burden group, whereas lung metastasis was associated with better PFS and OS than was M1b in the high-burden group. Differential prognostic factors were identified for patients with low- and high-burden metastatic prostate cancer. These results may assist in decision-making to select the optimal therapeutic strategies for patients with different metastatic burdens.. |
| 93. |
Satoshi Kobayashi, Jun Mutaguchi, Eiji Kashiwagi, Ario Takeuchi, Masaki Shiota, Junichi Inokuchi, Masatoshi Eto, Clinical advantages of robot-assisted partial nephrectomy versus laparoscopic partial nephrectomy in terms of global and split renal functions: A propensity score-matched comparative analysis., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14525, 28, 6, 630-636, 2021.06, OBJECTIVES: To identify predictors of renal function preservation, and to compare the global and split renal function outcomes of robot-assisted partial nephrectomy and laparoscopic partial nephrectomy. METHODS: Demographic, operative and pathological data, as well as renal function outcomes, of 251 patients who underwent laparoscopic (n = 104) and robot-assisted (n = 147) partial nephrectomy between 2008 and 2018 were retrospectively analyzed. Propensity score matching (1:1) was carried out to adjust for potential baseline confounders. Functional outcomes were assessed based on the estimated glomerular filtration rate and dynamic renal scintigraphy (using 99m Tc-mercaptoacetyltriglycine), including renal volumetric analysis. RESULTS: A total of 98 patients were allocated to each partial nephrectomy group. Ischemic (laparoscopic vs robot-assisted partial nephrectomy: 29 vs 15 min, P |
| 94. |
Kei Mizuno, Takayuki Sumiyoshi, Takatsugu Okegawa, Naoki Terada, Satoshi Ishitoya, Yu Miyazaki, Takahiro Kojima, Hiromichi Katayama, Naohiro Fujimoto, Shingo Hatakeyama, Masaki Shiota, Koji Yoshimura, Yoshiyuki Matsui, Shintaro Narita, Hiroaki Matsumoto, Ryoma Kurahashi, Hidenori Kanno, Katsuhiro Ito, Hiroko Kimura, Yuki Kamiyama, Takuro Sunada, Takayuki Goto, Takashi Kobayashi, Hitoshi Yamada, Norihiko Tsuchiya, Tomomi Kamba, Hideyasu Matsuyama, Tomonori Habuchi, Masatoshi Eto, Chikara Ohyama, Akihiro Ito, Hiroyuki Nishiyama, Hiroshi Okuno, Toshiyuki Kamoto, Akihiro Fujimoto, Osamu Ogawa, Shusuke Akamatsu, Clinical Impact of Detecting Low-Frequency Variants in Cell-Free DNA on Treatment of Castration-Resistant Prostate Cancer., Clinical cancer research : an official journal of the American Association for Cancer Research, 10.1158/1078-0432.CCR-21-2328, 27, 22, 6164-6173, 2021.11, 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 castration-resistant 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 |
| 95. |
Leandro Blas, Masaki Shiota, Shohei Nagakawa, Shigehiro Tsukahara, Takashi Matsumoto, Keisuke Monji, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Masatoshi Eto, Validation of models predicting lymph node involvement probability in patients with prostate cancer, International Journal of Urology, 10.1111/iju.14802, 2022.01, OBJECTIVES: There are many models to predict lymph node involvement in patients with prostate cancer. We aimed to externally validate several models in a Japanese cohort. METHODS: We considered patients who were treated with robotic-assisted radical prostatectomy with extended pelvic lymph node dissection for prostate cancer. The risk of lymph node involvement was calculated for each patient in several models. Model performance was assessed by calculating the receiver operating characteristic curve and the area under the curve, calibration plots, and decision curve analyses. RESULTS: We identified lymph node involvement in 61 (18.4%) of the 331 considered patients. Patients with lymph node involvement had a higher prostate-specific antigen level, percentage of positive biopsy cores, primary Gleason grade, Gleason group grade, and clinical T-stage category. The Memorial Sloan Kettering Cancer Center web calculator presented the highest area under the curve (0.78) followed by the Yale formula area under the curve (0.77), the updated version of Briganti nomogram of 2017 area under the curve (0.76), and the updated version of the Partin table by Tosoian et al. had an area under the curve of 0.75. However, the 95% confidence interval for these models overlapped. The calibration plot showed that the Memorial Sloan Kettering Cancer Center web calculator and the updated version of the Briganti nomogram calibrated better. In the decision curve analyses, all models showed net benefit; however, it overlapped among them. However, the Memorial Sloan Kettering Cancer Center web calculator and the updated Briganti nomogram presented the highest net benefit for lymph node involvement risks |
| 96. |
Masaki Shiota, Dai Takamatsu, Takahiro Kimura, Kojiro Tashiro, Yoshiyuki Matsui, Ryotaro Tomida, Ryoichi Saito, Masakazu Tsutsumi, Akira Yokomizo, Yoshiyuki Yamamoto, Kohei Edamura, Makito Miyake, Shuichi Morizane, Takayuki Yoshino, Akihiro Matsukawa, Shintaro Narita, Ryuji Matsumoto, Takashi Kasahara, Kohei Hashimoto, Hiroaki Matsumoto, Masashi Kato, Shusuke Akamatsu, Akira Joraku, Manabu Kato, Takahiro Yamaguchi, Toshihiro Saito, Tomoyuki Kaneko, Atsushi Takahashi, Takuma Kato, Shinichi Sakamoto, Hideki Enokida, Hidenori Kanno, Naoki Terada, Shigetaka Suekane, Naotaka Nishiyama, Masatoshi Eto, Hiroshi Kitamura, Radiotherapy plus androgen deprivation therapy for prostate-specific antigen persistence in lymph node-positive prostate cancer., Cancer science, 10.1111/cas.15383, 113, 7, 2386-2396, 2022.04, 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.. |
| 97. |
Sotaro Chikamatsu, Masaki Shiota, Shigetomo Yamada, Leandro Blas, Takashi Matsumoto, Eiji Kashiwagi, Junichi Inokuchi, Ken-ichiro Shiga, Akira Yokomizo, Masatoshi Eto, Prognostic significance of risk stratification in CHAARTED and LATITUDE studies among Japanese men with castration-resistant prostate cancer, Prostate International, 10.1016/j.prnil.2022.01.001, 10, 1, 7-13, 2022.03, Background: The CHAARTED and LATITUDE trials demonstrated a survival benefit of docetaxel and abiraterone for hormone-sensitive prostate cancer. In this study, we examined the impact of the risk stratification criteria used in the CHAARTED and LATITUDE trials on the prognosis of castration-resistant prostate cancer (CRPC). We also tested whether these risk stratification criteria could help in selecting effective initial treatment for CRPC. Method: Japanese patients with CRPC who were treated with docetaxel or androgen receptor pathway inhibitors such as abiraterone acetate or enzalutamide between 2014 and 2018 were included in this study. Clinicopathological factors, progression-free survival, and overall survival were investigated. Results: Of 215 patients, 110 men (51.2%) and 93 men (43.3%) were grouped as high volume by CHAARTED criteria and high risk by LATITUDE criteria, respectively. Median progression-free survival was 10.3/4.5 months (P |
| 98. |
Masaki Shiota, Leandro Blas, Satoshi Kobayashi, Takashi Matsumoto, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Ken-Ichiro Shiga, Akira Yokomizo, Masatoshi Eto, Predictive factors of survival outcomes in first-line therapy for metastatic castration-resistant prostate cancer., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14702, 29, 1, 26-32, 2022.01, OBJECTIVES: To investigate predictive factors of survival of metastatic castration-resistant prostate cancer patients undergoing first-line treatment with androgen receptor pathway inhibitors or docetaxel. METHODS: Japanese patients with metastatic castration-resistant prostate cancer treated with androgen receptor pathway inhibitor or docetaxel between 2008 and 2018 were included. The differential impact of various clinicopathological factors on the outcome, including progression-free survival and overall survival, was compared between treatment with androgen receptor pathway inhibitor and docetaxel. RESULTS: Of 254 patients with metastatic castration-resistant prostate cancer, 119 (46.9%) and 135 (53.2%) were treated with androgen receptor pathway inhibitor and docetaxel, respectively. The multivariate analysis showed that androgen receptor pathway inhibitor was an independent prognostic factor for better progression-free survival (hazard ratio 0.62, 95% confidence interval 0.42-0.92, P = 0.016) and overall survival (hazard ratio 0.61, 95% confidence interval 0.41-0.93, P = 0.021), compared with docetaxel. Pretreatment prostate-specific antigen levels and time to castration-resistant prostate cancer were differentially associated with progression-free survival and overall survival between androgen receptor pathway inhibitor or docetaxel. In patients who presented |
| 99. |
Naoki Terada, Rihito Aizawa, Keiji Nihei, Masaki Shiota, Takahiro Kojima, Takahiro Kimura, Takahiro Inoue, Hiroshi Kitamura, Mikio Sugimoto, Hiroyuki Nishiyama, Takashi Mizowaki, Toshiyuki Kamoto, Narrative review of local prostate and metastasis-directed radiotherapy in the treatment of metastatic prostate cancer., Japanese journal of clinical oncology, 10.1093/jjco/hyac035, 52, 6, 633-641, 2022.03, The role of local treatment in patients with de novo metastatic prostate cancer is controversial. In population-based retrospective studies, metastatic prostate cancer patients who received local treatment with prostate radiotherapy showed a better prognosis than those who did not. In addition, several prospective randomized studies demonstrated that prostate radiotherapy achieves a survival benefit for patients with oligo-metastasis. Moreover, the efficacy of metastasis-directed radiotherapy was evaluated, revealing a potential benefit for patients with oligo-metastasis. Importantly, these radiotherapies may reduce the occurrence of symptomatic local events. In this review, the rationale, efficacy and future perspectives for local prostate and metastasis-directed radiotherapy in the treatment of metastatic prostate cancer were described and summarized.. |
| 100. |
Yoshiyuki Nagumo, Mizuki Onozawa, Takahiro Kojima, Naoki Terada, Masaki Shiota, Koji Mitsuzuka, Hiroaki Yasumoto, Hiroaki Matsumoto, Hideki Enokida, Takayuki Sugiyama, Kentaro Kuroiwa, Toshihiro Saito, Akira Yokomizo, Naoki Kohei, Ken‐ichi Tabata, Atsushi Takahashi, Mikio Sugimoto, Hiroshi Kitamura, Toshiyuki Kamoto, Hiroyuki Nishiyama, Toru Shimazui, Takahiro Inoue, Takayuki Goto, Yasuhiro Hashimoto, Ryotaro Tomida, Toshihiko Sakurai, Kohei Hashimoto, Sadafumi Kawamura, Shogo Teraoka, Shinichi Sakamoto, Takahiro Kimura, Manabu Kamiyama, Shintaro Narita, Nobumichi Tanaka, Takuma Kato, Masashi Kato, Takahiro Osawa, Efficacy of combined androgen blockade therapy in patients with metastatic hormone‐sensitive prostate cancer stratified by tumor burden, International Journal of Urology, 10.1111/iju.14793, 29, 5, 398-405, 2022.01, OBJECTIVE: To determine the effect of combined androgen blockade with a first-generation anti-androgen on the prognoses of metastatic hormone-sensitive prostate cancer patients stratified by tumor burden. METHODS: We retrospectively analyzed the cases of metastatic hormone-sensitive prostate cancer patients who were treated with androgen deprivation therapy in 2008-2017 at 30 institutions in Japan. To compare the overall survival and progression-free survival rates of the patients treated with castration monotherapy and combined androgen blockade, we carried out a Cox proportional hazards regression analysis using both inverse probability of treatment weighting and instrumental variables methods. High-burden disease was defined as the presence of four or more bone metastases and/or visceral metastasis. RESULTS: Of 2048 patients, 702 (34.3%) and 1346 (65.7%) patients were classified as the low- and high-burden groups, respectively. In each group, >80% of the patients were treated with combined androgen blockade. Although there was no significant between-group difference in the overall survival according to the androgen deprivation therapy method, in the high-burden group the progression-free survival of the combined androgen blockade-treated patients was significantly better than that of patients treated with castration monotherapy: inverse probability of treatment weighting method, hazard ratio 0.49, 95% confidence interval 0.34-0.71; instrumental variables method, hazard ratio 0.80, 95% confidence interval 0.60-0.98. CONCLUSION: In the high-burden group, combined androgen blockade with a first-generation anti-androgen resulted in superior progression-free survival compared with castration monotherapy. For well-selected metastatic hormone-sensitive prostate cancer patients, the use of combined androgen blockade might still have some suitable scenarios.. |
| 101. |
Mizuki Kobayashi, Nobuhiro Fujiyama, Tokiyoshi Tanegashima, Shintaro Narita, Yoshiaki Yamamoto, Naohiro Fujimoto, Shohei Ueda, Ario Takeuchi, Kazuyuki Numakura, Tomonori Habuchi, Hideyasu Matsuyama, Masatoshi Eto, Masaki Shiota, Effect of HLA genotype on intravesical recurrence after bacillus Calmette-Guérin therapy for non-muscle-invasive bladder cancer., Cancer immunology, immunotherapy : CII, 10.1007/s00262-021-03032-0, 71, 3, 727-736, 2022.03, The intravesical administration of bacillus Calmette-Guérin (BCG) is widely used to control the intravesical recurrence of non-muscle-invasive bladder cancer (NMIBC). This study aimed to reveal the effects of zygosity on human leukocyte antigen (HLA) genes and individual HLA genotypes on intravesical recurrence after intravesical BCG therapy for NMIBC. This study included Japanese patients who had received intravesical BCG for NMIBC. HLA genotyping of HLA-A, B, C, and DRB1 was performed. The effect of HLA zygosity and HLA genotype on intravesical recurrence was evaluated. Among 195 patients, those homozygous for the HLA-B supertype were more likely than those heterozygous for the HLA-B supertype to experience intravesical recurrence by univariate analysis (hazard ratio [HR], 95% confidence interval [CI]; 1.87, 1.14-3.05, P = 0.012) and multivariate analysis (HR, 95% CI; 2.26, 1.02-5.01, P = 0.045). Patients with B07 or B44 had a decreased risk of intravesical recurrence by univariate analysis (HR, 95% CI; 0.43, 0.24-0.78, P = 0.0056) and multivariate analysis (HR, 95% CI; 0.36, 0.16-0.82, P = 0.016). This study suggests the importance of the diversity and specificity of HLA-B loci in the antitumor effect of BCG immunotherapy for NMIBC. These findings may contribute to the delineation of risk strata for BCG therapy and improve the medical management of NMIBC.. |
| 102. |
Masaki Shiota, Editorial Comment to Effect of upfront combination therapy on the overall survival of patients with metastatic castration‐sensitive prostate cancer: A multicenter retrospective study, International Journal of Urology, 10.1111/iju.14864, 2022.03. |
| 103. |
Hiroki Kobayashi, Masaki Shiota, Nobuaki Sato, Satoshi Kobayashi, Takashi Matsumoto, Keisuke Monji, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Ken-Ichiro Shiga, Akira Yokomizo, Masatoshi Eto, Differential prognostic impact of complete blood count-related parameters by prior use of novel androgen receptor pathway inhibitors in docetaxel-treated castration-resistant prostate cancer patients., Anti-cancer drugs, 10.1097/CAD.0000000000001170, 33, 1, e541-e547, 2022.01, There are multiple reports on the value of complete blood count (CBC)-related parameters on prognosis in docetaxel-treated castration-resistant prostate cancer (CRPC) patients before the emergence of androgen receptor pathway inhibitors (ARPIs). We investigated the prognostic significance of CBC-related parameters in docetaxel-treated CRPC patients. Patients treated with docetaxel chemotherapy for CRPC between 2008 and 2018 were included. We analyzed the relevance of CBC-related parameters to oncological prognosis in docetaxel chemotherapy, associated with prior use of novel ARPIs. Among 144 Japanese men treated with docetaxel, 49 men (34.0%) had already received ARPI therapy. A high neutrophil-lymphocyte ratio (NLR) was a prognostic factor for poor progression-free survival and overall survival (OS) in both univariate and multivariate analyses. In addition, a low hemoglobin (Hb) level and a high systemic immune-inflammation index (SII) were prognostic factors of poor OS in univariate analysis. Hb level was a prognostic factor of OS in both ARPI-naive and ARPI-treated patients. However, a high NLR and SII were only associated with a poor prognosis in ARPI-naive but not in ARPI-treated patients. Hb, NLR, and SII have been suggested to be prognosticators in docetaxel-treated CRPC patients. The differential prognostic value of NLR and SII between ARPI-naive and ARPI-treated patients may require caution when using these markers in docetaxel-treated CRPC patients.. |
| 104. |
Masaki Shiota, Naohiro Fujimoto, Yohei Sekino, Shigehiro Tsukahara, Shohei Nagakawa, Dai Takamatsu, Tatsuro Abe, Fumio Kinoshita, Shohei Ueda, Miho Ushijima, Takashi Matsumoto, Eiji Kashiwagi, Junichi Inokuchi, Takeshi Uchiumi, Yoshinao Oda, Masatoshi Eto, Clinical impact of HSD3B1 polymorphism by metastatic volume and somatic HSD3B1 alterations in advanced prostate cancer, Andrologia, 10.1111/and.14307, 54, 1, e14307, 2022.02, This study aimed to investigate the significance of HSD3B1 gene status including germline polymorphism and somatic alterations in prostate cancer. Patients with prostate cancer treated with androgen-deprivation therapy, as well as tissues from metastatic prostate cancer, were included. Genomic DNA was extracted from cancer tissues and whole blood samples, and HSD3B1 (rs1047303, 1245C) was genotyped by Sanger sequencing. The association of HSD3B1 genotype with progression-free survival according to metastatic volume was examined. Copy number alteration and gene expression of HSD3B1 were examined in prostate cancer cells and public datasets. Among 194 patients, 121 and 73 patients were categorized into low- and high-volume diseases respectively. In multivariate analysis, the adrenal-permissive genotype (AC/CC) was significantly associated with increased risk of progression compared with the adrenal-restrictive genotype (AA) in low volume, but not high-volume diseases. Somatic mutation in HSD3B1 was detected at least in two cases of castration-resistant prostate cancer tissues. HSD3B1 amplification and overexpression were detected in castration-resistant prostate cancer cells and tissues. The current findings suggest that both germline and somatic alterations of HSD3B1 may cooperatively promote castration resistance in prostate cancer and HSD3B1 as a promising biomarker for precision medicine, warranting further investigations.. |
| 105. |
Shintaro Narita, Naoki Terada, Kyoko Nomura, Shinichi Sakamoto, Shingo Hatakeyama, Takuma Kato, Yoshiyuki Matsui, Junichi Inokuchi, Akira Yokomizo, Ken-Ichi Tabata, Masaki Shiota, Takahiro Kimura, Takahiro Kojima, Takahiro Inoue, Takashi Mizowaki, Mikio Sugimoto, Hiroshi Kitamura, Toshiyuki Kamoto, Hiroyuki Nishiyama, Tomonori Habuchi, Cancer-specific and net overall survival in older patients with de novo metastatic prostate cancer initially treated with androgen deprivation therapy., International journal of urology : official journal of the Japanese Urological Association, 10.1111/iju.14938, 2022.05, OBJECTIVE: This study aimed to assess survival outcomes in older patients with de novo metastatic prostate cancer who initially received androgen deprivation therapy. METHODS: The retrospective multicenter study included 2784 men with metastatic prostate cancer who were treated with androgen deprivation therapy between 2008 and 2017. Patients were classified into |
| 106. |
Shigehiro Tsukahara, Masaki Shiota, Dai Takamatsu, Shohei Nagakawa, Takashi Matsumoto, Ryo Kiyokoba, Mikako Yagi, Daiki Setoyama, Nozomi Noda, Shinya Matsumoto, Tetsutaro Hayashi, Alberto Contreras-Sanz, Peter C Black, Junichi Inokuchi, Kenichi Kohashi, Yoshinao Oda, Takeshi Uchiumi, Masatoshi Eto, Dongchon Kang, Cancer genomic profiling identified dihydropyrimidine dehydrogenase deficiency in bladder cancer promotes sensitivity to gemcitabine., Scientific reports, 10.1038/s41598-022-12528-3, 12, 1, 8535-8535, 2022.05, Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.. |
| 107. |
Takashi Matsumoto, Masaki Shiota, Shigetomo Yamada, Leandro Blas, Hidekazu Naganuma, Ken Lee, Keisuke Monji, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Ken-Ichiro Shiga, Akira Yokomizo, Masatoshi Eto, Anticancer Effect of Second-line Treatment for Castration-Resistant Prostate Cancer Following First-line Treatment with Androgen Receptor Pathway Inhibitors., JMA journal, 10.31662/jmaj.2021-0163, 5, 1, 83-90, 2022.01, Introduction: Studies on the effect of androgen receptor pathway inhibitors (ARPI), docetaxel (DTX), and radium-223 (Ra-223) after first-line treatment with ARPI in patients with castration-resistant prostate cancer (CRPC) are scarce. This study compared the efficacy of treatment after ARPI for CRPC. Methods: Patients with CRPC who received ARPI as first-line treatment and different second-line treatments were retrospectively reviewed. Clinicopathological backgrounds and treatment outcomes, including maximum prostate-specific antigen (PSA) decrease, progression-free survival (PFS), and overall survival (OS), were compared between second-line treatments. Results: In total, 88 patients were enrolled. Forty-one (46.6%), 37 (42.0%), and 10 (11.4%) patients were treated with ARPI, DTX, and Ra-223, respectively. Patients whose PSA levels were not adequately reduced by first-line treatment with ARPI were eventually enrolled in the DTX treatment (P = 0.030). PSA decrease was not significantly different when comparing treatments. PFS in the DTX group was significantly better than in the other two groups (P = 0.023). In multivariate analysis, DTX was an independent prognostic factor for better PFS compared to ARPI (hazard ratio, 95% confidence interval; 0.44, 0.25-0.79, P = 0.006). Subgroup analysis showed a favorable impact of DTX on PFS in patients with Gleason score >8 (interaction P = 0.027) and a PSA decline >50% (interaction P = 0.019) during first-line treatment with ARPI. However, no significant difference in OS was observed between groups of different second-line treatments. Conclusions: This study suggests that in patients with CRPC, second-line treatment with DTX following progression in patients who received ARPI as first-line treatment is more beneficial compared with second-line treatment with ARPI or Ra-233.. |
| 108. |
Miho Ushijima, Masaki Shiota, Takashi Matsumoto, Eiji Kashiwagi, Junichi Inokuchi, Masatoshi Eto, An oral first-in-class small molecule RSK inhibitor suppresses AR variants and tumor growth in prostate cancer., Cancer science, 10.1111/cas.15280, 2022.02, Ribosomal S6 kinase has been shown to play a key role in cellular resistance to endocrine therapy in prostate cancer through its regulation of YB-1/androgen receptor (AR) signaling. PMD-026, an oral first-in-class small molecule kinase inhibitor, is the first identified ribosomal S6 kinase inhibitor. This study investigated the effect of PMD-026 on YB-1/AR signaling and its antitumor effect in prostate cancer in vitro and in vivo. Castration-resistant prostate cancer 22Rv1 cells that express high-level AR variants were used in this study. The effect of PMD-026 on YB-1/AR signaling was investigated by quantitative real-time PCR and western blot analysis. The effects of PMD-026 on prostate cancer cells were investigated by cytotoxicity analysis, apoptosis assay, and cell cycle assay in vitro and a mouse castration model in vivo. PMD-026 decreased YB-1 phosphorylation as well as AR V7 mRNA and AR variant expressions in 22Rv1 cells. PMD-026 suppressed cell proliferation alone and in combination with the second-generation antiandrogens enzalutamide and darolutamide by inducing cellular apoptosis and G2/M arrest. In a mouse xenograft model, PMD-026 suppressed tumor growth, and the combination of PMD-026 and enzalutamide inhibited tumor growth more prominently than single treatments. Our results demonstrate an excellent antitumor effect of the novel ribosomal S6 kinase inhibitor PMD-026 and the combination effect with the antiandrogen enzalutamide in castration-resistant prostate cancer. These findings warrant a clinical trial of PMD-026 in prostate cancer patients.. |
| 109. |
Blas L, Ieiri K, Shiota M, Nagakawa S, Tsukahara S, Matsumoto T, Kashiwagi E, Takeuchi A, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Prognostic Value of Lower Tract Urinary Symptoms in Clinically Regional Lymph Node-positive Prostate Cancer., Anticancer Res , 41(11): 5593-5598, 2021, 2021.11. |
| 110. |
Mizuno K, Sumiyoshi T, Okegawa T, Terada N, Ishitoya S, Miyazaki Y, Kojima T, Katayama H, Fujimoto N, Hatakeyama S, Shiota M, Yoshimura K, Matsui Y, Narita S, Matsumoto H, Kurahashi R, Kanno H, Ito K, Kimura H, Kamiyama Y, Sunada T, Goto T, Kobayashi T, Yamada H, Tsuchiya N, Kamba T, Matsuyama H, Habuchi T, Eto M, Ohyama C, Ito A, Nishiyama H, Okuno H, Kamoto T, Fujimoto A, Ogawa O,Akamatsu S:, Clinical impact of detecting low-frequency variants in cell-free DNA on treatment of castration-resistant prostate cancer., Clin Cancer Res , 27(22): 6164-6173, 2021, 2021.11. |
| 111. |
Nagakawa S, Shiota M, Fujimoto N, Yamamoto Y, Blas L, Tsukahara S, Matsumoto T, Kashiwagi E, Takeuchi A, Inokuchi J, Uchiumi T, Matsuyama H, Eto M., The impact of single-nucleotide polymorphisms on intravesical recurrence after bacillus Calmette-Guérin therapy for non-muscle invasive bladder cancer in a genome-wide association study, Urol Oncol , 39(10): 733.e17-733.e24, 2021, 2021.10. |
| 112. |
Shiota M, Terada N, Kitamura H, Kojima T, Saito T, Yokomizo A, Kohei N, Goto T, Kawamura S, Hashimoto Y, Takahashi A, Kimura T, Tabata KI, Tomida R, Hashimoto K, Sakurai T, Shimazui T, Sakamoto S, Kamiyama M, Tanaka N, Mitsuzuka K, Kato T, Narita S, Yasumoto H, Teraoka S, Kato M, Osawa T, Nagumo Y, Matsumoto H, Enokida H, Sugiyama T, Kuroiwa K, Inoue T, Sugimoto M, Mizowaki T, Kamoto T, Nishiyama H, Eto M; Japanese Urological Oncology Group:, Novel metastatic burden-stratified risk model in de novo metastatic hormone-sensitive prostate cancer., Cancer Sci , 112(9): 3616-3626, 2021, 2021.09. |
| 113. |
Chikamatsu S, Shiota M, Onozawa M, Hinotsu S, Kitagawa Y, Sakamoto S, Kawai T, Eto M, Kume H, Akaza H; Japan Study Group of Prostate Cancer (J-CaP):, Dynamics of conditional survival and risk factors in androgen deprivation therapy for prostate cancer using a multi-institutional Japan-wide database., Int J Urol , 28(9): 927-935, 2021, 2021.09. |
| 114. |
Babasaki T, Sentani K, Sekino Y, Kobayashi G, Thang Pham Q, Katsuya N, Akabane S, Taniyama D, Hayashi T, Shiota M, Oue N, Teishima J, Matsubara A, Yasui W:, Overexpression of claspin promotes docetaxel resistance and is associated with prostate-specific antigen recurrence in prostate cancer., Cancer Med, 10(16): 5574-5588, 2021, 2021.08. |
| 115. |
Blas L, Shiota M, Yamada S, Ieiri K, Nagakawa S, Tsukahara S, Matsumoto T, Kashiwagi E, Takeuchi A, Inokuchi J, Shiga KI, Yokomizo A,
Eto M:, Lactate Dehydrogenase Is a Serum Prognostic Factor in Clinically Regional Lymph Node-positive Prostate Cancer., Anticancer Res , 41(8): 3885-3889, 2021, 2021.08. |
| 116. |
Sekino Y, Pham QT, Kobatake K, Kitano H, Ikeda K, Goto K, Inoue S, Hayashi T, Shiota M, Yasui W, Teishima J:, HOXB5 Overexpression Is Associated with Neuroendocrine Differentiation and Poor Prognosis in Prostate Cancer., Biomedicines , 9(8): 893, 2021, 2021.08. |
| 117. |
Blas L, Onozawa M, Shiota M, Hinotsu S, Sakamoto S, Kitagawa Y, Kawai T, Eto M, Kume H, Akaza H; Japan Study Group of Prostate Cancer (J-CaP):, Long-term outcomes of androgen deprivation therapy in prostate cancer among Japanese men over 80 years old., Cancer Sci , 112(8): 3074-3082, 2021, 2021.08. |
| 118. |
Liu K, Ma Y, Yang Y, Lu J, Zhao J, Du S, Zhang X, Liu C, Del Giudice F, Shiota M, Hatakeyama S, Zhang X, Kang J:, Evaluation of the reporting quality of clinical practice guidelines on prostate cancer using the RIGHT checklist., Ann Transl Med , 9(14): 1173, 2021, 2021.07. |
| 119. |
Koura M, Shiota M, Ueda S, Matsumoto T, Kobayashi S, Monji K, Kashiwagi E, Takeuchi A, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Prognostic impact of prior local therapy in castration-resistant prostate cancer., Jpn J Clin Oncol , 51(7): 1142-1148, 2021, 2021.07. |
| 120. |
Matsumoto T, Shiota M, Nakamura M, Yokomizo A, Tomoda T, Sakamoto N, Seki N, Hasegawa S, Yunoki T, Harano M, Kuroiwa K, Eto M:, Efficacy and safety of cabazitaxel therapy in elderly (≥75 years) patients with castration-resistant prostate cancer: A multiinstitutional study., Prostate Int, 9(2): 96-100, 2021, 2021.06. |
| 121. |
Sekino Y, Han X, Babasaki T, Miyamoto S, Kobatake K, Kitano H, Ikeda K, Goto K, Inoue S, Hayashi T, Teishima J, Shiota M, Takeshima Y, Yasui W, Matsubara A:, TUBB3 is associated with PTEN, neuroendocrine differentiation, and castration resistance in prostate cancer., Urol Oncol , 39(6): 368.e1-368.e9, 2021, 2021.06. |
| 122. |
Machidori A, Shiota M, Kobayashi S, Matsumoto T, Monji K, Kashiwagi E, Takeuchi A, Takahashi R, Inokuchi J, Eto M:, Prognostic significance of complete blood count parameters in castration-resistant prostate cancer patients treated with androgen receptor pathway inhibitors., Urol Oncol , 39(6): 365.e1-365.e7, 2021, 2021.06. |
| 123. |
Kobayashi S, Mutaguchi J, Kashiwagi E, Takeuchi A, Shiota M, Inokuchi J, Eto M:, Clinical advantages of robot-assisted partial nephrectomy versus laparoscopic partial nephrectomy in terms of global and split renal functions: A propensity score-matched comparative analysis., Int J Urol , 28(6): 630-636, 2021, 2021.06. |
| 124. |
Shiota M, Fujimoto N, Matsumoto T, Tsukahara S, Nagakawa S, Ueda S, Ushijima M, Kashiwagi E, Takeuchi A, Inokuchi J, Uchiumi T, Eto M:, Differential Impact of TGFB1 Variation by Metastatic Status in Androgen-Deprivation Therapy for Prostate Cancer., Front Oncol, 11: 697955, 2021, 2021.05. |
| 125. |
Koura M, Shiota M, Ueda S, Matsumoto T, Kobayashi S, Monji K, Kashiwagi E, Takeuchi A, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Prognostic impact of prior local therapy in castration-resistant prostate cancer., Jpn J Clin Oncol., 2021 Feb 24, 2021.02. |
| 126. |
Machidori A, Shiota M, Kobayashi S, Matsumoto T, Monji K, Kashiwagi E, Takeuchi A, Takahashi R, Inokuchi J, Eto M:, Prognostic significance of complete blood count parameters in castration-resistant prostate cancer patients treated with androgen receptor pathway inhibitors., Urol Oncol. , 2020 Oct 16, 2020.10. |
| 127. |
Shiota M, Terada N, Saito T,Yokomizo A, Kohei N, Goto T, Kawamura S, Hashimoto Y, Takahashi A, Kimura T, Tabata KI, Tomida R, Hashimoto K, Sakurai T, Shimazui T, Sakamoto S, Kamiyama M, Tanaka N, Mitsuzuka K, Kato T, Narita S, Yasumoto H, Teraoka S, Kato M, Osawa T, Nagumo Y, Matsumoto H, Enokida H, Sugiyama T, Kuroiwa K, Inoue T,
Mizowaki T, Kamoto T, Kojima T, Kitamura H, Sugimoto M, Nishiyama H, Eto M, Urological Oncology Group Juog J:, Differential prognostic factors in low- and high-burden de novo metastatic hormone-sensitive prostate cancer patients., 112 (4): 1524-1533, 2021, 2021.04. |
| 128. |
Shiota M, Sumikawa R, Onozawa M, Hinotsu S, Kitagawa Y, Sakamoto S, Kawai T, Eto M, Kume H, Akaza H; Japan Study Group of Prostate Cancer (J-CaP):, Regional and facility disparities in androgen deprivation therapy for prostate cancer from a multi-institutional Japan-wide database., Int J Urol., 2021 Feb 24., 2021.05. |
| 129. |
Fujimoto N, Shiota M, Matsukawa T, Minato A, Tomisaki I, Ohnishi R, Eto M:, Three-month Prostate-specific Antigen Level After Androgen Deprivation Therapy Predicts Survival in Patients With Metastatic Castration-sensitive Prostate Cancer., In Vivo , 35 (2): 1101-1108, 2021, 2021.05. |
| 130. |
Koura M, Shiota M, Ueda S, Matsumoto T, Kobayashi S, Monji K, Kashiwagi E, Takeuchi A, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Prognostic impact of prior local therapy in castration-resistant prostate cancer., Jpn J Clin Oncol., 2021 Feb 24, 2021.05. |
| 131. |
Kobayashi S, Mutaguchi J, Kashiwagi E, Takeuchi A, Shiota M, Inokuchi J, Eto M:, Clinical advantages of robot-assisted partial nephrectomy versus laparoscopic partial nephrectomy in terms of global and split renal functions: A propensity score-matched comparative analysis., Int J Urol. , 2021 Mar 3., 2021.03. |
| 132. |
Shiota M, Akamatsu S, Narita S, Sumiyoshi T, Fujiwara M, Uchiumi T, Ogawa O, Habuchi T, Eto M:, The association between missense polymorphisms in SRD5A2 and HSD3B1 and treatment failure with abiraterone for castration-resistant prostate cancer., Pharmacogenomics J. , 2021 Mar 1. , 2021.03. |
| 133. |
Yamashita T, Shiota M, Machidori A, Kobayashi S, Matsumoto T, Monji K, Kashiwagi E, Takeuchi A, Takahashi R, Inokuchi J, Shiga KI, Yokomizo A, Eto M:, Efficacy and Safety of 4-Weekly Docetaxel for Castration-Resistant Prostate Cancer., Cancer Invest , 39 (3): 251-256, 2021, 2021.03. |
| 134. |
Matsumoto T, Shiota M, Uchiumi T, Ueda S, Tsukahara S, Toshima T, Matsumoto S, Noda N, Eto M, Kang D:, Genomic characteristics revealed by targeted exon sequencing of testicular germ cell tumors in Japanese men., Int J Urol , 28 (1): 40-46, 2021, 2021.01. |
| 135. |
Shiota M, Narita S, Habuchi T, Eto M:, Validated prognostic significance of YB-1 genetic variation in metastatic prostate cancer., Pharmacogenomics J , 21 (1): 102-105, 2021, 2021.02. |
| 136. |
Shiota M, Sekino Y, Tsukahara S, Abe T, Kinoshita F, Imada K, Ueda S, Ushijima M, Nagakawa S, Matsumoto T, Kashiwagi E, Takeuchi A, Inokuchi J, Uchiumi T, Oda Y, Eto M:, Gene amplification of YB-1 in castration-resistant prostate cancer in association with aberrant androgen receptor expression., Cancer Sci, 112 (1): 323–330, 2021, 2021.01. |
| 137. |
Kashiwagi E, Imada K, Abe T, Kinoshita F, Monji K, Shiota M, Takeuchi A, Inokuchi J, Tatsugami K, Eto M:, Thick perirenal fat predicts the growth pattern of renal cell carcinoma., Kidney Cancer , 4 (1): 41-48, 2020, 2020.03. |
| 138. |
Terada N, Mizowaki T, Saito T, Yokomizo A, Kohei N, Tabata KI, Shiota M, Takahashi A, Shimazui T, Goto T, Hashimoto Y, Fujii M, Tomida R, Sakurai T, Hashimoto K,
Kawamura S, Teraoka S, Sakamoto S, Kimura T, Kamiyama M, Narita S, Tanaka N, Kato T, Kato M, Osawa T, Kojima T, Inoue T, Sugimoto M, Nishiyama H,
Kamoto T; on behalf of Japanese Urological Oncology Group:, Potential effectiveness of local radiotherapy for extending survival and reducing symptomatic local events in patients with de novo metastatic prostate cancer., BJUI Compass, 1 (5): 165-173, 2020, 2020.11. |
| 139. |
Sato N, Shiota M, Shiga KI, Kashiwagi E, Takeuchi A, Inokuchi J, Yokomizo A, Naito S, Eto M:, Effect of Smoking on Oncological Outcome among Prostate Cancer Patients after Radical Prostatectomy with Neoadjuvant Hormonal Therapy., Cancer Invest , 38 (10): 559-564, 2020, 2020.11. |
| 140. |
Shiota M, Machidori A, Abe T, Monji K, Kashiwagi E, Takeuchi A, Takahashi R, Inokuchi J, Yokomizo A, Naito S, Eto M:, Impact of antiandrogen withdrawal syndrome in castration-resistant prostate cancer patients treated with abiraterone or enzalutamide., Int J Urol , 27 (12): 1109-1115, 2020, 2020.12. |
| 141. |
Shiota M, Endo S, Fujimoto N, Tsukahara S, Ushijima M, Kashiwagi E, Takeuchi A, Inokuchi J, Uchiumi T, Eto M:, Polymorphisms in androgen metabolism genes with serum testosterone levels and prognosis in androgen-deprivation therapy., Urol Oncol , 38 (11): 849.e11-849.e18, 2020, 2020.11. |
| 142. |
Ieiri K, Shiota M, Kashiwagi E, Takeuchi A, Takahashi R, Inokuchi J, Iwai H, Shiga KI, Yokomizo A, Yoshitake T, Shioyama Y, Ishigami K, Terashima H, Eto M:, The prognosis and the impact of radiotherapy in clinically regional lymph node-positive prostate cancer: Which patients are candidates for local therapy with radiation?, Urol Oncol , 38 (12): 931.e1-931.e7, 2020, 2020.12. |
| 143. |
Kashiwagi E, Abe T, Kinoshita F, Ushijima M, Masaoka H, Shiota M, Netto GJ, Eto M, Miyamoto H:, The role of adipocytokines and their receptors in bladder cancer: expression of adiponectin or leptin is an independent prognosticator., Am J Transl Res , 12(6): 3033–3045, 2020, 2020.06. |
| 144. |
Sekino Y, Han X, Babasaki T, Goto K, Inoue S, Hayashi T, Teishima J, Shiota M, Takeshima Y, Yasui W, Matsubara A:, Microtubule-associated protein tau (MAPT) promotes bicalutamide resistance and is associated with survival in prostate cancer., Urol Oncol , 38 (10): 795.e1-795.e8, 2020, 2020.10. |
| 145. |
Itsumi M, Shiota M, Sekino Y, Ushijima M, Kashiwagi E, Takeuchi A, Inokuchi J, Kajioka S, Uchiumi T, Eto M:, High-throughput Screen Identifies 5-HT Receptor as a Modulator of AR and a Therapeutic Target for Prostate Cancer., Prostate , 80 (11): 885-894, 2020, 2020.08. |
| 146. |
Kashiwagi E, Shiota M, Masaoka H, Imada K, Monji K, Takeuchi A, Inokuchi J, Tatsugami K, Eto M:, Relationship between body composition and hormone sensitivity for androgen deprivation therapy in patients with metastatic prostate cancer., Prostate Int , 8 (1) :22-26, 2020, 2020.03. |
| 147. |
Shiota M, Fujimoto N, Yamamoto Y, Takeuchi A, Tatsugami K, Uchiumi T, Matsuyama H, Eto M:, Genome-wide association study of genetic variations associated with treatment failure after intravesical bacillus Calmette-Guérin therapy for non-muscle invasive bladder cancer., Cancer Immunol Immunother, 69 (7): 1155-1163, 2020, 2020.07. |
| 148. |
Shiota M, Onozawa M, Hinotsu S, Eto M, Naito S, Akaza H; Japan Study Group of Prostate Cancer (J-CaP):, Family history in primary hormone therapy for prostate cancer: Analysis from a community-based multi-institutional Japan-wide database., Int J Urol , 27 (4): 313-318, 2020, 2020.04. |
| 149. |
Shiota M, Nakamura M, Yokomizo A, Tomoda T, Sakamoto N, Seki N, Hasegawa S, Yunoki T, Harano M, Kuroiwa K, Eto M:, Prognostic Impact of Prior Androgen Receptor Axis-targeting Agents in Cabazitaxel Chemotherapy After Docetaxel., Anticancer Res , 40 (1): 335-339, 2020, 2020.01. |
| 150. |
Masaki Shiota, Noriaki Tokuda, Takehiro Kanou, Humio Yamasaki, Incidence rate of injection-site granulomas resulting from the administration of Luteinizing hormone-releasing hormone analogues for the treatment of prostatic cancer, Yonsei Medical Journal, 10.3349/ymj.2007.48.3.421, 48, 3, 421-424, 2007.06, Purpose: Granulomas resulting from the administration of luteinizing hormone-releasing hormone analogues (LH-RH analogues) are thought to be very rare. We report on our clinical experience with injection-site granulomas that result from the administration of LH-RH analogues, and we evaluate the incidence rate of these granulomas. Materials and Methods: We used the clinical records of 118 patients who were administered LH-RH analogues in 2005. We describe the clinical data of patients who experienced injection-site granulomas and evaluated the incidence rate. Results: Five patients demonstrated mjection-site granulomas due to LH-RH analogue administration. The incidence rate was 4.2% (5 of 118 patients). Most of the granulomas occurred after the first or second administration of 11.25 mg of leuprorelin acetate. Conclusion: The occurrence of granulomas resulting from the administration of LH-RH analogues was thought to be very rare. Our study, however, revealed a higher incidence rate than expected, especially for leuprorelin acetate.. |
| 151. |
Satoshi Otsubo, Akira Yokomizo, Osamu Mochida, Masaki Shiota, Katsunori Tatsugami, Junich Inokuchi, Seiji Naito, Significance of prostate-specific antigen-related factors in incidental prostate cancer treated by holmium laser enucleation of the prostate, World Journal of Urology, 10.1007/s00345-014-1310-9, 33, 3, 329-333, 2015, Purpose: Recently, more vaporization techniques are available for the treatment of benign prostate hyperplasia (BPH). However, the detection of incidental prostate cancer (Pca) is impossible in vaporization techniques because of unavailability prostate tissue for histopathological analysis. To evaluate the clinical backgrounds and the usefulness of prostate-specific antigen (PSA)-related factors in incidental Pca, we employed our BPH patients cohort treated by holmium laser enucleation of the prostate (HoLEP).
Methods: A total of 365 HoLEPs were performed by a single surgeon. The pathological results and pre- and post-HoLEP PSA, PSA density and PSA velocity were analyzed retrospectively.
Results: Incidental Pca was identified in 25 (6.8 %) of the 365 patients treated with HoLEP. There were significant differences between BPH and Pca in terms of prostate volume (55.5 vs. 47 ml, p = 0.0365), preoperative PSA (4.50 vs. 7.14 ng/ml, p = 0.0107), PSA density (0.079 vs. 0.155 ng/ml/cm3, p = 0.0005), and postoperative PSA velocity (0.04 vs. 0.22 ng/ml/year, p = 0.0033), respectively. Comparisons of Gleason score subgroups in the 25 patients with incidental Pca identified significant differences in preoperative PSA (6.06 vs. 21.6 ng/ml, p = 0.0191) and postoperative PSA velocity (0.185 vs. 1.32 ng/ml/year, p = 0.0382) between the Gleason score 3 + 3 and Gleason score >3 + 3 groups, respectively.
Conclusions: Risk factors associated with incidental Pca were smaller prostate volume, higher preoperative PSA, and higher PSA density. Postoperative PSA velocity was also significantly increased in patients with incidental Pca, especially those with higher Gleason score. These finding may be useful in incident Pca patients treated by the vaporization technique.. |
| 152. |
Masaaki Sugimoto, Kenichi Kohashi, Kentaro Kuroiwa, Tatsuro Abe, Yuichi Yamada, Masaki Shiota, Kenjiro Imada, Seiji Naito, Yoshinao Oda, Renal cell carcinoma with rhabdoid-like features lack intracytoplasmic inclusion bodies and show aggressive behavior, Virchows Archiv, 10.1007/s00428-015-1885-6, 468, 3, 357-367, 2016.03, In renal cell carcinoma (RCC), tumor cells with rhabdoid features are characterized by eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm with intracytoplasmic inclusion bodies. In RCC, tumor cells have also been observed resembling rhabdomyoblasts or rhabdoid but without intracytoplasmic inclusion bodies, and here, we defined these rhabdoid-like features of these cells. To this end, we studied a series of clear cell RCC (ccRCC) with rhabdoid features and compared them with a series of ccRCC with rhabdoid-like features to clarify the differences in the immunohistochemical profile and biological behavior. From 695 cases of ccRCC (80.8% of all RCCs), 18 cases with rhabdoid features (2.1% of all RCCs) and 25 cases with rhabdoid-like features (2.9% of all RCCs) were investigated. The 5-year survival rate for ccRCC with rhabdoid features was 44.7% and for ccRCC with rhabdoid-like features 30.3%. Although ccRCC with rhabdoid features showed immunohistochemical co-expression of epithelial markers and vimentin as seen in malignant rhabdoid tumors, ccRCC with rhabdoid-like features showed no such co-expression. Multivariate analyses of cancer-specific survival revealed that perinephric tissues invasion was an independent prognostic factor in ccRCC with rhabdoid features (p = 0.0253) but not in ccRCC with rhabdoid-like features. In summary, although their prognosis is similar, the marker profile and pattern of extension of ccRCC with rhabdoid-like is different from that of ccRCC with rhabdoid features. Therefore, ccRCC with rhabdoidlike features should be distinguished from ccRCC with rhabdoid features.. |
| 153. |
Yohei Sekino, Xiangrui Han, Takashi Babasaki, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Jun Teishima, Masaki Shiota, Yukio Takeshima, Wataru Yasui, Akio Matsubara, Microtubule-associated protein tau (MAPT) promotes bicalutamide resistance and is associated with survival in prostate cancer, Urologic Oncology: Seminars and Original Investigations, 10.1016/j.urolonc.2020.04.032, 38, 10, 795.e1-795.e8, 2020.10, Introduction: Microtubule-associated protein tau (MAPT), facilitates tubulin assembly and microtubule stabilization. Several studies have shown that overexpression of MAPT is linked to poor prognosis and is involved in taxane resistance in cancer. This study aimed to assess the expression and function of MAPT in prostate cancer (CaP). Methods: The expression of MAPT was determined using immunohistochemistry in CaP. We analyzed the interaction between MAPT, Phosphatase and Tensin Homolog (PTEN), and androgen receptor and investigated the role of MAPT in bicalutamide resistance. Results: Immunohistochemistry in 155 CaP cases showed that 15% of them were positive for MAPT. High MAPT expression was significantly orrelated with high Gleason score and high T stage. Kaplan-Meier analysis showed that the high MAPT expression was significantly associated with poor prostate-specific antigen recurrence survival after radical prostatectomy. There was an inverse correlation between MAPT and PTEN. In the CaP cell lines, knockout of PTEN increased the expression of MAPT, whereas knockdown of MAPT suppressed the expression of androgen receptor and increased the sensitivity to bicalutamide. Furthermore, immunohistochemical staining of MAPT showed that high MAPT expression was significantly associated with poor overall survival in 74 CaP patients who were treated with androgen deprivation therapy. Conclusion: These results suggest that MAPT may be a promising predictive biomarker for survival and play an essential role in bicalutamide resistance in CaP.. |
| 154. |
Masaki Shiota, Satoshi Endo, Naohiro Fujimoto, Shigehiro Tsukahara, Miho Ushijima, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Takeshi Uchiumi, Masatoshi Eto, Polymorphisms in androgen metabolism genes with serum testosterone levels and prognosis in androgen-deprivation therapy, Urologic Oncology: Seminars and Original Investigations, 10.1016/j.urolonc.2020.06.033, 2020, Objective: Androgen metabolism is a key component in therapeutic resistance to androgen deprivation therapy (ADT). This study aimed to reveal the significance of genetic polymorphisms in genes involved in androgen metabolism, including CYP17A1, AKR1C3, and HSD17B, on serum testosterone levels during ADT, as well as the prognosis of men undergoing ADT for metastatic prostate cancer (CaP). Materials and methods: This study included 104 Japanese patients with metastatic CaP, for whom serum testosterone data during ADT were available for 80 patients. The association of CYP17A1 (rs743572), AKR1C3 (rs12529), HSD17B1 (rs605059), HSD17B3 (rs2066479), and HSD17B4 (rs7737181) with serum testosterone levels during ADT and prognosis (progression-free survival and overall survival) was examined. Enzymatic activity in AKR1C3 H5Q was examined using recombinant protein. Results: Homozygous wild-type (GG allele; median [interquartile range], 12.0 ng/ml [8.0–19.0 ng/ml]) AKR1C3 rs12529 was associated with higher serum testosterone levels during ADT compared with variant-type (GC/CC alleles; median [interquartile range], 9.0 ng/ml [6.4–10.8 ng/ml]). Consistently, variant-type (GC/CC alleles) AKR1C3 rs12529 showed significantly lower risk of progression (hazard ratio [95% confidence interval], 0.47 [0.24–0.96], P = 0.039) compared with homozygous wild-type (GG allele) on multivariate analysis. Meanwhile, other genetic variations were associated with neither serum testosterone during ADT nor prognosis. Enzyme activity of wild-type AKR1C3 was comparable to the H5Q mutant. Conclusions: Taken together, this study demonstrated that AKR1C3 polymorphism, which was associated with serum testosterone levels during ADT, may be a prognostic factor of the progression to castration-resistant prostate cancer in Japanese men with metastatic CaP.. |
| 155. |
Masaki Shiota, Takeshi Kobayashi, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Prognostic significance of antihypertensive agents in men with castration-resistant prostate cancer, Urologic Oncology: Seminars and Original Investigations, 10.1016/j.urolonc.2019.04.020, 37, 11, 813.e21-813.e26, 2019.11, Purpose: Comorbidity with hypertension (HTN) may affect the outcome of castration-resistant prostate cancer (CRPC). In this study, we evaluated the prognostic impact of antihypertensive agents in patients with CRPC treated with androgen receptor axis-targeting (ARAT) agents or docetaxel chemotherapy. Patients and methods: This study included 156 Japanese men with CRPC who were treated with ARAT agents (n = 85) or docetaxel (n = 71) at our hospital between 2008 and 2017. Associations between clinicopathological factors, HTN status, progression-free survival (PFS) and overall survival (OS) were evaluated by univariate and multivariate analysis. Results: When adjusted for age, prostate-specific antigen levels at pretreatment, Gleason score, and clinical M-stage, comorbid HTN was significantly associated with better OS (hazards ratio, 95% confidence interval: 0.41, 0.21–0.77; P = 0.0051), but not with PFS (hazards ratio, 95% confidence interval: 0.64, 0.38–1.11; P = 0.11) in patients treated with ARAT agent. However, HTN was not associated with PFS or OS for patients treated with docetaxel. Conclusions: Use of antihypertensive agents has prognostic significance for patients with CRPC treated with ARAT agent, but not docetaxel.. |
| 156. |
Masaki Shiota, Eiji Kashiwagi, Tomohiko Murakami, Ario Takeuchi, Kenjiro Imada, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Serum testosterone level as possible predictive marker in androgen receptor axis-targeting agents and taxane chemotherapies for castration-resistant prostate cancer, Urologic Oncology: Seminars and Original Investigations, 10.1016/j.urolonc.2018.10.020, 37, 3, 180.e19-180.e24, 2019.03, Purpose: Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC. Patients and methods: The present study included Japanese patients with metastatic prostate cancer whose serum testosterone levels during androgen-deprivation therapy were available. The antitumor outcomes when treated with enzalutamide, abiraterone, docetaxel, and cabazitaxel with clinicopathological parameters including serum testosterone levels during androgen-deprivation therapy, as well as prognoses including progression-free survival and overall survival, were examined. Results: Progression-free survival among men with higher serum testosterone level was superior to that among men with lower serum testosterone level when treated with enzalutamide. On the contrary, progression-free survival and overall survival among men with higher serum testosterone level were significantly inferior to those among men with lower serum testosterone level when treated with docetaxel and cabazitaxel, respectively. Conclusions: The present study indicated distinct prognostic values of serum testosterone level when treated with androgen receptor axis-targeting agent and taxane chemotherapy for CRPC, suggesting that serum testosterone level may be useful predictive biomarker to navigate the appropriate therapy in patients with CRPC.. |
| 157. |
Yoo Hyun Song, Masaki Shiota, Akira Yokomizo, Takeshi Uchiumi, Keijiro Kiyoshima, Kentaro Kuroiwa, Yoshinao Oda, Seiji Naito, Twist1 and Y-box-binding protein-1 are potential prognostic factors in bladder cancer, Urologic Oncology: Seminars and Original Investigations, 10.1016/j.urolonc.2012.11.003, 32, 1, 31.e1-31.e7, 2014.01, Objective: To investigate the expression and possible roles of Twist1 and Y-box-binding protein-1 (YB-1) in bladder cancer tissue. Twist1 belongs to the family of basic helix-loop-helix transcription factors. A functional link between Twist1 and YB-1 has recently been determined to play an important role in bladder cancer cell lines. Materials and methods: Frozen samples from 75 patients with bladder cancer were analyzed by quantitative real-time polymerase chain reaction (PCR). Formalin-fixed and paraffin-embedded tissues from 53 patients with bladder cancer were examined by immunohistochemistry. Results: Twist1 transcript levels were positively correlated with YB-1 transcript levels (coefficient of correlation = 0.42, P |
| 158. |
Naohiro Fujimoto, Masaki Shiota, Ikko Tomisaki, Akinori Minato, Katsuya Yahara, Reconsideration on clinical benefit of pelvic lymph node dissection during radical prostatectomy for clinically localized prostate cancer, Urologia Internationalis, 10.1159/000497280, 103, 2, 125-136, 2019.08, We conducted a review of the literature to identify the clinical benefits of pelvic lymph node dissection (PLND) during radical prostatectomy for clinically localized prostate cancer. The most recent guidelines recommend PLND, particularly extended PLND, during radical prostatectomy for localized prostate cancer. PLND is undoubtedly the most accurate method for nodal staging, and most patients, particularly those with high-risk cancer, are likely to undergo PLND during radical prostatectomy. Although many retrospective studies have assessed oncologic outcomes after PLND, its therapeutic benefit remains controversial. Patients with positive node(s) often have other more common unfavorable prognostic factors, such as seminal vesicle invasion, extra-prostatic extension, and positive surgical margins. Oncologic outcomes in patients who have not undergone PLND and those who have undergone PLND are almost identical. If an effective standard adjuvant therapy after prostatectomy is defined, the nodal status may be important and valuable. However, adjuvant treatment strategies for patients with a positive node have not been identified thus far. Therefore, determining the nodal status at surgery may not provide therapeutic benefit. PLND requires additional surgical time and is associated with several complications. Therefore, the indication for PLND should be considered carefully until well-designed prospective randomized trials establish high-quality clinical evidence.. |
| 159. |
Ario Takeuchi, Masatoshi Eto, Katsunori Tatsugami, Hisakata Yamada, Akira Yokomizo, Masaki Shiota, Momoe Itsumi, Junichi Inokuchi, Keijiro Kiyoshima, Takashi Dejima, Kenjiro Imada, Seiji Naito, Yasunobu Yoshikai, Renal cancer treatment with recipient lymphocyte infusion enhanced the antitumor effect of nonmyeloablative allogeneic stem cell transplantation, Transplant Immunology, 10.1016/j.trim.2014.12.001, 32, 2, 131-139, 2015.03, Background: Nonmyeloablative allogeneic stem cell transplantation (SCT) is an option for the treatment of metastatic renal cancer. Mature donor T cells cause graft versus-host disease (GVHD) although they are also the main mediators of the beneficial graft-versus-tumor (GVT) activity associated with this treatment. Hence, the segregation of GVT activity from GVHD is an important challenge in managing the clinical course of treatment. We previously reported a series of studies regarding the allograft tolerance induced by allogeneic spleen cells (with bone marrow cells) and cyclophosphamide in mice. Methods: The aim of the present study was to modify the cyclophosphamide-using cell therapy to reduce the risk of GVHD while preserving the antitumor activity against RENCA, a murine carcinogen-induced renal cell carcinoma with recipient lymphocyte infusion (RLI). Results: Regarding the in vivo antitumor effect, there was a significant difference between RLI and no lymphocyte infusion after the cyclophosphamide treatment, whereas the histologic findings of the small intestine showed that the cyclophosphamide-using cell therapy with RLI decreased the risk of GVHD as compared with donor lymphocyte infusion. In addition, the acquired immunity against RENCA was clearly observed in RLI-treated mice. Conclusions: Our results show that RLI during cyclophosphamide-using nonmyeloablative cell therapy can dissociate GVT effects from GVHD by reducing the risk of GVHD. We considered that this was the first report to provide the evidence of nonmyeloablative allogeneic SCT with RLI for the treatment of renal cell carcinoma which never induce complete chimerism. •The aim of the present study was to modify the cyclophosphamide-using cell therapy to reduce the risk of GVHD while preserving the antitumor activity against RENCA, a murine carcinogen-induced renal cell carcinoma with recipient lymphocyte infusion (RLI).•RLI during cyclophosphamide-using nonmyeloablative cell therapy can dissociate GVT effects from GVHD by reducing the risk of GVHD.•In addition, we showed that serum IFN-γ levels were significantly elevated in animals received RLI and that the origin of producing IFN-γ was host-derived CD4 and CD8 T cells in this model.. |
| 160. |
Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Seiji Naito, Risk factors for febrile neutropenia in patients receiving docetaxel chemotherapy for castration-resistant prostate cancer, Supportive Care in Cancer, 10.1007/s00520-014-2328-7, 22, 12, 3219-3226, 2014, Purpose: Docetaxel is a standard therapy for patients with castration-resistant prostate cancer (CRPC). However, docetaxel-associated adverse events (AEs) such as febrile neutropenia (FN) can impair quality of life and may become life-threatening. In this study, we clarified the AEs and risk factors associated with FN in clinical settings.
Methods: This study included 37 Japanese patients with CRPC who were treated with 70–75 mg/m2 docetaxel and 10 mg prednisone every 3 or 4 weeks between 2008 and 2012. AEs, risk factors for FN, and the prognostic significance of several clinicopathological factors were analyzed.
Results: Hematological AEs of ≥grade 3 included neutrocytopenia in 36 patients (97.3 %), leukopenia in 24 patients (64.9 %), lymphopenia in 10 patients (27.0 %), and FN in 4 patients (10.8 %). In addition, severe non-hematological AEs included colonic perforation, interstitial pneumonia, and acute respiratory distress syndrome in 1 patient each. Severe lymphopenia was positively associated with the incidence of FN. Low serum albumin and low lymphocyte count were identified as possible pre-treatment risk factors, while severe lymphopenia was identified as a post-treatment risk factor.
Conclusions: Non-hematological AEs as well as substantial hematological AEs were recognized in the Japanese population treated with docetaxel chemotherapy against CRPC. Pre- and post-treatment lymphopenia and pre-treatment serum albumin should be considered in order to minimize the risk of FN when selecting patients with prostate cancer for docetaxel therapy, and when considering dose modifications, and the prophylactic use of granulocyte colony-stimulating factor.. |
| 161. |
Eiji Kashiwagi, Masaki Shiota, Hiroyuki Masaoka, Kenjiro Imada, Keisuke Monji, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Relationship between body composition and hormone sensitivity for androgen deprivation therapy in patients with metastatic prostate cancer, Prostate International, 10.1016/j.prnil.2019.11.002, 8, 1, 22-26, 2020.03, Background: To evaluate the relationship between body composition and the oncological outcome of androgen deprivation therapy (ADT), we investigated whether body composition features including the psoas muscle may be predictive factors of ADT. Methods: This study enrolled patients with hormone-naïve metastatic prostate cancer who were treated with primary ADT from April 1996 to November 2013 at Kyushu University Hospital and who underwent a computed tomography scan before primary ADT for calculating body fat percentage, psoas muscle ratio (psoas muscle, cm3/height, cm), and body mass index. Results: Of the 178 patients enrolled, 60 patients died during follow-up. Median follow-up was 32 months, and progression-free survival and overall survival (OS) were 28 and 80 months, respectively. Multivariate analysis revealed that the psoas muscle ratio was correlated with OS (hazard ratio: 0.448; 95% confidence interval = 0.206–0.922; p = 0.028). Conclusions: This study demonstrated that higher psoas muscle ratio predicts longer OS among patients with nonlocalized prostate cancer treated with primary ADT.. |
| 162. |
Yu Hirata, Masaki Shiota, Takeshi Kobayashi, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Prognostic significance of diabetes mellitus and dyslipidemia in men receiving androgen-deprivation therapy for metastatic prostate cancer, Prostate International, 10.1016/j.prnil.2019.10.003, 7, 4, 166-170, 2019.12, Objective: The outcome of the androgen-deprivation therapy (ADT) may be affected by metabolic diseases such as diabetes mellitus (DM) and dyslipidemia and/or by their treatments. We aimed to evaluate the prognostic impact of these disorders and corresponding medications in Japanese men treated with ADT for prostate cancer. Methods: This study retrospectively included 121 patients with metastatic prostate cancer who were treated with primary ADT at our hospital between 2001 and 2013. All patients received primary ADT with castration and/or an antiandrogen agent (bicalutamide or flutamide). Associations between clinicopathological factors, metabolic disease profiles, medication use, and prognosis (progression-free survival [PFS] and overall survival [OS]) were evaluated by univariate and multivariate analysis. Results: The median follow-up time was 54.9 months, and the median PFS and OS were 23.9 months and 73.0 months, respectively. High serum glucose levels at baseline (hazard ratio [HR], 95% confidence interval [CI]: 2.12, 1.16–3.76; P = 0.015), and concurrent DM (HR, 95% CI: 2.07, 1.06–3.94; P = 0.034) were significantly associated with poorer OS after adjustment for age, prostate-specific antigen levels at diagnosis, Gleason score, and clinical stage. Treatment with sulfonylurea drugs was significantly associated with a reduced risk of disease progression in men with DM (HR, 95% CI: 0.36, 0.12–0.90; P = 0.028). Conclusions: Impaired glucose tolerance and treatment with sulfonylureas have prognostic significance in prostate cancer. These findings demonstrate the importance of managing DM during ADT and point to a possible favorable effect of sulfonylureas on prostate cancer.. |
| 163. |
Naoko Akitake, Masaki Shiota, Hirofumi Obata, Ario Takeuchi, Eiji Kashiwagi, Kenjiro Imada, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Neoadjuvant androgen-deprivation therapy with radical prostatectomy for prostate cancer in association with age and serum testosterone, Prostate International, 10.1016/j.prnil.2017.10.002, 6, 3, 104-109, 2018.09, Background: We aimed to identify the candidate prostate cancer patients suitable for neoadjuvant androgen-deprivation therapy (ADT) with radical prostatectomy (RP). Materials and methods: This study included 711 Japanese patients with clinically localized prostate cancer who were treated with RP between 2000 and 2013. Patients were treated with or without neoadjuvant ADT before RP. The prognostic significance of neoadjuvant ADT on biochemical recurrence (BCR) was analyzed according to various clinicopathological characteristics. Results: BCR occurred in 186 (26.2%) of 711 patients. The group treated with neoadjuvant ADT showed higher levels of prostate-specific antigen at diagnosis and advanced clinical T-stage, but suppressed pathological T-stage. Neoadjuvant ADT was not associated with the risk of BCR. In subgroup analysis, neoadjuvant ADT was significantly associated with increased BCR in patients aged >65 years [hazard ratio (95% confidence interval), 2.04 (1.13–3.43), P = 0.020]. Among the 53 patients with available serum testosterone levels, neoadjuvant ADT was associated with the risk of BCR according to serum testosterone levels. Conclusion: This study demonstrated that neoadjuvant ADT showed potential deleterious effects in older patients and patients with lower serum testosterone levels, while a possible improved prognosis in patients with high serum testosterone levels treated with neoadjuvant ADT was suggested, warranting further exploration.. |
| 164. |
M. Shiota, N. Fujimoto, A. Yokomizo, A. Takeuchi, E. Kashiwagi, T. Dejima, K. Kiyoshima, J. Inokuchi, K. Tatsugami, M. Eto, The prognostic impact of serum testosterone during androgen-deprivation therapy in patients with metastatic prostate cancer and the SRD5A2 polymorphism, Prostate Cancer and Prostatic Diseases, 10.1038/pcan.2016.2, 19, 2, 191-196, 2016.06, Background:Although testosterone suppression during androgen-deprivation therapy (ADT) and obesity have been reported to affect ADT efficacy, there are few comprehensive analyses on the impact on ADT outcome. Recently, we demonstrated that the SRD5A2 polymorphism was associated with metastatic prostate cancer prognosis. Therefore, in this study, we investigated the relationship between ADT serum testosterone levels or body mass index (BMI) and the prognosis among men treated with primary ADT for metastatic prostate cancer. In addition, we examined the association of serum testosterone levels during ADT with the SRD5A2 polymorphism.Methods:This study included 96 Japanese patients with metastatic prostate cancer. The relationship between clinicopathological parameters, including serum testosterone levels during ADT and BMI, and progression-free survival, overall survival and survival from progression following primary ADT treatment for metastatic prostate cancer was examined. Additionally, the association between the SRD5A2 gene polymorphism (rs523349) and serum testosterone levels during ADT was examined in 86 cases.Results:Among clinicopathological parameters, the lowest quartile of serum testosterone levels during ADT was a significant predictor of better overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis. The CC allele in the SRD5A2 gene (rs523349), encoding the less active 5α-reductase, was associated with lower serum testosterone levels during ADT.Conclusions:Taken together, these findings revealed a dramatic suppression of serum testosterone by ADT was associated with better survival among men with metastatic prostate cancer that have undergone primary ADT, which may be affected by the SRD5A2 gene polymorphism.. |
| 165. |
E. Kashiwagi, M. Shiota, A. Yokomizo, J. Inokuchi, T. Uchiumi, S. Naito, EP2 signaling mediates suppressive effects of celecoxib on androgen receptor expression and cell proliferation in prostate cancer, Prostate Cancer and Prostatic Diseases, 10.1038/pcan.2013.53, 17, 1, 10-17, 2014.03, Background:Non-steroidal anti-inflammatory drugs inhibit the activity of cyclooxygenases (COXs), and their usage reduces the risks associated with prostate cancer. Celecoxib is a selective COX-2 inhibitor and reported to prevent the progression of prostate cancer. However, the mechanisms involved remain unclear. In this study, we investigated the suppression of prostate cancer growth by celecoxib and elucidated the biological relevance of the inhibited pathway in prostate cancer cell lines.Methods:Western blotting, quantitative real-time PCR and cell proliferation assay were used to resolve the mechanism of celecoxib in prostate cancer cell line PC3, LNCaP and their derivatives.Results:Celecoxib induced apoptosis and downregulated EP2, CREB and androgen receptor (AR). Moreover, EP2 antagonist downregulated CREB as well as COX-2 and AR, resulting in the suppression of cell proliferation. Furthermore, EP2 and CREB knockdown induced AR downregulation, indicating that AR suppression by celecoxib is mediated by EP2/CREB signaling.Conclusions:Celecoxib exerts antitumor activity through EP2 signaling regulating AR and COX-2 expression. Furthermore, in addition to celecoxib, therapeutics targeting EP2 may also be promising against prostate cancers.. |
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N. Fujimoto, T. Kubo, H. Inatomi, H. T.T. Bui, M. Shiota, T. Sho, T. Matsumoto, Polymorphisms of the androgen transporting gene SLCO2B1 may influence the castration resistance of prostate cancer and the racial differences in response to androgen deprivation, Prostate Cancer and Prostatic Diseases, 10.1038/pcan.2013.23, 16, 4, 336-340, 2013.12, Background:Organic anion-transporting polypeptides (OATPs) encoded by SLCO mediate the cellular uptake of many compounds, including androgens. SLCO1B3 and SLCO2B1 are polymorphic, and single-nucleotide polymorphisms of those genes alter androgen transport efficiency. We aimed to investigate the association between genetic variations in SLCOs and the progression to castration-resistant prostate cancer (CRPC).Methods:We studied the progression to CRPC for the SLCO1B3 rs4149117 and SLCO2B1 rs12422149 genotypes in 87 prostate cancer patients who received androgen deprivation therapy (ADT). Data were analyzed using the χ 2 test, Kaplan-Meier survival analysis and Cox proportional hazard model.Results:SLCO3B1 genotypes were not significantly associated with the time to progression (TTP); however, patients carrying the active androgen transport SLCO2B1 genotype (GG allele) exhibited a median TTP that was 7 months shorter than that of patients with impaired androgen-transporting activity SLCO2B1 polymorphisms (GA/AA alleles) (10.0 vs 17.0 months, P=0.004). Active androgen transport genotypes of SLCO2B1 (GG allele) occurred more frequently in African and Caucasian populations than in Japanese and Han Chinese populations (P |
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Momoe Itsumi, Masaki Shiota, Yohei Sekino, Miho Ushijima, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto, High-throughput screen identifies 5-HT receptor as a modulator of AR and a therapeutic target for prostate cancer, Prostate, 10.1002/pros.24022, 80, 11, 885-894, 2020.08, Background: Eradication of persistent androgen receptor (AR) activity in castration-resistant prostate cancer may be a promising strategy to overcome castration resistance. We aimed to identify novel compounds that inhibit AR activity and could be potential therapeutic agents for prostate cancer. Methods: A high-throughput screening system involving cell lines stably expressing AR protein and AR-responsive luciferase was employed for the 1260 compound library. Molecular and antitumor effects on candidate pathways that interacted with AR signaling were examined in prostate cancer cells expressing AR. Results: The high-throughput screening identified various potential compounds that interfered with AR signaling through known and novel pathways. Among them, a 5-hydroxytryptamine 5A (5-HT5A) receptor antagonist suppressed AR activity through protein kinase A signaling, which was confirmed by 5-HT5A receptor knockdown. Consistently, 5-HT5A receptor inhibitors showed cytotoxic effects toward prostate cancer cells. Conclusions: Taken together, this study identifies 5-HT5A receptor as a promising therapeutic target for prostate cancer via its interaction with AR signaling.. |
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Masaki Shiota, Miho Ushijima, Kenjiro Imada, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Masatoshi Eto, Cigarette smoking augments androgen receptor activity and promotes resistance to antiandrogen therapy, Prostate, 10.1002/pros.23828, 79, 10, 1147-1155, 2019.07, Background: Cigarette smoking is associated with worse outcomes in prostate cancer, whose growth is dependent on androgen receptor (AR) signaling. We aimed to elucidate the biological effect of cigarette smoking on AR signaling and its clinical influence on oncological outcome. Methods: Gene expression levels after exposure to tobacco smoke condensate (TSC) were evaluated by quantitative real-time polymerase chain reaction and Western blot analysis in prostate cancer cells. Cellular sensitivities to enzalutamide and docetaxel after TSC exposure were evaluated using a prostate cancer cell proliferation assay. Prognosis was compared between current smokers and nonsmokers when treated with AR-axis-targeting (ARAT) agent enzalutamide and docetaxel. Results: Expression of AR variants as well as prostate-specific antigen was augmented after TSC exposure, which occurred after Akt phosphorylation. These inductions were suppressed by Akt inhibitor LY294002 as well as antioxidant N-acetylcysteine. Consistently, TSC exposure augmented cellular resistance to enzalutamide. In clinical data, cigarette smoking was associated with worse progression-free survival and cancer-specific survival when patients with prostate cancer were treated with ARAT agents but not docetaxel. Conclusions: It was suggested that cigarette smoking leads to detrimental oncological outcome when prostate cancer patients are treated with ARAT agents through induction of aberrant AR signaling. Accordingly, we recommend that patients with advanced prostate cancer should refrain from cigarette smoking.. |
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Masaki Shiota, Naohiro Fujimoto, Katuyoshi Higashijima, Kenjiro Imada, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto, Mineralocorticoid receptor signaling affects therapeutic effect of enzalutamide, Prostate, 10.1002/pros.23661, 78, 14, 1045-1052, 2018.10, Background: Corticosteroids play important roles in prostate cancer therapeutics. However, their role when combined with enzalutamide remains obscure. Then, we aimed to elucidate the functional and clinical impact of corticosteroids on steroid receptors in androgen receptor (AR)-targeting therapy utilizing enzalutamide. Methods: The therapeutic effect was studied according to concomitant use of corticosteroids in 86 men treated with enzalutamide. The sensitivity to various agents was evaluated using cytotoxicity assays in prostate cancer cells. Gene expression levels were evaluated by quantitative real-time polymerase chain reaction in prostate cancer cells and tissues. Results: The therapeutic effect of enzalutamide was particularly lessened with concomitant treatment with dexamethasone. Consistently, dexamethasone increased cellular resistance to enzalutamide while prednisolone and aldosterone decreased cellular resistance to enzalutamide in prostate cancer cells. Inversely, mineralocorticoid receptor (MR) knockdown augmented the activity of AR signaling and the cellular resistance to enzalutamide. Conclusions: MR plays a critical role in resistance to AR-targeting therapies, which may be overcome by activation of MR signaling.. |
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Kenjiro Imada, Masaki Shiota, Kentaro Kuroiwa, Masaaki Sugimoto, Tatsuro Abe, Kenichi Kohashi, Akira Yokomizo, Masatoshi Eto, Seiji Naito, Yoshinao Oda, FOXO3a Expression Regulated by ERK Signaling is Inversely Correlated With Y-Box Binding Protein-1 Expression in Prostate Cancer, Prostate, 10.1002/pros.23254, 77, 2, 145-153, 2017.02, BACKGROUND: FOXO3a is a member of the forkhead O transcription factors. FOXO3a induces the factors that contribute to cell cycle arrest and is considered a tumor suppressor in several malignant tumors. Y-box binding protein-1 (YB-1) is a multifunctional protein whose high expression is correlated with poor prognoses in various malignant tumors. In the current study, we investigated the relationship between FOXO3a and YB-1 to validate their functional roles in prostate cancer. METHODS: Western blotting and cytotoxicity assays were conducted in prostate cancer cells, LNCaP, and 22Rv1 cells. We also evaluated the protein expressions of FOXO3a and YB-1 in human prostate cancer tissues, using radical prostatectomy specimens. Then, we investigated the correlations between protein expressions and clinicopathologic parameters. RESULTS: We found that both FOXO3a and YB-1 proteins were phosphorylated by ERK signaling, resulting in FOXO3a inactivation and YB-1 activation in LNCaP and 22Rv1 cells. Inversely, inhibition of MEK or treatment with metformin activated FOXO3a through inactivation of ERK signaling and suppressed the viability of LNCaP and 22Rv1 cells in a dose-dependent manner. In immunohistochemical analysis, FOXO3a nuclear expression was inversely correlated with YB-1 nuclear expression (P |
| 171. |
Takashi Dejima, Kenjiro Imada, Ario Takeuchi, Masaki Shiota, Jeffrey Leong, Tabitha Tombe, Kevin Tam, Ladan Fazli, Seiji Naito, Martin E. Gleave, Christopher J. Ong, Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression, Prostate, 10.1002/pros.23269, 77, 3, 309-320, 2017.02, BACKGROUND: LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). METHODS: A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. RESULTS: The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. CONCLUSIONS: These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309–320, 2017.. |
| 172. |
Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Momoe Itsumi, Kenjiro Imada, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito, Inhibition of RSK/YB-1 signaling enhances the anti-cancer effect of enzalutamide in prostate cancer, Prostate, 10.1002/pros.22813, 74, 9, 959-969, 2014.06, BACKGROUND Previously, we have shown that Y-box binding protein-1 (YB-1) regulates androgen receptor (AR) expression and contributes to castration resistance. However, the mechanism of YB-1 activation remains unknown. In this study, we aimed to elucidate the mechanism and role of YB-1 activation in relation to castration resistance as well as enzalutamide resistance, with a view to developing a novel therapeutic concept for castration-resistant prostate cancer (CRPC) treatment. METHODS The expression and phosphorylation levels of ribosomal S6 kinase 1 (RSK1), YB-1 and AR were examined by quantitative PCR and Western blotting using prostate cancer cells. In addition, the effects of YB-1 inhibition using specific siRNA and small molecule inhibitor SL0101 on AR expression as well as combination treatment with enzalutamide and SL0101 were examined. RESULTS We found that androgen deprivation, as well as treatment with the next-generation anti-androgen enzalutamide, induced RSK1 and YB-1 activation followed by AR induction, which could be reversed by YB-1 shutdown and RSK inhibitor SL0101. SL0101 and enzalutamide exerted a synergistic tumor-suppressive effect on cell proliferation in androgen-dependent prostate cancer LNCaP cells, as well as castration-resistant C4-2 cells. Furthermore, the phosphorylation levels of RSK1 and YB-1 were elevated in castration- and enzalutamide-resistant cells, compared with their parental cells. CONCLUSIONS Taken together, these findings indicate that RSK1/YB-1 signaling contributes to castration as well as enzalutamide resistance, and that the therapeutic targeting of RSK1/YB-1 signaling would be a promising novel therapy against prostate cancer, especially CRPC when combined with enzalutamide. Prostate 74:959-969, 2014.. |
| 173. |
Masaki Shiota, Momoe Itsumi, Akira Yokomizo, Ario Takeuchi, Kenjiro Imada, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito, Targeting ribosomal S6 kinases/Y-box binding protein-1 signaling improves cellular sensitivity to taxane in prostate cancer, Prostate, 10.1002/pros.22799, 74, 8, 829-838, 2014.06, Background Taxanes are the only cytotoxic chemotherapeutic agents proved to prolong the survival in patients with castration-resistant prostate cancer. However, because of intrinsic and acquired resistances to taxanes, their therapeutical efficiencies are modest, bringing only a few months of survival benefit. Y-box binding protein-1 (YB-1) promotes cancer cell resistance to various anticancer treatments, including taxanes. Here, we aimed to elucidate the mechanism of taxane resistance by YB-1 and examined overcoming resistance by targeting YB-1 signaling. Methods Gene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. We evaluated the sensitivity of prostate cancer cells to taxanes using cytotoxicity assays. Results Natural taxane paclitaxel from Taxus brevifolia activated the Raf-1/extracellular signal-regulated kinase (ERK) pathway, leading to an activation of ribosomal S6 kinases (RSK)/YB-1 signaling. Activated Raf-1/ERK pathway was blunted by YB-1 knockdown in prostate cancer cells, indicating regulation between Raf-1/ERK signaling and YB-1. In addition, ERK or RSK was activated in taxane-resistant prostate cancer cells, resulting in YB-1 activation. YB-1 knockdown as well as RSK inhibition using RSK-specific siRNA or the small molecule inhibitor SL0101 successfully blocked activation of YB-1, leading to suppression of prostate cancer growth and sensitization to paclitaxel. ConclusionS Taken together, these findings indicate that RSK/YB-1 signaling contributes to taxane resistance, and implicate the therapeutics targeting RSK/YB-1 signaling such as RSK inhibitor as a promising novel therapy against prostate cancer, especially in combination with taxane.. |
| 174. |
Masaki Shiota, Eiji Kashiwagi, Akira Yokomizo, Ario Takeuchi, Takashi Dejima, Yoohyun Song, Katsunori Tatsugami, Junichi Inokuchi, Takeshi Uchiumi, Seiji Naito, Interaction between docetaxel resistance and castration resistance in prostate cancer
Implications of Twist1, YB-1, and androgen receptor, Prostate, 10.1002/pros.22681, 73, 12, 1336-1344, 2013.09, BACKGROUND Taxanes, including docetaxel, are currently the only cytotoxic chemotherapeutic agents proven to confer survival benefit in patients with castration-resistant prostate cancer (CRPC). However, the merits of taxanes remain modest, and efforts are needed to improve their therapeutic efficacy. METHODS We evaluated the sensitivity of prostate cancer cells to various agents using cytotoxicity assays. Gene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blotting analysis, respectively. RESULTS Hydrogen peroxide-resistant and castration-resistant cells that overexpressed Twist1 and Y-box binding protein-1 (YB-1) were cross-resistant to cytotoxic agents, including docetaxel. Twist1 regulated YB-1 expression in prostate cancer cells, supported by the induction of Twist1 and YB-1 by transforming-growth factor-β, which is critical for taxane resistance. Twist1 and/or YB-1 were activated in docetaxel-resistant prostate cancer cells, and YB-1 was activated by docetaxel treatment. Conversely, Twist1 and YB-1 knockdown sensitized prostate cancer cells to cytotoxic agents, including docetaxel. In addition, androgen receptor (AR) knockdown increased cellular sensitivity to docetaxel, though AR expression in docetaxel-resistant LNCaP cells was paradoxically lower than in parental cells. Intriguingly, androgen deprivation treatment was more effective in docetaxel-resistant LNCaP cells compared with parental cells. CONCLUSIONS Twist1/YB-1 and AR signaling promote docetaxel resistance in CRPC cells. However, docetaxel-resistant cells were collaterally sensitive to androgen deprivation because of down-regulation of AR expression, suggesting that the therapeutic effect of initial taxane treatment in hormone-naïve prostate cancer may be superior to that of salvage taxane treatment in CRPC.. |
| 175. |
Eiji Kashiwagi, Masaki Shiota, Akira Yokomizo, Momoe Itsumi, Junichi Inokuchi, Takeshi Uchiumi, Seiji Naito, Downregulation of phosphodiesterase 4B (PDE4B) activates protein kinase A and contributes to the progression of prostate cancer, Prostate, 10.1002/pros.21478, 72, 7, 741-751, 2012.05, Background Prostate cancer is the most commonly diagnosed non-cutaneous cancer in American men. Unfortunately, few successful therapies for castration-resistant prostate cancer (CRPC) exist. The protein kinase A (PKA) pathway is a critical mediator of cellular proliferation and differentiation in various normal and cancerous cells. However, the PKA activity and the mechanism of regulation in CRPC remain unclear. Then, in this study, we intended to reveal the PKA activity and the mechanism of regulation in CRPC. Methods Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis, and cell proliferation assay were used to resolve the regulatory role of PKA in prostate cancer cell line, LNCaP and their derivatives. Results cAMP-specific phosphodiesterase 4B (PDE4B) was downregulated and the PKA pathway was activated in castration-resistant LNCaP derivatives (CxR cells). Rolipram activated the PKA pathway via inhibition of PDE4B, resulting in AR transactivation while the PKA inhibitor, H89 reduced AR transactivation. In response to hydrogen peroxide and in hydrogen peroxide-resistant LNCaP derivatives (HPR50 cells) PDE4B was decreased and as a result PKA activity was increased. Moreover, PDE4B expression was reduced in advanced prostate cancer and PDE4B knockdown promoted castration-resistant growth of LNCaP cells. Conclusions Oxidative stress may suppress PDE4B expression and activate the PKA pathway. The PDE4B/PKA pathway contributed to progression of androgen-dependent prostate cancer to CRPC. This pathway may represent an attractive therapeutic molecular target.. |
| 176. |
Akira Yokomizo, Masaki Shiota, Eiji Kashiwagi, Kentaro Kuroiwa, Katsunori Tatsugami, Junichi Inokuchi, Ario Takeuchi, Seiji Naito, Statins reduce the androgen sensitivity and cell proliferation by decreasing the androgen receptor protein in prostate cancer cells, Prostate, 10.1002/pros.21243, 71, 3, 298-304, 2011.02, BACKGROUND Statins (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) are cholesterol-lowering drugs that are widely used to prevent and treat atherosclerotic cardiovascular disease. Recent epidemiological studies suggest that statins reduce serum prostate-specific antigen (PSA) levels and decrease the risk of prostate cancer. In the present study, we determined the molecular mechanisms related to the regulation of PSA, androgen receptor (AR) and cell proliferation in prostate cancer cell lines by statins. METHODS Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis and a cell proliferation assay were used to resolve the regulatory role of statins (mevastatin and simvastatin) in three prostate cancer cell lines, RWPE-1, 22Rv1, and LNCaP. RESULTS Western blotting revealed that both mevastatin and simvastatin downregulated AR and PSA protein. However, these statins did not downregulate AR mRNA expression, while they decreased PSA mRNA. The protease inhibitor MG132 inhibited the downregulation of AR protein which suggested that statins decreased AR protein levels by increasing AR proteolysis. Furthermore, statins reduced cell proliferation in AR positive cells but not in AR negative cells, suggesting that statins regulate cell proliferation via AR expression. In addition, cell proliferation assay at various concentrations of dihydrotestosterone (DHT) showed that statins decreased androgen sensitivity in LNCaP cells. CONCLUSIONS Statins decreased AR protein by proteolysis but not mRNA transcription. The drop in AR levels resulted in a reduction in androgen sensitivity and a decrease in cell proliferation in AR positive prostate cancer cells. Prostate 71:298-304, 2011. © 2010 Wiley-Liss, Inc.. |
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Masaki Shiota, Akira Yokomizo, Daisuke Masubuchi, Yasuhiro Tada, Junichi Inokuchi, Masatoshi Eto, Takeshi Uchiumi, Naohiro Fujimoto, Seiji Naito, Tip60 promotes prostate cancer cell proliferation by translocation of androgen receptor into the nucleus, Prostate, 10.1002/pros.21088, 70, 5, 540-554, 2010.04, BACKGROUND. There are currently few effective therapies for castration-resistant prostate cancer (CRPCa). CRPC which is resistant to castration is thought to result from increased activation of the androgen/androgen receptor (AR) signaling pathway, which may be augmented by AR coactivators. METHODS. Luciferase reporter assay, Western blotting, quantitative real-time polymerase chain reaction, fluorescence microscopy, cell proliferation assay, and flow cytometry for cell-cycle analysis were used to resolve a role of Tip60 regulating AR in PCa cells. RESULTS. Tip60 regulated transcriptions of AR target genes androgen independently. Tip60 knockdown induced translocation of AR into the cytoplasm. Acetylation-mimicking mutations in the nuclear localization signal sequence caused AR protein to mainly localize in the nucleus despite androgen starvation, whereas non-acetylation-mimicking mutations caused AR to mainly localize in the cytoplasm despite androgen stimulation. Tip60 overexpression in castration-resistant LNCaP derivative CxR cells resulted in increases in the acetylated form of AR and AR localization in the nucleus even without androgen. Consequently, Tip60 silencing suppressed the growth of AR-expressing PCa cells by inducing cell-cycle arrest at the G1 phase, similar to inhibition of androgen/AR signaling. Furthermore, Tip60 knockdown suppressed the cell growth of CxR cells. CONCLUSIONS. Tip60 is involved in the proliferation of PCa cells as an AR coactivator. Modulation of Tip60 expression or function may be a useful strategy for developing novel therapeutics for PCa, even CRPC, which remain dependent on AR signaling, by overexpressing AR and its coactivators.. |
| 178. |
Masaaki Sugimoto, Kenichi Kohashi, Momoe Itsumi, Masaki Shiota, Tatsuro Abe, Yuichi Yamada, Kentaro Kuroiwa, Seiji Naito, Yoshinao Oda, Epithelial to mesenchymal transition in clear cell renal cell carcinoma with rhabdoid features, Pathobiology, 10.1159/000445752, 83, 6, 277-286, 2016.08, Aims: The aims of this study were to investigate the association of renal cell carcinoma (RCC) displaying rhabdoid features and morphologically mesenchymal characteristics with epithelial to mesenchymal transition (EMT), and to clarify the expression of EMT markers. Methods: We investigated the expression of EMT markers (E-cadherin, vimentin, Snail, Slug, ZEB1, ZEB2 and Twist1) using immunohistochemistry, Western blotting and real-time polymerase chain reaction in 18 cases of clear cell RCC (ccRCC) with rhabdoid features and 74 ccRCC cases with Fuhrman grade 1-3 (G1 to G3). Results: In ccRCCs with rhabdoid features, low E-cadherin and high vimentin expression were found. In G1 to G3 ccRCCs, low E-cadherin expression and high expression of vimentin, ZEB1 and ZEB2 were found. There was no significant difference in the immunoexpression of E-cadherin and vimentin between the two ccRCC groups. Conclusions: The rhabdoid features may histologically and biologically be associated with EMT in ccRCC. There is a possibility that in G1 to G3 ccRCCs showing epithelial structures, other cell-cell adhesion mechanisms apart from E-cadherin adhesion may continue to work, and that ccRCC with rhabdoid features may be caused by an inactivation or loss of these mechanisms.. |
| 179. |
Masaki Shiota, Jennifer L. Bishop, Ario Takeuchi, Ka Mun Nip, Thomas Cordonnier, Eliana Beraldi, Hidetoshi Kuruma, Martin E. Gleave, Amina Zoubeidi, Inhibition of the HER2-YB1-AR axis with lapatinib synergistically enhances enzalutamide anti-tumor efficacy in castration resistant prostate cancer, Oncotarget, 10.18632/oncotarget.3602, 6, 11, 9086-9098, 2015, Incurable castration-resistant prostate cancer (CRPC) is driven by androgen receptor (AR) activation. Potent therapies that prevent AR signaling, such as Enzalutamide (ENZ), are mainstay treatments for CRPC; however patients eventually progress with ENZ resistant (ENZR) disease. In this study, we investigated one mechanism of ENZ resistance, and tried to improve therapeutic efficiency of ENZ. We found HER2 expression is increased in ENZR tumors and cell lines, and is induced by ENZ treatment of LNCaP cells. ENZ-induced HER2 overexpression was dependent on AKT-YB1 activation and modulated AR activity. HER2 dependent AR activation in LNCaP and ENZR cells was effectively blocked by treatment with the EGFR/HER2 inhibitor Lapatinib, which reduced cell viability and increased apoptosis. Despite efficacy in vitro, in vivo monotherapy with Lapatinib did not prevent ENZR tumor growth. However, combination treatment of Lapatinib with ENZ most effectively induced cell death in LNCaP cells in vitro and was more effective than ENZ alone in preventing tumor growth in an in vivo model of CRPC. These results suggest that while HER2 overexpression and subsequent AR activation is a targetable mechanism of resistance to ENZ, therapy using Lapatinib is only a rational therapeutic approach when used in combination with ENZ in CRPC.. |
| 180. |
Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Kenjiro Imada, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Saiji Ohga, Katsumasa Nakamura, Hiroshi Honda, Seiji Naito, Secondary bladder cancer after anticancer therapy for prostate cancer
Reduced comorbidity after androgen-deprivation therapy, Oncotarget, 10.18632/oncotarget.3817, 6, 16, 14710-14719, 2015, Radiotherapy for prostate cancer is associated with an increased incidence of secondary bladder cancer (BC). We investigated the incidence, clinicopathological characteristics, and prognosis of BC after radiotherapy, surgical therapy, and primary androgen-deprivation therapy (ADT) for prostate cancer. This study included 1,334 Japanese patients with prostate cancer treated with radiotherapy (n=631), surgical therapy (n=437), and primary ADT (n=266). During the median follow-up period of 51.2, 44.8, and 45.5 months, secondary BC occurred in 14 (2.2%), 5 (1.1%), and 0 (0%) of patients with prostate cancer treated with radiotherapy, surgical therapy, and primary ADT, respectively. The 10-year BC-free survival rate was 91.3% in the radiotherapy group, 97.4% in the surgical therapy group, and 100% in the primary ADT group. The rates of intravesical recurrence, progression to muscle-invasive BC, and BC-specific death might be higher in secondary BC after radiotherapy compared with after surgical therapy. There was a significant difference in the incidence of secondary BC among different therapeutic modalities for prostate cancer in Japanese men, indicating significantly lower comorbidity rates of secondary BC after primary ADT for prostate cancer compared with radiotherapy.. |
| 181. |
Yasuhiro Tada, Akira Yokomizo, Masaki Shiota, Yoohyun Song, Eiji Kashiwagi, Kentaro Kuroiwa, Yoshinao Oda, Seiji Naito, Ectonucleoside triphosphate diphosphohydrolase 6 expression in testis and testicular cancer and its implication in cisplatin resistance, Oncology reports, 10.3892/or.2011.1274, 26, 1, 161-167, 2011.07, The development of resistance to cisplatin during treatment of testicular cancer constitutes a major obstacle to the cure of testicular cancer. To resolve its mechanism will provide useful information for making clinical decisions. We found 4 and 15 gene expressions were, respectively, up-regulated and down-regulated in cisplatin-resistant testicular cancer NEC-8/DDP cells compared with their parental NEC-8 cells (about 2.5-fold) using cDNA microarray analysis. After screening, we selected the ENTPD6 among these 19 genes. ENTPD6 was less expressed in cancerous region compared with that in non-cancerous lesion. In addition, ENTPD6 expression in seminoma was higher than that in other testicular tumors. ENTPD6 expression was involved in cellular sensitivity to cisplatin through an interaction with E-cadherin. ENTFD6 is a promising molecular biomarker of cisplatin resistance in testicular cancer, and also a novel therapeutical target modulating cisplatin resistance in testicular cancer.. |
| 182. |
Yasutomo Momii, Hiroto Izumi, Masaki Shiota, Takamitsu Onitsuka, Tatsuya Abe, Hidenori Kobayashi, Naoya Miyamoto, Takeshi Uchiumi, Kimitoshi Kohno, p73γ transactivates the p21 promoter through preferential interaction with the p300/CBP-associated factor in human prostate cancer cells, Oncology reports, 10.3892/or.18.2.411, 18, 2, 411-416, 2007.08, Several p73 variants have been reported with different carboxy-terminal structures and transcriptional activities. We showed that p73γ had stronger transactivation activity than the other splicing variants such as α, β and δ by analysing p21 promoter activity in human prostate cancer PC3 cells. The transactivation activity of p73γ was similar to that of p53 and was enhanced by co-transfection with p300/CBP-associated factor (PCAF). In vitro pull-down assay, p73 variants were able to bind to PCAF with a similar extent. However, in vivo co-immunoprecipitation assays showed that p73γ interacted preferentially with PCAF. Neither in vitro-translated nor in vivo-immunoprecipitated p73γ were able to bind to oligonucleotides containing the p53 consensus binding site. However, p73γ acetylated by PCAF restored DNA binding activity. Differential functions of p73 variants are supposed to be regulated by the structural differences of carboxy-terminal region. Our results revealed that p21 promoter activity was affected by differential interactions of p73 variants with PCAF and its acetylation.. |
| 183. |
Akira Yokomizo, Ken Yamamoto, Kenji Furuno, Masaki Shiota, Katsunori Tatsugami, Kentaro Kuroiwa, Seiji Naito, Histopathologic subtype-specific genomic profiles of renal cell carcinomas identified by high-resolution whole-genome single nucleotide polymorphism array analysis, Oncology Letters, 10.3892/ol.2010.187, 1, 6, 1073-1078, 2010.11, To elucidate the novel and common genetic changes in histopathologic subtype-specific profiles of renal cell carcinomas (RCCs), a newly developed high-resolution whole-genome array analysis was applied. Human CNV370-Duo DNA Analysis BeadChip (genotype 370K) was used in a panel of 22 primary clear cell RCCs (ccRCCs), seven papillary RCCs (PRCCs) (six type II and one type I) and eight chromophobe RCCs (ChRCCs). In ccRCC, a chromosome 3p loss was identified in 95% of the carcinomas, suggesting that 3p loss is the first stage in ccRCC carcinogenesis. Other frequent changes included losses of 1p (23%), 3q (46%) and 8p (32%), and gains of 5q (32%), 7p (27%), 7q (27%) and 1q (23%). The most frequent chromosomal losses in PRCC (43%) were noted in 3p and 3q, followed by 29% of losses of 1p, 1q, 11q, 18q, 22p and 22q, and gains of 20q (57%), 20p (43%), 8q (43%) and 12q (43%). Loss of the entire chromosomes 1, 2, 6, 8, 10, 13 or 17 was noted in patients with ChRCC. A high-density single nucleotide polymorphism array analysis confirmed that partial chromosomal changes rarely occur in ChRCC. Additionally, 32 microdeletions and 10 microamplifications of less than 1 Mb were detected, which may represent potential candidate tumor suppressor genes and oncogenes, respectively.. |
| 184. |
Takashi Matsumoto, Takeshi Uchiumi, Keisuke Monji, Mikako Yagi, Daiki Setoyama, Rie Amamoto, Yuichi Matsushima, Masaki Shiota, Masatoshi Eto, Dongchon Kang, Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties
Importance of stem cell plasticity, Oncogenesis, 10.1038/s41389-017-0009-3, 6, 11, 2017.11, Tumor heterogeneity can be traced back to a small subset of cancer stem cells (CSCs), which can be derived from a single stem cell and show chemoresistance. Recent studies showed that CSCs are sensitive to mitochondrial targeting antibiotics such as doxycycline. However, little is known about how cancer cells undergo sphere formation and how antibiotics inhibit CSC proliferation. Here we show that under sphere-forming assay conditions, prostate cancer cells acquired CSC-like properties: promoted mitochondrial respiratory chain activity, expression of characteristic CSC markers and resistance to anticancer agents. Furthermore, those CSC-like properties could reversibly change depending on the culture conditions, suggesting some kinds of CSCs have plasticity in tumor microenvironments. The sphere-forming cells (i.e. cancer stem-like cells) showed increased contact between mitochondria and mitochondrial associated-endoplasmic reticulum (ER) membranes (MAM). Mitochondrial targeting doxycycline induced activating transcription factor 4 (ATF4) mediated expression of ER stress response and led to p53-upregulated modulator of apoptosis (PUMA)-dependent apoptosis only in the cancer stem-like cells. We also found that doxycycline effectively suppressed the sphere formation in vitro and blocked CD44v9-expressing tumor growth in vivo. In summary, these data provide new molecular findings that monolayer cancer cells acquire CSC-like properties in a reversible manner. These findings provide important insights into CSC biology and a potential new treatment of targeting mitochondria dependency.. |
| 185. |
M. Shiota, A. Yokomizo, Y. Tada, J. Inokuchi, E. Kashiwagi, D. Masubuchi, M. Eto, T. Uchiumi, S. Naito, Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression, Oncogene, 10.1038/onc.2009.322, 29, 2, 237-250, 2010.01, There are few successful therapies for castration-resistant prostate cancer (CRPC). Recently, CRPC has been thought to result from augmented androgen/androgen receptor (AR) signaling pathway, for most of which AR overexpression has been observed. In this study, Twist1, a member of basic helix-loop-helix transcription factors as well as AR was upregulated in response to hydrogen peroxide, and the response to which was abolished by an addition of N-acetyl-L-cysteine and Twist1 knockdown. In addition, castration-resistant LNCaP derivatives and hydrogen peroxide-resistant LNCaP derivatives exhibited a similar phenotype to each other. Then, both castration and AR knockdown increased intracellular reactive oxygen species level. Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance. Modulation of castration-induced oxidative stress or Twist1/AR signaling might be a useful strategy for developing a novel therapeutics in prostate cancer, even in CRPC, which remains dependent on AR signaling by overexpressing AR.. |
| 186. |
M. Shiota, H. Izumi, T. Onitsuka, N. Miyamoto, E. Kashiwagi, A. Kidani, G. Hirano, M. Takahashi, S. Naito, K. Kohno, Twist and p53 reciprocally regulate target genes via direct interaction, Oncogene, 10.1038/onc.2008.176, 27, 42, 5543-5553, 2008.09, Twist is basic helix-loop-helix transcription factor that binds to E-boxes in gene promoters. Twist possesses an oncogenic function by interfering with the tumor suppressor function of p53. Using a membrane pull-down assay, we found that Twist directly interacts with p53 and that this interaction underlies the inhibitory effects on p53 target gene expression. Twist interacted with the DNA-binding domain of p53 and suppressed the DNA-binding activity of p53. Transcriptional activation of the p21 promoter by p53 was significantly repressed by the expression of Twist. On the other hand, p53 interacted with the N-terminal domain of Twist and repressed Twist-dependent YB-1 promoter activity. Importantly, we found that p53-dependent growth suppression was canceled by the expression of either Twist or YB-1. Thus, our data suggest that Twist inhibits p53 function via a direct interaction with p53.. |
| 187. |
Masaki Shiota, Masatoshi Eto, Establishment of precision medicine in pharmacotherapy for castration-resistant prostate cancer, Nishinihon Journal of Urology, 81, 2, 155-160, 2019.04, Recently, several novel agents including abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223 have become available for the treatment of castration-resistant prostate cancer (CRPC) and as a result, prognosis has improved. However, the criteria for selection of a suitable therapy have not been established. Much research on the genome has been carried out to enable precision medicine to be applied in cases of CRPC. Among them, germline polymorphisms in genes involved in androgen metabolism, such as HSD3B1, have been supposed to be the critical determinants of therapeutic outcomes in hormone therapy. Moreover, somatic aberrations such as androgen receptor, DNA-repair genes and tumorsuppressor genes (PTEN, TP53 and RBI) are also expected to act as biomarkers for therapeutic selection in CRPC. We herein report the significance of genetic polymorphism and somatic gene aberration in pharmacotherapy for prostate cancer, and we also present the current status and future perspectives with regard to the development of novel therapeutics based on genome information.. |
| 188. |
Junichi Inokuchi, Ryo Namitome, Keijiro Kiyoshima, Ario Takeuchi, Masaki Shiota, Ryosuke Takahashi, Katsunori Tatsugami, Akira Yokomizo, Masatoshi Eto, External validation of preoperative nomograms predicting lymph node involvement in patients who underwent extended pelvic lymph node dissection during robot-assisted radical prostatectomy, Nishinihon Journal of Urology, 78, 9, 451-456, 2016.09, Objectives: To review the quality of our extended pelvic lymph node dissection (ePLND) and to evaluate the accuracy of preoperative nomograms predicting lymph node involvement (LNI) in patients who underwent ePLND during robot-assisted radical prostatectomy (RARP). Patients and methods: The study included 83 patients who underwent ePLND during RARP between November 2012 and May 2015. We performed ePLND in patients with T3 disease, DAmico high-risk disease, and in those where the risk of LNI was higher than 5% as estimated by the Japan PC Table. Preoperative and postoperative patient data were collected retrospectively. We carried out ROC analyses for external validation of preoperative LNI-predicting nomograms. Results: The median number of lymph nodes removed was 19. LNI was found in 15 of the 83 patients (18%). In the 15 patients with nodal metastasis, a total of 28 positive lymph nodes were detected, 30% of which were in the obturator area, 17% in the external iliac area and 48% in the internal iliac area. In the external validation of LNI prediction by preoperative nomograms using ROC analyses, AUC of the Briganti nomogram was 0.80 whereas that of the Japan PC Table was 0.68. Conclusions: The number of lymph nodes removed and lymph node positivity by ePLND during RARP in our institution were comparable to previous reports based on an open radical prostatectomy series. In this study, the Japan PC Table was inferior to the Briganti nomogram for prediction of LNI, and therefore the development of an updated nomogram for Japanese patients who undergo ePLND is required.. |
| 189. |
Masaki Shiota, Akira Yokomizo, Masatoshi Eto, Proper use of novel agents for castration-resistant prostate cancer, Nishinihon Journal of Urology, 78, 5, 221-228, 2016.05, Docetaxel is the only chemotherapy agent for castration-resistant prostate cancer (CRPC) that has been proven to prolong overall survival. In 2014, novel agents for CRPC including the CYP17 inhibitor, abiraterone, the antiandrogen agent, enzalutamide, and the taxane anticancer agent, cabazitaxel were also approved for use in Japan. These novel agents brought great advantages to both patients and physicians, but led to serious concerns as to how exactly these drugs should be used. There is no definitive answer as to how to use these agents with regard to proper sequence, proper patient selection, proper drug combination and proper administration timing. Accordingly, we utilize these agents sequentially based on a consensus set forward in guidelines, whilst considering some clinicopatholo- gical factors as well as the patient's condition and preferences. Several clinical trials have been on-going in an effort to obtain some answers to these problems, and these trials may reveal how to properly select a CRPC agent in the future. In addition, research into biomarkers for proper patient selection is being actively conducted, which may make it possible to select the mostbeneficial therapeutics based on information obtained from such biomarkers. In this review, we present the current status and future perspective on the proper use of therapeutic agents for CRPC.. |
| 190. |
Takashi Dejima, Takumi Adachi, Tomoko Maki, Hirofumi Obata, Kenjiro Imada, Masaki Shiota, Ario Takeuchi, Yoohyun Song, Ryosuke Takahashi, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Akira Yokomizo, Seiji Naito, Clinical statistics at the urological department of kyushu university hospital for the period 2012-2014, Nishinihon Journal of Urology, 78, 2, 88-93, 2016.02, A study of clinical statistics at our department for the period 2012-2014 revealed the following results: 1) The number of outpatients was 13, 785, including 3, 235 new patients (2, 406 males and 829 females). The most common diseases among the new patients were urogenital malignant tumor (43.1%), benign prostatic hyperplasia (12.0%), neurogenic bladder (7.7%), inflammatory disease (5.3%) and urogenital benign tumor (4.8 %). 2) The total number of inpatients was 2, 385 (2, 024 males and 361 females), and the majority of them comprised males aged 60-79 years. The main disease among the inpatients was urogenital neoplasm (67.7 96). 3) A total of 1, 357 cases underwent surgery, with 108 cases undergoing open surgery, 632 cases undergoing laparoscopic surgery and 556 cases undergoing endourological surgery, while 61 cases underwent ESWL and 54 cases underwent brachytherapy.. |
| 191. |
Yusuke Hayakawa, Keijiro Kiyoshima, Masaki Shiota, Ryosuke Takahashi, Junichi Inokuchi, Katsunori Tatsugami, Akira Yokomizo, Nephrogenic adenoma of the bladder
A report of 2 cases, Nishinihon Journal of Urology, 78, 2, 77-81, 2016.02, Nephrogenic adenoma is an uncommon, benign, tumor-like lesion within the urothelial mucosa of the urinary tract. To date, the etiology has been considered to be metaplastic change of the urothelial cells to renal tubular cells. The theory, however, that nephrogenic adenoma arises from implantation of renal tubular cells into the urinary bladder is the current focus of attention. Cystoscopic findings of nephrogenic adenoma often resemble those of urothelial carcinoma, and recurrence following transurethral resection has been reported. Accordingly, postoperative follow-up examinations are strongly recommended.. |
| 192. |
Masaki Shiota, Akira Yokomizo, Yoohyun Song, Ario Takeuchi, Kentaro Kuroiwa, Seiji Naito, Elucidating the mechanism behind prostate cancer progression resulting from oxidative stress and its application to the clinical setting, Nishinihon Journal of Urology, 75, 4, 164-169, 2013.04, Although it has been well known that oxidative stress promotes prostate carcinogenesis, the role of oxidative stress in the progression of prostate cancer, especially in castration-resistant progression, has remained obscure. Accordingly, we attempted to elucidate its mechanism and apply our findings to the clinical setting. To date we have been able to show that; (i) androgen-deprivation therapy induces oxidative stress in prostate cancer, and (ii) oxidative stress up-regulates the oncogenic transcription factors, Twistl and Y-box-binding protein-1 (YB-1), resulting in androgen receptor (AR) induction as well as activated AR signaling through the AR cofactor and intracellular signaling pathway, which contribute to castration-resistant progression. As regards application to the clinical setting, we have revealed promising results of antioxidant therapy as well as Twistl and YB-l-targeting therapies against prostate cancer combined with androgen-deprivation therapy. In conclusion, our results suggest that castration-resistant prostate cancer may be derived from pathways that activate invasion and metastasis by Twistl and resist cell death by YB-1, which can be reversed through the inhibition of these pathways.. |
| 193. |
Masaki Shiota, Akira Yokomizo, Yasuhiro Tada, Junichi Inokuchi, Seiji Naito, Oxidative stress and androgen receptor expression in castration-resistant prostate cancer, Nishinihon Journal of Urology, 72, 3, 97-102, 2010.03, There are few successful therapies for castration-resistant prostate cancer (CRPC). Recently, CRPC has been thought to result from augmentation of the androgen/androgen receptor (AR)-signaling pathway, with AR overexpression having been observed in most cases. In a previous study, we found that Twistl, a member of the basic helix-loop-helix transcription factors, regulated AR expression via binding to E-boxes within the AR promoter region. Twistl. which is known to be a stress-inducible factor, as well as AR, was upregulated in response to hydrogen peroxide. Furthermore, castration-resistant LNCaP derivatives and hydrogen peroxide-resistant LNCaP derivatives expressed high levels of both Twistl and AR, and they exhibited a castration-resistant phenotype, which was reversed by AR knockdown. Blockade of androgen/AR signaling by androgen deprivation and AR knockdown increased intracellular reactive oxygen species. Silencing of Twistl suppressed the cell growth of the LNCaP cells as well as the castration-resistant LNCaP derivatives by inducing cell-cycle arrest at the Gl phase and cellular apoptosis. These findings indicate that oxidative stress induced by castration may promote AR overexpression through Twistl overexpression, which could result in a gain of castration resistance. Modulation of castration-induced oxidative stress or Twistl/AR signaling may be a promising strategy for developing novel therapeutics in prostate cancer, even in cases of CRPC. Further intensive research in this field is essential in order to improve the outcome of therapy for advanced prostate cancer.. |
| 194. |
Masaki Shiota, Hideya Noma, Akito Yamaguchi, Shinji Kohno, Concordance of gleason score in prostate needle biopsy samples with radical prostatectomy specimen
Comparison of sextant needle biopsy and extended needle biopsy, Nishinihon Journal of Urology, 69, 4, 244-248, 2007.04, Since Gleason score is a major independent predictive factor of the outcome of prostate cancer treatment and prognosis, a correct evaluation of Gleason score is very important. We examined the concordance of Gleason score in prostate needle biopsy samples and the corresponding radical retropubic prostatectomy specimen. Radical prostatectomy was performed in 110 patients between January 2003 and February 2005. Diagnosis of prostate cancer was made in 68 cases by transrectal needle biopsy and in 42 cases by transperineal needle biopsy. Clinical characteristics were similar in the 2 groups. Gleason score of the biopsied sample was concordant with that of the prostatectomy specimen in 18 of the 67 cases (27%) and in 19 of the 42 cases (45%) for transrectal needle biopsy and transperineal needle biopsy, respectively. Transperineal needle biopsy (extended biopsy) increased the accuracy of the biopsy, with the Gleason score being more accurately evaluated with extended transperineal biopsy, compared to conventional sextant transrectal biopsy.. |
| 195. |
Masaki Shiota, Hideya Noma, Akito Yamaguchi, Radiotherapy for men with PSA failure following radical prostatectomy, Nishinihon Journal of Urology, 69, 3, 130-134, 2007.03, We evaluated the efficacy of salvage external beam radiotherapy (RT) to the prostate bed for men with prostate-specific antigen (PSA) failure following radical prostatectomy. Fourteen patients underwent RT for PSA failure following radical prostatectomy between 1999 and 2000. Median follow-up was 24 months. Median PSA level before RT was 0.51 ng/ml. Radiation dose was 60Gy or 61.4Gy. The 3-year actuarial biochemical disease-free survival (bDFS) rate was 40%. The biochemical effectiveness of RT was better in cases with a PSA level of less than 1 ng/ml compared to that in cases with a level higher than 1 ng/ml. The PSA level before RT and surgical margin involvement were identified as prognostic factors for bDFS. No patients experienced grade 3 toxicity. RT for PSA failure following radical prostatectomy seems to be very effective and was only slightly toxic during a limited follow-up period.. |
| 196. |
Masaki Shiota, Noriaki Tokuda, Takehiro Kanou, Daisuke Yokoo, Keisuke Taniguchi, Takashi Notomi, Tsunehiro Tsukahara, Masaharu Nanri, Ken Ichi Zinnouchi, Clinical study of prostatic cancers with a PSA level of more than 100 ng/ml at the first hospital visit, Nishinihon Journal of Urology, 69, 1, 1-5, 2007.01, We report the results of a clinical study of 77 patients with prostatic cancer who had a PSA level of more than 100 ng/ml at the first hospital visit between 2001 and 2005. The PSA levels ranged from 107 ng/ml to 14,455 ng/ml (median 301 ng/ml). Most of the patients had symptoms due to prostatic cancer, a high Gleason score and advanced clinical stage. Almost all the patients were treated with androgen deprivation therapy. However, many patients had PSA failure and their prognosis was poor, nevertheless, long-term PSA failure-free survival was achieved in some patients. We need to ascertain the precise prognostic marker to androgen deprivation therapy.. |
| 197. |
masaki shiota, Tetsuo Yasumasu, Masahiro Yoshikawa, Sclerosing lipogranuloma of the male genitalia
A case report, Nishinihon Journal of Urology, 65, 11, 644-646, 2003, We report a case of genital sclerosing lipogranuloma in a patient who had no history of foreign body infusion and no apparent reason for its development. The patient was a forty-one-year-old male who had a painless hard mass, which was Y-shaped, on the penile base in the scrotum. Partial tumor resection was performed for prevention of discomfort during penile erection, and to date there remains no evidence of re-growth, even though the patient received no antibiotics or anti-inflammatory agents.. |
| 198. |
Akira Yokomizo, Masaki Shiota, Molecular and anatomical mechanism of bone metastasis in prostate cancer, Nihon rinsho. Japanese journal of clinical medicine, 74, 145-148, 2016.05. |
| 199. |
Masaki Shiota, Akira Yokomizo, Prostate cancer and oxidative stress, Nihon rinsho. Japanese journal of clinical medicine, 74, 71-74, 2016.05. |
| 200. |
Seiji Naito, Masaki Shiota, The concept and mechanisms of castration-resistant prostate cancer, Nihon rinsho. Japanese journal of clinical medicine, 72, 12, 2090-2094, 2014.12, Castration-resistant prostate cancer (CRPC) is the term which has recently been raised instead of androgen-independent or hormone-refractory prostate cancer. CRPC is defined as the status of disease progression despite the serum testosterone level of castration ( |
| 201. |
Masaki Shiota, Akira Yokomizo, Seiji Naito, [The development of therapeutics targeting oxidative stress in prostate cancer], Nihon rinsho. Japanese journal of clinical medicine, 72, 12, 2131-2135, 2014.12, Oxidative stress is caused by increased reactive-oxygen species (ROS) due to augmented ROS production and impaired anti-oxidative capacity. Recently, oxidative stress has been revealed to promote castration resistance via androgen receptor(AR)-dependent pathway such as AR overexpression, AR cofactor, and AR post-translational modification as well as AR-independent pathway, leading to the emergence of castration-resistant prostate cancer (CRPC). Therefore, antioxidants therapy using natural and chemical ROS scavengers and inhibitors of ROS production seems to be a promising therapy for CRPC as well as preventing castration resistance. However, at present, the application to therapeutics is limited. Therefore, further research on oxidative stress in prostate cancer, as well as on the development for clinical application would be needed.. |
| 202. |
Masaki Shiota, Akira Yokomizo, Seiji Naito, Naohiro Fujimoto, [Alteration of androgen receptor cofactor in prostate cancer]., Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 5, 108-111, 2011.06. |
| 203. |
Naohiro Fujimoto, Tetsuro Matsumoto, Masaki Shiota, [Antiandrogen withdrawal syndrome]., Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 5, 481-484, 2011.06. |
| 204. |
Ario Takeuchi, Masaki Shiota, Katsunori Tatsugami, Akira Yokomizo, Shingo Tanaka, Kentaro Kuroiwa, Masatoshi Eto, Seiji Naito, p300 mediates cellular resistance to doxorubicin in bladder cancer, Molecular medicine reports, 10.3892/mmr.2011.593, 5, 1, 173-176, 2012.01, Bladder cancer is one of the most common urogenital malignancies. At the non-invasive stage, bladder cancer can be completely resected transurethrally. However, 70% of patients experience intravesical tumor recurrence within 5 years. Patients with advanced bladder cancer frequently receive a chemotherapy regimen containing doxorubicin. However, doxorubicin resistance is a major obstacle to cancer chemotherapy. Previously, we reported that the histone acetyltransferase p300/CBP-associated factor is involved in doxorubicin resistance in bladder cancer. However, the role of another histone acetyltransferase, p300, in bladder cancer resistance to doxorubicin remains unclear. In this study, we investigated the molecular mechanism of doxorubicin resistance in bladder cancer with regard to p300. The result showed that p300 expression was reduced in doxorubicin-resistant bladder cancer cells and in response to doxorubicin exposure. Furthermore, p300 suppression rendered bladder cancer cells resistant to doxorubicin. Taken together, the results from this study indicate that p300 may be a promising molecular therapeutic target through the modulation of cellular sensitivity to doxorubicin in bladder cancer.. |
| 205. |
Hidetoshi Kuruma, Hiroaki Matsumoto, Masaki Shiota, Jennifer Bishop, Francois Lamoureux, Christian Thomas, David Briere, Gerrit Los, Martin Gleave, Andrea Fanjul, Amina Zoubeidi, A novel antiandrogen, compound 30, suppresses castration-resistant and MDV3100-resistant prostate cancer growth In Vitro and In Vivo, Molecular cancer therapeutics, 10.1158/1535-7163.MCT-12-0798, 12, 5, 567-576, 2013.05, Resistance to antiandrogen drugs, like MDV3100, occurs in patients with castration-resistant prostate cancer (CRPC). Thus, preventing or treating antiandrogen resistance is a major clinical challenge. We identified a novel antiandrogen, Compound 30, and compared its efficacy with MDV3100. We found that Compound 30 inhibits androgen receptor (AR) activity in LNCaP cells, C4-2 cells, as well as MDV3100-resistant cell lines. Compared with MDV3100, Compound 30 treatment induces greater reduction in AR, prostate-specific antigen (PSA), and AR transcriptional activity, and prevents AR nuclear translocation in AR-sensitive LNCaP cells. Compound 30 has antiproliferative effects in LNCaP cells, in castrate-resistant C4-2 cells, and those resistant to MDV3100. Compound 30 was equally as effective as MDV3100 in reducing tumor volume and PSA in vivo. More importantly, Compound 30 is effective at inhibiting AR activity in MDV3100-resistant cell lines and significantly prevented tumor growth and PSA increases in mice bearing MDV3100-resistant xenografts. Together, our data show that Compound 30 strongly inhibited AR activity and suppressed castration-resistant LNCaP growth as well as MDV3100-resistant cell growth in vitro and in vivo. These data provide a preclinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of antiandrogen-resistant tumors.. |
| 206. |
Masafumi Kumano, Junya Furukawa, Masaki Shiota, Anousheh Zardan, Fan Zhang, Eliana Beraldi, Romina M. Wiedmann, Ladan Fazli, Amina Zoubeidi, Martin E. Gleave, Cotargeting stress-activated Hsp27 and autophagy as a combinatorial strategy to amplify endoplasmic reticular stress in prostate cancer, Molecular cancer therapeutics, 10.1158/1535-7163.MCT-12-0072, 11, 8, 1661-1671, 2012.08, Hsp27 is a stress-activated multifunctional chaperone that inhibits treatment-induced apoptosis and causes treatment resistance in prostate and other cancers. We previously showed that targeted suppression of Hsp27 sensitizes cancer cells to hormone and chemotherapy. However, mechanisms by which Hsp27 confers cell treatment resistance are incompletely defined. Here, we report that Hsp27 protects human prostate cancer cells against proteotoxic stress induced by proteasome inhibition, and that Hsp27 silencing using siRNA or antisense (OGX-427) induced both apoptosis and autophagy through mechanisms involving reduced proteasome activity and induction of endoplasmic reticulum (ER) stress. We found that autophagy activation protected against ER stress-induced cell death, whereas inhibition of autophagy activation following Hsp27 silencing using either pharmacologic inhibitors or atg3 silencing enhanced cell death. Importantly, cotargeting Hsp27 and autophagy by combining OGX-427 with the autophagy inhibitor, chloroquine, significantly delayed PC-3 prostate tumor growth in vivo. These findings identify autophagy as a cytoprotective, stress-induced adaptive pathway, activated following disruption of protein homeostasis and ER stress induced by Hsp27 silencing. Combinatorial cotargeting cytoprotective Hsp27 and autophagy illustrates potential benefits of blocking activation of adaptive pathways to improve treatment outcomes in cancer.. |
| 207. |
Ario Takeuchi, Masaki Shiota, Eliana Beraldi, Daksh Thaper, Kiyoshi Takahara, Naokazu Ibuki, Michael Pollak, Michael E. Cox, Seiji Naito, Martin E. Gleave, Amina Zoubeidi, Insulin-like growth factor-I induces CLU expression through Twist1 to promote prostate cancer growth, Molecular and Cellular Endocrinology, 10.1016/j.mce.2014.01.012, 384, 1-2, 117-125, 2014.03, Clusterin (CLU) is cytoprotective molecular chaperone that is highly expressed in castrate-resistant prostate cancer (CRPC). CRPC is also characterized by increased insulin-like growth factor (IGF)-I responsiveness which induces prostate cancer survival and CLU expression. However, how IGF-I induces CLU expression and whether CLU is required for IGF-mediated growth signaling remain unknown. Here we show that IGF-I induced CLU via STAT3-Twist1 signaling pathway. In response to IGF-I, STAT3 was phosphorylated, translocated to the nucleus and bound to the Twist1 promoter to activate Twist1 transcription. In turn, Twist1 bound to E-boxes on the CLU promoter and activated CLU transcription. Inversely, we demonstrated that knocking down Twist1 abrogated IGF-I induced CLU expression, indicating that Twist1 mediated IGF-I-induced CLU expression. When PTEN knockout mice were crossed with lit/. lit mice, the resultant IGF-I deficiency suppressed Twist1 as well as CLU gene expression in mouse prostate glands. Moreover, both Twist1 and CLU knockdown suppressed prostate cancer growth accelerated by IGF-I, suggesting the relevance of this signaling not only in an in vitro, but also in an in vivo. Collectively, this study indicates that IGF-I induces CLU expression through sequential activation of STAT3 and Twist1, and suggests that this signaling cascade plays a critical role in prostate cancer pathogenesis.. |
| 208. |
Masaki Shiota, Akira Yokomizo, Yasuhiro Tada, Junichi Inokuchi, Katsunori Tatsugami, Kentaro Kuroiwa, Takeshi Uchiumi, Naohiro Fujimoto, Narihito Seki, Seiji Naito, Peroxisome proliferator-activated receptor γ coactivator-1α interacts with the androgen receptor (AR) and promotes prostate cancer cell growth by activating the AR, Molecular Endocrinology, 10.1210/me.2009-0302, 24, 1, 114-127, 2010.01, There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was found to be an AR cofactor. PGC-1α interacted with the N-terminal domain of AR, was involved in the N- and C-terminal interaction of AR, and enhanced the DNA-binding ability of AR to androgen-responsive elements in the prostate-specific antigen enhancer and promoter regions to increase the transcription of AR target genes. Silencing of PGC-1α suppressed cell growth of AR-expressing prostate cancer (PCa) cells by inducing cell-cycle arrest at the G1 phase, similar to inhibition of androgen/AR signaling. Furthermore, PGC-1α knock-down also suppressed cell growth in the castration-resistant LNCaP-derivatives. These findings indicate that PGC-1α is involved in the proliferation of AR-expressing PCa cells by acting as an AR coactivator. Modulation of PGC-1α expression or function may offer a useful strategy for developing novel therapeutics for PCa, including CRPC, which depends on AR signaling by over-expressing AR and its coactivators.. |
| 209. |
Masaki Shiota, Amina Zoubeidi, Masafumi Kumano, Eliana Beraldi, Seiji Naito, Colleen C. Nelson, Poul H.B. Sorensen, Martin E. Gleave, Clusterin is a critical downstream mediator of stress-induced YB-1 transactivation in prostate cancer, Molecular Cancer Research, 10.1158/1541-7786.MCR-11-0379, 9, 12, 1755-1766, 2011.12, Clusterin is a stress-activated, cytoprotective chaperone that confers broad-spectrum treatment resistance in cancer. However, the molecular mechanisms mediating CLU transcription following anticancer treatment stress remain incompletely defined. We report that Y-box binding protein-1 (YB-1) directly binds to CLU promoter regions to transcriptionally regulate clusterin expression. In response to endoplasmic reticulum stress inducers, including paclitaxel, YB-1 is translocated to the nucleus to transactivate clusterin. Furthermore, higher levels of activated YB-1 and clusterin are seen in taxane-resistant, compared with parental, prostate cancer cells. Knockdown of either YB-1 or clusterin sensitized prostate cancer cells to paclitaxel, whereas their overexpression increased resistance to taxane. Clusterin overexpression rescued cells from increased paclitaxel induced apoptosis following YB-1 knockdown; in contrast, however, YB-1 over expression did not rescue cells from increased paclitaxel-induced apoptosis following clusterin knockdown. Collectively, these data indicate that YB-1 transactivation of clusterin in response to stress is a critical mediator of paclitaxel resistance in prostate cancer.. |
| 210. |
Akitake M, Kiyoshima K, Yokomizo A, Shiga K, Koga H, Takeuchi A, Shiota M, Inokuchi J, Tatsugami K, Yamaguchi A, Eto M:, A rational risk assessment for intravesical recurrence in primary low-grade Ta bladder cancer: A retrospective analysis of 245 cases., Mol Clin Oncol , 8 (6): 785-790, 2018, 2018.06. |
| 211. |
Murakami T, Otsubo S, Namitome R, Shiota M, Inokuchi J, Takeuchi A, Kashiwagi E, Tatsugami K, Eto M:, Clinical factors affecting perioperative outcomes in robot-assisted radical prostatectomy., Mol Clin Oncol , 9 (5): 575-581, 2018, 2018.11. |
| 212. |
Yoo Hyun Song, Masaki Shiota, Kentaro Kuroiwa, Seiji Naito, Yoshinao Oda, The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer, Modern Pathology, 10.1038/modpathol.2011.76, 24, 9, 1272-1280, 2011.09, Glycine N-methyltransferase (GNMT) has a role in the metabolism of methionine as well as in gluconeogenesis. It has recently been reported that the GNMT gene acts as a tumor-susceptible gene. However, little is known about the specific function of GNMT in carcinogenesis and malignant progression. To better our understanding of the function of GNMT in prostate cancer, we used siRNAs to examine the effects of GNMT knockdown on cell proliferation and the cell cycle. In addition, the relation between immunohistochemical GNMT expression and clinicopathologic parameters was investigated in 148 prostate cancer tissues. Here, we show that siRNA-mediated GNMT knockdown results in an inhibition of proliferation, and induces G1 arrest and apoptosis in prostate cancer cell lines. Moreover, high cytoplasmic GNMT expression was also correlated with a higher Gleason score (P |
| 213. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Efficacy and safety of cabazitaxel for castration-resistant prostate cancer in patients with > 10 cycles of docetaxel chemotherapy
a multi-institutional study, Medical Oncology, 10.1007/s12032-019-1257-1, 36, 4, 2019.04, This multi-institutional study aimed to investigate the efficacy and safety profiles of cabazitaxel after prior docetaxel chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 63 Japanese patients with CRPC who were treated with cabazitaxel from 2014 to 2017. The oncological outcomes and adverse events (AEs) were documented, and prognostic factors for oncological outcomes and predictive factors for AEs were analysed. PSA decline was observed in 68.3% of patients, including 25.4% who achieved a ≥ 50% decline. The median progression-free survival, treatment failure-free survival, and overall survival were 4.3, 4.1, and 9.0 months, respectively. More cycles of prior docetaxel therapy was identified as common favourable prognostic factors for progression-free survival, treatment failure-free survival, and overall survival. Severe neutropenia, febrile neutropenia, and severe non-haematological AEs were observed in 73.0%, 33.3%, and 23.8% of patients, respectively. However, > 10 cycles of docetaxel was not associated with increased incidence of AEs. In conclusion, cabazitaxel chemotherapy was still active in Japanese CRPC patients treated with > 10 cycles of docetaxel chemotherapy, with an acceptable risk of AE burden. Treatment with cabazitaxel after > 10 cycles of docetaxel may be an appropriate option when it can be administered.. |
| 214. |
Tomoko Maki, Shunichi Kajioka, Momoe Itsumi, Eljamal Kareman, Ken Lee, Masaki Shiota, Masatoshi Eto, Mirabegron induces relaxant effects via cAMP signaling-dependent and -independent pathways in detrusor smooth muscle, LUTS: Lower Urinary Tract Symptoms, 10.1111/luts.12247, 11, 2, O209-O217, 2019.04, Objective: We previously found that mirabegron exerts a relaxant effect in the presence of the β 3 -adrenoceptor antagonist SR58894A during carbachol-induced contraction in human and pig detrusor. The aim of this study was to explore the possible mechanism underlying the relaxant effects of mirabegron using detrusor smooth muscle. Methods: Human tissue was obtained from urinary bladders of patients undergoing radical cystectomy at Kyushu University and Harasanshin Hospital. Pig tissue was obtained from an abattoir. Tension force (organ bath experiments) was measured in intact or permeabilised (α-toxin or β-escin) detrusor smooth muscle strips. The contribution of cAMP-dependent signaling and the inhibition of Ca 2+ sensitization to the relaxant effects of mirabegron were characterized using 1 μM SR58894A, 100 μM SQ22536 (an adenylyl cyclase inhibitor), 10 μM H-89 (a protein kinase [PK] A inhibitor), 10 μM Y-27632 (a selective Rho kinase inhibitor), and 10 μM GF-109203X (a selective PKC inhibitor). Results: 30 μM Mirabegron impaired carbachol (0.03-1 μM)-induced contraction in human detrusor smooth muscle. SR58894A only partially attenuated the relaxant effects of mirabegron in human and pig detrusor strips precontracted with 1 μM carbachol. In α-toxin-permeabilized detrusor strips, tension force at 1 μM [Ca 2+ ] i was decreased by mirabegron in a concentration-dependent manner. The relaxant effect of mirabegron was only slightly attenuated by H-89 and not significantly affected by SQ22536. Y-27632 potentiated the relaxation response to mirabegron, but attenuated responses to cAMP; GF-109203X had little effect. Mirabegron but not cAMP had a notable relaxant effect in the pig detrusor smooth muscle permeabilized with β-escin. Conclusions: Mirabegron-induced relaxation of pig and human detrusor smooth muscle occurs via both a β 3 -adrenoceptor/cAMP-dependent and -independent pathway.. |
| 215. |
Masaki Shiota, Naohiro Fujimoto, Ario Takeuchi, Eiji Kashiwagi, Takashi Dejima, Junichi Inokuchi, Katsunori Tatsugami, Akira Yokomizo, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto, The Association of Polymorphisms in the Gene Encoding Gonadotropin-Releasing Hormone with Serum Testosterone Level during Androgen Deprivation Therapy and Prognosis of Metastatic Prostate Cancer, Journal of Urology, 10.1016/j.juro.2017.09.076, 199, 3, 734-740, 2018.03, Purpose: Serum testosterone suppression during androgen deprivation therapy has been reported to affect the efficacy of androgen deprivation therapy. However, the factors impacting hormonal variations during androgen deprivation therapy remain unclear. Therefore, in this study we investigated the significance of missense polymorphisms in the gene encoding GNRH in men treated with primary androgen deprivation therapy for metastatic prostate cancer. Materials and Methods: This study included 80 Japanese patients with metastatic prostate cancer with available serum testosterone levels during androgen deprivation therapy. We examined the association of GNRH1 (rs6185, S20W) and GNRH2 (rs6051545, A16V) gene polymorphisms with clinicopathological parameters, including serum testosterone levels during androgen deprivation therapy, as well as prognosis, including progression-free and overall survival. Results: The CT and CT/TT alleles in the GNRH2 gene (rs6051545) were associated with higher serum testosterone during androgen deprivation therapy compared with those of the CC allele. Consequently the CT alleles were associated with a higher risk of progression after adjustment for age and serum testosterone during androgen deprivation therapy (HR 1.73, 95% CI 1.00–3.00, p = 0.049). Conclusions: Taken together these findings suggest that rs6051545 (GNRH2) genetic variation may result in inadequate suppression of serum testosterone during androgen deprivation therapy. This may lead to detrimental effects of androgen deprivation therapy on prognosis in men with metastatic prostate cancer.. |
| 216. |
Masaki Shiota, Keijiro Kiyoshima, Akira Yokomizo, Ario Takeuchi, Eiji Kashiwagi, Takashi Dejima, Ryosuke Takahashi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Suppressed Recurrent Bladder Cancer after Androgen Suppression with Androgen Deprivation Therapy or 5α-Reductase Inhibitor, Journal of Urology, 10.1016/j.juro.2016.08.006, 197, 2, 308-313, 2017.02, Purpose We determined whether intravesical recurrence is affected by inhibition of androgen signaling among men with nonmuscle invasive bladder cancer. Materials and Methods We examined the intravesical recurrence rate among men treated with or without androgen suppression therapy by androgen deprivation therapy for prostate cancer or 5α-reductase inhibitor dutasteride for benign prostatic hyperplasia. Results We studied 228 men, including 32 with and 196 without androgen suppression therapy. During a median followup of 3.6 and 3.0 years intravesical recurrence developed in 4 (12.5%) and 59 men (30.1%) with and without androgen suppression therapy, respectively. On multivariate analysis multiple tumors (HR 1.82, p = 0.027), a large tumor (HR 2.13, p = 0.043) and ever smoking (HR 2.45, p = 0.020) as well as the presence of androgen suppression therapy (HR 0.36, p = 0.024) were independent risk factors for intravesical recurrence. Notably, tumor progressed to muscle invasive bladder cancer in 6 men (3.1%) without androgen suppression therapy. No man with androgen suppression therapy progressed to muscle invasive bladder cancer. Conclusions Our study suggests the possibility of androgen suppression therapy as prophylaxis for intravesical recurrence of bladder cancer. Further explorations are warranted of the prophylactic effect of androgen suppression therapy on bladder cancer pathogenesis.. |
| 217. |
Masaki Shiota, Ario Takeuchi, Akira Yokomizo, Eiji Kashiwagi, Katsunori Tatsugami, Kentaro Kuroiwa, Seiji Naito, Androgen receptor signaling regulates cell growth and vulnerability to doxorubicin in bladder cancer, Journal of Urology, 10.1016/j.juro.2012.02.2554, 188, 1, 276-286, 2012.07, Purpose: There are several reports of androgen receptor in bladder cancer cases but androgen receptor expression and the function of androgen/androgen receptor signaling in bladder cancer remain unclear. We investigated androgen receptor expression and the role of androgen/androgen receptor signaling in bladder cancer. Materials and Methods: We evaluated AR mRNA expression in bladder cancer tissue by quantitative real-time polymerase chain reaction. The role of androgen receptor in cell growth and drug sensitivity was also evaluated in vitro and in vivo in several bladder cancer cell lines. Results: AR mRNA expression inversely correlated with bladder cancer grade, stage and spread. Of several bladder cancer cell lines UMUC3 and MBT-2 markedly expressed androgen receptor transcript and protein. In each cell line androgen/androgen receptor signaling blockade using androgen deprivation, blockade knockdown and antiandrogen agents decreased cell growth, colony formation and cell viability. Androgen receptor expression was implicated in doxorubicin resistance. Inversely androgen receptor deprivation and knockdown made UMUC3 cells sensitive to doxorubicin. Finally, castration slightly suppressed UMUC3 tumor growth in vivo, although this did not attain statistical significance. Conclusions: AR transcript expression inversely correlates with bladder cancer clinicopathological characteristics. Androgen/androgen receptor signaling has an important role in the growth and vulnerability to doxorubicin of bladder cancer cells that express androgen receptor. Androgen/androgen receptor signaling might be a possible prophylactic and therapeutic target for bladder cancer that shows androgen receptor expression.. |
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Masaki Shiota, Ario Takeuchi, Akira Yokomizo, Eiji Kashiwagi, Katsunori Tatsugami, Seiji Naito, Methyltransferase inhibitor adenosine dialdehyde suppresses androgen receptor expression and prostate cancer growth, Journal of Urology, 10.1016/j.juro.2012.02.2553, 188, 1, 300-306, 2012.07, Purpose: Although most prostate cancers regress after androgen deprivation therapy is given at diagnosis, they eventually regrow in a castration resistant manner, spread systemically and end fatally. Thus, novel therapeutic compounds are needed for prostate cancer. We previously reported that methylation at histone H3 lysine 9 was increased in prostate cancer. In this study we examined the effects of the methyltransferase inhibitor adenosine dialdehyde (Sigma®) on the methylation state of histone H3 lysine 9 and AR gene expression as well as its possible usefulness for prostate cancer. Materials and Methods: The effect of adenosine dialdehyde on the methylation state of histone H3 lysine 9 and AR gene expression was examined by quantitative real-time polymerase chain reaction and Western blot. We compared methylation at histone H3 lysine 9 at the AR promoter region between androgen dependent and castration resistant prostate cancer by chromatin immunoprecipitation assay. The cytotoxic effect of adenosine dialdehyde on prostate cancer was also evaluated in vitro and in vivo. Results: Adenosine dialdehyde suppressed the monomethylation and dimethylation of histone H3 lysine 9 and inhibited Twist1 as well as androgen receptor expression, which are critical for the survival and growth of androgen dependent, androgen sensitive and castration resistant prostate cancer cells in which monomethylated histone H3 lysine 9 increased at the 5′ untranslated region of the AR gene. As a result, adenosine dialdehyde had a cytotoxic effect on androgen dependent, androgen sensitive and castration resistant prostate cancer cells in vitro. Adenosine dialdehyde also suppressed prostate cancer growth in vivo in a mouse xenograft model. Conclusions: Results indicate that the methyltransferase inhibitor adenosine dialdehyde is a promising, novel therapeutic compound for prostate cancer.. |
| 219. |
Masaki Shiota, Yoohyun Song, Ario Takeuchi, Akira Yokomizo, Eiji Kashiwagi, Kentaro Kuroiwa, Katsunori Tatsugami, Takeshi Uchiumi, Yoshinao Oda, Seiji Naito, Antioxidant therapy alleviates oxidative stress by androgen deprivation and prevents conversion from androgen dependent to castration resistant prostate cancer, Journal of Urology, 10.1016/j.juro.2011.09.147, 187, 2, 707-714, 2012.02, Prostate cancer progression from androgen dependence to castration resistance results at least in part from oxidative stress induced by androgen deprivation therapy. We elucidated the state and the role of oxidative stress induced by androgen deprivation therapy and the possibility of antioxidant therapy in human prostate cancer. We investigated 4-HNE (4-hydroxy-2-nonenal histidine adduct) staining, and Twist1, YB-1 and androgen receptor expression by immunohistochemistry in prostate cancer samples treated with or without neoadjuvant androgen deprivation therapy. Intracellular reactive oxygen species and protein expression were examined by CM-H 2DCFDA and Western blot analysis, respectively. A cell proliferation assay and a mouse xenograft model were used to assess tumor growth. Androgen deprivation therapy increased oxidative stress, as shown by 4-HNE staining in human prostate cancer tissue. Twist1 and YB-1 expression was up-regulated by androgen deprivation, resulting in androgen receptor over expression. In LNCaP and 22Rv1 cells androgen deprivation increased intracellular reactive oxygen species and evoked Twist1, YB-1 and androgen receptor over expression, resulting in cell growth in a castration resistant manner. Growth was alleviated by N-acetyl-cysteine, an electrophile that supports glutathione production. N-acetyl-cysteine also decreased LNCaP and 22Rv1 tumor growth in castrated and noncastrated mice. Androgen deprivation therapy induced oxidative stress in in vitro and human prostate cancer. Antioxidant therapy using N-acetyl-cysteine appears to be a promising therapeutic modality for prostate cancer.. |
| 220. |
Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Kenjiro Imada, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Seiji Naito, The feature of metabolic syndrome is a risk factor for biochemical recurrence after radical prostatectomy, Journal of Surgical Oncology, 10.1002/jso.23677, 110, 4, 476-481, 2014.09, Background and Objective To examine the association between the features of metabolic syndrome (MetS) (obesity, hypertension, diabetes mellitus, and dyslipidemia) and the risk of biochemical recurrence (BCR) after radical prostatectomy in patients with prostate cancer. Methods This study included 283 Japanese patients with localized prostate cancer who were treated with radical prostatectomy between 2008 and 2012. Their oncological outcomes and the prognostic significance of several clinicopathological factors, as well as the features of MetS, were analyzed. Results Of 283 men who underwent radical prostatectomy, 49 (17.2%) subsequently developed BCR with a median postoperative follow-up of 14.8 months. Among the clinicopathological factors, prostate-specific antigen (PSA) level at diagnosis, pathological stage, pathological Gleason score, and lymph-node involvement were independent risk factors for BCR in multivariate analysis. In addition, the number of metabolic risk factors was also an independent risk factor for BCR. Conclusions The features of MetS were linked with poorer outcome after radical prostatectomy among Japanese men. Further investigations are needed to determine the effect of improving MetS on prostate cancer prognosis.. |
| 221. |
Masaki Shiota, Noriaki Tokuda, Takehiro Kanou, Humio Yamasaki, Injection-site granulomas resulting from the administration of both leuprorelin acetate and goserelin acetate for the treatment of prostatic cancer, Journal of Nippon Medical School, 10.1272/jnms.74.306, 74, 4, 306-308, 2007.08, Although injection-site granulomas caused by leuprorelin acetate have been reported, there have been no reports of granulomas caused by both leuprorelin acetate and goserelin acetate. An 81-year-old man presented with subcutaneous nodules of the abdominal wall and upper arm, where 11.25 mg of leuprorelin acetate had been injected for the treatment of prostate cancer. Because of these nodules, treatment was changed to goserelin acetate. Nevertheless, he presented with another subcutaneous nodule at the injection site. Histological examination showed that these nodules consisted of numerous giant cells that were CD3-positive T lymphocytes and CD68-positive histiocytes associated with granulomatous changes. The granulomas had likely been caused by delayed-type hypersensitivity to leuprorelin acetate injection. The granuloma that formed after goserelin acetate injection might thus have developed owing to the immunogenicity of the previous leuprorelin acetate injections. The patient underwent surgical castration. The present case suggests that both leuprorelin acetate and goserelin acetate can cause injection-site disorders.. |
| 222. |
Momoe Itsumi, Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Eiji Kashiwagi, Takashi Dejima, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito, PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells, Journal of Molecular Endocrinology, 10.1530/JME-13-0303, 53, 1, 31-41, 2014.04, Phorbol 12-myristate 13-acetate (PMA) induces cellular apoptosis in prostate cancer cells, the growth of which is governed by androgen/androgen receptor (AR) signaling, but the mechanism by which PMA exerts this effect remains unknown. Therefore, in this study, we investigated the mechanistic action of PMA in prostate cancer cells with regard to AR. We showed that PMA decreased E2F1 as well as AR expression in androgen-dependent prostate cancer LNCaP cells. Furthermore, PMA activated JNK and p53 signaling, resulting in the induction of cellular apoptosis. In LNCaP cells, androgen deprivation and a novel anti-androgen enzalutamide (MDV3100) augmented cellular apoptosis induced by PMA. Moreover, castration-resistant prostate cancer (CRPC) C4-2 cells were more sensitive to PMA compared with LNCaP cells and were sensitized to PMA by enzalutamide. Finally, the expression of PKC, E2F1, and AR was diminished in PMA-resistant cells, indicating that the gain of independence from PKC, E2F1, and AR functions leads to PMA resistance. In conclusion, PMA exerted its anti-cancer effects via the activation of pro-apoptotic JNK/p53 and inhibition of pro-proliferative E2F1/AR in prostate cancer cells including CRPC cells. The therapeutic effects of PMA were augmented by androgen deletion and enzalutamide in androgen-dependent prostate cancer cells, as well as by enzalutamide in castrationresistant cells. Taken together, PMA derivatives may be promising therapeutic agents for treating prostate cancer patients including CRPC patients.. |
| 223. |
Masaki Shiota, Akira Yokomizo, Seiji Naito, Increased androgen receptor transcription
A cause of castration-resistant prostate cancer and a possible therapeutic target, Journal of Molecular Endocrinology, 10.1530/JME-11-0018, 47, 1, R25-R41, 2011.08, Few effective therapies exist for the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC may be caused by augmented androgen/androgen receptor (AR) signaling, generally involving AR overexpression. Aberrant androgen/AR signaling associated with AR overexpression also plays a key role in prostate carcinogenesis. Although AR overexpression could be attributed to gene amplification, only 10-20% of CRPCs exhibit AR gene amplification, and aberrant AR expression in the remaining instances of CRPC is thought to be attributed to transcriptional, translational, and post-translational mechanisms. Overexpression of AR at the protein level, as well as the mRNA level, has been found in CRPC, suggesting a key role for transcriptional regulation of AR expression. Since the analysis of the AR promoter region in the 1990s, several transcription factors have been reported to regulate AR transcription. In this review, we discuss the molecules involved in the control of AR gene expression, with emphasis on its transcriptional control by transcription factors in prostate cancer. We also consider the therapeutic potential of targeting AR expression.. |
| 224. |
Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Kenjiro Imada, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Seiji Naito, The oncological outcome and validation of Japan Cancer of the Prostate Risk Assessment score among men treated with primary androgen-deprivation therapy, Journal of Cancer Research and Clinical Oncology, 10.1007/s00432-014-1828-7, 141, 3, 495-503, 2014, Purpose: Although androgen-deprivation therapy (ADT) for prostate cancer is initially effective, most tumors eventually recur even during ADT. To predict their prognosis, the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score was developed. However, there is no validation of this model using data from a single institution. Therefore, in this study, we clarified the oncological outcome of primary ADT and its prognostic factors, as well as validated the J-CAPRA score model in our institution.
Methods: This study included 248 Japanese patients with hormone-naïve prostate cancer who were treated with primary ADT from 1996 through 2012. The oncological outcome and prognostic significance of several clinicopathological factors were analyzed. Also, J-CAPRA risk stratification model was validated in this cohort.
Results: During a median follow-up period of 42.2 months, the median progression-free survival (PFS) and overall survival (OS) were 89.3 and 103.3 months, respectively. Multivariate analysis identified clinical T-stage and M-stage for PFS and cancer-specific survival (CSS) and clinical M-stage for OS as significant predictors. The accuracy of J-CAPRA score model for predicting PFS, CSS, and OS was validated by high c-indices.
Conclusions: This study demonstrated the use of the J-CAPRA score system for predicting PFS, CSS, and OS among Japanese men treated with primary ADT in a single institution.. |
| 225. |
Rie Amamoto, Takeshi Uchiumi, Mikako Yagi, Keisuke Monji, Yoo Hyun Song, Yoshinao Oda, Masaki Shiota, Akira Yokomizo, Seiji Naito, Dongchon Kang, The expression of ubiquitous mitochondrial creatine kinase is downregulated as prostate cancer progressionz, Journal of Cancer, 10.7150/jca.13207, 7, 1, 50-59, 2016, Background: Mitochondria play crucial roles in cell signaling events, interorganellar communication, aging, cell proliferation and apoptosis, and mitochondrial impairment has been shown to accelerate or modulate cancer progression. Ubiquitous mitochondrial creatine kinase (uMtCK) is predominantly localized in the intermembrane space of mitochondria and catalyzes the reversible exchange of high-energy phosphate between adenosine tri-phosphate (ATP) and phosphocreatine. However, little is known about its expression and function in human prostate cancer progression. Method: We investigated the expression of uMtCK in 148 prostate carcinoma tissues and matched normal tissue by immunohistochemistry. The expression and localization of uMtCK and hexokinase II, a marker of glycolysis, were examined in prostate carcinoma cell lines using western blot and immunofluorescence. Results: MtCK expression was significantly lower in high Gleason grade carcinoma compared with normal prostate or low grade carcinoma. Western blot further revealed that uMtCK was highly expressed in LNCaP and 22Rv1 cell lines, as well as in the normal prostate cell line RWPE-1. However, uMtCK expression was almost absent in PC3 and DU145 cell lines, in correlation with absent or mutant p53 expression, respectively. In contrast, hexokinase II was overexpressed in PC3 cells. Moreover, in the low uMtCK expressing cell lines, glycolytic ATP production was increased, whereas mitochondrial ATP production was decreased. Conclusions: These data suggest that uMtCK is downregulated as prostate cancer progresses in correlation with a metabolic switch in ATP usage.. |
| 226. |
Naoya Miyamoto, Hiroto Izumi, Takako Noguchi, Yoshihiro Nakajima, Yoshihiro Ohmiya, Masaki Shiota, Akihiko Kidani, Akihiko Tawara, Kimitoshi Kohno, Tip60 is regulated by circadian transcription factor clock and is involved in cisplatin resistance, Journal of Biological Chemistry, 10.1074/jbc.M802332200, 283, 26, 18218-18226, 2008.06, Histone modification is important for maintaining chromatin structure and function. Recently, histone acetylation has been shown to have a critical regulatory role in both transcription and DNA repair. We report here that expression of histone acetyltransferase (HAT) genes is associated with cisplatin resistance. We found that Tip60 is overexpressed in cisplatin-resistant cells. The expression of two other HAT genes, HAT1 and MYST1, did not differ between drug-sensitive and -resistant cells. Knockdown of Tip60 expression rendered cells sensitive to cisplatin but not to oxaliplatin, vincristine, and etoposide. Tip 60 expression is significantly correlated with cisplatin sensitivity in human lung cancer cell lines. Interestingly, the promoter region of the Tip60 gene contains several E boxes, and its expression was regulated by the E-box binding circadian transcription factor Clock but not by other E-box binding transcription factors such as c-Myc, Twist, and USF1. Hyperacetylation of H3K14 and H4K16 was found in cisplatin-resistant cells. The microarray study reveals that several genes for DNA repair are down-regulated by the knockdown of Tip60 expression. Our data show that HAT gene expression is required for cisplatin resistance and suggest that Clock and Tip60 regulate not only transcription, but also DNA repair, through periodic histone acetylation.. |
| 227. |
Nobuaki Sato, Masaki Shiota, Ken ichiro Shiga, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Akira Yokomizo, Hirofumi Koga, Akito Yamaguchi, Seiji Naito, Masatoshi Eto, Smoking effect on oncological outcome among men with prostate cancer after radical prostatectomy, Japanese journal of clinical oncology, 10.1093/jjco/hyx013, 47, 5, 453-457, 2017.05, Objective: To analyze the association between smoking and oncological outcome after radical prostatectomy in patients with prostate cancer.Methods: This study included men who underwent radical prostatectomy between 2003 and 2013. The association of clinicopathological factors with smoking status and the prognostic significance of clinicopathological factors and smoking status on biochemical recurrence (BCR) were evaluated.Results: Of the 1165 included patients, 226 (19.4%) were current smokers and 939 (80.6%) were nonsmokers. The median observation period was 39 months (interquartile range, 15-75 months). Current smokers were younger than nonsmokers and had higher PSA levels, higher biopsy and pathological Gleason scores, and more frequent lymph-node involvement than nonsmokers. Pathological Gleason score, extracapsular extension, seminal vesicle invasion, positive surgical margin, lymph-node involvement, and current smoking (hazard ratio [95% confidence interval]; 1.31 [1.00-1.72], P = 0.046) were identified as significant risk factors of BCR on univariate analysis. However, smoking status was not an independent predictive marker on multivariate analysis.Conclusions: Current smokers had adverse clinicopathological characteristics including high PSA level, high Gleason score, and lymph node involvement, suggesting that smoking promoted the progression of prostate cancer.. |
| 228. |
Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Saiji Ohga, Tomonari Sasaki, Katsumasa Nakamura, Hiroshi Honda, Masatoshi Eto, Smoking effect on secondary bladder cancer after external beam radiotherapy for prostate cancer, Japanese journal of clinical oncology, 10.1093/jjco/hyw098, 46, 10, 952-957, 2016.10, Objective: Although it is well known that radiotherapy for prostate cancer increases comorbid rate of secondary bladder cancer, the effect of aging and smoking with radiotherapy on incidence rate of secondary bladder cancer remains unknown. Then, this study investigated the combinational effect of external beam radiotherapy for prostate cancer and aging or smoking on comorbid rate of secondary bladder cancer.Methods: This study included 754 Japanese patients with prostate cancer treated with radiotherapy (n = 319) and radical prostatectomy (n = 435) from 2000 through 2013. The relationship between therapeutic modality for prostate cancer as well as age or smoking status and comorbid rate of secondary bladder cancer was examined.Results: During the median follow-up period of 4.3 and 3.1 years, secondary bladder cancer occurred in 11 (3.4%) and 5 (1.1%) of patients with prostate cancer treated with external beam radiotherapy and radical prostatectomy, respectively. The 5-year bladder cancer-free survival rate was 97.3% in the external beam radiotherapy group and 99.4% in the radical prostatectomy group. Age (hazard ratio = 1.15, P = 0.027) and ever smoking (hazard ratio = 5.65, P = 0.011) were significant predictive factors of secondary bladder cancer incidence in the external beam radiotherapy cohort, but not in the radical prostatectomy cohort. Inversely, among men with ever smoking, but not among older men, external beam radiotherapy (hazard ratio = 9.64, P = 0.0052) was a significant risk factor of secondary bladder cancer.Conclusions: Taken together, these findings suggest that smoking history might be one of criteria to choose radical prostatectomy than external beam radiotherapy for prostate cancer, and that age would not be a criterion for therapeutic selection in terms of secondary bladder cancer.. |
| 229. |
Masaki Shiota, Akira Yokomizo, Takumi Adachi, Hirofumi Koga, Akito Yamaguchi, Kenjiro Imada, Ario Takeuchi, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Seiji Naito, The oncological outcomes and risk stratification in docetaxel chemotherapy for castration-resistant prostate cancer, Japanese journal of clinical oncology, 10.1093/jjco/hyu081, 44, 9, 860-867, 2014.09, Objective: To clarify the risk factors and develop a refined risk-stratification model to help in the appropriate selection of docetaxel chemotherapy in patients with castration-resistant prostate cancer. Methods: This study included 97 Japanese patients with castration-resistant prostate cancer who were treated with 70-75 mg/m2 docetaxel and 10 mg prednisone every 3 or 4 weeks from 2008 to 2013. The oncological outcomes and prognostic significance of clinicopathological factors were analyzed, and significant prognostic factors were used to develop a risk-stratification model. Results: Prostate-specific antigen decline was observed in 75 patients (77.3%), including 43 (44.3%) who achieved a prostate-specific antigen decline of ≥50%. The median progressionfree survival and overall survival were 5.1 and 20.8 months, respectively. Univariate analysis identified performance status, alkaline phosphatase value, visceral metastasis, duration from diagnosis, duration from initiation of hormone treatment and prior treatment with estramustine as significant predictors of overall survival. Among these, alkaline phosphatase value, visceral metastasis and duration from initiation of hormone treatment were independent prognostic factors in multivariate analysis. Furthermore, risk classification according to the number of independent risk factors present effectively stratified survival among docetaxel-treated castrationresistant prostate cancer patients. Conclusions: Oncologic outcomes in Japanese patients with castration-resistant prostate cancer receiving docetaxel chemotherapy were comparable to or slightly better than those in Western populations, and the risk-stratification model developed in this study may help to predict prognosis and contribute to the selection of suitable therapy after castration resistance.. |
| 230. |
Masaki Shiota, Primary androgen deprivation therapy for nonmetastatic prostate cancer in Asia
Unique or not?, JNCCN Journal of the National Comprehensive Cancer Network, 10.6004/jnccn.2019.7302, 17, 5, 523-524, 2019.01. |
| 231. |
Masaki Shiota, Shintaro Narita, Shusuke Akamatsu, Naohiro Fujimoto, Takayuki Sumiyoshi, Maki Fujiwara, Takeshi Uchiumi, Tomonori Habuchi, Osamu Ogawa, Masatoshi Eto, Association of Missense Polymorphism in HSD3B1 With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone, JAMA network open, 10.1001/jamanetworkopen.2019.0115, 2, 2, e190115, 2019.02, 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.. |
| 232. |
Shiota M, Fujimoto N, Imada K, Yokomizo A, Itsumi M, Takeuchi A, Kuruma H, Inokuchi J, Tatugami K, Uchiumi T, Oda Y, Naito S, Potential role for YB-1 in castration-resistant prostate cancer and resistance to enzalutamide through the androgen receptor V7., J Natl Cancer Inst, 10.1093/jnci/djw005, 108(7):djw005, 2016.07. |
| 233. |
Itsumi M, Shiota M, Yokomizo A, Kashiwagi E, Takeuchi A, Tatsugami K, Inokuchi J, Song Y, Uchiumi T, Naito S., Human heterochromatin protein 1 isoforms regulate androgen receptor signaling in prostate cancer., J Mol Endocrinol, 50 (3): 401-409, 2013, 2013.04. |
| 234. |
Yohei Sekino, Xiangrui Han, Takafumi Kawaguchi, Takashi Babasaki, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Jun Teishima, Masaki Shiota, Wataru Yasui, Akio Matsubara, TUBB3 reverses resistance to docetaxel and cabazitaxel in prostate cancer, International journal of molecular sciences, 10.3390/ijms20163936, 20, 16, 2019.08, Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.. |
| 235. |
Ario Takeuchi, Masatoshi Eto, Masaki Shiota, Katsunori Tatsugami, Akira Yokomizo, Kentaro Kuroiwa, Momoe Itsumi, Seiji Naito, Sunitinib enhances antitumor effects against chemotherapy-resistant bladder cancer through suppression of ERK1/2 phosphorylation, International journal of oncology, 10.3892/ijo.2012.1368, 40, 5, 1691-1696, 2012.05, Bladder cancer patients who are refractory to chemotherapy have a poor prognosis. Furthermore, additional chemotherapies provide little benefit to patients who have relapsed after an initial response. Recently, it was reported that several molecular pathways are implicated in bladder carcinogenesis, including the epidermal growth factor receptor (EGFR) pathway, the vascular endothelial growth factor (VEGF) pathway and the Ras-MAPK pathway. We hypothesized that sunitinib would be effective in bladder cancer as it is an oral inhibitor of multiple receptor tyrosine kinases, including VEGF receptors, platelet derived growth factor (PDGF) receptors and stem cell factor receptor (c-KIT), and is a standard first-line treatment of advanced clear cell renal carcinoma. In the present study, the antiproliferative effects of sunitinib were clearly demonstrated in KK47, KK47/DDP20 and KK47/ADR cell lines in vitro due to the suppression of ERK1/2 phosphorylation. In a mouse model, the antitumor effects of sunitinib were again clearly seen. Also, treatment with sunitinib decreased the abundance of regulatory T cells (Tregs). However, cytotoxic T lymphocyte (CTL) activity was not induced sufficiently as compared with an IFN-α-treated group. Our results suggested that sunitinib was effective in chemotherapy-resistant bladder cancer patients. On the other hand, these findings provided the rationale for combination therapy with sunitinib and immune-based cancer therapy for advanced malignancies to prevent the occurrence of rebound phenomena.. |
| 236. |
Yasuhiro Tada, Akira Yokomizo, Masaki Shiota, Toshiyuki Tsunoda, Christoph Plass, Seiji Naito, Aberrant DNA methylation of T-cell leukemia, homeobox 3 modulates cisplatin sensitivity in bladder cancer, International journal of oncology, 10.3892/ijo.2011.1049, 39, 3, 727-733, 2011.09, The development of resistance to cisplatin during treatment of bladder cancer constitutes a major obstacle to curing bladder cancer. The identification of epigenetic biomarker molecules for cisplatin resistance and the elucidation of the function of the identified genes in bladder cancer will provide useful information. We found that the candidate gene TLX3 was unmethylated in cisplatin sensitive cells and methylated in resistant cells. The suppression of TLX3 expression using TLX3-specific shRNA in parental cells increased cisplatin resistance. Contrarily, overexpression of TLX3 in resistant cells induced increased sensitivity to cisplatin. We found that 22 (21%) out of 110 clinical samples of bladder cancer showed the methylated pattern using the COBRA assay in TLX3. We found a correlation between TLX3 methylation and the sensitivity to cisplatin in the clinical samples by SDI test. Cisplatin sensitivity was closely associated with the methylation status of TLX3. These findings showed that the TLX3 methylation may be useful as a novel biomarker for cisplatin resistance and can be used to design therapies to counteract the resistance against cisplatin in bladder cancer.. |
| 237. |
Masaki Shiota, Masatoshi Eto, Akira Yokomizo, Yasuhiro Tada, Ario Takeuchi, Momoe Itsumi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito, Sensitivity of doxorubicin-resistant cells to sorafenib
Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation, International journal of oncology, 10.3892/ijo-0000700, 37, 2, 509-517, 2010.08, Patients with advanced cancer including breast cancer, hepatocellular cancer and urothelial cancer frequently receive a chemotherapy regimen containing doxorubicin. However, doxorubicin-resistance is a major obstacle for cancer chemotherapy. Recently, several molecular-targeted agents have become available. Sorafenib (BAY 43-9006) is known to target multiple kinases and has demonstrated activity in renal cell and hepatocellular cancer. In this study, sorafenib was found to inhibit phosphorylation of the eukaryotic initiation factor-2α (eIF2α), induce cell cycle arrest at G2 phase and increase cellular apoptosis in doxorubicin-resistant human urothelial cell lines. An eIF2α kinase, PERK was responsible for eIF2α phosphorylation and PERK knockdown induced cellular apoptosis similar to sorafenib treatment in doxorubicin-resistant cancer cells. Furthermore, sorafenib sensitized doxorubicin-resistant cancer cells, but not their parental cells to oxidative stress exerted by both hydrogen peroxide and doxorubicin. In addition, PERK knockdown sensitized doxorubicin-resistant cancer cells to oxidative stress. In conclusion, PERK inhibition using sorafenib with or without doxorubicin might be a promising therapeutic approach for doxorubicin-resistant cancers retaining high phosphorylation levels of eIF2α.. |
| 238. |
Masaki Shiota, Masatoshi Eto, Akira Yokomizo, Yasuhiro Tada, Ario Takeuchi, Daisuke Masubuchi, Junichi Inokuchi, Katsunori Tatsugami, Kentaro Kuroiwa, Takeshi Uchiumi, Narihito Seki, Seiji Naito, Sorafenib with doxorubicin augments cytotoxicity to renal cell cancer through PERK inhibition, International journal of oncology, 10.3892/ijo-00000639, 36, 6, 1521-1531, 2010.06, Although cytokine therapy involving interleukin-2 or interferon-α has been employed for metastatic renal cell cancer (RCC) treatment, these therapies yielded limited response and benefit. Recently, several molecular-targeted agents have become available, and one newly developed anti-RCC agent, sorafenib (BAY 43-9006), is known to target multiple kinases. In this study, sorafenib was found to inhibit phosphorylation of the eukaryotic initiation factor-2α (eIF2α) and induce cell cycle arrest at G2/M phase and increase cell death. One of eIF2α kinases, PERK was responsible for eIF2α phosphorylation in RCC cells and PERK knockdown induced cell death similar to sorafenib treatment. The efficiency of sorafenib treatment correlated with phosphorylation level of eIF2α and nuclear Nrf2 expression level in eight RCC cell lines. Furthermore, sorafenib made Caki-1 and 786-O cells, but not ACHN cells sensitive to oxidative stress exerted by both hydrogen peroxide and doxorubicin. In addition, PERK knockdown sensitized Caki-1 and 786-O cells, but not ACHN cells to oxidative stress. In conclusion, levels of phospho-eIF2α and nuclear Nrf2 expression level in RCC might be a predictor of outcome in sorafenib treatment. In addition, PERK inhibition as well as sorafenib plus doxorubicin might be a promising therapeutic approach for RCC characterized by high levels of phosphorylatedeI-F2α and nuclear Nrf2.. |
| 239. |
, Masaki Shiota, Mizuki Onozawa, Shiro Hinotsu, Masatoshi Eto, Seiji Naito, Hideyuki Akaza, Family history in primary hormone therapy for prostate cancer
Analysis from a community-based multi-institutional Japan-wide database, International Journal of Urology, 10.1111/iju.14184, 27, 4, 313-318, 2020.04, Objectives: To determine the association between hormone therapy and outcomes in a cohort of prostate cancer patients with a family history of prostate cancer. Methods: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 13 346 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival and overall survival, were compared between men with familial and men with sporadic prostate cancer. Results: A positive family history was identified in 220 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a possible favorable prognostic factor for overall survival among patients with a prostate-specific antigen level at diagnosis |
| 240. |
Masaki Shiota, Editorial Comment from Dr Shiota to Magnetic resonance imaging/transrectal ultrasonography fusion targeted prostate biopsy finds more significant prostate cancer in biopsy-naïve Japanese men compared with the standard biopsy, International Journal of Urology, 10.1111/iju.14156, 27, 2, 147-148, 2020.02. |
| 241. |
Masaki Shiota, Editorial Comment to Validation and development of the CHAARTED criteria in patients with hormone-naïve metastatic prostate cancer
A multi-institutional retrospective study in Japan, International Journal of Urology, 10.1111/iju.14143, 27, 1, 92, 2020.01. |
| 242. |
Masaki Shiota, Ryo Namitome, Takeshi Kobayashi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Prognostic significance of risk stratification in CHAARTED and LATITUDE studies among Japanese men with de novo metastatic prostate cancer, International Journal of Urology, 10.1111/iju.13870, 26, 3, 426-428, 2019.03. |
| 243. |
Masaki Shiota, Masatoshi Eto, Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone-sensitive prostate cancer, International Journal of Urology, 10.1111/iju.13091, 23, 5, 360-369, 2016.05, Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone-sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer-related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone-sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration-resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone-sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone-sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone-sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor-targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone-sensitive prostate cancer, and discusses future perspectives in this field.. |
| 244. |
Danilo Ranieri, Daniele Avitabile, Masaki Shiota, Akira Yokomizo, Seiji Naito, Mariano Bizzarri, Maria Rosaria Torrisi, Nuclear redox imbalance affects circadian oscillation in HaCaT keratinocytes, International Journal of Biochemistry and Cell Biology, 10.1016/j.biocel.2015.05.018, 65, 113-124, 2015.06, Circadian clock is regulated by a transcriptional/translational feedback loop (TTFL) lasting ∼24 h. Circadian oscillation of peroxiredoxins (PRDX1-6) redox status has been shown in mature erythrocytes. We have recently reported that nuclear levels of PRDX2 are circadian regulated in the HaCaT keratinocytes. In this study, we addressed whether PRDX2 translocation could influence the TTFL. A reporter HaCaT cell line stably expressing the luciferase gene under control of Bmal1 promoter was lentivirally transduced either with an empty vector (EV), a vector carrying a myc-tagged wild type PRDX2 (PRDX2-Myc) or the same gene with a nuclear localization sequence (PRDX2-MycNuc). PRDX2 overexpressing cells were protected from H2O2-induced oxidative stress. The amplitude of the Bmal1 promoter activity was significantly dampened in PRDX2-MycNuc versus EV cells when synchronized either by dexamethasone treatment or temperature cycles. Clock synchronization was not affected in PRDX2 silenced cells. N-acetyl cysteine or melatonin treatments, significantly dampened the Bmal1 promoter activity suggesting that sustained scavenging of ROS impairs clock synchronization. Noteworthy, H2O2 treatment rescued proper oscillation of the clock in synchronized PRDX2-MycNuc HaCaT cells. Since the histone deacetylase Sirtuin 1 (Sirt1) modulates clock gene expression amplitude, the effect of Sirt1 activator resveratrol or Sirt1 inhibitor nicotinamide were also investigated. Interestingly, NAM enhanced the molecular clock synchronization in PRDX2-MycNuc cells. Our findings demonstrate that PRDX2 regulates the TTFL oscillation by finely tuning the cellular redox status of the nucleus likely influencing the deacetilase activity of SIRT1 enzyme.. |
| 245. |
Thomas Cordonnier, Jennifer L. Bishop, Masaki Shiota, Ka Mun Nip, Daksh Thaper, Sepideh Vahid, Devon Heroux, Martin Gleave, Amina Zoubeidi, Hsp27 regulates EGF/β-catenin mediated epithelial to mesenchymal transition in prostate cancer, International Journal of Cancer, 10.1002/ijc.29122, 136, 6, E496-E507, 2015.03, Increased expression of the molecular chaperone Hsp27 is associated with the progression of prostate cancer (PCa) to castration-resistant disease, which is lethal due to metastatic spread of the prostate tumor. Metastasis requires epithelial to mesenchymal transition (EMT), which endows cancer cells with the ability to disseminate from the primary tumor and colonize new tissue sites. A wide variety of secreted factors promote EMT, and while overexpression and constitutive activation of epidermal growth factor (EGF) signaling is associated with poor prognosis of PCa, a precise role of EGF in PCa progression to metastasis remains unclear. Here, we show that Hsp27 is required for EGF-induced cell migration, invasion and MMPs activity as well as the expression of EMT markers including Fibronectin, Vimentin and Slug with concomitant decrease of E-cadherin. Mechanistically, we found that Hsp27 is required for EGF-induced AKT and GSK3β phosphorylation and β-catenin nuclear translocation. Moreover, silencing Hsp27 decreases EGF dependent phosphorylation of β-catenin on tyrosine 142 and 654, enhances β-catenin ubiquitination and degradation, prevents β-catenin nuclear translocation and binding to the Slug promoter. These data suggest that Hsp27 is required for EGF-mediated EMT via modulation of the β-catenin/Slug signaling pathway. Together, our findings underscore the importance of Hsp27 in EGF induced EMT in PCa and highlight the use of Hsp27 knock-down as a useful strategy for patients with advanced disease.. |
| 246. |
Masaki Shiota, Editorial Comment from Dr Shiota to Prognostic impact of young age on stage IV prostate cancer treated with primary androgen deprivation therapy, International Journal of Urology, 10.1111/iju.12397, 21, 6, 583-584, 2014.06. |
| 247. |
Ario Takeuchi, Masatoshi Eto, Katsunori Tatsugami, Masaki Shiota, Hisakata Yamada, Yoriyuki Kamiryo, Takashi Dejima, Eiji Kashiwagi, Keijiro Kiyoshima, Junichi Inokuchi, Ryosuke Takahashi, Akira Yokomizo, Naoya Ohara, Yasunobu Yoshikai, Antitumor activity of recombinant Bacille Calmette-Guérin secreting interleukin-15-Ag85B fusion protein against bladder cancer, International Immunopharmacology, 10.1016/j.intimp.2016.03.007, 35, 327-331, 2016.06, Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is used for the treatment of bladder cancer. The recruitment of neutrophlis to the bladder after BCG instillation exerts anti-tumor activity against bladder tumor. We have recently demonstrated that interleukin (IL)-17A produced by γδ T cells played a role in the recruitment of neutrophlis to the bladder after BCG instillation. IL-15 is known to play an important role in neutrophil migration during inflammation. We previously constructed a recombinant BCG strain expressing the fusion protein of IL-15 and Ag85B (BCG-IL-15) for prevention of Mycobacterium tuberculosis infection. Here we compared the efficacy of the BCG-IL-15 in protection against bladder cancer with that of rBCG-Ag85B (BCG). Six-week-old female C57BL/6 mice were inoculated with MB49 bladder tumor cells in the bladder and subsequently intravesically inoculated with BCG or BCG-IL-15. BCG-IL-15 treatment significantly prolonged survival of mice inoculated with bladder cancer cells compared with BCG treatment. Infiltration of neutrophils was significantly elevated in BCGB-IL-15 treated mice accompanied by increased chemokines (MIP-2 and MIP-1α) in the bladder. Thus, BCG-IL-15 exerted additive effect on Infiltration of neutrophils in the bladder. BCG-IL-15 may be a promising drug for non-muscle invasive bladder cancer.. |
| 248. |
masaki shiota, Noriaki Tokuda, Takehiro Kanou, Humio Yamasaki, Villous adenoma of female urethra
An investigation of the mechanism of development regarding glandular neoplasms in the urinary tract, Indian Journal of Urology, 10.4103/0970-1591.29132, 22, 4, 376-377, 2006.10, Villous adenomas are rare in the urinary tract. We herein report the fifth known such case while also making a review of the literature. A 54-year-old woman noticed a mass in her external genitalia and a tumor located on her external urethral orifice. The tumor was excised and pathologically confirmed to be a villous adenoma. Up to now, no sign of recurrence has been observed. However, we should be careful for malignant formation, because villous adenomas in the urinary tract frequently coexist with either adenocarcinoma or urothelial carcinoma.. |
| 249. |
Masaki Shiota, Oxidative stress and castration-resistant prostate cancer, Hormone Therapy and Castration Resistance of Prostate Cancer, 10.1007/978-981-10-7013-6_21, 201-214, 2018.05, Androgen deprivation therapy can induce oxidative stress by increasing reactive oxygen species levels and/or decreasing cellular antioxidant capacity, which in turn cause genetic and epigenetic effects in prostate cancer. Oxidative stress increases androgen receptor (AR) activation through several possible mechanisms, including AR overexpression, AR activation by co-regulators and intracellular signal transduction pathways, mutation of AR and AR-related proteins, expression of AR splice variants, de novo androgen synthesis, and changes in non-AR signaling. Alterations in AR and non-AR signaling appear to have pro-survival and anti-apoptotic effects on prostate cancer cells, resulting in the development of castration-resistant prostate cancer. Thus, antioxidant therapy could be a promising strategy for the treatment of prostate cancer. Oxidative stress also influences the activity of several prostate cancer therapies, such as taxanes, radiotherapy, and AR-targeting agents. Taken together, these observations suggest that oxidative stress-induced AR signaling is a critical resistance factor and a crucial target for prostate cancer treatment.. |
| 250. |
Yoohyun Song, Masaki Shiota, Sadafumi Tamiya, Kentaro Kuroiwa, Seiji Naito, Masazumi Tsuneyoshi, The significance of strong histone deacetylase 1 expression in the progression of prostate cancer, Histopathology, 10.1111/j.1365-2559.2011.03797.x, 58, 5, 773-780, 2011.04, Aims: Histone deacetylases (HDACs) play important roles in many types of cancer. Recently, it has been reported that HDAC1 expression in prostate cancer is significantly higher than in benign prostate cell lines and tissues. The expression of HDAC1 in association with the clinicopathological data was investigated to define its functional and pathological roles in prostate cancer. Methods and results: HDAC1 expression was examined immunohistochemically in 148 patients with prostate cancer. Strong expression of HDAC1 in benign prostate glands, high-grade prostatic intraepithelial neoplasia (PIN) and prostate cancer was observed in 17/148 (11%), 19/71 (27%) and 69/148 (47%) patients. Strong HDAC1 expression was correlated with high Gleason score (P=0.025) and high pT stage (P=0.012). Patients with strong HDAC1 expression had higher biochemical recurrence rates (P=0.0010). Furthermore, strong HDAC1 expression had a significant impact on patient biochemical recurrence rates in multivariate analysis (P=0.004). Conclusions: These results indicate that overexpression of HDAC1 contributes to progression and poor prognosis in prostate cancer. The findings may play an important role in the emergence of effective new approaches for therapy and prognostic markers of prostate cancer.. |
| 251. |
Ario Takeuchi, Masaki Shiota, Katsunori Tatsugami, Akira Yokomizo, Masatoshi Eto, BCG Immunotherapy Against Non-Muscle Invasive Bladder Cancer
Recent Results, Current Studies and Future Perspectives, Fukuoka igaku zasshi = Hukuoka acta medica, 107, 1, 8-11, 2016.01. |
| 252. |
Masaki Shiota, Noriaki Tokuda, Takehiro Kanou, Humio Yamasaki, Injection-site granulomas due to the administration of leuprorelin acetate for the treatment of prostatic cancer., Fukuoka igaku zasshi = Hukuoka acta medica, 98, 7, 301-304, 2007.07, Luteinizing hormone-releasing hormone (LH-RH) analogues have become the main focus of androgen deprivation therapy for prostatic cancer. The occurrence of injection-site granulomas due to the administration of LH-RH analogues has been thought to be a rare reaction. We herein report a rare case presenting injection-site granuloma due to the administration of leuprorelin acetate, mimicking metastatic nodule. A 90-year-old man presented with subcutaneous nodules at the injection-site of leuprorelin acetate 11.25 mg (for 3-month use). Ultrasound examination and computed tomography (CT) revealed two nodules in the bilateral abdominal walls mimicking metastatic nodule. Although he was surgically treated because of the possibility of malignancy, in the end, no evidence of malignancy was found. We should keep in mind that LH-RH analogues may cause injection-site granulomas mimicking metastatic nodule, and therefore we must inform patients undergoing the administration of leuprorelin acetate that it may cause injection-site granuloma and thus when a patient demonstrates a subcutaneous nodule it is essential to confirm whether or not he has received an injection of the LH-RH analogue at the site of nodule.. |
| 253. |
Masaki Shiota, Naohiro Fujimoto, Kenjiro Imada, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto, Prognostic impact of genetic polymorphism in mineralocorticoid receptor and comorbidity with hypertension in androgen-deprivation therapy, Frontiers in Oncology, 10.3389/fonc.2018.00635, 8, DEC, 2018, Mineralocorticoid receptor (MR) signaling which is closely associated with hypertension plays important roles in resistance to antiandrogen therapy in prostate cancer. However, its impact on the prognosis in androgen-deprivation therapy (ADT) has not been elucidated. Then, we investigated the impact of genetic variation in MR and comorbidity with hypertension on the prognosis in ADT. This study included 182 Japanese patients with prostate cancer treated with ADT, whose comorbidity status with hypertension were available. The associations of MR polymorphism (rs5522) and comorbidity with hypertension with clinicopathological parameters as well as progression-free survival and overall survival were examined. Clinicopathological characteristics were comparable between genetic variation in MR. However, homozygous variant in MR was associated with shorter time to castration resistance (P = 0.014) and any-cause death (P = 0.024). In patients' background, presence of comorbidity with hypertension showed the trend with lower PSA level at diagnosis and lower biopsy Gleason score, as well as significant association with less incidence of N1. Comorbidity with hypertension was associated with longer time to castration resistance (P = 0.043) and any-cause death (P = 0.046), which was diminished on multivariate analysis including age, PSA level at diagnosis, biopsy Gleason score, clinical stage, and the modality of hormonal therapy. Genetic variation in MR (rs5522) and comorbidity with hypertension were significantly and potentially associated with prognosis when treated with ADT, respectively. This suggests that the individual intensity of MR signaling may be associated with resistance to ADT and a promising biomarker in ADT.. |
| 254. |
Masaki Shiota, Akira Yokomizo, Masatoshi Eto, Taxane chemotherapy for hormone-naïve prostate cancer with its expanding role as breakthrough strategy, Frontiers in Oncology, 10.3389/fonc.2015.00304, 5, JAN, 2016, Historically, androgen-deprivation therapy (ADT) was the only primary treatment for metastatic prostate cancer. After prostate cancer develops into castration-resistant prostate cancer (CRPC), there are a few life-prolonging drugs, including taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, which have been proved in clinical trials. However, the prognosis of men with CRPC is still poor. The duration from initiation of ADT to CRPC has not improved in recent decades because no novel therapeutic options have emerged. However, recently, up-front docetaxel chemotherapy has been shown to prolong progression-free as well as overall survival in men with metastatic hormone-naïve prostate cancer. This offers a new way to expand the role of chemotherapy for hormone-naïve prostate cancer. In this review, we summarize the proof-of-concept as well as the current status of taxane chemotherapy for hormone-naïve prostate cancer, focusing on phase 3 clinical trials investigating oncological outcome, and discuss the future direction in this field.. |
| 255. |
Masaki Shiota, Akira Yokomizo, Seiji Naito, Oxidative stress and androgen receptor signaling in the development and progression of castration-resistant prostate cancer, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2011.07.011, 51, 7, 1320-1328, 2011.10, Aberrant androgen receptor (AR) signaling plays a critical role in androgen-dependent prostate cancer (PCa), as well as in castration-resistant PCa (CRPC). Oxidative stress seems to contribute to the tumorigenesis and progression of PCa, as well as the development of CRPC, via activation of AR signaling. This notion is supported by the fact that there is an aberrant or improper regulation of the redox status in these disorders. Additionally, androgen-deprivation-induced oxidative stress seems to be involved in the pathogenesis of several disorders caused by androgen-deprivation therapy (ADT), including osteoporosis, neurodegenerative disease, and cardiovascular disease. Oxidative stress can be suppressed with antioxidants or via a reduction in reactive oxygen species production. Thus, developing new therapeutic agents that reduce oxidative stress might be useful in preventing the conversion of androgen-dependent PCa into CRPC, as well as reducing the adverse effects associated with ADT. The objective of this review is to provide an overview regarding the relationship between oxidative stress and AR signaling in the context of PCa and especially CRPC. Additionally, we discuss the potential use of antioxidant therapies in the treatment of PCa.. |
| 256. |
Masaki Shiota, Akira Yokomizo, Eiji Kashiwagi, Ario Takeuchi, Naohiro Fujimoto, Takeshi Uchiumi, Seiji Naito, Peroxiredoxin 2 in the nucleus and cytoplasm distinctly regulates androgen receptor activity in prostate cancer cells, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2011.04.001, 51, 1, 78-87, 2011.07, Currently, few therapies are effective against castration-resistant prostate cancer. Increased activation of the androgen/androgen receptor (AR) signaling pathway is thought to promote castration-resistant prostate cancer. Herein, we report that peroxiredoxin (Prx) gene expression in castration-resistant prostate cancer and hydrogen peroxide-resistant cells was upregulated. Prx2 was overexpressed in castration-resistant prostate cancer at the mRNA and protein levels and was localized to the nucleus and cytoplasm. Overexpression of Prx2 increased AR transactivation, whereas Prx2 overexpression in the nucleus suppressed AR transactivation. These effects of Prx2 on AR activity were abolished by the introduction of function-disrupting mutations into Cys 51 and Cys 172. Silencing Prx2 reduced the expression of androgen-regulated genes and suppressed the growth of AR-expressing prostate cancer cells by inducing cell-cycle arrest at the G1 phase. Furthermore, Prx2 knockdown also suppressed cell growth in castration-resistant prostate cancer cells. These findings indicate that Prx2 is involved in the proliferation of AR-expressing prostate cancer cells by modulating AR activity. Designing therapeutics targeting Prx2 may offer a novel strategy for developing treatments for prostate cancer, including castration-resistant prostate cancer, which is dependent on AR signaling.. |
| 257. |
Mi Jeong Kim, Ah Reum Seong, Yoo Hyun Lee, Young Jun Kim, Masaki Shiota, Akira Yokomizo, Seiji Naito, Jeongmin Lee, Woojin Jun, Ho Geun Yoon, Histone Acetyltransferase Inhibitory Activity of Bokbunja (Rubus coreanus Miq.) ethanol extract on androgen receptor-dependent prostate cancer cell growth, Food Science and Biotechnology, 10.1007/s10068-010-0214-8, 19, 6, 1503-1511, 2010, In this study, we demonstrate that a bokbunja (Rubus coreanus) ethanol extract (RCE) exhibits the strong histone acetyltransferase (HAT) inhibitory activity, and shows specificity against the p300 HAT enzyme. RCE specifically inhibited p300 acetyltransferase activities with an IC50 of approximately 70 μg/mL, but did not inhibit other epigenetic enzymes. We found that RCE inhibited agonist-dependent androgen receptor (AR) acetylation and suppressed androgen-induced AR transcriptional activity. RCE treatment also decreased the enhancement of AR transcriptional activity caused by p300 overexpression, and combined treatment with RCE potentiated the activity of the AR antagonist flutamide. Finally, RCE treatment reduced the growth of LNCaP human prostate cancer cells via inhibition of cyclin D1 and cyclin E expression, and concomitantly induced apoptosis. Collectively, our results suggest that therapeutic targeting of AR acetylation by HATi could lead to a new class of antagonists for the treatment of prostate cancer.. |
| 258. |
Naohiro Fujimoto, Masaki Shiota, Tatsuhiko Kubo, Tetsuro Matsumoto, Novel therapeutic strategies following docetaxel-based chemotherapy in castration-resistant prostate cancer, Expert Review of Clinical Pharmacology, 10.1586/ecp.10.119, 3, 6, 785-795, 2010.11, Prolonged survival of patients with castration-resistant prostate cancer has been demonstrated following treatment with a combination of docetaxel and prednisone. This combination has, therefore, become the standard first-line chemotherapy for castration-resistant prostate cancer. Median survival, however, does not exceed 20 months and there are currently no approved second-line treatments for patients who progress after docetaxel treatment. The development of effective and safe treatment strategies is urgently required. Several clinical trials are currently evaluating the use of cytotoxic, antiandrogenic and molecular targeting agents. Preclinical studies are identifying the mechanisms responsible for docetaxel resistance and means of enhancing docetaxel activity. The results of these studies will provide the basis for rationally designed therapeutic approaches. This article summarizes the results of recent preclinical and clinical studies and discusses future perspectives.. |
| 259. |
Masaki Shiota, Akira Yokomizo, Re
Robert J. van Soest, Ellen S. de Morrée, Charlotte F. Kweldam, et al. Targeting the Androgen Receptor Confers in Vivo Cross-resistance between Enzalutamide and Docetaxel, but Not Cabazitaxel, in Castration-resistant Prostate Cancer. Eur Urol 2015;67:981-5, European Urology, 10.1016/j.eururo.2015.07.025, 69, 3, e41-e42, 2016.03. |
| 260. |
Masaki Shiota, Naohiro Fujimoto, Akira Yokomizo, Ario Takeuchi, Momoe Itsumi, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito, SRD5A gene polymorphism in Japanese men predicts prognosis of metastatic prostate cancer with androgen-deprivation therapy, European Journal of Cancer, 10.1016/j.ejca.2015.06.122, 51, 14, 1962-1969, 2015.06, Aim De novo androgen synthesis is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). During androgen synthesis, 5α-reductase encoded by SRD5A catalyses testosterone into more active dihydrotestosterone and may be involved in the progression to CRPC. Then, this study aimed to reveal the association between genetic variations in SRD5A and the prognosis in metastatic prostate cancer. Methods We studied the polymorphisms rs518673 and rs166050 in SRD5A1, and rs12470143, rs523349, rs676033 and rs2208532 in SRD5A2 as well as the time to CRPC progression and overall survival in 104 patients with metastatic prostate cancer that had undergone primary ADT. The association between the polymorphisms and the progression to CRPC as well as overall survival was examined. Results Patients carrying the more active GG genotype in SRD5A2 rs523349 exhibited a higher risk of the progression (hazard ration [95% confidence interval], 1.93 [1.14-3.14], p = 0.016) and death (hazard ration [95% confidence interval], 2.14 [1.16-3.76], p = 0.016), compared with less active GC/CC genotypes in SRD5A2 rs523349. Conclusions High 5α-reductase activity due to the polymorphism in SRD5A2 may contribute to resistance to ADT. Furthermore, SRD5A2 rs523349 polymorphism may be a promising biomarker for metastatic prostate cancer patients treated with primary ADT and a molecular target for advanced prostate cancer.. |
| 261. |
Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Eiji Kashiwagi, Takashi Dejima, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Masatoshi Eto, Protein kinase C regulates Twist1 expression via NF-κB in prostate cancer, Endocrine-Related Cancer, 10.1530/ERC-16-0384, 24, 4, 171-180, 2017.04, The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that protein kinase C (PKC) activation followed by Twist1 and androgen receptor (AR) induction played a critical role in castration resistance, but the precise molecular mechanism remains unknown. This study aimed to elucidate the relevant molecular mechanism, focusing on NF-κB transcription factor. We examined the activity of NF-κB after PKC inhibition, and the expression of Twist1 and AR after inhibition of NF-κB in human prostate cancer cells. We also investigated the status of PKC/NF-κB after inhibition of AR signaling in cells resistant to hormonal therapy. As a result, inhibition of PKC signaling using knockdown and smallmolecule inhibition of PKC suppressed RelA activity, while blocking NF-κB suppressed Twist1 and AR expression. Conversely, inhibition of AR signaling by androgen depletion and the novel antiandrogen enzalutamide induced PKC and RelA activation, resulting in Twist1/AR induction at the transcript level. Moreover, inhibition of NF-κB signaling prevented enzalutamide-induced Twist1 and AR induction. Finally, NF-κB was activated in both castration-resistant and enzalutamide-resistant cells. In conclusion, NF-κB signaling was responsible for Twist1 upregulation by PKC in response to AR inhibition, resulting in aberrant activation of AR. NF-κB signaling thus appears to play a critical role in promoting both castration resistance and enzalutamide resistance in PKC/Twist1 signaling in prostate cancer.. |
| 262. |
Masaki Shiota, Momoe Itsumi, Ario Takeuchi, Kenjiro Imada, Akira Yokomizo, Hidetoshi Kuruma, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Yoshinao Oda, Seiji Naito, Crosstalk between epithelialmesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer, Endocrine-Related Cancer, 10.1530/ERC-15-0225, 22, 6, 889-900, 2015.12, Although invasive and metastatic progression via the epithelial-mesenchymal transition (EMT) and acquisition of resistance to castration are both critical steps in prostate cancer, the molecular mechanism of this interaction remains unclear. In this study, we aimed to elucidate the interaction of signaling between castration resistance and EMT, and to apply this information to the development of a novel therapeutic concept using transforming growth factor-b (TGF-b) inhibitor SB525334 combined with androgen-deprivation therapy against prostate cancer usinganin vivomodel. This study revealedthat anEMTinducer (TGF-b) induced full-length androgen receptor (AR) and AR variant expression. In addition, a highly invasive clone showed augmented full-length AR and AR variant expression as well as acquisition of castration resistance. Conversely, full-length AR and AR as well as Twist1 and mesenchymal molecules variant expression were up-regulated in castration-resistant LNCaP xenograft. Finally, TGF-b inhibitor suppressed Twist1 and AR expression as well as prostate cancer growth combined with castration. Taken together, these results demonstrate that Twist1/AR signaling was augmented in castration resistant as well as mesenchymal-phenotype prostate cancer, indicating the molecular mechanism of mutual and functional crosstalk between EMTand castration resistance, which may play a crucial role in prostate carcinogenesis and progression.. |
| 263. |
Eiji Kashiwagi, Masaki Shiota, Akira Yokomizo, Momoe Itsumi, Junichi Inokuchi, Takeshi Uchiumi, Seiji Naito, Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells, Endocrine-Related Cancer, 10.1530/ERC-12-0344, 20, 3, 431-441, 2013.06, Although numerous epidemiological studies show aspirin to reduce risk of prostate cancer, the mechanism of this effect is unclear. Here, we first confirmed that aspirin downregulated androgen receptor (AR) and prostate-specific antigen in prostate cancer cells. We also found that aspirin upregulated prostaglandin receptor subtype EP3 but not EP2 or EP4. The EP3 antagonist L798106 and EP3 knockdown increased AR expression and cell proliferation, whereas the EP3 agonist sulprostone decreased them, indicating that EP3 affects AR expression. Additionally, EP3 (PTGER3) transcript levels were significantly decreased in human prostate cancer tissues compared with those in normal human prostate tissues, suggesting that EP3 is important to prostate carcinogenesis. Decreased EP3 expression was also seen in castration-resistant subtype CxR cells compared with parental LNCaP cells. Finally, we found that aspirin and EP3 modulators affected prostate cancer cell growth. Taken together, aspirin suppressed LNCaP cell proliferation via EP3 signaling activation; EP3 downregulation contributed to prostate carcinogenesis and to progression from androgen-dependent prostate cancer to castration-resistant prostate cancer by regulating AR expression. In conclusion, cyclooxygenases and EP3 may represent attractive therapeutic molecular targets in androgen-dependent prostate cancer.. |
| 264. |
Masaki Shiota, Akira Yokomizo, Seiji Naito, Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer, Endocrine-Related Cancer, 10.1530/ERC-12-0232, 19, 6, R243-R253, 2012.12, Oxidative stress caused by an increase in reactive oxygen species levels or a decrease in cellular antioxidant capacity can evoke the modulation of various cellular events including androgen receptor (AR) signaling via direct or indirect interactions. In this review, we summarize the mechanisms of AR activation by oxidative stress including: i) AR overexpression; ii) AR activation by AR co-regulators or intracellular signal transduction pathways; iii) generation of AR mutations or splice variants; and iv) de novo androgen synthesis. AR signaling augmented by oxidative stress appears to contribute to pro-survival and anti-apoptotic effects in prostate cancer cells in response to androgen deprivation therapy. In addition, AR signaling suppresses anti-survival and pro-apoptotic effects in prostate cancer cells in response to various cytotoxic and tumorsuppressive interventions including taxanes and radiation through the modulation of bIII-tubulin and ataxia telangiectasia-mutated kinase expression respectively. Taken together, AR signaling appears to render prostate cancer cells refractory to various therapeutic interventions including castration, taxanes, and radiation, indicating that AR signaling is a comprehensive resistant factor and crucial target for prostate cancer treatment.. |
| 265. |
Masaki Shiota, Ario Takeuchi, Yoo Hyun Song, Akira Yokomizo, Eiji Kashiwagi, Takeshi Uchiumi, Kentaro Kuroiwa, Katsunori Tatsugami, Naohiro Fujimoto, Yoshinao Oda, Seiji Naito, Y-box binding protein-1 promotes castration-resistant prostate cancer growth via androgen receptor expression, Endocrine-Related Cancer, 10.1530/ERC-11-0017, 18, 4, 505-517, 2011.08, The androgen receptor (AR) is well known to play a central role in the pathogenesis of prostate cancer (PCa). In several studies, AR was overexpressed in castration-resistant PCa (CRPC). However, the mechanism of AR overexpression in CRPC is not fully elucidated. Y-box binding protein-1 (YB-1) is a pleiotropic transcription factor that is upregulated in CPRC. We aimed to elucidate the role of YB-1 in castration resistance of PCa and identify therapeutic potential of targeting YB-1. Using immunohistochemistry, we found that nuclear YB-1 expression significantly correlated with the Gleason score and AR expression in PCa tissues. In PCa cells, YB-1 regulated AR expression at the transcriptional level. Furthermore, YB-1 expression and nuclear localization were upregulated in CRPC cells. Overexpression of AR, as well as YB-1, conferred castrationresistant growth in LNCaP and 22Rv1 cells. Conversely, knocking down YB-1 resulted in suppressed cell growth and induced apoptosis, which was more efficient than knocking down AR in LNCaP cells. In other types of PCa cells, such as CRPC cells, knocking down YB-1 resulted in a significant reduction of cell growth. In conclusion, these findings suggested that YB-1 induces castration resistance in androgen-dependent PCa cells via AR expression. Thus, YB-1 may be a promising therapeutic target for PCa, as well as CRPC.. |
| 266. |
M. Shiota, Y. Song, A. Yokomizo, Y. Tada, K. Kuroiwa, M. Eto, Y. Oda, J. Inokuchi, T. Uchiumi, N. Fujimoto, N. Seki, S. Naito, Human heterochromatin protein 1 isoform HP1β enhances androgen receptor activity and is implicated in prostate cancer growth, Endocrine-Related Cancer, 10.1677/ERC-09-0321, 17, 2, 455-467, 2010.06, There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, heterochromatin protein 1β (HP1β), but not HP1α or HP1γ was found to be an AR cofactor. HP1β interacted with the AR, and enhanced the DNA-binding ability of AR to androgen-responsive element in the prostate-specific antigen enhancer and promoter regions, and to increase the transcription of AR target genes. In prostate cancer (PCa) tissues, HP1β expressions correlated with Gleason score and tri-methylation levels of histone H3 lysine 9. Silencing of HP1β suppressed the growth of AR-expressing PCa cells by inducing cell-cycle arrest at the G1 phase, similar to inhibition of androgen/AR signaling. Furthermore, HP1β was overexpressed in castration-resistant LNCaP derivative CxR cells, and HP1β knockdown also suppressed the cell growth in CxR cells. These findings indicate that HP1β is involved in the proliferation of AR-expressing PCa cells and progression to CRPC as an AR coactivator. Modulation of HP1β expression or function might be a useful strategy for developing novel therapeutics for PCa, even in CRPC.. |
| 267. |
Minako Inoue, Ken Okamura, Chie Kitaoka, Fumio Kinoshita, Ryo Namitome, Udai Nakamura, Masaki Shiota, Kenichi Goto, Toshio Ohtsubo, Kiyoshi Matsumura, Yoshinao Oda, Masatoshi Eto, Takanari Kitazono, Metyrapone-responsive ectopic acth-secreting pheochromocytoma with a vicious cycle via a glucocorticoid-driven positive-feedback mechanism, Endocrine Journal, 10.1507/endocrj.EJ18-0025, 65, 7, 755-767, 2018, In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor.18F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, while123I-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing’s syndrome. A glucocorticoid-driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained.. |
| 268. |
James W. Peacock, Ario Takeuchi, Norihiro Hayashi, Liangliang Liu, Kevin J. Tam, Nader Al Nakouzi, Nastaran Khazamipour, Tabitha Tombe, Takashi Dejima, Kevin C.K. Lee, Masaki Shiota, Daksh Thaper, Wilson C.W. Lee, Daniel H.F. Hui, Hidetoshi Kuruma, Larissa Ivanova, Parvin Yenki, Ivy Z.F. Jiao, Shahram Khosravi, Alice L.F. Mui, Ladan Fazli, Amina Zoubeidi, Mads Daugaard, Martin E. Gleave, Christopher J. Ong, SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1, EMBO Molecular Medicine, 10.15252/emmm.201707689, 10, 2, 219-238, 2018.02, Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1. SEMA3C expression levels increase in castration-resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide-resistant progression. Plexin B1 sema domain-containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post-castration in vivo. SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.. |
| 269. |
Masaki Shiota, Akira Yokomizo, Naohiro Fujimoto, Hidetoshi Kuruma, Seiji Naito, Castration-resistant prostate cancer
Novel therapeutics pre- or post-taxane administration, Current Cancer Drug Targets, 10.2174/15680096113139990078, 13, 4, 444-459, 2013, Until 2010 docetaxel was the only agent with a proven survival benefit in the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC is caused by augmented androgen/androgen receptor (AR) signaling involving AR hypersensitivity, promiscuous activation of the AR, de novo production of androgens and activation of the AR by cytokines and growth factors; these findings have led to the development of novel agents targeting AR signaling. Several novel drugs targeting the AR axis, including the cytochrome P17 inhibitor abiraterone acetate and anti-androgen enzalutamide (MDV3100), have shown promising results in prolonging survival in clinical trials in a postchemotherapy setting. Because of these encouraging findings, these drugs have also been evaluated in a pre-chemotherapy setting. In addition, several novel drugs targeting non-AR signaling, including the novel taxoid compound cabazitaxel, antisense oligonucleotide OGX-011 (custirsen), sipuleucel-T immunotherapy and Alpharadin-based radiotherapy, have also been demonstrated to improve overall survival in CRPC. However, there is no consensus with regard to the sequence in which these novel drugs and taxanes should be used in the treatment of CRPC. In this review, we summarize recently developed and developing novel agents for use against CRPC. We also discuss the sequence of use of these agents and taxanes, mainly from the standpoint of factors related to drug resistance.. |
| 270. |
Masaki Shiota, Akira Yokomizo, Naohiro Fujimoto, Seiji Naito, Androgen receptor cofactors in prostate cancer
Potential therapeutic targets of castration-resistant prostate cancer, Current Cancer Drug Targets, 10.2174/156800911796798904, 11, 7, 870-881, 2011.09, Androgens, acting through the androgen receptor (AR), are responsible for many male reproductive and nonreproductive functions. Moreover, aberrant androgen/AR signaling plays a critical role in androgen-dependent prostate cancer (PCa) as well as castration-resistant prostate cancer (CRPC). The formation of a productive AR transcriptional complex requires AR cofactors that interact functionally and structurally with the AR. Since the discovery of the first such cofactor in 1995, an ever increasing number of proteins have been identified as AR coactivators or corepressors. The expression and function of several AR cofactors have been investigated in PCa, and a clear link between AR cofactors and the development and progression of PCa has been identified. Recently, AR splice variants in CRPC were reported, which display significant constitutive activity in the absence of ligand. Then, this discovery revolutionized the concept of AR cofactors in CRPC. The current review aims to provide an overview of AR cofactor proteins in the context of PCa. In addition, we discuss the potential of AR cofactors as novel therapeutic targets for PCa, particularly for CRPC.. |
| 271. |
Masaki Shiota, Naohiro Fujimoto, Shigehiro Tsukahara, Miho Ushijima, Ario Takeuchi, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Masatoshi Eto, Genetic Polymorphism in Sex Hormone-binding Globulin With a Prognosis of Androgen Deprivation Therapy in Metastatic Prostate Cancer Among Japanese Men, Clinical Genitourinary Cancer, 10.1016/j.clgc.2019.03.021, 17, 3, e387-e393, 2019.06, Introduction: Testosterone suppression in serum during androgen deprivation therapy (ADT) can affect the oncologic outcome of ADT. Although genetic variants in sex hormone-binding globulin (SHBG) were reported to be correlated with serum testosterone level, the association with serum testosterone during ADT remains unclear. Therefore, this study investigated the impact of a missense polymorphism in the SHBG gene among men treated with primary ADT for metastatic prostate cancer. Patients and Methods: This study included 104 Japanese men with metastatic prostate cancer. The association of SHBG gene polymorphism (rs6259, D356N) with clinicopathologic parameters including serum testosterone levels during ADT, as well as prognosis, including progression-free survival and overall survival, was examined. Results: The serum testosterone levels during ADT were comparable between men carrying the homozygous wild-type (GG) and heterozygous/homozygous variant (GA/AA) in the SHBG gene. When adjusted for age, Gleason score, initial prostate-specific antigen, and clinical T-stage, the heterozygous/homozygous variant (GA/AA) in the SHBG gene was associated with a higher risk of progression (hazard ratio, 2.20; 95% confidence interval, 1.10-4.18; P =.027) and any-cause death (hazard ratio, 3.21; 95% confidence interval, 1.31-7.35; P =.012). Conclusions: This study suggested genetic variation in SHBG (rs6259) might be an independent prognostic biomarker among men treated with primary ADT for metastatic prostate cancer.. |
| 272. |
Naohiro Fujimoto, Masaki Shiota, Ikko Tomisaki, Akinori Minato, Gene Polymorphism-related Individual and Interracial Differences in the Outcomes of Androgen Deprivation Therapy for Prostate Cancer, Clinical Genitourinary Cancer, 10.1016/j.clgc.2017.01.006, 15, 3, 337-342, 2017.06, Among patients with prostate cancer, the prognosis after androgen deprivation therapy differs significantly among individuals and among races; however, the reasons underlying these differences are poorly understood. Several single nucleotide polymorphisms in genes associated with prostate cancer progression or castration resistance might serve as the host factor that influences prognosis and, thus, accounts for these individual and racial gaps in treatment outcomes. Accordingly, single nucleotide polymorphisms associated with treatment outcomes could be used as predictive and/or prognostic biomarkers for patient stratification and to identify personalized treatment and follow-up protocols. The present review has summarized the genetic polymorphisms that have been reported to associate with androgen deprivation therapy outcomes among patients with prostate cancer and compared the allele frequencies among different ethnic groups.. |
| 273. |
Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Kenjiro Imada, Eiji Kashiwagi, Yoohyun Song, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito, Inhibition of protein kinase C/twist1 signaling augments anticancer effects of androgen deprivation and enzalutamide in prostate cancer, Clinical Cancer Research, 10.1158/1078-0432.CCR-13-1809, 20, 4, 951-961, 2014, Purpose: The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that the transcription factor Twist1, which promotes epithelial- mesenchymal transition, was involved in castration-resistant progression. Similarly, protein kinase C (PKC) has been implicated in both metastatic progression and castration resistance in prostate cancer. Experimental Design: In this study, we aimed to elucidate the role of PKC/Twist1 signaling in castration resistance, and to apply this information to the development of a novel therapeutic concept using PKC inhibitor Ro31-8220 against prostate cancer using various prostate cancer cell lines. Results: Androgen deprivation and the next-generation antiandrogen enzalutamide induced PKC activation and Twist1 expression, which were reversed by the PKC inhibitor Ro31-8220. Ro31-8220 suppressed cell proliferation in androgen-dependent prostate cancer LNCaP cells, which was augmented by its combination with androgen deprivation or enzalutamide. The favorable anticancer effects of the combination of Ro31-8220 and enzalutamide were also observed in castration-resistant C4-2 and 22Rv1 cells. Furthermore, PKC phosphorylation was elevated in castration-resistant and enzalutamide-resistant cells compared with their parental cells, leading to persistent sensitivity to Ro-31-8220 in castration- and enzalutamide-resistant cells. Conclusions: Taken together, these findings indicate that PKC/Twist1 signaling contributes to castration resistance as well as enzalutamide resistance in prostate cancer, and suggest that therapeutics targeting PKC/ Twist1 signaling, such as PKC inhibitors, represent a promising novel therapeutic strategy for prostate cancer, especially castration-resistant prostate cancer, when combined with enzalutamide.. |
| 274. |
Kenjiro Imada, Masaki Shiota, Kenichi Kohashi, Kentaro Kuroiwa, Yoo Hyun Song, Masaaki Sugimoto, Seiji Naito, Yoshinao Oda, Mutual regulation between Raf/MEK/ERK signaling and Y-box-binding protein-1 promotes prostate cancer progression, Clinical Cancer Research, 10.1158/1078-0432.CCR-12-3705, 19, 17, 4638-4650, 2013.09, Purpose: Y-box-binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer. Experimental Design: Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses. Results: EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor [HR, 7.947; 95% confidence interval (CI), 3.527-20.508; P |
| 275. |
Masaki Shiota, Yoo Hyun Song, Akira Yokomizo, Keijiro Kiyoshima, Yasuhiro Tada, Hiroshi Uchino, Takeshi Uchiumi, Junichi Inokuchi, Yoshinao Oda, Kentaro Kuroiwa, Katsunori Tatsugami, Seiji Naito, Foxo3a suppression of urothelial cancer invasiveness through twist1, Y-box-binding protein 1, and E-cadherin regulation, Clinical Cancer Research, 10.1158/1078-0432.CCR-10-0376, 16, 23, 5654-5663, 2010.12, Purpose: Invasion and metastasis are key steps in the progression of urothelial cancer (UC) into a critical disease. Foxo3a is a member of the Foxo transcription factor family that modulates the expression of various genes. We aimed to elucidate the role of Foxo3a in UC invasion. Experimental Design: Foxo3a mRNA and protein expressions in UC samples were investigated by gene expression assays and immunohistochemistry, respectively. Foxo3a expression was compared with clinicopathologic characteristics and patient prognoses based on UC samples. Quantitative real-time polymerase chain reaction, Western blotting, and migration assays were also conducted in UC cells. Results: Foxo3a expression decreased in invasive UC; patients with low Foxo3a expression had poor disease-free survival, cancer-specific survival, and overall survival; Foxo3a knockdown in UC cells increased cellular motility. Foxo3a negatively regulated Twist1 and Y-box-binding protein 1 (YB-1), and positively regulated E-cadherin in KK47 and TCC sup cells that expressed Twist 1, but not in T24 cells that did not express Twist1. Foxo3a-associated acetyltransferase p300 and Foxo3a acetylation status also affected UC motility. Conclusion: The results of this study indicate that Foxo3a regulates motility of UC through negative regulation of Twist1 and YB-1, and through positive regulation of E-cadherin. This suggests that Foxo3a could act as an independent prognostic factor in UC and could represent a promising molecular target for cancer therapeutics.. |
| 276. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Efficacy and safety of 4-weekly cabazitaxel for castration-resistant prostate cancer
a multi-institutional study, Cancer chemotherapy and pharmacology, 10.1007/s00280-019-03874-7, 84, 3, 561-566, 2019.09, Objective: This study aimed to reveal the efficacy and safety profiles of 4-weekly cabazitaxel in patients with castration-resistant prostate cancer (CRPC). Methods: The study included 62 Japanese patients who were treated for CRPC with ≥ 2 courses of cabazitaxel between 2014 and 2017. The oncological outcomes and adverse events were compared between 16 (25.8%) and 46 (74.2%) men who were treated with standard 3-weekly and alternative 4-weekly regimens, respectively. Results: The prostate-specific antigen (PSA) response was comparable between the 3-weekly and 4-weekly regimens (median [interquartile range]: − 9.9% [− 64.5 to 13.0%] and − 30.7% [− 52.8 to 10.9%], P = 0.89), respectively. For patients on the 4-weekly regimen, the risks of progression (hazard ratio [HR], 95% confidence interval [CI] 1.27, 0.71–2.43, P = 0.44), treatment failure (HR, 95% CI 0.84, 0.48–1.55, P = 0.57) and any-cause mortality (HR, 95% CI 1.09, 0.58–2.17, P = 0.79) were comparable to those for patients on the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. Conclusions: 3-weekly and 4-weekly regimens of cabazitaxel showed similar efficacy and safety profiles in a real-world clinical setting. These data suggest that a 4-weekly regimen may be acceptable for selected patients.. |
| 277. |
Masaki Shiota, Naohiro Fujimoto, Shigehiro Tsukahara, Miho Ushijima, Ario Takeuchi, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Masatoshi Eto, The impact of genetic polymorphism on CYP19A1 in androgen-deprivation therapy among Japanese men, Cancer chemotherapy and pharmacology, 10.1007/s00280-019-03811-8, 2019.01, Purpose: Inadequate suppression of testosterone during androgen-deprivation therapy impairs its efficacy. This study investigated the significance of genetic polymorphism in CYP19A1, which encodes aromatase that catalyzes androgens into estrogens, among men treated with primary ADT for metastatic prostate cancer. Methods: This study included 80 Japanese patients with metastatic prostate cancer whose serum testosterone levels during ADT were available. The association of CYP19A1 gene polymorphism (rs1870050) with clinicopathological parameters including serum testosterone levels during ADT as well as progression-free survival and overall survival was examined. Results: Serum testosterone levels during ADT of men carrying homozygous wild-type (AA) in the CYP19A1 gene [median (interquartile range); 11.6 (8.3–20.3) ng/dl] were higher than those in men carrying the heterozygous/homozygous variant (AC/CC) [median (interquartile range); 10.0 (6.4–12.8) ng/dl]. When adjusted by Gleason score, initial PSA, M-stage and serum testosterone level during ADT, heterozygous/homozygous variant (AC/CC) in the CYP19A1 gene was associated with a lower risk of progression to castration resistance [hazard ratio (95% confidence interval), 0.53 [0.29–0.92], p = 0.025], but not to any-cause death [hazard ratio (95% confidence interval), 0.74 [0.36–1.49], p = 0.40]. Conclusions: These findings suggest that genetic variation in CYP19A1 (rs1870050) might affect the prognosis of patients with metastatic prostate cancer when treated with ADT by regulating serum testosterone levels.. |
| 278. |
Masaki Shiota, Takashi Dejima, Yoshiaki Yamamoto, Ario Takeuchi, Kenjiro Imada, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto, Collateral resistance to taxanes in enzalutamide-resistant prostate cancer through aberrant androgen receptor and its variants, Cancer Science, 10.1111/cas.13751, 109, 10, 3224-3234, 2018.10, Currently, the optimal sequential use of androgen receptor (AR) axis-targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide-resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane-resistant cells showed no collateral resistance to enzalutamide; taxane-resistant cells expressed comparable protein levels of full-length AR and AR variants. Knockdown of both full-length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full-length AR rendered cells resistant to taxanes. Consistently, the prostate-specific antigen response and progression-free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance.. |
| 279. |
Ario Takeuchi, Masaki Shiota, Katsunori Tatsugami, Akira Yokomizo, Masatoshi Eto, Junichi Inokuchi, Kentaro Kuroiwa, Keijiro Kiyoshima, Seiji Naito, Sorafenib augments cytotoxic effect of S-1 in vitro and in vivo through TS suppression, Cancer chemotherapy and pharmacology, 10.1007/s00280-011-1660-6, 68, 6, 1557-1564, 2011.12, Purpose: Sorafenib, a multikinase and tyrosine-kinase inhibitor, has anti-tumor activity in patients with advanced renal cell carcinoma (RCC). Recently, we reported that S-1 was active and well tolerated for the treatment of cytokine-refractory metastatic RCC. Therefore, we hypothesized that S-1 might be a good candidate for combination therapy with molecular targeting agents. In this study, we examined the mechanisms underlying for the synergism between S-1 and Sorafenib for RCC treatment in vitro and in tumor-bearing murine models. Methods: Human RCC cell lines were used for the in vitro cell proliferation assay. ACHN and 786-O tumors were subcutaneously transplanted into NCr-nu/nu-mice. Mice were treated with S-1 and/or Sorafenib, and tumor growth and side effects were monitored. Results: Synergistic anti-proliferative effects of Sorafenib and S-1 were clearly demonstrated in ACHN and 786-O cell lines in vitro due to the suppression of TS and E2F-1 expression. In the NCr-nu/nu model, the synergistic anti-tumor effects of S-1 and Sorafenib were again clearly seen, indicating direct synergistic effects of each drug on tumor growth. Conclusions: Our results demonstrate the synergistic activity of S-1 and Sorafenib and provided the rationale for combination therapy with S-1 and Sorafenib for the treatment of patients with advanced RCC.. |
| 280. |
Momoe Itsumi, Masaki Shiota, Ario Takeuchi, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Takeshi Uchiumi, Seiji Naito, Masatoshi Eto, Akira Yokomizo, Equol inhibits prostate cancer growth through degradation of androgen receptor by S-phase kinase-associated protein 2, Cancer Science, 10.1111/cas.12948, 107, 7, 1022-1028, 2016.07, Chemopreventive and potential therapeutic effects of soy isoflavones have been shown to be effective in numerous preclinical studies as well as clinical studies in prostate cancer. Although the inhibition of androgen receptor signaling has been supposed as one mechanism underlying their effects, the precise mechanism of androgen receptor inhibition remains unclear. Thus, this study aimed to clarify their mechanism. Among soy isoflavones, equol suppressed androgen receptor as well as prostate-specific antigen expression most potently in androgen-dependent LNCaP cells. However, the inhibitory effect on androgen receptor expression and activity was less prominent in castration-resistant CxR and 22Rv1 cells. Consistently, cell proliferation was suppressed and cellular apoptosis was induced by equol in LNCaP cells, but less so in CxR and 22Rv1 cells. We revealed that the proteasome pathway through S-phase kinase-associated protein 2 (Skp2) was responsible for androgen receptor suppression. Taken together, soy isoflavones, especially equol, appear to be promising as chemopreventive and therapeutic agents for prostate cancer based on the fact that equol augments Skp2-mediated androgen receptor degradation. Moreover, because Skp2 expression was indicated to be crucial for the effect of soy isoflavones, soy isoflavones may be applicable for precancerous and cancerous prostates.. |
| 281. |
Masaki Shiota, Akira Yokomizo, Yasuhiro Tada, Takeshi Uchiumi, Junichi Inokuchi, Katsunori Tatsugami, Kentaro Kuroiwa, Ken Yamamoto, Narihito Seki, Seiji Naito, P300/CBP-associated factor regulates Y-box binding protein-1 expression and promotes cancer cell growth, cancer invasion and drug resistance, Cancer Science, 10.1111/j.1349-7006.2010.01598.x, 101, 8, 1797-1806, 2010.08, Twist1 has been proposed to have oncogenic properties. Although Twist1 was reported to interact with p300/CBP-associated factor (PCAF) and to inhibit the functions of PCAF, it remains unclear how PCAF affects the functions of Twist1, cell growth, invasive ability, and cellular sensitivity to anticancer agents. We found that PCAF, Twist1, and Y-box binding protein-1 (YB-1) expressions were elevated in cisplatin- and doxorubicin-resistant cancer cells. Luciferase reporter assays revealed that PCAF manipulation modulated YB-1 transcription in a Twist1-dependent manner. In addition, PCAF regulated the Twist1 intracellular localization and the Twist1 transcriptional activity through its acetylation function to the Twist1. Suppression of PCAF expression reduced YB-1 expression in human urothelial cancer KK47 cells. As a result, the cell growth and invasive ability of KK47 cells was retarded by PCAF knockdown, and PCAF knockdown rendered KK47 cells sensitive to cisplatin and doxorubicin, but not to 5-fluorouracil. The present data suggest that Twist1 and YB-1 as well as PCAF may be promising molecular therapeutic targets. (Cancer Sci 2010).. |
| 282. |
Masaki Shiota, Akira Yokomizo, Eiji Kashiwagi, Yasuhiro Tada, Junichi Inokuchi, Katsunori Tatsugami, Kentaro Kuroiwa, Takeshi Uchiumi, Narihito Seki, Seiji Naito, Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin, Cancer Science, 10.1111/j.1349-7006.2010.01503.x, 101, 5, 1177-1185, 2010.05, Many advanced cancers receive cisplatin-based chemotherapy. However, cisplatin resistance is a major obstacle for cancer chemotherapy. Foxo3a is a member of the Foxo transcription factor family, which modulates the expression of genes involved in DNA damage repair, apoptosis, and other cellular processes. In this study, we found that cisplatin-resistant cells were more sensitive to the anticancer agent mithramycin than their parental cells, and had a decreased level of Foxo3a expression. Foxo3a knockdown increased cell proliferation and resistance to cisplatin. On the other hand, mithramycin stimulated Foxo3a expression through reactive oxygen species production and sensitized cells to cisplatin, which was abolished by Foxo3a knockdown, while the acetylation status of Foxo3a was decreased in response to cisplatin treatment and was lower in cisplatin-resistant cells. Knockdown of Foxo3a-associated acetyltransferase p300 promoted cancer-cell growth and cisplatin resistance. In addition, non-acetylation-mimicking Foxo3a overexpression decreased cancer cell growth and sensitized cells to cisplatin less than wild-type Foxo3a overexpression. The current work may contribute to the evaluation of the therapeutic potential of inducing the Foxo3a pathway and acetylating the Foxo3a transcription factor, and lead to the reevaluation of cancer treatments based on mithramycin.. |
| 283. |
Masaki Shiota, Hiroto Izumi, Naoya Miyamoto, Takamitsu Onitsuka, Eiji Kashiwagi, Akihiko Kidani, General Hirano, Mayu Takahashi, Mayumi Ono, Michihiko Kuwano, Seiji Naito, Yasuyuki Sasaguri, Kimitoshi Kohno, Ets regulates peroxiredoxin1 and 5 expressions through their interaction with the high-mobility group protein B1, Cancer Science, 10.1111/j.1349-7006.2008.00912.x, 99, 10, 1950-1959, 2008, Peroxiredoxins (Prdxs) are thiol-specific antioxidant proteins that are highly expressed in human cancer cells. Prdxs have been shown to be involved in tumor cell proliferation under conditions of microenvironmental stress such as hypoxia. We hypothesized that Prdxs could be categorized into two groups, stress-inducible and non-inducible ones. In this study, we analyzed the promoter activity and expression levels of five Prdx family members in human cancer cells. We found that both Prdx1 and Prdx5 are inducible after treatment with hydrogen peroxide or hypoxia, but that Prdx2, Prdx3, and Prdx4 are not or are only marginally inducible. We also found that Ets transcription factors are the key activators for stress-inducible expression. High-mobility group protein HMGB1 was shown to function as a coactivator through direct interactions with Ets transcription factors. The DNA binding of Ets transcription factors was significantly enhanced by HMGB1. Silencing of Ets1, Ets2, Prdx1, and Prdx5 expression sensitized cells to oxidative stress. These data indicate that transcription of Prdx genes mediated by Ets/HMG proteins might protect cells from oxidative stress.. |
| 284. |
Ichiro Niina, Takeshi Uchiumi, Hiroto Izumi, Takayuki Torigoe, Tetsuro Wakasugi, Tomonori Igarashi, Naoya Miyamoto, Takamitsu Onitsuka, Masaki Shiota, Ryuichi Okayasu, Kazuo Chijiiwa, Kimitoshi Kohno, DNA topoisomerase inhibitor, etoposide, enhances GC-box-dependent promoter activity via Sp1 phosphorylation, Cancer Science, 10.1111/j.1349-7006.2007.00476.x, 98, 6, 858-863, 2007.06, Modification of transcription factors by anticancer agents plays an important role in both apoptotic and survival signaling. Here we report that both DNA topoisomerase I and II inhibitors such as SN-38 and etoposide, but not cisplatin, 5-fluorouracil or actinomycin D, can induce phosphorylation of the transcription factor Sp1. Furthermore, DNA topoisomerase inhibitors were shown to transactivate GC-box-dependent promoters such as the SV40 and vascular endothelial growth factor promoters. The phosphorylated form of Sp1 was detectable within 30 min of etoposide treatment and was greatly diminished by the presence of the PI3K inhibitor wortmannin and by DNA-dependent protein kinase (DNA-PK) knockdown. We also confirmed that the phosphorylated form of DNA-PK was increased by treatment with both etoposide and SN-38. Taken together, these findings demonstrate a novel genomic response to anticancer agents that induce Sp1 phosphorylation, and might contribute to tumor progression and drug resistance.. |
| 285. |
Hiroaki Matsumoto, Yoshiaki Yamamoto, Masaki Shiota, Hidetoshi Kuruma, Eliana Beraldi, Hideyasu Matsuyama, Amina Zoubeidi, Martin Gleave, Cotargeting androgen receptor and clusterin delays castrate-resistant prostate cancer progression by inhibiting adaptive stress response and AR stability, Cancer Research, 10.1158/0008-5472.CAN-13-0359, 73, 16, 5206-5217, 2013.08, Although androgen receptor (AR) pathway inhibitors prolong survival in castrate-resistant prostate cancer (CRPC), resistance rapidly develops and is often associated with increased stress-activated molecular chaperones like clusterin (CLU) and continued AR signaling. Because adaptive pathways activated by treatment facilitate development of acquired resistance, cotargeting the stress response, activated by AR inhibition and mediated through CLU, may create conditional lethality and improve outcomes. Here, we report that CLU is induced by AR antagonism and silencing using MDV3100 and antisense, respectively, to become highly expressed in castrateand MDV3100-resistant tumors and cell lines. CLU, as well as AKT and mitogen-activated protein kinase (MAPK) signalosomes, increase in response to MDV3100-induced stress. Mechanistically, this stress response is coordinated by a feed-forward loop involving p90rsk (RPS6KA)-mediated phosphoactivation of YB-1 with subsequent induction of CLU. CLU inhibition repressed MDV3100-induced activation of AKT and MAPK pathways. In addition, when combined with MDV3100, CLU knockdown accelerated AR degradation and repressed AR transcriptional activity through mechanisms involving decreased YB-1-regulated expression of the AR cochaperone, FKBP52. Cotargeting the AR (with MDV3100) and CLU (with OGX-011) synergistically enhanced apoptotic rates over that seen with MDV3100 or OGX-011 monotherapy and delayed CRPC LNCaP tumor and prostate-specific antigen (PSA) progression in vivo. These data indicate that cotargeting adaptive stress pathways activated by AR pathway inhibitors, and mediated through CLU, creates conditional lethality and provides mechanistic and preclinical proof-of-principle to guide biologically rational combinatorial clinical trial design.. |
| 286. |
Masaki Shiota, Jennifer L. Bishop, Ka Mun Nip, Anousheh Zardan, Ario Takeuchi, Thomas Cordonnier, Eliana Beraldi, Jenny Bazov, Ladan Fazli, Kim Chi, Martin Gleave, Amina Zoubeidi, Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer, Cancer Research, 10.1158/0008-5472.CAN-12-3979, 73, 10, 3109-3119, 2013.05, Defining the mechanisms underlying metastatic progression of prostate cancer may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-tomesenchymal transition (EMT), and the mechanisms that control the process of EMT in cancer cells are still emerging. Here, we report that the molecular chaperone Hsp27 (HSPB1) drives EMT in prostate cancer, whereas its attenuation reverses EMT and decreases cell migration, invasion, and matrix metalloproteinase activity. Mechanistically, silencing Hsp27 decreased IL-6-dependent STAT3 phosphorylation, nuclear translocation, and STAT3 binding to the Twist promoter, suggesting that Hsp27 is required for IL-6-mediated EMT via modulation of STAT3/Twist signaling. We observed a correlation between Hsp27 and Twist in patients with prostate cancer, with Hsp27 and Twist expression each elevated in high-grade prostate cancer tumors. Hsp27 inhibition by OGX-427, an antisense therapy currently in phase II trials, reduced tumor metastasis in a murine model of prostate cancer. More importantly, OGX-427 treatment decreased the number of circulating tumor cells in patients with metastatic castration-resistant prostate cancer in a phase I clinical trial. Overall, this study defines Hsp27 as a critical regulator of IL-6-dependent and IL-6-independent EMT, validating this chaperone as a therapeutic target to treat metastatic prostate cancer. Cancer Res; 73(10); 3109-19.. |
| 287. |
Masaki Shiota, Anousheh Zardan, Ario Takeuchi, Masafumi Kumano, Eliana Beraldi, Seiji Naito, Amina Zoubeidi, Martin E. Gleave, Clusterin mediates TGF-β-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells, Cancer Research, 10.1158/0008-5472.CAN-12-0254, 72, 20, 5261-5272, 2012.10, TGF-β promotes epithelial-mesenchymal transition (EMT) and induces clusterin (CLU) expression, linking these genes to cancer metastasis. CLU is a pleiotropic molecular chaperone that confers survival and proliferative advantage to cancer cells. However, the molecular mechanisms by which TGF-β regulates CLU expression and CLU affects metastasis remain unknown. In this study, we report that the transcription factor Twist1 mediates TGF-β-induced CLU expression. By binding to E-boxes in the distal promoter region of CLU gene, Twist1 regulated basal and TGF-β-induced CLU transcription. In addition, CLU reduction reduced TGF-β induction of the mesenchymal markers, N-cadherin and fibronectin, thereby inhibiting the migratory and invasive properties induced by TGF-β. Targeted inhibition of CLU also suppressed metastasis in an in vivo model. Taken together, our findings indicate that CLU is an important mediator of TGF-β-induced EMT, and suggest that CLU suppression may represent a promising therapeutic option for suppressing prostate cancer metastatic progression.. |
| 288. |
Masaki Shiota, M. Hiroto Izumi, Akihide Tanimoto, Mayu Takahashi, Naoya Miyamoto, Eiji Kashiwagi, Akihiko Kidani, Gen Hirano, Daisuke Masubuchi, Yasushi Fukunaka, Yoshihiro Yasuniwa, Seiji Naito, Shigeru Nishizawa, Yasuyuki Sasaguri, Kimitoshi Kohno, Programmed cell death protein 4 down-regulates Y-Box binding protein-1 expression via a direct interaction with twistl to suppress cancer cell growth, Cancer Research, 10.1158/0008-5472.CAN-08-2334, 69, 7, 3148-3156, 2009.04, Programmed cell death protein 4 (PDCD4) has recently been shown to be involved in both transcription and translation1and to regulate cell growth. However, the mechanisms underlying PDCD4 function are not well understood. In this study, we show that PDCD4 interacts directly with the transcription factor Twistl and leads to reduced cell growth through the down-regulation of the Twistl target gene Y-box binding protein-1 (YB-I). PDCD4 interacts with the DNA binding domain of Twistl, inhibiting its DNA binding ability and YB-I expression. Immunohistochemical analysis showed that an inverse correlation between nuclear PDCD4 and YB-I expression levels was observed in 37 clinical prostate cancer specimens. Growth suppression by PDCD4 expression was completely recovered by either Twistl or YB-I expression.Moreover, PDCD4-overexpressing cells are sensitive to cis-platin and paclitaxel but not to etoposide or 5-fluorouracil. In summary, PDCD4 negatively regulates YB-I expression via its interaction with Twistl and is involved in cancer cell growth and chemoresistance.. |
| 289. |
Masaki Shiota, Hiroto Izumi, Takamitsu Onitsuka, Naoya Miyamoto, Eiji Kashiwagi, Akihiko Kidani, Akira Yokomizo, Seiji Naito, Kimitoshi Kohno, Twist promotes tumor cell growth through YB-1 expression, Cancer Research, 10.1158/0008-5472.CAN-07-2981, 68, 1, 98-105, 2008.01, YB-1 controls gene expression through both transcriptional and translational mechanisms and is involved in various biological activities such as brain development, chemoresistance, and tumor progression. We have previously shown that YB-1 is overexpressed in cisplatin-resistant cells and is involved in resistance against DNA-damaging agents. Structural analysis of the YB-1 promoter reveals that several E-boxes may participate in the regulation of YB-1 expression. Here, we show that the E-box-binding transcription factor Twist is overexpressed in cisplatin-resistant cells and that YB-1 is a target gene of Twist. Silencing of either Twist or YB-1 expression induces G1 phase cell cycle arrest of tumor cell growth. Significantly, reexpression of YB-1 led to increase colony formation when Twist expression was down-regulated by small interfering RNA. However, cotransfection of Twist expression plasmid could not increase colony formation when YB-1 expression was down-regulated. Collectively, these data suggest that YB-1 is a major downstream target of Twist. Both YB-1 and Twist expression could induce tumor progression, promoting cell growth and driving oncogenesis in various cancers. Thus, both YB-1 and Twist may represent promising molecular targets for cancer therapy.. |
| 290. |
Masaki Shiota, Naohiro Fujimoto, Yoshiaki Yamamoto, Ario Takeuchi, Katsunori Tatsugami, Takeshi Uchiumi, Hideyasu Matsuyama, Masatoshi Eto, Genome-wide association study of genetic variations associated with treatment failure after intravesical bacillus Calmette–Guérin therapy for non-muscle invasive bladder cancer, Cancer Immunology, Immunotherapy, 10.1007/s00262-020-02533-8, 69, 7, 1155-1163, 2020.07, Bacillus Calmette–Guérin (BCG) instillation is a key therapy to manage non-muscle invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in approximately half of the patients, leading to recurrence and progression. We aimed to reveal the genetic variations associated with treatment failure after intravesical BCG therapy for NMIBC. This study included 91 Japanese patients treated with BCG instillation for NMIBC. Genomic DNA was obtained from patient whole-blood samples, and a genome-wide association study and genotyping for target regions were performed. The association between genetic variation and treatment failure was analyzed by genome-wide association in 44 patients as the discovery cohort. As a validation study, candidate single nucleotide polymorphisms (SNPs) were examined among 47 patients in another cohort. The genome-wide association study indicated 19 candidate SNPs (rs1607282, rs7825442, rs1319325, rs3738088, rs4250, rs11894207, rs161448, rs2764326, rs2814707, rs3787194, rs58081719, rs3095966, rs73520681, rs16877113, rs16887173, rs10269584, rs11772249, rs118137814, and rs61094339) associated with BCG failure. Following the cumulative analysis of candidate SNPs, 2-gene (rs73520681 and rs61094339) and 4-gene (rs4250, rs11894207, rs73520681, and rs61094339) models successfully predicted treatment failure after intravesical BCG therapy. This study showed that several SNPs were possibly associated with outcome after intravesical BCG therapy in a Japanese population with NMIBC. The cumulative models of these SNPs may have value in clinical applications, although this should be confirmed in future studies.. |
| 291. |
Ario Takeuchi, Masaki Shiota, Katsunori Tatsugami, Akira Yokomizo, Kentaro Kuroiwa, Takashi Dejima, Shingo Tanaka, Momoe Itsumi, Masatoshi Eto, Seiji Naito, YB-1 suppression induces STAT3 proteolysis and sensitizes renal cancer to interferon-α, Cancer Immunology, Immunotherapy, 10.1007/s00262-012-1356-8, 62, 3, 517-527, 2013.03, Renal cell carcinoma (RCC) accounts for 80-95 % of kidney tumors, and approximately 30 % of RCC patients have metastatic disease at diagnosis. Conventional chemotherapy is not effective in patients with metastatic RCC (MRCC); therefore, immunotherapy with interferon-α (IFN-α) has been employed to improve survival. However, the response rate of MRCC to IFN-α therapy is low. We previously reported that a signal transducer and activator 3 (STAT3) polymorphism was a useful diagnostic marker to predict the response to IFN-α therapy in patients with MRCC. Therefore, we hypothesized the inhibition of STAT3 in the addition of IFN-α therapy might be useful. Moreover, the blockage of STAT3 itself has been reported to enhance the antitumor effects. However, because IFN-α is thought to elicit its therapeutic effect via enhancement of an antitumor immune response mediated by lymphocytes that can be activated by IFN-α administrations, it is probable that the suppression of STAT3 in vivo relates to autoimmune disorders. In the present study, we found Y-box binding protein-1 (YB-1) was poorly expressed in T lymphocytes, as compared with cancer tissues. YB-1 was reported to have an important effect on the STAT3 pathway. Suppression of STAT3 by YB-1 inhibition did not seem to enhance the potential risk for autoimmune disorders. Moreover, we found sensitivity to IFN-α was increased by YB-1 suppression, and this suppression did not down-regulate IFN-α activation of T lymphocytes.. |
| 292. |
Masaki Shiota, Akira Yokomizo, Seiji Naito, Oxidative Stress and Prostate Cancer, Cancer
Oxidative Stress and Dietary Antioxidants, 10.1016/B978-0-12-405205-5.00002-7, 15-22, 2014.04, Prostate cancer is one of the most commonly diagnosed cancers in developed countries, affecting mainly older men. Elevated intracellular levels of reactive oxygen species (ROS), derived from increased ROS production or impaired antioxidant defenses, cause oxidative damage to various cellular components including DNA, proteins, and lipids, as well as activation of intracellular proto-oncogenic signaling. Through these channels, ROS can participate in a wide range of intracellular physiological and pathological processes, including cell proliferation, cell-cycle progression, antiapoptosis, invasion, metastasis, and angiogenesis, which contribute to malignant transformation and cancer progression. Aging, race, and family history are well-known and established risk factors for prostate cancer; other possible risk factors include androgens, inflammation, diet, and lifestyle. These definitive and potential risk factors can be linked to oxidative stress.In this chapter, we summarize the findings regarding the functional links between oxidative stress and prostate cancer.. |
| 293. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, E. T.O. Masatoshi, Prognostic impact of prior androgen receptor axis-targeting agents in cabazitaxel chemotherapy after docetaxel, Anticancer research, 10.21873/anticanres.13957, 40, 1, 335-339, 2020, Background/Aim: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents. Patients and Methods: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy. Results: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents. Conclusion: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the postdocetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.. |
| 294. |
Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Ken Ichiro Shiga, Hirofumi Koga, Akito Yamaguchi, Seiji Naito, Masatoshi Eto, Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare, BJU international, 10.1111/bju.13483, 118, 6, 880-884, 2016.12, Objective: To investigate the potential relationship of steroid usage with prostate-specific antigen (PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10–20% of patients with metastatic castration-resistant prostate cancer during docetaxel chemotherapy. Patients and Methods: This study included 71 patients with metastatic castration-resistant prostate cancer treated by docetaxel chemotherapy with co-introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease. Results: PSA flare was recognized in 7.0–23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression-free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure. Conclusions: Our results suggest that de novo steroid co-introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure.. |
| 295. |
Masaki Shiota, Akira Yokomizo, Momoe Itsumi, Takeshi Uchiumi, Yasuhiro Tada, Yoohyun Song, Eiji Kashiwagi, Daisuke Masubuchi, Seiji Naito, Twist1 and Y-box-binding protein-1 promote malignant potential in bladder cancer cells, BJU international, 10.1111/j.1464-410X.2010.09810.x, 108, 2 B, E142-E149, 2011.07, What's known on the subject? and What does the study add? So far, transcription factor Twist1 has been reported to regulate Y-box binding protein-1 (YB-1) expression and play important roles in tumour growth, invasion and drug resistance. This study revealed that in bladder cancer cells, Twist1 regulated YB-1 transcription and both Twist1 and YB-1 promote malignant potentials including tumour growth, invasion and anticancer-drug resistance. Although the relation between Twist1/YB-1 signaling and cancer malignant potentials including tumour growth, invasion and anticancer-drug resistance have been suggested, their roles in bladder cancer remain unknown. This study revealed their functional importance in bladder cancer, indicating that both Twist1 and YB-1 are promising molecular targets in bladder cancer. Objective: To investigate the roles of Twist1 and Y-box binding protein-1 (YB-1) and their potential as therapeutic targets in bladder cancer (BC), as both have been suggested to play important roles in tumour growth, invasion and drug resistance. Materials and methods: Bladder cancer cell lines (TCCsup, UMUC3, T24 and KK47 cells) were used. Twist1 and YB-1 expression levels were assessed by luciferase reporter assay, quantitative real-time polymerase chain reaction (PCR) and western blot analysis. Tumour growth and cell cycle were analysed by cell proliferation assay and flow cytometry, respectively. Invasive and motile abilities were investigated by scratch-wound test and migration assay, respectively. Cytotoxicity assay was performed to determine drug sensitivity. Results: The findings showed that Twist1 regulated YB-1 expression in BC cells. Both Twist1 and YB-1 were involved in cell growth, invasion, motility and resistance to cisplatin and doxorubicin, but not to 5-fluorouracil (5-FU). Conclusion: The present study showed that Twist1 regulates YB-1 expression and that both Twist1 and YB-1 promote malignant potentials, including tumour growth, invasion and anti-cancer-drug resistance, indicating that both Twist1 and YB-1 are novel molecular targets in BC.. |
| 296. |
Masaki Shiota, Toshiyuki Tsunoda, Yoohyun Song, Akira Yokomizo, Yasuhiro Tada, Yoshinao Oda, Seiji Naito, Enhanced S100 calcium-binding protein P expression sensitizes human bladder cancer cells to cisplatin, BJU international, 10.1111/j.1464-410X.2010.09535.x, 107, 7, 1148-1153, 2011.04, OBJECTIVE: To investigate the role of S100 calcium-binding protein P (S100P) in the gain of cis-diamminedichloroplatinum (II) (cisplatin) resistance in bladder cancer, having previously found, with cDNA microarrays using two pairs of parental (T24, KK47) and their cisplatin-resistant bladder cancer cell lines (T24/DDP10, KK47/DDP20), that S100P mRNA expression was significantly reduced in cisplatin-resistant cells. MATERIALS AND METHODS S100P mRNA and protein expression levels were investigated by northern and western blot analyses, respectively. Intracellular S100P localization was examined by immunocytochemistry and immunohistochemistry. S100P over-expression, obtained by transfection with S100P expression plasmid, was used to investigate whether or not S100P affected cellular resistance to cisplatin. RESULTS S100P mRNA showed increased expression by cisplatin stimulation in parental cell lines. On the other hand, S100P mRNA and protein expression levels were markedly reduced in cisplatin-resistant cells. The over-expression of S100P in resistant cells resulted in an increased sensitivity to cisplatin. CONCLUSIONS In bladder cancer cells, S100P was expressed and localized mainly in the nucleus. S100P expression was also involved in cisplatin sensitivity. S100P might thus represent a molecular marker predicting cisplatin sensitivity and a molecular therapeutic target for cisplatin-based chemotherapy.. |
| 297. |
Kyung Chul Choi, Si Yong Park, Beom Jin Lim, Ah Reum Sung, Yoo Hyun Lee, Masaki Shiota, Akira Yokomizo, Seiji Naito, Younghwa Na, Ho Geun Yoon, Procyanidin B3, an inhibitor of histone acetyltransferase, enhances the action of antagonist for prostate cancer cells via inhibition of p300-dependent acetylation of androgen receptor, Biochemical Journal, 10.1042/BJ20100980, 433, 1, 235-244, 2011.01, Increasing evidence suggests that AR (androgen receptor) acetylation is critical for prostate cancer cell growth. In the present study, we identified Pro-B3 (procyanidin B3) as a specific HAT (histone acetyltransferase) inhibitor. Pro-B3 selectively inhibited the activity of HATs, but not other epigenetic enzymes. Pro-B3 substantially inhibited the p300-mediated AR acetylation, both in vitro and in vivo. Pro-B3 inhibited both p300-dependent and agonist-induced AR transcription. We demonstrate that the p300-mediated AR acetylation is critical for the hormone responsiveness of AR. Interestingly, B3 treatment efficiently enhanced the antagonist activity of flutamide through suppression of p300 HAT activity, demonstrating that relative p300 activity is critical for the antagonist action. Finally, Pro-B3 treatment inhibited acetylation-dependent prostate cell proliferation and expression of cell-cycle control genes, subsequently increasing cell death, indicating the functional importance of AR acetylation for prostate cancer cell growth.. |
| 298. |
Masakazu Akitake, Akito Yamaguchi, Masaki Shiota, Kenjiro Imada, Katsunori Tatsugami, Akira Yokomizo, Seiji Naito, Masatoshi Eto, Predictive factors for residual cancer in second transurethral resection for non-muscle-invasive bladder cancer, Anticancer research, 10.21873/anticanres.13598, 39, 8, 4325-4328, 2019, Background/Aim: The significance of second transurethral resection (TUR), and identification of predictive factors for residual cancer remain unrevealed. This study aimed to find residual cancer and up-staging rates, as well as predictive factors for residual cancer, in patients who undergo second TUR for non-muscle-invasive bladder cancer (NMIBC). Patients and Methods: Patients who underwent second TURs for NMIBC between 2015 and 2017, were included in the study and their clinicopathological characteristics were analyzed for predictors of residual cancer. Results: Among 143 Japanese patients whose tumors were initially diagnosed as high-risk NMIBC, residual cancers detected at second TURs were, Tis: n=22 (15.4%), Ta: n=15 (10.5%) and T1: n=29 (20.3%). No patients showed upstaging from NMIBC to MIBC. The presence of carcinoma-in situ at initial TUR was an independent risk factor for any residual cancer (Tis, Ta and T1), non-flat residual cancer (Ta and T1), and flat residual cancer (Tis). Conclusion: The presence of carcinoma-in situ is suggested to be an independent predictor of residual cancer. This may help guide decisions to perform second TUR.. |
| 299. |
Takeshi Kobayashi, Ryo Namitome, Yu Hirata, Masaki Shiota, Kenjiro Imada, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Serum Prognostic Factors of Androgen-deprivation Therapy among Japanese Men with De Novo Metastatic Prostate Cancer, Anticancer research, 10.21873/anticanres.13457, 39, 6, 3191-3195, 2019, Background/Aim: To date, several serum prognostic factors have been reported in metastatic prostate cancer. In this study, we examined the prognostic value of these serum markers in Japanese men. Patients and Methods: This study included 104 patients with metastatic prostate cancer who were treated with primary androgen-deprivation therapy from 2001 to 2013. Clinicopathological factors including several serum markers were investigated for association with progression-free (PFS) and overall (OS) survival. Results: During a median follow-up of 48.1 months, median PFS and OS were 24.0 months and 67.4 months, respectively. When adjusted by age, prostate-specific antigen at diagnosis, Gleason score, and clinical stage, serum lactate dehydrogenase value was significantly associated with PFS [hazard ratio (HR)=1.42, 95% confidence interval (CI)=1.15-1.74; p=0.0004] and OS (HR=1.46, 95% CI=1.13-1.82; p=0.0014), in addition to alkaline phosphatase value for OS (HR=1.04; 95% CI=1.00-1.07; p=0.015). Conclusion: This study demonstrates the prognostic significance of alkaline phosphatase and lactate dehydrogenase values in Japanese men with de novo metastatic hormone-sensitive prostate cancer.. |
| 300. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Therapeutic outcome of >10 cycles of cabazitaxel for castration-resistant prostate cancer
A Multi-institutional Study, Anticancer research, 10.21873/anticanres.13612, 39, 8, 4411-4414, 2019, Background/Aim: Cabazitaxel use has usually been limited to up to 10 cycles in most countries according to the protocol in the TROPIC trial. Therefore, clinical data on cabazitaxel use beyond 10 cycles is limited. The aim of this study was to report the therapeutic outcome of cabazitaxel chemotherapy administered for >10 cycles. Patients and Methods: This study included 74 Japanese patients with prostate cancer between 2014 and 2017. Patients background, and treatment outcomes including PSA decline, progression-free survival, treatment-failure-free survival, overall survival, and adverse events were investigated, comparing patients treated with ≤10 and >10 cycles. Results: Patients characteristics were favorable as indicated by the higher number of cycles of prior docetaxel chemotherapy, absence of pain, and absence of bony and visceral metastases among men who received >10 cycles of cabazitaxel. PSA response, progression-free survival, treatment-failure-free survival and overall survival were better among patients treated with >10 cycles of cabazitaxel compared to those treated with ≤10 cycles. The incidence of severe adverse events was similar between the two groups. Conclusion: Taken together, this study suggested that continuous chemotherapy with cabazitaxel beyond 10 cycles may be beneficial.. |
| 301. |
Hirofumi Obata, Masaki Shiota, Naoko Akitake, Ario Takeuchi, Eiji Kashiwagi, Takashi Dejima, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Differential risk of castration resistance after initial radical prostatectomy or radiotherapy for prostate cancer, Anticancer research, 10.21873/anticanres.11998, 37, 10, 5631-5637, 2017.10, Background/Aim: Salvage androgen-deprivation therapy (ADT) is standard treatment for recurrent prostate cancer after curative therapy. However, the prognostic impact of different treatment modalities on the time to castration resistance remains unclear. In this study, we investigated the prognosis of men treated with salvage ADT after initial radical prostatectomy or radiotherapy for prostate cancer. Patients and Methods: Between 2000 and 2013, 149 Japanese men with recurrent prostate cancer who were initially treated with radical prostatectomy (n=95) or radiotherapy (n=54) and were subsequently treated with salvage ADT after disease recurrence were enrolled in this study. The prognostic significance of the curative treatment modality and clinicopathological findings were analyzed. Results: During a median follow-up period of 4.7 years after recurrence, castration-resistant progression was observed in 22 men. The 5-year progression-free survival, metastasis-free survival, cause-specific survival, and overall survival rates for all patients were 86.3%, 81.4%, 95.7%, and 94.5%, respectively. Multivariate analysis identified the biopsy Gleason score at initial diagnosis and the initial curative treatment modality as significant predictors of castration resistance. Conclusion: This study showed that low biopsy Gleason score (≤7) at diagnosis and radical prostatectomy as the curative treatment may be favorable prognostic factors for treatment with salvage ADT.. |
| 302. |
Keijiro Kiyoshima, Masakazu Akitake, Masaki Shiota, Ario Takeuchi, Ryosuke Takahashi, Junichi Inokuchi, Katsunori Tatsugami, Akira Yokomizo, Masatoshi Eto, Prognostic Significance of Preoperative Urine Cytology in Low-grade Non-muscle-invasive Bladder Cancer, Anticancer research, 36, 2, 799-802, 2016.02, AIM: To examine the clinical significance of preoperative urine cytology in patients with low-grade bladder cancer.
PATIENTS AND METHODS: We retrospectively investigated the records of 155 patients diagnosed with primary low-grade (Ta) urothelial carcinoma of the bladder between January 2000 and September 2014.
RESULTS: Patients with class III or greater cytology had significantly higher-grade (G2) (p=0.01), larger tumors (≥15 mm, p=0.0009) and significantly shorter recurrence-free survival compared to patients with class II or lower cytology (pCONCLUSION: Preoperative urine cytology, in addition to tumor size, might be a useful predictor of intravesical recurrence of bladder cancer.. |
| 303. |
Masaki Shiota, Ario Takeuchi, Masaaki Sugimoto, Eiji Kashiwagi, Takashi Dejima, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Akira Yokomizo, Prognostic Impact of Serum Testosterone and Body Mass Index Before Androgen-deprivation Therapy in Metastatic Prostate Cancer, Anticancer research, 35, 12, 6925-6932, 2015.12, AIM: Although the impact of testosterone or obesity on the efficacy of androgen-deprivation therapy (ADT) has been reported, there exist few comprehensive analyses on the impact of these factors on ADT outcome. Therefore, in the present study, we investigated the relationship between serum testosterone or body mass index (BMI) and prognosis among men treated with primary ADT for metastatic prostate cancer.
PATIENTS AND METHODS: The study included fifty-six Japanese patients with prostate cancer treated at our Institution from 2000 through 2012. The relationship between serum testosterone or BMI and progression-free survival, cancer-specific survival, and overall survival among men with metastatic prostate cancer treated with primary ADT was examined.
RESULTS: The median of serum testosterone and BMI were 397 ng/dl (interquartile range (IQR), 278-464 ng/dl) and 21.9 kg/m(2) (IQR, 19.2-23.6 kg/m(2)), respectively. Median progression-free survival, cancer-specific survival, and overall survival were 23.2 months, 68.9 months, and 68.1 months, respectively. Among clinicopathological parameters, the lowest-quartile group of serum testosterone level was a significant predictor of poor cancer-specific survival and overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis.
CONCLUSION: Serum testosterone level, but not obesity, is a prognostic factor for outcome including survival after getting castration-resistant prostate cancer in men with metastatic prostate cancer having undergone primary ADT.. |
| 304. |
Murakami T, Obata H, Akitake N, Shiota M, Takeuchi A, Kashiwagi E, Inokuchi J, Tatsugami K, Eto M:, Prognostic and Predictive Factors for Anti-androgen Withdrawal in Castration-resistant Prostate Cancer., Anticancer Res , 38 (7): 4115-4121, 2018, 2018.07. |
| 305. |
Masaki Shiota, Ario Takeuchi, Masaaki Sugimoto, Takashi Dejima, Eiji Kashiwagi, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Akira Yokomizo, Low serum testosterone but not obesity predicts high gleason score at biopsy diagnosed as prostate cancer in patients with serum PSA lower than 20 ng/ml, Anticancer research, 35, 11, 6137-6145, 2015.11, Background/Aim: The impact of testosterone or obesity on the pathological grade of prostate cancer remains controversial. Therefore, in this study, we investigated the relationship of serum testosterone and body mass index (BMI) to Gleason score at biopsy. Patients and Methods: This study included 128 Japanese patients diagnosed with prostate cancer from 2000 through 2012 whose serum testosterone level and BMI were measured before treatment. Associations between clinical parameters, including pre-treatment serum testosterone level and BMI, and Gleason score at biopsy were examined. Results: The median serum testosterone and BMI were 434 ng/dl (interquartile range=362-542 ng/dl) and 23.5 kg/m2 (interquartile range=21.7-25.4 kg/m2), respectively. Gleason score at biopsy was 7 for 58 patients (45.3%), 52 patients (40.6%) and 18 patients (14.1%), respectively. On univariate analysis, positive finding at digital rectal examination (DRE), high prostate-specific antigen level at diagnosis and low serum testosterone level, but not BMI, were correlated with high Gleason score at biopsy. Multivariate analysis identified positive finding at DRE and low serum testosterone level as significant predictors of a high Gleason score at prostate biopsy. By combining these parameters, the predictive ability of a high Gleason score was improved. Conclusion: This study showed that positive finding at DRE and a low pre-treatment serum testosterone level, but not obesity, may be factors predictive of aggressive prostate cancer, indicating the diagnostic value of serum testosterone, as well as DRE findings, in risk assessment.. |
| 306. |
Shiota M, Fujimoto N, Itsumi M, Takeuchi A, Inokuchi J, Tatsugami K, Yokomizo A, Kajioka S, Uchiumi T, Eto M, Gene polymorphisms in antioxidant enzymes correlate with the prognosis of androgen-deprivation therapy for metastatic prostate cancer with implications of oxidative stress., Ann Oncol, 10.1093/annonc/mdw646, 28(3):569-575., 2017.03. |
| 307. |
Masaki Shiota, Motonobu Nakamura, Akira Yokomizo, Toshihisa Tomoda, Naotaka Sakamoto, Narihito Seki, Shuji Hasegawa, Takakazu Yunoki, Masahiko Harano, Kentaro Kuroiwa, Masatoshi Eto, Prognostic significance of lactate dehydrogenase in cabazitaxel chemotherapy for castration-resistant prostate cancer
a multi-institutional study, Anti-cancer drugs, 10.1097/CAD.0000000000000884, 31, 3, 298-303, 2020.03, This multi-institutional study aimed to identify prognostic factors for cabazitaxel treatment of castration-resistant prostate cancer (CRPC). This study included 74 Japanese patients with CRPC who were treated with cabazitaxel between 2014 and 2017. Associations between clinicopathological factors including serum markers and progression-free survival (PFS) and overall survival (OS) were investigated. On multivariate analysis, high Gleason score [≥9 vs. ≤7; hazard ratio (HR), 95% confidence interval (CI): 2.00 (1.01-4.34); P = 0.047], presence of pain [HR, 95% CI: 2.02 (1.14-3.58); P = 0.016], and lactate dehydrogenase (LDH) level [HR, 95% CI: 47.31 (3.79-577.49); P = 0.0019] were significantly associated with PFS. Similarly, number of docetaxel cycles [HR, 95% CI: 0.050 (0.0037-0.45); P = 0.0057], performance status [≥2 vs. 0; HR, 95% CI: 5.07 (1.57-16.24); P |
| 308. |
Eiji Kashiwagi, Kenjiro Imada, Keisuke Monji, Ario Takeuchi, Masaki Shiota, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Psoas muscle volume is correlated with sexual activity and erectile dysfunction among patients with localised prostate cancer, Andrologia, 10.1111/and.13354, 51, 9, 2019.10, Several endocrinological and physical activities orchestrate men's sexual activities. To determine whether body composition calculated by computed tomography measurements is useful for estimating sexual function, we evaluated sexual function of localised prostate cancer patients using the Sexual Health Inventory for Men score, an original questionnaire, and computed tomography and magnetic resonance imaging. The imaging was performed to determine body composition, particularly the psoas muscle. Univariate and multivariate analyses were performed to identify factors affecting sexual activity. The multivariate analysis showed that the volume of the psoas muscle was significantly correlated with sexual activity (odds ratio [95% confidence interval]) (2.507 [1.029–6.109], p = 0.043) and erectile dysfunction (0.261 [0.098–0.692], p = 0.006). We concluded that the psoas muscle is an important predictor of sexual activity and erectile function.. |
| 309. |
Masaki Shiota, Eiji Kashiwagi, Tomohiko Murakami, Ario Takeuchi, Kenjiro Imada, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto, Serum testosterone before and during androgen-deprivation therapy, and prognosis between cigarette smokers and nonsmokers with metastatic prostate cancer, Andrologia, 10.1111/and.13119, 50, 10, 2018.12, Cigarette smoking is suggested to influence androgen milieu, which is closely associated with pathogenesis and prognosis of prostate cancer. In this study, we investigated the association between serum testosterone level before or during androgen-deprivation therapy (ADT) as well as prognoses and cigarette smoking status among men with metastatic prostate cancer. Serum testosterone level before ADT in current smokers (n = 6, median [interquartile range, IQR]; 454 ng/ml [426–478 ng/ml]) was significantly higher than that in nonsmokers (n = 26, median [IQR]; 397 ng/ml [312–435 ng/ml]). Serum testosterone level during ADT in current smokers (n = 7, median [IQR]; 7 ng/ml [3–11 ng/ml]) was comparable with that in nonsmokers (n = 55, median [IQR]; 9 ng/ml [3–20 ng/ml]). Progression-free survival and overall survival were comparable between current smokers and nonsmokers when adjusted with serum testosterone level before ADT or during ADT. These results suggest adequate pharmacological effect of ADT, even in current smokers. However, serum testosterone level before ADT was higher in current smokers. Thus, we need to interpret serum testosterone level in current smokers with caution.. |
| 310. |
Masaki Shiota, Ario Takeuchi, Masaaki Sugimoto, Eiji Kashiwagi, Takashi Dejima, Keijiro Kiyoshima, Junichi Inokuchi, Katsunori Tatsugami, Akira Yokomizo, Masatoshi Eto, The Differential Impact of Body Mass Index and the Feature of Metabolic Syndrome on Oncological Outcomes Following Different Surgical Procedures in Japanese Men with Prostate Cancer, Annals of Surgical Oncology, 10.1245/s10434-016-5705-2, 24, 5, 1443-1450, 2017.05, Purpose: This study aimed to examine the differential impact of body mass index and the feature of metabolic syndrome (MetS; obesity, hypertension, diabetes mellitus, and dyslipidemia) on biochemical recurrence (BCR) following radical prostatectomy (RP) treatment for prostate cancer using different surgical procedures. Methods: This study included 283 Japanese patients with clinically localized prostate cancer who were treated with RP between 2008 and 2012. The prognostic significance of overweight and the feature of MetS were analyzed according to surgical procedures. Results: BCR occurred in 68/283 (24.0%) men. Overweight and the feature of MetS were predictors of BCR in patients who had undergone open RP (ORP), but not in those treated with laparoscopic surgery. Multivariate analyses incorporating preoperative and postoperative risk factors revealed that overweight and the feature of MetS were independent BCR risk factors when treated with ORP. Conclusions: In Japanese men, overweight and the feature of MetS were associated with worse outcomes following RP, particularly ORP, compared with those following laparoscopic surgery. These results suggest that laparoscopic surgery can overcome the surgical challenges associated with abdominal obesity.. |
