Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Junichi Inokuchi Last modified date:2021.11.04

Associate Professor / Department of Clinical Medicine / Faculty of Medical Sciences


Papers
1. 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.
2. 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.
3. 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, 2021.05.
4. 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.
5. Inokuchi J, Kuroiwa K, Nishiyama H, Kojima T, Kakehi Y, Sugimoto M, Takenaka A, Fujimoto K, Yamaguchi R, Habuchi T, Hashine K, Mizusawa J, Eba J, Naito S; Urologic Oncology Study Group of the Japan Clinical Oncology Group (JCOG):, Significance of the timing of ureteral ligation on prognosis during radical nephroureterectomy for upper urinary tract urothelial cancer., Int J Urol , 28 (2): 208-214, 2021, 2021.02.
6. 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.
7. Tohi Y, Kato T, Matsumoto R, Shinohara N, Shiga K, Yokomizo A, Nakamura M, Kume H, Mitsuzuka K, Sasaki H, Egawa S, Matsumura M, Hashine K, Inokuchi J, Eto M, Baba H, Ichikawa T, Kinoshita H, Matsuda T, Kakehi Y, Sugimoto M:, The impact of complications after initial prostate biopsy on repeat protocol biopsy acceptance rate. Results from the Prostate Cancer Research International: Active Surveillance JAPAN study., Int J Clin Oncol , 25 (12): 2107-2114, 2020, 2020.12.
8. Kobayashi S, Cho B, Mutaguchi J, Inokuchi J, Tatsugami K, Hashizume M, Eto M:, Surgical Navigation Improves Renal Parenchyma Volume Preservation in Robot-Assisted Partial Nephrectomy: A Propensity Score-matched Comparative Analysis., J Urol , 204 (1): 149-156, 2020, 2020.07.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. Toshiyuki Tsunoda, Junichi Inokuchi, Iwai Baba, Koji Okumura, Seiji Naito, Senji Shirasawa, A novel mechanism of nuclear factor κB activation through the binding between inhibitor of nuclear factor-κBα and the processed NH2-terminal region of Mig-6, Cancer Research, 62, 20, 5668-5671, 2002.10, Mitogene-inducible gene-6 (Mig-6), an adaptor molecule containing the Cdc42/Rac interaction and binding (CRIB) domain, is rapidly induced by mitogenic and stressful stimuli, and sustained mig-6 expression is observed in chronic pathological conditions. The function of this molecule has remained elusive. We find that mig-6 is constitutively expressed in many human cancer cell lines, and Mig-6 is cleaved into the NH2-terminal region containing the CRIB domain and the remainder of the COOH-terminal region by limited proteolytic processing. We report here that full-length Mig-6, but not CRIB domain-deleted Mig-6 (ΔMig-6) or uncleavable mutant of Mig-6 (Mig-6-S38A), induces transcriptional activation of nuclear factor of κB (NFκB), which is inhibited by inhibitor of κBα (IκBα), and that the processed NH2-terminal region of Mig-6 but not the full length is bound with IκBα through its NFκB binding region. These findings suggest that the processed CRIB domain of Mig-6 will compete with NFκB for IκBα and result in NFκB activation. This novel NFκB activation pathway provides new insights regarding tumorigenesis, and the specific inhibition of the cleavage of Mig-6 may be a target for clinical treatment..
15. Kunihisa Yamaguchi, Takamitsu Inoue, Tomonori Habuchi, Junichi Inokuchi, Akira Yokomizo, Masatoshi Eto, Hiro Omi Kanayama, An in Vitro Study of a New Device
Evaluation of Novel Wide-Angle Lens Flexible Cystoscope Using Phantom Bladder Model, Journal of Endourology, 10.1089/end.2017.0371, 31, 10, 1073-1078, 2017.10, Introduction: The features and usefulness of a novel wide-angle lens flexible cystoscope were assessed with a view to its practical application. Materials and Methods: A phantom bladder model, on which a total of 12 markers that resemble lesions were arranged, was created for this study. Twenty-six urologists at three institutions observed this phantom bladder model using a conventional flexible cystoscope and a novel wide-angle lens flexible cystoscope, and they compared the observation time, marker detection rate, number of misidentified marker locations, overlooked locations, and misidentified location sites of both devices. Specific observation procedures that make use of the features of a wide-angle lens flexible cystoscope were also investigated. Results: The observation time tended to be shorter with the wide-angle lens cystoscope than with a conventional cystoscope (104.9 seconds vs 113.6 seconds, p = 0.123). The marker detection rate was higher with the wide-angle lens cystoscope (90.2% vs 85.1%, p = 0.005). The number of marker location misidentifications did not differ between the two devices. Using a specifically designed observation procedure with the wide-angle lens cystoscope tended to further improve the marker detection rate (91.4% vs 88.1%, p = 0.157). Conclusion: Compared with a conventional cystoscope, a wide-angle lens cystoscope improved the lesion detection rate and has the potential to reduce observation time. The novel wide-angle lens flexible cystoscope is regarded as a useful device that offers advantages not available with a conventional cystoscope..
16. Junichi Inokuchi, Navneet Narula, David S. Yee, Douglas W. Skarecky, Alice Lau, David K. Ornstein, Darren R. Tyson, Annexin A2 positively contributes to the malignant phenotype and secretion of IL-6 in DU145 prostate cancer cells, International Journal of Cancer, 10.1002/ijc.23928, 124, 1, 68-74, 2009.01, Several groups, including ours, have reported that annexin A2 (ANXA2) expression is reduced in most prostate cancer (CaP). More recently, however, we reported that ANXA2 is expressed in some high-grade tumors, but the biologic consequence of this is currently unknown. To elucidate the function of ANXA2 in CaP, we reduced its expression in DU145 cells using shRNA and tested the impact on characteristics of malignancy. Reduction of ANXA2 suppressed anchorage-dependent and -independent cell growth without affecting invasiveness. Interestingly, interleukin-6 (IL-6) secretion was reduced concomitantly with the reduction of ANXA2 but independently of S100A10. IL-6 expression was restored when wild type but not mutant ANXA2 was reexpressed in these cells. In a retrospective study of radical prostatectomy specimens from patients with nonmetastatic CaP, 100% of patients with ANXA2-positive tumors (n = 4) had a biochemical relapse while only 50% of patients with ANXA2 negative tumors (n = 20) relapsed, suggesting that ANXA2 expression in prostate tumors may be predictive of biochemical relapse. Significant cytoplasmic staining of ANXA2 was detected in 3 of 4 ANXA2-positive tumors, whereas ANXA2 is localized to the plasma membrane in benign prostatic glands. These finding, taken together, suggests a possible mechanism whereby ANXA2 expression positively contributes to an aggressive phenotype in a subset of CaP and suggest that ANXA2 has markedly different functions depending on its cellular context. Finally, this is the first description of a role for ANXA2 in IL-6 expression, and ANXA2 represents a new therapeutic target for reducing IL-6 in high-grade prostate cancer..
17. 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..
18. Akihiro Nishie, Daisuke Kakihara, Yoshiki Asayama, Kousei Ishigami, Yasuhiro Ushijima, Yukihisa Takayama, Daisuke Okamoto, Nobuhiro Fujita, Koichiro Morita, Yuichiro Kubo, Junichi Inokuchi, Hiroshi Honda, Apparent diffusion coefficient
An associative factor for recurrence after nephrectomy in localized renal cell carcinoma, Journal of Magnetic Resonance Imaging, 10.1002/jmri.24984, 43, 1, 166-172, 2016.01, Purpose To investigate whether the apparent diffusion coefficient (ADC) of a tumor is associated with recurrence after nephrectomy in renal cell carcinoma (RCC) Materials and Methods We retrospectively studied 49 patients with localized RCC who underwent 1.5T magnetic resonance imaging (MRI) including diffusion-weighted imaging preoperatively. Fifteen patients had recurrent disease after surgery. The ADC was measured by placing a region-of-interest in a solid region of each tumor on the ADC map. We named the average value of the three ADC values the "average ADC" and the lowest ADC value among the three as the "minimum ADC." The correlations between clinicopathological factors including patient age and gender, tumor side, tumor size, growth/invasion pattern, Fuhrman grade, histological subtype, venous invasion, average and minimum ADCs, and disease-free survival were analyzed by Cox proportional hazards model. Results In univariate analysis, tumor size, venous invasion, mean ADC, and minimum ADC showed significant correlations with disease-free survival (P < 0.05). In multivariate analysis, only venous invasion and minimum ADC were significant (P < 0.05). The 5-year disease-free survival rate of the low minimum ADC group was 51.6%, while that of the high minimum ADC group was 85.1%. Conclusion The minimum ADC of a tumor, although not as pronounced as venous invasion, was found to be an independent associative factor for recurrence after nephrectomy in patients with localized RCC..
19. Tomoyuki Hida, Akihiro Nishie, Yoshiki Asayama, Kousei Ishigami, Yasuhiro Ushijima, Yukihisa Takayama, Nobuhiro Fujita, Dai Shimamoto, Akira Yokomizo, Katsunori Tatsugami, Junichi Inokuchi, Yuichiro Kubo, Hiroshi Honda, Apparent diffusion coefficient characteristics of various adrenal tumors, Magnetic Resonance in Medical Sciences, 10.2463/mrms.2013-0113, 13, 3, 183-189, 2014.09, Purpose: Using pathologically proven tumors and 3 methods of apparent diffusion coefficient (ADC) measurement, we examined the potential of diffusion-weighted imaging (DWI) to differentiate adrenal tumors.
Methods: We evaluated adrenal tumors of 52 patients who underwent magnetic resonance (MR) examination including DWI and adrenal resection or biopsy between July 2006 and August 2011. Tumors included 25 cortical adenomas, 14 pheochromocytomas, 6 adrenal metastases, and seven others. We defined the tumor’s “solid” region as an enhancing area on contrast-enhanced MR or computed tomography (CT) and measured the ADC of the tumor’s “entire” and “solid” regions within a region of interest (ROI) placed on an ADC map (“entire” and “solid” ADCs). We obtained a “minimum” ADC by placing an ROI in an area showing the lowest ADC within the “solid” region. We also calculated the ratio of “non-solid” area to “entire” tumor and compared the average “entire,” “solid,” and “minimum” ADCs and the ratio of “non-solid” area to “entire” tumor between benign and malignant groups.
Results: The average “entire” ADC was significantly higher for the benign (1.35 ± 0.38 × 10-3mm2/s) than malignant group (1.01 ± 0.17 × 10-3mm2/s), and the average “solid” and “minimum” ADC and the ratio of “non-solid” area to “entire” tumor did not differ significantly between the benign and malignant groups.
Conclusion: The higher “entire” ADC value of the benign group, which might be obtained incidentally, can be considered dependent on the condition of necrosis, hemorrhage, and degeneration. ADC measurement of a tumor’s “solid” region was not useful for differentiating pathologically proven adrenal tumors..
20. 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..
21. Katsunori Tatsugami, Shingo Tanaka, Satoshi Ohtsubo, Junichi Inokuchi, Akira Yokomizo, Kentaro Kuroiwa, Yoo Hyun Song, Seiji Naito, Causes of diminished renal function in the affected kidney after partial nephrectomy., BJU international, 110, 8 Pt B, E357-361, 2012.10, To determine the cause of diminished renal function in the affected kidney after partial nephrectomy (PN) for renal tumour, we analyzed the relationship between operative data and postoperative recovery with respect to renal function. From May 2005 to December 2010, pre- and postoperative (1 week and 3 months after the procedure) renal function was evaluated by 99mTc- mercaptoacetyltriglycine clearance in 51 patients treated with open partial nephrectomy (OPN; n = 24) and laparoscopic partial nephrectomy (LPN; n = 27). LPN was performed via retroperitoneal (RPLPN; n = 14) or transperitoneal (TPLPN; n = 13) routes. Renal cooling was performed after renal hilar clamping in OPN and RPLPN, although not in TPLPN. There were 10 patients (two in OPN, six in TPLPN, two in RPLPN) who had diminished renal function in the affected kidney from 1 week to 3 months after PN. Warm ischaemia (versus cold ischaemia; P = 0.017) during renal hilar clamping resulted in diminished renal function. Using multivariate analysis, renal cooling influenced postoperative diminished renal function (P = 0.008). Successful preservation of renal function after PN depends on renal cooling during renal hilar clamping. Cold ischaemia for avoiding renal damage is recommended if renal hilar clamping is necessary for tumour extraction..
22. 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..
23. 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..
24. Satoshi Otsubo, Akira Yokomizo, Katsunori Tatsugami, Kentaro Kuroiwa, Takakazu Yunoki, Junichi Inokuchi, Keijiro Kiyoshima, Song Yh, Takahito Negishi, Shingo Tanaka, Kunikazu Miyoshi, Eiji Kashiwagi, Hidenori Iwai, Takeshi Kobayashi, Seiji Naito, Clinical statistics at the urological department of kyushu university hospital for the period 2008-2010, Nishinihon Journal of Urology, 74, 12, 724-728, 2012.12, A study of the clinical stastics at our department for the period 2008-2010 revealed the following results: 1) The number of outpatients was 12, 782, including 4, 031 new patients (2, 739 males and 1, 292 females). The most common diseases among the new patients were urogenital malignant tumors (31.7%), benign prostatic hyperplasia (13.7%), inflammatory diseases (9.7%) and neurogenic bladder (7.4%). 2) The total number of inpatients was 2, 054 (1, 678 males and 376 females), and the majority of them comprised males aged 60∼79 years. The main disease among the inpatients was urogenital neoplasms (59.9%). 3) A total of 1, 227 cases underwent surgery, with 229 cases undergoing open surgery, 315 cases undergoing laparoscopic surgery, 565 cases undergoing endourological surgery and 118 cases undergoing ESWL..
25. Michitaka Nakashima, Motonobu Nakamura, Masatoshi Eto, Manami Aishima, Ryousuke Takahashi, Akira Hirata, Jun Ichi Inokuchi, Chikako Kano, Tatsuya Kikuchi, Hiroyuki Nomura, Masumitsu Hamaguchi, Katsuaki Masuda, Shuro Yano, Nobuyuki Kai, Toshiyuki Tsunoda, Futoshi Morokuma, Takatoshi Konishi, Kyohei Kajio, Toshiro Migita, Tatsuo Nagafuji, Hideya Noma, Osamu Mochida, Takenari Yamasaki, Shuji Hasegawa, Naotaka Sakamoto, Yasuhiro Koikawa, Masashi Haraoka, Shuji Koto, Shunji Sakuma, Narihito Seki, Kouichi Takahashi, Hirofumi Koga, Misao Sakumoto, Takanori Yamaguchi, Noriaki Tokuda, Yasusuke Kimoto, Masatoshi Tanaka, Jiro Uozumi, Tetsuro Matsumoto, Joichi Kumazawa, Seiji Naito, Clinical statistics at the urological department of Kyushu University Hospital from 1996 to 1998, Nishinihon Journal of Urology, 61, 8, 660-663, 1999.08, Clinical statistical studies at our department from 1996 to 1998 revealed the following results: 1) The number of outpatients was 6,690, including 3,094 new patients (1,928 males and 1,166 females). The most common diseases among the new outpatients were hematuria (12.3%), inflammatory diseases (12.2%), benign prostatic hyperplasia (12.1%), neurogenic bladder (9.3%) and urogenital malignant tumors (9.2%). 2) The total number of inpatients was 906 (645 males and 261 females). The main diseases among the inpatients were urogenital malignant tumors (42.2%), urolithiasis (15.4%), urogenital benign tumors (5.9%), benign prostatic hyperplasia (5.4%) and urogenital anomalies (5.2%). 3) A total of 795 cases underwent surgery, with 325 cases of open surgery, 341 cases of endourology and 129 cases of ESWL..
26. 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..
27. 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..
28. Shuichi Morizane, Masashi Honda, Satoshi Fukasawa, Atsushi Komaru, Junichi Inokuchi, Masatoshi Eto, Masaki Shimbo, Kazunori Hattori, Yoshiaki Kawano, Atsushi Takenaka, Comparison of the diagnostic efficacy and perioperative outcomes of limited versus extended pelvic lymphadenectomy during robot-assisted radical prostatectomy
a multi-institutional retrospective study in Japan, International Journal of Clinical Oncology, 10.1007/s10147-017-1223-x, 23, 3, 568-575, 2018.06, Background: We conducted a retrospective study to compare the perioperative course and lymph node (LN) counts of patients undergoing limited pelvic lymphadenectomy (lPLND) or extended pelvic lymphadenectomy (ePLND) during robot-assisted radical prostatectomy in an initial Japanese series. Methods: The cohort included 1333 patients who underwent either lPLND (n = 902) or ePLND (n = 431) during robot-assisted radical prostatectomy at five institutions in Japan. All complications within 28 days of surgery were recorded, and clinical data were collected retrospectively. The outcomes and complications were compared relative to the extent of lymphadenectomy, and we conducted univariate and multivariate logistic regression analyses to assess the predictors of the major complications. Results: On multivariate analysis for evaluating the associations between major complications and perioperative characteristics, console time (p = 0.001) was significantly associated with major complications, although the extent of lymphadenectomy (p = 0.272) was not significantly associated with major complications. In the distribution of positive LNs removed in the extended pelvic lymphadenectomy cohort, 60.4% of patients had positive LNs only in the obturator/internal iliac region. However, 22.6% of the patients with positive LNs had no positive LNs in the obturator/internal iliac region, but only in the external/common iliac region. Conclusions: ePLND, which significantly increased the console time and blood loss but nearly quadrupled the lymph node yield, is considered a relatively safe and acceptable procedure. Moreover, the results of this study suggest that ePLND improves staging and removes a greater number of metastatic nodes..
29. Shiota M, Itsumi M, Takeuchi A, Imada K, Akira Yokomizo, Kuruma H, Inokuchi J, Tatsugami K, Uchiumi T, Oda Y, Naito S, Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer., Endocr Relat Cancer , 22 (6): 889-900, 2015, 2015.12.
30. Darren R. Tyson, Junichi Inokuchi, Toshiyuki Tsunoda, Alice Lau, David K. Ornstein, Culture requirements of prostatic epithelial cell lines for acinar morphogenesis and lumen formation in vitro
Role of extracellular calcium, Prostate, 10.1002/pros.20628, 67, 15, 1601-1613, 2007.11, BACKGROUND. Three-dimensional (3D) culture of benign prostatic epithelial cell lines can recapitulate acinar morphogenesis in vitro, but the broad applicability of this approach has not been described. The present studies examine the culture conditions important for prostatic acinar morphogenesis in vitro and the role of extracellular calcium in this process. METHODS. With optimized culture conditions, RWPE-1, pRNS-1-1, PZ-HPV-7, PNT1A, BPH-1, and PrEC were analyzed for their ability to undergo acinar morphogenesis in 3D culture and by immunoblotting. RWPE-1 cells were further examined for the effects of calcium on morphology, E-cadherin membrane localization and multicellular layering in 2D culture and for acinar morphogenesis, luminal apoptosis, and luminal filling in 3D. RESULTS. Cell lines grown in low-calcium medium have the ability to form acinar structures with lumens, which correlates with E-cadherin expression, but low calcium is not required for this process. Adding CaCl 2 to the medium strongly inhibits lumen formation, luminal apoptosis and induces luminal filling, and luminal filling is blocked by an interfering antibody. CONCLUSIONS. Optimized medium composition allows nearly all seeded RWPE-1 cells to undergo acinar morphogenesis, forming consistent structures representative of normal adult prostate glands. Low-calcium-containing medium appears selective for cells capable of undergoing acinar morphogenesis in vitro, and branching and luminal space within the acini are strongly influenced by extracellular calcium levels, likely through the actions of E-cadherin. These results provide important information about a relevant in vitro model with which to study prostate development and carcinogenesis and highlight the importance of extracellular calcium in regulating 3D morphology..
31. Junichi Inokuchi, Misako Komiya, Iwai Baba, Seiji Naito, Takehiko Sasazuki, Senji Shirasawa, Deregulated expression of KRAP, a novel gene encoding actin-interacting protein, in human colon cancer cells, Journal of Human Genetics, 10.1007/s10038-003-0106-3, 49, 1, 46-52, 2004.02, We have identified a novel gene, designated KRAP (Ki-ras-induced actin-interacting protein), encoding a protein of 1,259 amino acids with coiled-coil regions and transmembrane regions, from the cDNA library of human colon cancer HCT116 cells, as one of the genes upregulated by activated Ki-ras. While KRAP was rarely expressed in normal colon epithelium, deregulated constitutive KRAP expression was observed in some other colon cancer cells. In normal tissues, KRAP was strongly expressed in pancreas and testis. Anti-KRAP polyclonal antibodies detected endogenous KRAP as the molecular size of M r 180,000, and immunofluorescence microscopy and cytochalasin E treatment revealed that KRAP was clearly associated with the actin filaments. Furthermore, KRAP was localized as a membrane-bound form with extracellular regions. These results together suggested KRAP might be involved in the regulation of filamentous actin and signals from the outside of the cells..
32. Senji Shirasawa, Shigeru Sugiyama, Iwai Baba, Junichi Inokuchi, Sayaka Sekine, Keiko Ogino, Yuki Kawamura, Taeko Dohi, Manabu Fujimoto, Takehiko Sasazuki, Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.0404217101, 101, 38, 13921-13926, 2004.09, Epidermal growth factor (EGF) family members, including epiregulin (EP), play a fundamental role in epithelial tissues; however, their roles in immune responses and the physiological role of EP remain to be elucidated. The skin has a versatile system of immune surveillance. Biologically active IL-1α is released to extracellular space upon damage from keratinocytes and is a major player in skin inflammation. Here, we show that EP is expressed not only in keratinocytes but also in tissue-resident macrophages, and that EP-deficient (EP-/-) mice develop chronic dermatitis. Wound healing in the skin in EP-/- mice was not impaired in vivo, nor was the growth rate of keratinocytes from EP-/- mice different from that of WT mice in vitro. Of interest is that in WT keratinocytes, both IL-1α and the secreted form of EP induced down-regulation of IL-18 mRNA expression, which overexpression in the epidermis was reported to induce skin inflammation in mice, whereas the down-regulation of IL-18 induced by IL-1α was impaired in EP-/- keratinocytes. Although bone marrow transfer experiments indicated that EP deficiency in non-bone-marrow-derived cells is essential for the development of dermatitis, production of proinflammatory cytokines by EP-/- macrophages in response to Toll-like receptor agonists was much lower, compared with WT macrophages, whose dysfunction in EP-/- macrophages was not compensated by the addition of the secreted form of EP. These findings, taken together, suggested that EP plays a critical role in immune/inflammatory-related responses of keratinocytes and macrophages at the barrier from the outside milieu and that the secreted and membrane-bound forms of EP have distinct functions..
33. 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..
34. , Takuya Koie, Chikara Ohyama, Hiroyuki Fujimoto, Hiroyuki Nishiyama, Jun Miyazaki, Shiro Hinotsu, Eiji Kikuchi, Mizuaki Sakura, Junichi Inokuchi, Tomohiko Hara, Masato Fujisawa, Hirotsugu Uemura, Kazuhiro Suzuki, Masatoshi Eto, Seiji Naito, Isao Hara, Akio Matsubara, Norio Nonomura, Hiroyuki Nakanishi, Tsuneharu Miki, Hiroomi Kanayama, Tomoharu Fukumori, Diversity in treatment modalities of Stage II/III urothelial cancer in Japan
Sub-analysis of the multi-institutional national database of the Japanese Urological Association, Japanese journal of clinical oncology, 10.1093/jjco/hyw005, 46, 5, 468-474, 2016.01, Objective: We aimed to survey treatment modalities for the patients with Stage II/III urothelial cancer in Japan. Methods: We used the multi-institutional national database of the Japanese Urological Association from 348 Japanese institutions, in which a total of 3707 patients with muscle-invasive bladder cancer and 1538 with upper urinary tract urothelial carcinoma were registered in 2008 and 2011, respectively. Primary treatment was classified as surgery alone, surgery with chemotherapy, surgery with radiation, radiation alone, chemotherapy alone, combination of radiation and chemotherapy and observation. Overall and cancer-specific survivals were examined using the Kaplan-Meier method, and survival in the subgroups was analyzed using the log-rank test. Results: In Stage II/III bladder cancer patients, 49.7% of thosewere treated with radical operation and 22.3% received observation only. A total 97.2% of Stage II/III upper urinary tract urothelial carcinoma patients treated with radical surgery. A total 30.4% of Stage II/III bladder cancer patients received chemotherapy. Majority of the patients received cisplatin-based regimen, however, regimens of chemotherapy was rich in variety up to 13 regimens. Chemotherapy regimens for the patients with upper urinary tract urothelial carcinoma were also various up to eight regimens. Overall and cancer-specific survivals were statistically significantly stratified according to the clinical stage. The upper urinary tract urothelial carcinoma patients diagnosed with clinical stage T3 had significantly poor prognosis compared with those diagnosed with clinical stage T2. Conclusions: This study demonstrated the variety of treatments used for Japanese patients with Stage II/III urothelial cancer. Treatment standardization for these entities may be necessary..
35. 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..
36. 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..
37. 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..
38. Junichi Inokuchi, Akira Yokomizo, Extended pelvic lymph node dissection in robot-assisted radical prostatectomy, Japanese Journal of Clinical Urology, 69, 10, 832-838, 2015.09.
39. 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..
40. 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..
41. Masaki Shiota, N. Fujimoto, M. Itsumi, A. Takeuchi, J. Inokuchi, K. Tatsugami, A. Yokomizo, S. Kajioka, T. Uchiumi, M. Eto, Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress, Annals of Oncology, 10.1093/annonc/mdw646, 28, 3, 569-575, 2017.01, Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castrationresistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). This study investigated the association between genetic variations in antioxidant enzymes and the efficacy of ADT as well as its biological background. Patients and methods: The non-synonymous or promoter-locating polymorphisms of antioxidant enzymes were examined as well as the time to CRPC progression and overall survival in 104 and 92 patients treated with ADT for metastatic and nonmetastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells. Results: In metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 and CT/TT allele in CAT rs564250 were associated with a significantly lower risk of progression to CRPC and all-cause death compared with homozygotes of the major AA allele (hazard ratio [HR]; [95% confidence interval (CI)], 0.55 [0.34-0.86], P=0.0086) and CC allele (HR; [95% CI], 0.48 [0.24-0.88], P=0.016), respectively. On multivariate analyses, only GSTM3 rs7483 was associated with significant progression risk (AG/GG versus AA; HR; [95% CI], 0.45 [0.25-0.79], P=0.0047) even after Bonferroni adjustment. In non-metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 was associated with a significantly lower risk of progression to CRPC (HR; [95% CI], 0.35 [0.10-0.93], P=0.034) and all-cause death (HR; [95% CI], 0.26 [0.041-0.96], P=0.043) compared with the AA allele. Intracellular reactive oxygen species levels were increased, accompanied with augmented GSTM3 expression in both castration-resistant and enzalutamide-resistant cells. Conclusions: Differential activity of antioxidant enzymes caused by the polymorphism in GSTM3 may contribute to resistance to hormonal therapy through oxidative stress. The GSTM3 rs7483 polymorphism may be a promising biomarker for prostate cancer patients treated with ADT..
42. 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..
43. Junichi Inokuchi, Yukihiro Inoue, Takeshi Kurozumi, Hiroo Yagi, Tetsuo Omoto, Ryuji Nakano, Huge renal capsular leiomyoma
A case report, Nishinihon Journal of Urology, 60, 12, 831-834, 1998.12, A case of huge retroperitoneal leiomyoma arising from the renal capsule is reported. A 56-year-old female was admitted with the complaint of microscopic hematuria. Abdominal ultrasonogram, CT-scan and MRI showed a huge solid mass in contact with the right kidney forming an indistinguishable plane between the tumor and the kidney. The tumor mass weighing 1,200g and measuring 16 x 14 x 9cm, was resected with the attached renal subcapsular tissue. The huge tumor was well-demarcated and composed of smooth muscle cells without mitotic figures, derived from the renal capsule. In addition, we discuss renal capsular tumors in general..
44. Shiota M, Song Y, Yokomizo A, Tada Y, Kuroiwa K, Eto M, Oda Y, Inokuchi J, Uchiumi T, Fujimoto N, Seki N, Naito S., Human heterochromatin protein 1 isoform HP1{beta} enhances androgen receptor activity and is implicated in prostate cancer growth., Endocrine-Related Cancer, 17 (2): 455-467, 2010, 2010.05.
45. Momoe Itsumi, Masaki Shiota, Akira Yokomizo, Eiji Kashiwagi, Ario Takeuchi, Katsunori Tatsugami, Junichi Inokuchi, Yoohyun Song, Takeshi Uchiumi, Seiji Naito, Human heterochromatin protein 1 Isoforms regulate androgen receptor signaling in prostate cancer, Journal of Molecular Endocrinology, 10.1530/JME-13-0024, 50, 3, 401-409, 2013.03, Androgen receptor (AR) signaling is critical for the tumorigenesis and development of prostate cancer, as well as the progression to castration-resistant prostate cancer. We previously showed that the heterochromatin protein 1 (HP1) b isoform plays a critical role in transactivation of AR signaling as an AR coactivator that promotes prostate cancer cell proliferation. However, the roles of other HP1 isoforms, HP1a and HP1g, in AR expression and prostate cancer remain unclear. Here, we found that knockdown of HP1g, but not HP1a, reduced AR expression and cell proliferation by inducing cell cycle arrest at G1 phase in LNCaP cells. Conversely, overexpression of full-length HP1a and its C-terminal deletion mutant increased AR expression and cell growth, whereas overexpression of HP1g had no effect. Similarly, HP1a overexpression promoted 22Rv1 cell growth, whereas HP1g knockdown reduced the proliferation of CxR cells, a castration-resistant LNCaP derivative. Taken together, HP1 isoforms distinctly augment AR signaling and cell growth in prostate cancer. Therefore, silencing of HP1b and HP1g may be a promising therapeutic strategy for treatment of prostate cancer..
46. 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..
47. , Kentaro Kuroiwa, Junichi Inokuchi, Hiroyuki Nishiyama, Takahiro Kojima, Yoshiyuki Kakehi, Mikio Sugimoto, Toshiki Tanigawa, Hiroyuki Fujimoto, Momokazu Gotoh, Naoya Masumori, Osamu Ogawa, Masatoshi Eto, Chikara Ohyama, Akira Yokomizo, Hideyasu Matsuyama, Tomohiko Ichikawa, Junki Mizusawa, Junko Eba, Seiji Naito, Impact of Previous, Simultaneous or Subsequent Bladder Cancer on Prognosis after Radical Nephroureterectomy for Upper Urinary Tract Urothelial Carcinoma, The Journal of urology, 10.1097/JU.0000000000000422, 202, 6, 1127-1135, 2019.12, PURPOSE: We investigated the impact of previous, simultaneous or subsequent bladder cancer on the clinical outcomes of upper urinary tract urothelial carcinoma. MATERIALS AND METHODS: We retrospectively collected data on 2,668 patients who underwent radical nephroureterectomy of nonmetastatic upper urinary tract urothelial carcinoma in 1995 to 2009. We evaluated the impact of bladder cancer on overall mortality and the factors predictive of subsequent bladder cancer. RESULTS: A total of 631 patients (23.7%) had previous or simultaneous bladder cancer. Patients with previous or simultaneous bladder cancer had significantly shorter overall survival than patients without previous or simultaneous bladder cancer (HR 1.29, 95% CI 1.09-1.53, p=0.0026). Of the 2,037 patients without previous or simultaneous bladder cancer 683 (33.5%) subsequently had bladder cancer after radical nephroureterectomy. Of patients with pT0-2 disease those with subsequent bladder cancer had significantly shorter overall survival than patients without subsequent bladder cancer (HR 1.81, 95% CI 1.23-2.67, p=0.0025). In patients with pT3-4 disease subsequent bladder cancer was not associated with worse overall survival. On multivariable analyses independent predictors of subsequent bladder cancer were gender, preoperative urine cytology and clinical node status in the preoperative setting, and gender, adjuvant chemotherapy and pathological node status in the postoperative setting. CONCLUSIONS: Bladder cancer was significantly associated with worse clinical outcomes after radical nephroureterectomy of upper urinary tract urothelial carcinoma. Preventing subsequent bladder cancer in patients with pT0-2 upper urinary tract urothelial carcinoma may lead to better prognosis in those who undergo radical nephroureterectomy..
48. Katsunori Tatsugami, Masatoshi Eto, Akira Yokomizo, Kentaro Kuroiwa, Junichi Inokuchi, Yasuhiro Tada, Ario Takeuchi, Narihito Seki, Seiji Naito, Impact of cold and warm ischemia on postoperative recovery of affected renal function after partial nephrectomy, Journal of Endourology, 10.1089/end.2010.0502, 25, 5, 869-873, 2011.05, Purpose: To determine the influence of warm or cold ischemia on postoperative renal function, we conducted preoperative and postoperative analysis by renal scintigraphy of patients who were undergoing open partial nephrectomy (OPN) and laparoscopic partial nephrectomy (LPN). Patients and Methods: From May 2005 to February 2010, the preoperative and postoperative renal function was evaluated by 99mTc-mercaptoacetyltriglycine (MAG3) clearance in 37 patients who were treated with OPN (n=13) and LPN (n=24). LPN were achieved via retroperitoneal (RPLPN; n=12) or transperitoneal (TPLPN; n=12) routes. Renal cooling was performed after renal hilar clamping in OPN and RPLPN, but not TPLPN. Renal function was evaluated according to the ratio of affected to contralateral renal MAG3 clearance. Results: Mean ischemic time was 29.5 minutes in OPN, 25.5 minutes in TPLPN, and 50 minutes in RPLPN (P<0.01); median blood loss was 230 mL in OPN (P<0.05), 110 mL in TPLPN, and 53 mL in RPLPN. There was no significant difference in postoperative total renal function between the groups. Although ischemic time in RPLPN was longer than in TPLPN, the postoperative recovery of affected renal function from 1 week to 3 months for RPLPN and OPN (cold ischemia) was significantly better than for TPLPN (P<0.01). Conclusions: Cold ischemia has an advantage of postoperative recovery of affected renal function. If a patient has a risk of renal dysfunction, cold ischemia during renal hilar clamping is recommended to avoiding deterioration..
49. , Junichi Inokuchi, Masatoshi Eto, Tomohiko Hara, Hiroyuki Fujimoto, Hiroyuki Nishiyama, Jun Miyazaki, Eiji Kikuchi, Shiro Hinotsu, Takuya Koie, Chikara Ohyama, Hiroomi Kanayama, Tsuneharu Miki, Kazuhiro Suzuki, Hiroyuki Nakanishi, Tomoharu Fukumori, Seiji Naito, Impact of lymph node dissection on clinical outcomes during nephroureterectomy in patients with clinically node-negative upper urinary tract urothelial cancer
Subanalysis of a multi-institutional nationwide case series of the Japanese Urological Association, Japanese journal of clinical oncology, 10.1093/jjco/hyx051, 47, 7, 652-659, 2017.07, Objective: To evaluate the impact of lymph node dissection (LND) on the clinical outcomes during radical nephroureterectomy (RNU) in patients with clinically node-negative upper urinary tract urothelial cancer (UTUC).Methods: Within the nationwide case series of the Japanese Urological Association, which comprises 1509 patients with UTUC diagnosed in 2005, we identified 823 patients with clinically node-negative UTUC who underwent RNU. The extent of limited LND was defined as the renal hilar region only for renal pelvic cancer and as either the pelvic region or para-aortic/paracaval region only for ureteral cancer, while the extent of wider LND was defined as at least one perilesional LND region in addition to limited LND. Multivariate analysis with a Cox regression hazard model was used to evaluate the survival benefit. Results: Among the 823 patients, LND was performed in 197 (23.9%) patients, and 26 (13.2%) of them had pathologically node-positive disease. Of 197 patients who underwent LND, limited and wider LND was performed in 119 (60.4%) and 78 (39.6%) patients, respectively. Patients with node-positive disease showed significantly shorter overall survival than those with node-negative disease. No LND-associated survival improvement was observed in a direct comparison between patients with and without LND. In addition, limited or wider LND was not associated with overall survival or cancer-specific survival. Conclusions: The therapeutic benefit obtained by LND remains unclear regardless of the extent of LND, although LND has diagnostic value with respect to the prediction of a poor prognosis especially in patients with clinically muscle-invasive disease..
50. , Junichi Inokuchi, Seiji Naito, Hiroyuki Fujimoto, Tomohiko Hara, Mizuaki Sakura, Hiroyuki Nishiyama, Jun Miyazaki, Eiji Kikuchi, Shiro Hinotsu, Takuya Koie, Chikara Ohyama, Hiroomi Kanayama, Tsuneharu Miki, Kazuhiro Suzuki, Masatoshi Eto, Hiroyuki Nakanishi, Tomoharu Fukumori, Impact of multimodal treatment on prognosis for patients with metastatic upper urinary tract urothelial cancer
Subanalysis of the multi-institutional nationwide case series study of the Japanese Urological Association, International Journal of Urology, 10.1111/iju.13031, 23, 3, 224-230, 2016.03, Objectives: To describe the nature of metastatic upper urinary tract urothelial cancer and determine the prognostic predictors or treatment modality associated with all-cause mortality. Methods: Within the nationwide case series study of the Japanese Urological Association, consisting of 1509 patients with urinary tract urothelial cancer diagnosed in 2005, we identified 102 patients with metastatic urinary tract urothelial cancer. Univariate and multivariate survival analyses identified prognostic outcome variables. Results: Predominant sites of distant metastasis at diagnosis were the lungs (54.9%), distant lymph nodes (37.3%), bone (32.4%) and liver (19.6%). Of 102 patients, 70 patients (68.6%) died during the median follow-up period of 6 months, and the 2-year overall survival rate was estimated at 22%. The median survival time to all-cause mortality was 8.5 months (95% confidence interval 6.4-10.7 months). On multivariate analysis, independent predictive factors for all-cause mortality were age (hazard ratio 2.36, P = 0.015) and liver metastasis (hazard ratio 2.35, P = 0.037). Patients who received multimodal treatment including chemotherapy and surgery showed significantly better prognosis (median survival time 25.8 months) compared with patients treated with chemotherapy alone (median survival time 7.3 months) or best supportive care (median survival time 4.3 months). Conclusions: Age at diagnosis and the presence of liver metastasis seem to have an impact on survival of metastatic urinary tract urothelial cancer patients. Multimodal treatment including systemic chemotherapy and surgery might result in better prognosis in some of these patients..
51. , Jun Miyazaki, Hiroyuki Nishiyama, Hiroyuki Fujimoto, Chikara Ohyama, Takuya Koie, Shiro Hinotsu, Eiji Kikuchi, Mizuaki Sakura, Junichi Inokuchi, Tomohiko Hara, Hiro omi Kanayama, Tsuneharu Miki, Kazuhiro Suzuki, Masatoshi Eto, Hiroyuki Nakanishi, Tomoharu Fukumori, Seiji Naito, Impact of smoking on the age at diagnosis of upper tract urothelial carcinoma
Subanalysis of the Japanese Urological Association multi-institutional national database, International Journal of Urology, 10.1111/iju.12886, 22, 11, 1023-1027, 2015.11, Objectives: To examine the influence of smoking history on the diagnosis and other tumor characteristics of upper tract urothelial carcinoma in Japan. Methods: A total of 1509 patients with upper tract urothelial carcinoma who were diagnosed in 2005 from 348 Japanese institutions were registered using the multi-institutional national database of the Japanese Urological Association and included in this analysis. Clinical data of the patients were collected in 2011. The associations between the patients' self-reported smoking history and their age at the diagnosis of upper tract urothelial carcinoma, sex, pathological T stage and tumor grade were analyzed. Results: The mean age at the diagnosis of upper tract urothelial carcinoma was approximately 5 years earlier for the 238 current smokers than for the 618 current non-smokers (P < 0.0001). Similar associations between smoking and the early diagnosis of upper tract urothelial carcinoma were shown in the sex subgroups and in subgroups stratified by pathological T stages. Among the current smokers, the age at diagnosis for the smoking ≥20 cigarettes per day group was 6.5 years lower than that of the <20 cigarettes per day group, which was significantly different (P < 0.0001). Conclusion: Current smoking is a significant risk factor for the earlier diagnosis of upper tract urothelial carcinoma. The finding is important from the perspective of both healthcare and medical economies..
52. 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..
53. 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, 2014.02, 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..
54. Toshiyuki Tsunoda, Hirofumi Koga, Akira Yokomizo, Katsunori Tatsugami, Masatoshi Eto, Junichi Inokuchi, Akira Hirata, Katsuaki Masuda, Koji Okumura, Seiji Naito, Inositol 1,4,5-trisphosphate (IP3) receptor type1 (IP 3R1) modulates the acquisition of cisplatin resistance in bladder cancer cell lines, Oncogene, 10.1038/sj.onc.1208313, 24, 8, 1396-1402, 2005.02, To investigate the molecules that regulate the acquisition of cis-diamminedichloroplatinum (II) (cisplatin) resistance, we performed cDNA microarrays using two pairs of parental and cisplatin-resistant bladder cancer cell lines. We found a markedly reduced expression of inositol 1,4,5-trisphosphate (IP3) receptor type1 (IP3R1), endoplasmic reticulum membrane protein, in cisplatin-resistant cells. The suppression of IP3R1 expression using small interfering RNA in parental cells prevented apoptosis and resulted in decreased sensitivity to cisplatin. Contrarily, overexpression of IP3R1 in resistant cells induced apoptosis and increased sensitivity to cisplatin. These results suggest that cisplatin-induced downregulation of IP3R1 expression was closely associated with the acquisition of cisplatin resistance in bladder cancer cells..
55. 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..
56. Miyazaki J, Nishiyama H, Fujimoto H, Ohyama C, Koie T, Hinotsu S, Kikuchi E, Sakura M, Inokuchi J, Hara T, Laparoscopic Versus Open Nephroureterectomy in Muscle-Invasive Upper Tract Urothelial Carcinoma: Subanalysis of the Multi-Institutional National Database of the Japanese Urological Association., J Endourol, 30 (5): 520-525, 2016, 2016.05.
57. Jun Miyazaki, Hiroyuki Nishiyama, Hiroyuki Fujimoto, Chikara Ohyama, Takuya Koie, Shiro Hinotsu, Eiji Kikuchi, Mizuaki Sakura, Junichi Inokuchi, Tomohiko Hara, Laparoscopic Versus Open Nephroureterectomy in Muscle-Invasive Upper Tract Urothelial Carcinoma
Subanalysis of the Multi-Institutional National Database of the Japanese Urological Association, Journal of Endourology, 10.1089/end.2015.0757, 30, 5, 520-525, 2016.05, Objectives: Open nephroureterectomy (ONU) is the current standard for muscle-invasive upper tract urothelial carcinoma (UTUC) in the European Association of Urology/Japanese Urological Association (JUA) guidelines. In this study, we compared the postsurgical survival of muscle-invasive UTUC patients treated with ONU or with laparoscopic nephroureterectomy (LNU), using the multi-institutional national database of the JUA. Methods: The 1509 patients with UTUC who were diagnosed at 348 Japanese institutions in 2005 were registered. We collected the clinical data of the patients in 2011. The muscle-invasive UTUC patients who underwent ONU or LNU were identified, and survival curves were estimated using the Kaplan-Meier method. Results: Overall, 749 pT2≥cNxM0 patients underwent a nephroureterectomy (ONU, n = 527 and LNU, n = 222). The overall survival and cause-specific survival rates were not significantly different between the ONU and LNU groups (p = 0.1263 and p = 0.0893, respectively). In addition, 459 of the 749 (61.3%) patients experienced disease recurrence (bladder recurrence, local recurrence, or distant metastasis), with no significant difference between the ONU and LNU groups. Even when patients were stratified by pT3/pT4 and/or pN+, overall survival was not significantly different between the ONU and LNU groups (p = 0.2876). The results of a univariate analysis showed that lymphovascular invasion was an independent prognostic factor for overall survival, but the surgical approaches were not found to be associated with overall survival. Conclusions: Our data suggest that there is no evidence that the oncologic outcome of LNU is inferior to that of ONU in muscle-invasive UTUC, when the appropriate patients are selected..
58. Junichi Inokuchi, Alice Lau, Darren R. Tyson, David K. Ornstein, Loss of annexin A1 disrupts normal prostate glandular structure by inducing autocrine IL-6 signaling, Carcinogenesis, 10.1093/carcin/bgp078, 30, 7, 1082-1088, 2009.07, Annexin A1 (ANXA1) expression is commonly reduced in premalignant lesions and prostate cancer, but a causal relationship of ANAX1 loss with carcinogenesis has not been established. ANXA1 levels have been shown to inversely correlate with interleukin 6 (IL-6) expression in other cell types and IL-6 has been suggested to enhance prostate cancer initiation and promotion. To investigate whether loss of ANXA1 may contribute to prostate carcinogenesis, ANXA1 expression was reduced using RNA interference in non-tumorigenic human prostatic epithelial cells (RWPE-1/rA1). No effect on morphology, apoptosis, migration or anchorage-dependent or -independent growth was detected. However, IL-6 mRNA and secreted protein levels were elevated in RWPE-1/rA1 cells. In addition, re-expression of ANXA1 in these cells suppressed IL-6 secretion, and altering ANXA1 levels in prostate cancer cells had similar effects on IL-6. The effects of ANXA1 loss and increased IL-6 expression on prostate epithelium were examined using an assay of acinar morphogenesis in vitro. Acini formed by RWPE-1/rA1 cells had delayed luminal clearing and larger mean diameters than control cells. The RWPE-1/rA1 phenotype was recapitulated by treating control cells with recombinant IL-6 and was reversed in RWPE-1/rA1 cells by blocking IL-6 bioactivity. Taken together, these data support a direct role for decreased ANXA1 expression in prostate carcinogenesis and enhancing tumor aggressiveness via the upregulation of IL-6 expression and activity..
59. Shiota M, Takeuchi A, Sugimoto M, Dejima T, Kashiwagi E, Kiyoshima K, Inokuchi J, Tatsugami K, Yokomizo A, 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 Res , 35 (11): 6137-6145, 2015
, 2015.11.
60. 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, 7 and >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..
61. Tomoyuki Hida, Akihiro Nishie, Yoshiki Asayama, Kousei Ishigami, Nobuhiro Fujita, Junichi Inokuchi, Seiji Naito, Sadamu Ando, Hiroshi Honda, MR imaging of focal medullary sponge kidney
Case report, Magnetic Resonance in Medical Sciences, 10.2463/mrms.11.65, 11, 1, 65-69, 2012.07, We present a case of focal medullary sponge kidney (MSK) that mimicked a renal tumor. Evaluation of a patient with history of macrohematuria revealed a left renal mass of 3-cm diameter. T 1-weighted magnetic resonance (MR) images revealed a mass of mixed intensity protruding toward the renal sinus. On fat-saturated T 2-weighted MR images, the lesion's remarkable hyperintensity suggested the presence of an aggregation of tiny cysts. On diffusion-weighted MR images, the mass also demonstrated high intensity, and its apparent diffusion coefficient was partly decreased (1.12×10 -3 mm 2/s). On computed tomography, precontrast images revealed no calcification in the mass. Although slight enhancement was seen in the corticomedullary phase, thick and dense streaks of contrast radiating peripherally were identified in the mass in the excretory phase. Focal MSK was diagnosed. We discuss the potential of MR imaging for diagnosing focal MSK..
62. 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..
63. , Kazuto Ito, Shiro Saito, Atsunori Yorozu, Shinsuke Kojima, Takashi Kikuchi, Satoshi Higashide, Manabu Aoki, Hirofumi Koga, Takefumi Satoh, Toshio Ohashi, Katsumasa Nakamura, Norihisa Katayama, Nobumichi Tanaka, Masahiro Nakano, Naoyuki Shigematsu, Takushi Dokiya, Masanori Fukushima, Yutaka Takahashi, Iwao Tsukiyama, Yasutomo Nasu, Masaoki Harada, Takashi Fukagai, Takashi Yamashita, Akio Matsubara, Mikio Igawa, Shin Egawa, Yoshiyuki Kakehi, Youji Katsuoka, Hiroshi Kanetake, Yoshinobu Kubota, Hiromi Kumon, Ichiro Yamasaki, Kazuhiro Suzuki, Takashi Deguchi, Munehisa Ueno, Seiji Naito, Mikio Namiki, Shiro Baba, Kazushige Hayakawa, Yoshihiko Hirao, Tomoaki Fujioka, Shigeo Horie, Tsuneharu Miki, Masaru Murai, Hideki Yoshida, Jun Itami, Toshihiko Inoue, Yutaka Imai, Masaaki Kataoka, Atsushi Kubo, Nationwide Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS)
first analysis on survival, International Journal of Clinical Oncology, 10.1007/s10147-018-1309-0, 23, 6, 1148-1159, 2018.12, Background: Investigating oncological outcomes in patients registered in the Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS) in terms of biochemical relapse-free survival (bRFS) by the Phoenix and the newly developed J-POPS definitions, exploration of predictive factors for bRFS, and preliminary verification of pitfalls of prostate-specific antigen (PSA) failure definitions. Methods: Between July 2005 and June 2007, 2316 clinically localized patients underwent permanent seed implantation. The primary endpoint was bRFS. One of the secondary endpoints was overall survival (OS). Results: The median age was 69 and performance status was 0 in 99.1% of participants. The median biologically effective dose (BED) was about 180 Gy 2 . During a median follow-up of 60.0 months, 8.4 and 5.9% had PSA failure by the Phoenix and the J-POPS definitions, respectively. The 5-year bRFSs based on the Phoenix and the J-POPS definitions were 89.1 and 91.6%, respectively. The 5-year OS was 97.3%. According to multivariate analyses, only age affected bRFS based on the Phoenix definition, whereas the risk group and BED independently affected bRFS based on the J-POPS definition. A spontaneous PSA decrease was seen in 91.1% of participants after PSA failure based on the Phoenix definition alone, but in only 22.2% after PSA failure based on the J-POPS definition alone. Conclusion: The world’s largest registration study, J-POPS, consisted of patients with longevity, and a highly quality-controlled BED resulted in excellent bRFS and OS. The high likelihood of PSA bounce by the Phoenix definition should be taken into account, especially in younger patients. Clinical trial information: NCT00534196..
64. 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..
65. 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..
66. Masatoshi Tanaka, Shinichiro Irie, Ken Nakagawa, Hiroaki Nishimatsu, Junichi Inokuchi, Masatoshi Eto, Nonischemic or Ischemic Laparoscopic Partial Nephrectomy Using a Newly Developed Hybrid Energy Device in a Porcine Model, Journal of Endourology, 10.1089/end.2019.0435, 34, 1, 82-87, 2020.01, Purpose: To compare the efficacy of a newly developed hybrid pencil-type energy device (HD) generating simultaneously monopolar high-frequency electric energy and ultrasonic energy with that of a conventional device (CD) during laparoscopic partial nephrectomy (LPN). Materials and Methods: A total of 16 female pigs (32 kidneys) were divided into 4 groups of 4 animals (8 kidneys) each: nonischemic and ischemic HD-LPN groups, and nonischemic and ischemic CD-LPN groups. We performed bilateral LPN for each pig. HD alone was used in the HD-LPN group, whereas commercially available monopolar scissors and a soft coagulation system were used in the CD-LPN group. After observing the postoperative course for 14 days, we euthanized the animals and harvested the kidneys for histopathological observations. Results: We completed an LPN on a total of 32 kidneys. There were no cases of conversion to open surgery, nor were there any deaths or complications requiring treatment. For nonischemic LPN, LPN time was significantly shorter in the HD-LPN group than in the CD-LPN group (11.4 ± 4.8 vs 17.7 ± 5.3 minutes, p = 0.027). The decrease in postoperative hemoglobin was equally low in both groups. However, the frequency of TachoSil® use was significantly higher in the CD-LPN group than in the HD-LPN group (6/8 [75%] vs 0/8 [0%], p = 0.007). For ischemic LPN, we found no significant differences in parameters such as LPN time and using TachoSil between the two groups. The depth of thermal injury was the most superficial in the nonischemic HD-LPN group in comparison with the other three groups. Conclusions: The application of an HD allowed nonischemic LPN to be performed safely in a short time with less blood loss and less thermal injury to the kidney in the porcine model. Additional clinical investigations of human kidneys are required..
67. 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..
68. 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)..
69. 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..
70. Akihiro Nishie, Yoshiki Asayama, Kousei Ishigami, Daisuke Kakihara, Tomohiro Nakayama, Yasuhiro Ushijima, Yukihisa Takayama, Akira Yokomizo, Katsunori Tatsugami, Junichi Inokuchi, Nobuhiro Fujita, Yuichiro Kubo, Shinichi Aishima, Masakazu Hirakawa, Hiroshi Honda, Pathological manifestation of difference in washout pattern of adrenal hyperplasia on dynamic CT, Journal of Medical Imaging and Radiation Oncology, 10.1111/1754-9485.12211, 58, 5, 559-564, 2014.10, Introduction: The relationship between the washout pattern and constituent cell in adrenal hyperplasia (AH) has not been fully investigated. The purpose of this study was to elucidate the radiological or pathological factors determining the washout pattern of AH on dynamic CT. Methods: Ten patients with 14 surgically proven AHs were enrolled. Dynamic CT was scanned before (pre-contrast image) and 60 seconds (early phase) and 240 seconds (delayed phase) after administration of iodine contrast. The absolute percentage washout (APW) of each nodular lesion was calculated using the following formula: APW(%) = (TAearly-TAdelay)/(TAearly- TApre) x 100, when TApre, TAearly and TAdelay were defined as tumour attenuation values of pre-contrast, early and delayed phases, respectively. Pathologically, the clear cell ratio (CCR) constituting each nodular lesion was qualitatively assessed. Regression analysis was performed to evaluate a correlation between each pair of CCR, TApre, (TAearly-TAdelay) and APW. Results: There was a significant correlation between each pair of CCR, TApre and APW. CCR decreased as TApre increased (r = 0.81, P < 0.001). APW increased as CCR decreased (r = 0.80, P < 0.001) or as TApre increased (r = 0.74, P < 0.01). Conclusions: The key factors of washout pattern of AH on dynamic CT were CCR and TApre. The difference in constituent cell was associated with variability in APW of AH..
71. Junichi Inokuchi, Akira Yokomizo, Naotaka Nishiyama, Hiroshi Kitamura, Masatoshi Eto, Hiroyuki Nishiyama, Yoshihiko Tomita, Perioperative therapies for urological cancers, Japanese journal of clinical oncology, 10.1093/jjco/hyaa013, 50, 4, 357-367, 2020.04, Although surgery with curative intent is critical for management of many localized cancers, multimodal therapy including neoadjuvant and adjuvant therapy has been introduced to increase the effectiveness of local control of surgery and prolong survival. However, strong evidence supporting the utility of such multimodal therapy is limited. The utility of perioperative chemotherapy has been extensively investigated in bladder cancer, and several randomized controlled trials have indicated the benefit of neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Regrettably, perioperative therapy for other urological cancers is controversial; therefore, no definitive conclusions have been drawn. Recently, the number of trials has rapidly increased due to the development of immune checkpoint inhibitors, used alone or in combination with other modalities. In this review, we summarize the current status and supporting evidence for perioperative therapies such as neoadjuvant and adjuvant therapies for urological cancers, including prostate cancer, urothelial cancer and renal cell carcinoma..
72. David S. Finley, Valerie S. Calvert, Junichi Inokuchi, Alice Lau, Navneet Narula, Emanuel F. Petricoin, Frank Zaldivar, Rosanne Santos, Darren R. Tyson, David K. Ornstein, Periprostatic Adipose Tissue as a Modulator of Prostate Cancer Aggressiveness, Journal of Urology, 10.1016/j.juro.2009.06.015, 182, 4 SUPPL., 1621-1627, 2009.10, Purpose: Adipose tissue has been suggested to contribute to the pathogenesis of various disease states, including prostate cancer. We investigated the association of cytokines and growth factors secreted by periprostatic adipose tissue with pathological features of aggressive prostate cancer. Materials and Methods: Periprostatic adipose tissue was harvested from patients undergoing radical prostatectomy and cultured for 24 hours to generate conditioned medium or snap frozen immediately for functional signaling profiling. Multiplex analysis of the periprostatic adipose tissue conditioned medium was used to detect cytokine levels and compared to patient matched serum from 7 patients. Interleukin-6 in serum and periprostatic adipose tissue conditioned medium was further analyzed by enzyme-linked immunosorbent assay and correlated with clinical variables, such as age, body mass index and Gleason score, in 45 patients. Interleukin-6 expression in periprostatic adipose tissue was determined by immunohistochemistry. Reverse phase protein microarray technology was used to analyze cell signaling networks in periprostatic adipose tissue. Results: Interleukin-6 in periprostatic adipose tissue conditioned medium was approximately 375 times greater than that in patient matched serum and levels correlated with pathological grade. This finding was further extended by cell signaling analysis of periprostatic adipose tissue, which showed greater phosphorylation on Stat3 with high grade tumors (any component of Gleason score 4 or 5). Conclusions: Higher Gleason score correlated with high levels of conditioned medium derived interleukin-6. Moreover, cell signaling analysis of periprostatic adipose tissue identified activated signaling molecules, including STAT3, that correlated with Gleason score. Since STAT3 is interleukin-6 regulated, these findings suggest that periprostatic adipose tissue may have a role in modulating prostate cancer aggressiveness by serving as a source of interleukin-6. Also, we found low numbers of inflammatory cells in the fat, suggesting that adipocytes are the major secretors of interleukin-6..
73. 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..
74. Ken Yamamoto, Miki Sonoda, Junichi Inokuchi, Senji Shirasawa, Takehiko Sasazuki, Polycomb Group Suppressor of Zeste 12 Links Heterochromatin Protein 1α and Enhancer of Zeste 2, Journal of Biological Chemistry, 10.1074/jbc.M307344200, 279, 1, 401-406, 2004.01, Drosophila suppressor of zeste 12 (Su(z)12) is a Polycomb group (PcG) transcriptional repressor and is present in E(z)-ESC, a multiprotein complex with methylation activity specific for lysine 9 and 27 of histone H3. Although PcG- and heterochromatin-mediated gene silencing have been considered distinct, mutant flies of Su(z)12 showed not only homeotic transformation but also position effect variegation. We now report that the mammalian SU(Z)12 directly interacts with heterochromatin protein 1α (HP1α) and PcG enhancer of zeste 2 (EZH2), the mammalian counterpart of E(z), in vitro and in vivo. Two distinct domains in SU(Z)12 are involved in these interactions, the region between the zinc finger motif and the VEFS (VRN2-EMF2-FIS2-Su(z)12) box for HP1α (amino acid residues 479-536) and the VEFS box for EZH2 (amino acid residues 600-639), which are not mutually exclusive. Interestingly this region of the VEFS box has been shown to be critical for the phenotype of the Su(z)12 mutant fly. In addition SU(Z)12 represses transcription activity in the presence of HP1α in a reporter assay. These results provide a molecular explanation for the functional link of these epigenetic silencing processes mediated by Su(z)12..
75. Masaki Shiota, Naohiro Fujimoto, Kenjiro Imada, Akira Yokomizo, Momoe Itsumi, Ario Takeuchi, Hidetoshi Kuruma, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Yoshinao Oda, Seiji Naito, Potential role for YB-1 in castration-resistant prostate cancer and resistance to enzalutamide through the androgen receptor V7, Journal of the National Cancer Institute, 10.1093/jnci/djw005, 108, 7, 2016.01, Background: Although androgen deprivation therapy for advanced prostate cancer initially exerts excellent anticancer effects, most prostate cancer treated with androgen deprivation therapy eventually recurs as castration-resistant prostate cancer (CRPC). Although aberrant kinase activation has been proposed as a mechanism of castration resistance, comprehensive kinase profiles in CRPC remain unknown. Therefore, we aimed to elucidate the kinome in CRPC as well as the role of key molecules. Methods: We utilized a kinome array in androgen-dependent LNCaP and castration-resistant CxR cells. The effect of Y-box binding protein-1 (YB-1) on androgen receptor (AR) expression was examined by quantitative polymerase chain reaction and western blot analysis. The association between polymorphisms in the YB-1 gene determined by genotyping and YB-1 expression evaluated by immunohistochemistry in prostate cancer tissues, as well as outcome in metastatic prostate cancer, were investigated by the Cochran-Armitage test and the Cox proportional hazards model, respectively. All statistical tests were two-sided. Results: One hundred fifty-six of 180 kinase phosphorylation sites, including ERK and RSK, were activated in CRPC cells, leading to increased phosphorylation of YB-1, which is a key molecule in the progression to CRPC. YB-1 signaling regulated AR V7 expression, and YB-1 inhibition augmented the anticancer effect of enzalutamide. Moreover, polymorphism (rs12030724) in the YB-1 gene affected YB-1 expression in 93 prostate cancer tissues (YB-1 positive rate; 14.3% in TT, 40.0% in AT, and 52.9% in AA, P = .04) and associated with probability of progression in 104 metastatic prostate cancer case patients (AT/TT vs AA, hazard ratio = 0.49, 95% confidence interval = 0.32 to 0.77, P = .001). Conclusions: YB-1 appears to be a promising target to inhibit the development of castration resistance, even at the AR variant-expressing stage. Polymorphism in the YB-1 gene may be a promising predictive biomarker in hormonal therapy..
76. 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..
77. 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 (p<0.0001). However, Cox proportional hazards analysis for recurrence-free survival only identified tumor size (≥15 mm) (hazard ratio=5.97, 95% confidence interval=2.39-17.29; p<0.0001) as a predictor of poor prognosis, although patients with class III or higher preoperative cytology showed a tendency towards frequent intravesical recurrence (hazard ratio=1.98, 95% confidence interval=0.96-4.2; p=0.063).
CONCLUSION: Preoperative urine cytology, in addition to tumor size, might be a useful predictor of intravesical recurrence of bladder cancer..
78. Tomohiko Murakami, Hirofumi Obata, Naoko Akitake, Masaki Shiot, 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<0.0001] and overall survival (HR=0.0042, 95% CI=0.0001-0.089, p<0.0001). Age (HR=7.19, 95% CI=1.08-54.27, p=0.041) and radiological/ clinical progression (HR=3.14, 95% CI=1.35-6.43, p=0.010) were associated with worse overall survival. Intriguingly, radiological/clinical progression was associated with the differential effect of anti-androgen withdrawal on overall survival (interaction p=0.031). Conclusion: Patients who suffer radiological/clinical progression are unsuitable candidates for anti-androgen withdrawal..
79. , Tomohiko Hara, Hiroyuki Fujimoto, Mizuaki Sakura, Junichi Inokuchi, Hiroyuki Nishiyama, Jun Miyazaki, Chikara Ohyama, Takuya Koie, Eiji Kikuchi, Shiro Hinotsu, Hiro omi Kanayama, Tsuneharu Miki, Kazuhiro Suzuki, Masatoshi Eto, Hiroyuki Nakanishi, Tomoharu Fukumori, Seiji Naito, Prognostic factors of recurrent disease in upper urinary tract urothelial cancer after radical nephroureterectomy
Subanalysis of the multi-institutional national database of the Japanese Urological Association, International Journal of Urology, 10.1111/iju.12884, 22, 11, 1013-1020, 2015.11, Objectives: To explore predictive factors of disease recurrence after radical nephroureterectomy in patients with upper urinary tract urothelial cancer. Methods: A multi-institutional national database promoted by the Japanese Urological Association including 293 institutions and 1172 patients was used for the present study. Patient with non-metastatic upper urinary tract urothelial cancer who underwent primary radical nephroureterectomy with curative intent were analyzed. Univariate analysis using the Kaplan-Meier method and multivariate Cox regression models with stepwise selection was used to evaluate time to recurrence after surgery. Results: The median duration of follow up was 55.8 months, and disease recurred in 325 (27.7%) patients at a median of 11.4 months after radical nephroureterectomy. According to a Cox proportional hazards model, the Union International Contre le Cancer 2002 pathological stage of the primary tumor, lymph node status, presence of lymphatic and/or vascular invasion, infiltrative growth pattern, and age were independent predictors (P < 0.05) of recurrence-free survival. Conclusions: Despite several limitations, our analysis suggests that pathological tumor stage, lymph node status, lymphovascular invasion, infiltrative growth pattern and age represent important prognostic variables after radical nephroureterectomy in Japanese patients with upper urinary tract urothelial cancer. This information could be potentially used to select patients for adjuvant systemic therapy..
80. 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, 2018.01, 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..
81. 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..
82. 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..
83. 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.
84. 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..
85. 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..
86. 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..
87. Daniel P. Petrylak, Ronald de Wit, Kim N. Chi, Alexandra Drakaki, Cora N. Sternberg, Hiroyuki Nishiyama, Daniel Castellano, Syed A. Hussain, Aude Fléchon, Aristotelis Bamias, Evan Y. Yu, Michiel S. van der Heijden, Nobuaki Matsubara, Boris Alekseev, Andrea Necchi, Lajos Géczi, Yen Chuan Ou, Hasan Senol Coskun, Wen Pin Su, Jens Bedke, Georgios Gakis, Ivor J. Percent, Jae Lyun Lee, Marcello Tucci, Andrey Semenov, Fredrik Laestadius, Avivit Peer, Giampaolo Tortora, Sufia Safina, Xavier Garcia del Muro, Alejo Rodriguez-Vida, Irfan Cicin, Hakan Harputluoglu, Scott T. Tagawa, Ulka Vaishampayan, Jeanny B. Aragon-Ching, Oday Hamid, Astra M. Liepa, Sameera Wijayawardana, Francesca Russo, Richard A. Walgren, Annamaria H. Zimmermann, Rebecca R. Hozak, Katherine M. Bell-McGuinn, Thomas Powles, Suet Lai Shirley Wong, Thean Hsiang Tan, Elizabeth Jane Hovey, Timothy Dudley Clay, Siobhan Su Wan Ng, Annemie Rutten, Jean Pascal Machiels, Herlinde Dumez, Susanna Yee Shan Cheng, Cristiano Ferrario, Lisa Sengeloev, Niels Viggo Jensen, Constance Thibault, Brigitte Laguerre, Florence Joly, Stéphane Culine, Catherine Becht, Günter Niegisch, Michael Stöckle, Marc Oliver Grimm, Christina A. Schwentner, Wolfgang Schultze-Seemann, Haralambos Kalofonos, Dimitrios Mavroudis, Christos Papandreou, Vasilis Karavasilis, Janos Révész, Eli Rosenbaum, Raya Leibowitz-Amit, Daniel Kejzman, David Sarid, Giorgio Vittorio Scagliotti, Sergio Bracarda, Francesco Massari, Takahiro Osawa, Naoto Miyajima, Nobuo Shinohara, Fumimasa Fukuta, Chikara Ohyama, Wataru Obara, Shinichi Yamashita, Yoshihiko Tomita, Koji Kawai, Satoshi Fukasawa, Masafumi Oyama, Junji Yonese, Masayoshi Nagata, Motohide Uemura, Kazuo Nishimura, Mutsushi Kawakita, Hiroyuki Tsunemori, Katsuyoshi Hashine, Junichi Inokuchi, Akira Yokomizo, Satoshi Nagamori, Hyo Jin Lee, Se Hoon Park, Sun Young Rha, Yu Jung Kim, Yun Gyoo Lee, Leticia Vazquez Cortés, Claudia Lorena Urzua Flores, Reinoud J.B. Blaisse, Fransiscus L.G. Erdkamp, Maureen J.B. Aarts, Joanna Wojcik-Tomaszewska, Piotr Tomczak, Bozena Sikora-Kupis, Michael Schenker, Alina Amalia Herzal, Anghel Adrian Udrea, Petr Karlov, Roman Fomkin, Pablo Gajate Borau, Enrique Grande, Juan Ignacio Delgado Mignorance, Yu Li Su, Jian Ri Li, Chien Liang Lin, Chia Chi Lin, Su Peng Yeh, Mustafa Erman, Yuksel Urun, Yuriy Golovko, Igor Bondarenko, Ivan Sinielnikov, Simon J. Crabb, Isabel Syndikus, Robert Huddart, Santhanam Sundar, Simon Chowdhury, Naveed Sarwar, Thomas W. Flaig, Chong Xian Pan, James K. Schwarz, Jennifer Lyn Cultrera, Peter Istvan Acs, John D. Hainsworth, Benjamin T. Herms, William Eyre Lawler, Thomas Eugene Lowe, Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE)
overall survival and updated results of a randomised, double-blind, phase 3 trial, The Lancet Oncology, 10.1016/S1470-2045(19)30668-0, 21, 1, 105-120, 2020.01, Background: Ramucirumab—an IgG1 vascular endothelial growth factor receptor 2 antagonist—plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5–13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3–4·8] vs 2·8 months [2·6–2·9]; HR 0·696 [95% CI 0·573–0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9–11·4) in the ramucirumab group versus 7·9 months (7·0–9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724–1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company..
88. , Daniel P. Petrylak, Ronald de Wit, Kim N. Chi, Alexandra Drakaki, Cora N. Sternberg, Hiroyuki Nishiyama, Daniel Castellano, Syed Hussain, Aude Fléchon, Aristotelis Bamias, Evan Y. Yu, Michiel S. van der Heijden, Nobuaki Matsubara, Boris Alekseev, Andrea Necchi, Lajos Géczi, Yen Chuan Ou, Hasan Senol Coskun, Wen Pin Su, Miriam Hegemann, Ivor J. Percent, Jae Lyun Lee, Marcello Tucci, Andrey Semenov, Fredrik Laestadius, Avivit Peer, Giampaolo Tortora, Sufia Safina, Xavier Garcia del Muro, Alejo Rodriguez-Vida, Irfan Cicin, Hakan Harputluoglu, Ryan C. Widau, Astra M. Liepa, Richard A. Walgren, Oday Hamid, Annamaria H. Zimmermann, Katherine M. Bell-McGuinn, Thomas Powles, Suet Lai Shirley Wong, Thean Hsiang Tan, Elizabeth Jane Hovey, Timothy Dudley Clay, Siobhan Su Wan Ng, Annemie Rutten, Jean Pascal Machiels, Herlinde Dumez, Susanna Yee Shan Cheng, Cristiano Ferrario, Lisa Sengeloev, Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE)
a randomised, double-blind, phase 3 trial, The Lancet, 10.1016/S0140-6736(17)32365-6, 390, 10109, 2266-2277, 2017.11, Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company..
89. 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..
90. 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..
91. 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, 2014.01, 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..
92. Junichi Inokuchi, Kentaro Kuroiwa, Yoshiyuki Kakehi, Mikio Sugimoto, Toshiki Tanigawa, Hiroyuki Fujimoto, Momokazu Gotoh, Naoya Masumori, Osamu Ogawa, Masatoshi Eto, Chikara Ohyama, Akito Yamaguchi, Hideyasu Matsuyama, Tomohiko Ichikawa, Tomohiko Asano, Junki Mizusawa, Junko Eba, Seiji Naito, Role of lymph node dissection during radical nephroureterectomy for upper urinary tract urothelial cancer
multi-institutional large retrospective study JCOG1110A, World Journal of Urology, 10.1007/s00345-017-2049-x, 35, 11, 1737-1744, 2017.11, Purpose: To evaluate the impact of lymph node dissection (LND) on clinical outcome during radical nephroureterectomy (RNU) for patients with upper urinary tract urothelial cancer (UTUC). Methods: We, the Urologic Oncology Study Group of the Japan Clinical Oncology Group (JCOG), retrospectively collected data from patients with non-metastatic UTUC who underwent RNU in 30 centers in 1995–2009. Ineligible patients and patients with previous and/or synchronous bladder cancer were excluded, and the remaining 2037 patients were analyzed. We compared overall and cancer-specific mortality between patients who underwent LND (LND group) and those without LND (no-LND group). Results: Among 2037 patients, LND was performed in 1046 (51.4%) patients, and 223 (10.9%) patients had pathological node-positive (pN+) disease. All-cause mortality was observed in 503 patients (24.7%) during follow-up (median 45.8 months), including 363 patients (17.8%) who died of UTUC. Patients with pN+ disease showed significantly shorter overall survival (OS) compared with pN0 patients, and the estimated 5-year OS for pN+ patients was 30%. Older age, ≥cT3, and clinical node-positive disease were found as preoperative predictors for pN+ disease by multivariate analysis. In the comparison of OS and cancer-specific mortality between LND and no-LND groups, there was no significant improvement by LND in multivariate analysis. The median number of lymph nodes removed was six (IQR 3–11). There was no significant association between the number of lymph nodes removed and OS. Conclusions: The present study indicates that there is no therapeutic benefit of LND during RNU for UTUC, although pathologically positive LN status can predict poor prognosis..
93. 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..
94. 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, 2015.01, 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..
95. 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, 2019.01, 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..
96. 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..
97. 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..
98. 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..
99. 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..
100. 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, 2015.01, 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..
101. 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..
102. 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..
103. 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..
104. 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..
105. 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..
106. 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..
107. 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..
108. Yayoi Matsuda, Hisaya Kawate, Yuka Okishige, Ichiro Abe, Masahiro Adachi, Keizo Ohnaka, Naoichi Satoh, Junichi Inokuchi, Katsunori Tatsugami, Seiji Naito, Masatoshi Nomura, Ryoichi Takayanagi, Successful management of cryptococcosis of the bilateral adrenal glands and liver by unilateral adrenalectomy with antifungal agents
A case report, BMC Infectious Diseases, 10.1186/1471-2334-11-340, 11, 2011.12, Background: Cryptococcus species usually affect the central nervous system and lungs in immunocompromised hosts. Although the adrenal glands can be involved in disseminated cryptococcosis, primary adrenal insufficiency caused by the fungal infection is uncommon.Case presentation: We present a case of primary adrenal insufficiency with bilateral adrenal masses and liver invasion in a 43-year-old man with mild type 2 diabetes mellitus. Cryptococcosis was diagnosed by fine-needle aspiration biopsy of the liver mass. The serum cryptococcal antigen titer was elevated to 1:256. After 6 months of antifungal therapy with fluconazole and amphotericin B, the size of the liver mass was decreased, but no significant changes were observed in the bilateral adrenal masses and the serum cryptococcal antigen titer remained elevated at 1:128. To control the cryptococcosis, a laparoscopic left adrenalectomy was performed, followed by antifungal therapy. After the unilateral adrenalectomy, the size of the remaining right adrenal mass was reduced and the serum cryptococcal antigen titer declined to 1:4.Conclusions: This is the first report describing adrenal cryptococcosis with adrenal insufficiency and liver invasion without central nervous system involvement. Adrenal cryptococcosis should be considered in the differential diagnosis for patients with bilateral adrenal masses with primary adrenal deficiency. Unilateral adrenalectomy was quite effective in controlling the cryptococcosis in this case. Even in patients with bilateral adrenal cryptococcosis, unilateral adrenalectomy should be an option for treatment of disseminated cryptococcosis..
109. 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..
110. 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..
111. Ryo Murayama, Akihiro Nishie, Tomoyuki Hida, Shingo Baba, Junichi Inokuchi, Yoshinao Oda, Hiroshi Honda, Uptake of 18F-FDG in Adrenal Adenomas Is Associated with Unenhanced CT Value and Constituent Cells, Clinical nuclear medicine, 10.1097/RLU.0000000000002759, 44, 12, 943-948, 2019.12, Purpose The purposes of this study were to investigate the correlation between unenhanced CT attenuation values and 18F-FDG uptake in adrenal adenomas, and to clarify the mechanism of FDG uptake in adrenal adenomas based on immunohistochemical findings. Materials and Methods In 57 adrenal adenomas, the correlation between SUVmax on 18F-FDG PET and unenhanced CT attenuation was retrospectively investigated. In the 11 surgically resected nodules, the clear cell ratio (CCR) and expression levels of glucose transporters (GLUTs) 1 to 4 were pathologically evaluated. The GLUT expression levels were scored at 0 to 3 points for each transporter, and the sum of these expression levels was defined as the GLUT score. The relationships between CCR and either the CT attenuation number or SUVmax, and between the GLUT score and each of the CT attenutation value, SUVmax, or CCR were evaluated. Results There was a significant positive correlation between SUVmax and the CT attenuation value for the group of 57 adenomas (R = 0.44, P = 0.0007). For the 11 surgically resected cases, there was a nonsignificant trend of negative correlation between SUVmax and CCR (R = 0.57, P = 0.06). There was a significant positive correlation between GLUT score and CT attenuation value (R = 0.68, P = 0.02), and a significant negative correlation between GLUT score and CCR (R = 0.60, P = 0.003). Conclusions Adrenal adenomas composed of many compact cells or having high attenuation on unenhanced CT showed high FDG uptake. FDG uptake of adrenal adenomas may depend on the constituent cells..
112. Junki Maehara, Akihiro Nishie, Yoshiki Asayama, Kousei Ishigami, Yasuhiro Ushijima, Yukihisa Takayama, Daisuke Okamoto, Nobuhiro Fujita, Masaaki Sugimoto, Junichi Inokuchi, Hiroshi Honda, Tumor enhancement on dynamic CT
A predictive factor for recurrence after nephrectomy in localized T1 clear cell renal cell carcinoma, Anticancer research, 10.21873/anticanres.12486, 38, 4, 2377-2383, 2018.04, Aim: To investigate whether radiological parameters obtained on dynamic computed tomography (CT), especially those related to tumor enhancement, are predictive factors for recurrence after nephrectomy in localized stage T1 clear cell renal cell carcinoma (ccRCC). Materials and Methods: We retrospectively studied 88 patients with localized stage T1 ccRCC who underwent dynamic CT preoperatively. Seven patients had recurrent disease after surgery. Tumor attenuations were measured by placing a region of interest in the solid region. TApre and TAneph were defined as the tumor attenuation values of the pre-contrast and nephrographic phase, respectively. The correlations between disease-free survival and clinicopathological factors, including the radiological parameter TAneph – TApre (ΔTAneph), were analyzed by Cox proportional hazards model or Kaplan–Meier method with the log-rank test. Results: Only ΔTAneph was significantly and positively correlated with disease-free survival (p<0.05). Tumor size also tended to be negatively correlated with disease-free survival (p<0.1). The 5- and 10-year disease-free survival rates of the group with high ΔTAneph (≥86 HU) were 97.4% and 97.4%, while those of the group with low ΔTAneph (<86 HU) were 89.6% and 71.6%, respectively. Conclusion: Tumor enhancement in the nephrographic phase of CT was a predictive factor for recurrence after nephrectomy in patients with localized stage T1 ccRCC..
113. 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..
114. 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..
115. 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, 2014.01, 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..
116. 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..