Details of a Researcher - Oya, Mototsugu

Papers - Oya, Mototsugu

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Clinical evaluation of two consecutive UroVysion fluorescence in situ hybridization tests to detect intravesical recurrence of bladder cancer

Kojima Takahiro, Nishiyama Hiroyuki, Ozono Seiichiro, Hinotsu Shiro, Keino Naoto, Yamaguchi Akito, Sakai Hideki, Enomoto Yutaka, Horie Shigeo, Fujimoto Kiyohide, Matsuyama Hideyasu, Okamura Takehiko, Kanimoto Yusuke, Oya Mototsugu, Nonomura Norio, Naito Seiji, Akaza Hideyuki

International Journal of Clinical Oncology 1 - 8 2018.07

Joint Work, ISSN 1341-9625

Background: We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT). Methods: In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests. Results: Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2–64.8%) sensitivity and 72.4% (68.3–76.8%). Urine cytology had 4.5% (0.0–10.7%) sensitivity and 99.8% (99.3–100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.157). Interestingly, the patients with two consecutive positive UroVysion test results had the highest cancer detection rate (14.8%), which is greater than those of the patients with a positive result in either (7.2%) or neither (1.2%) of the two tests at the 3-month follow-up. Conclusions: The UroVysion test provided higher sensitivity than urine cytology to detect bladder cancer during post-TURBT follow-up. Two consecutive UroVysion tests might be a better indicator to predict intravesical recurrence.

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Androgen receptor signaling reduces radiosensitivity in bladder cancer

Ide Hiroki, Inoue Satoshi, Mizushima Taichi, Jiang Guiyang, Chuang Kuang Hsiang, Oya Mototsugu, Miyamoto Hiroshi

Molecular Cancer Therapeutics (Molecular Cancer Therapeutics) 17 ( 7 ) 1566 - 1574 2018.07

Research paper (scientific journal), Joint Work, ISSN 1535-7163

Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, dihydrotestosterone treatment lowered the effects of irradiation. Meanwhile, an antiandrogen hydroxyflutamide enhanced them in AR-positive cells cultured in the presence of androgens. AR knockdown or hydroxyflutamide treatment also resulted in a delay in DNA double-strand break repair 4-24 hours after irradiation. We then established "radiation-resistant" sublines and found considerable elevation of the expression of AR as well as DNA repair genes, such as ATR, CHEK1, and PARP-1, in these sublines, compared with respective controls. Furthermore, dihydrotestosterone induced the expression of these DNA repair genes in irradiated AR-positive cells, and hydroxyflutamide antagonized the androgen effects. Finally, in a mouse xenograft model, low-dose flutamide was found to enhance the inhibitory effects of irradiation, and its tumor size was similar to that of AR knockdown line with radiation alone. These findings suggest that AR activity inversely correlates with radiosensitivity in bladder cancer. Accordingly, antiandrogenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer.

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Recombinant Thrombomodulin Alpha Protects Kidney Graft from Damage after Long Cold Ischemia Time in a Rat Kidney Transplant Model

Shinoda Kazunobu, Tamaki Satoshi, Morita Shinya, Shimoda Masayuki, Oya Mototsugu

TRANSPLANTATION (LIPPINCOTT WILLIAMS & WILKINS) 102 S710 - S710 2018.07

Joint Work, ISSN 0041-1337

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RELATIONSHIP BETWEEN RADIATION DOSES AND DEVELOPMENT OF ERECTILE DYSFUNCTION IN PATIENTS TREATED WITH PERMANENT PROSTATE BRACHYTHERAPY FOR LOCALIZED PROSTATE CANCER

Hayakawa N, Kikuchi E, Shigeta K, Mizuno R, Oya M

JOURNAL OF SEXUAL MEDICINE 15 ( 7 ) S287 - S287 2018.07

Joint Work, ISSN 1743-6095

PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer

Yasumizu Yota, Hongo Hiroshi, Kosaka Takeo, Mikami Shuji, Nishimoto Koshiro, Kikuchi Eiji, Oya Mototsugu

Oncotarget (Oncotarget) 9 ( 45 ) 27698 - 27707 2018.06

Research paper (scientific journal), Joint Work, ISSN 1949-2553

The aim of this study was to explore the efficacy of mTOR inhibitor for castrationresistant prostate cancer (CRPC) under hypoxia. Although under normoxia C4-2AT6, it is a CRPC cell line, expressed elevated pAkt, pS6 and Pyruvate kinase M2 (PKM2) accompanied by elevated HIF-1a expression, 5% hypoxic condition further induced expression of these proteins. These results indicate hypoxic environment elevated PI3K/ Akt/mTOR pathway in aggressive prostate cancer. However, C4-2AT6 cells treated with mTOR inhibitor under hypoxia less decreased compared to cells treated with the same dose drugs under normoxia. Western blot analysis showed mTOR inhibitor: RAD001 not only inhibited pS6, but also increased the expression of PKM2 in a dose and time dependent manner. Pyruvate kinase acts on glycolysis. PKM2, which is frequently express in tumor cells, is one isoform of pyruvate kinase. PKM2 is reported to act as a transcription factor. In the present study overexpression of PKM2 in C4-2AT6 induced resistance to RAD001 under normoxia. To evaluate the therapeutic effect of targeting PKM2, we inhibited PKM2 in C4-2AT6 under hypoxia using si-PKM2. The number of C4-2AT6 under chronic hypoxia exposed to siPKM2 significantly decreased compared to intact C4-2AT6 under chronic hypoxia. Furthermore, si-PKM2 improved resistance to mTOR inhibitor in C4-2AT6. When examined using clinical samples, high PKM2 expression was correlated with a high Gleason score and poor PSA free survival. These results suggested that up-regulation of PKM2 is one possibility of resistance to mTOR inhibitor in CRPC. And it is possible that PKM2 is a useful therapeutic target of CRPC.

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Evaluation of efficacy and safety of sorafenib in kidney cancer patients aged 75 years and older

Tatsugami Katsunori, Oya Mototsugu, Kabu Koki, Akaza Hideyuki

British Journal of Cancer 1 - 7 2018.06

Joint Work, ISSN 0007-0920

Background: The average age of patients diagnosed with renal cell carcinoma (RCC) is increasing, but a limited number of reports have described therapy of tyrosine kinase inhibitor for elderly RCC patients. Hence, we analysed the efficacy and safety of sorafenib in elderly patients aged ≥75 years with advanced RCC. Methods: Data were extracted from <75-year-old and ≥75-year-old patient groups, matching those demographics considered to affect prognosis. Differences in patients’ characteristics, dose modification, adverse events, tumour response, progression-free survival, and renal function (glomerular filtration) were evaluated between the groups. Results: From 2536 and 703 patients aged <75 and ≥75 years, respectively, 397 pairs were matched. Median daily dose was higher and duration of treatment longer in patients <75 years; however, progression-free survival and tumour response were similar in both age groups. Incidence of all adverse events was not significantly different between groups. The proportion of patients discontinuing treatment was higher in patients ≥75 years, but there was no significant difference between groups in the number patients discontinuing due to adverse events. Conclusions: For patients aged ≥75 years, sorafenib treatment had minimal additional negative impact compared to younger patients and showed similar efficacy and safety without reducing renal function.

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The starburst galaxy NGC 253 revisited by H.E.S.S. and Fermi-LAT

H. E. S. S. Collaboration, H. Abdalla, F. Aharonian, F. Ait Benkhali, E. O. Angüner, M. Arakawa, C. Arcaro, C. Armand, M. Arrieta, M. Backes, M. Barnard, Y. Becherini, J. Becker Tjus, D. Berge, S. Bernhard, K. Bernlöhr, R. Blackwell, M. Böttcher, C. Boisson, J. Bolmont, S. Bonnefoy, P. Bordas, J. Bregeon, F. Brun, P. Brun, M. Bryan, M. Büchele, T. Bulik, T. Bylund, M. Capasso, S. Caroff, A. Carosi, S. Casanova, M. Cerruti, N. Chakraborty, S. Chandra, R. C. G. Chaves, A. Chen, S. Colafrancesco, B. Condon, I. D. Davids, C. Deil, J. Devin, P. de Wilt, L. Dirson, A. Djannati-Ataï, A. Dmytriiev, A. Donath, L. O'C. Drury, J. Dyks, K. Egberts, G. Emery, J. -P. Ernenwein, S. Eschbach, S. Fegan, A. Fiasson, G. Fontaine, S. Funk, M. Füßling, S. Gabici, Y. A. Gallant, T. Garrigoux, F. Gaté, G. Giavitto, D. Glawion, J. F. Glicenstein, D. Gottschall, M. -H. Grondin, J. Hahn, M. Haupt, G. Heinzelmann, G. Henri, G. Hermann, J. A. Hinton, W. Hofmann, C. Hoischen, T. L. Holch, M. Holler, D. Horns, D. Huber, H. Iwasaki, A. Jacholkowska, M. Jamrozy, D. Jankowsky, F. Jankowsky, L. Jouvin, I. Jung-Richardt, M. A. Kastendieck, K. Katarzyński, M. Katsuragawa, U. Katz, D. Kerszberg, D. Khangulyan, B. Khélifi, J. King, S. Klepser, W. Kluźniak, N. Komin, K. Kosack, S. Krakau, M. Kraus, P. P. Krüger, G. Lamanna, J. Lau, J. Lefaucheur, A. Lemière, M. Lemoine-Goumard, J. -P. Lenain, E. Leser, T. Lohse, M. Lorentz, R. López-Coto, I. Lypova, D. Malyshev, V. Marandon, A. Marcowith, C. Mariaud, G. Martí-Devesa, R. Marx, G. Maurin, P. J. Meintjes, A. M. W. Mitchell, R. Moderski, M. Mohamed, L. Mohrmann, E. Moulin, T. Murach, S. Nakashima, M. de Naurois, H. Ndiyavala, F. Niederwanger, J. Niemiec, L. Oakes, P. O'Brien, H. Odaka, S. Ohm, M. Ostrowski, I. Oya, M. Padovani, M. Panter, R. D. Parsons, C. Perennes, P. -O. Petrucci, B. Peyaud, Q. Piel, S. Pita, V. Poireau, A. Priyana Noel, D. A. Prokhorov, H. Prokoph, G. Pühlhofer, M. Punch, A. Quirrenbach, S. Raab, R. Rauth, A. Reimer, O. Reimer, M. Renaud, F. Rieger, L. Rinchiuso, C. Romoli, G. Rowell, B. Rudak, E. Ruiz-Velasco, V. Sahakian, S. Saito, D. A. Sanchez, A. Santangelo, M. Sasaki, R. Schlickeiser, F. Schüssler, A. Schulz, U. Schwanke, S. Schwemmer, M. Seglar-Arroyo, M. Senniappan, A. S. Seyffert, N. Shafi, I. Shilon, K. Shiningayamwe, R. Simoni, A. Sinha, H. Sol, F. Spanier, A. Specovius, M. Spir-Jacob, Ł. Stawarz, R. Steenkamp, C. Stegmann, C. Steppa, I. Sushch, T. Takahashi, J. -P. Tavernet, T. Tavernier, A. M. Taylor, R. Terrier, L. Tibaldo, D. Tiziani, M. Tluczykont, C. Trichard, M. Tsirou, N. Tsuji, R. Tuffs, Y. Uchiyama, D. J. van der Walt, C. van Eldik, C. van Rensburg, B. van Soelen, G. Vasileiadis, J. Veh, C. Venter, A. Viana, P. Vincent, J. Vink, F. Voisin, H. J. Völk, T. Vuillaume, Z. Wadiasingh, S. J. Wagner, P. Wagner, R. M. Wagner, R. White, A. Wierzcholska, A. Wörnlein, R. Yang, D. Zaborov, M. Zacharias, R. Zanin, A. A. Zdziarski, A. Zech, F. Zefi, A. Ziegler, J. Zorn, N. Żywucka

A&A 617, A73 (2018) 2018.06

(Abridged) Context. NGC 253 is one of only two starburst galaxies found to
emit $\gamma$-rays from hundreds of MeV to multi-TeV energies. Accurate
measurements of the very-high-energy (VHE) (E $>$ 100 GeV) and high-energy (HE)
(E $>$ 60 MeV) spectra are crucial to study the underlying particle
accelerators and cosmic-ray interaction and transport.
Aims. The measurement of the VHE $\gamma$-ray emission of NGC 253 published
in 2012 by H.E.S.S. was limited by large systematic uncertainties. Here, a
measurement of the $\gamma$-ray spectrum of NGC 253 is investigated in both HE
and VHE $\gamma$-rays.
Methods. The data of H.E.S.S. observations are reanalysed using an updated
calibration and analysis chain. The $Fermi$-LAT analysis employs more than 8
years of data processed using pass 8. The cosmic-ray particle population is
evaluated from the combined HE--VHE $\gamma$-ray spectrum using NAIMA.
Results. The VHE $\gamma$-ray energy spectrum is best fit by a power-law with
a flux normalisation of
$(1.34\,\pm\,0.14^{\mathrm{stat}}\,\pm\,0.27^{\mathrm{sys}}) \times 10^{-13}
\mathrm{cm^{-2} s^{-1} TeV^{-1}}$ at 1 TeV -- about 40 \% above, but compatible
with the value obtained in Abramowski et al. (2012). The spectral index $\Gamma
= 2.39 \pm 0.14^{\mathrm{stat}} \pm 0.25^{\mathrm{sys}}$ is slightly softer
than but consistent with the previous measurement. At energies above $\sim$3
GeV the HE spectrum is consistent with a power-law ranging into the VHE part of
the spectrum measured by H.E.S.S.
Conclusions. Two scenarios for the starburst nucleus are tested, in which the
gas in the starburst nucleus acts as a target for hadronic cosmic rays. In
these two models, the level to which NGC\,253 acts as a calorimeter is
estimated to a range of $f_{\rm cal} = 0.1$ to $1$ while accounting for the
measurement uncertainties.

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Prognostic Value of Pretreatment Albumin-to-Globulin Ratio in Patients With Non–Muscle-Invasive Bladder Cancer

Niwa Naoya, Matsumoto Kazuhiro, Ide Hiroki, Nagata Hirohiko, Oya Mototsugu

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 16 ( 3 ) e655 - e661 2018.06

Research paper (scientific journal), Joint Work, ISSN 1558-7673

In an investigation of the relationship between albumin-to-globulin ratio (AGR) and oncologic outcomes in 364 non–muscle-invasive bladder cancer (NMIBC) patients, those with AGR < 1.6 had significantly poorer recurrence-free and progression-free survival than those with AGR ≥ 1.6. Multivariate analysis revealed that AGR < 1.6 is significantly associated with tumor recurrence. Low AGR is an independent risk factor for recurrence in NMIBC patients. Purpose: To investigate the relationship between albumin-to-globulin ratio (AGR) and oncologic outcomes in patients with non–muscle-invasive bladder cancer (NMIBC). Patients and Methods: We identified 364 patients with primary NMIBC who underwent transurethral surgery between 2000 and 2015. The association between pretreatment AGR and clinicopathologic variables, including oncologic outcomes, was statistically evaluated. Results: One hundred twenty patients (33.0%) experienced at least one tumor recurrence, and 23 (6.3%) developed muscle-invasive disease. The median (interquartile range) pretreatment AGR was 1.73 (1.53-1.89). The Kaplan-Meier curve revealed that tumor recurrence was strongly predicted in patients with pretreatment AGR < 1.6, and similar results were observed for disease progression (P <.01 and P <.01, respectively). On multivariate analysis, we found that pretreatment AGR < 1.6 is an independent risk factor for tumor recurrence (hazard ratio, 0.53; P <.01). On univariate analysis, pretreatment AGR < 1.6 was also associated with disease progression (hazard ratio, 0.24; P <.01). Conclusion: Low pretreatment AGR is an independent risk factor for tumor recurrence and is one risk factor for disease progression in NMIBC patients. This inexpensive and easily accessible biomarker may become useful in selecting patients with NMIBC with higher risk of recurrence and progression.

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Does switching the bacillus Calmette-Guérin strain affect clinical outcome in patients with recurrent non–muscle-invasive bladder cancer after initial bacillus Calmette-Guérin therapy?

Niwa N., Kikuchi E., Matsumoto K., Kosaka T., Mizuno R., Oya M.

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 36 ( 6 ) 306.e1 - 306.e8 2018.06

ISSN 10781439

© 2018 Elsevier Inc. Purpose: It is still unknown whether switching the bacillus Calmette-Guérin (BCG) strain at the second induction course of BCG therapy has a therapeutic benefit in patients with tumor recurrence after the initial BCG therapy (BCG-relapsing tumor). Materials and methods: We retrospectively reviewed the clinicopathological features of 97 patients treated with a second induction course of BCG therapy between 1986 and 2014. Among the patients initially treated with BCG Tokyo-172, the second course was either BCG Tokyo-172 in 56 (57.8%) or BCG Connaught in 15 (15.5%). Among those who were initially treated with BCG Connaught, the corresponding numbers were 13 (13.4%) or 13 (13.4%), respectively. Twenty-eight (28.9%) patients were given a different BCG strain at the 2 BCG therapies (switching group), and 69 (71.1%) patients were given the same BCG strain (non-switching group). Result: The 5-year recurrence-free survival rate of the switching group was 64.7 ± 9.6%, which was not significantly different from that of the non-switching group (54.8 ± 6.9%, P = 0.427). Switching or not switching the BCG strain was not significantly associated with tumor recurrence after the second BCG therapy. The 5-year progression-free survival rate of the switching group was 95.4 ± 2.6%, which was also not significantly different from that of the non-switching group (96.0 ± 3.9%, P = 0.674). Patients treated with BCG Tokyo-172 to Tokyo-172 had significantly higher incidences of side effects during the second BCG therapy. Conclusions: The results of this study indicate that in patients with a BCG-relapsing tumor after the initial BCG therapy, the same BCG strain as that administered at the initial BCG therapy could be utilized effectively for the second BCG therapy. Patients treated with BCG Tokyo-172 for an initial tumor had a higher incidence of side effects during the second BCG therapy using the same strain.

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Recombinant Thrombomodulin alpha Attenuates Kidney Graft Damage after Long Cold Ischemia Time in a Rat Kidney Transplant Model.

Tamaki S, Shinoda K, Shimoda M, Morita S, Asanuma H, Oya M

AMERICAN JOURNAL OF TRANSPLANTATION 18 362 - 362 2018.06

Joint Work, ISSN 1600-6135

腎盂尿管癌に対するBCGの上部尿路注入療法に関する実態調査

大園誠一郎, 大家基嗣, 西山博之, 窪田吉信, 塚本泰司, 内藤誠二, 赤座英之

泌尿器外科 (医学図書出版(株)) 31 ( 6 ) 985 - 988 2018.06

Joint Work, ISSN 0914-6180

Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma

Guo Jun, Jin Jie, Oya Mototsugu, Uemura Hirotsugu, Takahashi Shunji, Tatsugami Katsunori, Rha Sun Young, Lee Jae Lyun, Chung Jinsoo, Lim Ho Yeong, Wu Hsi Chin, Chang Yen Hwa, Azad Arun, Davis Ian D., Carrasco-Alfonso Marlene J., Nanua Bhupinder, Han Jackie, Ahmad Qasim, Motzer Robert

Journal of Hematology and Oncology 11 ( 1 ) 2018.05

Joint Work, ISSN 1756-8722

Background: The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. Methods: Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off). Results: Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%). Conclusions: A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations. Trial registration: ClinicalTrials.gov, NCT00720941, Registered July 22, 2008 ClinicalTrials.gov, NCT01147822, Registered June 22, 2010

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Association between expression of programmed cell death-1 and smoking status in patients with upper tract urothelial carcinoma treated by radical nephroureterectomy.

Nozomi Hayakawa, Eiji Kikuchi, Kimiharu Takamatsu, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 15 ) 2018.05

Joint Work, ISSN 0732-183X

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The clinical impact of serum C-reactive protein levels in metastatic renal-cell carcinoma patients treated by second-line molecular targeted therapies

Kimiharu Takamatsu, Ryuichi Mizuno, Nozomi Hayakawa, Takeo Kosaka, Eiji Kikuchi, Shuji Mikami, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 15 ) 2018.05

Joint Work, ISSN 0732-183X

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Does neoadjuvant chemotherapy affect postoperative complication rates in elderly patients treated with radical cystectomy for bladder cancer?

Nozomi Hayakawa, Eiji Kikuchi, Ryuichi Mizuno, Mototsugu Oya, Kimiharu Takamatsu

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 15 ) 2018.05

Joint Work, ISSN 0732-183X

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Constitutive activation of mTOR pathways in renal cell carcinoma arising in dialyzed patients

Ryuichi Mizuno, Shuji Mikami, Kimiharu Takamatsu, Nozomi Hayakawa, Takeo Kosaka, Eiji Kikuchi, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 15 ) 2018.05

Joint Work, ISSN 0732-183X

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New targeted approach to CRPC

Kosaka T., Oya M.

Hormone Therapy and Castration Resistance of Prostate Cancer (Hormone Therapy and Castration Resistance of Prostate Cancer) 375 - 385 2018.05

Joint Work

© Springer Nature Singapore Pte Ltd. 2018. All rights reserved. Our understanding of the heterogeneity and genetic characteristics of CRPC demonstrates underlying their complexity, which has been thought to be associated with their intractability. Recent advance of integrative next generation sequencing unveiled the extensive mutational landscape of metastatic CRPC, many of which can be a targetable mutation and been linked to ongoing clinical trials. Molecular stratification of patient groups will clearly be critical to successful drug development and clinical trials from the view point of precision medicine. In this review, we discuss the potential of new targeted approach to impact the clinical management of CRPC.

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Clinical Role of Programmed Cell Death-1 Expression in Patients with Non-muscle-invasive Bladder Cancer Recurring After Initial Bacillus Calmette–Guérin Therapy

Fukumoto Keishiro, Kikuchi Eiji, Mikami Shuji, Hayakawa Nozomi, Matsumoto Kazuhiro, Niwa Naoya, Oya Mototsugu

Annals of Surgical Oncology (Annals of Surgical Oncology) 25 ( 8 ) 1 - 8 2018.05

Research paper (scientific journal), Joint Work, ISSN 1068-9265

Background: The programmed cell death-1 (PD-1) pathway has been suggested to play an important role in tumor immune escape. We evaluated changes in PD-1 expression before and after Bacillus Calmette–Guérin (BCG) therapy and its prognostic significance in non-muscle-invasive bladder cancer (NMIBC) patients.Methods: We examined 78 paired tissue samples of NMIBC in tumors just before BCG therapy and BCG-relapsing tumors, defined as recurrence after achieving disease-free status by initial BCG instillations for 6 months. We counted PD-1-positive cells, and PD-1 expression was defined as high when the number of PD-1-positive cells was more than 18 under ×200 magnification. Results: The median number of PD-1-positive cells in tumors just before BCG therapy was 3.5, significantly lower than that in BCG-relapsing tumors (17.0, p < 0.001). High PD-1 expression was observed in 20 tumors just before BCG therapy (25.6%) and 36 BCG-relapsing tumors (46.2%). Fifty-two cases (66.6%) showed an increase in the number of PD-1-positive cells in BCG-relapsing tumors. High PD-1 expression in BCG-relapsing tumors was independently associated with subsequent tumor recurrence (p = 0.011) and stage progression (p = 0.033). The 5-year recurrence-free and progression-free survival rates were 40.7 and 74.1% in patients with high PD-1 expression in BCG-relapsing tumors, significantly lower than those in their counterparts (72.9 and 94.1%, respectively). Conclusions: PD-1 was induced by BCG therapy, and its expression in BCG-relapsing tumors may be an important indicator for predicting worse clinical outcomes in NMIBC patients treated with BCG therapy.

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Change of the 5 alpha/5 beta ratio of urinary steroid metabolites in benign prostatic hyperplasia patients treated with dutasteride

Maeda, Takahiro, Kikuchi, Eiji, Hasegawa, Masanori, Homma, Keiko, Yasumizu, Yota, Hattori, Seiya, Kosaka, Takeo, Shinoda, Kazunobu, Miyajima, Akira, Oya, Mototsugu

CLINICAL BIOCHEMISTRY 55 36 - 41 2018.05

Research paper (scientific journal), ISSN 0009-9120

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Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma: Asian versus non-Asian subgroup analysis of the COMPARZ trial

Guo, Jun, Jin, Jie, Oya, Mototsugu, Uemura, Hirotsugu, Takahashi, Shunji, Tatsugami, Katsunori, Rha, Sun Young, Lee, Jae-Lyun, Chung, Jinsoo, Lim, Ho Yeong, Wu, Hsi Chin, Chang, Yen Hwa, Azad, Arun, Davis, Ian D., Carrasco-Alfonso, Marlene J., Nanua, Bhupinder, Han, Jackie, Ahmad, Qasim, Motzer, Robert

JOURNAL OF HEMATOLOGY & ONCOLOGY (Journal of Hematology and Oncology) 11 ( 1 ) E655 - E661 2018.05

Research paper (scientific journal), Single Work, ISSN 1756-8722

© 2018 The Author(s). Background: The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. Methods: Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off). Results: Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most

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