Details of a Researcher - Oya, Mototsugu

Papers - Oya, Mototsugu

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Predictors of renal dysfunction during everolimus treatment in patients with metastatic renal cell carcinoma

Mizuno Ryuichi, Takahashi Ryohei, Shinojima Toshiaki, Kosaka Takeo, Miyajima Akira, Oya Mototsugu

JOURNAL OF CLINICAL ONCOLOGY 33 ( 15 ) 88 - 88 2015.05

Research paper (scientific journal), Joint Work, ISSN 0732-183X

Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer

Ito Yujiro, Kikuchi Eiji, Tanaka Nobuyuki, Kosaka Takeo, Suzuki Eriko, Mizuno Ryuichi, Shinojima Toshiaki, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

BMC Cancer 15 ( 1 ) 2015.04

Background: No previous study has addressed the efficacy of NF-κ B blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κ B activation and therapeutic impact of NF-κ B blockade by the novel NF-κ B inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells. Methods: Two human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κ B was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro. Results: Intranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively. Conclusion: There was a distinct change in the activation level of NF-κ B between T24 and T24PR cells, suggesting strong nuclear localization of NF-κ B could be a promising target after developing acquired platinum-resistance in bladder cancer.

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Therapeutic effect of intravesical administration of paclitaxel solubilized with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) in an orthotopic bladder cancer model

Tamura Koetsu, Kikuchi Eiji, Konno Tomohiro, Ishihara Kazuhiko, Matsumoto Kazuhiro, Miyajima Akira, Oya Mototsugu

BMC Cancer 15 ( 1 ) 2015.04

Background: To evaluate the effects of intravesical administration of paclitaxel (PTX-30W), which was prepared by solubilization with a water-soluble amphiphilic polymer composed of PMB30W, a copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate, in an orthotopic bladder cancer model. Methods: The cytotoxicities of PMB30W were examined in MBT-2 cell cultures and the results were compared with those of the conventional paclitaxel solubilizer Cremophor. In an orthotopic MBT-2 bladder cancer model, the effect of intravesical administration of PTX-30W was compared with that of paclitaxel solubilized with Cremophor (PTX-CrEL). The paclitaxel concentration in bladder tumors after the intravesical treatment was also evaluated using liquid chromatography tandem mass spectrometry (LC-MS/MS) system. Results: In vitro, Cremophor exhibited dose-dependent cytotoxicity towards MBT-2 cells, whereas no cytotoxicity was observed with PMB30W. In the orthotopic bladder cancer model, intravesical administration of PTX-30W resulted in a significant reduction of bladder wet weight compared with that of PTX-CrEL. The paclitaxel concentration in bladder tumors after the intravesical treatment was significantly higher in PTX-30W treated mice than in PTX-CrEL treated mice. Conclusions: Intravesically administered PTX-30W can elicit stronger antitumor effects on bladder tumors than conventional paclitaxel formulated in Cremophor, presumably because of its better penetration into tumor cells. PTX-30W might be a promising antitumor agent for intravesical treatment of non-muscle invasive bladder cancer.

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The efficacy of enzalutamide in castration resistant prostate cancer

Kosaka Takeo, Oya Mototsugu

Japanese Journal of Clinical Urology 69 ( 5 ) 386 - 392 2015.04

ISSN 0385-2393

Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high risk patients with upper tract urothelial carcinoma

Shirotake Suguru, Kikuchi Eiji, Tanaka Nobuyuki, Matsumoto Kazuhiro, Miyazaki Yasumasa, Kobayashi Hiroaki, Ide Hiroki, Obata Jun, Hoshino Katsura, Kaneko Gou, Hagiwara Masayuki, Kosaka Takeo, Kanao Kent, Kodaira Kiichiro, Hara Satoshi, Oyama Masafumi, Momma Tetsuo, Miyajima Akira, Nakagawa Ken, Hasegawa Shintaro, Nakajima Yosuke, Oya Mototsugu

Journal of Urology 193 ( 4 ) 1122 - 1128 2015.04

ISSN 0022-5347

Purpose Current guidelines do not yet provide any recommendations for adjuvant chemotherapy in patients with upper tract urothelial carcinoma managed with radical nephroureterectomy. We evaluated whether an adjuvant chemotherapeutic regimen would affect the clinical outcome in patients with high risk upper tract urothelial carcinoma. Materials and Methods We identified 873 patients who had undergone radical nephrouretectomy for localized upper tract urothelial carcinoma at 14 Japanese institutions between 1993 and 2011. We assessed whether the type of regimen, such as methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and cisplatin, in an adjuvant setting, could affect the subsequent clinical outcome of patients with upper tract urothelial carcinoma. Results On multivariate analysis pathological T stage, tumor grade, lymphovascular invasion and lymph node involvement were prognostic factors for recurrence-free survival and cancer specific survival. We defined 229 patients with 3 or more of these factors as the high risk group. In an analysis according to adjuvant regimen, Kaplan-Meier curves showed that the 1 and 2-year recurrence-free survival rates in the methotrexate, vinblastine, doxorubicin and cisplatin treated group were 71.4% and 47.9%, which were significantly higher than in the gemcitabine and cisplatin treated group (48.2% and not reached, p=0.022) or those not treated with adjuvant chemotherapy (53.4% and 39.6%, p=0.039). Similar results were observed in terms of cancer specific survival. Conclusions Our study showed that pT3-4, tumor grade 3, positive lymphovascular invasion and lymph node involvement were independent risk factors for disease mortality in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. In the high risk group methotrexate, vinblastine, doxorubicin and cisplatin adjuvant chemotherapy contributed to improve subsequent mortality compared to gemcitabine and cisplatin or no adjuvant chemotherapy.

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Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas

Mikami Shuji, Mizuno Ryuichi, Kosaka Takeo, Saya Hideyuki, Oya Mototsugu, Okada Yasunori

International Journal of Cancer 136 ( 7 ) 1504 - 1514 2015.04

ISSN 0020-7136

Tumor necrosis factor-α (TNF-α) is involved in epithelial-mesenchymal transition (EMT) and expression of CD44, a cancer stem cell marker, in several cancers. This study was performed to clarify the significance of TNF-α and CD44 in clear cell renal cell carcinomas (ccRCCs). Expression of TNF-α and CD44 was examined by immunohistochemistry in 120 ccRCCs. Involvement of TNF-α in EMT and induction of CD44 was analyzed by monitoring expression of EMT-related genes and CD44, and invasion in cultured ccRCC cell lines. TNF-α and CD44 were immunolocalized mainly to carcinoma cells of high-grade ccRCCs with positive correlations with primary tumor stage. A positive correlation was also obtained between TNF-α and CD44 expression, and co-upregulation of TNF-α and CD44 was associated with primary tumor stage, distant metastasis, and poor prognosis. TNF-αenhanced migration and invasion of ccRCC cells together with down-regulation of E-cadherin expression and up-regulation of matrix metalloproteinase 9 and CD44 expression. TNF-α also up-regulated the expression of TNF-α itself in ccRCC cells. Among the 25 ccRCC patients treated with sunitinib for metastatic disease, high CD44 expression was associated with poor treatment outcome. Importantly, residual carcinoma cells in the sunitinib-treated metastatic ccRCCs were strongly positive for CD44, and the CD44 expression was significantly higher in the tumors from the sunitinib-treated patients than in those from untreated ones. Our data show that TNF-α plays an important role in progression of ccRCCs by inducing EMT and CD44 expression, and suggest that CD44 induced by TNF-α may be involved in the resistance to the sunitinib treatment.

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How does visceral obesity affect surgical performance in laparoscopic radical nephrectomy?

Yuge Kazuyuki, Miyajima Akira, Jinzaki Masahiro, Kaneko Gou, Hagiwara Masayuki, Hasegawa Masanori, Takeda Toshikazu, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 ( 4 ) 373 - 377 2015.04

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer

Ito Yujiro, Kikuchi Eiji, Tanaka Nobuyuki, Kosaka Takeo, Suzuki Eriko, Mizuno Ryuichi, Shinojima Toshiaki, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

BMC CANCER 15 2015.04

Research paper (scientific journal), Joint Work, ISSN 1471-2407

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Clinical efficacy and prognostic factors of tumor progression in Japanese patients with advanced renal cell carcinoma treated with sorafenib

Kondo Tsunenori, Nakazawa Hayakazu, Oya Mototsugu, Kimura Go, Fujii Yasuhisa, Hatano Takashi, Kawata Nozomu, Kume Haruki, Morita Masashi, Nakajima Koichi, Ohno Yoshio, Okegawa Takatsugu, Takahashi Shunji, Wakumoto Yoshiaki, Horie Shigeo

Japanese Journal of Clinical Oncology 45 ( 3 ) 274 - 280 2015.03

ISSN 0368-2811

Objective: Result of clinical trial for registration purpose is often difficult to generalize because of its limited population in number and inclusion criteria. Methods: To understand the efficacy of sorafenib under daily medical practice, we retrospectively investigated therapeutic outcomes of 175 Japanese patients with advanced renal cell carcinoma treated with sorafenib at 15 centers. Results: The objective response rate and disease control rate were 15.4 and 77.1%, respectively, being similar to those in the Phase II study in Japanese patients (19.4 and 73.6 months). Any tumor shrinkage was observed with 53% of patients, while tumor control without growth was in 61%. Lung lesions were more sensitive to sorafenib than other lesions, in terms of any tumor shrinkage (54%) and the extent of maximal shrinkage, while tumor control was better in lymph node metastases (77%) than in lung (69%). Liver was worse in any tumor shrinkage (35%), tumor control (55%) and the extent of tumor growth. Slightly, shorter median overall survival of 21.1 months compared with Phase II clinical trial (25.3 months) is likely to be attributable to different patient population, because median overall survival was improved to 26.4 months when the population was matched to that in Phase II trial. Univariate and multivariate analyses identified prognostic factors for worse overall survival, including intermediate and poor Memorial Sloan-Kettering Cancer Center risk, Eastern Cooperative Oncology Group performance status ≥1, the presence of non-clear cell component and the presence of liver metastasis.Conclusions: In conclusion, the present study confirmed the efficacy of sorafenib in the real-world setting on advanced renal cell carcinoma.

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Prognostic Impact of Renin–Angiotensin System Blockade on Renal Cell Carcinoma After Surgery

Miyajima Akira, Yazawa Satoshi, Kosaka Takeo, Tanaka Nobuyuki, Shirotake Suguru, Mizuno Ryuichi, Kikuchi Eiji, Oya Mototsugu

Annals of Surgical Oncology 22 ( 11 ) 3751 - 3759 2015.02

ISSN 1068-9265

Background: Angiotensin 2 is a key biologic peptide in the renin–angiotensin system (RAS) that regulates blood pressure and renal hemodynamics. The potential role of the RAS in the promotion of tumor growth, angiogenesis, and metastasis also has been shown in the past few decades. This study investigated the prognostic impact of RAS blockade on patients with renal cell carcinoma (RCC) after surgery. Methods: The study identified 557 patients with pathologically diagnosed RCC (pT1-4 N0M0) and evaluated the prognostic factors after surgery for patients administered or not administered angiotensin-converting enzyme inhibitors (ACEs) or angiotensin 2 receptor blockers (ARBs). Results: The median follow-up period was 5.1 years. Radical nephrectomy was performed for 349 patients (62.7 %), whereas the remaining 208 patients (37.3 %) underwent partial nephrectomy. A total of 104 patients (18.7 %) were administered RAS inhibitors: ACEs (n = 22) or ARBs (n = 82). Multivariate analysis showed that administration of RAS inhibitors (P = 0.044; HR 2.69), longer tumor length (P < 0.001; HR 1.02), high-grade tumor (P < 0.001; HR 3.55), and positive microvascular invasion (P < 0.003; HR 3.13) were not independent risk factors for a decrease in subsequent disease-specific survival after surgery for RCC. The 5-year disease-specific survival rate was 96.8 % among the patients administered RAS inhibitors and 89.8 % among their counterparts (P = 0.019). Conclusions: The authors propose renin–angiotensin blockade as a possible potent choice for effective treatment after surgical treatment of RCC.

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Effect and adverse event of enzalutamide and abiraterone in prostate cancer

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 73 308 - 312 2015.02

ISSN 0047-1852

Visceral obesity is associated with better recurrence-free survival after curative surgery for Japanese patients with localized clear cell renal cell carcinoma

Kaneko Gou, Miyajima Akira, Yuge Kazuyuki, Yazawa Satoshi, Mizuno Ryuichi, Kikuchi Eiji, Jinzaki Masahiro, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 ( 2 ) 210 - 216 2015.02

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Bladder metastasis from renal cell carcinoma: retrospective analysis of 65 reported cases

Matsumoto Kazuhiro, Hayakawa Nozomi, Nakamura So, Oya Mototsugu

CLINICAL & EXPERIMENTAL METASTASIS 32 ( 2 ) 135 - 141 2015.02

Research paper (scientific journal), Joint Work, ISSN 0262-0898

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New year's greetings

Oya Mototsugu

International Journal of Urology 22 ( 1 ) 1 2015.01

ISSN 0919-8172

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Evidenced-based clinical practice guideline for upper tract urothelial carcinoma (summary - Japanese Urological Association, 2014 edition)

Oya Mototsugu, Kikuchi Eiji

International Journal of Urology 22 ( 1 ) 3 - 13 2015.01

ISSN 0919-8172

Upper tract urothelial carcinoma is more rare than bladder cancer, although they are both categorized as urothelial carcinoma. Because of the low incidence, little clinical evidence is available regarding the treatment of the former. However, recently such evidence has slowly begun to accumulate. The guideline presented herein was compiled for the purpose of ensuring proper diagnosis and treatment by physicians involved in the treatment of upper tract urothelial carcinoma. We carefully selected 16 clinical questions essential for daily clinical practice and grouped them into four major categories: epidemiology, diagnosis, surgery and systemic chemotherapy/other matters. Related literature was searched using PubMed and Japan Medical Abstracts Society databases for articles published between 1987 and 2013. If the judgment was made on the basis of insufficient or inadequate evidence, the grade of recommendation was determined on the basis of committee discussions and resultant consensus statements. Here, we present a short English version of the original guideline, and overview its key clinical issues.

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Bladder metastasis from renal cell carcinoma

Matsumoto Kazuhiro, Hayakawa Nozomi, Nakamura So, Oya Mototsugu

Clinical and Experimental Metastasis 32 ( 2 ) 135 - 141 2015

ISSN 0262-0898

This study was carried out to clarify the presentation, treatment options, and prognosis of renal cell carcinoma (RCC) metastasis to the bladder in which we do not yet have a comprehensive understanding. A systematic Medline, Web of Science, Embase, Google, and Ichushi Web search was performed to identify articles describing RCC metastasis to the bladder. The final cohort included 65 patients. The majority (75 %) experienced gross hematuria at the point of diagnosis of RCC. RCC metastasis to the bladder occurred both synchronously (23 %) and metachronously (77 %), and the median time for metachronous bladder metastasis following the diagnosis of RCC was 33 months. Of the 58 patients whose metastatic data were available, 36 (62 %) had metastasis to the bladder only, while 22 (38 %) had additional sites of metastasis. On pathology, clear cell carcinoma was the most common histology (92 %) and all bladder tumors were consistent with RCC metastasis; the median tumor size was 2.1 cm, and two-thirds of cases were superficial (non-muscle invasive) disease. The 2-year cancer-specific survival rate in patients with solitary bladder metastasis was 71.1 %, which was significantly higher than in patients with additional distant metastasis (25.8 %, p = 0.007). Regarding the interval after the diagnosis of primary RCC, the 2-year cancer-specific survival rate in patients who experienced bladder metastasis after more than a 1 year follow-up was 58.4 %, compared to 34.6 % in their counterparts (p = 0.063). A curative resection may provide a good possibility of long-term survival, particularly in those with a solitary bladder metastasis and/or a long interval after nephrectomy.

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Limited in vitro efficacy of CYP17A1 inhibition on human castration resistant prostate cancer

Kosaka Takeo, Miyajima Akira, Yasumizu Yota, Miyazaki Yasumasa, Kikuchi Eiji, Oya Mototsugu

Steroids 92 39 - 44 2014.12

ISSN 0039-128X

Although accumulating evidence indicates high expression of CYP17A1(P45017A1) allows castration resistant prostate cancer (CRPC) to maintain high intratumoral androgen levels, the potential P45017A1 activity has not been characterized yet. The aim of this study was to examine the potential CYP17A1 activity including 17α-hydroxylase and 17,20-lyase activities in human CRPC and the effect of a CYP17A inhibitor. We used three human CRPC cell lines: C4-2 and C4-2AT6 which was established from C4-2 under androgen ablation conditions for 6 months, and PC3. To ascertain the potential CYP17A1 activity, we cultured with the steroid precursors: ¹³C-[2,3,4]-progesterone (13C-Prog), and analyzed the sequential biosynthesis ¹³C-[2,3,4]-17-hydroxyprogesterone (13C-17OHP) and ¹³C-[2,3,4]-androstenedione(13C-Adione) by liquid chromatography/mass spectrometry (LC/MS/MS).The C4-2AT6 cells showed significantly higher CYP17A1 expression than C4-2 cells (p < 0.001). LC/MS/MS analysis enabled us to detect the 13C-17-OHP and 13C-A-dione in these cell lines. The concentration ratio of 13C-Adione/13C-17OHP (Adione-17OHP ratio), which is thought to reflect the differences between 17-hydroxylase and 17,20-lyase activities, was then determined. The Adione-17OHP ratio in C4-2AT6 cells was significantly higher than that of C4-2 cells (p < 0.001). Abiraterone were able to inhibit the CYP17A activities, although abiraterone did not have anti-proliferative effects on C4-2 and C4-2AT6 cells at clinically achievable concentrations of <1000 nM in vitro. The present study clearly demonstrates CRPC have the dual activities of CYP17A1 mediated by 17-hydroxylase activity and 17,20-lyase activity. Abiraterone doesn't have an in vitro anti-proliferative efficacy in CRPC cells, suggesting limited efficacy in vitro.

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Complete response to ethnylestradiol prolonged for almost two years in patients with castration-resistant prostate cancer

Hongo Hiroshi, Kosaka Takeo, Oya Mototsugu

Journal of the Canadian Urological Association 8 ( 11-12 DECEMBER ) e921 - e923 2014.12

ISSN 1911-6470

An 80-year-old man with an elevated prostate-specific antigen (PSA) level of 120 ng/mL) presented to the hospital in February 2011. A prostate needle biopsy was performed, and pathological examination revealed prostatic adenocarcinoma. The Gleason score was 4+5=9. Computed tomography revealed metastases of the pelvic lymph nodes. Combined androgen blockade was started. The PSA concentration decreased to 1.68 ng/mL, but started increasing again in August 2012 to 6.08 ng/mL. Although bicalutamide was discontinued due to antiandrogen withdrawal syndrome, the PSA concentration increased even more. The PSA concentration reached 21.62 ng/mL in September 2012, at which time ethnylestradiol was started. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2 years. To our knowledge, this is first case report describing a complete response to ethnylestradiol that lasted for almost 2 years in a patient with castration-resistant prostate cancer.

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[Molecular targeting drug of kinase inhibitors for castration resistant prostate cancer]

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 72 ( 12 ) 2186 - 2192 2014.12

ISSN 0047-1852

Prostate cancer (PCa) is the most common cancer type in men. One of the most troublesome aspects of PCa is that androgen-dependent PCa inevitably progresses to highly aggressive and life-threatening castration resistant prostate cancer (CRPC). Kinases are key regulators of critical cancer processes such as cancer cell proliferation, invasion, differentiation or angiogenesis. Recent advances have shed light on molecular targeting inhibitors of kinases in CRPC. Aberrant expression of certain kinases has been implicated in the development and progression of PCa. Among them, some kinase inhibitors have emerged as promising drug targets for CRPC. In this review, we provide an overview of new therapeutic agents which arrived in an advanced stage of clinical testing, especially focusing on the targets of HGF/c-Met and PI3K/AKT/mTOR signaling pathways.

Complete response to ethnylestradiol prolonged for almost two years in patients with castration-resistant prostate cancer

Hongo Hiroshi, Kosaka Takeo, Oya Mototsugu

CUAJ-CANADIAN UROLOGICAL ASSOCIATION JOURNAL 8 ( 11-12 ) E921 - E923 2014.12

Research paper (scientific journal), Joint Work, ISSN 1911-6470

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