Details of a Researcher - Oya, Mototsugu

Papers - Oya, Mototsugu

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Tumour length of the largest focus predicts prostate-specific antigen-based recurrence after radical prostatectomy in clinically localized prostate cancer

Mizuno Ryuichi, Nakashima Jun, Mukai Makio, Okita Hajime, Kosugi Michio, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Ohigashi Takashi, Oya Mototsugu

BJU INTERNATIONAL 104 ( 9 ) 1215 - 1218 2009.11

Research paper (scientific journal), Joint Work, ISSN 1464-4096

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Docetaxel in combination with prednisolone for hormone refractory prostate cancer

Ide Hiroki, Kikuchi Eiji, Kono Hidaka, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Ohigashi Takashi, Nakashima Jun, Oya Mototsugu

Japanese Journal of Clinical Oncology 40 ( 1 ) 2009.10

ISSN 0368-2811

Objective: The objective of this study was to evaluate the efficacy and toxicity of docetaxel in combination with prednisolone in Japanese patients with hormone refractory prostate cancer. Methods: Twenty patients with hormone refractory prostate cancer (HRPC) were administered a treatment regimen consisting of docetaxel 75 mg/m² once every 3 or 4 weeks and prednisolone 5 mg twice daily at our institution between 2006 and 2008. Results: The patients received a median of 5.5 cycles of treatment (range, 2-12 cycles). Nine of the 20 patients (45%) had a ≥50% decrease in serum prostate-specific antigen (PSA). The median duration of response was 4 months (range, 1-11 months). The number of cycles performed, the presence of bone metastasis and the extent of disease had statistically significant associations with the response. Three patients had a transient PSA rise among the patients who ultimately had a response. Grade 3/4 leukopenia and neutropenia occurred in 80.0% and 85.0% of the patients, respectively. Interstitial pneumonia occurred in only one patient; however, the patient recovered. Finally, no treatment-related deaths were seen during the observation period. Conclusions: The combination of docetaxel 75 mg/m² every 3 weeks and prednisolone 10 mg daily was effective and well tolerated in Japanese patients with HRPC. The results of this study suggest that a decision concerning discontinuation of this treatment should be carefully considered because a transient PSA rise was observed. Although interstitial pneumonia was rare, the potential risk of its development should be taken into consideration.

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Renal Damage Inhibited in Mice Lacking Angiotensinogen Gene Subjected to Unilateral Ureteral Obstruction

Uchida Yasumitsu, Miyajima Akira, Kikuchi Eiji, Kozakai Norihide, Kosaka Takeo, Ieda Masaki, Fukuda Keiichi, Ohigashi Takashi, Oya Mototsugu

Urology 74 ( 4 ) 938 - 943 2009.10

ISSN 0090-4295

Objectives: To determine how angiotensin II (Ang II) contributes to renal interstitial fibrosis, the inflammatory response, and tubular cell apoptosis and proliferation in unilateral ureteral obstruction using mice genetically deficient in angiotensinogen (Agt^-/-). Methods: The left kidney of wild-type mice (WT; C57BL/6) and Agt^-/- mice was obstructed for 2 weeks, and then both kidneys were harvested. The serum Ang II levels were determined by radioimmunoassay. The expression of transforming growth factor-β in renal tissue was assessed using enzyme-linked immunosorbent assay. The renal tissue was stained with Masson's trichrome. Renal tubular proliferation and apoptosis was detected by immunostaining for proliferating cell nuclear antigen and single-stranded DNA, respectively. Interstitial leukocyte and macrophage infiltration was investigated by immunostaining for CD45 and F4/80, respectively. Results: The serum Ang II levels in the Agt^-/- mice were significantly lower than those in the WT mice (P < .01), and tissue transforming growth factor-β in the obstructed kidney of Agt^-/- mice was significantly lower than that in WT mice (P < .05). Interstitial collagen deposition was significantly lower in the Agt^-/- obstructed kidneys than in the WT obstructed kidneys (P < .01). Tubular proliferation was significantly greater and tubular apoptosis was significantly lower in the Agt^-/- obstructed kidneys than in the WT obstructed kidneys (P < .01 and P < .01, respectively). Interstitial infiltration by leukocytes and macrophages was significantly lower in the Agt^-/- obstructed kidneys than in the WT obstructed kidneys (P < .01 and P < .01, respectively). Conclusions: The results of the present study support the targeting of Ang II as a reasonable approach by which to prevent renal tissue damage in unilateral ureteral obstruction.

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Adjuvant Chemotherapy for High Risk Upper Tract Urothelial Carcinoma

Hellenthal Nicholas J., Shariat Shahrokh F., Margulis Vitaly, Karakiewicz Pierre I., Roscigno Marco, Bolenz Christian, Remzi Mesut, Weizer Alon, Zigeuner Richard, Bensalah Karim, Ng Casey K., Raman Jay D., Kikuchi Eiji, Montorsi Francesco, Oya Mototsugu, Wood Christopher G., Fernandez Mario, Evans Christopher P., Koppie Theresa M.

Journal of Urology 182 ( 3 ) 900 - 906 2009.09

ISSN 0022-5347

Purpose: There is relatively little literature on adjuvant chemotherapy after radical nephroureterectomy in patients with upper tract urothelial carcinoma. We determined the incidence of adjuvant chemotherapy in high risk patients and the ensuing effect on overall and cancer specific survival. Materials and Methods: Using an international collaborative database we identified 1,390 patients who underwent nephroureterectomy for nonmetastatic upper tract urothelial carcinoma between 1992 and 2006. Of these cases 542 (39%) were classified as high risk (pT3N0, pT4N0 and/or lymph node positive). These patients were divided into 2 groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine overall and cancer specific survival in the cohorts. Results: Of high risk patients 121 (22%) received adjuvant chemotherapy. Adjuvant chemotherapy was more commonly administered in the context of increased tumor grade and stage (p <0.001). Median survival in the entire cohort was 24 months (range 0 to 231). There was no significant difference in overall or cancer specific survival between patients who did and did not receive adjuvant chemotherapy. However, age, performance status, and tumor grade and stage were significant predictors of overall and cancer specific survival. Conclusions: Adjuvant chemotherapy is infrequently used to treat high risk upper tract urothelial carcinoma after nephroureterectomy. Despite this finding it appears that adjuvant chemotherapy confers minimal impact on overall or cancer specific survival in this group.

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Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas

Mikami Shuji, Katsube Ken Ichi, Oya Mototsugu, Ishida Masaru, Kosaka Takeo, Mizuno Ryuichi, Mochizuki Satsuki, Ikeda Tohru, Mukai Makio, Okada Yasunori

Journal of Pathology 218 ( 4 ) 530 - 539 2009.08

ISSN 0022-3417

Receptor activator of NF-κB ligand (RANKL) and its receptor, receptor activator of NF-κB (RANK), play a key role in osteoclastogenesis, and osteoprotegerin (OPG) acts as a decoy receptor for RANKL. We investigated the role of the RANKL-RANK-OPG system in renal cell carcinomas (RCCs), which frequently metastasize to bones. Real-time quantitative PCR revealed that RANKL mRNA expression was higher in clear cell RCCs than in papillary and chromophobe RCCs. Similarly, RANKL protein expression level in clear cell RCCs was higher than that in papillary and chromophobe RCCs, showing positive correlations with the primary tumour stage and distant metastasis. There was no significant association between the expression level of RANK, OPG and histological subtypes of RCC. RANKL and RANK expression was observed in metastatic RCCs in the bone and other organs, suggesting that they play a role in metastasis to the bone and other organs. Recombinant RANKL protein stimulated migration of a clear cell RCC cell line, Caki-1, in vitro, and this enhanced migration was inhibited by the administration of recombinant OPG protein. Furthermore, multivariate Cox analysis revealed that elevated RANKL and RANK expression with low-OPG expression was a significant and independent predictor of recurrence, bone metastasis and a poor prognosis. These data suggest that the RANKL-RANK-OPG system is involved not only in the bone metastasis of RCCs but also in metastasis to other organs through the stimulation of cancer cell migration.

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Comparison of Oncologic Outcomes for Open and Laparoscopic Nephroureterectomy

Capitanio Umberto, Shariat Shahrokh F., Isbarn Hendrik, Weizer Alon, Remzi Mesut, Roscigno Marco, Kikuchi Eiji, Raman Jay D., Bolenz Christian, Bensalah Karim, Koppie Theresa M., Kassouf Wassim, Fernández Mario I., Ströbel Philipp, Wheat Jeffrey, Zigeuner Richard, Langner Cord, Waldert Matthias, Oya Mototsugu, Guo Charles C., Ng Casey, Montorsi Francesco, Wood Christopher G., Margulis Vitaly, Karakiewicz Pierre I.

European Urology 56 ( 1 ) 1 - 9 2009.07

ISSN 0302-2838

Background: Data regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce. Objective: We compared recurrence and cause-specific mortality rates of ONU and LNU. Design, setting, and participants: Thirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC). Measurements: Univariable and multivariable survival models tested the effect of procedure type (ONU [n = 979] vs LNU [n = 270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, ureteral cuff management, previous urothelial bladder cancer, and previous endoscopic treatment. Results and limitations: Median follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p < 0.001) and less lymphovascular invasion (14.8% vs 21.3%, p = 0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p = 0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p < 0.001] and 2.0 [p = 0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p = 0.1 for both). Conclusions: Short-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Long-term follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC.

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Discontinuance of Bacille Calmette-Guérin Instillation Therapy for Nonmuscle-invasive Bladder Cancer Has Negative Effect on Tumor Recurrence

Takeda Toshikazu, Kikuchi Eiji, Yuge Kazuyuki, Matsumoto Kazuhiro, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Urology 73 ( 6 ) 1318 - 1322 2009.06

ISSN 0090-4295

Objectives: To investigate whether the occurrence of side effects or discontinuance of bacille Calmette-Guérin (BCG) therapy because of side effects is associated with its therapeutic efficacy. Methods: We analyzed the data from 145 patients who had had nonmuscle-invasive bladder cancer (Stage pTa, pT1, or pTis) and had undergone an initial course of adjuvant BCG therapy after transurethral resection of bladder tumor from 1996 and 2006 at Keio University Hospital. Side effects were classified as minor and major, and the association between the occurrence of side effects or discontinuance of BCG therapy because of side effects and tumor recurrence or progression was analyzed. Results: Side effects occurred in 106 patients (73.1%) during BCG instillation. Of these 106 patients, 38 had major side effects and 95 had minor; 27 patients had both. BCG therapy was discontinued in 19 patients (13.1%) because of severe hematuria in 2, high fever in 8, and severe lower urinary tract symptoms in 9. Multivariate analyses demonstrated that discontinuance of BCG therapy (P = .018) was an independent predictor for tumor recurrence, in addition to multiplicity (P = .043). However, the occurrence of side effects was not an independent predictor for tumor recurrence (P = .935). Multivariate analyses also demonstrated that neither discontinuance of BCG therapy (P = .308) nor the occurrence of side effects (P = .333) was an independent predictor for tumor progression. Conclusions: Discontinuation of BCG therapy has a significantly deleterious effect on reducing the incidence of tumor recurrence. When major side effects occur, it might be preferable to attempt to mitigate the major side effects to maintain the BCG therapy on schedule.

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Discontinuance of Bacille Calmette-Guerin Instillation Therapy for Nonmuscle-invasive Bladder Cancer Has Negative Effect on Tumor Recurrence

Takeda Toshikazu, Kikuchi Eiji, Yuge Kazuyuki, Matsumoto Kazuhiro, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

UROLOGY 73 ( 6 ) 1318 - 1322 2009.06

Research paper (scientific journal), Joint Work, ISSN 0090-4295

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Brain metastasis of a papillary renal cell carcinoma, identified as type 2

Hasegawa Masanori, Kikuchi Eiji, Yasumizu Yota, Hattori Seiya, Takeda Toshikazu, Morita Shinya, Kosaka Takeo, Miyajima Akira, Horiguchi Takashi, Mikami Shuji, Oya Mototsugu

International Journal of Clinical Oncology 14 ( 3 ) 270 - 272 2009.06

ISSN 1341-9625

Papillary renal cell carcinomas (PRCCs) tend to metastasize to lymph nodes, while metastasis to the brain is extremely rare. We report the case of a man who had a brain metastasis of PRCC type 2. He was brought to our hospital due to the sudden onset of convulsions. Diagnostic imaging studies showed a metastatic brain tumor in the left parietal lobe, and a primary renal tumor in the right kidney, with paraaortal lymph node metastases. An excision of brain tumor was performed. The brain tumor had a papillary structure with eosinophilic cytoplasm. Five weeks later nephrectomy was carried out. Histological analysis of the nephrectomy specimen revealed the same papillary structure, which was compatible with PRCC type 2.

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PROGNOSTIC SIGNIFICANCE OF SNAIL EXPRESSION IN PATIENTS WITH UPPER URINARY TRACT UROTHELIAL CARCINOMA (UUT-UC)

Kosaka Takeo, Kikuchi Eiji, Mikami Shuji, Miyajima Akira, Ishida Masaru, Nakagawa Ken, Oya Mototsugu

JOURNAL OF UROLOGY 181 ( 4 ) 69 - 69 2009.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

Angiotensin II Type 1 Receptor Antagonist Enhances Cis-dichlorodiammineplatinum-Induced Cytotoxicity in Mouse Xenograft Model of Bladder Cancer

Kosugi Michio, Miyajima Akira, Kikuchi Eiji, Kosaka Takeo, Horiguchi Yutaka, Murai Masaru, Oya Mototsugu

Urology 73 ( 3 ) 655 - 660 2009.03

ISSN 0090-4295

Objectives: To examine whether candesartan enhances the cytotoxicity of cis-dichlorodiammineplatinum (CDDP) in mice with bladder cancer as a method to enhance the therapeutic effects of CDDP. CDDP is an antitumor agent conventionally used against bladder cancer; however, its therapeutic efficacy appears to not be fully satisfactory. Recent studies have shown the antitumor activity of the angiotensin II type 1 receptor antagonist candesartan. Methods: A xenograft model was prepared in nude mice using human bladder cancer cells (KU-19-19). Candesartan (1 mg/kg/d) was administered daily by oral gavage from the day of implantation plus 28 days, and CDDP (1 mg/kg/d) was administered intraperitoneally from days 5 to 9. The microvessel density, vascular endothelial growth factor expression, and apoptosis were investigated immunohistochemically. Results: Candesartan, CDDP, and candesartan-CDDP suppressed tumor growth to 41.9%, 33.8%, and 13.2%, respectively, of the tumor volume in the control group, showing that combined treatment significantly inhibited tumor growth compared with each single agent alone. The microvessel density was significantly decreased in the candesartan and candesartan-CDDP groups compared with the control group. Vascular endothelial growth factor expression was significantly decreased in the candesartan, CDDP, and candesartan-CDDP groups compared with the control group. The apoptotic index was significantly increased in the CDDP and candesartan-CDDP groups compared with the control and candesartan groups. Conclusions: It is quite likely that candesartan and CDDP suppressed tumor growth by inhibiting angiogenesis and inducing apoptosis, respectively. Furthermore, combined treatment with candesartan enhanced CDDP-induced cytotoxicity by further suppressing angiogenesis. These results suggest that candesartan could be a candidate for innovational therapy of bladder cancer.

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Renal cell carcinoma

Oya Mototsugu

Keio Journal of Medicine 58 ( 1 ) 1 - 11 2009.03

ISSN 0022-9717

Cancer cells are characterized by indefinite proliferation, invasiveness and metastases. These characteristics are usually related to one another. Namely, cancer cells that proliferate rapidly tend to invade and metastasize. Renal cell carcinoma (RCC) typically does not proliferate rapidly nor does it invade the surrounding tissues, but it does metastasize. RCC has several peculiar characteristics that are not observed in other cancers: a relatively late recurrence, a high frequency of paraneoplastic syndrome, hypervascularity and the spontaneous regression of metastatic lesions after the excision of the primary tumor. These clinical observations suggest that cytokines or growth factors are important contributors to microenvironments favoring the growth of cancer cells. Thus, the blockade of cell-to-cell communication might have some therapeutic potential. Accordingly, a popular strategy for molecular-targeted therapy for RCC targets the vasculization of RCC induced by vascular endothelial growth factor (VEGF). This review highlights the biological features of RCC that are relevant to molecular-targeted therapy.

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Clinical outcome of tumor recurrence for Ta, T1 non-muscle invasive bladder cancer from the data on registered bladder cancer patients in Japan

Kikuchi Eiji, Fujimoto Hiroyuki, Mizutani Yoichi, Okajima Eijiro, Koga Hiroshi, Hinotsu Shiro, Shinohara Nobuo, Oya Mototsugu, Miki Tsuneharu

International Journal of Urology 16 ( 3 ) 279 - 286 2009.03

ISSN 0919-8172

Objective: To characterize the clinical outcome in a large contemporary series of Japanese patients with newly diagnosed Ta, T1 non-muscle invasive bladder cancer who underwent transurethral bladder tumor resection with or without intravesical chemotherapy or Bacillus Calmette-Guérin (BCG) therapy. Methods: We developed a database incorporating newly diagnosed non-muscle invasive bladder cancer data and outcomes from a Japanese bladder cancer registry between 1999 and 2001 and identified a study population of 3237 consecutive patients who had complete data based on pathological features. Median patient age was 69.9 years. Results: The 1-year, 3-year, and 5-year overall recurrence-free survival rates were 77.0%, 61.3%, and 52.8%, respectively. In multivariate analyses, the multiplicity of bladder tumors, tumor size greater than 3 cm, pathological stage T1, tumor grade G3, and the absence of adjuvant intravesical instillation were independent risk factors for tumor recurrence. Overall, 1710 patients (52.8%) received intravesical instillation; chemotherapy in 1314 (76.8%) and BCG treatment in 396 (23.2%). In patients treated with intravesical chemotherapy in which an anthracycline chemo-agent was used in 90.5% of the cases, multivariate analyses demonstrated that male gender, multiple bladder tumors, a tumor size greater than 3 cm, and pathological stage T1 were associated with tumor recurrence. Conclusions: The accumulation and analysis of data from the Japanese National Bladder Cancer Registry made it possible to determine the clinical characteristics, management trends, and survival rates for the period studied. Further study with a dataset created from longer follow-up data would be warranted to analyze tumor progression and disease survival.

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Lymphovascular invasion predicts clinical outcomes in patients with node-negative upper tract urothelial carcinoma

Kikuchi Eiji, Margulis Vitaly, Karakiewicz Pierre I., Roscigno Marco, Mikami Shuji, Lotan Yair, Remzi Mesut, Bolenz Christian, Langner Cord, Weizer Alon, Montorsi Francesco, Bensalah Karim, Koppie Theresa M., Fernández Mario I., Raman Jay D., Kassouf Wassim, Wood Christopher G., Suardi Nazareno, Oya Mototsugu, Shariat Shahrokh F.

Journal of Clinical Oncology 27 ( 4 ) 612 - 618 2009.02

ISSN 0732-183X

Purpose: To assess the association of lymphovascular invasion (LVI) with cancer recurrence and survival in a large international series of patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). Patients and Methods: Data were collected on 1,453 patients treated with RNU at 13 academic centers and combined into a relational database. Pathologic slides were rereviewed by genitourinary pathologists according to strict criteria. LVI was defined as presence of tumor cells within an endothelium-lined space. Results: LVI was observed in 349 patients (24%). Proportion of LVI increased with advancing tumor stage, high tumor grade, presence of tumor necrosis, sessile tumor architecture, and presence of lymph node metastasis (all P < .001). LVI was an independent predictor of disease recurrence and survival (P < .001 for both). Addition of LVI to the base model (comprising pathologic stage, grade, and lymph node status) marginally improved its predictive accuracy for both disease recurrence and survival (1.1%, P = .03; and 1.7%, P < .001, respectively). In patients with negative lymph nodes and those in whom a lymphadenectomy was not performed (n = 1,313), addition of LVI to the base model improved the predictive accuracy of the base model for both disease recurrence and survival by 3% (P < .001 for both). In contrast, LVI was not associated with disease recurrence or survival in node-positive patients (n = 140). Conclusion: LVI was an independent predictor of clinical outcomes in nonmetastatic patients who underwent RNU for UTUC. Assessment of LVI may help identify patients who could benefit from multimodal therapy after RNU. After confirmation, LVI should be included in staging of UTUC.

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Preoperative Prognostic Nomogram (Probability Table) for Renal Cell Carcinoma Based on TNM Classification

Kanao Kent, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Ohigashi Takashi, Nakashima Jun, Oya Mototsugu

Journal of Urology 181 ( 2 ) 480 - 485 2009.02

ISSN 0022-5347

Purpose: Recently several prognostic nomograms have been developed to predict the prognosis of malignant diseases, including renal cell carcinoma. However, to our knowledge a preoperative prognostic nomogram that predicts survival in patients with renal cell carcinoma is not available. We developed a preoperative nomogram based on the TNM classification that predicts cause specific survival in patients with renal cell carcinoma. Materials and Methods: A total of 545 patients with renal cell carcinoma, including metastatic disease, who underwent radical nephrectomy or nephron sparing surgery at our institution were included in the study. Cases were staged according to the 2002 UICC TNM system, 6th edition. T, N and M factors were used as prognostic factors and a Cox proportional hazards regression model was developed to predict cause specific survival. A nomogram to predict cause specific survival was developed by repeating the analysis on 200 bootstrap samples. To validate the nomogram a concordance index was estimated and calibration was also examined by plotting the predictions made by the nomogram. Results: Overall 1, 3 and 5-year patient survival was 95.2%, 92.0% and 89.9%, respectively. T, N and M factors were significant prognostic factors in the Cox proportional hazards regression model. Using the combined TNM factors we developed a nomogram predicting 1, 3 and 5-year cause specific survival rates. The nomogram had excellent ability to discriminate, as evidenced by a concordance index of 0.81, and it was generally well calibrated. Conclusions: The preoperative information shown by this nomogram may be important for obtaining informed consent from patients with renal cell carcinoma who have indications for surgery.

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Evidence-based Sex-related Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

Fernández Mario I., Shariat Shahrokh F., Margulis Vitaly, Bolenz Christian, Montorsi Francesco, Suardi Nazareno, Remzi Mesut, Wood Christopher G., Roscigno Marco, Kikuchi Eiji, Oya Mototsugu, Zigeuner Richard, Langner Cord, Weizer Alon, Lotan Yair, Koppie Theresa M., Raman Jay D., Karakiewizc Pierre, Bensalah Karim, Schultz Marcela, Bernier Pablo

Urology 73 ( 1 ) 142 - 146 2009.01

ISSN 0090-4295

Objectives: To assess the sex differences in the clinical and pathologic characteristics of upper tract urothelial carcinoma (UTUC) and to determine the effect on prognosis after radical nephroureterectomy (RNU) in a large multicenter series. Methods: The records of 1363 patients who had undergone RNU were reviewed from the UTUC Collaboration database. The median follow-up was 47 months (range 0-250). The pathologic slides were re-evaluated by genitourinary pathologists unaware of the original findings from the slides and the clinical outcomes. The endpoints were freedom from tumor recurrence and disease-specific survival. Results: The male-to-female ratio was 2.1:1. The women were older than the men at diagnosis (70 ± 11 vs 68 ± 11 years; P < .001). No significant sex-related differences were found in the presence of symptoms at presentation (P = .70), pathologic stage (P = .98), tumor grade (P = .28), tumor architecture (P = .27), presence of lymphovascular invasion (P = .42), presence of concomitant carcinoma in situ (P = .08), or the presence of lymph node metastases (P = .24). Recurrence developed in 379 patients (28%), and 313 patients (23%) died of their disease. Sex was not associated with disease recurrence (P = .07) or disease-specific survival (P = .13). An adjustment for the effects of the pathologic features did not change the lack of association of sex with the clinical outcomes. Conclusions: To our knowledge, this is the largest series analyzing the effect of sex on the outcomes after RNU. No difference was found in the clinicopathologic features or prognosis between women and men treated with RNU for UTUC. The results of this large, international series show that RNU provides durable local control and disease-specific survival for both men and women with UTUC.

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Angiotensin II type 1 receptor antagonist as an angiogenic inhibitor in urogenital cancer

Miyajima Akira, Kikuchi Eiji, Kosaka Takeo, Oya Mototsugu

Reviews on Recent Clinical Trials 4 ( 2 ) 75 - 78 2009

ISSN 1574-8871

The potential for angiotensin II (AII) to promote tumor growth has been suspected based on its known hormonal actions and its vasoconstrictor effect. It has been suggested that angiotensin-converting enzyme (ACE) inhibitors may offer protection against cancer and may prevent carcinogenesis. Several studies report that AII can induce neovascularization in experimental systems by way of the AII type 1 receptor (AT1R). AT1R is also frequently expressed in such human tumors as skin cancer, renal cell carcinoma, and breast cancer. A growing number of recent studies focusing on treatment with an AT1R antagonist have demonstrated that angiotensin receptor blockade (ARB) appears to inhibit not only the growth of cancer cells but also tumor angiogenesis. We describe here the effects of AT1R blockade that implicate tumor angiogenesis in urogenital cancer since ARB may be an alternative modality for anti-cancer treatment.

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The checkpoints for the diagnosis of renal neoplasms

Jinzaki Masahiro, Oya Mototsugu

Japanese Journal of Clinical Urology 63 ( 9 ) 671 - 678 2009

ISSN 0385-2393

Gemcitabine and paclitaxel chemotherapy for advanced urothelial carcinoma in patients who have received prior cisplatin-based chemotherapy

Kanai Kunimitsu, Kikuchi Eiji, Ohigashi Takashi, Miyajima Akira, Nakagawa Ken, Nakashima Jun, Oya Mototsugu

International Journal of Clinical Oncology 13 ( 6 ) 510 - 514 2008.12

ISSN 1341-9625

Background. The objective of this study was to evaluate the efficacy and toxicity of combination chemotherapy with gemcitabine and paclitaxel as a second-line regimen in patients with advanced urothelial carcinoma. Methods. Twenty patients with advanced urothelial carcinoma who were resistant to an M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy regimen were administered chemotherapy consisting of intravenous gemcitabine 2500 mg/m² and paclitaxel 150 mg/m² (GP) every 2 or 3 weeks. Results. The patients received a median of 7.7 cycles of treatment (range, 2-20 cycles). Six of the 20 patients (30%; 95% confidence interval [CI], 10%-50%) had a major response to treatment (a complete response [CR] in 5% and a partial response [PR] in 25%). Seven patients (35%) had stable disease (SD). The median duration of response was 4.5 months (range, 1-9 months) and the disease control rate (CR + PR + SD) was 65%. The median survival was 11.5 months (range, 2-22 months) and the 1-year survival rate was 35%. The patients tolerated this regimen well, with only grade 3-4 neutropenia being observed in 6 patients (30%), anemia in 3 (15%), and thrombocytopenia in 1 (5%). The response rate to M-VAC in the first-line chemotherapy was significantly associated with the response to GP as the second-line chemotherapy. Conclusion. The combination of gemcitabine and paclitaxel is active and well tolerated as a second-line treatment in patients with advanced urothelial carcinoma.

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Expression of heparanase in renal cell carcinomas

Mikami Shuji, Oya Mototsugu, Shimoda Masayuki, Mizuno Ryuichi, Ishida Masaru, Kosaka Takeo, Mukai Makio, Nakajima Motowo, Okada Yasunori

Clinical Cancer Research 14 ( 19 ) 6055 - 6061 2008.10

ISSN 1078-0432

Purpose: Heparanase activity has been detected in many malignant tumors, showing a correlation with the metastatic potential. The present study was undertaken to investigate the expression of heparanase and its prognostic significance in renal cell carcinomas (RCC). Experimental Design: Nineteen RCCs and 6 nonneoplastic renal tissues were analyzed for heparanase mRNA expression by real-time PCR. Heparanase protein expression was semiquantitatively investigated by immunohistochemistry in 70 RCCs. Involvement of heparanase in the invasiveness of RCC cell lines, 786-O and Caki-2 cells, was examined by down-regulating the gene expression with small interfering RNA (siRNA) using the Matrigel invasion assay. Results: The expression level of heparanase mRNA was significantly higher in clear cell RCCs than in papillary RCCs, chromophobe RCCs, and nonneoplastic renal tissues. Heparanase was predominantly immunolocalized to cell surface and cytoplasm of clear cell RCCs and mean expression levels of heparanase were significantly higher in clear cell RCCs than in papillary and chromophobe RCCs. The protein expression levels were positively correlated with primary tumor stage, distant metastasis, and histologic grade. Targeting of heparanase mRNA expression in 786-O and Caki-2 cells with siRNA down-regulated the mRNA expression and inhibited the Matrigel invasion by these cells, whereas nonsilencing siRNA showed no effect. Multivariate Cox analysis revealed that elevated heparanase expression was a significant and an independent predictor of disease-specific survival (odds ratio, 8.814; P = 0.019). Conclusions: These data suggest that heparanase plays an important role in invasion and metastasis and silencing of the gene might be a potential therapeutic target in clear cell RCCs.

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