Details of a Researcher - Kosaka, Takeo

Papers - Kosaka, Takeo

Division display >> ／ All the affair displays 1 - 201 of about 201

MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

Yasumizu Y., Rajabi H., Jin C., Hata T., Pitroda S., Long M.D., Hagiwara M., Li W., Hu Q., Liu S., Yamashita N., Fushimi A., Kui L., Samur M., Yamamoto M., Zhang Y., Zhang N., Hong D., Maeda T., Kosaka T., Wong K.K., Oya M., Kufe D.

Nature Communications (Nature Communications) 11 ( 1 ) 2020.12

© 2020, The Author(s). Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.

Access to Document (DOI)

A Japanese patient with ductal carcinoma of the prostate carrying an adenomatosis polyposis coli gene mutation: a case report

Umeda K., Kosaka T., Nakamura K., Takeda T., Mikami S., Nishihara H., Oya M.

Diagnostic Pathology (Diagnostic Pathology) 15 ( 1 ) 2020.08

© 2020 The Author(s). Background: Ductal carcinoma of the prostate is a histological subtype with a higher mortality than acinar adenocarcinoma. The number of cases is small and there are no treatment guidelines. We believe that this is the first report of ductal carcinoma of the prostate with an adenomatosis polyposis coli (APC) gene mutation in Japan. Case presentation: An 85-year-old man presented with gross hematuria, and a papillary tumor in the prostatic urethra that was diagnosed as ductal carcinoma of the prostate following transurethral resection. Genetic analysis found an APC mutation with loss of heterozygosity. Immunostaining revealed focal nuclear translocation of β-catenin. APC mutations associated with loss of β-catenin degradation in the Wnt signaling pathway and result in over accumulation of β-catenin are thought to increase mortality. In this patient, β-catenin migrated into tumor cell nuclei. Conclusion: To the best of our knowledge, this is the first report of ductal carcinoma of the prostate with an APC mutation in Japan. The development of a therapeutic Wnt inhibitor is discussed.

Access to Document (DOI)

Type of patients in whom biochemical recurrence after radical prostatectomy can be observed without salvage therapy

Matsumoto K., Niwa N., Hagiwara M., Kosaka T., Tanaka N., Takeda T., Morita S., Mizuno R., Shinojima T., Hara S., Asanuma H., Oya M.

World Journal of Urology (World Journal of Urology) 38 ( 7 ) 1749 - 1756 2020.07

ISSN 07244983

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: To examine the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation. Methods: The study population consisted of 431 patients, all of whom underwent radical prostatectomy and developed BCR (PSA > 0.2 ng/mL). According to the two risk factors [Gleason score ≥ 8 and PSA-doubling time (DT) < 6 months], we divided the patients into two groups. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group. We set the starting point at the timing of BCR, and the endpoints were development to castration-resistant prostate cancer (CRPC) and cancer-specific death. Results: During the mean follow-up period of 8.3 years after BCR, CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. We first divided the 191 high/intermediate-risk patients according to the PSA level (PSA < 1.0 ng/mL, PSA 1.0–4.0, and PSA > 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. We found that delayed (PSA > 4.0 ng/mL) or no salvage therapy was significantly associated with CRPC and cancer-specific death. In the 240 low-risk patients, Kaplan–Meier curves demonstrated no significant difference in CRPC-free survival or cancer-specific survival within 10 years from the timing of BCR. Conclusions: Observation after BCR without salvage therapy or delayed administration may be an option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months when their life expectancy is within 10 years.

Access to Document (DOI)

External validation of the "optimal PSA follow-up schedule after radical prostatectomy” in a new cohort

Yanai Y., Matsumoto K., Kosaka T., Takeda T., Tanaka N., Morita S., Mizuno R., Shinojima T., Asanuma H., Oya M.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 25 ( 7 ) 1393 - 1397 2020.07

ISSN 13419625

© 2020, Japan Society of Clinical Oncology. Background: Biochemical recurrence (BCR) after radical prostatectomy (RP) is most commonly diagnosed by detecting an increase in asymptomatic prostate-specific antigen (PSA). We previously reported the “optimal PSA follow-up schedule after RP”. The aim of this study was to confirm the usefulness and safety of that follow-up schedule in another cohort. Methods: We retrospectively reviewed the clinicopathological data of 798 consecutive patients who underwent radical prostatectomy between 2009 and 2017. We examined all PSA values measured during follow-up. Furthermore, we estimated the PSA value when we observed the “optimal PSA follow-up schedule” at each timing in the virtual follow-up. BCR was defined as an elevation of PSA to greater than 0.2 ng/ml, and the ideal PSA range for detection of BCR was regarded to be 0.2–0.4 ng/ml. Results: During the mean follow-up period of 5.8 years, BCR occurred in 115 (14.9%) patients and the frequency of virtual follow-up was significantly lower than the actual frequency. However, overlooking of BCR (detecting BCR when PSA exceeded 0.4 ng/ml) was observed in 17 patients, which is higher than the actual frequency of overlooking (12 patients). Therefore, we modified the follow-up schedule, which could achieve the lower follow-up frequency and a limited number of overlooking of BCR (7 patients). Conclusion: This external validation study revealed that the "modified optimal PSA follow-up schedule after RP" can reduce the frequency of PSA measurement with a limited risk of overlooking BCR.

Access to Document (DOI)

Appropriate timing for a biochemical evaluation after adrenalectomy for unilateral aldosterone-producing adenoma

Takamatsu K., Takeda T., Hattori S., Tanaka N., Morita S., Matsumoto K., Kosaka T., Mizuno R., Shinojima T., Kikuchi E., Asanuma H., Kurihara I., Itoh H., Oya M.

Clinical Endocrinology (Clinical Endocrinology) 92 ( 6 ) 503 - 508 2020.06

ISSN 03000664

© 2020 John Wiley & Sons Ltd Context: The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear. Objective: To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy. Design and patients: A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM). Results: PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P <.001). ARC did not increase from baseline at 1POM, but significantly increased at 3POM (presurgery; 4.43, 1POM; 4.87, 3POM; 11.3 pg/mL, P <.001). ARR significantly decreased at 1POM (presurgery; 146.9, 1 POM; 26.3, P <.001) although ARC did not increase at 1POM. Among the 34 patients who had hypokalaemia presurgery, it was resolved in 28 (82%) at 1POM and in all (100%) at 3POM. The biochemical outcomes at 1POM were 131 (79%) complete, 20 (12%) partial and 15 (9%) absent successes, while at 3POM, 147 (89%) were complete, 9 (5%) partial and 10 (6%) absent. Twenty-three (14%) patients were reclassified into different biochemical outcomes between 1 and 3POM, whereas only 5 (3%) changed between 3 and 6POM. Conclusion: The appropriate timing for a biochemical evaluation of unilateral APA patients treated with laparoscopic adrenalectomy appears to be 3 months or more after surgery.

Access to Document (DOI)

Aggressive prostate cancer with somatic loss of the homologous recombination repair gene FANCA: A case report

Hongo H., Kosaka T., Aimono E., Nishihara H., Oya M.

Diagnostic Pathology (Diagnostic Pathology) 15 ( 1 ) 2020.01

© 2020 The Author(s). Background: Precision medicine based on genomic analysis of germline or tumor tissue is attracting attention. However, there is no consensus on how to apply the results of genomic analysis to treatment. Case presentation: A 59-year-old man diagnosed with metastatic prostate cancer was diagnosed with castration-resistant prostate cancer. Although he was sequentially treated with enzalutamide and abiraterone, bone metastasis progression was identified by skeletal scintigraphy. Therefore, we sequentially performed docetaxel therapy followed by cabazitaxel. After the third cycle of cabazitaxel, his prostate-specific antigen level was stable at < 10 ng/mL, and no radiological progression was detected. The patient's formalin-fixed paraffin-embedded tumor biopsy specimen underwent multiple-gene testing by next-generation sequencing, which identified a FANCA homodeletion. No significant germline mutation was observed. Conclusions: We describe a case of aggressive, castration-resistant prostate cancer with FANCA homodeletion. Genomic analysis of prostate cancer tissue can be useful to determine optimal treatment of such cancers.

Access to Document (DOI)

The efficacy of mirabegron for the relief of ureteral stent-related symptoms

Otsuki H., Yamasaki T., Hori S., Aoki H., Kosaka T., Uehara S., Fujio K.

Acta Medica Okayama (Acta Medica Okayama) 74 ( 2 ) 145 - 150 2020

ISSN 0386300X

© 2020 by Okayama University Medical School. To investigate the efficacy of mirabegron for lower urinary tract symptoms in patients with an indwelling ureteral stent after ureterorenoscopic lithotripsy. This was a prospective follow-up study of 76 patients with stent-related symptoms (SRSs). Patients with upper urinary calculi who were pre-stented for > 2 weeks before lithotripsy were examined for the presence of SRSs by tests including the International Prostate Symptom Score (IPSS), OAB Symptom Score (OABSS), and urinary bother and pain measured by a Visual Analogue Scale (VAS) before lithotripsy. Mirabegron (50 mg/day) was prescribed post-lithotripsy for 2 weeks. SRSs were assessed at the time of stent removal. The IPSS scores improved significantly from 16.2 to 14.3 (p<0.001) and the IPSS-QoL scores decreased significantly from 5.0 to 4.6 (p=0.012). The OABSS scores improved significantly from 7.7 to 6.8 (p=0.006), and the urinary urgency scores (OABSS-Q3) decreased significantly from 3.24 to 2.68 (p<0.001). The number of nocturia episodes decreased significantly from 2.5 to 2.2 (p=0.045). Urinary bother and pain assessed by the VAS declined from 4.2 and 3.1 to 3.8 (p=0.15) and 2.5 (p=0.075), respectively. Mirabegron significantly improved SRSs and the number of nocturia episodes due to a ureteral stent.

Role of the MUC1-C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma

Shigeta K., Hasegawa M., Kikuchi E., Yasumizu Y., Kosaka T., Mizuno R., Mikami S., Miyajima A., Kufe D., Oya M.

Cancer Science (Cancer Science) 2020

ISSN 13479032

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Mucin 1 C-terminal subunit (MUC1-C) has been introduced as a key regulator for acquiring drug resistance in various cancers, but the functional role of MUC1-C in urothelial carcinoma (UC) cells remains unknown. We aimed to elucidate the molecular mechanisms underlying the acquisition of cisplatin (CDDP) resistance through MUC1-C oncoprotein in UC cells. MUC1-C expression was examined immunohistochemically in tumor specimens of 159 UC patients who received CDDP-based perioperative chemotherapy. As a result, moderate to high MUC1-C expression was independently associated with poor survival in UC patients. Using human bladder cancer cell lines and CDDP-resistant (CR) cell lines, we compared the expression levels of MUC1-C, multiple drug resistance 1 (MDR1), the PI3K-AKT-mTOR pathway, and x-cystine/glutamate transporter (xCT) to elucidate the biological mechanisms contributing to the acquisition of chemoresistance. MUC1-C was strongly expressed in CR cell lines, followed with MDR1 expression via activation of the PI3K-AKT-mTOR pathway. MUC1-C also stabilized the expression of xCT, which enhanced antioxidant defenses by increasing intracellular glutathione (GSH) levels. MUC1 down-regulation showed MDR1 inhibition along with PI3K-AKT-mTOR pathway suppression. Moreover, it inhibited xCT stabilization and resulted in significant decreases in intracellular GSH levels and increased reactive oxygen species (ROS) generation. The MUC1-C inhibitor restored sensitivity to CDDP in CR cells and UC murine xenograft models. In conclusion, we found that MUC1-C plays a pivotal role in the acquisition of CDDP resistance in UC cells, and therefore the combined treatment of CDDP with a MUC1-C inhibitor may become a novel therapeutic option in CR UC patients.

Access to Document (DOI)

Significance of tumor microenvironment in acquiring resistance to vascular endothelial growth factor-tyrosine kinase inhibitor and recent advance of systemic treatment of clear cell renal cell carcinoma

Mikami S., Mizuno R., Kosaka T., Tanaka N., Kuroda N., Nagashima Y., Okada Y., Oya M.

Pathology International (Pathology International) 2020

ISSN 13205463

© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.

Access to Document (DOI)

Relationship between radiation doses and erectile function deterioration in patients with localized prostate cancer treated with permanent prostate brachytherapy

Shigeta K., Kikuchi E., Matsushima M., Ogihara K., Kosaka T., Mizuno R., Tanaka T., Shigematsu N., Oya M.

International Journal of Urology (International Journal of Urology) 2020

ISSN 09198172

© 2020 The Japanese Urological Association Objectives: To investigate the relationship between radiation doses in prostate brachytherapy and deterioration of erectile function in patients with localized prostate cancer. Methods: A longitudinal survey study was carried out among 261 prostate cancer patients who received prostate brachytherapy. A total of 48 patients were potent at baseline and they did not receive any supplemental therapy preoperatively. Dosimetry parameters of the whole prostate gland, prostate apex, urethra and rectum were collected using the VariSeed 8.0 treatment planning system (Varian Medical Systems, Palo Alto, CA, USA). We carried out a logistic regression analysis to clarify the relationship between radiation doses and erectile function deterioration, which was assessed using the International Index of Erectile Function-15 questionnaire. Results: The median patient age was 66 years (range 53–70 years) with a median follow-up time of 44 months (36–71 months). The mean total International Index of Erectile Function-15 score decreased from 49.9 at baseline to 34.7 after 12 months (P < 0.001), but gradually plateaued within 36 months. Erectile function deterioration was noted in 32 (66.7%) patients 36 months after prostate brachytherapy. In an analysis of risk factors for erectile function deterioration after prostate brachytherapy, age ≥70 years (P = 0.029), prostate V100 ≥95% (P = 0.024), apex V100 ≥95% (P = 0.024), apex V150 ≥70% (P = 0.009) and apex D90 ≥150 Gy (P = 0.011) correlated with erectile function deterioration. A multivariate analysis identified an age of ≥70 years (odds ratio 7.91, P = 0.024) and apex V150 ≥70% (odds ratio 7.75, P = 0.007) as independent risk factors for erectile function deterioration after prostate brachytherapy. Conclusions: An excessive radiation dose, particularly to the prostate apex area, and an advanced age might have a negative impact on the preservation of potency after prostate brachytherapy.

Access to Document (DOI)

Evaluation of Gleason Grade Group 5 in a Contemporary Prostate Cancer Grading System and Literature Review

Kamitani R., Matsumoto K., Kosaka T., Takeda T., Hashiguchi A., Tanaka N., Morita S., Mizuno R., Shinojima T., Asanuma H., Oya M.

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 2020

ISSN 15587673

© 2020 Elsevier Inc. Introduction: The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5. Patients and Methods: We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC). Results: The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4+5 and 29 patients with GS 5+4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4+5, and GS 5+4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4+5 than in GS 5+4 or higher (P < .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4+5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5+4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P < .001) greatly affected BCR. Conclusion: Our follow-up study revealed that men with GS 4+5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4+5 and GS 5+4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients.

Access to Document (DOI)

Splenic cord capillary hemangioma with non-islet cell tumor hypoglycemia: A case report

Daimon T., Kosaka T., Horinaga M., Saito J., Ueyama Y., Matsuzaki S., Oya M.

Diagnostic Pathology (Diagnostic Pathology) 14 ( 1 ) 2019.12

© 2019 The Author(s). Background: Splenic cord capillary hemangioma is a rare benign vascular lesion classified as a splenic hamartoma. On the other hand, non-islet cell tumor hypoglycemia (NICTH) is one of the rare causes of spontaneous hypoglycemia and is considered to be one of the paraneoplastic syndromes. To the best of our knowledge, this is the first reported case of a splenic cord capillary hemangioma with NICTH. Case presentation: A 25-year-old male was referred to our hospital with hypoglycemia. Except for his low blood sugar, there were no abnormal findings from laboratory tests, which included an endocrinological examination. Enhanced computed tomography confirmed the presence of a solid mass measuring about 6 cm in the retroperitoneum, and a tumorectomy was performed. During this operation, it became clear that the tumor turned out to be a splenic parenchyma, and as a result, a total splenectomy was performed. Microscopically, we diagnosed this as a cord capillary hemangioma, and through immunohistochemistry, we found that some tumor cells were positive for insulin-like growth factor -II. Fortunately, the hypoglycemia-related symptoms disappeared after surgical resection was performed. The patient is still alive and well without evidence of local tumor recurrence 15 years after the operation. Conclusions: Splenic cord capillary hemangioma, one of the types of splenic hamartomas, is a very rare benign vascular lesion and might be associated with hypoglycemia thought to be NICTH.

Access to Document (DOI)

Prediction of extraprostatic extension by MRI tumor contact length: difference between anterior and posterior prostate cancer

Matsumoto K., Akita H., Narita K., Hashiguchi A., Takamatsu K., Takeda T., Kosaka T., Mizuno R., Kikuchi E., Oya M., Jinzaki M.

Prostate Cancer and Prostatic Diseases (Prostate Cancer and Prostatic Diseases) 22 ( 4 ) 539 - 545 2019.12

ISSN 13657852

© 2019, Springer Nature America, Inc. Background: Tumor contact length (TCL) is defined as the extent of contact between prostate cancer and the prostatic capsule, and its predictive value for microscopic extraprostatic extension (EPE) has been reported. However, the impact of the zonal origin (anterior or posterior tumor) of the tumor on the diagnosis of EPE is controversial. Methods: We retrospectively analyzed the records of 233 consecutive patients who underwent preoperative MRI and radical prostatectomy. We designated their tumors as anterior or posterior, and evaluated the correlation between the TCL measured by MRI and microscopic EPE in the radical prostatectomy specimen. Then, we created the predicted probability curves for EPE versus TCL for anterior and posterior prostate cancer. Results: There were 109 patients (47%) with an anterior tumor and 124 patients (53%) with a posterior tumor. Postoperative pathological analysis confirmed pT3 in 18 patients (17%) with an anterior tumor and in 53 patients (43%) with a posterior tumor. Multivariate analysis demonstrated that the zonal origin of the tumor was an independent predictive factor for EPE. We developed separate probability curves of EPE versus TCL for anterior and posterior prostate cancer, which revealed that anterior tumors were less likely to invade the extraprostatic tissues. Among patients whose TCL was 10–20 mm, 9/32 patients (28%) with an anterior tumor had EPE compared with 24/45 patients (53%) with a posterior tumor (p = 0.036). The decision curve of this EPE predictive model had high clinical efficacy. Conclusions: Our results indicate that anterior tumors have more favorable pathological characteristics than posterior tumors with the same TCL measured by MRI. We constructed two separate predicted probability curves for EPE after discriminating anterior and posterior tumors, which will be useful for decision making in clinical practice.

Access to Document (DOI)

A first Japanese case of neuroendocrine prostate cancer accompanied by lung and brain metastasis with somatic and germline BRCA2 mutation

Kosaka T., Hongo H., Aimono E., Matsumoto K., Hayashida T., Mikami S., Nishihara H., Oya M.

Pathology International (Pathology International) 69 ( 12 ) 715 - 720 2019.12

ISSN 13205463

© 2019 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd Germline mutations and copy number changes in DNA damage repair (DDR) genes such as BRCA2 are associated with aggressive forms of prostate cancer (PCa). Although the prevalence of BRCA2 variants in PCa is increasing in Japan, the genomic and biological implications in Japanese patients are unclear. An 81-year-old male presented with prostatic adenocarcinoma with neuroendocrine differentiation accompanied by metastatic lung nodule and brain metastases. Platinum-based doublet chemotherapy combined with etoposide resulted in partial and complete remissions of brain and lung metastases, respectively. Next-generation sequencing of biopsy and peripheral blood samples demonstrated a somatic BRCA2 mutation at c.7008-2A>C and a germline mutation at p.E2877*. The patient's son had been diagnosed with breast cancer 2.5 years ago and was found to have the same germline BRCA2 mutation. BRCA2 mutation increases the risks of aggressive PCa and other cancer types in Japanese males. These forms may be highly responsive to platinum-based chemotherapy.

Access to Document (DOI)

TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells

Niwa N., Tanaka N., Hongo H., Miyazaki Y., Takamatsu K., Mizuno R., Kikuchi E., Mikami S., Kosaka T., Oya M.

Laboratory Investigation (Laboratory Investigation) 99 ( 11 ) 1702 - 1713 2019.11

ISSN 00236837

© 2019, The Author(s), under exclusive licence to United States and Canadian Academy of Pathology. Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.

Access to Document (DOI)

Japanese Case of Enzalutamide-Resistant Prostate Cancer Harboring a SPOP Mutation With Scattered Allelic Imbalance: Response to Platinum-Based Therapy

Watanabe K., Kosaka T., Aimono E., Hongo H., Mikami S., Nishihara H., Oya M.

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 17 ( 5 ) e897 - e902 2019.10

ISSN 15587673

Access to Document (DOI)

Ductal adenocarcinoma of the prostate

Kosaka T., Hagiwara M., Oya M.

Japanese Journal of Clinical Urology (Japanese Journal of Clinical Urology) 73 ( 11 ) 846 - 849 2019.10

ISSN 03852393

Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients

Takamatsu K., Mizuno R., Tanaka N., Takeda T., Morita S., Matsumoto K., Kosaka T., Shinojima T., Kikuchi E., Asanuma H., Oyama M., Mikami S., Oya M.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 24 ( 9 ) 1069 - 1074 2019.09

ISSN 13419625

© 2019, Japan Society of Clinical Oncology. Background: The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. Methods: We retrospectively reviewed 82 consequent intermediate-risk mRCC patients who received second-line molecular targeted therapy. We classified patients who had serum CRP higher than 0.5 mg/dl in elevated CRP group because the median baseline serum CRP level before second-line treatment was 0.51 mg/dl. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS). Results: Thirty-three out of 82 (40%) patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group was 11.5 (95% CI 5.4–17.5) and 29.4 (95% CI 25.5–33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5, 95% CI 1.4–4.2, p = 0.001). Conclusions: The serum CRP levels after first-line treatment termination could divide intermediate risk group mRCC patients into two prognostic subgroups in second-line targeted treatment setting.

Access to Document (DOI)

The prognostic value of zonal origin and extraprostatic extension of prostate cancer for biochemical recurrence after radical prostatectomy

Takamatsu K., Matsumoto K., Shojo K., Tanaka N., Takeda T., Morita S., Kosaka T., Mizuno R., Shinojima T., Kikuchi E., Asanuma H., Oya M.

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 37 ( 9 ) 575.e19 - 575.e25 2019.09

ISSN 10781439

© 2019 Elsevier Inc. Objective: To investigate the influence of the zonal origin of prostate cancer and extraprostatic extension on biochemical recurrence (BCR). Patients and methods: We included 638 consecutive patients undergoing radical prostatectomy between 2005 and 2015 who did not receive neoadjuvant/adjuvant therapy. The largest lesion was defined as the index tumor. We categorized each patient into the transition zone (TZ) or peripheral zone (PZ) group based on the lesion where the index tumor existed. Differences in the BCR defined as increasing prostate-specific antigen rate between groups were examined by Kaplan-Meier analysis and the Cox proportional hazards model. Results: There were 293 (46%) patients with TZ cancer and 345 (54%) with PZ cancer. TZ cancer was significantly associated with a higher prostate-specific antigen (P = 0.012), lower biopsy positive core rate (P = 0.020), lower pathological Gleason score (P = 0.017), lower pathological stage (P = 0.002), and lower rate of seminal vesicle invasion (P = 0.002). During a median follow-up period of 59 months, 79 patients (12%) developed BCR. In the entire cohort, the PZ origin (hazard ratio: 1.68, P = 0.033) and extraprostatic extension were independent risk factors for BCR. The 3-, 5-, and 7-year BCR-free survival rates of patients with pT3a TZ cancer were 89%, 88%, and 86%, respectively, which were significantly better than those of patients with pT3a PZ cancer (80%, 74%, and 62%, P = 0.012), but were similar to those of the pT2 cancer cohort (92%, 91%, and 90%, P = 0.376). Conclusion: TZ cancer had more favorable pathological characteristics and oncological outcome than PZ cancer especially in pT3a cases.

Access to Document (DOI)

Impact of pegfilgrastim as primary prophylaxis for metastatic castration-resistant prostate cancer patients undergoing cabazitaxel treatment: An open-label study in Japan

Kosaka T., Uemura H., Sumitomo M., Harada K., Sugimoto M., Hayashi N., Yoshimura K., Fukasawa S., Ecstein-Fraisse E., Sunaga Y., Oya M.

Japanese Journal of Clinical Oncology (Japanese Journal of Clinical Oncology) 49 ( 8 ) 766 - 771 2019.08

ISSN 03682811

© The Author(s) 2019. Published by Oxford University Press. Background: Cabazitaxel is an efficacious treatment for patients with metastatic castration-resistant prostate cancer who have previously progressed on docetaxel, but febrile neutropenia during the first cycle is a frequent complication. Asian patients are at increased risk of febrile neutropenia. Although primary prophylaxis with granulocyte colony-stimulating factor can reduce the incidence, its efficacy has not been prospectively demonstrated in Japanese patients with cabazitaxel treatment. Methods: PEGAZUS, a prospective, single-arm study conducted at eight clinical sites in Japan, enrolled 21 heavily pretreated patients with metastatic castration-resistant prostate cancer. Patients received cabazitaxel 25 mg/m2 every 3 weeks, up to 10 cycles. Oral prednisolone 10 mg was taken daily. Pegfilgrastim 3.6 mg was administered at least 24 h after the cabazitaxel infusion. The primary endpoint was the incidence of febrile neutropenia in the first cycle. Results: The median number of treatment cycles was seven. The relative dose intensity of cabazitaxel was 67.4% (range, 53.2–91.3%). Two of 21 patients (9.5%) experienced febrile neutropenia in the first cycle. This rate was lower than the rate (43%) previously observed without prophylactic granulocyte colony-stimulating factor in a similar patient population. Six patients showed a prostate-specific antigen response (28.6%). Three of four patients evaluable for tumor response had stable disease and one had progressive disease. Grade ≥3 diarrhea was not observed. Primary prophylaxis with granulocyte colony-stimulating factor significantly reduced the incidence of febrile neutropenia in this study. Conclusions: Cabazitaxel plus granulocyte colony-stimulating factor is safe and effective for Japanese patients with metastatic castration-resistant prostate cancer who have previously progressed on docetaxel.

Access to Document (DOI)

Interstitial pneumonitis in a castration-resistant prostate cancer patient receiving cabazitaxel after thoracic radiation therapy: A case report

Yanai Y., Kosaka T., Hongo H., Oya M.

BMC Cancer (BMC Cancer) 19 ( 1 ) 2019.07

© 2019 The Author(s). Background: Interstitial pneumonitis is a rare reaction in a previously irradiated area of pulmonary or thoracic lesion after treatment with anticancer drugs such as taxanes. Case presentation: A 66-year-old man presented with a fever and dyspnea after treatment with cabazitaxel for castration-resistant prostate cancer. He was treated with an intravenous broad-spectrum antimicrobial agent, however he complained of dyspnea and had a pulse oximetric saturation of 80% while breathing room air. The patients had been treated for bone metastases with 37.5 Gy to the thoracic spine (Th 7) as a local radiotherapy. Radiological images showed pulmonary interstitial opacities in the irradiated field of the both lungs. The steroid pulse therapy was started. The patient's dyspnea disappeared and the interstitial opacities had also improved. Conclusions: This report is a case of interstitial pneumonitis in a castration-resistant prostate cancer patient receiving cabazitaxel after thoracic radiation therapy.

Access to Document (DOI)

Complete response with early introduction of cabazitaxel in a patient with multiple lung metastases of castration-resistant prostate cancer following the early detection of metastases using liquid biopsy: A case report

Kosaka T., Hongo H., Oya M.

BMC Cancer (BMC Cancer) 19 ( 1 ) 2019.06

© 2019 The Author(s). Background: Cabazitaxel (CBZ) chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) is believed to be palliative because the radiological response rate is low and a durable response is rare. Here, we describe a rare case of a patient with mCRPC who was treated with CBZ chemotherapy and showed a durable radiological response and a complete biochemical response. Case presentation: A 43-year-old man with prostate cancer and metastasis of the pubic bone underwent neoadjuvant androgen deprivation and docetaxel therapy, followed by laparoscopic prostatectomy, extended lymphadenectomy, and metastatectomy in 2014. Pathological examination revealed residual adenocarcinoma in the prostate and pubic bone (pathological T stage 3b, positive surgical margin). Following the operation, he received adjuvant radiation therapy (66 Gy) to the pelvic floor. His serum prostate-specific antigen (PSA) level decreased to < 0.01 ng/mL but gradually increased following docetaxel chemotherapy. Imaging findings indicated five tiny nodules in the bilateral lungs. Biopsy specimens are difficult to obtain and might not reflect the precise extent of the disease owing to heterogeneity in patients with CRPC. Thus, we performed liquid biopsy to isolate circulating tumor cells (CTCs), and overall 156 CTCs were detected per 7.5 mL. Almost all CTCs were androgen receptor-negative in the nucleus. We diagnosed the five nodules as lung metastases from docetaxel-resistant CRPC with few AR-signaling-dependent cancer cells. The patient was initiated on CBZ chemotherapy (25 mg/m2) according to the standard protocol in August 2016, instead of using a second-generation AR-targeting agent. After 2 cycles of CBZ chemotherapy, PSA level decreased to < 0.01 ng/mL and the lung metastases completely disappeared, with a reduced CTC count of < 5. To date, the patient has been receiving intermittent CBZ chemotherapy. Conclusions: We presented a rare case of a patient with mCRPC who was successfully treated with early CBZ chemotherapy. The early detection of metastasis using liquid biopsy enabled the introduction of early CBZ chemotherapy for docetaxel-resistant mCRPC.

Access to Document (DOI)

Castration-resistant prostate cancer patients who had poor response on first androgen deprivation therapy would obtain certain clinical benefit from early docetaxel administration

Shigeta K., Kosaka T., Hongo H., Yanai Y., Matsumoto K., Morita S., Mizuno R., Shinojima T., Kikuchi E., Oya M.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 24 ( 5 ) 546 - 553 2019.05

ISSN 13419625

© 2019, Japan Society of Clinical Oncology. Background: Our specific aim was to investigate the prognostic value of effective duration of first androgen deprivation therapy (ADT) and to evaluate the clinical impact on early docetaxel administration with oncological outcomes in castration-resistant prostate cancer (CRPC) patients treated with docetaxel. Methods: We identified 148 mCRPC patients who were treated with 75 mg/m2 docetaxel. We defined 16 months as the threshold for the effective duration of ADT, and defined 12 months as the cut-off time for starting docetaxel from the onset of CRPC. Univariate and multivariate analyses were conducted to investigate the prognostic indicators that influenced the survival outcomes. Results: Overall, 81 (54.7%) patients died. The median 1st ADT response was 22.2 months and the median time interval from CRPC onset to docetaxel treatment was 11.7 months. Multivariate analysis indicated that visceral metastasis, bone metastasis extent of disease (EOD) ≥ 2, and effective duration of ADT < 16 months were the independent prognostic indicators for progression-free survival (PFS). Referring to cancer-specific survival (CSS), besides visceral metastasis and effective duration of ADT < 16 months, late docetaxel treatment ≥ 12 months became as the predictors for poor prognosis. Among the ADT poor-responder group (ADT < 16 months), Kaplan–Meier method showed that 1-year and 2-year CSS rates were 96.0% and 80.0% in the patients who introduced docetaxel in early setting (< 12 months), which were significantly higher than those who introduced in late settings (93.6% and 30.8%, respectively, p < 0.001). Conclusion: CRPC patients who had poor response during 1st ADT would obtain survival benefit by introducing docetaxel treatment in early stage.

Access to Document (DOI)

Sulfasalazine could modulate the CD44v9-xCT system and enhance cisplatin-induced cytotoxic effects in metastatic bladder cancer

Ogihara K., Kikuchi E., Okazaki S., Hagiwara M., Takeda T., Matsumoto K., Kosaka T., Mikami S., Saya H., Oya M.

Cancer Science (Cancer Science) 110 ( 4 ) 1431 - 1441 2019.04

ISSN 13479032

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. The prognostic role of CD44v9, a variant isoform of CD44 and a new cell surface marker of cancer stem cells, remains unclear in bladder cancer (BC) patients. Furthermore, limited information is available on the functional role of sulfasalazine (SSZ), which could modulate the CD44v9-xCT system in order to enhance cisplatin (CDDP)-induced cytotoxicity and inhibit the metastatic potential of BC. CD44v9 protein expression was examined immunohistochemically in 63 muscle invasive BC (MIBC) patients who underwent radical cystectomy. CD44v9 expression was independently associated with disease recurrence and cancer-specific death in MIBC. Cytotoxic effects, glutathione levels, and reactive oxygen species production by SSZ and CD44v9 and phospho-p38 MAPK protein expression by SSZ with or without CDDP were assessed in MBT-2V cells with highly metastatic potential. Sulfasalazine exerted cytotoxic effects against MBT-2V cells by inhibiting glutathione levels and inducing the production of reactive oxygen species. Sulfasalazine in combination with CDDP appeared to exert strong cytotoxic effects against MBT-2V cells by inhibiting CD44v9 expression and upregulating phospho-p38 MAPK expression. The inhibitory effects of SSZ with or without CDDP were also investigated using an MBT-2V lung metastatic model. In the murine lung metastatic BC model, SSZ significantly prolonged animal survival. Furthermore, the combination of SSZ with CDDP exerted stronger inhibitory effects on the establishment of lung tumor nodules than SSZ or CDDP alone. CD44v9 expression could be a clinical biomarker for predicting poor outcomes in MIBC patients. Sulfasalazine in combination with CDDP has potential as a novel therapy against metastatic BC.

Access to Document (DOI)

Three-year follow-up of a phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer and bone metastases

Uemura H., Uemura H., Nagamori S., Wakumoto Y., Kimura G., Kikukawa H., Yokomizo A., Mizokami A., Kosaka T., Masumori N., Kawasaki Y., Yonese J., Nasu Y., Fukasawa S., Sugiyama T., Kinuya S., Hosono M., Yamaguchi I., Akagawa T., Matsubara N.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 2019

ISSN 13419625

© 2019, The Author(s). Background: Radium-223 is a first-in-class targeted alpha therapy to prolong overall survival (OS) in castration-resistant prostate cancer with bone metastases (mCRPC). The aim of the present analysis was to assess the long-term safety with radium-223 in Japanese patients with mCRPC. Methods: Patients with symptomatic mCRPC, ≥ 2 bone metastases and no known visceral metastases received up to 6 injections of radium-223 (55 kBq/kg), one every 4 weeks. Adverse events (AEs) considered to be related to radium-223 were reported until 3 years after the first injection. Pre-specified conditions, such as acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer, or other primary malignancies, were reported regardless of causality. Results: Of the 49 patients enrolled in the study, 44 (89.8%) entered the survival follow-up period and 33 (67.3%) died. Throughout the entire study, there were no reports of second primary malignancy or other pre-specified conditions. Eight patients (16.3%) experienced post-treatment drug-related AEs, which were all hematological (anemia and decreased lymphocyte, platelet, and white blood cell counts). No serious post-treatment drug-related AEs were reported. Updated median OS was 19.3 months (95% CI: 14.2, 28.5). Conclusions: In Japanese patients with symptomatic mCRPC and bone metastases, radium-223 had a favorable long-term safety profile with no second primary malignancies reported. Taken together with median OS, which was comparable to that in the pivotal phase III ALSYMPCA study, these results support continued benefit from radium-223 in Japanese patients with mCRPC.

Access to Document (DOI)

Clinical outcome of high dose rate brachytherapy with external beam radiotherapy for high-risk prostate cancer: A single institutional retrospective study

Shirotake S., Makino S., Suzuki K., Araki R., Kosaka T., Nishimoto K., Oyama M., Kato S.

Japanese Journal of Clinical Oncology (Japanese Journal of Clinical Oncology) 49 ( 1 ) 87 - 91 2019

ISSN 03682811

© The Author(s) 2018. Published by Oxford University Press. All rights reserved. Objectives: This study investigated the clinical outcome of neoadjuvant androgen deprivation therapy followed by high dose rate brachytherapy (HDR-BT, called NEH) with external beam radiotherapy (EBRT) in high-risk prostate cancer (PCa) patients in our institution. Methods: From 2007 to 2012, 192 high-risk PCa patients underwent neoadjuvant treatment—EBRT—NEH (n = 192). Relations between clinical factors (prostate-specific antigen; PSA, cT stage, Gleason score) and biochemical recurrence were retrospectively analyzed. Results: The 5- and 7-year overall survival rates were 97.9 and 91.1%. By PSA levels (PSA ≤ 20 ng/ml, 20 ng/ml < PSA≤50 ng/ml and PSA > 50 ng/ml), 5-year biochemical recurrence-free survival rates were 85.7, 84.7 and 54.5%, respectively. There were no significant differences between biochemical recurrence and cT stage or Gleason score. Conclusions: We found that NEH can contribute to better biochemical recurrence free survival of high-risk PCa patients with PSA below 50 ng/ml. High-risk PCa patients with PSA over 50 ng/ml may require more aggressive local or systemic treatment.

Access to Document (DOI)

No significant impact of patient age and prior treatment profile with docetaxel on the efficacy of cabazitaxel in patient with castration-resistant prostate cancer

Kosaka T., Hongo H., Watanabe K., Mizuno R., Kikuchi E., Oya M.

Cancer Chemotherapy and Pharmacology (Cancer Chemotherapy and Pharmacology) 82 ( 6 ) 1061 - 1066 2018.12

ISSN 03445704

© 2018, The Author(s). Background: The correlation of the oncological outcomes of docetaxel and cabazitaxel in Japanese metastatic castration-resistant prostate cancer (mCRPC) patients has not been unclear. Materials and methods: This study included a total of 47 consecutive Japanese mCRPC patients treated with cabazitaxel and assessed the prognostic significance of cabazitaxel, focusing on patient age and the correlation of efficacy between docetaxel and cabazitaxel. Results: Prostate-specific antigen (PSA) decline was observed in 27 patients (57.4%), including 19 (40.0%) achieving the response defined by PSA decline ≥ 30%. The median overall survival (OS) periods after the introduction of cabazitaxel was 16.1 months. Twenty (42.6%) were judged to have responded to cabazitaxel with a PSA decrease ≥ 30% from the baseline. A 30% PSA response to cabazitaxel was achieved in 4 (50.0%) patients with ≧ 75 years (n = 8) and 16 (41.0%) patients with less than 75 years (n = 39). There was no significant correlation between the PSA response and patients’ age (p = 0.707). A 30% PSA response to cabazitaxel was achieved in 13 (46.4%) and 7 (36.8%) patients with and without that to docetaxel, respectively. A 30% PSA response to cabazitaxel was achieved in 5 (16.6%) and 7 (41.2%) patients who had treated with less than 10 cycles docetaxel or 10 ≦ cycles, respectively. Univariate and multivariate analyses revealed that there were no significant correlation of patient age (p = 0.537), the response to prior docetaxel therapy (p = 0.339) or cycles of docetaxel therapy (p = 0.379) with shorter OS. Conclusion: These results indicate that the introduction of cabazitaxel for Japanese mCRPC patients could result in oncological outcomes without any association with patient’s age and the profiles of previous docetaxel therapy.

Access to Document (DOI)

Single-cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63

Tanaka N., Katayama S., Reddy A., Nishimura K., Niwa N., Hongo H., Ogihara K., Kosaka T., Mizuno R., Kikuchi E., Mikami S., Miyakawa A., Arenas E., Kere J., Oya M., Uhlén P.

Cancer Medicine (Cancer Medicine) 7 ( 12 ) 6193 - 6204 2018.12

© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Cancers acquire resistance to systemic treatment with platinum-based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single-cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA-seq, we uncovered a novel gene, COX7B, associated with platinum-resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA-seq data from platinum-naïve cancer cells demonstrated a low-COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low-COX7B subclone behaved as cells with acquired platinum-resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum-resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.

Access to Document (DOI)

Aldosterone and 18-oxocortisol coaccumulation in aldosterone-producing lesions

Sugiura Y., Takeo E., Shimma S., Yokota M., Higashi T., Seki T., Mizuno Y., Oya M., Kosaka T., Omura M., Nishikawa T., Suematsu M., Nishimoto K.

Hypertension (Hypertension) 72 ( 6 ) 1345 - 1354 2018.12

ISSN 0194911X

© 2018 American Heart Association, Inc. Primary aldosteronism is a secondary hypertensive disease caused by autonomous aldosterone production that often caused by an aldosterone-producing adenoma (APA). Immunohistochemistry of aldosterone synthase (CYP11B2) shows the presence of aldosterone-producing cell clusters (APCCs) even in non-primary aldosteronism adult adrenal cortex. An APCC-like structure also exists as possible APCC-to-APA transitional lesions (a speculative designation) in primary aldosteronism adrenals. However, whether APCCs produce aldosterone or 18-oxocortisol, a potential serum marker of APA, remains unknown because of lack of technology to visualize adrenocorticosteroids on tissue sections. To address this obstacle, in this study, we used highly sensitive Fourier transform ion cyclotron resonance mass spectrometry to image various adrenocorticosteroids, including 18-oxocortisol, in adrenal tissue sections from 8 primary aldosteronism patients with APCC (cases 1-4), possible APCC-to-APA transitional lesions (case 5), and APA (cases 6-8). Further analyses by tandem mass spectrometry imaging allowed us to differentially visualize aldosterone from cortisone, which share identical mass-to-charge ratio value (m/z). In conclusion, these advanced imaging techniques revealed that aldosterone and 18-oxocortisol coaccumulated within CYP11B2-expressing lesions. These imaging outcomes along with a growing body of aldosterone research led us to build a progressive development hypothesis of an aldosterone-producing pathology in the adrenal glands.

Access to Document (DOI)

Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer

Hongo H., Kosaka T., Oya M.

Cancer Science (Cancer Science) 109 ( 9 ) 2937 - 2945 2018.09

ISSN 13479032

© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Cabazitaxel (CBZ) is approved for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, efficacy of CBZ for CRPC is limited and there are no effective treatments for CBZ-resistant CRPC. In order to investigate the CBZ-resistant mechanism, the establishment of a CBZ-resistant cell line is urgently needed. We established CBZ-resistant CRPC cell lines DU145CR and PC3CR by incubating DU145 and PC3 cells with gradually increasing concentrations of CBZ for approximately 2 years. We analyzed the gene expression profiles and cell cycle changes using microarray and flow cytometry. Pathway analysis revealed DU145CR cells had enhanced gene clusters of cell division and mitotic nuclear division. Enhancement of ERK signaling was detected in DU145CR cells. DU145CR cells had resistance to G2/M arrest induced by CBZ through ERK signaling activation. The MEK inhibitor PD184352 significantly inhibited cell proliferation of DU145CR. In contrast to DU145CR, PC3CR cells had enhancement of PI3K/AKT signaling. The PI3K/mTOR inhibitor NVP-BEZ 235 had a significant antitumor effect in PC3CR cells. Cabazitaxel -resistant CRPC cells established in our laboratory had enhancement of cell cycle progression signals and resistance to G2/M arrest induced by CBZ. Enhancement of ERK signaling or PI3K/AKT signaling were detected in the cell lines, so ERK or PI3K/AKT could be therapeutic targets for CBZ-resistant CRPC.

Access to Document (DOI)

Incidence and timing of inadvertent nephrostomy catheter displacement in patients with ureteral obstruction

Niwa Naoya, Matsumoto Kazuhiro, Kikuchi Eiji, Yazawa Satoshi, Takeda Toshikazu, Morita Shinya, Kosaka Takeo, Shinoda Kazunobu, Mizuno Ryuichi, Shinojima Toshiaki, Asanuma Hiroshi, Oya Mototsugu

Clinical Nephrology (Clinical Nephrology) 90 ( 2 ) 112 - 116 2018.08

ISSN 0301-0430

Introduction: To evaluate nephrostomy catheter displacement, we assessed the cumulative nephrostomy catheter displacement rate in patients with percutaneous nephrostomy and compared the nephrostomy displacement rates between pigtail and balloon catheters. Materials and methods: Between 2003 and 2011, 87 patients who underwent percutaneous nephrostomy catheter placement and more than one subsequent catheter replacement were retrospectively identified. We evaluated their inadvertent nephrostomy catheter displacement. Results: 20 patients (23.0%) experienced incidental nephrostomy catheter displacement during the follow-up period. Kaplan-Meier analysis revealed that the 1-year nephrostomy catheter displacement-free survival rate was 62 ± 9%. No significant independent risk factors for predicting nephrostomy catheter displacement were identified, including the type of catheter. The median time from initial placement to displacement of pigtail catheters was shorter than that of balloon catheters. Conclusion: There were no significant differences in the nephrostomy catheter displacement-free survival rates between the two types of catheters. Regardless of the type of catheter, our results indicated that careful handling and guiding during catheter placement are important for all patients because of the high risk of inadvertent events.

Access to Document (DOI)

Fatal Intracranial Hemorrhage Due to Thrombocytopenia in a Patient with Castration-Resistant Prostate Cancer Showing Extensive Bone Uptake of Injected 223Ra Dichloride

Nakahara Tadaki, Owaki Yoshiki, Kosaka Takeo, Fukada Junichi, Ichimura Akira, Jinzaki Masahiro

Clinical Nuclear Medicine (Clinical Nuclear Medicine) 43 ( 7 ) 546 - 547 2018.07

ISSN 0363-9762

A 64-year-old man with castration-resistant prostate cancer received ²²³Ra injection to treat bone metastases. The patient underwent a ²²³Ra SPECT scan after the first ²²³Ra injection in which there was increased uptake all over the spine. Spine-to-background activity ratio in the patient was approximately three times greater than normal spine-to-background activity ratios in ²²³Ra SPECT obtained from the other patients. Eight days after the fifth injection, the patient exhibited a very poor neurologic examination and died of intracranial hemorrhage due to severe thrombocytopenia (platelet counts, 23,000/mm³). The extensive radiation to the spine may have enhanced myelophthisic process in this case.

Access to Document (DOI)

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

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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

ISSN 9789811070129

© 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.

Access to Document (DOI)

Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer

Hagiwara Masayuki, Kikuchi Eiji, Tanaka Nobuyuki, Kosaka Takeo, Mikami Shuji, Saya Hideyuki, Oya Mototsugu

BMC Cancer (BMC Cancer) 18 ( 1 ) 2018.01

ISSN 1471-2407

Background: Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer. However, the effectiveness of these treatments is severely limited due to the development of cisplatin resistance. Cancer stem cells have been documented as one of the key hypotheses involved in chemoresistance. CD44v8-10 has been identified as one of the new cancer stem cells markers and was recently shown to enhance the antioxidant system by interaction with xCT, a subunit of the cystine transporter modulating intracellular glutathione synthesis. The aim of the present study was to investigate the clinical role of CD44v8-10 and the molecular mechanism underlying the acquisition of cisplatin resistance through CD44v8-10 in urothelial cancer. Methods: We analyzed the clinical significance of the immunohistochemical CD44v9 expression, which detects the immunogen of human CD44v8-10, in 77 urothelial cancer patients treated with cisplatin-based systemic chemotherapy for recurrence and/or metastasis. We then evaluated the biological role of CD44v8-10 in the acquisition of cisplatin resistance using the urothelial cancer cell lines, T24 and T24PR, which were generated to acquire resistance to cisplatin. Results: The 5-year cancer-specific survival rate was significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.008). Multivariate analyses revealed that CD44v9 positivity was an independent risk factor of cancer-specific survival (P = 0.024, hazard ratio = 5.16) in urothelial cancer patients who had recurrence and/or metastasis and received cisplatin-based chemotherapy. The expression of CD44v8-10 and xCT was stronger in T24PR cells than in T24 cells. The amount of intracellular glutathione was significantly higher in T24PR cells than in T24 cells (p < 0.001), and intracellular reactive oxygen species production by cisplatin was lower in T24PR cells than in T24 cells. Furthermore, the knockdown of CD44v8-10 by siRNA led to the recovery of cisplatin sensitivity in T24PR cells. Conclusions: CD44v9 in tumor specimens has potential as a novel indicator for identifying a cisplatin-chemoresistant population among urothelial cancer patients. CD44v8-10 contributes to reactive oxygen species defenses, which are involved in chemoresistance, by promoting the function of xCT, which adjusts the synthesis of glutathione.

Access to Document (DOI)

Vasohibin-1 as a novel microenvironmental biomarker for patient risk reclassification in low-risk prostate cancer

Kobayashi Hiroaki, Kosaka Takeo, Mikami Shuji, Miyazaki Yasumasa, Matsumoto Kazuhiro, Kikuchi Eiji, Miyajima Akira, Kameyama Kaori, Sato Yasufumi, Oya Mototsugu

Oncotarget (Oncotarget) 9 ( 12 ) 10203 - 10210 2018.01

ISSN 1949-2553

Background: We previously reported high expression of vasohibin-1 (VASH1), which is specifically expressed in activated vascular endothelial cells, was a prognostic indicator of disease progression in prostate cancer. The aim of this study was to assess whether VASH1 expression at the area of normal prostatic tissue as well as that of intratumoral tissue could reflect the grade of malignancy of prostate cancer. Results: Pathological upgrade of Gleason Score ≥7 by radical prostatectomy was observed in 48 patients (upgraded group). The median VASH1 densities of the intratumoral and normal areas were 9.7 ± 9.5 and 13.3 ± 11.8, respectively, and the median MVDs were 58.6 ± 20.3 and 64.1 ± 23.5, respectively. We detected a strong positive correlation with each other for both VASH1 density (ρ = 0.589, p < 0.001) and MVD (ρ = 0.342, p < 0.001). VASH1 density was significantly higher in the upgreaded group than in the non-upgraded group regardless of prostatic location (intratumoral area: p < 0.001, normal area: p < 0.001). Conclusions: Even if the tumor volume was low in biopsy samples, VASH1 density reflected the grade of malignancy throughout the prostate. These results suggested that VASH1 expression could be a novel microenvironmental biomarker for patient risk reclassification in low-risk prostate cancer. Materials and Methods: Among the 1177 patients who underwent radical prostatectomy, 104 patients diagnosed with Gleason Score ≤6 and positive cores ≤3 were included. We immunohistochemically examined the microvessels positive for anti-CD34 as microvessel density (MVD), and those with activated endothelial cells as VASH1 density using prostatic biopsy samples, and evaluated the association between their expressions and clinicopathological findings.

Access to Document (DOI)

Purified Protein Derivative Skin test prior to bacillus Calmette-Guérin Therapy May have Therapeutic Impact in Patients with Nonmuscle Invasive Bladder Cancer

Niwa Naoya, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Oya Mototsugu

Journal of Urology (Journal of Urology) 199 ( 6 ) 1446 - 1451 2018.01

ISSN 0022-5347

Purpose: We investigated the clinical impact of the purified protein derivative skin test prior to bacillus Calmette-Guérin therapy in patients with nonmuscle invasive bladder cancer treated with adjuvant bacillus Calmette-Guérin therapy. Materials and Methods: A total of 498 patients with nonmuscle invasive bladder cancer treated with adjuvant bacillus Calmette-Guérin were included in study, of whom 320 underwent the purified protein derivative skin test 1 to 2 weeks prior to therapy. Oncologic outcomes and the rate of bacillus Calmette-Guérin related side effects were statistically evaluated. Results: The mean ± SD 5-year recurrence-free survival rate in patients who did vs did not undergo the purified protein derivative skin test was 66.6% ± 2.8% and 59.1% ± 4.1%, respectively, which was significantly different (p = 0.048). No significant difference was observed in the progression-free survival rate between patients who did vs did not undergo the test. Multivariate Cox regression analysis revealed that a history of recurrence (HR 1.59, p = 0.02), multiple tumors (HR 1.95, p <0.01), the bacillus Calmette-Guérin Connaught strain (HR 0.71, p = 0.04), 7 or more bacillus Calmette-Guérin instillations (HR 0.70, p = 0.04) and undergoing the purified protein derivative skin test (HR 0.72, p = 0.04) were independently associated with tumor recurrence. Major bacillus Calmette-Guérin related side effects were noted in 77 of the 320 patients (24.1%) who did vs 27 of the 178 (15.2%) who did not undergo the test, which was significantly different (p = 0.02). Conclusions: The purified protein derivative skin test prior to bacillus Calmette-Guérin treatment enhances the therapeutic effects of this treatment and potentially results in a higher incidence of major bacillus Calmette-Guérin related side effects. Combination therapy with bacillus Calmette-Guérin using the purified protein derivative skin test may improve the oncologic outcomes of that therapy.

Access to Document (DOI)

Change of the 5α/5β 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 (Clinical Biochemistry) 55 36 - 41 2018.01

ISSN 0009-9120

Background: The effects of the administration of dutasteride (DUT) on steroid metabolite pathways in BPH patients have not been examined. Methods: Urine and blood samples as well as clinical parameters were prospectively collected after the administration of DUT to 60 BPH patients, and after its withdrawal in another set of 25 BPH patients. Urine samples were assessed using gas chromatography/mass spectrometry for the urinary steroid profile (USP), which simultaneously measures 63 steroid metabolites. We examined pharmacological changes in the 5α/5β ratio of urinary metabolites and their relationships with clinical parameters in patients treated with DUT. Results: The mean urinary androsterone/etiocholanolone (An/Et) ratio in sex-steroid pathways significantly decreased from 1.39 to 0.02 (p < 0.01). Urinary metabolites in other steroid pathways such as 5αTHF/5βTHF in the glucocorticoid pathway and 5αTHB/5βTHB in the mineralocorticoid pathway also significant decreased after the DUT treatment. As compared to baseline level, the mean An/Et ratios in patients with the withdrawal of DUT were 0.7%, 1.4%, 12.6%, and 82.4% at just before, one month, 3 months, and 6 months after the withdrawal of DUT, respectively. All other steroid pathways changed in a similar manner without the aggravation of urinary symptoms. The recovery ratio of An/Et in USP before and 3 months after the withdrawal of DUT correlated with the recovery ratio of serum PSA levels (ρ = 0.61, p < 0.01). Conclusion: Urinary 5α/5β metabolites in all pathways were strongly suppressed after the administration of DUT for one month and the pharmacological effect of DUT prolonged even after withdrawal of DUT.

Access to Document (DOI)

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 Naoya, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2018.01

ISSN 1078-1439

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.

Access to Document (DOI)

Establishment of the optimal follow-up schedule after radical prostatectomy

Matsumoto Kazuhiro, Niwa Naoya, Hattori Seiya, Takeda Toshikazu, Morita Shinya, Kosaka Takeo, Mizuno Ryuichi, Shinojima Toshiaki, Kikuchi Eiji, Asanuma Hiroshi, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 36 ( 7 ) 341.e9 - 341.e14 2018.01

ISSN 1078-1439

Purpose: Monitoring the serum level of prostate specific antigen (PSA) is indispensable for surveillance after radical therapy, and the aim of this study was to establish the optimal follow-up schedule. Materials and methods: We retrospectively reviewed the clinicopathological data of 1,010 consecutive patients who underwent radical prostatectomy. After excluding patients who received neoadjuvant or adjuvant therapy and those without a nadir PSA level<0.2 ng/ml, the remaining 779 patients were enrolled. Biochemical recurrence (BCR) was defined as elevation of PSA to >0.2 ng/ml. We investigated the PSA doubling time (PSA-DT) following BCR at various times after surgery. Results: During a mean follow-up of 8.8 years, BCR occurred in 180/779 patients. The annual BCR rate was 6% in the first year after surgery, 6% between 1 and 2 years, 3% between 2 and 3 years, 3% between 3 and 5 years, and 2% at >5 years postoperatively. During these periods, the minimum PSA-DT after BCR was 1.6, 2.4, 3.1, 6.1, and 6.4 months, respectively. These minimum PSA-DTs were used to determine the optimal follow-up interval during each period after surgery. If the baseline level is 0.1 ng/ml, PSA should be measured at approximately 3-month intervals for the first year, at 4-month intervals between 1 and 2 years, at 6-month intervals between 2 and 3 years, and annually thereafter to definitely detect BCR before the serum PSA level exceeds 0.4 ng/ml. Conclusion: The PSA-DT following BCR varies according to the time after surgery. Our data on minimum PSA-DT values after BCR are useful for setting the optimal follow-up schedule.

Access to Document (DOI)

Prognostic significance of grade 3/4 neutropenia in Japanese prostate cancer patients treated with cabazitaxel

Kosaka Takeo, Shinojima Toshiaki, Morita Shinya, Oya Mototsugu

Cancer Science (Cancer Science) 109 ( 5 ) 1570 - 1575 2018.01

ISSN 1347-9032

The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen. In this retrospective study, 41 patients with mCRPC treated with cabazitaxel at Keio University Hospital were retrospectively reviewed. Cabazitaxel at a dose of 20-25 mg/m² was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). An upfront dose-reduction was required in 52.5% of patients due to their reduced general condition or advanced age. Prophylactic G-CSF was prescribed to all the patients. Grade ≥3 neutropenia and febrile neutropenia occurred in 21 patients (53.6%) and 3 patients (6.8%), respectively. Treatment was generally well tolerated, with a median of 5 cycles (range 1-17). Median PFS and OS from the start of cabazitaxel treatment were 4.4 and 15.0 months (95% CI 8.9-21.2), respectively. Waterfall plot analysis revealed that a prostate-specific antigen (PSA) decline >50% was noticed in n = 11 patients receiving cabazitaxel (26.8%). Univariate analysis revealed that poor performance status, PSA ≥100 ng/mL prior to cabazitaxel treatment, visceral metastasis, absence of grade 3/4 neutropenia during cabazitaxel therapy and neutrophil-lymphocyte ratio were significantly associated with shorter overall survival. Multivariate analysis revealed that poor performance status, visceral metastasis, and the absence of grade 3/4 neutropenia during cabazitaxel therapy were the independent prognostic indicators for OS. The practical implication of our results might be to tailor cabazitaxel dosing on the basis of its hematological effects.

Access to Document (DOI)

Prognostic Value of Baseline Serum C-Reactive Protein Level in Intermediate-Risk Group Patients With Metastatic Renal-Cell Carcinoma Treated by First-Line Vascular Endothelial Growth Factor–Targeted Therapy

Takamatsu Kimiharu, Mizuno Ryuichi, Omura Minami, Morita Shinya, Matsumoto Kazuhiro, Shinoda Kazunobu, Kosaka Takeo, Takeda Toshikazu, Shinojima Toshiaki, Kikuchi Eiji, Asanuma Hiroshi, Oyama Masafumi, Mikami Shuji, Oya Mototsugu

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 16 ( 4 ) e927 - e933 2018.01

ISSN 1558-7673

Because accumulating evidence underlines the association of systemic inflammation with metastatic renal-cell carcinoma (mRCC) progression, we evaluated baseline C-reactive protein (CRP) levels as a prognostic marker in 107 intermediate-risk mRCC patients treated with first-line targeted therapy. Baseline CRP could be a biomarker correlated with overall survival in the intermediate-risk group. Its cost efficacy and availability make CRP a helpful tool for reclassifying the intermediate-risk group. Background: Almost half of patients with metastatic renal-cell carcinoma (mRCC) are classified as intermediate risk by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. The aim of this study was to evaluate whether baseline C-reactive protein (CRP) levels predict overall survival (OS) in intermediate-risk group mRCC patients. Patients and Methods: Data from 107 intermediate-risk group mRCC patients receiving first-line targeted therapy were retrospectively reviewed. We evaluated the correlation between baseline CRP levels as well as other indices and OS. Results: Of the 107 patients with intermediate-risk disease, 46 patients (43%) were classified as having elevated CRP levels. The elevation of pretreatment serum CRP levels was the independent prognostic factor of OS in patients with intermediate risk (hazard ratio, 4.609; P =.001). The 1- and 3-year survival rates of patients with intermediate–nonelevated CRP were 90.0% and 64.7% compared to the favorable-risk group, at 92.1% and 68.5%, respectively. In contrast, the 1- and 3-year survival rates of patients with intermediate–elevated CRP were 80.5% and 37.4% compared to the poor-risk group, at 65.2% and 24.2%, respectively. Conclusion: Baseline CRP levels could divide mRCC patients in the intermediate-risk group into 2 prognostic subgroups.

Access to Document (DOI)

Prostate-specific antigen nadir within 12 months as an early surrogate marker of biochemical failure and distant metastasis after low-dose-rate brachytherapy or external beam radiotherapy for localized prostate cancer

Nishimura Shuichi, Ohashi Toshio, Momma Tetsuo, Sakayori Masanori, Eriguchi Takahisa, Tanaka Tomoki, Yamashita Shoji, Kosaka Takeo, Oya Mototsugu, Shigematsu Naoyuki

Cancer Medicine (Cancer Medicine) 7 ( 5 ) 1794 - 1801 2018.01

Prostate-specific antigen nadir (nPSA) after radiotherapy for localized prostate cancer has been investigated as a predictor. However, nPSA usually requires several years, limiting its clinical utility. We investigated the significance of nPSA within 12 months (nPSA12) after low-dose-rate prostate brachytherapy (LDR-PB) or external beam radiotherapy (EBRT) on treatment outcomes. Between 2006 and 2014, 663 patients with prostate cancer were treated with LDR-PB or EBRT at two institutions. Four hundred and seventy-four men received LDR-PB and 189 men received EBRT, without androgen deprivation therapy. The Kaplan-Meier method was used for biochemical failure (BF)-free survival (BFFS) and distant metastasis (DM)-free survival (DMFS) analyses, and multivariable Cox regression analysis was performed. The median follow-up was 61.3 months. The median nPSA12 in the LDR-PB and EBRT cohorts was 0.7 and 1.0 ng/mL, respectively. The 7-year BFFS and DMFS rates in LDR-PB patients with nPSA12 ≤ 0.7 ng/mL were 99.1% and 99.5%, respectively; when nPSA12 was >0.7 ng/mL, they were 90.2% and 94.8%, respectively. In EBRT patients with nPSA12 ≤ 1.0 ng/mL, BFFS and DMFS rates were 85.4% and 98.5%, respectively; when nPSA12 was >1.0 ng/mL, they were 67.1% and 87.2%, respectively. nPSA12 was an independent predictor of BF and DM in both cohorts (LDR-PB, P = 0.004 and 0.020, respectively; EBRT, P = 0.005 and 0.041, respectively). The nPSA12 after LDR-PB or EBRT is significantly associated with treatment outcomes of prostate cancer. Higher nPSA12 may identify patients at high risk of relapse who might benefit from salvage treatment.

Access to Document (DOI)

Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer

Matsubara Nobuaki, Nagamori Satsohi, Wakumoto Yoshiaki, Uemura Hirotsugu, Kimura Go, Yokomizo Akira, Kikukawa Hiroaki, Mizokami Atsushi, Kosaka Takeo, Masumori Naoya, Kawasaki Yoshihide, Yonese Junji, Nasu Yasutomo, Fukasawa Satoshi, Sugiyama Takayuki, Kinuya Seigo, Hosono Makoto, Yamaguchi Iku, Tsutsui Hirokazu, Uemura Hiroji

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 23 ( 1 ) 1 - 8 2017.08

ISSN 1341-9625

Background: Radium-223 dichloride (radium-223) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with bone metastases. This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases. Methods: In this open-label, multicenter, phase II study, patients with progressive, symptomatic CRPC and bone metastases were treated with radium-223 (55 kBq/kg, intravenously) in a 4-week cycle for six cycles. The primary endpoint was the percent change in total alkaline phosphatase (ALP) from baseline at 12 weeks. Secondary endpoints included the percent ALP change from baseline to end of treatment (EOT), ALP response rates, percent change in prostate-specific antigen (PSA) from baseline to 12 weeks and EOT, PSA response rates, overall survival (OS), and time to symptomatic skeletal events (SSEs). Adverse events were monitored throughout the study period. Results: Of the 49 Japanese patients (median age 74 years), 28 completed all infusions. Mean percent change in total ALP and PSA from baseline to 12 weeks was −19.3 and +97.4%, respectively. One-year OS and SSE-free rate at the end of active follow-up were 78 and 89%, respectively. The ALP response rate was 31%, while the PSA response rate was 6%. Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients included decreased lymphocyte count (14%), anemia (14%), anorexia (10%), and bone pain (10%). Conclusions: Radium-223 is effective and well tolerated in Japanese patients with CRPC and bone metastases. Results were comparable with the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. Clinical trial registration: ClinicalTrials.gov NCT01929655.

Access to Document (DOI)

Increased vasohibin-1 expression is associated with metastasis and poor prognosis of renal cell carcinoma patients

Mikami Shuji, Oya Mototsugu, Kosaka Takeo, Mizuno Ryuichi, Miyazaki Yasumasa, Sato Yasufumi, Okada Yasunori

Laboratory Investigation 97 ( 7 ) 854 - 862 2017.07

ISSN 0023-6837

The microvascular density detected by markers of endothelial cells (ECs), such as CD31 and CD34, is considered to be a biomarker for angiogenesis, and it is generally associated with the malignant potential of solid tumors. However, there is a conflicting relationship between the microvascular density and prognosis in clear-cell renal cell carcinoma (ccRCC) patients. It may be explained by the suggestion that the microvascular density cannot fully reflect the angiogenic activity in ccRCC, as the markers of ECs are expressed by both quiescent and activated ECs. To investigate the real angiogenic activity, we examined vasohibin-1 (VASH1), a recently identified regulator of angiogenesis, which was demonstrated to be specifically expressed by ECs of newly formed blood vessels. Expression of VASH1 and CD34 were immunohistochemically examined in 116 primary untreated ccRCCs, 10 metastatic untreated ccRCCs, and 9 metastatic ccRCCs treated with sunitinib. ECs in the tumor microvessels were sporadically immunostained for VASH1, although no VASH1 staining was observed in the non-neoplastic renal tissues. CD34 was ubiquitously expressed by all ECs in both ccRCC and non-neoplastic renal tissues. Multivariate Cox analysis indicated that an elevated VASH1 density, but not microvascular density, was a significant and independent predictor of overall survival (odds ratio, 7.71; P=0.003). The microvascular density was significantly decreased in the sunitinib-treated metastases compared with untreated tumors (P=0.001). On the other hand, the VASH1 density was significantly higher in the metastatic ccRCCs treated with sunitinib compared with non-treated ones (P=0.010), indicating that VASH1 may be associated with the resistance of ECs to sunitinib treatment. Thus, VASH1 expression may reflect the actual activity of angiogenesis, and VASH1 can serve as a new prognostic and predictive biomarker in patients with ccRCC.

Access to Document (DOI)

Determining When to Stop Prostate Specific Antigen Monitoring after Radical Prostatectomy

Matsumoto Kazuhiro, Komatsuda Akari, Yanai Yoshinori, Niwa Naoya, Kosaka Takeo, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

Journal of Urology 197 ( 3 ) 655 - 661 2017.03

ISSN 0022-5347

Purpose We analyzed long-term followup data after radical prostatectomy to determine how long we should follow patients in whom the serum prostate specific antigen level measured by an ultrasensitive assay was consistently low. Materials and Methods We retrospectively reviewed clinicopathological data for 582 consecutive patients who underwent open or laparoscopic radical prostatectomy between 1995 and 2004, excluding 4 patients who received adjuvant therapy. We stratified the patients according to prostate specific antigen at 3 and 5 years after surgery, and examined subsequent biochemical recurrence (elevation of prostate specific antigen to greater than 0.2 ng/ml) during followup. Mean followup was 9.7 years. Results At 3 years after surgery prostate specific antigen levels were measured by an ultrasensitive assay in 323 patients who had not experienced biochemical recurrence. In 187 patients with undetectable prostate specific antigen levels (less than 0.01 ng/ml) the 10 and 15-year biochemical recurrence-free survival rates were 99% and 96%, respectively. At 5 years after surgery prostate specific antigen was measured in 315 patients by the ultrasensitive assay. In 162 patients with undetectable prostate specific antigen levels the 10 and 15-year biochemical recurrence-free survival rates were both 100%. In this group the prostate specific antigen level at last followup was less than 0.01 ng/ml in 132 patients, 0.01 to 0.03 ng/ml in 27 patients, and 0.06 ng/ml, 0.07 ng/ml and 0.11 ng/ml in 1 patient each. Conclusions This long-term review indicates that if patients have continuously undetectable prostate specific antigen levels by an ultrasensitive assay for 5 years, prostate specific antigen monitoring can be stopped with an extremely low risk of subsequent biochemical recurrence.

Access to Document (DOI)

Somatic KCNJ5 mutation occurring early in adrenal development may cause a novel form of juvenile primary aldosteronism

Tamura Ai, Nishimoto Koshiro, Seki Tsugio, Matsuzawa Yoko, Saito Jun, Omura Masao, Gomez-Sanchez Celso E., Makita Kohzoh, Matsui Seishi, Moriya Nobukazu, Inoue Atsushi, Nagata Maki, Sasano Hironobu, Nakamura Yasuhiro, Yamazaki Yuto, Kabe Yasuaki, Mukai Kuniaki, Kosaka Takeo, Oya Mototsugu, Suematsu Sachiko, Nishikawa Tetsuo

Molecular and Cellular Endocrinology 441 134 - 139 2017.02

ISSN 0303-7207

We report a case of non-familial juvenile primary aldosteronism (PA). Super-selective adrenal venous sampling identified less aldosterone production in the right inferior adrenal segment than others. Bilateral adrenalectomy sparing the segment normalized blood pressure and improved PA. Both adrenals had similar histologies, consisting of a normal adrenal cortex and aldosterone synthase-positive hyperplasia/adenoma. An aldosterone-driving KCNJ5 mutation was detected in the lesions, but not in the histologically normal cortex. After taking into account that the two adrenal glands displayed a similar histological profile, as well as the fact that hyperplastic lesions in both glands exhibited a common KCNJ5 mutation, we conclude that the specific mutation may have occurred at an adrenal precursor mesodermal cell, at an early stage of development; its daughter cells were mixed with non-mutant cells and dispersed into both adrenal glands, resulting into a form of the condition known as genetic mosaicism.

Access to Document (DOI)

Immunohistochemistry of aldosterone synthase leads the way to the pathogenesis of primary aldosteronism

Nishimoto Koshiro, Koga Minae, Seki Tsugio, Oki Kenji, Gomez-Sanchez Elise P., Gomez-Sanchez Celso E., Naruse Mitsuhide, Sakaguchi Tomokazu, Morita Shinya, Kosaka Takeo, Oya Mototsugu, Ogishima Tadashi, Yasuda Masanori, Suematsu Makoto, Kabe Yasuaki, Omura Masao, Nishikawa Tetsuo, Mukai Kuniaki

Molecular and Cellular Endocrinology 441 124 - 133 2017.02

ISSN 0303-7207

Our group previously purified human and rat aldosterone synthase (CYP11B2 and Cyp11b2, respectively) from their adrenals and verified that it is distinct from steroid 11β-hydroxylase (CYP11B1 or Cyp11b1), the cortisol- or corticosterone-synthesizing enzyme. We now describe their distributions immunohistochemically with specific antibodies. In rats, there is layered functional zonation with the Cyp11b2-positive zona glomerulosa (ZG), Cyp11b1-positive zona fasciculata (ZF), and Cyp11b2/Cyp11b1-negative undifferentiated zone between the ZG and ZF. In human infants and children (<12 years old), the functional zonation is similar to that in rats. In adults, the adrenal cortex remodels and subcapsular aldosterone-producing cell clusters (APCCs) replace the continuous ZG layer. We recently reported possible APCC-to-APA transitional lesions (pAATLs) in 2 cases of unilateral multiple adrenocortical micro-nodules. In this review, we present 4 additional cases of primary aldosteronism, from which the extracted adrenals contain pAATLs, with results of next generation sequencing for these lesions. Immunohistochemistry for CYP11B2 and CYP11B1 has become an important tool for the diagnosis of and research on adrenocortical pathological conditions and suggests that APCCs may be the origin of aldosterone-producing adenoma.

Access to Document (DOI)

Purified protein derivative skin test reactions are associated with clinical outcomes of patients with nonmuscle invasive bladder cancer treated with induction bacillus Calmette-Guérin therapy

Niwa Naoya, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 36 ( 2 ) 77.e15 - 77.e21 2017.01

ISSN 1078-1439

Objectives: To investigate the relationship between purified protein derivative (PPD) skin test reactions before bacillus Calmette-Guérin (BCG) therapy and the clinical outcomes of BCG-naïve nonmuscle invasive bladder cancer patients treated with adjuvant BCG therapy. Materials and methods: A total of 288 nonmuscle invasive bladder cancer patients subjected to the PPD skin test before BCG therapy were included. PPD skin test reactions were categorized into 3 groups: positive, slightly positive, and negative. The presence of an induration was positive. If an induration was absent, erythema of 10. mm or more and less than 10. mm corresponded to slightly positive and negative, respectively. Results: A total of 66 (22.9%), 149 (51.7%), and 73 (25.3%) patients exhibited a positive, slightly positive, and negative to PPD skin test, respectively. The 5-year recurrence-free survival rate of patients with positive PPD skin test reactions was 89.4 ± 4.1%, which was significantly higher than those of patients with slightly positive (65.5 ± 4.2%, P = 0.001) and negative reactions (56.4 ± 6.6%, P<0.001). A multivariate Cox regression analysis revealed that a positive PPD skin test reaction was independently associated with tumor recurrence (hazard ratio of 0.233, P<0.001), but not with stage progression. The incidence of fever persisting for more than 2 days or fever of ≥38°C was significantly higher in patients with a positive PPD skin test reaction (18.2%) than in patients with slightly positive (8.7%) and negative PPD skin test reactions (4.1%). Conclusions: The PPD skin test reactions before BCG therapy may predict clinical outcomes following BCG therapy and help clinicians counsel patients exhibiting strong therapeutic effects with BCG therapy and potentially major BCG-related side effects.

Access to Document (DOI)

Headache caused by brain metastases of castration-resistant prostate cancer during cabazitaxel therapy

Watanabe Keitaro, Kosaka Takeo, Hongo Hiroshi, Tamaki Satoshi, Oya Mototsugu

Keio Journal of Medicine 66 ( 4 ) 65 - 71 2017.01

ISSN 0022-9717

We describe the case of a 55-year-old man who underwent four cycles of cabazitaxel therapy for castration- resistant prostate cancer (CRPC). After the fourth cycle of cabazitaxel, the patient experienced severe headaches. Brain gadolinium (Gd) contrast-enhanced magnetic resonance imaging (MRI) revealed multiple brain metastases. A few days later, the patient suffered impaired consciousness that progressed rapidly. The patient was treated for the symptoms of increased intracranial pressure and underwent whole-brain radiation. One month later, the patient’s consciousness level and headache had improved. Although brain metastases of prostate cancer are rare, the possibility of brain metastases should be considered for prostate cancer patients, especially when a CRPC patient complains of headache. Additionally, even if major conditions such as cerebral hemorrhage are excluded by the use of non-contrast enhanced computed tomography, brain Gd contrast-enhanced MRI should be performed in consideration of the possibility of brain metastases of prostate cancer.

Access to Document (DOI)

Novel algorithm for management of acute epididymitis

Hongo Hiroshi, Kikuchi Eiji, Matsumoto Kazuhiro, Yazawa Satoshi, Kanao Kent, Kosaka Takeo, Mizuno Ryuichi, Miyajima Akira, Saito Shiro, Oya Mototsugu

International Journal of Urology 24 ( 1 ) 82 - 87 2017.01

ISSN 0919-8172

Objectives: To identify predictive factors for the severity of epididymitis and to develop an algorithm guiding decisions on how to manage patients with this disease. Methods: A retrospective study was carried out on 160 epididymitis patients at Keio University Hospital. We classified cases into severe and non-severe groups, and compared clinical findings at the first visit. Based on statistical analyses, we developed an algorithm for predicting severe cases. We validated the algorithm by applying it to an external cohort of 96 patients at Tokyo Medical Center. The efficacy of the algorithm was investigated by a decision curve analysis. Results: A total of 19 patients (11.9%) had severe epididymitis. Patient characteristics including older age, previous history of diabetes mellitus and fever, as well as laboratory data including a higher white blood cell count, C-reactive protein level and blood urea nitrogen level were independently associated with severity. A predictive algorithm was created with the ability to classify epididymitis cases into three risk groups. In the Keio University Hospital cohort, 100%, 23.5%, and 3.4% of cases in the high-, intermediate-, and low-risk groups, respectively, became severe. The specificity of the algorithm for predicting severe epididymitis proved to be 100% in the Keio University Hospital cohort and 98.8% in the Tokyo Medical Center cohort. The decision curve analysis also showed the high efficacy of the algorithm. Conclusions: This algorithm might aid in decision-making for the clinical management of acute epididymitis.

Access to Document (DOI)

Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer

Kosaka Takeo, Hongo Hiroshi, Miyazaki Yasumasa, Nishimoto Koshiro, Miyajima Akira, Oya Mototsugu

Oncotarget 8 ( 50 ) 87675 - 87683 2017

ISSN 1949-2553

Reactive oxygen species (ROS) production induced by taxanes in cancer cells may influence the taxane-induced cell death or the drug resistance. We investigated the correlation between the cytotoxic effect of taxanes and ROS production in human castration-resistant prostate cancer (CRPC) cell lines. Three human prostate cancer cell lines were treated with increasing concentrations of docetaxel or cabazitaxel in vitro. Cabazitaxel showed significantly higher cytotoxic efficacy than docetaxel in human CRPC cells, accompanied by elevated ROS production detected by FACS analysis. To investigate whether cabazitaxel-mediated cell death was caused by the ROS generation induced by cabazitaxel, we treated CRPC cells in the presence of antioxidant NAC. NAC reduced the cytotoxic effect induced by cabazitaxel. We found that ROS elimination by Sestrin-3 (SESN3) was significantly inhibited by cabazitaxel, but not by docetaxel. These results indicate higher sensitivity of human CRPC to cabazitaxel compared to docetaxel involves ROS production through inhibiting the expression of antioxidant enzyme SESN3.

Access to Document (DOI)

Ra-223 SPECT for semi-quantitative analysis in comparison with Tc-99m HMDP SPECT

Owaki Yoshiki, Nakahara Tadaki, Kosaka Takeo, Fukada Junichi, Kumabe Atsuhiro, Ichimura Akira, Murakami Mikoto, Nakajima Kiyotaka, Fukushi Masahiro, Inoue Kazumasa, Oya Mototsugu, Jinzaki Masahiro

EJNMMI Research 7 2017

ISSN 2191-219X

Background: Image-based measurement of absorbed dose of Ra-223 dichloride may be useful in predicting therapeutic outcome in patients with castration-resistant prostate cancer (CRPC). In general, SPECT has been found to be more accurate than planar imaging in terms of lesion-based analysis. The aims of this study were to assess the feasibility and clinical usefulness of Ra-223 SPECT. The energy spectrum of Ra-223 and SPECT images of a cylindrical phantom with a hot rod were obtained to determine the collimator candidates and energy window settings suitable for clinical Ra-223 SPECT (basic study A). Another phantom with a tube-shaped chamber and two spheres simulating bowel activity and metastatic lesions in the lumbar spine was scanned with medium-energy general-purpose (MEGP) and high-energy general-purpose (HEGP) collimators (basic study B). Ten patients with CRPC underwent SPECT imaging 2 h after Ra-223 injection successively with MEGP and HEGP collimators in random order for 30 min each. Lesion detectability and semi-quantitative analyses of bone metastasis (i.e. lesion-to-background ratio (LBR)) were performed compared to Tc-99m HMDP SPECT. Results: Basic study A revealed that an 84-keV photopeak ± 20% using the HEGP collimator offers better SPECT image quality than the other imaging conditions. Basic study B showed that uptake in one of the spheres was overestimated by overlapped activity of the tube-shaped chamber in planar imaging whereas the spheres had similar counts and significantly higher sphere-to-background ratio in SPECT. On both planar and SPECT images, HEGP gave higher image contrast than MEGP (p < 0.01). In the clinical study, Ra-223 SPECT at 84 keV ± 20% depicted more lesions with the HEGP than with the MEGP collimator (51 vs 36, p = 0.013). There was a positive correlation between LBR in Tc-99m SPECT and in Ra-223 SPECT (r = 0.67 with the MEGP and 0.69 with the HEGP collimator, p < 0.01). LBRs were significantly higher with the HEGP than with the MEGP collimator (p < 0.01). Conclusions: We recommended the use of the HEGP collimator at 84 keV ± 20% for Ra-223 SPECT imaging. Lesion-based semi-quantitative analysis in the human study revealed a good correlation between Ra-223 and Tc-99m HMDP SPECT in the early phase (2–3 h post injection).

Access to Document (DOI)

Prognostic significance of erythrocyte protein band 4.1-like5 expression in upper urinary tract urothelial carcinoma

Daimon Tatsuaki, Kosaka Takeo, Kikuchi Eiji, Mikami Shuji, Miyazaki Yasumasa, Hashimoto Ari, Hashimoto Shigeru, Mizuno Ryuichi, Miyajima Akira, Okada Yasunori, Sabe Hisataka, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2016.12

ISSN 1078-1439

Objectives: The erythrocyte protein band 4.1-like5 (EPB4.1L5) regulates E-cadherin in cancer invasion and metastasis inducing epithelial-to-mesenchymal transition. This study aimed to investigate the biological significance of EPB4.1L5 in upper urinary tract urothelial carcinoma (UTUC). Methods: Retrospective analysis of the clinical records of 165 patients with UTUC (Ta-4N0M0) subjected to radical nephroureterectomy and immunohistochemical examination of EPB4.1L5 expression in those tissues. Results: The median follow-up period was 62.2 months (interquartile range = 77.0). The score of EPB4.1L5 significantly correlated with tumor grade, pathological T stage, and lymphovascular invasion (all P<0.001). The 5-year Kaplan-Meier recurrence-free survival and cancer-specific survival rates were 54.1% and 59.5% in patients with high EPB4.1L5 expression, compared with 81.6% and 87.2%, (all P<0.001) in their counterparts. Multivariate analyses revealed that high expression of EPB4.1L5 was one of the independent prognostic factors for tumor recurrence (P = 0.022, HR = 2.40) and cancer-specific survival (P = 0.015, HR = 2.94). Conclusion: High EPB4.1L5 expression was related to worse clinical outcome in patients with UTUC. These results indicated that EPB4.1L5 could provide prognostic information in patients with UTUC regarding epithelial-to-mesenchymal transition.

Access to Document (DOI)

Plasma fibrinogen level

Obata Jun, Tanaka Nobuyuki, Mizuno Ryuichi, Kanao Kent, Mikami Shuji, Matsumoto Kazuhiro, Kosaka Takeo, Kikuchi Eiji, Jinzaki Masahiro, Oya Mototsugu

BJU International 118 ( 4 ) 598 - 603 2016.10

ISSN 1464-4096

Objectives: To investigate the impact of perioperative plasma fibrinogen level as a biomarker of oncological outcome in localised renal cell carcinoma (RCC). Patients and methods: We consecutively identified 601 patients with localised RCC who underwent curative surgery at a single institution. Subsequent disease recurrence and cancer-specific survival (CSS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic impact of plasma fibrinogen level, multivariate analysis was performed for these outcomes. Results: Using the defined threshold level of preoperative plasma fibrinogen of ≥420 mg/dL as elevated, we found 56 patients (9.3%) with an elevated plasma fibrinogen level preoperatively. In Kaplan–Meier analysis, there was a significant difference in disease-free survival and CSS rates between patients with and without preoperative plasma fibrinogen levels of ≥420 mg/dL. Multivariate analysis showed that elevated preoperative plasma fibrinogen level was an independent predictor of subsequent disease recurrence and cancer-specific mortality. In a subgroup analysis of the elevated preoperative plasma fibrinogen level group, postoperative normalisation of plasma fibrinogen level was significantly associated with CSS, showing that patients with non-normalised plasma fibrinogen levels tended to have a higher incidence of cancer-specific mortality after surgery. Conclusion: Patients with elevated preoperative plasma fibrinogen levels could be significantly predicted to have subsequent tumour metastasis and cancer-specific mortality, while there was a significant difference in CSS between patients in the normalised and non-normalised postoperative plasma fibrinogen groups. While these are hypothesis generating results, plasma fibrinogen levels may be a useful biomarker due to its low cost and ease of assessment.

Access to Document (DOI)

High Absolute Monocyte Count Predicts Poor Clinical Outcome in Patients with Castration-Resistant Prostate Cancer Treated with Docetaxel Chemotherapy

Shigeta Keisuke, Kosaka Takeo, Kitano Shigehisa, Yasumizu Yota, Miyazaki Yasumasa, Mizuno Ryuichi, Shinojima Toshiaki, Kikuchi Eiji, Miyajima Akira, Tanoguchi Hitoshi, Hasegawa Shintaro, Oya Mototsugu

Annals of Surgical Oncology 1 - 8 2016.06

ISSN 1068-9265

Background: The association of peripheral monocyte count and prostate cancer progression is not well characterized. Objective: Our aim was to investigate the prognostic value of absolute monocyte count (AMC), which is thought to modulate immune response in the tumor microenvironment, in castration-resistant prostate cancer (CRPC) patients treated with docetaxel chemotherapy. Methods: We retrospectively reviewed the medical records of 214 CRPC patients who received docetaxel therapy and were used as the training and validation set. Docetaxel at a dose of 75 mg/m² was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). Results: In the training set, the median age was 73.0 years, and the median prostate-specific antigen (PSA) value was 31.7 ng/ml at initial treatment. The median OS and PFS were 23.0 months (range 1.20–84.0) and 11.2 months (range 3.6–78.0), respectively. According to multivariable Cox regression analysis, AMC ≥400/uL, PSA level ≥20 ng/ml, and Hb

Access to Document (DOI)

Patient age was an independent predictor of cancer-specific survival in male patients with upper tract urothelial carcinoma treated by radical nephroureterectomy

Kobayashi Hiroaki, Kikuchi Eiji, Tanaka Nobuyuki, Shirotake Suguru, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Matsumoto Kazuhiro, Kaneko Gou, Hagiwara Masayuki, Kosaka Takeo, Oyama Masafumi, Nakajima Yosuke, Oya Mototsugu

Japanese Journal of Clinical Oncology 46 ( 6 ) 554 - 559 2016.06

ISSN 0368-2811

Objective: We hypothesized that there may be a prognostic difference in age between the genders and evaluated the influence of gender-adjusted age on prognosis in upper tract urothelial carcinoma patients. Methods: A total of 839 patients with upper tract urothelial carcinoma from a retrospective multi-institutional cohort were included. The patients were divided into four groups consisting of males (N = 610) and females (N = 229) according to age ((i) <60 years, (ii) 60-69.9 years, (iii) 70-79.9 years and (iv) ≥ 80 years), and we evaluated the associations of patient age and gender with clinicopathological features and oncological outcomes following radical nephroureterectomy. The median follow-up duration was 34 months. Results: Disease recurrence occurred in 249 patients and 192 patients died of upper tract urothelial carcinoma. The 3-year cancer-specific survival rates were (i) 84.3%, (ii) 80.2%, (iii) 77.1% and (iv) 71.5% in the entire patient population (P = 0.001); (i) 84.5%, (ii) 81.1%, (iii) 76.8% and (iv) 69.7% in males (P = 0.010); and (i) 83.3%, (ii) 76.9%, (iii) 77.7% and (iv) 72.9% in females (P = 0.287), respectively. No significant differences between disease recurrence and age were found in the male or female population. In multivariate analysis, older age was an independent predictor of cancer-specific survival, in addition to advanced pT stage, the presence of lymphovascular invasion and lymph node involvement in males. In contrast, age was not associated with cancer-specific survival in females, while high grade, advanced pT stage, the presence of lymph node involvement and multifocal tumor were independent predictors. Conclusion: The results indicate that gender-adjusted age might be a new prognostic factor in upper tract urothelial carcinoma patients.

Access to Document (DOI)

Stem cell biology in prostate cancer

Kosaka Takeo, Oya Mototsugu

2016.05

ISSN 0047-1852

The prognostic significance of OCT4 expression in patients with prostate cancer

Kosaka Takeo, Mikami Shuji, Yoshimine Shunsuke, Miyazaki Yasumasa, Daimon Tatsuaki, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

Human Pathology 51 1 - 8 2016.05

ISSN 0046-8177

Accumulating evidence suggests that OCT4 participates in tumorigenicity and malignancy in human cancers. However, the prognostic significance of OCT4 expression in prostate cancer (PCa) or predictive significance of OCT4 in docetaxel sensitivity in castration-resistant prostate cancer (CRPC) remains unclear. The aim of this study was to assess the prognostic value of OCT4 expression in PCa. We retrospectively analyzed the clinical records and evaluated the OCT4 expression in 205 patients with PCa who underwent radical prostatectomy. We examined the change of OCT4 expression in 3 patients with CRPC who underwent transurethral resection for local progression before and after docetaxel chemotherapy. OCT4 expression was significantly associated with higher pathological T stage (P <.001). The 5-year prostate-specific antigen recurrence-free survival rate was 56.8% in patients with higher OCT4 expression and 90.6% in patients with lower OCT4 expression (P <.001). Multivariate analysis revealed that high OCT4 expression was an independent prognostic indicator of prostate-specific antigen recurrence (P <.001). Elevated strong OCT4 expression in residual CRPC cells after docetaxel chemotherapy was observed in all CRPC patients, compared with before chemotherapy in corresponding specimens. Higher OCT4 expression represents a clinically relevant predictor of patient prognosis in PCa and may be a new biomarker that will provide additional prognostic information in CRPC when treated with docetaxel.

Access to Document (DOI)

Spontaneous Regression of Epstein-Barr Virus-Positive Primary Diffuse Large Cell B-Cell Lymphoma of the Urinary Bladder after the Cessation of Enzalutamide

Ogihara Koichiro, Kosaka Takeo, Kikuchi Eiji, Hongo Hiroshi, Mikami Shuji, Oya Mototsugu

Clinical Genitourinary Cancer 14 ( 2 ) e215 - e218 2016.04

ISSN 1558-7673

Access to Document (DOI)

Placebo-Induced Severe Diarrhea in a Patient with Metastatic Castration-Resistant Prostate Cancer Participating in a Double-Blind, Randomized, Phase III International Trial

Niwa Naoya, Kosaka Takeo, Oya Mototsugu

Clinical Genitourinary Cancer 14 ( 2 ) e219 - e220 2016.04

ISSN 1558-7673

Access to Document (DOI)

Erectile function status is highly associated with prostate-specific antigen bounce in localized prostate cancer patients treated with permanent prostate brachytherapy

Matsushima Masashi, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Ohashi Toshio, Mikami Shuji, Miyajima Akira, Shigematsu Naoyuki, Oya Mototsugu

International Journal of Urology 23 ( 3 ) 247 - 252 2016.03

ISSN 0919-8172

Objectives: To examine the relationship between erectile function status and prostate-specific antigen bounce after prostate brachytherapy for localized prostate cancer. Methods: We identified 154 patients who were followed up for at least 24 months after brachytherapy. Erectile function status was assessed prospectively before brachytherapy (baseline), and 3, 6, 12, 18, 24 and 36 months postoperatively using the International Index of Erectile Function-15 questionnaire. Prostate-specific antigen bounce was defined as an increase of at least 0.4 ng/mL from a previous prostate-specific antigen level with a subsequent decline equal to, or less than, the initial nadir without treatment. A logistic regression analysis was used to identify a significant set of independent predictors of prostate-specific antigen bounce after brachytherapy. Results: Prostate-specific antigen bounce was observed in 38 (24.7%) men. The prostate-specific antigen bounce group had a higher erectile function domain score, higher orgasmic function domain score, and higher total International Index of Erectile Function-15 score before (at baseline) and after brachytherapy (3, 6, 12, 18, 24 and 36 months after brachytherapy) than their counterparts (P <0.05). Of the 77 patients who completed the International Index of Erectile Function-15 questionnaire 18 months after brachytherapy (the median time of prostate-specific antigen bounce), sexual desire and intercourse satisfaction domain scores, and total International Index of Erectile Function scores 18 months after brachytherapy correlated with the occurrence of prostate-specific antigen bounce. A multivariate analysis identified the intercourse satisfaction domain score 18 months after brachytherapy as an independent indicator for the occurrence of prostate-specific antigen bounce (P = 0.008). Conclusions: International Index of Erectile Function-15 score seems to be correlated with the prostate-specific antigen bounce in prostate cancer patients undergoing brachytherapy, and an occurrence of prostate-specific antigen bounce seems to be more likely in those who are more sexually active.

Access to Document (DOI)

Relationship Between Increased Expression of the Axl/Gas6 Signal Cascade and Prognosis of Patients with Upper Tract Urothelial Carcinoma

Hattori Seiya, Kikuchi Eiji, Kosaka Takeo, Miyazaki Yasumasa, Tanaka Nobuyuki, Miyajima Akira, Mikami Shuji, Oya Mototsugu

Annals of Surgical Oncology 23 ( 2 ) 663 - 670 2016.02

ISSN 1068-9265

Purpose: Axl, which is in the TAM family of receptor tyrosine kinases, and its ligand, growth arrest-specific gene 6 (Gas6), have been associated with worse prognoses after the surgical treatment of some types of cancers. We herein investigated the biological significance of the protein expression of Axl and Gas6 on the outcomes of patients with upper tract urothelial carcinoma (UTUC). Methods: The protein expression of Axl and Gas6 was evaluated by immunohistochemistry, and their relationships with clinicopathological features were investigated in surgical specimens obtained from 161 patients who had been surgically treated for UTUC. Results: Axl labeling was strong in 67 of 161 (42 %) cases, while Gas6 labeling was strong in 72 of 161 (45 %) cases. The strong expression of Axl correlated with that of Gas6. A high pathological stage (p = 0.009), strong expression of Gas6 (p = 0.038), and strong expression of Axl (p = 0.016) were independent factors for predicting worse cancer-specific survival (CSS). In a subgroup analysis of patients with pT

Access to Document (DOI)

Should We Try Antiandrogen Withdrawal in Castration-Resistant Prostate Cancer Patients? Insights From a Retrospective Study

Hongo Hiroshi, Kosaka Takeo, Mizuno Ryuichi, Ezaki Taisuke, Matsumoto Kazuhiro, Morita Shinya, Shinoda Kazunobu, Shinojima Toshiaki, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

Clinical Genitourinary Cancer 2016.01

ISSN 1558-7673

Background: It remains uncertain whether those with response to antiandrogen withdrawal (AAW) have a better prognosis. We investigated the predictors of a better response to AAW and overall survival after acquiring resistance to first-line androgen deprivation therapy inpatients with castration-resistant prostate cancer (CRPC). Patients and Methods: We retrospectively reviewed the medical records of 87 CRPC patients treated at Keio University Hospital. Sixty-seven of 87 CRPC patients underwent AAW. We analyzed clinicopathologic parameters to identify predictors of survival in CRPC patients and investigated predictors of good response to AAW. Results: Younger age, longer duration of androgen deprivation therapy before CRPC development, and better response to AAW were independent favorable prognostic factors for overall survival. Although better response to AAW was a favorable prognostic factor in this study, trying AAW was not significantly related to overall survival. Duration of hormone therapy was significantly longer in those whose disease responded to AAW (69.9 ± 11.0 months) than those with no response (45.3 ± 5.2 months). Conclusion: The prognostic benefit of AAW was not clearly determined in this study. However, AAW might be beneficial in patients who have favorable prognostic factors for a response to AAW-that is, those who have received hormone therapy for a long period. However, AAW should not be done in patients who do not have favorable factors and who had a high prostate-specific antigen level at the time of their prostate cancer diagnosis.

Access to Document (DOI)

Variant isoforms of CD44 expression in upper tract urothelial cancer as a predictive marker for recurrence and mortality

Hagiwara Masayuki, Kikuchi Eiji, Kosaka Takeo, Mikami Shuji, Saya Hideyuki, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2016.01

ISSN 1078-1439

Purpose: The variant isoforms of CD44 (CD44v), which has been associated with treatment resistance and tumor recurrence, are contributed to the feature of some of the new cell surface markers for cancer stem cells. The aim of this study is to address the prognostic significant of CD44v expression in upper tract urothelial cancer (UTUC). Materials and methods: We retrospectively analyzed the medical records of 110 patients treated surgically for≥pT2 UTUC. To determine the biological significance of CD44v in UTUC, we examined the immunohistochemical expression of CD44v9 and its association with clinical features and oncological outcomes. Results: During the mean follow-up of 4.8 years, tumor recurrence, including local and distant metastasis, was observed in 57 patients (51.8%), and 42 patients (38.2%) died of the disease. The incidence of ureter cancers was significantly higher in patients expressing CD44v9. In this series, 37 patients in the CD44v9-positive group (45.1%) and 5 (17.9%) in the CD44v9-negative group died of the disease. Kaplan-Meier curves revealed that cancer-specific survival and recurrence-free survival rates were significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.032 and P = 0.038, respectively). A multivariate analysis identified the expression of CD44v9 as one of the independent risk factors for cancer-specific survival (P = 0.040, hazard ratio = 2.67) in addition to tumor grade G3, and also for recurrence-free survival (P = 0.028, hazard ratio = 2.33), in addition to tumor grade G3 and lymphovascular invasion. Conclusions: The expression of CD44v9 may be a new biomarker of malignant potential in muscle invasive UTUC and provide additional prognostic information in patients with UTUC.

Access to Document (DOI)

Syndrome of inappropriate antidiuretic hormone secretion in a patient with castration-resistant prostate cancer treated with enzalutamide

Yanai Yoshinori, Matsumoto Kazuhiro, Niwa Naoya, Kosaka Takeo, Kikuchi Eiji, Miyajima Akira, Ito Hiroshi, Oya Mototsugu

Acta Oncologica 55 ( 3 ) 399 - 400 2016.01

ISSN 0284-186X

Access to Document (DOI)

Case report

Nishimoto Koshiro, Seki Tsugio, Kurihara Isao, Yokota Kenichi, Omura Masao, Nishikawa Tetsuo, Shibata Hirotaka, Kosaka Takeo, Oya Mototsugu, Suematsu Makoto, Mukai Kuniaki

Journal of Clinical Endocrinology and Metabolism 101 ( 1 ) 6 - 9 2016.01

ISSN 0021-972X

Context: We previously reported that the human adrenal cortex remodels to form subcapsular aldosterone-producing cell clusters (APCCs).SomeAPCCs were recently found to carry aldosteroneproducing adenoma (APA)-associated somatic mutations in ion channel/pump genes, which implied that APCCs produce aldosterone autonomously and are an origin of APA. However, there has been no report describing an APCC-to-APA transitional lesion. Case Description: A histological examination revealed unilateral multiple adrenocortical micronodules in the adrenals of two patients with primary aldosteronism (PA). Based on immunohistochemistry for aldosterone synthase, some of the micronodules were identified as possible APCC-to-APA transitional lesions (pAATLs; a tentative term used in this manuscript), which consisted of a subcapsular APCC-like portion and an inner micro-APA-like (mAPA-like) portion without an apparent histological border. GenomicDNAsamples prepared from pAATL histological sections were analyzed by next-generation sequencing for the known APA-associated mutations. The mAPA-like portions from two of the three large pAATLs examined harbored mutations (KCNJ5 [p.G151R] in pAATL 3 and ATP1A1 [p.L337M] in pAATL 7), whereas their corresponding APCC-like portions did not, suggesting their role in the formation of mAPA. Another lesion carried novel mutations in ATP1A1 (p.Ile322-Ile325del and p.Ile327Ser) in both the mAPA-like and APCC-like portions, thereby supporting these portions having a clonal origin. Conclusion: A novel aldosterone-producing pathology, pAATL that causes unilateral PA, was detected in the adrenals of two patients. Next-generation sequencing analyses of the large pAATLs suggested that the introduction of APA-associated mutations in the ion channel/pump genes may be involved in the development of mAPA from existing APCCs.

Access to Document (DOI)

Prostate cancer stem cell and drug resistance

Kosaka Takeo, Oya Mototsugu

2016.01

ISSN 0047-1852

Cancer tissues are comprised of cell population including a variety of cells, such as stem cell-like cancer cells, upon which a hierarchical society is constructed. This hypothesis has been applied not only to leukemia, in which the hypothesis was first experimentally confirmed, but also to solid cancers. Recent topics shed light on the modified heterogeneity by various treatments which evolve disease progression. In prostate cancer, the identification of cancer stem cells using surface markers and the relationship with prostate origin are of current interest. This article reviews studies related to the development of prostate cancer and introduce recent progress of our project, focusing on cancer stemness and drug resistance.

Sufficient Volume Ablation with Photoselective Vaporization of the Prostate Delivers 5-Year Durability and Improves Symptom Relief for Larger Prostates

Otsuki Hideo, Kuwahara Yoshitaka, Kosaka Takeo, Nakamura Kenzo, Tsukamoto Takuji

Journal of Endourology 30 ( 1 ) 102 - 108 2016.01

ISSN 0892-7790

Objectives: To assess the long-term durability of photoselective vaporization of the prostate (PVP) for symptomatic benign prostatic enlargement (BPE) or benign prostatic obstruction (BPO) and treatment efficacy for large BPE. Methods: Four hundred fifty-seven patients with symptomatic BPE underwent PVP between January 2006 and April 2009. Efficacy was evaluated with the International Prostate Symptoms Score (IPSS), Quality of Life (QOL) score, urinary peak flow (Qmax), postvoid residual volume (PVR), and prostate volume. Parameters were checked preoperatively, and at 1, 3, and 5 years postoperatively. One hundred fifty-three patients completed 5-year follow-up. To assess treatment effects, patients were divided into two groups according to the preoperative prostate volume: group A (60 mL, n=49). Results: Mean IPSS, QOL score, Qmax, and PVR improved significantly and were maintained for 5 years with no significant differences; at year 1, prostate volume had decreased significantly from 54.0 mL to 30.6 mL (43% of volume ablation) and remained at that level until year 5. Investigations according to prostate size demonstrate that IPSS and QOL scores in group B remained at significantly lower levels, and Qmax in group B improved more than in group A. 1.1% of patients needed transurethral resection of the prostate due to BPO recurrence. Conclusions: PVP is effective and provides durable results for 5 years, with sustained symptom relief and improved urinary flow rate, as well as a 43% volume reduction of prostate volume. Our data indicate PVP is more efficacious for larger prostates under sufficient volume ablation.

Access to Document (DOI)

Recent advances in renal cell carcinoma from a pathological point of view

Mikami Shuji, Oya Mototsugu, Mizuno Ryuichi, Kosaka Takeo, Ishida Masaru, Kuroda Naoto, Nagashima Yoji, Katsube Ken ichi, Okada Yasunori

Pathology International 2016

ISSN 1320-5463

The purpose of this article is to review the recent advances in renal cell carcinoma (RCC) from a pathological point of view. Because the genetic features and morphological characteristics have become major criteria for the classification of RCC, special techniques, such as immunohistochemistry, are essential to the differential diagnosis of renal tumors. Metastasis is frequently observed among the RCC patients with curative nephrectomy, and extracellular matrix-degrading enzymes, such as matrix metalloproteinases (MMP) and heparanase, play a key role in invasion and metastasis of RCC. Snail and Slug, transcription factors of epithelial-mesenchymal transition (EMT), accelerate cancer cell invasion through downregulation of E-cadherin and up-regulation of MMP. Therapies targeted at the vascular endothelial growth factor pathway have become the standard treatment of metastatic RCC. Although they lead to tumor shrinkage mainly by inhibiting angiogenesis, they have typically been associated with drug resistance. The mechanism of the resistance remains largely unknown, but complex events including re-activation of angiogenesis, EMT and cancer stem cells, and immune escape are implicated in the refractory response to the therapy. Recent advances of the research on RCC have caused the changes of classification and therapy, and pathologists should take overall view of these as integrated pathology.

Access to Document (DOI)

Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation

Nishimoto Koshiro, Seki Tsugio, Hayashi Yuichiro, Mikami Shuji, Al-Eyd Ghaith, Nakagawa Ken, Morita Shinya, Kosaka Takeo, Oya Mototsugu, Mitani Fumiko, Suematsu Makoto, Kabe Yasuaki, Mukai Kuniaki

International Journal of Endocrinology 2016 2016

ISSN 1687-8337

Background. The immunohistochemical detection of aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) has enabled the identification of aldosterone-producing cell clusters (APCCs) in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time. Purposes. To investigate changes in human adrenocortical zonation with age. Methods. We retrospectively analyzed adrenal tissues prepared from 33 autopsied patients aged between 0 and 50 years. They were immunostained for CYP11B2 and CYP11B1. The percentage of APCC areas over the whole adrenal area (AA/WAA, %) and the number of APCCs (NOA, APCCs/mm²) were calculated by four examiners. Average values were used in statistical analyses. Results. Adrenals under 11 years old had layered zona glomerulosa (ZG) and zona fasciculata (ZF) without apparent APCCs. Some adrenals had an unstained (CYP11B2/CYP11B1-negative) layer between ZG and ZF, resembling the rat undifferentiated cell zone. Average AA/WAA and NOA correlated with age, suggesting that APCC development is associated with aging. Possible APCC-to-APA transitional lesions were incidentally identified in two adult adrenals. Conclusions. The adrenal cortex with layered zonation remodels to possess APCCs over time. APCC generation may be associated with hypertension in adults.

Access to Document (DOI)

Prostate Cancer Cells in Different Androgen Receptor Status Employ Different Leucine Transporters

Otsuki Hideo, Kimura Toru, Yamaga Takashi, Kosaka Takeo, Suehiro Jun ichi, Sakurai Hiroyuki

Prostate 2016

ISSN 0270-4137

BACKGROUND: Leucine stimulates cancer cell proliferation through the mTOR pathway, therefore, inhibiting leucine transporters may be a novel therapeutic target for cancer. L-type amino acid transporter (LAT) 1, a Na⁺-independent amino acid transporter, is highly expressed in many tumor cells. However, leucine transporter(s) in different stages of prostate cancer, particularly in the stages of castration resistance with androgen receptor (AR) expression, is unclear. METHODS: LNCaP and DU145 and PC-3 cell lines were used as a model of androgen dependent, and metastatic prostate cancer. A new "LN-cr" cell line was established after culturing LNCaP cells for 6 months under androgen-free conditions, which is considered a model of castration resistant prostate cancer (CRPC) with androgen AR expression. The expression of leucine transporters was investigated with quantitative PCR and immunofluorescence. Uptake of ¹⁴C Leucine was examined in the presence or absence of BCH (a pan-LAT inhibitor), JPH203 (an LAT1-specific inhibitor), or Na⁺. Cell growth was assessed with MTT assay. siRNA studies were performed to evaluate the indispensability of y⁺LAT2 on leucine uptake and cell viability in LN-cr. RESULTS: Cell viability showed a 90% decrease in the absence of leucine in all four cell lines. LNCaP cells principally expressed LAT3, and their leucine uptake was more than 90% Na⁺-independent. BCH, but not JPH203, inhibited leucine uptake, and cell proliferation (IC_50BCH:15mM). DU145 and PC-3 cells predominantly expressed LAT1. Leucine uptake and cell growth were suppressed by BCH or JPH203 in a dose-dependent manner (IC_50BCH: ∼20mM, IC_50JPH203: ∼5μM). In LN-cr cells, Na⁺-dependent uptake of leucine was 3.8pmol/mgprotein/min, while, Na⁺-independent uptake was only 0.52 (P<0.05). Leucine uptake of LN-cr was largely (∼85%) Na⁺-dependent. y⁺LAT2 expression was confirmed in LN-cr. Knockdown of y⁺LAT2 lead to significant leucine uptake inhibition (40%) and cell growth inhibition (20%). CONCLUSIONS: New CRPC cell line with increased expression of y⁺LAT2 as a leucine transporter was established in vitro. Anti-leucine transporter therapy could be an important option against prostate cancer. Prostate

Access to Document (DOI)

Continuous use of enzalutamide in a patient who developed enzalutamide-induced thrombocytopenia

Sato Atsuko, Kosaka Takeo, Oya Mototsugu

BMJ Case Reports 2015 2015.11

Drug-induced thrombocytopenia (DIT) is known to be caused by many drugs. In daily clinical practice, it is not uncommon to observe cases of thrombocytopenia related to enzalutamide. We report the case of a 69-year-old patient with metastatic castration-resistant prostate cancer (CRPC) who was started on enzalutamide at a dose of 160 mg/day. Two weeks after starting enzalutamide, asymptomatic thrombocytopenia (platelet count 14 000/μL) occurred. Enzalutamide was withdrawn and the patient received platelet transfusions. The platelet count recovered immediately. Because the prostate-specific antigen (PSA) level had started to fall during treatment with enzalutamide, the patient was restarted on enzalutamide, but at a dose of 80 mg/day. He has continued to use enzalutamide without developing thrombocytopenia and the PSA level has kept falling. This case suggests that it is possible to again use enzalutamide in patients who have developed enzalutamide-induced thrombocytopenia.

Access to Document (DOI)

Hemorrhagic cystitis in a patient without a past history of radiation therapy who was treated with cabazitaxel for CRPC

Kosaka T., Oya M.

Annals of Oncology 26 ( 11 ) 2355 - 2356 2015.11

ISSN 0923-7534

Access to Document (DOI)

Clinical background analysis about transurethral electrocoagulation

Katsui Masahiro, Kikuchi Eiji, Yazawa Satoshi, Hagiwara Masayuki, Morita Shinya, Shinoda Kazunobu, Kosaka Takeo, Mizuno Ryuichi, Shinojima Toshiaki, Asanuma Hiroshi, Miyajima Akira, Oya Mototsugu

Japanese Journal of Urology 106 ( 4 ) 255 - 263 2015.10

ISSN 0021-5287

(Purpose) Transurethral electrocoagulation (TUC) is a rare event but occurs in a constant manner with various causes or disorders and reduces patient quality of life. So far there have been no reports focusing on the details of TUC. We focused on the clinical background and related causes in cases of TUC in our institution. (Patients and methods) We identified 76 cases (65 patients) who underwent TUC at Keio University Hospital between April 2001 and March 2011. We focused on patient background, especially with respect to the primary disease, treatment modality, use of antiplatelet or anticoagulant agent, timing of TUC, type of electrosurgical device, and the incidence of transfusion. (Results) The primary disease for TUC included bladder tumor (BT) in 31 cases, benign prostate hyperplasia (BPH) in 13, prostate cancer (PCa) in 13, idiopathic bladder bleeding in 4, periarteritis nodosa in 3, uterine cervical cancer in 3, and others in 9. TUC after transurethral resection (TUR) was found in 38 cases, including transurethral resection of bladder tumor (TURBT) in 26 of 31 BT cases and transurethral resection of prostate (TURP) in 12 of 13 BPH cases. After TURBT, TUC was performed before removal of a urethral catheter in 7 cases, and after removal of a urethral catheter in 19 cases. With regard to TUC associated with TURP, the average estimated prostate volume in TUC cases before removal of the urethral catheter was 66.2 ml, which was significantly larger than that in TUC cases after removal of the urethral catheter (46.1 ml, p = 0.045). TUC after the radiation therapy was observed in 21 cases, and the average time from the radiation therapy to TUC was 3.4 years (7 months-10 years). (Conclusion) TUC was caused by multiple causes or disorders, and 75% of our TUC was associated with BT, BPH or PCa. TUC associated with TURBT frequently occurred within 1 week after TURBT but was still observed after 1 month following the operation. All TUC associated with TURP occurred within 3 weeks after operation. The average period from radiation therapy to TUC was 3.4 years (7 months-10 years) and TUC associated with radiation cystitis could occur beyond 5 years after radiation.

Nicotine induces tumor growth and chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer

Yuge Kazuyuki, Kikuchi Eiji, Hagiwara Masayuki, Yasumizu Yota, Tanaka Nobuyuki, Kosaka Takeo, Miyajima Akira, Oya Mototsugu

Molecular Cancer Therapeutics 14 ( 9 ) 2112 - 2120 2015.09

ISSN 1535-7163

Continued smoking is highly associated with not only a higher incidence but also greater risk of tumor recurrence, progression, and acquired chemoresistance of urothelial carcinoma. We investigated whether nicotine affects urothelial carcinoma, and the detailed mechanism by which nicotine could induce tumor growth and any associated chemoresistance. Cell viability was evaluated in the human bladder cancer cell line T24 exposed to nicotine with or without cisplatin (CDDP) and NVP-BEZ235 as a PI3K/mTOR dual inhibitor by the WST-1 assay. Protein expression of the PI3K/Akt/mTOR pathway was investigated by Western blotting or immunohistochemical analysis. The influence of nicotine on tumor growth was also evaluated with or without CDDP and/or NVP-BEZ235 in a subcutaneous bladder tumor model. The result demonstrated that cell proliferation was increased in T24 cells after exposure to nicotine. Phospho-specific Akt (pAkt) and phospho-specific p70 S6 kinase (pS6) were significantly upregulated by nicotine exposure. Tumor growth in vivo was significantly induced by nicotine exposure in accordance with increased pS6 expression. Nicotine attenuated inhibition of T24 cell growth by CDDP and further upregulated pS6 expression in vitro and in vivo. NVP-BZE235 inhibited T24 cell proliferation and pAkt and pS6 expression induced after exposure to nicotine and/or CDDP. In conclusion, nicotine increases tumor growth and induces acquired chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer.

Access to Document (DOI)

Renin-angiotensin system blockade

Miyajima Akira, Kosaka Takeo, Kikuchi Eiji, Oya Mototsugu

International Journal of Urology 22 ( 8 ) 721 - 730 2015.08

ISSN 0919-8172

Angiotensin II is a key biological peptide in the renin-angiotensin system that regulates blood pressure and renal hemodynamics, and extensive experimental studies have shown that angiotensin II promotes diverse fibrotic changes and induces neovascularization in several inflammatory diseases. It is known that angiotensin II can be controlled using renin-angiotensin system blockade when angiotensin II is the main factor inducing a particular disease, and renin-angiotensin system blockade has assumed a central role in the treatment of inflammatory nephritis, cardiovascular disorders and retinopathy. In contrast, renin-angiotensin system blockade was found to have not only these effects but also other functions, such as inhibition of cancer growth, angiogenesis and metastasis. Numerous studies have sought to elucidate the mechanisms and support these antitumor effects. However, a recent meta-analysis showed that renin-angiotensin system blockade use might in fact increase the incidence of cancer, so renin-angiotensin system blockade use has become somewhat controversial. Although the renin-angiotensin system has most certainly made great contributions to experimental models and clinical practice, some issues still need to be resolved. The present review discusses the contribution and controversy surrounding the renin-angiotensin system up to the present time.

Access to Document (DOI)

Impact of Combined Use of Blood-based Inflammatory Markers on Patients with Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Shirotake Suguru, Miyazaki Yasumasa, Kobayashi Hiroaki, Kaneko Gou, Hagiwara Masayuki, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Kosaka Takeo, Hara Satoshi, Nakagawa Ken, Jinzaki Masahiro, Oya Mototsugu

European Urology Focus 1 ( 1 ) 54 - 63 2015.08

Background: Previous studies showed the prognostic impact of preoperative levels of neutrophil-to-lymphocyte ratio (NLR), plasma fibrinogen, and serum C-reactive protein (CRP) in surgically treated upper tract urothelial carcinoma; however, few papers have discussed the proper use of these indices. Objective: To investigate whether combinations of these three markers, as a cumulative marker score (CMS), improve the accuracy of prognostic models following radical nephroureterectomy (RNU). Design, setting, and participants: A total of 394 patients from multiple institutions were included. Median follow-up was 30 mo. Intervention: All patients underwent RNU without neoadjuvant chemotherapy. Outcome measurements and statistical analysis: Associated outcomes were assessed using multivariate analysis. The CMS was defined as the number of elevated levels of preoperative NLR, plasma fibrinogen, and serum CRP. Results and limitations: Multivariate analyses revealed that an increasing CMS was independently associated with high rates of disease recurrence, cancer-specific mortality, and all-cause mortality following RNU. Addition of the CMS to a model that included standard clinicopathologic predictors significantly improved predictive accuracy by 2.7% for disease recurrence, 3.9% for cancer-specific mortality, and 4.0% for all-cause mortality, which were the highest among other prognostic models using each marker alone or combinations of two. The study is limited by its retrospective nature. Conclusions: Although the use of each inflammatory marker alone may be as predictive as clinicopathologic indices for prognosis, combinations like CMS can provide more accurate prognostic models following RNU. Patient summary: Elevation of blood-based inflammatory markers may be useful for predicting prognosis because of their low cost and accessibility. Among blood-based indices, we examined the efficacy of preoperative neutrophil-to-lymphocyte ratio, plasma fibrinogen, and serum C-reactive protein levels. Although use of each marker alone provides additional prognostic information, the combination of all three markers would be more predictive than any single marker or combinations of two.

Access to Document (DOI)

Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke

Ishida Masaru, Mikami Shuji, Shinojima Toshiaki, Kosaka Takeo, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Okada Yasunori, Oya Mototsugu

International Journal of Cancer 137 ( 2 ) 299 - 310 2015.07

ISSN 0020-7136

Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through MatrigelTM were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down-regulated CYPs, and inhibited cancer cell invasion together with the down-regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.

Access to Document (DOI)

Intravesical dual PI3K/mTOR complex 1/2 inhibitor NVP-BEZ235 therapy in an orthotopic bladder cancer model

Matsushima Masashi, Kikuchi Eiji, Matsumoto Kazuhiro, Hattori Seiya, Takeda Toshikazu, Kosaka Takeo, Miyajima Akira, Oya Mototsugu

International Journal of Oncology 47 ( 1 ) 377 - 383 2015.07

ISSN 1019-6439

NVP-BEZ235 is an inhibitor of both phosphati-dylinositol 3-kinase (PI3K) and mammalian target of rapamycin complex 1/2 (mTORCl/2), and its antitumor activity is expected to be higher than that of mTORCl inhibitors because it inhibits the upregulation of pAkt through mTORC2. We examined the efficacy of intravesical NVP-BEZ235 therapy in the treatment of bladder cancer using an orthotopic bladder cancer model. The cytotoxic effects of various concentrations of NVP-BEZ235 in MBT-2 cells were examined using a WST assay. The expression of pAkt, pS6 and p4EBPl was evaluated in MBT-2 cells treated with NVP-BEZ235 using western blotting. Orthotopic models were established by implanting MBT-2 cells into the bladders of female C3H/He mice. We assigned C3H/He mice to 2 groups: a control group treated with vehicle control (n=15), and a group intravesically administered 40 μM (18.78 mg/1) of NVP-BEZ235 (n=15). NVP-BEZ235 inhibited the viability of MBT-2 cells in a dose-dependent manner. Furthermore, the expression of pAkt, pS6, and p4EBPl was inhibited in NVP-BEZ235-treated MBT-2 cells. Bladder weights were significantly lower in the NVP-BEZ235-treated group than in the control group (P<0.05). An analysis of the tumor tissues revealed that the NVP-BEZ235 treatment strongly reduced pAkt, pS6 and p4EBPl levels. An immunohistochemical analysis showed that NVP-BEZ235 significantly inhibited the expression of pS6. Intravesically administered NVP-BEZ235 exerted significant antitumor effects in the orthotopic bladder cancer model by inhibiting the PI3K/Akt/mTOR pathway. The intravesical instillation of a dual PI3K/mTORC1/2 inhibitor may represent a novel therapy for the treatment of bladder cancer.

Access to Document (DOI)

Coincident detection of lung metastasis of prostate cancer and primary lung cancer

Muro Yusuke, Kosaka Takeo, Hato Tai, Mikami Shuji, Oya Mototsugu

Canadian Urological Association Journal 9 ( 7-8 ) E524 - E526 2015.07

ISSN 1920-1214

We report an extremely rare case of 79-year-old man, who was discovered with coincidental lung metastasis of prostate cancer and primary lung cancer. The patient presented with low prostatespecific antigen and two lung lesions: one in the right lower lobe, and one in the right upper lobe, 3 years after he was treated with external beam radiotherapy for Gleason score 4+3=7, cT3aN0M0 prostate cancer. A computed tomography-guided needle biopsy of a nodule in the right lower lobe revealed suspicious metastasis of prostate cancer. Thoracoscopic excisions of both lesions were performed, and each lung lesion was diagnosed as being metastatic prostate cancer and primary lung cancer.

Access to Document (DOI)

Predictive factors for severe and febrile neutropenia during docetaxel chemotherapy for castration-resistant prostate cancer

Shigeta Keisuke, Kosaka Takeo, Yazawa Satoshi, Yasumizu Yota, Mizuno Ryuichi, Nagata Hirohiko, Shinoda Kazunobu, Morita Shinya, Miyajima Akira, Kikuchi Eiji, Nakagawa Ken, Hasegawa Shintaro, Oya Mototsugu

International Journal of Clinical Oncology 20 ( 3 ) 605 - 612 2015.06

ISSN 1341-9625

Background: The aim of this study is to identify factors that increase the occurrence of severe neutropenia (SN) and febrile neutropenia (FN) during docetaxel treatment for castration-resistant prostate cancer (CRPC). Methods: We retrospectively reviewed 258 courses during the first three cycles among 95 patients. Docetaxel at a dose of 75 mg/m2 was administered every 3 or 4 weeks. Patient background, laboratory data, and bone scan results were collected to assess predictive factors for SN and FN. We defined SN as an absolute neutrophil count (ANC) of <500/mm3 and defined FN as an ANC of <1000/mm3 with a body temperature of >38.3 °C. Results: The mean age of the patients was 72.6 ± 6.4 years and the mean prostate-specific antigen was 135.4 ± 290.9 ng/ml. During the first three courses of treatment, SN occurred in 72.6 % of patients and FN occurred in 9.5 % of patients. Univariate analysis demonstrated that age ≥75 years (p = 0.002), number of comorbidities ≥1.2 (p = 0.008 and p = 0.006) and previous external beam radiation therapy (EBRT) (p = 0.001) were predictive factors for the development of SN or FN. In multivariate analysis, significant predictors of SN or FN were age ≥75 years (hazard ratio [HR] 5.77; p = 0.004) and previous EBRT (HR 14.5; p = 0.012). According to the subgroup analysis dividing SN and FN separately, multivariate analysis also revealed that age ≥75 years and previous EBRT were also significant predictors for developing SN (HR 5.09; p = 0.023, HR 12.7; p = 0.020, respectively) and for developing FN (HR 5.45; p = 0.042, HR 7.72; p = 0.015, respectively). Conclusions: Patients aged ≥75 years and with a history of localized radiation therapy are at higher risk for significant neutropenic events and require closer surveillance.

Access to Document (DOI)

Efficacy of treatment with a GnRH antagonist in prostate cancer patients previously treated with a GnRH agonist

Ezaki Taisuke, Kosaka Takeo, Mizuno Ryuichi, Shinojima Toshiaki, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

Cancer Chemotherapy and Pharmacology 76 ( 2 ) 301 - 306 2015.06

ISSN 0344-5704

Purpose: The efficacy of switching from a GnRH agonist to a GnRH antagonist for prostate cancer patients resistant to treatment with the GnRH agonist has not been fully characterized yet. We aimed to evaluate the efficacy of the switch to a GnRH antagonist in patients with PSA failure after hormonal therapy with a GnRH agonist. Methods: We retrospectively examined 18 patients with prostate cancer who received androgen-deprivation therapy and who were treated with a GnRH antagonist (degarelix) after they showed an elevated PSA while on GnRH agonist therapy. We evaluated the characteristics of the patients and analyzed some clinical factors for their potential association with the patient response to the switch. Results: The median PSA at the switch was 7.9 (0.37-1709) ng/ml, and the median testosterone level was 0.17 (<0.08-0.81) ng/ml. Three months after the switch, the median PSA level was 11.3 (0.22-2636) ng/ml, and the median testosterone level was 0.14 (<0.08-0.23) ng/ml. The PSA decreased in six patients (33.3 %) 1 month after the switch, and in three of them it decreased by more than 50 % by 3 months after the switch. Univariate analyses revealed that the lower number of prior treatment lines for prostate cancer before the switch was associated with a favorable decrease in PSA. Conclusions: Switching from GnRH agonist to GnRH antagonist therapy was effective for some prostate cancer patients with PSA failure. The small number of prior treatment lines for prostate cancer before the switch was significantly associated with a good PSA response.

Access to Document (DOI)

Evaluation of histopathological findings at the injection site following degarelix administration

Maeda Takahiro, Kosaka Takeo, Honda Aki, Okata Utako, Hayakawa Nozomi, Ito Yujiro, Nagata Hirohiko, Chen Ko Ron, Nakamura So, Oya Mototsugu

Supportive Care in Cancer 23 ( 5 ) 1377 - 1381 2015.05

ISSN 0941-4355

Purpose: The aims of the present study were to investigate the incidence of injection site reactions (ISRs) following administration of 240 mg degarelix and identify the risk factors for ISRs. Methods: This study was conducted in 50 consecutive men treated with degarelix for the first time. ISRs after an initial degarelix dose of 240 mg (administered subcutaneously as two 3 ml subcutaneous injection) were evaluated using the five categories of the Common Terminology Criteria for Adverse Events Version 4 of the National Cancer Institute. We also assessed the differences in patient background between patients with and without an ISR. Results: The mean age of patients and prostate-specific antigen (PSA) level just before degarelix administration were 75.6 and 198.4 ng/ml, respectively. Hormonal therapy with degarelix was administered for the first time to 33 patients; 11 of the 50 patients were receiving an oral steroid, 6 for prostate cancer, 1 for hematological disease, and 4 for allergic conditions. ISRs were observed in 25 patients, and all of the ISRs were categorized as grade 1 or 2; however, 2 patients discontinued this procedure due to the ISR. Significant differences in the first experience with subcutaneous therapy (p = 0.007) and rate of combination with a steroid (p = 0.017) were observed between patients with and without ISRs. Conclusion: The incidences of ISRs in patients receiving subcutaneous therapy for the first time and in patients also receiving an oral steroid were 64 and 18 %, respectively. Patients should be provided with information concerning the possible occurrence of ISR due to degarelix prior to the administration, particularly patients who are not receiving steroids and patients who have no experience with subcutaneous injections.

Access to Document (DOI)

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.

Access to Document (DOI)

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

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.

Access to Document (DOI)

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.

Access to Document (DOI)

Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer

Nozawa Masahiro, Mukai Hirofumi, Takahashi Shunji, Uemura Hiroji, Kosaka Takeo, Onozawa Yusuke, Miyazaki Jun, Suzuki Kazuhiro, Okihara Koji, Arai Yoichi, Kamba Tomomi, Kato Masashi, Nakai Yasutomo, Furuse Hiroshi, Kume Haruki, Ide Hisamitsu, Kitamura Hiroshi, Yokomizo Akira, Kimura Takahiro, Tomita Yoshihiko, Ohno Keiji, Kakehi Yoshiyuki

International Journal of Clinical Oncology 20 ( 5 ) 1026 - 1034 2015.03

ISSN 1341-9625

Background: We previously reported the pharmacokinetic profile and preliminary tolerability of cabazitaxel in a phase I study in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). Here we report the final safety profile and anti-tumor activity of cabazitaxel in a larger population, including all patients enrolled in the expansion cohort of the study. Methods: Japanese patients with mCRPC previously treated with docetaxel received cabazitaxel intravenously every 3 weeks plus daily prednisolone. In patients treated with the maximum tolerated dose of 25 mg/m² we evaluated adverse events including treatment-related neutropenia, prostate-specific antigen (PSA) response and objective response. Results: In total, 44 patients were treated with the maximum tolerated dose. The most frequent adverse events (any grade) were neutropenia (100 %), febrile neutropenia (54.5 %), fatigue (54.5 %), nausea (52.3 %) and diarrhea (50.0 %). There were no deaths due to treatment-related adverse events. Neutropenia with prior docetaxel did not appear to influence the probability of febrile neutropenia with cabazitaxel. Most patients received therapeutic granulocyte colony-stimulating factor (G-CSF; cycle 1: 86.4 %; cycle 2 or later: 81.8 %). In the efficacy population, two of 12 patients with measurable disease had partial response (objective response rate: 16.7 %), while 10 had stable disease. PSA response rate was 29.3 % (12/41 patients). Median time to PSA progression was 3.68 months (95 % confidence interval 1.35–4.63). Conclusions: In this heavily pretreated Japanese population, the occurrence of neutropenia and febrile neutropenia was high, suggesting G-CSF prophylaxis may be required as part of toxicity management. However, the efficacy of cabazitaxel was consistent with global studies. ClinicalTrials.gov identifier: NCT01324583.

Access to Document (DOI)

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.

Access to Document (DOI)

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

[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

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.

Access to Document (DOI)

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

Research paper (scientific journal), ISSN 0039-128X

Access to Document (DOI)

A Multi-Institutional Validation of the Prognostic Value of the Neutrophil-to-Lymphocyte Ratio for Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy

Tanaka, Nobuyuki, Kikuchi, Eiji, Kanao, Kent, Matsumoto, Kazuhiro, Shirotake, Suguru, Miyazaki, Yasumasa, Kobayashi, Hiroaki, Kaneko, Gou, Hagiwara, Masayuki, Ide, Hiroki, Obata, Jun, Hoshino, Katsura, Hayakawa, Nozomi, Kosaka, Takeo, Hara, Satoshi, Oyama, Masafumi, Momma, Tetsuo, Nakajima, Yosuke, Jinzaki, Masahiro, Oya, Mototsugu

ANNALS OF SURGICAL ONCOLOGY 21 ( 12 ) 4041 - 4048 2014.11

Research paper (scientific journal), ISSN 1068-9265

Access to Document (DOI)

Independent Predictors for Bladder Outcomes after Treatment of Intravesical Recurrence following Radical Nephroureterectomy in Patients with Primary Upper Tract Urothelial Carcinoma

Tanaka, Nobuyuki, Kikuchi, Eiji, Kanao, Kent, Matsumoto, Kazuhiro, Shirotake, Suguru, Kobayashi, Hiroaki, Miyazaki, Yasumasa, Ide, Hiroki, Obata, Jun, Hoshino, Katsura, Hayakawa, Nozomi, Hagiwara, Masayuki, Kosaka, Takeo, Oyama, Masafumi, Miyajima, Akira, Momma, Tetsuo, Nakagawa, Ken, Jinzaki, Masahiro, Hasegawa, Shintaro, Nakajima, Yosuke, Oya, Mototsugu

ANNALS OF SURGICAL ONCOLOGY 21 ( 9 ) 3151 - 3158 2014.09

Research paper (scientific journal), ISSN 1068-9265

Access to Document (DOI)

Prognostic value of preoperative multiparametric magnetic resonance imaging (MRI) for predicting biochemical recurrence after radical prostatectomy

Hattori, Seiya, Kosaka, Takeo, Mizuno, Ryuichi, Kanao, Kent, Miyajima, Akira, Yasumizu, Yota, Yazawa, Satoshi, Nagata, Hirohiko, Kikuchi, Eiji, Mikami, Shuji, Jinzaki, Masahiro, Nakagawa, Ken, Tanimoto, Akihiro, Oya, Mototsugu

BJU INTERNATIONAL 113 ( 5 ) 741 - 747 2014.05

Research paper (scientific journal), ISSN 1464-4096

Access to Document (DOI)

Metastatic behavior of upper tract urothelial carcinoma after radical nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Kobayashi Hiroaki, Ide Hiroki, Miyazaki Yasumasa, Obata Jun, Hoshino Katsura, Shirotake Suguru, Akita Hirotaka, Kosaka Takeo, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Hasegawa Shintaro, Nakajima Yosuke, Jinzaki Masahiro, Oya Mototsugu

Annals of Surgical Oncology 21 ( 3 ) 1038 - 1045 2014.03

ISSN 1068-9265

Purpose: To investigate the site-specific pattern of disease recurrence and/or metastasis and the associated patient outcomes after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). Methods: A total of 733 patients with UTUC from a retrospective multi-institutional cohort were included, with a median follow-up of 34 months. Associated patient outcomes were analyzed by multivariate analysis. To evaluate the influence of primary tumor location, we divided it into four areas: renal pelvis, and upper, middle, and lower ureter. Results: A total of 218 patients experienced disease recurrence, with the majority of relapses occurring within the first 3 years. Cumulative incidence rates of first disease recurrence at 1 and 3 years were 18.9 and 29.8 %, respectively. Of these patients, 38.5 % developed distant recurrence; 17.4 % experienced both local and distant recurrences; and 44.0 % developed isolated local recurrence. The predominant sites of distant metastasis were lung, liver, and bone. Multivariate analysis revealed that the prevalence of local recurrence and lung metastasis was significantly associated, with primary tumor location being independent of other clinicopathological variables. Lower/middle ureter tumors had a higher rate of local recurrence in the pelvic cavity, and renal pelvic tumors had a higher prevalence of distant relapse in the lungs. Similar results were obtained when rerunning the data set by excluding patients who received adjuvant chemotherapy (n = 131). Conclusions: This multi-institutional study provided a detailed picture of metastatic behavior after RNU, and primary tumor locations were associated with unique patterns of metastatic spread in UTUC patients.

Access to Document (DOI)

Metastatic Behavior of Upper Tract Urothelial Carcinoma After Radical Nephroureterectomy: Association with Primary Tumor Location

Tanaka, Nobuyuki, Kikuchi, Eiji, Kanao, Kent, Matsumoto, Kazuhiro, Kobayashi, Hiroaki, Ide, Hiroki, Miyazaki, Yasumasa, Obata, Jun, Hoshino, Katsura, Shirotake, Suguru, Akita, Hirotaka, Kosaka, Takeo, Miyajima, Akira, Momma, Tetsuo, Nakagawa, Ken, Hasegawa, Shintaro, Nakajima, Yosuke, Jinzaki, Masahiro, Oya, Mototsugu

ANNALS OF SURGICAL ONCOLOGY 21 ( 3 ) 1038 - 1045 2014.03

Research paper (scientific journal), ISSN 1068-9265

Access to Document (DOI)

Safety and efficacy of teneligliptin

Otsuki Hideo, Kosaka Takeo, Nakamura Kenzo, Shimomura Fumihiko, Kuwahara Yoshitaka, Tsukamoto Takuji

International Urology and Nephrology 46 ( 2 ) 427 - 432 2014.02

ISSN 0301-1623

Purpose: Teneligliptin is a novel DPP-4 inhibitor in development for treating type 2 diabetes mellitus that does not require dose adjustment for diabetic patients with end-stage renal disease; however, it had not been known whether or not teneligliptin is safe or potent in dialysis patients. We conducted a prospective study to assess the utility of teneligliptin for diabetic patients undergoing hemodialysis. Methods: Blood glucose, glycated albumin, and HbA1c were measured every 4 weeks, at 4, 12, 20, and 28 weeks, and every 8 weeks, respectively, for patients treated with teneligliptin (n = 14; 7 patients newly started and 7 that switched from other medications) and patients of a control group who continued ongoing antidiabetic therapy (n = 29). Results: Blood glucose level showed a 36.7 mg/dl decrease from 4 weeks in the teneligliptin group (p < 0.05). The differences in glycated albumin (at 28 w) and HbA1c (at 24 w) between the teneligliptin group and the control group were -3.1 % (p < 0.05) and -0.57 % (p = 0.057), respectively. These parameters also decreased in patients who switched from voglibose 0.2 mg t.i.d. or vildagliptin 50 mg qd after teneligliptin administration. No case with hypoglycemia was identified. One patient had the dose of a laxative administered for constipation increased; however, no patient ceased teneligliptin due to side effects. Conclusion: Teneligliptin 20 mg is well tolerated, safe, and significantly improves glycemic control in diabetic patients with end-stage renal disease. Teneligliptin 20 mg once daily was considered to be more potent than voglibose 0.2 mg t.i.d. or vildagliptin 50 mg qd.

Access to Document (DOI)

The predictive value of positive urine cytology for outcomes following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Shirotake Suguru, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Kosaka Takeo, Oyama Masafumi, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Jinzaki Masahiro, Nakajima Yosuke, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 32 ( 1 ) 2014.01

ISSN 1078-1439

Background and objective: Few studies have addressed the predictive value of positive urine cytology for prognosis in patients with upper tract urothelial carcinoma (UTUC). We investigated whether the status of preoperative urine cytology could provide additional prognostic information following radical nephroureterectomy (RNU). Materials and methods: The study included 474 patients with primary nonmetastatic UTUC (pTa-4N0M0) from a retrospective multi-institutional cohort. The median follow-up period was 35 months. Associations between the status of urine cytologic evaluation and outcomes were analyzed using multivariate Cox regression models. Urine cytology was evaluated preoperatively using voided samples. Disease recurrence was defined as any relapse in nonbladder lesions and was coded separately from intravesical recurrence. Results: Positive urine cytology was detected in 184 patients (38.8%) preoperatively. Disease recurrence occurred in 127 patients, while intravesical recurrence occurred in 219 patients; 83 patients died of UTUC during follow-up. Kaplan-Meier analysis revealed that only the incidence of intravesical recurrence was significantly associated with the status of urine cytologic evaluation (P = 0.024); the intravesical recurrence-free survival rates at 1 and 3 years following RNU were 61.4% and 46.2% in patients with positive urine cytology and 71.1% and 51.6% in their counterparts, respectively. Multivariate analysis showed that gender (hazard ratio [HR] = 1.74, 95% confidence interval [CI]; 1.28-2.43), tumor multifocality in RNU specimens (HR = 1.64, 95% CI; 1.09-2.47), and positive urine cytology (HR = 1.41, 95% CI; 1.08-1.85) were independent risk factors for subsequent intravesical recurrence. Conclusions: The results showed the prognostic value of positive urine cytology in patients with primary UTUC, and preoperative positive urine cytology may be associated with a significant increase in the prevalence of intravesical recurrence following RNU.

Access to Document (DOI)

Dual PI3K/mTOR Inhibitor NVP-BEZ235 Sensitizes Docetaxel in Castration Resistant Prostate Cancer

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

JOURNAL OF UROLOGY 191 ( 1 ) 227 - 234 2014.01

Research paper (scientific journal), ISSN 0022-5347

Access to Document (DOI)

The predictive value of positive urine cytology for outcomes following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma: A multi-institutional study

Tanaka, Nobuyuki, Kikuchi, Eiji, Kanao, Kent, Matsumoto, Kazuhiro, Shirotake, Suguru, Kobayashi, Hiroaki, Miyazaki, Yasumasa, Ide, Hiroki, Obata, Jun, Hoshino, Katsura, Hayakawa, Nozomi, Kosaka, Takeo, Oyama, Masafumi, Miyajima, Akira, Momma, Tetsuo, Nakagawa, Ken, Jinzaki, Masahiro, Nakajima, Yosuke, Oya, Mototsugu

UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS 32 ( 1 ) 247 - 251 2014.01

Research paper (scientific journal), ISSN 1078-1439

Access to Document (DOI)

Dual PI3K/mTOR inhibitor NVP-BEZ235 sensitizes docetaxel in castration resistant prostate cancer

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

Journal of Urology 191 ( 1 ) 227 - 234 2014.01

ISSN 0022-5347

Purpose: Effective therapeutic strategies that can achieve long-term improvement in patients with castration resistant prostate cancer are urgently needed. We recently reported that the activated PI3K/Akt/mTOR signaling pathway induced by docetaxel explains resistance to docetaxel in castration resistant prostate cancer. In this study we explored the efficacy of NVP-BEZ235, a dual PI3K and mTORC1/2 inhibitor, for docetaxel resistant castration resistant prostate cancer. Materials and Methods: We used the 2 human castration resistant prostate cancer cell lines C4-2 and C4-2AT6. At our laboratory C4-2AT6 cells were established from C4-2 under androgen ablated treatment for 6 months. We investigated the efficacy of NVP-BEZ235 monotherapy and NVP-BEZ235 combined with docetaxel in vitro and in vivo. Results: Increased phosphorylated Akt in C4-2AT6 cells was significantly inhibited by NVP-BEZ235 in a dose and time dependent manner. WST cell proliferation assay results in C4-2AT6 cells revealed that combined administration of NVP-BEZ235 and docetaxel had significant, synergistically greater cytotoxicity than NVP-BEZ235 or docetaxel monotherapy. Combined NVP-BEZ235 (40 mg/kg) and docetaxel (4 mg/kg) in vivo in a castrated mouse xenograft model inhibited C4-2AT6 tumor growth to a greater degree than in the monotherapy groups. Also, NVP-BEZ235 showed significant efficacy with docetaxel at a low concentration in vivo, suggesting that NVP-BEZ235 effectively decreased resistance to docetaxel. Conclusions: Results suggest that inhibition of the PI3K/Akt/mTOR signaling pathway by NVP-BEZ235 can overcome docetaxel resistance in human castration resistant prostate cancer. Our findings provide a molecular basis for the clinical use of combined administration of NVP-BEZ235 and docetaxel in patients with castration resistant prostate cancer.

Access to Document (DOI)

The predictive value of C-reactive protein for prognosis in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Shirotake Suguru, Kanao Kent, Matsumoto Kazuhiro, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Ito Yujiro, Kosaka Takeo, Kodaira Kiichiro, Oyama Masafumi, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Ueno Munehisa, Oya Mototsugu

European Urology 65 ( 1 ) 227 - 234 2014.01

ISSN 0302-2838

Background: Few studies have discussed the prognostic impact of serum C-reactive protein (CRP) level in upper tract urothelial carcinoma (UTUC). Objective: To investigate whether the perioperative level of CRP provides additional prognostic information following radical nephroureterectomy (RNU). Design, setting, and participants: A total of 564 patients with UTUC from a retrospective multi-institutional cohort were included. The median follow-up was 32 mo. Intervention: All patients underwent RNU without neoadjuvant chemotherapy, while 106 patients (18.8%) received adjuvant chemotherapy. Outcome measurements and statistical analysis: Associations between perioperative CRP level and outcome were assessed using multivariate analysis. A serum CRP level >0.50 mg/dl was defined as elevated. Results and limitations: Preoperative CRP (pre-CRP) level was elevated in 136 patients (24.1%). Multivariate analysis showed that pre-CRP elevation was an independent predictor of subsequent disease recurrence (hazard ratio [HR]: 1.47 for CRP 0.51-2.00; HR: 1.89 for CRP >2.00). Five-year recurrence-free survival rates were 69.2% in patients with pre-CRP levels ≤0.50 mg/dl, 54.3% in patients with pre-CRP levels between 0.51 and 2.00 mg/dl, and 35.4% in patients with pre-CRP levels >2.00 mg/dl (p < 0.001). Similar results were found in cancer-specific mortality, showing that pre-CRP elevation was an independent predictor of worse outcome (HR: 1.74 for CRP 0.51-2.00; HR: 2.31 for CRP >2.00). In a subgroup analysis of the elevated pre-CRP group, postoperative normalisation of CRP level was an independent predictor of better outcome. This study is limited by its retrospective nature as well as its heterogeneous group of patients and variable follow-up protocols resulting from the multi-institution design. Conclusions: Serum CRP may become a possible biomarker in UTUC, suggesting that patients with an elevated pre-CRP level could be predicted to have subsequent disease recurrence and cancer-specific mortality, while postoperative normalisation of CRP level was an independent predictor for prognosis.

Access to Document (DOI)

Ureteral metastasis from prostate cancer

Hongo Hiroshi, Kosaka Takeo, Yoshimine Shunsuke, Oya Mototsugu

BMJ Case Reports 2014 2014

A 59-year-old man had an elevated prostate-specific antigen (PSA) concentration (439 ng/mL) in December 2008. We diagnosed prostatic adenocarcinoma by prostate needle biopsy. CT and MRI showed a prostatic tumour with bone and lymph node metastases. Combined androgen blockade therapy reduced the PSA level temporarily. After the PSA level gradually started to increase again and reached 27.27 ng/mL in October 2010, the patient was diagnosed with castration-resistant prostate cancer and treated with docetaxel chemotherapy. Radiological examination detected left hydronephrosis and a tumour in the left lower ureter in March 2011. Retrograde pyelography and urine cytology of class 3 from the left ureter indicated that the ureteral mass was a urothelial carcinoma. A left nephroureterectomy was performed. After the operation, the pathological examination showed a metastatic prostate carcinoma, accompanied by a decrease in the serum PSA level from 59.56 to 45.33 ng/mL.

Access to Document (DOI)

Complete response to bicalutamide withdrawal prolonged for almost 2 years in patients with metastatic prostate cancer

Hongo Hiroshi, Kosaka Takeo, Oya Mototsugu

Urology Case Reports 2 ( 5 ) 150 - 151 2014

ISSN 2214-4420

This is the first case report describing a complete response to bicalutamide withdrawal that lasted for almost 2years in a patient with metastatic prostate cancer. An 80-year-old man who had prostate-specific antigen (PSA) level elevation (168.1ng/mL) visited our hospital in February 2010. Bone scintigraphy showed pelvic metastases. We started hormonal therapy with leuprorelin and bicalutamide. The PSA concentration decreased to <0.1ng/mL but started increasing again and reached 1.64ng/mL in October 2012, at which time bicalutamide administration was discontinued. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2years.

Access to Document (DOI)

Independent predictors for bladder outcomes after treatment of intravesical recurrence following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Shirotake Suguru, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Hagiwara Masayuki, Kosaka Takeo, Oyama Masafumi, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Jinzaki Masahiro, Hasegawa Shintaro, Nakajima Yosuke, Oya Mototsugu

Annals of Surgical Oncology 21 ( 9 ) 3151 - 3158 2014

ISSN 1068-9265

Background. Few studies have described the clinical courses and outcomes in the bladder after treatment of intravesical recurrence after radical nephroureterectomy (RNU) in patients with primary upper tract urothelial carcinoma (UTUC). We investigated the indicators for predicting subsequent bladder outcomes after treatment of intravesical recurrence after RNU. Methods. A total of 241 patients with primary UTUC (pTa-4N0M0) who experienced intravesical recurrence after RNU were included. Of these patients, 101 (41.9 %) underwent Bacillus Calmette-Guérin treatments, whereas 49 (20.3 %) underwent intravesical chemotherapy. The median follow-up period after initial transurethral resection of the bladder tumor was 33 months. Relationships with bladder outcomes were analyzed by using multivariable analysis. Results. Ninety-six patients experienced intravesical recurrence, and bladder progression was observed in 13. Cumulative incidence rates of intravesical recurrence at 1 and 5 years after treatment of the first intravesical recurrence were 31.0 and 48.4 %, whereas those of bladder progression at 1 and 5 years thereafter were 2.4 and 8.0 %. Multivariate analysis showed that the number of recurrent tumors and pT1 tumors at the time of the first intravesical relapse were independent risk factors for subsequent intravesical recurrence. With respect to bladder progression, multivariate analysis showed that pT1 tumors, the appearance of concomitant carcinoma-in situ at the time of the first intravesical relapse, and the absence of the Bacillus Calmette-Guérin treatment were independent risk factors. Conclusions. This retrospective study presents a detailed picture of further bladder outcomes after intravesical recurrence after RNU in primary UTUC patients. The results may assist physicians to develop a more rational protocol in bladder surveillance.

Access to Document (DOI)

Invasion and metastasis of renal cell carcinoma

Mikami Shuji, Oya Mototsugu, Mizuno Ryuichi, Kosaka Takeo, Katsube Ken Ichi, Okada Yasunori

Medical Molecular Morphology 47 ( 2 ) 63 - 67 2014

ISSN 1860-1480

Renal cell carcinoma (RCC) represents over 80 % of kidney cancer, and about 30 % of the patients with RCC develop metastasis after the surgery. Invasion of basement membrane (BM) and extracellular matrix (ECM) is an essential event in tumor invasion and metastasis. Matrix metalloproteinases (MMPs), which digest the main components of BM and ECM, are expressed in RCC. Heparanase, which degrades heparan sulfate proteoglycans, is predominantly expressed in high-grade RCCs with a positive correlation with pathological tumor stage and poor prognosis. Bone metastasis is common among the patients with RCC, and increased osteoclastic activity was observed at metastatic sites. Receptor activator of nuclear factor κB ligand (RANKL), which plays an important role in osteoclastogenesis, is predominantly expressed in high-grade RCC and its expression level is associated with bone metastasis and prognosis. Epithelial-mesenchymal transition (EMT), a switch of epithelial cells to sarcomatoid phenotype, is considered to be critical step during metastasis, and Snail, a major regulator of EMT, is predominantly expressed in high-grade RCC, and high Snail expression is a worse prognostic factor. Accordingly, heparanase, RANKL and Snail may be targets for the development of anti-tumor therapies for RCCs.

Access to Document (DOI)

Is DHT production by 5a-reductase friend or foe in prostate cancer?

Kosaka Takeo, Miyajima Akira, Oya Mototsugu

2014

ISSN 2234-943X

The first advance in the history of studies on prostate cancer (PCa) and androgens was the development of treatment with castration and administration of estrogen by Charles B. Huggins, who won the Nobel Prize in Physiology and Medicine. Since then, and for 70 years, androgen deprivation therapy has been the standard therapy for advanced PCa and the center of studies on PCa. However, recent advances have shed light on the relationship between androgens and the development or the progression of PCa. The use of 5AR inhibitors to prevent progression of PCa continues to be widely discussed. Discussion has been fueled by the findings of two large randomized, placebo-controlled trials: the Prostate Cancer Prevention Trial with finasteride and the Reduction by Dutasteride of Prostate Cancer Events trial. Does the development of PCa or progression to castration-resistant PCa depend on dihydrotestosterone (DHT)? Here, we summarize and discuss recent topics of local androgen production of DHT in PCa.

Malignant lymphoma of mucosa-associated lymphoid tissue involving the renal pelvis and the entire ureter

Otsuki Hideo, Ito Keiichi, Sato Ken, Kosaka Takeo, Shimazaki Hideyuki, Kaji Tatsumi, Asano Tomohiko

Oncology Letters 5 ( 5 ) 1625 - 1628 2013.10

ISSN 1792-1074

Mucosa-associated lymphoid tissue (MALT) lymphoma occurs in various sites, but rarely in the urinary tract. Imaging studies of a 69-year-old male revealed a left hydronephrosis and diffuse thickening of the renal pelvic and upper ureteral wall. Retrograde pyelography revealed a narrowing in this region, and brush cytology specimens contained atypical cells. As the lesion was considered to be malignant, surgical excision was performed. Histological analysis revealed an intense lymphoid infiltrate mainly consisting of B cells. The immunohistochemistry results demonstrated that the lesion was positive for CD20 and CD79a and negative for CD5 and cyclin D1. These findings led to a diagnosis of MALT lymphoma. Pathological exploration disclosed a focally dense invasion of lymphoma cells into not only the renal pelvis, but the whole ureteral wall and surrounding tissue; therefore, the patient underwent eight courses of rituximab treatment. Diffuse invasion of lymphoma cells into the whole ureter was rarely observed. Since the surgery, the patient has survived for 78 months without evidence of a recurrence of lymphoma.

Access to Document (DOI)

Editorial Comment to Circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy

Kosaka Takeo

International Journal of Urology 20 ( 10 ) 979 2013.10

ISSN 0919-8172

Access to Document (DOI)

Identification of drug candidate against prostate cancer from the aspect of somatic cell reprogramming

Kosaka, Takeo, Nagamatsu, Go, Saito, Shigeru, Oya, Mototsugu, Suda, Toshio, Horimoto, Katsuhisa

CANCER SCIENCE 104 ( 8 ) 1017 - 1026 2013.08

Research paper (scientific journal), ISSN 1347-9032

Access to Document (DOI)

Patient characteristics and outcomes in metastatic upper tract urothelial carcinoma after radical nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Shirotake Suguru, Hayakawa Nozomi, Kosaka Takeo, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Hasegawa Shintaro, Nakajima Yosuke, Oya Mototsugu

BJU International 112 ( 2 ) 2013.07

ISSN 1464-4096

Objectives To investigate oncological outcomes and prognostic factors in patients with upper tract urothelial carcinoma (UTUC) who experienced disease recurrence after radical nephroureterectomy (RNU). Few studies have focused on the clinical courses of patients who experienced disease recurrence after RNU. Patients and Methods A total of 204 UTUC patients who experienced disease recurrence from a retrospective multi-institutional cohort were included in the present study. Associated patient outcomes were analyzed using multivariate analysis. Results The mean time from RNU to first disease recurrence was 15.0 months and ≈90% of patients experienced disease recurrence within the first 3 years after RNU. During a median follow-up of 8.1 month after disease recurrence, 165 patients died from UTUC and five patients died from other causes. In the 204 cohorts, 1- and 3-year cancer-specific survival rates were 40.2% and 9.7%, respectively, and 1- and 3-year overall survival rates were 39.5% and 9.4%, respectively. After disease recurrence, 132 patients underwent systemic chemotherapy, and a subgroup analysis of patients who underwent systemic chemotherapy multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently prognostic of cancer-specific and overall survival after relapsing. According to three significant variables, 1- and 3-year cancer-specific survival rates were 72.7% and 20.8% in patients with no risk factors, 46.5% and 7.5% in patients with one risk factor, and 26.4% and 4.4% in patients with two or three risk factors, respectively (P < 0.001). Conclusions Most patients died from UTUC within 3 years, even though systemic chemotherapies were administered after relapsing. Multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently related to poor survival after systemic chemotherapy.

Access to Document (DOI)

Patient characteristics and outcomes in metastatic upper tract urothelial carcinoma after radical nephroureterectomy: the experience of Japanese multi-institutions

Tanaka, Nobuyuki, Kikuchi, Eiji, Kanao, Kent, Matsumoto, Kazuhiro, Kobayashi, Hiroaki, Miyazaki, Yasumasa, Ide, Hiroki, Obata, Jun, Hoshino, Katsura, Shirotake, Suguru, Hayakawa, Nozomi, Kosaka, Takeo, Miyajima, Akira, Momma, Tetsuo, Nakagawa, Ken, Hasegawa, Shintaro, Nakajima, Yosuke, Oya, Mototsugu

BJU INTERNATIONAL 112 ( 2 ) E28 - E34 2013.07

Research paper (scientific journal), ISSN 1464-4096

Access to Document (DOI)

Prognostic significance of Bcl-xL expression and efficacy of Bcl-xL targeting therapy in urothelial carcinoma

Yoshimine S., Kikuchi E., Kosaka T., Mikami S., Miyajima A., Okada Y., Oya M.

British Journal of Cancer 108 ( 11 ) 2312 - 2320 2013.06

ISSN 0007-0920

Background: Bcl-xL has an important role in the control of cell death through its inhibition of apoptosis. The aim of this study was to investigate the clinicopathological significance of Bcl-xL in upper urinary tract urothelial carcinoma (UTUC) and the therapeutic effect of targeting Bcl-xL protein in urothelial carcinoma (UC) cells. Methods: We evaluated the immunohistochemical expression of Bcl-xL in 175 UTUC patients to determine the clinical role of BclxL expression in clinical outcome. We used bafilomycin A1 (BMA) as a specific inhibitor of Bcl-xL to examine the biological effects in UC cells in vitro and in vivo. Results: Immunohistochemical analysis of Bcl-xL expression revealed that patients with a high Bcl-xL score had a significantly lower 5-year cancer-specific survival (CSS) rate (53.2%) than those with a low Bcl-xL score (77.2%) (P = 0.0011). Multivariate analysis indicated that a high Bcl-xL score was an independent prognostic factor of CSS (P = 0.023). BMA inhibited UMUC-3 cell proliferation in vitro by induction of apoptosis. Treatment with BMA significantly inhibited tumour growth in UMUC-3 tumours in this mouse xenograft model accompanied by an elevated apoptosis induction. Conclusion: Bcl-xL appears to be a significant molecular marker for the prognosis of UTUCs. Targeting Bcl-xL may be a promising therapeutic strategy for patients with UC.

Access to Document (DOI)

The prognostic significance of vasohibin-1 expression in patients with prostate cancer

Kosaka T., Miyazaki Y., Miyajima A., Mikami S., Hayashi Y., Tanaka N., Nagata H., Kikuchi E., Nakagawa K., Okada Y., Sato Y., Oya M.

British Journal of Cancer 108 ( 10 ) 2123 - 2129 2013.05

ISSN 0007-0920

Background:We recently isolated vasohibin-1 (VASH1), a novel angiogenic molecule that is specifically expressed in activated vascular endothelial cells (ECs), and the status of VASH1 expression has been documented in various cancer angiogenesis. The aim of this study was to assess the prognostic value of VASH1 expression in prostate cancer (PCa).Methods:In this study, we retrospectively analysed the clinical records and evaluated the VASH1 expression of tumour microvessels in 167 patients with PCa who underwent radical prostatectomy. We immunohistochemically examined the microvessels positive for anti-CD34 as microvessel density (MVD) and the microvessels with activated ECs positive for VASH1 density.Results:We found that the VASH1 expression was restricted to ECs in the tumour stroma. VASH1 density was significantly associated with pathological T stage, Gleason score and MVD. The 5-year PSA recurrence-free survival rate was 58.8% in patients with higher VASH1 density (≧12 per mm 2) and 89.1% in patients with lower VASH1 density (<12 per mm 2), respectively (P<0.001). Microvessel density was not an independent predictor of PSA recurrence. Multivariate analysis revealed that high VASH1 density was an independent prognostic indicator of PSA recurrence (P=0.007, HR=2.950).Conclusion:VASH1 density represents a clinically relevant predictor of patient prognosis and can be a new biomarker that would provide additional prognostic information in PCa.

Access to Document (DOI)

Malignant lymphoma of mucosa-associated lymphoid tissue involving the renal pelvis and the entire ureter: A case report

Otsuki, Hideo, Ito, Keiichi, Sato, Ken, Kosaka, Takeo, Shimazaki, Hideyuki, Kaji, Tatsumi, Asano, Tomohiko

ONCOLOGY LETTERS 5 ( 5 ) 1625 - 1628 2013.05

Research paper (scientific journal), ISSN 1792-1074

Access to Document (DOI)

Efficacy and safety of docetaxel-based chemotherapy in Japanese men over 80 years old with castration-resistant prostate cancer.

Kosaka, Takeo, Yasumizu, Yota, Mizuno, Ryuichi, Miyajima, Akira, Kikuchi, Eiji, Shinya, Morita, Kono, Hidaka, Nakagawa, Ken, Oya, Mototsugu

JOURNAL OF CLINICAL ONCOLOGY 31 ( 15 ) 287 - 295 2013.05

Research paper (international conference proceedings), ISSN 0732-183X

How can lymphocele development be prevented after laparoscopic radical prostatectomy?

Yasumizu Yota, Miyajima Akira, Maeda Takahiro, Takeda Toshikazu, Hasegawa Masanori, Kosaka Takeo, Kikuchi Eiji, Oya Mototsugu

Journal of Endourology 27 ( 4 ) 447 - 451 2013.04

ISSN 0892-7790

Objectives: Lymphocele development is the most frequently reported postoperative complication of pelvic lymph node dissection (PLND) performed with laparoscopic radical prostatectomy (LRP). This study evaluated the efficacy of a vessel-sealing device (VSD) for the prevention of lymphocele development. Methods: A total of 120 patients who underwent LRP with PLND were prospectively enrolled. The patients were randomly assigned to one of the two groups: PLND using a conventional technique (group 1), and PLND performed with VSD (group 2). All patients underwent computed tomography (CT) scanning 1 month postoperatively to evaluate the maximum sectional area of the lymphoceles. Results: Lymphoceles developed in 63 cases (52.5%). One case (0.8%) was symptomatic with infection, and drainage tube placement was required. In the other 62 patients, the lymphoceles developed asymptomatically and were detected by CT scanning. There was no significant difference in the lymphocele development ratio between the two groups. However, when we defined a lymphocele over 1500 mm² as being a significant size, lymphoceles were present in 16 of 60 patients in group 1 and 4 of 60 patients in group 2. The incidence of significant lymphoceles over 1500 mm² in the group using VSD was much lower than that of the group without VSD (p<0.01). Multivariate analysis demonstrated that VSD was the only independent factor that had an effect on preventing the development of lymphoceles over 1500 mm² (p<0.01, odds ratio=4.96). Conclusion: The results indicate that the development of large lymphoceles can be prevented by using VSD in LRP with PLND.

Access to Document (DOI)

How Can Lymphocele Development Be Prevented After Laparoscopic Radical Prostatectomy?

Yasumizu, Yota, Miyajima, Akira, Maeda, Takahiro, Takeda, Toshikazu, Hasegawa, Masanori, Kosaka, Takeo, Kikuchi, Eiji, Oya, Mototsugu

JOURNAL OF ENDOUROLOGY 27 ( 4 ) 447 - 451 2013.04

Research paper (scientific journal), ISSN 0892-7790

Access to Document (DOI)

Induction of pluripotent stem cells from primordial germ cells by single reprogramming factors

Nagamatsu Go, Kosaka Takeo, Saito Shigeru, Honda Hiroaki, Takubo Keiyo, Kinoshita Taisuke, Akiyama Hideo, Sudo Tetsuo, Horimoto Katsuhisa, Oya Mototsugu, Suda Toshio

Stem Cells 31 ( 3 ) 479 - 487 2013.03

ISSN 1066-5099

Germ cells are similar to pluripotent stem cells in terms of gene expression patterns and the capacity to convert to pluripotent stem cells in culture. The factors involved in germ cell development are also able to reprogram somatic cells. This suggests that germ cells are useful tools for investigating the mechanisms responsible for somatic cell reprograming. In this study, the expression of reprograming factors in primordial germ cells (PGCs) was analyzed. PGCs expressed Oct3/4, Sox2, and c-Myc but not Klf4. However, Klf2, Klf5, Essrb, or Essrg, which were expressed in PGCs, could compensate for Klf4 during somatic cell reprograming. Furthermore, PGCs could be converted to a pluripotent state by infection with any of the known reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc). These cells were designated as multipotent PGCs (mPGCs). Contrary to differences in the origins of somatic cells in somatic cell reprogramming, we hypothesized that the gene expression levels of the reprogramming factors would vary in mPGCs. Candidate genes involved in the regulation of tumorigenicity and/or reprogramming efficiency were identified by comparing the gene expression profiles of mPGCs generated by the exogenous expression of c-Myc or L-Myc.

Access to Document (DOI)

β3-Adrenoceptor agonist mirabegron is effective for overactive bladder that is unresponsive to antimuscarinic treatment or is related to benign prostatic hyperplasia in men

Otsuki Hideo, Kosaka Takeo, Nakamura Kenzo, Mishima Junnji, Kuwahara Yoshitaka, Tsukamoto Takuji

International Urology and Nephrology 45 ( 1 ) 53 - 60 2013.02

ISSN 0301-1623

Purpose To investigate the safety and efficacy of mirabegron for patients with overactive bladder (OAB) that is unresponsive to antimuscarinic agents or is related to benign prostatic hyperplasia (BPH). Methods Fifty-two newly diagnosed OAB patients (M group) and 45 patients with OAB that was unresponsive to antimuscarinics (S group) received mirabegron 50 mg once daily and were evaluated by OAB symptom score (OABSS), IPSS-QOL index, and IPSS at the time of baseline, 4 and 8 weeks. Newly diagnosed OAB patients treated with antimuscarinic agents were compared as controls. Results Mirabegron was effective for 85.2 % in M group. Significant improvements were seen in each domain of OABSS, and there was no significant difference with antimuscarinic therapy. Mirabegron was efficacious for 61.6 % of S group, and significant decreases of OABSS and IPSS-QOL index were observed. Significant improvements were also seen in voiding symptoms in men. Post-void residual urine volumes before and after treatment were 32.1 and 34.8 ml, and 26.2 and 31.3 ml in M and S group, respectively, and there was no significant difference. The incidence of adverse events was 8.4 %, although none were serious, and the patients recovered spontaneously after mirabegron was discontinued. Conclusion The present study suggests mirabegron is as effective as antimuscarinics for OAB. It improves OAB symptoms in patients with OAB for which antimuscarinic agents are insufficient. This study revealed that mirabegron improves not only OAB symptoms related to BPH, but also voiding symptoms in men. Low and mild incidences of side effects support the safe utility of mirabegron.

Access to Document (DOI)

Human castration resistant prostate cancer rather prefer to decreased 5 alpha-reductase activity

Kosaka, Takeo, Miyajima, Akira, Nagata, Hirohiko, Maeda, Takahiro, Kikuchi, Eiji, Oya, Mototsugu

SCIENTIFIC REPORTS 3 247 - 251 2013.02

Research paper (scientific journal), ISSN 2045-2322

Access to Document (DOI)

beta 3-Adrenoceptor agonist mirabegron is effective for overactive bladder that is unresponsive to antimuscarinic treatment or is related to benign prostatic hyperplasia in men

Otsuki, Hideo, Kosaka, Takeo, Nakamura, Kenzo, Mishima, Junnji, Kuwahara, Yoshitaka, Tsukamoto, Takuji

INTERNATIONAL UROLOGY AND NEPHROLOGY 45 ( 1 ) 53 - 60 2013.02

Research paper (scientific journal), ISSN 0301-1623

Access to Document (DOI)

Does laparoendoscopic single-site adrenalectomy increase surgical risk in patients with pheochromocytoma?

Hattori, Seiya, Miyajima, Akira, Maeda, Takahiro, Hasegawa, Masanori, Takeda, Toshikazu, Kosaka, Takeo, Kikuchi, Eiji, Nakagawa, Ken, Oya, Mototsugu

SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES 27 ( 2 ) 593 - 598 2013.02

Research paper (scientific journal), ISSN 0930-2794

Access to Document (DOI)

Human castration resistant prostate cancer rather prefer to decreased 5α-reductase activity

Kosaka Takeo, Miyajima Akira, Nagata Hirohiko, Maeda Takahiro, Kikuchi Eiji, Oya Mototsugu

Scientific Reports 3 2013

Physiologically relevant steroid 5α-reductase (SRD5A) activity that is essential for dihydrotestosterone (DHT) biosynthesis in human castration-resistant prostate cancer (CRPC) has not been fully characterized yet. In this study to ascertain the potential SRD5A activity, we cultured two human CRPC cell lines, C4-2 and C4-2AT6, with the steroid precursor: ¹³C-[2,3,4]-androstenedione (¹³C-Adione), and analyzed the sequential biosynthesis of ¹³C-[2,3,4]-testosterone ( ¹³C-T) and ¹³C-[2,3,4]-DHT (¹³C-DHT) by liquid chromatography/mass spectrometry (LC/MS/MS). The ¹³C-DHT/ ¹³C-T concentration ratio detected by LC/MS/MS in C4-2AT6 cells appeared to reflect the SRD5A activity. The ratio in C4-2AT6 was significantly lower than that in C4-2. An increased concentration of DHT did not have a positive effect on cell proliferation, rather it exhibited inhibitory effects. 5α-reductase inhibitors did not have any inhibitory effect at clinically achievable concentrations. These results indicate that CRPC cells may have an unknown regulation system to protect themselves from an androgenic suppressive effect mediated by SRD5A activity.

Access to Document (DOI)

Risk factors for perioperative complications of laparoscopic adrenalectomy including single-site surgery

Hattori Seiya, Miyajima Akira, Maeda Takahiro, Hasegawa Masanori, Takeda Toshikazu, Kosaka Takeo, Kikuchi Eiji, Nakagawa Ken, Shibata Hirotaka, Oya Mototsugu

Journal of Endourology 26 ( 11 ) 1463 - 1467 2012.11

ISSN 0892-7790

Purpose: To determine predictive factors for perioperative complications of laparoscopic adrenalectomy (LA) including single-site surgery performed or supervised by experienced laparoscopic surgeons. Patients and Methods: We retrospectively reviewed 265 consecutive unilateral LAs performed at a single institution from 2001 to 2011. All surgical procedures were performed or supervised by one of two experienced laparoscopic surgeons. The transabdominal approach was used in 248 patients, while a retroperitoneal approach was used in 17 patients. Laparoendoscopic single-site adrenalectomy was performed in 58 patients. Predictive factors for postoperative complications were analyzed. Results: There were no postoperative deaths. At least one postoperative complication occurred in 12 (4.6%) patients. No patient underwent reoperation for a complication. Only one (0.4%) patient's procedure was converted to open surgery, and only this patient needed a blood transfusion during the operation. One patient who underwent laparoendoscopic single-site adrenalectomy had the procedure converted to conventional laparoscopic adrenalectomy. Multivariable logistic regression analysis showed that an American Society of Anesthesiologists-physical status grade 3 or above was the only predictive factor for perioperative complications. Conclusion: American Society of Anesthesiologists-physical status grade 3 or above was a statistically significant factor for perioperative complications associated with laparoscopic adrenalectomy that involved laparoendoscopic single-site adrenalectomy, which was performed or supervised by an experienced laparoscopic surgeon. According to the findings of this retrospective study, single-site operation, obesity, adrenal tumor size, and tumor type may not be considered as risk factors for perioperative complications after LA performed or supervised by an experienced laparoscopic surgeon.

Access to Document (DOI)

[The molecular mechanisms of resistance to androgen deprivation therapy in prostate cancer].

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 8 353 - 359 2012.11

ISSN 0047-1852

Risk Factors for Perioperative Complications of Laparoscopic Adrenalectomy Including Single-Site Surgery

Hattori, Seiya, Miyajima, Akira, Maeda, Takahiro, Hasegawa, Masanori, Takeda, Toshikazu, Kosaka, Takeo, Kikuchi, Eiji, Nakagawa, Ken, Shibata, Hirotaka, Oya, Mototsugu

JOURNAL OF ENDOUROLOGY 26 ( 11 ) 1463 - 1467 2012.11

Research paper (scientific journal), ISSN 0892-7790

Access to Document (DOI)

Prognostic value of renin-angiotensin system blockade in non-muscle-invasive bladder cancer

Yuge Kazuyuki, Miyajima Akira, Tanaka Nobuyuki, Shirotake Suguru, Kosaka Takeo, Kikuchi Eiji, Oya Mototsugu

Annals of Surgical Oncology 19 ( 12 ) 3987 - 3993 2012.11

ISSN 1068-9265

Background. To determine whether the administration of renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), affect disease outcome in non-muscle-invasive bladder cancer (NMIBC). Methods. A total of 330 patients with initially diagnosed NMIBC were identified. We retrospectively investigated the clinical outcomes after transurethral resection of bladder tumor (TUR-BT) in patients who did or did not receive RAS inhibitors. The median follow-up period was 4.1 years. Results. A total of 128 patients (38.8 %) experienced subsequent tumor recurrence, and stage progression was observed in 17 patients (5.2 %) during follow-up. Fifty-one patients (15.5 %) had received ACEI or ARB administration at transurethral resection. Multivariate analysis demonstrated that tumor multiplicity, absence of bacillus Calmette-Guérin instillation, and no administration of ACEI or ARB (P = 0.010, hazard ratio 2.26) were independent risk factors for subsequent tumor recurrence. The 5-year recurrence-free survival rate was 78.4 % in patients administered ACEIs or ARBs, and 53.3 % in their counterparts (P = 0.011). Conclusions. The absence of RAS inhibitor administration was an independent risk factor for subsequent tumor recurrence in patients with initially diagnosed NMIBC. Our data support further investigation of the role of RAS inhibitors as a potential therapy to decrease tumor recurrence in NMIBC.

Access to Document (DOI)

Optimal ratio of transcription factors for somatic cell reprogramming

Nagamatsu Go, Saito Shigeru, Kosaka Takeo, Takubo Keiyo, Kinoshita Taisuke, Oya Mototsugu, Horimoto Katsuhisa, Suda Toshio

Journal of Biological Chemistry 287 ( 43 ) 36273 - 36282 2012.10

ISSN 0021-9258

Somatic cell reprogramming is achieved by four reprogramming transcription factors (RTFs), Oct3/4, Sox2, Klf4, and c-Myc. However, in addition to the induction of pluripotent cells, these RTFs also generate pseudo-pluripotent cells, which do not show Nanog promoter activity. Therefore, it should be possible to fine-tune the RTFs to produce only fully pluripotent cells. For this study, a tagging system was developed to sort induced pluripotent stem (iPS) cells according to the expression levels of each of the four RTFs. Using this system, the most effective ratio (Oct3/4-high, Sox2-low, Klf4-high, c-Myc-high) of the RTFs was 88 times more efficient at producing iPS cells than the worst effective ratio (Oct3/4-low, Sox2-high, Klf4-low, c-Myclow). Among the various RTF combinations, Oct3/4-high and Sox2-low produced the most efficient results. To investigate the molecular basis, microarray analysis was performed on iPS cells generated under high (Oct3/4-high and Sox2-low) and low (Oct3/4-low and Sox2-high) efficiency reprogramming conditions. Pathway analysis revealed that the G protein-coupled receptor (GPCR) pathway was up-regulated significantly under the high efficiency condition and treatment with the chemokine, C-C motif ligand 2, a member of the GPCR family, enhanced somatic cell reprogramming 12.3 times. Furthermore, data from the analysis of the signature gene expression profiles of mouse embryonic fibroblasts at 2 days after RTF infection revealed that the genetic modifier, Whsc1l1 (variant 1), also improved the efficiency of somatic cell reprogramming. Finally, comparison of the overall gene expression profiles between the high and low efficiency conditions will provide novel insights into mechanisms underlying somatic cell reprogramming.

Access to Document (DOI)

Metastatic urothelial carcinoma to pericardia manifested by dyspnea from cardiac tamponade during systemic chemotherapy

Hattori Seiya, Miyajima Akira, Maeda Takahiro, Takeda Toshikazu, Morita Shinya, Kosaka Takeo, Kikuchi Eiji, Oya Mototsugu

Journal of the Canadian Urological Association 6 ( 5 ) 2012.10

ISSN 1911-6470

A 53-year-old man presented for further evaluation due to microscopic hematuria and left lumbar pain. Computed tomography revealed a large tumour in the left renal pelvis with multiple metastases. Despite effective systemic chemotherapy, he developed dyspnea, and was diagnosed with cardiac tamponade. Pericardial involvement in an advanced malignancy is common, but symptomatic cardiac metastasis from urothelial carcinoma is rare. Of the reports of symptomatic cardiac metastasis from urothelial carcinoma, only 3 cases presented as cardiac tamponade. We report here a rare case of cardiac tamponade caused by a renal pelvic carcinoma with positive cytodiagnosis of pericardial effusion. We also summarize and discuss the symptoms, treatment, and prognosis of the pathological condition, and present a brief review of previously published reports.

Access to Document (DOI)

Optimal Ratio of Transcription Factors for Somatic Cell Reprogramming

Nagamatsu, Go, Saito, Shigeru, Kosaka, Takeo, Takubo, Keiyo, Kinoshita, Taisuke, Oya, Mototsugu, Horimoto, Katsuhisa, Suda, Toshio

JOURNAL OF BIOLOGICAL CHEMISTRY 287 ( 43 ) 36273 - 36282 2012.10

Research paper (scientific journal), ISSN 0021-9258

Access to Document (DOI)

Does pelvic lymph node dissection improve the biochemical relapse-free survival in low-risk prostate cancer patients treated by laparoscopic radical prostatectomy?

Daimon Tatsuaki, Miyajima Akira, Maeda Takahiro, Hattori Seiya, Yasumizu Yota, Hasegawa Masanori, Kosaka Takeo, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Journal of Endourology 26 ( 9 ) 1199 - 1202 2012.09

ISSN 0892-7790

Background and Purpose: The roles and criteria for pelvic lymph node dissection (PLND) are not fully evaluated in patients with low-risk prostate cancer who are treated by laparoscopic radical prostatectomy (LRP). In this study, the outcome of PLND was assessed in terms of the biochemical relapse-free survival rates of low-risk prostate cancer patients who had undergone LRP. Patients and Methods: Included were 286 consecutive patients who were treated with LRP without previous endocrine therapy between 2002 and 2006 at our institution. Failure rates for LRP were compared in 139 patients with low-risk prostate cancer between those who underwent PLND (n=85) and those who did not (n=54). Biochemical relapse-free survival for each group was estimated by Kaplan-Meier analysis. Results: The mean number of retrieved lymph nodes was 5.4±0.4 (range 2-22). The 5- and 7-year biochemical relapse-free survival rates were 90.1% and 88.3% in patients with PLND, and 82.4% and 82.4% in those without PLND (P=0.278), respectively (median follow-up 69.4 mos). None of the 85 patients undergoing PLND had positive lymph nodes. Only one patient had symptomatic lymphocele, and he was treated as an inpatient. The average time needed for PLND was 16 minutes, which corresponded to 7% of the entire operative time. Conclusion: These results indicate that the dissection of pelvic lymph nodes is not related to biochemical relapse-free survival. The omission of PLND in patients with low-risk prostate cancer not only does not adversely affect biochemical relapse-free survival, but might decrease the incidence of complication and operative time of LRP.

Access to Document (DOI)

Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma

Ide, Hiroki, Kikuchi, Eiji, Hasegawa, Masanori, Kozakai, Norihide, Kosaka, Takeo, Miyajima, Akira, Oya, Mototsugu

BMC CANCER 12 763 - 770 2012.09

Research paper (scientific journal), ISSN 1471-2407

Access to Document (DOI)

The prognostic significance of vasohibin-1 expression in patients with upper urinary tract urothelial carcinoma

Miyazaki Yasumasa, Kosaka Takeo, Mikami Shuji, Kikuchi Eiji, Tanaka Nobuyuki, Maeda Takahiro, Ishida Masaru, Miyajima Akira, Nakagawa Ken, Okada Yasunori, Sato Yasufumi, Oya Mototsugu

Clinical Cancer Research 18 ( 15 ) 4145 - 4153 2012.08

ISSN 1078-0432

Purpose: Vasohibin-1 (VASH1) is a novel angiogenic molecule that is specifically expressed in activated vascular endothelial cells, and the status of VASH1 expression has been documented in cancer angiogenesis. The aim of this study was to address the prognostic value of VASH1 expression in upper urinary tract urothelial carcinomas (UTUC). Experimental Design: We retrospectively analyzed the clinical records of 171 patients with locally advanced UTUC (Ta-3N0M0). The median follow-up period was 3.8 years. We immunohistochemically examined the accomplished microvessels with anti-CD34 as microvessel density (MVD) and the microvessels with activated endothelial cells as VASH1 density. Then, we analyzed the association between immunohistochemical expression and clinical outcomes. Results: Forty-two patients experienced tumor recurrence and of these 34 died of the disease during follow-up. VASH1 density was significantly associated with tumor grade, pathologic T stage, and MVD. The 5-year recurrence-free and cancer-specific survival rates were 66.1% and 72.8% in patients with VASH1 density (≥ 40/mm²) and 81.0% and 86.5% in their counterparts, respectively (P < 0.05). MVD was not an independent predictor of tumor recurrence or cancer-specific survival. Multivariate analyses revealed that high VASH1 density was an independent prognostic indicator of both tumor recurrence (P = 0.024, HR = 2.10) and cancer-specific survival (P = 0.031, HR = 2.23) as well as other standard prognostic factors including high tumor grade and lymphovascular invasion. Conclusions: VASH1 density represents a clinically relevant predictor of patient prognosis in UTUC. The results suggest that VASH1 density could become a new biomarker and provide additional prognostic information in patients with UTUC.

Access to Document (DOI)

Renal cell carcinoma arising from a horseshoe kidney in a chronic hemodialysis patient

Miyazaki Yasumasa, Miyajima Akira, Maeda Takahiro, Ito Yujiro, Tanaka Nobuyuki, Kosaka Takeo, Masuda Aya, Mizuno Ryuichi, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Clinical and Experimental Nephrology 16 ( 4 ) 647 - 651 2012.08

ISSN 1342-1751

A 60-year-old man undergoing hemodialysis for 13 years was referred to our department for evaluation of gross hematuria and a right renal mass. Voided urine cytology was negative. Computed tomography and magnetic resonance imaging demonstrated a right renal mass (32 × 22 × 20 mm in diameter). We clinically diagnosed the tumor as renal cell carcinoma staged T1aN0M0 arising from a horseshoe kidney, and performed right heminephrectomy. Pathological examination of the surgical specimen showed a grade 2, pT1a, clear cell carcinoma and negative surgical margin. To our knowledge, this is a rare case of a renal cell carcinoma arising from a horseshoe kidney in a chronic hemodialysis patient.

Access to Document (DOI)

A case of spinal and bulbar muscular atrophy with high-stage and high-gleason score prostate cancer responded to maximal androgen blockade therapy

Kosaka Takeo, Miyajima Akira, Kikuchi Eiji, Takahashi Shinichi, Suzuki Norihiro, Oya Mototsugu

Journal of Andrology 33 ( 4 ) 563 - 565 2012.07

ISSN 0196-3635

Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of CAG triplets in the androgen receptor. Because the length of CAG repeat is inversely related with androgen receptor function, patients with a longer CAG repeat are expected to have a lower incidence of prostate cancer. Here, we report an extremely rare case of highstage prostate cancer in a patient with spinal and bulbar muscular atrophy, which responded to maximal androgen blockade therapy.

Access to Document (DOI)

Tracing the conversion process from primordial germ cells to pluripotent stem cells in mice

Nagamatsu Go, Kosaka Takeo, Saito Shigeru, Takubo Keiyo, Akiyama Hideo, Sudo Tetsuo, Horimoto Katsuhisa, Oya Mototsugu, Suda Toshio

Biology of Reproduction 86 ( 6 ) 2012.06

ISSN 0006-3363

To understand mechanisms underlying acquisition of pluripotency, it is critical to identify cells that can be converted to pluripotent stem cells. For this purpose, we focused on unipotent primordial germ cells (PGCs), which can be reprogrammed into pluripotent embryonic germ (EG) cells under defined conditions. Treatment of PGCs with combinations of signaling inhibitors, including inhibitors of MAP2K (MEK), GSK3B (GSK-3beta), and TGFB (TGFbeta) type 1 receptors, induced cells to enter a pluripotent state at a high frequency (12.1%) by Day 10 of culture. When we employed fluorescence-activated cell sorting to monitor conversion of candidate cells to a pluripotent state, we observed a cell cycle shift to S phase, indicating enrichment of pluripotent cells, during the early phase of EG formation. Transcriptome analysis revealed that PGCs retained expression of some pluripotent stem cell-associated genes, such as Pou5f1 and Sox2, during EG cell formation. On the other hand, PGCs lost their germ lineage characteristics and acquired expression of pluripotent stem cell markers, such as Klf4 and Eras. The overall gene expression profiles revealed by this system provide novel insight into how pluripotency is acquired in germcommitted cells.

Access to Document (DOI)

Tracing the Conversion Process from Primordial Germ Cells to Pluripotent Stem Cells in Mice

Nagamatsu, Go, Kosaka, Takeo, Saito, Shigeru, Takubo, Keiyo, Akiyama, Hideo, Sudo, Tetsuo, Horimoto, Katsuhisa, Oya, Mototsugu, Suda, Toshio

BIOLOGY OF REPRODUCTION 86 ( 6 ) 1443 - 1458 2012.06

Research paper (scientific journal), ISSN 0006-3363

Access to Document (DOI)

Extrapancreatic solid pseudopapillary tumor

Miyazaki Yasumasa, Miyajima Akira, Maeda Takahiro, Yuge Kazuyuki, Hasegawa Masanori, Kosaka Takeo, Kikuchi Eiji, Kameyama Kaori, Jinzaki Masahiro, Nakagawa Ken, Oya Mototsugu

International Journal of Clinical Oncology 17 ( 2 ) 165 - 168 2012.04

ISSN 1341-9625

A 22-year-old woman complained of abdominal discomfort. Ultrasonography, computed tomography, and an endocrinologic work-up revealed a 7-cm nonfunctional tumor at the left adrenal lesion. A transumbilical laparo-endoscopic single-site adrenalectomy was successfully completed in 166 min. The postoperative period was uneventful. The pathologic examination confirmed the solid pseudopapillary tumor occurred in the retroperito-neum. There are only five previous reports of extrapan-creatic solid pseudopapillary tumors. In this case, the tumor was separated from the pancreas and no ectopic pancreas was histologically observed. To the best of our knowledge, this case is the first report of a solid pseudopapillary tumor of the retroperitoneum.

Access to Document (DOI)

ACQUIRED PLATINUM RESISTANCE INDUCES ANGIOGENIC AGGRESSIVENESS THROUGH UPREGULATION OF ANGIOTENSIN II TYPE 1 RECEPTORS IN BLADDER CANCER

Tanaka, Nobuyuki, Miyajima, Akira, Kosaka, Takeo, Miyazaki, Yasumasa, Shirotake, Suguru, Shirakawa, Hiroshi, Kikuchi, Eiji, Oya, Mototsugu

JOURNAL OF UROLOGY 187 ( 4 ) E358 - E358 2012.04

Research paper (scientific journal), ISSN 0022-5347

Extrapancreatic solid pseudopapillary tumor: case report and review of the literature

Miyazaki, Yasumasa, Miyajima, Akira, Maeda, Takahiro, Yuge, Kazuyuki, Hasegawa, Masanori, Kosaka, Takeo, Kikuchi, Eiji, Kameyama, Kaori, Jinzaki, Masahiro, Nakagawa, Ken, Oya, Mototsugu

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 17 ( 2 ) 165 - 168 2012.04

Research paper (scientific journal), ISSN 1341-9625

Access to Document (DOI)

Transurethral resection in saline vaporization

Otsuki Hideo, Kuwahara Yoshitaka, Kosaka Takeo, Tsukamoto Takuji, Nakamura Kenzo, Shiroki Ryoichi, Hoshinaga Kiyotaka

Urology 79 ( 3 ) 665 - 669 2012.03

ISSN 0090-4295

Objective: To assess the efficacy and safety of transurethral resection in saline vaporization for symptomatic bladder outlet obstruction and the change in prostate volume. Methods: A total of 106 patients with symptomatic bladder outlet obstruction underwent transurethral resection in saline vaporization. The effectiveness of the treatment was evaluated using the International Prostate Symptom Score (IPSS), quality of life score, urinary peak flow, and prostate volume preoperatively and at 1, 3, 6, and 12 months postoperatively. To assess the treatment effect, the patients were divided into 3 groups according to the preoperative prostate volume: group 1 (≥45 cm ³, n = 40), group 2 (<45 but ≥65 cm ³, n = 34), and group 3 (<65 cm ³, n = 32). Results: The mean perioperative hemoglobin loss was 1.2 g/dL. The mean IPSS, quality of life score, and prostate volume decreased significantly from 24.3, 5.2, and 52.8 cm ³ to 11.1, 2.7, and 29.9 cm ³, respectively (P <.01) and the mean urinary peak flow had increased significantly from 7.3 to 15.1 (P <.01) at 1 month. Moreover, the IPSS, quality of life score, and prostate volume had significantly decreased to 8.8, 2.3, and 26.1 cm ³ at 3 months (P <.05). The investigation of groups classified by prostate size demonstrated that the IPSS in group 3 continued at a significantly lower level than that in groups 1 and 2. The prostate volume decreased gradually and resulted in 52.8% volume reduction for ≤12 months. No significant complications were seen; however, irritative symptoms occurred frequently (11.3%). Conclusion: Transurethral resection in saline vaporization was a safe and effective treatment option and was more efficacious for patients with a larger prostate. The bother scores and prostate volume gradually decreased for ≤12 months.

Access to Document (DOI)

Transurethral Resection in Saline Vaporization: Evaluation of Clinical Efficacy and Prostate Volume

Otsuki, Hideo, Kuwahara, Yoshitaka, Kosaka, Takeo, Tsukamoto, Takuji, Nakamura, Kenzo, Shiroki, Ryoichi, Hoshinaga, Kiyotaka

UROLOGY 79 ( 3 ) 665 - 669 2012.03

Research paper (scientific journal), ISSN 0090-4295

Access to Document (DOI)

Regulation of Monocyte Chemoattractant Protein-1 Through Angiotensin II Type 1 Receptor in Prostate Cancer

Shirotake, Suguru, Miyajima, Akira, Kosaka, Takeo, Tanaka, Nobuyuki, Kikuchi, Eiji, Mikami, Shuji, Okada, Yasunori, Oya, Mototsugu

AMERICAN JOURNAL OF PATHOLOGY 180 ( 3 ) 1008 - 1016 2012.03

Research paper (scientific journal), ISSN 0002-9440

Access to Document (DOI)

Regulation of monocyte chemoattractant protein-1 through angiotensin II type 1 receptor in prostate cancer

Shirotake Suguru, Miyajima Akira, Kosaka Takeo, Tanaka Nobuyuki, Kikuchi Eiji, Mikami Shuji, Okada Yasunori, Oya Mototsugu

American Journal of Pathology 180 ( 3 ) 1008 - 1016 2012.03

ISSN 0002-9440

Monocyte chemoattractant protein-1 (MCP-1/CCL2) is reported to contribute to tumor progression and is regulated by the renin-angiotensin system in hypertensive disease. In this study, we investigated the clinical outcome of MCP-1 expression in patients with prostate cancer (CaP) and the regulation of MCP-1 through angiotensin II (AngII) type 1 receptor (AT1R) in CaP. Specimens were obtained from 138 CaP patients and analyzed by immunostaining for both MCP-1 and macrophages. We investigated the regulation of MCP-1 expression through AT1R both in vivo and in vitro using three human prostate cancer cell lines: LNCaP, C4-2, and C4-2AT6. Specimens with a high Gleason score (<7) and a high pathological classification (≤pT3), and those with castration-resistant prostate cancer showed significantly higher MCP-1 expression and higher macrophage infiltration than low malignant potential CaP. High MCP-1 expression in CaP correlated significantly with high prostate-specific antigen (PSA) recurrence rates. AngII induced significantly higher MCP-1 levels in C4-2AT6 than in LNCaP, whereas AT1R blockade (ARB) inhibited MCP-1 production via the inhibition of the PI3K/Akt pathway in C4-2AT6. ARB also significantly suppressed MCP-1 expression in C4-2AT6 tumors. Our study is the first to demonstrate that both high MCP-1 expression and high macrophage infiltration in CaP specimens correlate with a high PSA recurrence rate and that ARB inhibits MCP-1 expression through the PI3K/Akt pathway and blocks macrophage infiltration in castration-resistant prostate cancer.

Access to Document (DOI)

Prognonstic impact of renin-angiotensin system blockade in localised upper-tract urothelial carcinoma

Tanaka N., Miyajima A., Kikuchi E., Matsumoto K., Hagiwara M., Ide H., Kosaka T., Masuda T., Nakamura S., Oya M.

British Journal of Cancer 106 ( 2 ) 290 - 296 2012.01

ISSN 0007-0920

Background: The potential role of the renin-angiotensin system (RAS) in the promotion of tumour growth has been investigated, and the administration of RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), may improve disease control in malignancy. We investigated the prognostic impact of RAS inhibitors by analysing data from patients with upper-tract urothelial carcinoma (UTUC). Methods: A total of 279 patients who underwent nephroureterectomy for localised UTUC (pTa-3N0M0) were identified at our three institutions. We retrospectively investigated the prognostic outcomes following nephroureterectomy in patients administered or not administered ACEIs or ARBs. Results: The median follow-up period was 3.4 years. RAS inhibitors were administered to 48 patients (17.2%). Multivariate analysis showed that the appearance of pathological T3, positive lymphovascular invasion, and no RAS inhibitor administration (P=0.027 HR=3.14) were independent risk factors for a decrease in subsequent metastasis-free survival. The 5-year metastasis-free survival rate was 93.0% in patients who administered RAS inhibitors, and 72.8% in their counterparts who did not (P=0.008). Conclusion: The absence of RAS inhibitor administration was an independent risk factor for subsequent tumour metastasis in patients with localised UTUC. We propose RAS inhibitors may be a potent choice as an effective treatment following nephroureterectomy.

Access to Document (DOI)

Low-dose docetaxel enhances the sensitivity of S-1 in a xenograft model of human castration resistant prostate cancer

Hasegawa, Masanori, Miyajima, Akira, Kosaka, Takeo, Yasumizu, Yota, Tanaka, Nobuyuki, Maeda, Takahiro, Shirotake, Suguru, Ide, Hiroki, Kikuchi, Eiji, Oya, Mototsugu

INTERNATIONAL JOURNAL OF CANCER 130 ( 2 ) 431 - 442 2012.01

Research paper (scientific journal), ISSN 0020-7136

Access to Document (DOI)

A Case of Spinal and Bulbar Muscular Atrophy With High-Stage and High-Gleason Score Prostate Cancer Responded to Maximal Androgen Blockade Therapy

Kosaka, Takeo, Miyajima, Akira, Kikuchi, Eiji, Takahashi, Shinichi, Suzuki, Norihiro, Oya, Mototsugu

JOURNAL OF ANDROLOGY 33 ( 4 ) 563 - 565 2012.01

Research paper (scientific journal), ISSN 0196-3635

Access to Document (DOI)

A case of angiomyolipoma of the renal sinus

Shirotake, Suguru, Yoshimura, Ichiro, Kosaka, Takeo, Matsuzaki, Shoji

CLINICAL AND EXPERIMENTAL NEPHROLOGY 15 ( 6 ) 953 - 956 2011.12

Research paper (scientific journal), ISSN 1342-1751

Access to Document (DOI)

Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type 1 receptor in bladder cancer

Tanaka N., Miyajima A., Kosaka T., Miyazaki Y., Shirotake S., Shirakawa H., Kikuchi E., Oya M.

British Journal of Cancer 105 ( 9 ) 1331 - 1337 2011.10

ISSN 0007-0920

Background: We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type 1 receptor (AT1R) after the development of acquired platinum resistance in bladder cancer. Methods: Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months. Results: Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher AT1R expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased AT1R expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of AT1R blockade at suppressing the growth of platinum-resistant xenograft model. Conclusion: Our findings indicate a new molecular mechanism for upregulated AT1R signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of AT1R blockade for platinum-resistant bladder cancers.

Access to Document (DOI)

Phosphorylated Akt up-regulates angiotensin II type-1 receptor expression in castration resistant prostate cancer

Kosaka Takeo, Miyajima Akira, Shirotake Suguru, Kikuchi Eiji, Oya Mototsugu

Prostate 71 ( 14 ) 1510 - 1517 2011.10

ISSN 0270-4137

BACKGROUND Accumulating evidences has suggested that the renin-angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that castration-resistant prostate cancer (CRPC) showed significantly higher angiotensin II (Ang II) type-1 receptor (AT1R) expression, and that AT1R blockade (ARB) exerted protective effects by inhibiting angiogenesis. However, the detailed molecular mechanisms for the increase of AT1R expression in CRPC has not been fully elucidated yet. METHODS In this study we used C4-2 and C4-2AT6 cells, which were PTEN-null, androgen receptor (AR) positive, PSA-producing CRPC cell lines. We investigated the association between phosphorylated Akt (pAkt) and AT1R expression, and used LY294002 as a PI3K/Akt inhibitor. RESULTS Western blot analysis revealed C4-2AT6 cells showed significantly higher pAkt expression than C4-2 cells, although there were no significant differences in total Akt (tAkt) expression. Immunohistochemical (IHC) analysis also revealed significant higher pAkt expression in C4-2AT6 tumors obtained from castrated male nude mice. These results indicated that C4-2AT6 cells acquired elevated pAkt status under androgen-ablated treatment in vitro. Treatment with LY294002 at the same dose reduced the viability of C4-2AT6 more effectively than that of C4-2, reflecting the dependency of cancer cells on PI3K/Akt pathway. The up-regulated AT1R expression in C4-2AT6 cells was reduced by LY294002 in a dose-dependent manner. On the other hand, in C4-2 cells, serum starvation induced pAkt up-regulation, which led to an increase of AT1R expression. CONCLUSIONS These findings indicated that up-regulation of pAkt contributed to elevated AT1R expression in CRPC.

Access to Document (DOI)

Expression of snail and slug in renal cell carcinoma

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

Laboratory Investigation 91 ( 10 ) 1443 - 1458 2011.10

ISSN 0023-6837

The Snail family transcription factors have been proposed as important mediators of epithelial-mesenchymal transition because of their role in down-regulation of E-cadherin and up-regulation of matrix metalloproteinases (MMPs). The present study was undertaken to investigate the expression of Snail, Slug and their associations with cancer invasion and prognosis in renal cell carcinomas (RCCs). Ninety-seven primary RCCs were analyzed for the protein expression of Snail, Slug, MMP2 and MMP9 by immunohistochemistry. Snail protein expression level was positively correlated with pathological tumor stage, histological grade and the presence of sarcomatoid carcinoma. On the contrary, Slug protein expression level was negatively correlated with pathological tumor stage, suggesting that Slug was down-regulated in advanced RCCs. Because Snail was positively associated with malignant potential of RCCs, involvement of Snail in the invasiveness of an RCC cell line 786-O was examined in the Matrigel invasion assay by down-regulating the gene expression with small interfering RNA (siRNA). Targeting the Snail, not Slug, expression in 786-O cells with siRNA caused down-regulation of the gene expression of Snail, vimentin, MMP2 and MMP9, but up-regulated the E-cadherin. Invasion of the cells through Matrigel in vitro was inhibited under this condition. Furthermore, expression levels of MMP2 and MMP9 were positively correlated with pathological tumor stage and the presence of sarcomatoid carcinoma. Statistical analysis indicated that elevated Snail, MMP2 and MMP9 protein expression are significantly worse predictors of disease-free and disease-specific survival of the patients with RCC. In conclusion, these data suggest that Snail has an important role in invasion and metastasis, and that silencing the gene may be a potential therapeutic target in RCCs.

Access to Document (DOI)

Expression of Snail and Slug in renal cell carcinoma: E-cadherin repressor Snail is associated with cancer invasion and prognosis

Mikami, Shuji, Katsube, Ken-Ichi, Oya, Mototsugu, Ishida, Masaru, Kosaka, Takeo, Mizuno, Ryuichi, Mukai, Makio, Okada, Yasunori

LABORATORY INVESTIGATION 91 ( 10 ) 1443 - 1458 2011.10

Research paper (scientific journal), ISSN 0023-6837

Access to Document (DOI)

Phosphorylated Akt Up-Regulates Angiotensin II Type-1 Receptor Expression in Castration Resistant Prostate Cancer

Kosaka, Takeo, Miyajima, Akira, Shirotake, Suguru, Kikuchi, Eiji, Oya, Mototsugu

PROSTATE 71 ( 14 ) 1510 - 1517 2011.10

Research paper (scientific journal), ISSN 0270-4137

Access to Document (DOI)

Long-term androgen ablation and docetaxel up-regulate phosphorylated Akt in castration resistant prostate cancer

Kosaka Takeo, Miyajima Akira, Shirotake Suguru, Suzuki Eriko, Kikuchi Eiji, Oya Mototsugu

Journal of Urology 185 ( 6 ) 2376 - 2381 2011.06

ISSN 0022-5347

Purpose: There are still few effective therapeutic options for advanced prostate cancer. One of the most troublesome aspects of prostate cancer is that androgen dependent prostate cancer inevitably progresses to highly aggressive, life threatening castration resistant prostate cancer after androgen ablation therapy. To our knowledge it remains unknown how sensitivity to docetaxel changes during progression to more aggressive castration resistant prostate cancer under androgen ablation. Materials and Methods: We investigated sensitivity to docetaxel and phosphorylated Akt status in C4-2 and C4-2AT6 cells established at our institution. Results: C4-2AT6 cells established under androgen ablation conditions for 6 months showed significantly higher resistance to docetaxel than C4-2 cells in vivo and in vitro. Resistance was accompanied by increased phosphorylated Akt. In C4-2AT6 cells phosphorylated Akt activity was significantly up-regulated by docetaxel in a dose dependent manner. After treatment with docetaxel and a phosphatidylinositol 3-kinase/Akt inhibitor the sensitivity of C4-2AT6 cells to docetaxel markedly increased through enhanced apoptotic death. Conclusions: Findings indicated that up-regulation of phosphorylated Akt during androgen ablation and its further activation by docetaxel explains at least in part the resistance to docetaxel and progression to castration resistant prostate cancer under androgen ablation conditions.

Access to Document (DOI)

Long-Term Androgen Ablation and Docetaxel Up-Regulate Phosphorylated Akt in Castration Resistant Prostate Cancer

Kosaka, Takeo, Miyajima, Akira, Shirotake, Suguru, Suzuki, Eriko, Kikuchi, Eiji, Oya, Mototsugu

JOURNAL OF UROLOGY 185 ( 6 ) 2376 - 2381 2011.06

Research paper (scientific journal), ISSN 0022-5347

Access to Document (DOI)

A case report of retroaortic left renal vein with tumor thrombus of renal cell carcinoma

Otsuki, Hideo, Kuroda, Kenji, Kosaka, Takeo, Ito, Keiichi, Hayakawa, Masamichi, Asano, Tomohiko

CLINICAL AND EXPERIMENTAL NEPHROLOGY 15 ( 3 ) 438 - 441 2011.06

Research paper (scientific journal), ISSN 1342-1751

Access to Document (DOI)

[History and current review of basic research for prostate cancer].

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 5 7 - 12 2011.06

ISSN 0047-1852

Hemodialysis case in which rcc was identified after disappearance of perirenal hematoma following spontaneous renal rupture treated by transcatheter arterial embolization

Otsuki Hideo, Ito Keiichi, Kosaka Takeo, Hamada Shinsuke, Takahashi Masahiro, Isono Makoto, Nakamura Kenzo, Kuwahara Yoshitaka, Kaji Tatsumi, Asano Tomohiko

Acta Urologica Japonica 57 ( 5 ) 247 - 250 2011.05

ISSN 0018-1994

A 55-year-old man who had been undergoing hemodialysis for 9 years visited our institution after the sudden onset of severe left flank pain. He presented with hypotension and was admitted immediately because computed tomography (CT) revealed a massive perirenal hematoma. Renal arteriography showed contrast media leakage at the lower branch of the left renal artery, and spontaneous renal rupture was diagnosed. Five months after the bleeding was stopped by selective transcatheter embolization of the branch of renal artery, CT showed an enhanced mass at the upper pole of left kidney and renal cell carcinoma (RCC) was suspected. Radical nephrectomy was performed, the pathological diagnosis was clear cell carcinoma, and the man has not experienced recurrence within 36 months after the surgery. RCC did not appear to be the cause of the original hemorrhage because there was a small residual hematoma in the middle of the renal parenchyma that was separated from the RCC. In cases of spontaneous renal rupture, re-evaluation by imaging studies is mandatory after disappearance of perirenal hematoma because imaging studies at the time of the rupture sometimes do not reveal the cause of the hemorrhage.

Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells

Kinoshita Taisuke, Nagamatsu Go, Kosaka Takeo, Takubo Keiyo, Hotta Akitsu, Ellis James, Suda Toshio

Biochemical and Biophysical Research Communications 407 ( 2 ) 321 - 326 2011.04

ISSN 0006-291X

During cell division, one of the major features of somatic cell reprogramming by defined factors, cells are potentially exposed to DNA damage. Inactivation of the tumor suppressor gene p53 raised reprogramming efficiency but resulted in an increased number of abnormal chromosomes in established iPS cells. Ataxia-telangiectasia mutated (ATM), which is critical in the cellular response to DNA double-strand breaks, may also play an important role during reprogramming. To clarify the function of ATM in somatic cell reprogramming, we investigated reprogramming in ATM-deficient (ATM-KO) tail-tip fibroblasts (TTFs). Although reprogramming efficiency was greatly reduced in ATM-KO TTFs, ATM-KO iPS cells were successfully generated and showed the same proliferation activity as WT iPS cells. ATM-KO iPS cells had a gene expression profile similar to ES cells and WT iPS cells, and had the capacity to differentiate into all three germ layers. On the other hand, ATM-KO iPS cells accumulated abnormal genome structures upon continuous passages. Even with the abnormal karyotype, ATM-KO iPS cells retained pluripotent cell characteristics for at least 20 passages. These data indicate that ATM does participate in the reprogramming process, although its role is not essential.

Access to Document (DOI)

Angiotensin II type 1 receptor expression and microvessel density in human bladder cancer

Shirotake Suguru, Miyajima Akira, Kosaka Takeo, Tanaka Nobuyuki, Maeda Takahiro, Kikuchi Eiji, Oya Mototsugu

Urology 77 ( 4 ) 2011.04

ISSN 0090-4295

Objectives: To determine whether angiotensin II type 1 receptor (AT1R) expression and tumor angiogenesis in human bladder cancer (BCa) specimens acquired by transurethral resection (TUR). It has recently been reported that AT1R is expressed in several tumors and is involved in tumor angiogenesis. However, no study has investigated AT1R expression in association with angiogenesis in clinical specimens of bladder cancer. Methods: Surgical specimens were obtained from 108 patients who had undergone TUR for bladder cancer. All specimens were pathologically diagnosed as urothelial carcinoma. AT1R expression and microvessel density (MVD) were determined by immunostaining. The clinical and pathologic characteristics were retrospectively reviewed. Results: The MVD was greater in muscle-invasive BCa (MIBC; 29 cases, 34.4 ± 4.1/0.25 mm²) than in non-MIBC (NMIBC; 79 cases, 17.4 ± 1.1/0.25 mm², P < .0001). AT1R expression was greater in the MIBC (P = .0004) and high-grade (P = .0063) specimens than in the NMIBC and low-grade specimens. In addition, the greater expression of AT1R was significantly associated with MVD (P < .05). In NMIBC, the factors significantly affecting recurrence-free survival on univariate analysis were AT1R (P = .02), MVD (P < .0001), tumor multiplicity (P = .0007), and bacille Calmette-Guérin intravesical instillation after TUR (P = .0026). Multivariate analysis revealed that tumor multiplicity and no BCG intravesical instillation after TUR were independent predictors of 5-year recurrence-free survival, and AT1R and MVD were independent predictors of 1-year recurrence-free survival (P < .01). Conclusions: AT1R expression and MVD were related to early intravesical recurrence in NMIBC. The results suggest that AT1R could become a new molecular target and a prognostic factor for NMIBC.

Access to Document (DOI)

Angiotensin II Type 1 Receptor Expression and Microvessel Density in Human Bladder Cancer

Shirotake, Suguru, Miyajima, Akira, Kosaka, Takeo, Tanaka, Nobuyuki, Maeda, Takahiro, Kikuchi, Eiji, Oya, Mototsugu

UROLOGY 77 ( 4 ) 1443 - 1458 2011.04

Research paper (scientific journal), ISSN 0090-4295

Access to Document (DOI)

Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to gnomic instability in iPS cells

Kinoshita, Taisuke, Nagamatsu, Go, Kosaka, Takeo, Takubo, Keiyo, Hotta, Akitsu, Ellis, James, Suda, Toshio

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 407 ( 2 ) 321 - 326 2011.04

Research paper (scientific journal), ISSN 0006-291X

Access to Document (DOI)

A germ cell-specific gene, Prmt5, works in somatic cell reprogramming

Nagamatsu Go, Kosaka Takeo, Kawasumi Miyuri, Kinoshita Taisuke, Takubo Keiyo, Akiyama Hideo, Sudo Tetsuo, Kobayashi Takashi, Oya Mototsugu, Suda Toshio

Journal of Biological Chemistry 286 ( 12 ) 10641 - 10648 2011.03

ISSN 0021-9258

Germ cells possess the unique ability to acquire totipotency during development in vivo as well as give rise to pluripotent stem cells under the appropriate conditions in vitro. Recent studies in which somatic cells were experimentally converted into pluripotent stem cells revealed that genes expressed in primordial germ cells (PGCs), such as Oct3/4, Sox2, and Lin28, are involved in this reprogramming. These findings suggest that PGCs may be useful for identifying factors that successfully and efficiently reprogram somatic cells into toti- and/or pluripotent stem cells. Here, we show that Blimp-1, Prdm14, and Prmt5, each of which is crucial forPGCdevelopment, have the potential to reprogram somatic cells into pluripotent stem cells. Among them, Prmt5 exhibited remarkable reprogramming of mouse embryonic fibroblasts into which Prmt5, Klf4, and Oct3/4 were introduced. The resulting cells exhibited pluripotent gene expression, teratoma formation, and germline transmission in chimeric mice, all of which were indistinguishable from those induced with embryonic stem cells. These data indicate that some of the factors that play essential roles in germ cell development are also active in somatic cell reprogramming.

Access to Document (DOI)

A Germ Cell-specific Gene, Prmt5, Works in Somatic Cell Reprogramming

Nagamatsu, Go, Kosaka, Takeo, Kawasumi, Miyuri, Kinoshita, Taisuke, Takubo, Keiyo, Akiyama, Hideo, Sudo, Tetsuo, Kobayashi, Takashi, Oya, Mototsugu, Suda, Toshio

JOURNAL OF BIOLOGICAL CHEMISTRY 286 ( 12 ) 10641 - 10648 2011.03

Research paper (scientific journal), ISSN 0021-9258

Access to Document (DOI)

Transumbilical laparo-endoscopic single site surgery for adrenal cortical adenoma inducing primary aldosteronism

Miyajima Akira, Maeda Takahiro, Hasegawa Masanori, Takeda Toshikazu, Ishida Masaru, Kosaka Takeo, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

BMC Research Notes 4 2011

Background: We have started using laparo-endoscopic single-site surgery (LESS) in urologic surgery, although its use has not gained momentum due to its level of difficulty. We here report our initial experience with transumbilical LESS for adrenal cortical adenoma by using a single port with a multichannel cannula (SILS port) and bent laparoscopic instrumentation. Findings. A multichannel port (SILS port), bent laparoscopic instrument (Roticulator Endo Mini-Shears) and Opti4 laparoscopic electrodes were used in all cases. The intraperitoneal space was approached through the umbilicus. The SILS port was placed through a 2 cm incision at the inner edge of the umbilicus. A 5 mm flexible laparoscope was introduced to keep the laparoscope outside, and surgical specimens were extracted using an Endocatch bag. In addition, as a case control study, we compared perioperative data of LESS adrenalectomy (LESS-A) with that of conventional laparoscopic adrenalectomy (LA). We performed transumbilical LESS-A for adrenal cortical adenoma in 12 cases, beginning in December, 2009. All procedures were successfully completed, with only one incision through the umbilicus, and without conversion to a standard laparoscopic approach. Mean operative time for LESS-A was 121.2± 7.8 min, which was slightly longer than LA (110.2± 7.3 min). For right adrenal tumors, we used a miniport (2 mm port) in addition to a SILS port, and were able to successfully perform adrenalectomy "with no visible scaring". Tumor laterality and patient BMI did not affect surgical morbidity in these procedures. Moreover, there was no significant difference between LESS-A and LA in blood loss, analgesic requirement, hospital stay, and scar satisfaction. Conclusions: The transumbilical approach in LESS for adrenalectomy is safe and feasible and also improves cosmetic outcome compared with standard laparoscopic procedures. Improvements in surgical devices may aid the further development of this approach.

Access to Document (DOI)

Expression of snail in upper urinary tract urothelial carcinoma

Kosaka Takeo, Kikuchi Eiji, Mikami Shuji, Miyajima Akira, Shirotake Suguru, Ishida Masaru, Okada Yasunori, Oya Mototsugu

Clinical Cancer Research 16 ( 23 ) 5814 - 5823 2010.12

ISSN 1078-0432

Purpose: There are few molecular markers known to predict upper urinary tract urothelial carcinomas (UTUC) prognosis. Snail, which contributes to epithelial-mesenchymal transition (EMT), has been documented in cancer progression, but not clear yet in UTUC. We therefore addressed the expression and biological significance of Snail in UTUC. Experimental Design: To elucidate the biological significance of Snail in UTUC, we examined the immunohistochemical expression of snail in UTUC and analyzed its clinical significance in 150 patients with UTUC. Biological effects of Snail in EMT and invasion were evaluated by using small interfering RNA (siRNA) specific for Snail in urothelial carcinoma cell lines and the Matrigel invasion assay. Results: Nuclear Snail staining was very weak in superficial UTUC. In contrast, strong Snail staining was observed in many of the nucleus of invasive UTUC. Snail expression was significantly higher in the high tumor stage, high grade, and in tumors showing lymphovascular invasion (LVI). Multivariate Cox regression analysis revealed that elevated Snail expression was a significant and an independent prognostic predictor of recurrence-free survival and cancer-specific survival. Patients with positive LVI and high Snail expression showed the worse outcome. Targeting of Snail mRNA expression in UMUC-3 cells with Snail-specific siRNA downregulated the mRNA expression of Snail, Vimentin, MMP2, and MMP9. Furthermore, the cells with siRNA for Snail showed decreased invasion activity in comparison with the cells transfected with a nontargeting siRNA. Conclusion: Snail-induced EMT represents a clinically relevant mechanism of UTUC progression and an attractive target for the treatment of patients with UTUC.

Access to Document (DOI)

Expression of Snail in Upper Urinary Tract Urothelial Carcinoma: Prognostic Significance and Implications for Tumor Invasion

Kosaka, Takeo, Kikuchi, Eiji, Mikami, Shuji, Miyajima, Akira, Shirotake, Suguru, Ishida, Masaru, Okada, Yasunori, Oya, Mototsugu

CLINICAL CANCER RESEARCH 16 ( 23 ) 5814 - 5823 2010.12

Research paper (scientific journal), ISSN 1078-0432

Access to Document (DOI)

Cis-dichlorodiammineplatinum upregulates angiotensin II type 1 receptors through reactive oxygen species generation and enhances VEGF production in bladder cancer

Tanaka Nobuyuki, Miyajima Akira, Kosaka Takeo, Shirotake Suguru, Hasegawa Masanori, Kikuchi Eiji, Oya Mototsugu

Molecular Cancer Therapeutics 9 ( 11 ) 2982 - 2992 2010.11

ISSN 1535-7163

We previously reported that angiotensin II type 1 receptor (AT1R) antagonists enhanced the cytotoxity of cis-dichlorodiammineplatinum (CDDP) in a bladder cancer xenograft model. To elucidate the synergistic mechanism, we investigated whether reactive oxygen species (ROS) generation induced by CDDP may affect the regulation of AT1R expression. Five invasive human bladder cancer cell lines, T24, UMUC-3, 5637, KU-1, and KU-19-19, were used in the in vitro study. For the in vivo study, T24 cells were used. We also examined AT1R and vascular endothelial growth factor (VEGF) expression in human bladder cancer specimens that had been treated with CDDP-based chemotherapy. The in vitro study showed that AT1R expression was significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. On the other hand, AT1R expression was not changed in UMUC-3 and 5637 cells. ROS generation was also significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. The upregulation of AT1R expression induced by CDDP was significantly suppressed by scavenging free radicals. Angiotensin II induced VEGF production in CDDP-treated cells; however, the AT1R antagonist significantly inhibited the increase in VEGF. The in vivo study results also showed that CDDP treatment upregulated AT1R expression, resulting in increased VEGF. Clinical specimens from patients who underwent cystectomy after neoadjuvant CDDP-based chemotherapy showed significantly higher AT1R and VEGF expression than corresponding transurethral resection specimens. Our findings indicate that CDDP upregulates AT1R expression though ROS generation and enhances VEGF production. Therefore, AT1R blockade may be an effective strategy for bladder cancer in combination with CDDP-based chemotherapy.

Access to Document (DOI)

Cis-dichlorodiammineplatinum Upregulates Angiotensin II Type 1 Receptors through Reactive Oxygen Species Generation and Enhances VEGF Production in Bladder Cancer

Tanaka, Nobuyuki, Miyajima, Akira, Kosaka, Takeo, Shirotake, Suguru, Hasegawa, Masanori, Kikuchi, Eiji, Oya, Mototsugu

MOLECULAR CANCER THERAPEUTICS 9 ( 11 ) 2982 - 2992 2010.11

Research paper (scientific journal), ISSN 1535-7163

Access to Document (DOI)

Regulation of human dendritic cells by a novel specific nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin

Shinoda Kazunobu, Nakagawa Ken, Kosaka Takeo, Tanaka Nobuyuki, Maeda Takahiro, Kono Hidaka, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

Human Immunology 71 ( 8 ) 763 - 770 2010.08

ISSN 0198-8859

Regulation of antigen-presenting cells (APC) is crucial in controlling allograft rejection. Dendritic cells (DC) are the most potent APC and must mature to present antigens to T-cell receptors. During DC maturation, nuclear factor-κB (NF-κB) is a key transcriptional factor. We synthesized dehydroxymethylepoxyquinomicin (DHMEQ), which specifically inhibits the final step of nuclear translocation of activated NF-κB proteins and examined its immunoregulatory effects on human monocyte-derived DC (Mo-DC). Regulatory Mo-DC were generated by pretreatment with DHMEQ before LPS stimulation, which were termed dl-DC. DHMEQ pretreatment (5 μg/ml) completely inhibited nuclear translocation of activated NF-κB. DHMEQ significantly inhibited DC production of κproinflammatory cytokines (IL-6, TNF-α, and IL-12 p70) in a dose-dependent manner. IL-12 was most potently inhibited. However, IL-10 production by dl-DC was only moderately affected by DHMEQ. Although CD40 and the expression of HLA-DR (HLA-DR) expression on dl-DC was downregulated, CD80 and CD86 expression was moderately upregulated. Induction of T helper 1 cell responses was efficiently impaired by dl-DC. This confirmed that DHMEQ-treated Mo-DC exhibited immunoregulatory effects. These findings suggest that DHMEQ has potential as an immunosuppressive drug for human immune cells.

Access to Document (DOI)

Regulation of human dendritic cells by a novel specific nuclear factor-kappa B inhibitor, dehydroxymethylepoxyquinomicin

Shinoda, Kazunobu, Nakagawa, Ken, Kosaka, Takeo, Tanaka, Nobuyuki, Maeda, Takahiro, Kono, Hidaka, Mizuno, Ryuichi, Kikuchi, Eiji, Miyajima, Akira, Umezawa, Kazuo, Oya, Mototsugu

HUMAN IMMUNOLOGY 71 ( 8 ) 763 - 770 2010.08

Research paper (scientific journal), ISSN 0198-8859

Access to Document (DOI)

Adrenocortical zonation in humans under normal and pathological conditions

Nishimoto Koshiro, Nakagawa Ken, Li Dan, Kosaka Takeo, Oya Mototsugu, Mikami Shuji, Shibata Hirotaka, Itoh Hiroshi, Mitani Fumiko, Yamazaki Takeshi, Ogishima Tadashi, Suematsu Makoto, Mukai Kuniaki

Journal of Clinical Endocrinology and Metabolism 95 ( 5 ) 2296 - 2305 2010.05

ISSN 0021-972X

Context: Aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiationofhumanadrenocortical cells. Little isknown, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions. Objective: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other. Results: Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-producing cell cluster,andaCYP11B1- expressing area. Aldosterone-producing adenomas differed in cell populations expressing CYP11B2 from one another, whereas CYP11B1-expressing and double-negative cells were also intermingled. Adenomas from patients with Cushing's syndrome expressed CYP11B1 entirely but not CYP11B2, resulting in atrophic nontumor glands. The nontumor portions of both types of adenomas bore frequently one or more aldosterone-producing cell clusters, which sustained CYP11B2 expression markedly under the conditions of the suppressed renin-angiotensin system. Conclusion: Immunohistochemistry of the human normal adrenal cortex for CYP11B2 and CYP11B1 revealed a variegated zonation with cell clusters constitutively expressing CYP11B2. This technique may provide a pathological confirmatory diagnosis of adrenocortical adenomas.

Access to Document (DOI)

Adrenocortical Zonation in Humans under Normal and Pathological Conditions

Nishimoto, Koshiro, Nakagawa, Ken, Li, Dan, Kosaka, Takeo, Oya, Mototsugu, Mikami, Shuji, Shibata, Hirotaka, Itoh, Hiroshi, Mitani, Fumiko, Yamazaki, Takeshi, Ogishima, Tadashi, Suematsu, Makoto, Mukai, Kuniaki

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 95 ( 5 ) 2296 - 2305 2010.05

Research paper (scientific journal), ISSN 0021-972X

Access to Document (DOI)

Role of Pelvic Lymph Node Dissection in Lymph Node-Negative Patients with Invasive Bladder Cancer

Shirotake, Suguru, Kikuchi, Eiji, Matsumoto, Kazuhiro, Yazawa, Satoshi, Kosaka, Takeo, Miyajima, Akira, Nakagawa, Ken, Oya, Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 ( 3 ) 247 - 251 2010.03

Research paper (scientific journal), ISSN 0368-2811

Access to Document (DOI)

Ets-1 and hypoxia inducible factor-1α inhibition by angiotensin II type-1 receptor blockade in hormone-refractory prostate cancer

Kosaka Takeo, Miyajima Akira, Shirotake Suguru, Kikuchi Eiji, Hasegawa Masanori, Mikami Shuji, Oya Mototsugu

Prostate 70 ( 2 ) 162 - 169 2010.02

ISSN 0270-4137

BACKGROUND. Accumulating evidences have suggested that the renin-angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that hormone-refractory prostate cancer (HRPC) showed significantly higher angiotensin II (Ang II) type-1 receptor (AT1R) expression, and that the AT1R blocker (ARB) exerted protective effects by inhibiting angiogenesis. However, the downstream transcriptional factors induced by Ang II in prostate cancer cells have not been fully elucidated yet. METHODS. Three human prostate cancer cell lines: LNCap, C4-2 and C4-2AT6 were used and analyzed. C4-2AT6 cells were established by culture in androgen-ablated conditioned medium for 6 months. RESULTS. C4-2AT6 cells showed significantly higher AT1R expression, accompanied by higher HIF-1α and Ets-1 expression in the nucleus. In C4-2AT6 cells, VEGF production was significantly higher than in C4-2 cells and LNCaP cells. These results suggested that HRPC exhibited aggressive angiogenic properties, accompanied by up-regulated HIF-1α and Ets-1. Ang II stimulated VEGF production in C4-2 cells and C4-2AT6 cells but not in LNCaP cells. ARB significantly inhibited VEGF production. Western blot analysis demonstrated that AngII induced nuclear expression of HIF-1α and Ets-1 in C4-2 and C4-2AT6 cells, but not in LNCaP cells. ARB significantly inhibited HIF-1α and Ets-1 induction in C4-2 and C4-2AT6 cells. CONCLUSIONS. This study suggests that AT1R blockade may have a significant impact on HRPCthrough the inhibition of HIF-1α and Ets-1 and the resulting suppression of angiogenesis. Our results provide the molecular basis of the clinical benefit of ARB as an angiogenic inhibitor in HRPC.

Access to Document (DOI)

Ets-1 and Hypoxia Inducible Factor-1 alpha Inhibition by Angiotensin II Type-1 Receptor Blockade in Hormone-Refractory Prostate

Kosaka, Takeo, Miyajima, Akira, Shirotake, Suguru, Kikuchi, Eiji, Hasegawa, Masanori, Mikami, Shuji, Oya, Mototsugu

PROSTATE 70 ( 2 ) 162 - 169 2010.02

Research paper (scientific journal), ISSN 0270-4137

Access to Document (DOI)

Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer

Ishida, Masaru, Mikami, Shuji, Kikuchi, Eiji, Kosaka, Takeo, Miyajima, Akira, Nakagawa, Ken, Mukai, Makio, Okada, Yasunori, Oya, Mototsugu

CARCINOGENESIS 31 ( 2 ) 287 - 295 2010.02

Research paper (scientific journal), ISSN 0143-3334

Access to Document (DOI)

Role of pelvic lymph node dissection in lymph node-negative patients with invasive bladder cancer

Shirotake Suguru, Kikuchi Eiji, Matsumoto Kazuhiro, Yazawa Satoshi, Kosaka Takeo, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Japanese Journal of Clinical Oncology 40 ( 3 ) 247 - 251 2009.11

ISSN 0368-2811

Objectives: The role of pelvic lymphadenectomy in patients with lymph node-negative bladder cancer at radical cystectomy (RC) has not yet been examined in detail. We retrospectively reviewed patients who underwent RC with pelvic lymphadenectomy for bladder cancer from January 1987 to March 2008. Methods: We identified consecutive data on 169 patients who underwent RC for bladder cancer. The mean follow-up was 64 months (range: 1-253 months). Node-positive status (pN(+)) was seen in 16 patients and 91 were diagnosed as node-negative (pN(-)). The lymph node status of the remaining 62 patients was unclear (pN(x)). We analysed the association between lymph node status and cancer-specific survival (CSS), and examined the role of the number of retrieved lymph nodes, particularly in pN(-). Results: The median number of retrieved nodes was 12.9 and 10.2 for stage pN(+) and stage pN(-), respectively. In 91 patients with pN(-), multivariate analysis revealed that pathological T3-4 (P = 0.0276) and less than nine retrieved lymph nodes (P = 0.0108) were independent risk factors for CSS. In a subgroup of 83 patients with pT3-4, Kaplan-Meier curves showed that the 5-year CSS rate in pN(-) patients with less than nine retrieved lymph nodes was 38.8%, which was extremely similar to the 40.8% in pN(+) and 45.1% in pN(x). Conclusions: Our results demonstrate that at least nine lymph nodes should be removed to improve the survival of pN(-) patients at RC and lymphadenectomy, and would provide information not only on prognosis but also on the therapeutic impact on pT3-4 invasive bladder cancer.

Access to Document (DOI)

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

Research paper (scientific journal), ISSN 0090-4295

Access to Document (DOI)

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

Research paper (scientific journal), ISSN 0022-3417

Access to Document (DOI)

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

Research paper (scientific journal), ISSN 1341-9625

Access to Document (DOI)

A Case of Vesicocutaneous Fistula to the Thigh

Kosaka, Takeo, Asano, Tomohiko, Azuma, Ryuuichi, Yoshii, Hidehiko, Yamanaka, Yoshinori, Hayakawa, Masamichi

UROLOGY 73 ( 4 ) 2982 - 2992 2009.04

Research paper (scientific journal), ISSN 0090-4295

Access to Document (DOI)

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

Research paper (scientific journal), ISSN 0090-4295

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

The novel NF-κB activation inhibitor dehydroxymethyl-epoxyquinomicin suppresses anti-thy1.1-induced glomerulonephritis in rats

Kosaka Takeo, Miyajima Akira, Kikuchi Eiji, Horiguchi Yutaka, Umezawa Kazuo, Ohigashi Takashi, Nakashima Jun, Asano Tomohiko, Oya Mototsugu

Nephron - Experimental Nephrology 110 ( 1 ) 2008.09

ISSN 1660-2129

Background: NF-κB participates in the transcriptional regulation of numerous genes, and many studies have confirmed the activation of NF-κB in inflammatory renal diseases. Therefore, NF-κB is a promising target for the treatment of these diseases. We tested the effects of dehydroxymethyl- epoxyquinomicin (DHMEQ), a novel NF-κB activation inhibitor, on anti-thy1.1 antibody-induced glomerulonephritis (Thy1.1 GN). Methods: Thy1.1 GN was induced in Sprague-Dawley rats (6/group) by intravenous injection of anti-thy 1.1 antibody. The effects of DHMEQ (8 mg/kg/day) on the glomerular disease were evaluated using periodic acid-Schiff and Masson trichrome stains, immunohistochemistry for proliferating cell nuclear antigen, fibronectin and CD45 (leukocyte common antigen) and TUNEL staining. NF-κB activation was analyzed by a fluorescent electrophoretic mobility shift assay. Results: On day 7, DHMEQ treatment resulted in marked inhibition of NF-κB, decreased proteinuria (223.2 ± 42.3 vs. 434.8 ± 16.5 mg/kg/day, p < 0.05), preserved creatinine clearance (1.93 ± 0.38 vs. 1.07 ± 0.29 l/day, p < 0.01), decreased glomerular cell proliferation (15.8 ± 1.2 vs. 31.2 ± 0.8 nuclei/glomerular cross-section) and mesangial matrix deposition, and an increase in glomerular and tubular apoptosis without inducing any obvious adverse effects. Conclusion: DHMEQ inhibited NF-κB and thereby suppressed the inflammatory renal responses in rats with Thy1.1 GN.

Access to Document (DOI)

Papillary renal cell carcinoma

Kosaka Takeo, Mikami Shuji, Miyajima Akira, Kikuchi Eiji, Nakagawa Ken, Ohigashi Takashi, Nakashima Jun, Oya Mototsugu

Clinical and Experimental Nephrology 12 ( 3 ) 195 - 199 2008.06

ISSN 1342-1751

Background: Two different subtypes of papillary renal cell carcinoma (PRCC) have so far been identified, type-1 with small cells and pale cytoplasm and type-2 with large cells and eosinophilic cytoplasm. It has generally been accepted that type-1 tumors have favorable features in comparison with type-2 tumors, suggesting that these subtypes could be different clinicopathological entities, and, as a result, that the subtypes need to be characterized. Forty cases of PRCCs were reviewed, with special attention to the distinct clinicopathological difference and the response to cytokine therapy. Methods: Thirty-five cases of PRCC diagnosed between January 1997 and August 2007 were reviewed. PRCCs were classified according to the criteria of Delahunt and Eble. Results: Of these 40 patients, 20 and 20 were diagnosed to be type-1 and type-2 PRCCs, respectively. No lymphatic or vascular invasion or distant metastasis were observed in patients with type-1 PRCC. The nuclear grade in all type-1 PRCCs was low grade. The nuclear grade (P ≤ 0.01) and the positive rate of vascular invasion (P ≤ 0.05) was significantly higher in type-2 than in type-1 PRCCs. Distant metastasis was detected preoperatively in three patients with type-2 PRCC. One patient with metastatic type-2 PRCCs demonstrated a response to IL-2 therapy. Conclusion: PRCCs include two distinct morphological types of tumor and type-2 PRCCs tends to have unfavorable features in comparison with type-1 PRCCs. These results support the clinical basis for the need to perform morphological subtyping of PRCCs when clinically evaluating such patients.

Access to Document (DOI)

Metastatic type-2 papillary renal cell carcinoma responded to interleukin-2 therapy

Kosaka Takeo, Mikami Shuji, Miyajima Akira, Oya Mototsugu

Clinical and Experimental Nephrology 12 ( 2 ) 155 - 158 2008.04

ISSN 1342-1751

This report documents a case of metastatic papillary renal cell carcinoma (PRCC) which successfully responded to interleukin-2 (IL-2) therapy. A 59-year-old male presented with a left renal mass measuring 3.0 cm in diameter and a right adrenal mass measuring 5.0 cm in diameter. He underwent a left partial nephrectomy and a right adrenalectomy. The histological findings revealed pT1bN1M1 type-2 PRCC and metastatic renal cell carcinoma in the right adrenal gland. The patient was given interferon-α (IFN-α) after the operation for 3 months. A CT scan revealed a metastatic nodule measuring 6.0 cm in diameter near the surface of the liver at 4 months after the opereation. The patient was given interleukin-2 (IL-2), 7 × 10⁵ units/day intravenously, for 3 days per week. A CT scan revealed this hepatic nodule to have decreased in size from 6.0 to 4.0 cm after 4 months of IL-2 therapy. However, a new metastatic nodule measuring 6.0 cm in diameter was found which came in contact with the spleen. Next, the patient was given an increased dose of IL-2 from 7 × 10⁵ to 1.4 × 10⁶ units/day intravenously, for 3 days per week. At 9 months of follow-up after the dose escalation, a CT scan revealed a dramatic decrease in the size of these two metastatic nodules to 1.5 and 0.5 cm, respectively. This is a very rare case in that it represents a type-2 PRCC which dramatically responded to low-dose IL-2 therapy.

Access to Document (DOI)

Giant lymphocele arising after extraperitoneal laparoscopic radical prostatectomy

Mikami Hiroshi, Ito Keiichi, Yoshii Hidehiko, Kosaka Takeo, Miyajima Akira, Kaji Tatsumi, Asano Tomohiko, Hayakawa Masamichi

Acta Urologica Japonica 54 ( 1 ) 23 - 27 2008.01

ISSN 0018-1994

A 68-year-old male visited our division with an elevation of PSA level. He underwent a needle biopsy of the prostate, and the histopathological diagnosis was poorly differentiated adenocarcinoma (Gleason score 4 + 3). The cancer was clinically diagnosed as T2aN0M0, and he underwent extraperitoneal laparoscopic radical prostatectomy and bilateral pelvic lymphadenectomy. Cystography 14 days after the operation still showed leakage at the vesico-urethral anastomosis and a dumbbell shaped bladder. A few days later, prominence of lower abdomen and a slight swelling of right leg presented with a high fever. Computed tomography revealed a giant lymphocele in the retroperitoneal space. We percutaneously punctured the lymphocele by using ultrasonography, inserted a pigtail catheter, and drained 1,000 ml of lymphatic fluid. After the puncture, sclerotherapy with minocycline was performed four times. Twenty days after the puncture, the lymphocele cavity was found to have shrunken and the pigtail catheter was removed. The lymphocele was diminished and did not recur thereafter.

Laparoscopic radical nephrectomy in acdk-associated renal cell carcinoma accompanied by duplicated IVC

Ito Keiichi, Asano Tomohiko, Kosaka Takeo, Yoshii Hidehiko, Kaji Tatsumi, Sumitomo Makoto, Hayakawa Masamichi

Acta Urologica Japonica 53 ( 12 ) 875 - 878 2007.12

ISSN 0018-1994

A 59-year-old male patent who had undergone chronic dialysis for 13 years presented with gross hematuria. Radiological examinations showed a cystic renal tumor in the left kidney, multiple renal cysts due to acquired cystic disease of the kidney (ACDK), and a duplicated inferior vena cava (IVC). Although we suspected that the branches of the left IVC might be anormalous with regard to number and location, we could not obtain information about the left renal vein by 3-dimensional computed tomography because of the decreased blood flow in the end-stage kidney. Laparoscopic radical nephrectomy was performed using a transperitoneal approach. We first identified the left IVC and then exposed its surface widely so that we could identify the veins draining into it. We identified and divided two renal veins and also identified an adrenal vein and a gonadal vein draining directly into the left IVC. The enlarged kidney with multiple renal cysts was removed in a purely laparoscopic procedure.

Adrenal metastasis of lung adenocarcinoma with unusual sites of lymph node metastasis and concomitant renal cell carcinoma

Otsuki Hideo, Ito Keiichi, Kosaka Takeo, Mikami Hiroshi, Yoshii Hidehiko, Asakuma Junnichi, Kaji Tatsumi, Asano Tomohiko, Hayakawa Masamichi

Acta Urologica Japonica 53 ( 12 ) 879 - 882 2007.12

ISSN 0018-1994

A 58-year-old male presented to a clinic with general weakness. Right adrenal tumor was found by computed tomography and he was referred to our hospital. Imaging studies revealed right adrenal tumor (8 cm) with marked swelling of surrounding lymph nodes and synchronous left renal tumor (2 cm) that was weakly enhanced by contrast media. Needle biopsy of the left kidney proved to be clear cell type renal cell carcinoma (RCC) and the preoperative diagnosis was left RCC and right primary adrenal cancer with lymph node metastasis. We performed right adrenalectomy, lymph node dissection and left radical nephrectomy. Pathological findings of right adrenal tumor and lymph nodes were both metastatic adenocarcinoma, which was not consistent with RCC or adrenal-derived carcinoma. Then, we extensively reviewed preoperative radiological examinations and found a small lesion in the left upper lung. This lesion was attached to the mediastinal shadow and there was no obvious lymph node swelling around this lesion. According to pathological findings and an elevation of carcinoembryogenic antigen, the adrenal lesion was diagnosed as adrenal metastasis of lung adenocarcinoma.

Effect of angiotensin II type 1 receptor antagonist on tumor growth and angiogenesis in a xenograft model of human bladder cancer

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

HUMAN CELL 20 ( 1 ) 1 - 9 2007.02

Research paper (scientific journal), ISSN 0914-7470

Access to Document (DOI)

Angiotensin II type I receptor antagonist as an angiogenic inhibitor in prostate cancer

Kosaka, Takeo, Miyajima, Akira, Takayama, Eiji, Kikuchi, Eiji, Nakashima, Jun, Higashi, Takashi, Asano, Tomohiko, Sakamoto, Michiie, Okita, Hajime, Murai, Masaru, Hayakawa, Masamichi

PROSTATE 67 ( 1 ) 41 - 49 2007.01

Research paper (scientific journal), ISSN 0270-4137

Access to Document (DOI)

Atorvastatin ameliorates renal tissue damage in unilateral ureteral obstruction

Mizuguchi Yasunori, Miyajima Akira, Kosaka Takeo, Asano Takako, Asano Tomohiko, Hayakawa Masamichi

Journal of Urology 172 ( 6 I ) 2456 - 2459 2004.12

ISSN 0022-5347

Purpose: The current study was done to determine whether atorvastatin, the HMGCoA (3-hydroxy-3-methylglutaryl CoA) reductase inhibitor, could decrease renal transforming growth factor-β (TGF-β) levels in unilateral ureteral obstruction (UUO) and concomitantly affect renal tissue damage in UUO. Materials and Methods: Atorvastatin (20 mg/kg) was administered to rats 1 day prior to UUO and every day thereafter. Kidneys were harvested at day 14 after UUO. Tissue TGF-β was measured by bioassay using mink lung epithelial cells. Renal tubular proliferation and apoptosis were detected by immunostaining proliferating cell nuclear antigen and polyclonal antisingle strand DNA antibody, respectively. Fibrosis was assessed by measuring collagen deposition with trichrome stained slides. Interstitial leukocyte was detected by immunostaining CD45. Results: TGF-β bioassay showed that the obstructed kidney in the control group contained significantly higher TGF-β than the unobstructed kidney in the control group (mean ± SD 79.1 ± 48.5 vs 28.7 ± 13.7 pg/mg tissue) and atorvastatin significantly decrease tissue TGF-β in the obstructed kidney (53.4 ± 37.0 pg/mg tissue). Immunostaining polyclonal antisingle strand DNA antibody demonstrated that the obstructed kidney in the control group has significantly more tubular apoptosis than the unobstructed counterpart (4.8 ± 2.8 vs 2.1 ± 1.2 nuclei per high power field) and atorvastatin significantly decreased renal tubular apoptosis in the obstructed kidney (1.1 ± 0.7 nuclei per high power field). In addition, immunostaining proliferating cell nuclear antigen showed that the obstructed kidney in the atorvastatin group had significantly more renal tubular proliferation than the obstructed kidney in the control group (48.7 ± 20.8 vs 17.3 ± 10.6 per high power field). Control obstructed kidney showed significantly more fibrosis, which was also blunted by atorvastatin. Conclusions: Atorvastatin significantly decreases tissue TGF-β, resulting in a decrease in tubular damage and interstitial fibrosis. This suggests that atorvastatin is a promising agent for preventing renal tubular damage in UUO.

Access to Document (DOI)

Novel nuclear factor κB activation inhibitor prevents inflammatory injury in unilateral ureteral obstruction

Miyajima Akira, Kosaka Takeo, Seta Kaori, Asano Tomohiko, Umezawa Kazuo, Hayakawa Masamichi

Journal of Urology 169 ( 4 ) 1559 - 1563 2003.04

ISSN 0022-5347

Purpose: We determined whether the novel nuclear factor κB activation inhibitor dehydroxymethylepoxyquinomicin (DHMEQ), which is derived from epoxyquinomicin C, affects renal inflammatory responses in unilateral ureteral obstruction. Materials and Methods: DHMEQ (8 mg./kg.) was administered to rats 1 day after unilateral ureteral obstruction and every day thereafter. Kidneys were harvested at day 7 after unilateral ureteral obstruction. Tissue nuclear factor κB activity and transforming growth factor-β were determined by electrophoretic mobility shift assay and bioassay using mink lung epithelial cells, respectively. Renal tubular proliferation and apoptosis were detected by immunostaining proliferating cellular nuclear antigen and the TUNEL (Intergen, Purchase, New York) assay, respectively. Leukocyte infiltration was detected by immunostaining for CD45. Fibrosis was assessed by measuring tissue hydroxyproline content. Results: Unilateral ureteral obstruction for 7 days significantly activated nuclear factor κB, induced tubular apoptosis, proliferation and interstitial fibrosis in the obstructed kidney of the control group compared with their unobstructed counterparts (30.3 ± 4.5 nuclei per high power field versus 1.7 ± 0.4, 25.7 ± 3.3 nuclei per high power field versus 3.2 ± 0.4 and 6.2 ± 0.3 μmol. hydroxyproline per gm. tissue versus 3.4 ± 0.1, respectively). Conversely daily administration of DHMEQ (8 mg./kg.) significantly inhibited nuclear factor κB activation and decreased mean tubular apoptosis (9.5 ± 2.1 nuclei per high power field), proliferation (10.2 ± 2.4 nuclei per high power field) and interstitial fibrosis (4.9 ± 0.4 μmol. hydroxyproline per gm. tissue) in the obstructed kidney. Conclusions: Specific inhibition of nuclear factor κB can prevent inflammatory renal responses, suggesting that targeting nuclear factor κB activation may be feasible for preventing inflammatory kidney diseases.

Access to Document (DOI)

Angiotensin II type I antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting tumor angiogenesis

Miyajima Akira, Kosaka Takeo, Asano Tomohiko, Asano Takako, Seta Kaori, Kawai Toshiaki, Hayakawa Masamichi

Cancer Research 62 ( 15 ) 4176 - 4179 2002.08

ISSN 0008-5472

Angiotensin II (AII) is a potent vasoconstrictor peptide from the reninangiotensin system in the kidney. The AII type 1 receptor (AT1R) is reportedly expressed in several tumors including renal cell carcinoma, and AII is involved in tumor angiogenesis. We p.o. administered the long-acting AT1R antagonist, candesartan (10 mg/kg), to the 16 days mouse renal cancer lung metastasis model to test the preventive effects in tumor metastasis. Pulmonary metastases of renal cancer showed prominent AT1R expression in both mice and humans, and candesartan treatment dramatically prevented lung metastatic nodules (14.9 ± 1.8; P < 0.0001; n = 12) in mice along with the inhibition of neovascularization and vascular endothelial growth factor expression, compared with control metastatic mice (123.3 ± 8.6; n = 13). Candesartan is widely used clinically, so it seems to be a reasonable therapy for patients with lung metastases of renal cell carcinoma.

　 Previous page - Next page 　