Kazunori Kihara

Glucocorticoids Suppress Tumor Angiogenesis and In vivo Growth of Prostate Cancer Cells

Purpose: Glucocorticoids, such as prednisone, hydrocortisone, and dexamethasone, are known to produce some clinical benefit for patients with hormone-refractory prostate cancer (HRPC). However, the underlying mechanisms by which glucocorticoids affect HRPC growth are not well established as yet. Here, we hypothesize that the therapeutic effect of glucocorticoids on HRPC can be attributed to a direct inhibition of angiogenesis through the glucocorticoid receptor by down-regulating two major angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Experimental Design: The effects of dexamethasone on VEGF and IL-8 expression and cell proliferation were examined using DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on DU145 xenografts were determined by analyzing VEGF and IL-8 gene expression, microvessel density, and tumor volume. Results: Dexamethasone significantly down-regulated VEGF and IL-8 gene expression by 50% (P < 0.001) and 89% (P < 0.001), respectively, and decreased VEGF and IL-8 protein production by 55% (P < 0.001) and 74% (P < 0.001), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF and IL-8 gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF and IL-8 expression. In DU145 xenografts, dexamethasone significantly decreased tumor volume and microvessel density and down-regulated VEGF and IL-8 gene expression, whereas dexamethasone did not affect the in vitro proliferation of the cells. Conclusion: Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasing VEGF and IL-8 production directly through glucocorticoid receptor in vivo.

Long-term outcome of bladder papillary urothelial neoplasms of low malignant potential

To evaluate the long‐term outcome of bladder papillary urothelial neoplasms of low malignant potential (PUNLMP).

Glucocorticoids Suppress Tumor Lymphangiogenesis of Prostate Cancer Cells

Purpose: Glucocorticoids such as prednisone, hydrocortisone, and dexamethasone are known to provide some clinical benefit for patients with hormone-refractory prostate cancer. However, the underlying mechanisms by which glucocorticoids affect hormone-refractory prostate cancer progression are not well established as yet. Our previous study has shown that glucocorticoids inhibit tumor angiogenesis possibly by down-regulation of vascular endothelial growth factor (VEGF) and interleukin 8. Here, we hypothesized that the therapeutic effect of dexamethasone on hormone-refractory prostate cancer can be partly attributed to a direct inhibition of lymphangiogenesis through the glucocorticoid receptor by down-regulating a major lymphangiogenic factor, VEGF-C. Experimental Design: The effects of dexamethasone on the expression of VEGF-C and its receptor, VEGF receptor-3 (VEGFR-3), were examined using an androgen-independent human prostate cancer cell line, DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on tumor-associated lymphangiogenesis in DU145 xenografts were determined by analyzing VEGF-C gene expression, lymphatic vessel density, and relative lymphatic vessel area. Results: Dexamethasone significantly down-regulated VEGF-C gene expression and protein production by 48% (P = 0.003) and 44% (P = 0.002), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF-C gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF-C gene expression. In DU145 xenografts, dexamethasone significantly down-regulated VEGF-C gene expression and decreased lymphangiogenesis. Dexamethasone did not affect VEGFR-3 gene expression in vitro and in vivo. Conclusion: Glucocorticoids suppressed tumor-associated lymphangiogenesis by down-regulating VEGF-C through glucocorticoid receptor in androgen-independent prostate cancer cells in vivo.

Portless endoscopic radical nephrectomy via a single minimum incision in 80 patients

Abstract Aim: To assess the feasibility of our portless endoscopic radical nephrectomy via a single minimum incision, which narrowly permitted extraction of the specimen in the initial 80 patients.

Portless endoscopic adrenalectomy via a single minimal incision using a retroperitoneal approach: Experience with initial 30 cases

Abstract Aim: To assess the feasibility of portless endoscopic adrenalectomy via a single minimum incision that narrowly permits extraction of the specimen.

Loss of uroplakin III expression is associated with a poor prognosis in patients with urothelial carcinoma of the upper urinary tract

To investigate the association between the expression of uroplakin III (UPIII) and the prognosis of patients with urothelial carcinoma of the upper urinary tract, as uroplakins are urothelium‐specific markers of terminal urothelial differentiation.

Localization and Role of Nitric Oxide Synthase and Endogenous Nitric Oxide Synthase Inhibitors in the Rabbit Lower Urinary Tract

PURPOSEnWe investigated the possible role of endogenous methylarginine derivatives, such as NG-monomethyl-L-arginine (L-NMMA), asymmetrical NG, NG-dimethyl-L-arginine (ADMA) and symmetrical NG, NG-dimethyl-L-arginine (SDMA), for regulating nitric oxide synthase in the rabbit lower urinary tract.nnnMATERIALS AND METHODSnStrips of detrusor, trigone and proximal urethra were processed for the determination of endogenous methylarginines and L-arginine by automated high performance liquid chromatography. We also compared nitric oxide synthase activity and nitric oxide mediated functional responses to electrical field stimulation in the 3 regions. Nitric oxide synthase activity was measured by determining the conversion of [3H] L-arginine to [3H] L-citrulline.nnnRESULTSnL-NMMA, ADMA and SDMA were detectable by high performance liquid chromatography in the detrusor, trigone and proximal urethra. Electrical field stimulation induced nitric oxide mediated prominent relaxation in the trigone and proximal urethra, while no relaxation response was observed in the detrusor. Exogenously applied 1 to 100 microM. L-NMMA and 1 to 100 microM. ADMA but not 100 microM. SDMA dependently inhibited Ca2+ dependent nitric oxide synthase activity in all regions, and electrical field stimulation induced relaxation in the trigone and proximal urethra. Inhibition with L-NMMA and ADMA was blocked in the presence of 3 mM. L-arginine but not by 3 mM. D-arginine.nnnCONCLUSIONSnThree methylarginines and nitric oxide synthase are localized throughout the rabbit lower urinary tract. Endogenous L-NMMA and ADMA may be involved in regulating nitric oxide biosynthesis of the micturition reflex in the normal or disease state.

Regeneration of hypogastric nerve using a polyglycolic acid (PGA)-collagen nerve conduit filled with collagen sponge proved electrophysiologically in a canine model.

The hypogastric nerve (HGN) is a sympathetic nerve in the peritoneal cavity and controls urinary and seminal functions. In this study, the regeneration of HGN was determined by using a new type of an artificial nerve conduit, polyglycolic acid (PGA)-collagen nerve conduit filled with collagen sponge in two dogs. A PGA-collagen nerve conduit (diameter=2mm) was interposed in a 10 mm gap of the right HGN. The regeneration of the HGN was evaluated electrophysiologically 8 months after the operation. The intraluminal pressure of spermatic duct and the bladder neck were elevated 80 mmHg and 25 mmHg respectively by the stimulation across the regenerated HGN. The prostate contraction was also elicited. The responses diminished after the excision of the regenerated portion of HGN. These results proved the regeneration of HGN and this nerve conduit will be great help for patients who suffer from urinary and seminal disturbances.

Expression failure of the notch signaling system is associated with the pathogenesis of testicular germ cell tumor.

Objectives: The expression of Notch 1 and its ligand Jagged 2, critical factors in cell type specification, in testicular germ cell tumors was examined in order to evaluate its possible relationship with their pathogenesis. Methods: Northern blot analysis and immunohistochemical staining for Notch 1 and Jagged 2 were done in 139 samples of testicular germ cell tumors. Results: Notch 1 and Jagged 2 transcripts were expressed in noncancerous testicular tissues and Notch 1 and Jagged 2 proteins were positive in the spermatids. However, the expressions of transcript and protein were negative for both Jagged 2 and Notch 1 in seminomas, they were negative for Jagged 2 but were positive for Notch 1 in embryonal carcinomas and choriocarcinomas, and they were positive for Jagged 2 and Notch 1 in teratomas. Conclusions: Our results offer, for the first time, the possibility that the activity of the Notch signaling system, one of the cell proliferation and differentiation pathways, correlates with the different histological subtypes of germ cell tumor, which may be responsible for characteristics of cancer cells such as responses to chemotherapy and/or irradiation.

Deferred combined androgen blockade therapy using bicalutamide in patients with hormone-refractory prostate cancer during androgen deprivation monotherapy.

To assess the effect of adding bicalutamide on serum prostate‐specific antigen (PSA) levels in patients with hormone‐refractory prostate cancer (HRPC) during androgen deprivation monotherapy (ADMT).