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OBJECTIVE: To evaluate long-term clinical outcomes in cT1c-T3a prostate cancer patients following delayed-combined androgen blockade therapy. METHODS: From January 2001 to December 2004, 92 cT1c-T3a prostate cancer cases were enrolled. Medical castration and anti-androgen treatment were used sequentially as delayed-combined androgen blockade therapy. Time to prostate-specific antigen biochemical failure was estimated, and risk factors for prostate-specific antigen biochemical failure were evaluated. RESULTS: The average patient age was 76.4 years (range, 59-91 years), the median observation period was 52.8 months (range, 26-106.6 months) and the median pre-treatment prostate-specific antigen level was 14 ng/ml (range, 3.68-492 ng/ml). The TNM classification distribution was as follows: T1c, n= 27; T2a, n = 39; T2b, n = 20; and T3a, n = 6. In the multivariate analysis, Gleason's score ≥8 (P 1.4 ng/ml (P = 0.001; hazard ratio, 8.76) and a half-life of the prostate-specific antigen level >1.2 months (P < 0.005; hazard ratio, 6.3) during the initial 6 months of luteinizing hormone-releasing hormone agonist monotherapy were significant independent risk factors for prostate-specific antigen biochemical failure with luteinizing hormone-releasing hormone agonist monotherapy. The high-risk group, which had at least one of these three risk factors, had a shorter time to prostate-specific antigen biochemical failure than the low-risk group, during luteinizing hormone-releasing hormone agonist monotherapy (P < 0.0001). For the total delayed-combined androgen blockade therapy observation period, the free-prostate-specific antigen biochemical failure rate was 88.3% at 5 years. Only a maintenance period following luteinizing hormone-releasing hormone agonist monotherapy (P < 0.005; hazard ratio, 16.8) was revealed to be a significant independent risk factor for prostate-specific antigen biochemical failure with total delayed-combined androgen blockade. CONCLUSIONS: The free-prostate-specific antigen biochemical failure rate of delayed-combined androgen blockade therapy in our study was as valuable as those in other androgen deprivation therapy of previous reports.

The balance between androgens and estrogens is very important in the development of the prostate, and even small changes in estrogen levels, including those of estrogen-mimicking chemicals, can lead to serious changes. Bisphenol A (BPA), an endocrine-disrupting chemical, is a well-known, ubiquitous, estrogenic chemical. To investigate the effects of fetal exposure to low-dose BPA on the development of the prostate, we examined alterations of the in situ sex steroid hormonal environment in the mouse urogenital sinus (UGS). In the BPA-treated UGS, estradiol (E(2)) levels and CYP19A1 (cytochrome P450 aromatase) activity were significantly increased compared with those of the untreated and diethylstilbestrol (DES)-treated UGS. The mRNAs of steroidogenic enzymes, Cyp19a1 and Cyp11a1, and the sex-determining gene, Nr5a1, were up-regulated specifically in the BPA-treated group. The up-regulation of mRNAs was observed in the mesenchymal component of the UGS as well as in the cerebellum, heart, kidney, and ovary but not in the testis. The number of aromatase-expressing mesenchymal cells in the BPA-treated UGS was approximately twice that in the untreated and DES-treated UGS. The up-regulation of Esrrg mRNA was observed in organs for which mRNAs of steroidogenic enzymes were also up-regulated. We demonstrate here that fetal exposure to low-dose BPA has the unique action of increasing in situ E(2) levels and CYP19A1 (aromatase) activity in the mouse UGS. Our data suggest that BPA might interact with in situ steroidogenesis by altering tissue components, such as the accumulation of aromatase-expressing mesenchymal cells, in particular organs.

Objective: To determine optimal predictors with which to select the crucial patients enrolled in delayed-combined androgen blockade (CAB) trials, based on risk factors. Methods: From January 2001 to December 2004, 92 prostate cancer patients with T1c, T2 and T3aN0M0 were enrolled in a clinical trial. Medical castration and anti-androgen treatment were used sequentially as delayed-CAB. The prostate specific antigen (PSA) nadir was determined following medical castration only. Anti-androgen treatment was administered if a PSA progression was observed and the subsequent PSA response was evaluated. Time to PSA biochemical failure, induced by medical castration or with anti-androgen treatment, was estimated. Risk factors of PSA failure were evaluated by multivariate analysis. Results: During luteinizing hormone‐releasing hormone (LH‐RH) monotherapy, a Kaplan‐ Meier analysis estimated that the proportion of patients without PSA progression was 64.8% at 5 years. In the multivariate analysis of the prediction of PSA progression with LH‐RH monotherapy, a Gleason score over 8, initial PSA .20 ng/ml and PSA nadir .0.2 ng/ml were significant independent risk factors that affected PSA biochemical failure. The PSA progression-free rate in the lower PSA nadir group was significantly lower than that in the other. The 25 patients in the higher PSA nadir group were treated with anti-androgen therapy. Under anti-androgen therapy, the PSA progression-free rate was 62.6% at 5 years. Only PSA nadir .0.2 ng/ml was a significant independent risk factor. The PSA progression-free rate in the lower PSA nadir group was significantly lower than the other. Conclusions: PSA nadir was the optimal predictive for low stage, non-metastatic population during delayed-CAB.

Objective: The purpose of this study was to assess the changes in health-related quality of life (HRQoL) during follow-up period in patients treated with percutaneous radiofrequency ablation (RFA) or laparoscopic surgery for small renal cell carcinoma. Methods: From December 2004 through September 2006, for 37 consecutive patients, who were diagnosed with renal cell carcinoma and underwent percutaneous RFA (n ¼ 20) or laparoscopic radical nephrectomy (n ¼ 17) at our institution,. HRQoL was evaluated prospectively using SF-36 Health survey pre- and post-operatively (1, 4, 12 and 24 weeks after surgery). Results: Four of the eight scale scores of SF-36 were significantly lower pre-operatively in the RFA group than in the laparoscopic surgery group. The QoL scores in physical functioning, role-physical functioning and role-emotional functioning were significantly reduced one week after laparoscopic surgery. However, there was no reduction of the SF-36 QoL scores one week after operation in the RFA group. Furthermore, HRQoL scores in the RFA group showed a tendency to improve during follow-up periods. Conclusions: This is the first study to evaluate HRQoL changes (up to 24 weeks) in patients who have undergone RFA or laparoscopic radical nephrectomy for small renal cell carcinoma. No reduction, but rather an improvement, in HRQoL was seen in the RFA group during follow-up periods. From the point of view of QoL, RFA could be a viable alternative treatment for selected patients with small renal cell carcinoma.RFA could be a viable alternative treatment for the selected patients with small renal cell carcinoma

Good molecular markers for investigating the biochemical differences between renal cancer and surrounding tissues have not yet been developed. Sixteen kidney samples (clear cell RCC) were investigated to determine the differences in the protein components between renal cancer and surrounding tissues, using HPLC analysis. The metallothionein (MT) and zinc levels were consistently lower in renal cancer tissues compared with in surrounding tissues. The mean concentration of MT in normal tissues surrounding renal tumors was about 15 times higher than that in cancer tissues. An immunohistochemical study confirmed that the expression of MT in renal cancer tissues was lower than that in adjacent normal tissues. The activities of aminopeptidases (APs) were significantly decreased in renal cancer tissues compared with in adjacent normal tissues. An immunohistochemical study and Western blot analysis confirmed that the expression of AP-N in renal cancer tissues was also lower than in adjacent normal tissues. These results suggest that the immunohistochemical detection of MT and AP-N could provide useful information as a pathological diagnostic tool for classifying renal cancer and surrounding tissues.

The prostate gland is unique in that it undergoes rapid regression following castration but regenerates completely once androgens are replaced. Residual ductal components play an important role in the regeneration of a fully functional prostate. In this study, to examine how androgen status affects prostate structure and components, we conducted histopathological studies of the involuted and regenerated mouse dorsolateral prostate (DLP). In the castrated mouse DLP, the number of luminal epithelial cells decreased in a time-dependent manner. On Day 14 postandrogen replacement, the number of luminal epithelial cells was completely restored to the baseline level. In contrast, the number of basal epithelial cells gradually increased in the castrated mouse prostate. The Ki67-labeling index of prostate basal epithelial cells was significantly increased after castration. The number of basal epithelial cells decreased to baseline after androgen replacement. After castration, mRNA expression levels of specific growth factors, such as Fgf2, Fgf7, Hgf, Tgfa, and Tgfb, were relatively abundant in whole mouse DLPs. In organ culture experiments, basal epithelial proliferation was recapitulated in the absence of dihydrotestosterone (DHT). The proliferation of basal epithelial cells in the absence of DHT was suppressed by treatment with an FGF receptor inhibitor (PD173074). Moreover, FGF2 treatment directly stimulated the proliferation of basal epithelial cells. Taken together, these data indicated that the FGF2-FGF receptor signal cascade in the prostate gland may be one of the pathways stimulating the proliferation of basal epithelial cells in the absence of androgens.

Ductal morphogenesis and adult ductal branching patterns were examined in the rat prostate by a microdissection method. The rat prostate consists of paired (right and left) subdivisions which correspond in large part to the classically defined lobes: ventral prostate, lateral prostate, dorsal prostate, and coagulating gland. Of particular interest was the finding that the lateral prostate consists of two different ductal zones: (1) lateral type 1 prostate with 5-7 long main ducts (resembling miniature palm trees) that extend cranially towards both the seminal vesicle and dorsal prostate to arborize near the bladder neck, and (2) lateral type 2 prostate with 5-6 short main ducts that arborize caudal to the bladder neck and give rise to compact bushy glands. Both lateral prostatic groups had a ductal-acinar organization. The adult structure of the other rat prostatic lobes was also examined, and closely resembled their mouse counterparts. The ventral prostate, which had 2-3 pairs of slender main ducts per side, and the coagulating gland, which had 1 main duct per side, was completely ductal in structure. In contrast, the dorsal prostate, which had 5-6 pairs of main ducts per side, had a ductal-acinar structure. Ductal branching morphogenesis occurred at different rates in different lobes and was essentially complete in the prostate at the 30 days. Immunocytochemical studies with an antibody to DP-1, a major secretory protein of the rat dorsal prostate, revealed that secretory function was initiated at approximately 30 days after birth in the coagulating gland, the dorsal prostate, and lateral type 1 prostate. A consistent feature of the lateral type 2 prostate was the absence of DP-1. On Western blots, DP-1 was detected in the secretion of the coagulating gland, lateral type 1 and dorsal prostate, but not in the ventral and lateral type 2 prostate. Polyacrylamide gel electrophoresis confirmed this result and demonstrated that the lateral type 2 prostate expressed several low-molecular weight secretory proteins not found in the other lobes of the prostate. On the whole, the rat prostate exhibited considerable heterogeneity both between and within lobes in developmental processes, ductal patterning, histology, and functional expression.

Ventral and dorsolateral prostatic lobes (VP and DLP), obtained from mice at different ages and at different intervals after castration or treatment of castrated males with testosterone propionate (TP), were microdissected into two-dimensional arrays and incubated in vitro with 14C-thymidine. Labeled whole-mount specimens were fixed and dried onto glass slides, dipped into photographic emulsion, and processed autoradiographically. The morphological pattern of DNA synthetic activity was similar in the VP and DLP. During early postnatal periods (10-15 days after birth), DNA synthetic activity was highest at the distal ductal tips (near the capsule) and considerably lower in proximal ducts (near the urethra). At 30 days of age, DNA synthesis was almost totally confined to the distal ducts, with exceedingly low labeling in the proximal ductal areas. In the prostate of the intact or castrated adult, DNA synthesis was nearly absent throughout the gland, but silver grains were still observed on the ductal tips. During androgen-induced prostatic regeneration, DNA synthesis was detectable only in distal ducts 24 h after TP was administered. Labeling intensity reached a maximum on the third day of TP treatment in both distal and proximal ductal areas, thereafter, it subsided to focal labeling confined mostly to distal ducts. These results demonstrate that levels of DNA synthetic activity vary considerably within the prostate on a regional basis. Explanation of this heterogeneity in DNA synthetic activity within the prostate gland is fundamental to understanding the mechanism of androgenic regulation of prostatic growth and development.