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LONGER AC REPEATS IN 5ALPHA-STEROID REDUCTASE TYPE III ARE ASSOCIATED WITH INCREASED BENIGN PROSTATIC HYPERPLASIA RISK
THE JOURNAL OF UROLOGY®
502
Vol. 181, No. 4, Supplement, Tuesday, April 28, 2009
setting after surgery. The survival outcomes were combined in metaanalysis and measured as Hazard Ratio (HR) and 95% confidence interval (95%CI). The primary endpoint of interest was overall survival. Secondary endpoints were disease-free survival and incidence of grade III and IV adverse events related to the adjuvant treatment. RESULTS: More than 390 references were analyzed and 11 trials could be included, with data from 2,835 patients. The metaanalyses detected no differences in overall survival (HR 1.11; 95%CI 0.95 to 1.29; p=0.20; heterogeneity 2%), and in disease-free survival (HR 1.02; 95%CI 0.89 to 1.17; p=0.75; heterogeneity 0%) in the group treated with adjuvant therapy compared to control group. There were significant higher incidence of grade III and IV toxicities in the treatment group (p<0.00001). CONCLUSIONS: Adjuvant therapy after surgery is not capable to enhance overall survival or disease-free survival in patients with renal cell carcinoma. Furthermore, it is related to higher incidence of moderate to severe adverse events. New studies evaluating different therapeutic strategies are needed to change the prognosis of these patients. Source of Funding: None
Benign Prostatic Hyperplasia: Basic Research Moderated Poster 46 Tuesday, April 28, 2009
10:30 am - 12:30 pm
1404 LONGER AC REPEATS IN 5ALPHA-STEROID REDUCTASE TYPE III ARE ASSOCIATED WITH INCREASED BENIGN PROSTATIC HYPERPLASIA RISK Young Seop Chang*, Daejeon, Republic of Korea; Donald E Riley, Seattle, WA; Dong Seok Han, Yong-Gil Na, Ju Hyun Shin, Seung Mo Yuk, Daejeon, Republic of Korea; In Rae Cho, Koyang, Republic of Korea; Hong Sup Kim, Sang-Kuk Yang, Chungju, Republic of Korea; Hyung-Jee Kim, Cheonan, Republic of Korea; Jae Mann Song, Wonju, Republic of Korea; Chong Koo Sul, Ki Hak Song, Daejeon, Republic of Korea; John N Krieger, Seattle, WA INTRODUCTION AND OBJECTIVES: Testicular androgens are necessary for prostate growth and development. 5 alpha-steroid reductase converts testosterone to dihydro-testosterone, the most potent natural androgen. Recently, a novel gene, 5 alpha-steroid reductase type III (SRD5A3), important in androgen metabolism was found to be polymorphic. These observations led us to hypothesize that SRD5A3 polymorphisms might be associated with a genetic predisposition to develop symptomatic benign prostatic hyperplasia (BPH). METHODS: We compared SRD5A3 short tandem repeat (STR) allele sizes in 99 patients with symptomatic BPH undergoing TURP with 38 control subjects selected from general clinics who did not have symptomatic BPH. STR allele sizes were determined using an ABI 310 genetic analyzer after polymerase chain reaction (PCR)-based copying of the SRD5A3 STR region. Allele sizes were compared by calculating Fisher’s exact test and by logistic regression modeling. RESULTS: BPH patients had a higher frequency of large STRs (>38 repeats, OR =0.40; 95%CI =0.25-0.64; p = 0.0004) than controls (Table). CONCLUSIONS: Our results suggest that longer 5 alphareductase type III polymorphisms merit further investigation as a potential marker for the risk of developing symptomatic BPH and might provide insights into the pathophysiologic mechanisms.
SRD5A3-CA Repeat Lengths for Paired Alleles in 99 BPH and 38 Controls No. STR Relative Risk 95% Confidence Interval <38
>38
Control (N = 38) 21 (55%) 17 (45%) BPH* (N=99)
22 (22%) 77 (78%)
Reference 0.40
0.25-0.64^
*; Symptomatic benign prostatic hyperplasia. ^ ^ Fisher’s exact p=0.0004, two sided.
Source of Funding: None
1405 THE EFFECTS OF PURIFIED NEWLY DEVELOPED BOTULINUM NEUROTOXIN TYPE A IN RAT AND HUMAN PROSTATE Teruhiko Yokoyama*, Ryoei Hara, Norio Kondo, Tomohiro Fujii, Yoshimasa Jo, Yoshiyuki Miyaji, Atsushi Nagai, Kurashiki, Japan; Hiromi Kumon, Okayama, Japan INTRODUCTION AND OBJECTIVES: Several papers suggested that intraprostatic injection of botulinum toxin type A (BTX-A) demonstrated the efficacy for patients with symptomatic benign prostatic hyperplasia (BPH). Neurotoxins (NTX) associate with non-toxic components, and form large complexes designated progenitor toxins (PTX). In general, PTX are used because they are easily obtained and are more stable than NTX. However, it has a side effect for some patients in whom antiPTX, including anti-NTX antibodies produced after several injections. We purified NTX without non-toxic components by a simple procedure. In this study, we investigated the efficacy of this newly purified NTX for male rat prostate and also men with symptomatic BPH. METHODS: Adult male S.D. rats were injected with 5 units of NTX or saline into the prostate which were harvested and weighed after 1 or 4 weeks. The effects of NTX on prostate were histologically and immunohistochemically studied using H.E., synaptophysin, and TUNEL staining. In addition, 10 BPH patients refractory to alpha-blockers were treated with intraprostatic injection of NTX after approval by the Ethics Committee of our institute. NTX at 100 U (2 men, for a prostate volume of a30ml) or 200 U (8men, for a prostate volume of > 30ml) was injected into the prostate. RESULTS: A mean prostatic weight was significantly different between saline and NTX injection 0.39±0.03g vs. 0.25±0.02g (p=0.0093), and 0.78±0.03g vs. 0.61±0.02g (p=0.0051) at 1 and 4 weeks, respectively. In NTX treated rats, NTX induced a generalized atrophy of prostatic glands at 4 weeks later of injection. There was wide evidence of apoptosis at in epithelial cells and stromal cells on TUNEL staining at 1 week later of NTX injection. Moreover, synaptophysin positive cells in the epithelium were decreased after NTX injection. Clinically, 7 of the 10 patients noted improvement within 1 month. The mean IPSS score decreased from 23.8±2.2 to 16.3±3.3 (p=0.0093) at 1 month, to 14.9±2.6 (p=0.0074) at 3 months, and to 16.9±2.6 (p=0.018) at 12 months. The mean prostatic volume decreased from 47.8±6.7 to 40.2±5.8 ml (p=0.0169) at 1 month. CONCLUSIONS: Intraprostatic NTX injection induces prostate apoptosis and atrophic change in rat prostate and is effective for men with symptomatic BPH. These results suggest that the NTX is a promising material for treatment of patients with BPH refractory to alpha-blockers. Source of Funding: None
1406 EFFECT OF PARTIAL BLADDER OUTLET OBSTRUCTION ON THE MORPHOLOGY OF ELASTIN IN RABBIT BLADDER SMOOTH MUSCLE Koichi Sugimoto*, Osaka-sayama, Japan; Seiji Matsumoto, Sakai, Japan; Hiroyuki Itoh, Hirotsugu Uemura, Osaka-sayama, Japan INTRODUCTION AND OBJECTIVES: Elastin, in association with collagen, allows the body’s organs to stretch and relax. Collagen and elastin fibers, the major components of connective tissue, are
502
Vol. 181, No. 4, Supplement, Tuesday, April 28, 2009
setting after surgery. The survival outcomes were combined in metaanalysis and measured as Hazard Ratio (HR) and 95% confidence interval (95%CI). The primary endpoint of interest was overall survival. Secondary endpoints were disease-free survival and incidence of grade III and IV adverse events related to the adjuvant treatment. RESULTS: More than 390 references were analyzed and 11 trials could be included, with data from 2,835 patients. The metaanalyses detected no differences in overall survival (HR 1.11; 95%CI 0.95 to 1.29; p=0.20; heterogeneity 2%), and in disease-free survival (HR 1.02; 95%CI 0.89 to 1.17; p=0.75; heterogeneity 0%) in the group treated with adjuvant therapy compared to control group. There were significant higher incidence of grade III and IV toxicities in the treatment group (p<0.00001). CONCLUSIONS: Adjuvant therapy after surgery is not capable to enhance overall survival or disease-free survival in patients with renal cell carcinoma. Furthermore, it is related to higher incidence of moderate to severe adverse events. New studies evaluating different therapeutic strategies are needed to change the prognosis of these patients. Source of Funding: None
Benign Prostatic Hyperplasia: Basic Research Moderated Poster 46 Tuesday, April 28, 2009
10:30 am - 12:30 pm
1404 LONGER AC REPEATS IN 5ALPHA-STEROID REDUCTASE TYPE III ARE ASSOCIATED WITH INCREASED BENIGN PROSTATIC HYPERPLASIA RISK Young Seop Chang*, Daejeon, Republic of Korea; Donald E Riley, Seattle, WA; Dong Seok Han, Yong-Gil Na, Ju Hyun Shin, Seung Mo Yuk, Daejeon, Republic of Korea; In Rae Cho, Koyang, Republic of Korea; Hong Sup Kim, Sang-Kuk Yang, Chungju, Republic of Korea; Hyung-Jee Kim, Cheonan, Republic of Korea; Jae Mann Song, Wonju, Republic of Korea; Chong Koo Sul, Ki Hak Song, Daejeon, Republic of Korea; John N Krieger, Seattle, WA INTRODUCTION AND OBJECTIVES: Testicular androgens are necessary for prostate growth and development. 5 alpha-steroid reductase converts testosterone to dihydro-testosterone, the most potent natural androgen. Recently, a novel gene, 5 alpha-steroid reductase type III (SRD5A3), important in androgen metabolism was found to be polymorphic. These observations led us to hypothesize that SRD5A3 polymorphisms might be associated with a genetic predisposition to develop symptomatic benign prostatic hyperplasia (BPH). METHODS: We compared SRD5A3 short tandem repeat (STR) allele sizes in 99 patients with symptomatic BPH undergoing TURP with 38 control subjects selected from general clinics who did not have symptomatic BPH. STR allele sizes were determined using an ABI 310 genetic analyzer after polymerase chain reaction (PCR)-based copying of the SRD5A3 STR region. Allele sizes were compared by calculating Fisher’s exact test and by logistic regression modeling. RESULTS: BPH patients had a higher frequency of large STRs (>38 repeats, OR =0.40; 95%CI =0.25-0.64; p = 0.0004) than controls (Table). CONCLUSIONS: Our results suggest that longer 5 alphareductase type III polymorphisms merit further investigation as a potential marker for the risk of developing symptomatic BPH and might provide insights into the pathophysiologic mechanisms.
SRD5A3-CA Repeat Lengths for Paired Alleles in 99 BPH and 38 Controls No. STR Relative Risk 95% Confidence Interval <38
>38
Control (N = 38) 21 (55%) 17 (45%) BPH* (N=99)
22 (22%) 77 (78%)
Reference 0.40
0.25-0.64^
*; Symptomatic benign prostatic hyperplasia. ^ ^ Fisher’s exact p=0.0004, two sided.
Source of Funding: None
1405 THE EFFECTS OF PURIFIED NEWLY DEVELOPED BOTULINUM NEUROTOXIN TYPE A IN RAT AND HUMAN PROSTATE Teruhiko Yokoyama*, Ryoei Hara, Norio Kondo, Tomohiro Fujii, Yoshimasa Jo, Yoshiyuki Miyaji, Atsushi Nagai, Kurashiki, Japan; Hiromi Kumon, Okayama, Japan INTRODUCTION AND OBJECTIVES: Several papers suggested that intraprostatic injection of botulinum toxin type A (BTX-A) demonstrated the efficacy for patients with symptomatic benign prostatic hyperplasia (BPH). Neurotoxins (NTX) associate with non-toxic components, and form large complexes designated progenitor toxins (PTX). In general, PTX are used because they are easily obtained and are more stable than NTX. However, it has a side effect for some patients in whom antiPTX, including anti-NTX antibodies produced after several injections. We purified NTX without non-toxic components by a simple procedure. In this study, we investigated the efficacy of this newly purified NTX for male rat prostate and also men with symptomatic BPH. METHODS: Adult male S.D. rats were injected with 5 units of NTX or saline into the prostate which were harvested and weighed after 1 or 4 weeks. The effects of NTX on prostate were histologically and immunohistochemically studied using H.E., synaptophysin, and TUNEL staining. In addition, 10 BPH patients refractory to alpha-blockers were treated with intraprostatic injection of NTX after approval by the Ethics Committee of our institute. NTX at 100 U (2 men, for a prostate volume of a30ml) or 200 U (8men, for a prostate volume of > 30ml) was injected into the prostate. RESULTS: A mean prostatic weight was significantly different between saline and NTX injection 0.39±0.03g vs. 0.25±0.02g (p=0.0093), and 0.78±0.03g vs. 0.61±0.02g (p=0.0051) at 1 and 4 weeks, respectively. In NTX treated rats, NTX induced a generalized atrophy of prostatic glands at 4 weeks later of injection. There was wide evidence of apoptosis at in epithelial cells and stromal cells on TUNEL staining at 1 week later of NTX injection. Moreover, synaptophysin positive cells in the epithelium were decreased after NTX injection. Clinically, 7 of the 10 patients noted improvement within 1 month. The mean IPSS score decreased from 23.8±2.2 to 16.3±3.3 (p=0.0093) at 1 month, to 14.9±2.6 (p=0.0074) at 3 months, and to 16.9±2.6 (p=0.018) at 12 months. The mean prostatic volume decreased from 47.8±6.7 to 40.2±5.8 ml (p=0.0169) at 1 month. CONCLUSIONS: Intraprostatic NTX injection induces prostate apoptosis and atrophic change in rat prostate and is effective for men with symptomatic BPH. These results suggest that the NTX is a promising material for treatment of patients with BPH refractory to alpha-blockers. Source of Funding: None
1406 EFFECT OF PARTIAL BLADDER OUTLET OBSTRUCTION ON THE MORPHOLOGY OF ELASTIN IN RABBIT BLADDER SMOOTH MUSCLE Koichi Sugimoto*, Osaka-sayama, Japan; Seiji Matsumoto, Sakai, Japan; Hiroyuki Itoh, Hirotsugu Uemura, Osaka-sayama, Japan INTRODUCTION AND OBJECTIVES: Elastin, in association with collagen, allows the body’s organs to stretch and relax. Collagen and elastin fibers, the major components of connective tissue, are