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1401PERCUTANEOUS PRIMARY TUMOR BIOPSY IS UNRELIABLE TO PREDICT HIGH RISK PATHOLOGIC FEATURES IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA

E Jason Abel*, Stephen H Culp, Lambros Stamatakis, Kate Lynn Bill, Pheroze Tamboli, Vitaly Margulis, David A Swanson, Christopher G Wood, Houston, TX

INTRODUCTION AND OBJECTIVES: As treatment options evolve for patients with metastatic renal cell carcinoma, there is a need for predictive information to stratify patients and guide therapy. Frequently, decisions may be made on information gained from percutaneous primary tumor biopsy. We investigated the accuracy of percutaneous biopsy to determine histologic subtype, grade and presence of sarcomatoid differentiation in patients with metastatic RCC undergoing cytoreductive nephrectomy.

METHODS: Using an institutional database, we reviewed the records of patients who had percutaneous primary tumor biopsy prior to cytoreductive nephrectomy. Patients who had biopsy at outside institution had pathology reviewed at our institution. For statistical comparison, Fuhrman grades 1 or 2 and Fuhrman grades 3 or 4 were considered low and high grade lesions, respectively.

RESULTS: A total of 162 patients had biopsy data available prior to cytoreductive nephrectomy between 1993 and 2007. Mean pathologic tumor size was 10.2 ±4.9 cm (2-32cm.) Biopsy and nephrectomy pathology results are shown in the table. There were 80 patients with a histologic subtype of RCC assigned to the biopsy. Of these, 13/80 (16.2%) patients had a different subtype reported on the nephrectomy specimen. There were 104 patients (64.2%) who had nuclear grade assigned to the biopsy. When compared with the nephrectomy specimen, 31 showed increased grade, 68 had the same grade, and 5 had decreased grade. Sarcomatoid dedifferentiation was found in 35/162 (21.6%) patients on the nephrectomy specimen. Only 2 of these 35 (5.71%) had sarcomatoid features identified on pre-operative kidney biopsy. One patient had sarcomatoid features identified on biopsy, but not in the nephrectomy specimen.

CONCLUSIONS: In patients with metastatic RCC, percutaneous renal biopsy has poor accuracy for assessment of pathologic grade or sarcomatoid features. Physicians should be cautious when using biopsy results to guide therapy.

Pathologic Assessment of Tumor Biopsy vs. Nephrectomy

Percutaneous Biopsy n (%) Nephrectomy n (%)

Grade 1 2 (1.9) 0 (0)

Grade 2 33 (31.7) 8 (8.6)

Grade 3 52 (50.0) 30 (28.8)

Grade 4 13 (12.5) 61 (58.6)

Sarcomatoid dedifferentiation 3 (1.85) 35 (21.6)

Clear cell 68 (42.0) 133 (79.1)

Papillary 11 (6.5) 8 (4.9)

Other, unclassified 78 (48.1) 27 (16.1)

No tumor identified 5 (3.1) 0 (0)

Source of Funding: None

1402SEQUENTIAL USE OF THE TYROSIN KINASE INHIBITORS SORAFENIB AND SUNITINIB

Roman Heuer*, Christian Eichelberg, Mario Zacharias, Hans Heinzer, Hamburg, Germany

INTRODUCTION AND OBJECTIVES: Little data are available about sequential use of the tyrosine kinase inhibitors (TKI) sorafenib and sunitinib for treatment of metastatic renal cell carcinoma (mRCC). We recently published our experience with sequential therapy of TKI

treatment. Purpose of this study was to give an update on our previously published data to confirm that an objective response could be obtained for patients progressing under treatment with sorafenib by changing medication to sunitinib.

METHODS: Patients who had progressive mRCC under sorafenib subsequently received sunitinib. We retrospectively identified 44 patients treated with sorafenib and the sunitinib between May 2005 and Oct 2008. Radiologic evaluation of treatment was performed every 3 mo according to the criteria for Response Evaluation Criteria in Solid Tumos (RECIST) Adverse events and abnormalities were documented during regular visits.

RESULTS: 84% of the patients had clear cell carcinoma. 65% had different kinds of immunotherapy before sequential TKI treatment was initiated. 39 (88,6%) of patients responded to initial sorafenib treatment by stable disease or partial response. 24 (54.4%) benefited from secondary TKI use with sunitinib by new disease stabilisation or partial response. 20 Patients did not respond to treatment switch and had progressive disease on first scan. Median progression free survival under treatment with sorafenib was 9,2 mo and 5,7 mo in median until second progression under treatment with sunitinib. The overall treatment time until second progression under TKI treatment was 19 mo. Overall treatment duration for sunitinib responder was significantly longer.

CONCLUSIONS: This update to our previously published data supports the hypothesis that sequential TKI therapy has clinical activity for patients with mRCC. Patients suffering progressive disease under initial therapy with sorafenib may benefit from further treatment with sunitinib.

Source of Funding: None

1403ADJUVANT THERAPY AFTER SURGERY IN RENAL CELL CARCINOMA: SYSTEMATIC REVIEW WITH META-ANALYSIS.

Leonardo O Reis, Sr*, A J o Scherr, E C Sasse, C S.P Lima, J P Lima, A D Sasse, Ubirajara Ferreira, Sr, Campinas - Sp, Brazil

INTRODUCTION AND OBJECTIVES: Patients with locally advanced renal cell carcinoma are of high risk of local recurrence or metastasis after surgery. Nevertheless, there is not consensus regarding adjuvant therapy after surgery. The existence of conflicting results from clinical trials demands a systematic review to determine the real role of adjuvant treatment in renal cell carcinoma.

METHODS: We performed a systematic review with meta-analysis. We searched electronic databases (EMBASE, MEDLINE, CENTRAL e LILACS) and proceedings for relevant trials. We included all randomized trials that compared observation or placebo to immunotherapy, hormonal therapy and/or chemotherapy in the adjuvant

Vol. 181, No. 4, Supplement, Tuesday, April 28, 2009502 THE JOURNAL OF UROLOGY®

setting after surgery. The survival outcomes were combined in meta-analysis 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 meta-analyses 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

1404LONGER 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 alpha-reductase 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. STRRelative Risk 95% Confidence Interval

<38 >38

Control (N = 38) 21 (55%) 17 (45%) Reference

BPH* (N=99) 22 (22%) 77 (78%) 0.40 0.25-0.64^

*; Symptomatic benign prostatic hyperplasia. ^ ^ Fisher’s exact p=0.0004, two sided.

Source of Funding: None

1405THE 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 anti-PTX, 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 30ml) 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

1406EFFECT 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