Faculty Bibliography

PURPOSE: Although transitional cell carcinoma of the bladder (TCC) metastasizes frequently with devastating consequences, no marker has been available to monitor this process. Uroplakins are a group of specific markers for normal urothelium and are continuously expressed by the majority of TCCs. Detection of uroplakin-positive cells in the circulation would be a strong indication of hematogenous dissemination of tumor cells in patients with TCC. MATERIALS AND METHODS: Total RNAs were extracted from peripheral blood of 60 patients with TCC (50 non-metastatic and 10 metastatic) and 10 healthy controls, reverse-transcribed and subjected to polymerase chain reaction amplification (RT-PCR) using oligonucleotide primers of human uroplakin II gene. A uroplakin-expressing human bladder cancer cell line (RT4) was used as a positive control to establish the sensitivity of the RT-PCR assay. RESULTS: We showed that the PCR-amplification of the mRNA encoding uroplakin II (UPII), a 15-kDa urothelium-specific marker, constitutes a highly sensitive and specific assay for detecting 100% of transitional cell carcinoma tissue, and that this assay can detect a single bladder cancer cell in a 5-ml. blood sample. UPII mRNA was detected in the blood samples of 2 patients with metastatic bladder cancer without chemotherapy and 1 out of 8 such patients with chemotherapy, but not in those of 50 non-metastatic patients or normal controls. CONCLUSIONS: Uroplakin II is a highly specific marker for human TCC and the detection of uroplakin II in the peripheral blood is associated with metastatic spread of bladder cancer cells. The specific and sensitive detection of uroplakin II provides a useful adjunct for detecting bladder cancer metastasis, staging, and monitoring chemotherapeutic response

PURPOSE: The response to sildenafil after radical retropubic prostatectomy (RRP) has been reported to be approximately 40% by the Sildenafil Study Group. We undertook a study in a large cohort of post-RRP erectile dysfunction (ED) patients in order to examine the relationship between satisfaction with sildenafil and time from surgery to start of sildenafil treatment. METHODS: Pre- and post-operative erectile function was assessed by the O'Leary Brief Sexual Function Inventory questionnaire. Patient satisfaction with sildenafil before and after sildenafil treatment was assessed by the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire. Between April and October 1998, EDITS questionnaires were given to 579 patients who had undergone RRP between 1994 and 1998. 316 (55%) patients returned questionnaires. Of these, 198 (63%) had sildenafil treatment and completed post-treatment questionnaires and were included in the study group. RESULTS: In the study group, mean age was 61y. Pre-operatively, 92% had erections sufficient for vaginal penetration, 95% had bilateral nerve-sparing (NS) RRP. There was a significant increase in the treatment satisfaction rate with increasing time from surgery. Between zero and six months after surgery, the treatment satisfaction rate was 26%, which improved with time, peaking at 60% between 18 months and 2y. Self-perceived erectile function as determined by post-RRP pre-sildenafil treatment O'Leary questionnaires was not as predictive of response to sildenafil as time from surgery. CONCLUSIONS: The response to sildenafil appears to be dependent upon the interval between RRP and the start of sildenafil. The treatment satisfaction rate was found to peak at 60% between 18 months and 2y. Early nonresponders to sildenafil should not be disheartened, as they will more likely later respond

BACKGROUND: Medical management of benign prostatic hyperplasia (BPH) giving rise to lower urinary tract symptomatology (LUTS) has emerged as the mainstay for first-line therapy. Prostate-specific antigen (PSA) is the most important method of detecting prostate carcinoma. The effect of finasteride on PSA has been widely reported. Little data exist with respect to alpha-adrenergic blocking therapy in men treated for BPH. In the present investigation we set out to evaluate the effect of these two forms of therapy. METHODS: Patients enrolled in the VA Cooperative Study #359 trial were evaluated. This study evaluated men with moderate LUTS owing to BPH in four treatment groups: placebo (P), finasteride (F), terazosin (T), and combination of finasteride plus terazosin (C). Men were recruited at 31 VA medical centers and had a baseline in 52-week PSA determination at the respective sites. RESULTS: There was no significant difference in baseline PSA between four groups (mean range, 2.0-2.9 ng/ml). Statistically significant reduction in PSA levels was observed at 52 weeks in the F and C arms (P < 0.001), whereas significant increases were observed in the T and P arms (P < 0.01). Additionally, there was no significant difference in PSA response between the T and P arms. Thirty percent of men in the C or F arms had more than 40-60% reduction of PSA. In contrast, the majority of men on T or P had less than 40% change in PSA. Only 35% of men on F or C had the expected 40-60% reduction in PSA level. CONCLUSIONS: These data demonstrate no clinically significant effect of T on PSA level. The heterogeneity of PSA response to F may make monitoring patients for the development of prostate cancer problematic.

Biologically active kinin peptides are released from precursor kininogens by kallikreins. Kinins act on kinin receptors to mediate diverse biological functions including smooth muscle contraction, inflammation, pain and mitogenicity. All components of the kallikrein-kinin system exist in human male genital secretions suggesting that these molecules participate in physiological and pathophysiological genitourinary function. The objective of this study was to assess the consequences of kinin action on prostate cells. Primary cultures of prostate secretory epithelial (PE) and prostate fibromuscular stromal (PS) cells were established from human prostate tissue. Transcripts encoding both the human B1 and B2 bradykinin receptor subtypes were detected in human prostate transition-zone tissue and in cultured cells by RT-PCR. In receptor binding assays, the B1 subtype predominated on PE cell membranes and the B2 subtype predominated on PS cell membranes. In PS cells, but not in PE cells, BK induced significant inositol phosphate accumulation and [3H]-thymidine uptake. These responses were mediated through the B2 receptor subtype. The use of signal transduction inhibitors indicated that mitogenic activation by BK occurred through both protein kinase C (PKC) and protein tyrosine kinase dependent mechanisms. PMA (phorbol 12-myristate 13-acetate) produced maximal [3H]-thymidine uptake by PS cells, resulted in cell elongation and caused the alpha-actin fibres present in PS smooth muscle cells to became organized into parallel arrays along the length of the elongated cells. In summary, the prostate contains a functional kallikrein-kinin system, which could be significant in physiological and pathophysiological prostate function

PURPOSE: We determine the impact of radical retropubic prostatectomy on lower urinary tract symptoms and quality of life due to urinary problems in men with clinically localized prostate cancer. MATERIALS AND METHODS: The American Urological Association (AUA) symptom index, a symptom problem index and a quality of life due to urinary problems question were administered to 104 men before and 12 months after radical prostatectomy. Urinary continence and satisfaction with the decision to undergo radical prostatectomy were also examined. RESULTS: In men with moderate or severe baseline urinary symptoms (AUA score 8 or greater) the total AUA symptom, symptom problem and quality of life question scores decreased by 51 (-6.39), 57 (-4.22) and 25% (-0.65), respectively, after radical prostatectomy. Except for nocturia statistically significant improvements were observed for all questions captured by the AUA symptom index. Radical prostatectomy did not significantly change mean AUA symptom score or symptom problem index in men with mild urinary symptoms (AUA score less than 8). In men with moderate or severe urinary symptoms radical prostatectomy significantly improved quality of life due to urinary problems. Although 10% of men exhibited some degree of clinically relevant stress incontinence, 98% were very satisfied or satisfied with the decision to undergo radical prostatectomy. CONCLUSIONS: In men with moderate or severe urinary symptoms radical prostatectomy improves lower urinary tract symptoms and quality of life due to urinary problems. The overall beneficial impact on voiding makes radical prostatectomy an attractive treatment option for clinically localized prostate cancer

PURPOSE: To determine the expression and localization of the alpha1A-1, alpha1B and alpha1D-adrenoceptor (AR) subtypes in hyperplastic and non-hyperplastic human prostate tissue. MATERIALS AND METHODS: The expression of the alpha1-AR subtypes was examined at the mRNA level by quantitative solution hybridization, and at the protein level by immunohistochemistry using subtype selective antibodies. RESULTS: While the overall level of alpha1-AR mRNA was not significantly different between hyperplastic and non-hyperplastic tissue, there were significant differences in the ratio of the alpha1-AR subtypes expressed in the two tissue types. The most significant finding from these studies was the reduced expression of the alpha1b-AR mRNA in both glandular and stromal hyperplasia. By immunohistochemistry, the alpha1A-1-AR was detected in the stroma and not in the glandular epithelium. The alpha1B-AR was localized predominantly in the epithelium and was weakly present in the stroma. Lower levels of the alpha1B-AR were detected in the hyperplastic prostatic epithelium. The alpha1D-AR was detected in areas of stroma and was abundantly present in blood vessels. CONCLUSIONS: The alpha1A-1-, alpha1B- and alpha1D-AR subtypes are differentially localized in human prostate, and the expression levels of all three subtypes are altered in BPH. Alterations in a1-AR subtype expression (particularly the alpha1B-AR) in BPH cannot be solely attributed to changes in tissue morphometry resulting from hyperplasia and may be of significance in the pathogenesis of BPH

There have been anecdotal reports of a decrease in penile size in men with erectile dysfunction (ED) after nerve-sparing radical retropubic prostatectomy (NSRRP). Penile circumference and length measurements are obtained by one physician from 100 men, age 47 to 74, who presented at various intervals (1.7&endash;27.6 months) for the treatment of ED after NSRRP from 1994 through 1997. All patients were asked to complete a brief male sexual function inventory at their initial visit. Penile measurements were obtained both in the flaccid and erect states, with erections being induced with intracorporal injections of Trimix. The sexual inventory scores were compared with those of an age-matched control cohort of 130 men presenting for evaluation of ED during the same time period and 132 age-matched men who completed the inventory at the time of a prostate screening. By self-report, men experiencing ED after NSRRP had better libido but more severe ED than men presenting with ED of other causes. There was a decrease in all penile dimensions after NSRRP. The flaccid and erect measurements of length and circumference decreased 8% and 9%, respectively after surgery (p > 0.05). The most substantial change occurred between the first 4 and 8 months postoperatively. The average change in volume between the first 4 and 8 months was 19% to 22% in the flaccid and erect state, respectively. There is a significant decrease in penile size in men with ED after NSRRP. The etiology may be denervation smooth muscle atrophy, apoptosis, or hypoxia-induced damage to the corpora. Further research is needed to elucidate the nature of these postoperative changes.

PURPOSE: Radical retropubic prostatectomy is often performed with preservation of the bladder neck. We examine the incidence of benign and malignant prostatic tissue at the bladder neck margin in men undergoing radical retropubic prostatectomy with preservation of the bladder neck for clinically localized prostate cancer. MATERIALS AND METHODS: The study included 100 cases of radical retropubic prostatectomy with preservation of the bladder neck performed by a single surgeon (H. L.). A 2 mm. thick circumferential specimen was excised from the bladder neck, divided into 4 quadrants (anterior, posterior, right and left) and submitted for frozen section examination. The permanent sections from these bladder neck biopsies and the entire surgical specimens were analyzed by a single pathologist (J. M.). RESULTS: The frozen section diagnosis from the bladder neck biopsies were adenocarcinoma, benign prostatic tissue and no prostatic tissue in 3, 38 and 59 cases, respectively. The permanent section diagnosis of the bladder neck biopsies was adenocarcinoma, benign prostatic tissue and no prostatic tissue in 4, 57 and 39 cases, respectively. The sensitivity specificity, and positive and negative predictive values for examination of the surgical specimen to identify benign prostatic tissue was 67, 90, 90 and 65%, respectively. The bladder neck was re-biopsied because of the findings of adenocarcinoma and benign prostatic tissue in 3 and 8 cases, respectively. The initial bladder neck biopsy resulted in pathological down staging to pT2c in only 1 case. Repeat resection of the bladder neck in all cases with 10% or less benign prostatic tissue showed no prostatic tissue, whereas 50% of the cases with more than 10% benign prostatic tissue demonstrated residual benign prostatic tissue. Serum prostate specific antigen was undetectable immediately after radical retropubic prostatectomy in all cases with benign prostatic tissue only. CONCLUSIONS: Preservation of the bladder neck during radical retropubic prostatectomy does not significantly compromise total extirpation of the malignant process. Benign prostatic tissue at the bladder neck margin is relatively common. Examination of the surgical specimen has limited sensitivity, and negative and positive predictive values for the presence of benign prostatic tissue at the bladder neck margin. The impact of benign prostatic tissue as it relates to future malignant transformation is unknown. Submitting frozen section specimens from the bladder neck is reasonable for the younger man who may be at risk from benign prostatic tissue at the bladder neck margin

Despite the well-characterized histology associated with benign prostatic hyperplasia, very little is known about the underlying etiology of the disease on a molecular basis. The objective of this study was to use the technique of mRNA differential display in order to identify genes differentially expressed in human transition zone prostate tissue with high stromal density, with high epithelial density, and with nonhyperplastic histology. The extracellular matrix chondroitin/dermatan sulfate proteoglycan (CDSP) mRNA was more abundantly expressed in tissue with high stromal density, consistent with earlier findings that dermatan and chondroitin 6-sulfate glycosaminoglycans are increased in hyperplastic prostates. Messenger RNA encoding the negative regulator of cell cycle progression, BTG2, was more abundantly expressed in tissue with high epithelial densities. CDSP mRNA was abundantly expressed in primary cultures of stromal cells but was undetectable in epithelial cells. BTG2 mRNA was expressed in primary cultures of both cell types, but more abundantly in epithelial cells. BTG2 mRNA, but not CDSP mRNA, was subject to significant growth cycle regulation in cultured stromal and epithelial cells, with maximum expression occurring in quiescent cells. Generation of specific antibodies to BTG2 revealed that this protein was expressed at low levels in stroma, nonhyperplastic glands, and in hyperplastic glands. Consistent with a role in cell-cycle regulation, BTG2 protein was abundantly expressed in atrophic glands and preatrophic glands.