Faculty Bibliography

PURPOSE: The safety and effects on hematocrit of recombinant human erythropoietin (epoetin alfa) were evaluated in men undergoing radical retropubic prostatectomy. MATERIALS AND METHODS: Between February 1, 1997 and November 2, 1998, 305 men with clinically localized adenocarcinoma of the prostate underwent radical retropubic prostatectomy performed by a single surgeon (H. L.). Of these men 283 with a baseline hematocrit of less than 48% received 600 IU/kg. epoetin alfa 14 days (-14) and 7 days (-7) before radical retropubic prostatectomy. Hematocrit was measured at baseline on day -14, on day -7, just before anesthesia induction on day 0, immediately postoperatively and on the day of discharge home. The number of allogeneic units transfused, and all intraoperative and postoperative complications were recorded. RESULTS: Mean hematocrit at baseline on day -14 and at induction on day 0 was 42.9% and 45.8%, respectively (p = 0.0001). The frequency of hematocrit decreasing, showing no change or increasing 0.1 to 1.9, 2.0 to 3.9 or greater than 4.0 hematocrit points was 16.5%, 0.5%, 23%, 22% and 38%, respectively. Of the men 17% had no increase in hematocrit. A weak correlation existed between baseline hematocrit and the erythropoietic response to epoetin alfa (r2 = 0.06). Mean change in hematocrit after treatment with epoetin alfa in the quartile baseline hematocrit groups 34.2 to 41.4, 41.5 to 43.2, 43.3 to 44.9 and 45.0 to 48.0 hematocrit points was 3.71, 2.45, 3.86 and 1.02 hematocrit points, respectively. Of the surgical candidates 22 (9.1%) achieved an induction hematocrit of greater than 51%. Of the 283 men receiving epoetin alfa 21 (7.4%) also received an allogeneic transfusion. The transfusion rate did not correlate with induction hematocrit. The only adverse cardiovascular event was an uncomplicated postoperative pulmonary embolus. CONCLUSIONS: Our prospective study demonstrates that epoetin alfa given preoperatively in 2 doses of 600 IU/kg. is safe for significantly increasing hematocrit in men before radical retropubic prostatectomy. It is intuitive that the significant increase in hematocrit decreases the requirement for allogeneic blood transfusion

Two prostatic epithelial lines, one of basal origin and one of luminal origin, were established from the dorsolateral prostates of p53 null mice. The cell lines are nontumorigenic when inoculated subcutaneously under the renal capsule or intraprostatically in syngeneic mice. The luminal cell line (PE-L-1) expresses cytokeratins 8 and 18 and the basal cell line (PE-B-1) expresses cytokeratins 5 and 14. The basal cells require serum for growth, whereas the luminal cells grow only in serum-free medium. Both cell lines require the presence of growth factors for optimal growth in culture, with EGF and FGF-2 having the greatest effect on the growth rate. Both lines express androgen receptor (AR) mRNA and protein. Androgen stimulates growth of the basal cell line, indicating that the ARs are functional, whereas growth of the luminal cells is unaffected by androgens. The luminal line is significantly inhibited by exogenous TGF-beta and produces low levels of endogenous TGF-beta. In contrast, the basal cell line produces significant amounts of TGF-beta and its growth is not influenced by this cytokine. Coculture of luminal cells with prostatic smooth muscle cells results in the generation of increased levels of biologically active TGF-beta, indicating a paracrine mechanism of TGF-beta activation that may be involved in the maintenance of normal prostatic function. To our knowledge this is the first report describing both basal and luminal prostatic cell lines from a single inbred animal species and the first indication that prostatic epithelial and stromal cells interact to generate the biologically active form of TGF-beta. These lines will provide an important model for determining basal/luminal interactions in both in vitro and in vivo assays.

PURPOSE: We determined the mechanism of adverse events associated with alpha1-blockers for treating benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We randomized 1,229 men with clinical BPH at 31 Veterans Affairs medical centers into equal treatment groups, including those who received placebo, terazosin, finasteride, and combined terazosin and finasteride therapy, respectively. Adverse events were captured at all study visits during our 1-year study. Our current review of adverse events is limited to patients randomized to the placebo and terazosin groups. We compared the incidence of orthostatic blood pressure change, postural symptoms and orthostatic hypotension in men who were normotensive and hypertensive at baseline, respectively. We also determined the association of changes in systolic blood pressure with the incidence of treatment related adverse events. RESULTS: The treatment related rates of dizziness, asthenia, postural hypotension and syncope were 19%, 6%, 6% and 1%, respectively. Of these adverse events only postural hypotension was associated with orthostatic blood pressure changes. The incidence of asthenia, dizziness and postural hypotension was not significantly greater in patients with a systolic blood pressure decrease of 5 or greater and less than 5 mm. Hg, respectively. CONCLUSIONS: Dizziness and asthenia are not associated with changes in blood pressure, suggesting that these treatment related adverse events associated with alpha1-blockers are not related to vascular events. Designing a subtype selective alpha1 antagonist that has less effect on blood pressure may not result in marked improvement in tolerability over commercially available alpha1-blockers

PURPOSE: We evaluated the ability of a newly developed continence index to predict the return of urinary continence 3 months after radical retropubic prostatectomy. MATERIALS AND METHODS: We developed and used a continence index to determine continence level after removal of the urinary catheter on postoperative day 15 in 145 men. A total of 20 patients were evaluated independently by 2 nurse specialists to assess continence index reliability. We evaluated continence level, pad use and degree of bothersomeness due to incontinence 3 months after catheter removal. The association of continence score with outcome variables was calculated using the Mantel-Haenszel trend test and the predictive ability of the continence score was determined by logistic regression to produce cumulative odds ratios. RESULTS: The intraclass correlation coefficient was 0.995 for the independently assessed continence index ratings and the Cronbach coefficient alpha was 0.65 for the 5 continence index parameters. Complete continence or continence with heavy activity but not always was achieved by 96%, 85% and 68% of the men in tertiles 1 (continence score 18), 2 (continence score 15 to 17) and 3 (continence score 14 or less), respectively. The cumulative odds ratio of 2.9 (95% confidence interval [CI] 1.9 to 4. 6) per tertile indicated a 2.9-fold increased chance of incontinence for each successively lower tertile. In addition, 96%, 82% and 68% of the men in tertiles 1 to 3, respectively, required no or 1 small pad daily. The cumulative odds ratio for pad use was 2.3 (95% CI 1.5 to 3.5) per tertile. Of the patients in tertiles 1 to 3 100%, 97% and 80%, respectively, had no or slight bothersomeness due to urinary incontinence. The cumulative odds ratio for bothersomeness level was 2.7 (95% CI 1.7 to 4.3) per tertile. The Mantel-Haenszel trend test showed a significant association of continence score with all 3 outcome variables (p < or =0.001). CONCLUSIONS: Our continence index is a simple and reliable instrument that provides useful prognostic information on the early return of continence after radical retropubic prostatectomy

A prostatic smooth muscle cell line (PSMC1) was established from the dorsolateral prostate of p53 null mice. The cell line is nontumorigenic when inoculated subcutaneously, under the renal capsule or intraprostatically in syngeneic mice. These cells express alpha-smooth muscle actin (alpha-SMA), indicating their smooth muscle origin, and TGF-beta significantly enhances expression of alpha-SMA. The cells express both androgen receptor (AR) mRNA and protein, and respond mitogenically to physiological concentrations of androgens. PSMC1 cells produce significant amounts of TGF-beta, which stimulates growth by an autocrine mechanism. Dihydrotestosterone (DHT) increases proliferation of PSMC1 cells by promoting TGF-beta secretion. Considering the significant inhibitory effect of TGF-beta on prostatic epithelial cells and its stimulatory effect on the PSMC1 cells, we postulate that TGF-beta produced by prostatic smooth muscle cells may have a paracrine effect on the prostatic epithelium. We also postulate that TGF-beta may be involved in the etiology of benign prostatic hyperplasia (BPH) by stimulating excessive stromal proliferation. Line PSMC1 is the first reported androgen-responsive murine smooth muscle cell line. It will be useful for in vivo and in vitro experiments to study the mechanisms of androgen action on prostatic stroma and for delineating the interactions that occur between prostatic smooth muscle and epithelium that may lead to prostatic diseases such as BPH

The storage (irritative) and voiding (obstructive) symptoms associated with benign prostatic hyperplasia are generally attributed to prostate enlargement and increased prostatic smooth muscle tone mediated by the prevailing alpha(1)-adrenoceptors in the bladder neck and prostate. This results in obstruction and subsequent secondary changes to the bladder. However, there is growing evidence that many of these symptoms may be due to changes in extraprostatic alpha(1)-adrenoceptors, possibly alpha(1D)-adrenoceptors. Findings from the VA cooperative trial challenge the current theory that the common side effects associated with these agents are due to vascular action of alpha(1)-adrenoceptor blockers. Prostate Cancer and Prostatic Diseases (2000) 3, 76-83

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.

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.