Francois Benard

A Nomogram Predicting 10-Year Life Expectancy in Candidates for Radical Prostatectomy or Radiotherapy for Prostate Cancer

PURPOSE Candidates for definitive therapy for localized prostate cancer (PCa) should have life expectancy (LE) in excess of 10 years. However, LE estimation is difficult. To circumvent this problem, we developed a nomogram predicting 10-year LE for patients treated with either radical prostatectomy (RP) or external-beam radiation therapy (EBRT) and compared it with an existing tool. PATIENTS AND METHODS Between 1989 and 2000, 9,131 men were treated with either RP (n = 5,955) or EBRT (n = 3,176), without any secondary therapy and all deaths were considered unrelated to PCa. Age and Charlson comorbidity index (CCI) predicted 10-year LE in Cox regression models. We used 200 bootstrap resamples to internally validate the nomogram. RESULTS Median age was 66 years, median CCI was 1, median follow-up was 5.9 years and median actuarial survival was 13.8 years. Advanced age (P < .001), elevated CCI score (P < .001) and treatment type (EBRT v RP, P < .001) were independent predictors of poor 10 year LE. The nomogram predicting 10 year LE after either RP or EBRT was 84.3% accurate in split sample validation and was 2.9% (P = .007) more accurate than the existing tool. A cutoff of 70% or less was 84% accurate in identifying men who did not survive beyond 10 years. CONCLUSION Our nomogram can accurately identify those individuals who do not have sufficient LE to warrant definitive PCa treatment and can help optimizing therapy decision-making.

Acetylcholine as a Possible Neurotransmitter in Penile Erection

We investigated the erectile response to intracavernous injection of increasing doses of acetylcholine (0.5 to 500 micrograms.) in 10 monkeys. To differentiate between nicotinic (ganglionic) and muscarinic (parasympathetic postganglionic) effects, acetylcholine was likewise administered after 1.6 mg. trimethaphan camsylate and 0.1 mg. atropine, alone or sequentially. Erections were induced by cavernous nerve stimulation before and after atropine. Acetylcholine induced a dose-dependent, triphasic erectile response: a first tumescence phase followed by contraction and a subsequent second phase of tumescence. Atropine reduced but did not abolish the erectile response to acetylcholine: attainment of maximal intracavernous pressure after neurostimulation was both delayed and reduced (mean 25 cm. H2O). Only after combined nicotinic and muscarinic blockade was the erectile response to acetylcholine completely abolished. Histologic staining for acetylcholinesterase in five additional monkeys that had not received acetylcholine showed dense staining within the cavernous erectile tissue and around the cavernous arteries. Our data suggest that acetylcholine is a possible neurotransmitter for penile erection in monkeys.

A possible role for calcitonin-gene-related peptide in the regulation of the smooth muscle tone of the bladder and penis.

We investigated the effect of calcitonin-gene-related peptide (CGRP) on bladder contractions and penile erection in 12 dogs. In a system in which the arteries were tied bilaterally to ensure delivery of high drug levels to the bladder, arterial injections of CGRP significantly reduced the peak intravesical pressure of bladder contractions induced by pelvic nerve stimulation or arterial injection of carbachol. When given intravenously, CGRP had no effect on bladder contractions consequent to neural stimulation. Intravesical instillation of CGRP, however, reduced the bladder contractions significantly. Histologic staining showed CGRP-immunoreactive nerve fibers within the smooth muscle layers of the bladder wall. Intracavernous CGRP increased cavernous arterial flow and induced cavernous smooth muscle relaxation and venous outflow occlusion. Muscarinic blockade had no effect on the canine intracavernous pressure response to intracavernous injection of CGRP. Histologic staining for CGRP-immunoreactivity showed nerve-fiber-like staining within the cavernous arterial wall, the nerves running near the cavernous arteries, and the cavernous smooth muscles. Our results suggest a possible role for CGRP in the regulation of the smooth muscle tone of the bladder and penis.

Local and systemic effects of chronic intracavernous injection of papaverine, prostaglandin E1, and saline in primates

To compare the local and systemic effects of chronic intracavernous injection of papaverine, prostaglandin E1, and saline on erectile tissue, eight pigtail monkeys underwent 75 injections over a nine-month period. Monkeys were divided into three groups; each group received papaverine (10 mg.), prostaglandin E1 (20 micrograms.), or saline (one ml.). The erectile response was closely observed for two hours after each injection to monitor the onset, degree, and duration of erection. Liver function tests were performed every three months to detect early systemic metabolic changes. After sacrifice, the simian penises were perfused in situ and examined histologically with both light and electron microscopy. Papaverine resulted in an initially strong erectile response, but this was maintained throughout the length of the study in only two monkeys. In contrast, prostaglandin E1 resulted in tumescence that was maintained in all monkeys over the nine-month period. In addition, the papaverine group had elevated liver enzymes and significant histologic changes with loss of normal architecture on both light and electron microscopy. The other two groups showed only minimal histologic changes or none.

Penile detumescence: characterization of three phases.

In 22 dogs in which erection was induced by cavernous nerve stimulation, we analyzed the intracavernous pressure changes during detumescence without and with acute clamping of the aorta or electrostimulation of the lumbar sympathetic chains. Additionally, the degree of venous outflow obstruction was assessed by saline perfusion of the cavernous body during aortic occlusion. Detumescence had three distinct phases: an initial phase exhibiting a small pressure increase; a second phase showing a slow pressure decrease; and a third phase in which a fast decrease occurred. The first phase was abolished by aortic clamping, whereas the other phases were not significantly affected. Sympathetic stimulation abolished or prevented the second phase. Perfusion of the cavernous body during the second phase resulted in a pressure rise to off-scale values; however, when initiated during the terminal phase or in the nonstimulated penis, the pressure increase was slight. Our study indicates that the arterial flow rate influences the duration of the first phase of detumescence and that venous drainage is completely restored in the third phase. Furthermore, sympathetic stimulation causes an almost immediate full restoration of venous drainage, as cavernous perfusion initiated with an intracavernous pressure about twice as high as without sympathetic stimulation failed to increase pressure to off-scale values.

CALCITONIN GENE-RELATED PEPTIDE: POSSIBLY NEUROTRANSMITTER CONTRIBUTES TO PENILE ERECTION IN MONKEYS

The distribution of calcitonin gene-related peptide (CGRP) immunoreactivity in the cavernous tissue and the erectile response to intracavernous injection of CGRP was investigated in 7 monkeys. Intracavernous CGRP increased cavernous arterial flow and induced cavernous smooth muscle relaxation and venous outflow occlusion. Intracavernous injection of CGRP antibody did not significantly change the erectile response to cavernous nerve stimulation. Histologic staining for CGRP immunoreactivity showed nerve fiber-like staining within the cavernous arterial wall and the cavernous smooth muscles. These data suggest that CGRP may contribute to penile erection in monkeys.

The Effect of Venous Incompetence and Arterial Insufficiency on Erectile Function: An Animal Model

We designed an animal model to elucidate the effect of venous leakage and arterial insufficiency on erectile function. In 10 dogs, electrodes were implanted around the cavernous nerves for electroerection and blood flow in the internal pudendal artery was recorded. Venous leakage was mimicked by inserting needles of varying gauges (30 to 16G) into the corpus cavernosum and the erectile response to neurostimulation was recorded before and after the creation of the leak. The relationship between the size and the amount of the venous leakage, the changes in the intracavernous pressure (peak and drop), and the changes in the peak and maintenance arterial blood flow were documented. Arterial blood flow was then reduced by 25 and 50 per cent by means of a screw clamp on the terminal aorta. The erectile response to neurostimulation was again determined, with the same electrical parameters, first with reduced blood flow alone, then in combination with leakage of varying size. Our results showed that minor cavernous vein leakage in the presence of normal arterial flow and a healthy sinusoidal system had a minimal effect on erectile function owing to a compensatory increase in penile blood flow. However, when reduction of arterial blood flow was superimposed on venous leakage, even of a minor degree, the erectile response to neurostimulation was markedly impaired.

Effect of Intracavernous Simultaneous Injection of Acetylcholine and Vasoactive Intestinal Polypeptide on Canine Penile Erection

We investigated the effects of intracavernous injection of a combination of acetylcholine (ACh) and vasoactive intestinal polypeptide (VIP) on the erectile response in eleven adult male dogs. The minimum dose of ACh which increased the intracavernous pressure in eight dogs varied from 0.2 to 40 micrograms, and the minimum dose of VIP varied from 0.2 to 5 micrograms. When the minimum doses of ACh and VIP were injected simultaneously, a strong increase of intracavernous pressure (the mean increase was 102 cm. H2O from the baseline level) and a sustained erection (mean 5 min.) were observed in all eight dogs. The effect of simultaneous injection of both drugs was not additive but synergistic. Pretreatment with VIP-antibody and atropine intracavernously suppressed the erectile response induced by cavernous nerve stimulation. VIP may increase the affinity of muscarinic receptors for ACh in canine corpus cavernosum because pretreatment with atropine alone before the simultaneous injection of ACh and VIP completely abolished the effect of the combination. We conclude that ACh and VIP may play a cooperative role in canine penile erection.

The sympathetic role as an antagonist of erection

SummaryThe effects of the lumbar and pelvic sympathetic system on penile erection were studied in a canine model. Erection was induced by cavernous nerve stimulation and detumescence by sympathetic trunk stimulation. Erection induced by cavernous nerve stimulation normally subsides slowly. After discontinuation of electrical stimulation the intracavernous pressure drops within a mean of 291 s to 50% and after a mean of 372 s to 10% of the highest level. However, stimulation of the sympathetic trunk at the level of L4-S1 applied directly after discontinuation of cavernous nerve stimulation accelerated this drop of intracavernous pressure significantly: to 50% after a mean of 19 s and to 10% after a mean of 36 s. If stimulation of the sympathetic trunk was initiated 20 s before cavernous nerve stimulation, the pressure rise was aborted completely. Neurostimulation of the hypogastric nerves alone or in combination with cavernous nerve stimulation did not change the intracavernous pressure. These results were not altered after neurotomy of the pudendal or hypogastric nerves. The main pathway of the fibers from the sympathetic trunk to the penis seems to run via the pelvic plexus. The stimulation voltage and frequency to induce erection or detumescence were equivalent. Our results suggest that an elevated central sympathetic tone may be one of the causes of psychogenic impotence.

Men with Mild Erectile Dysfunction Benefit from Sildenafil Treatment

INTRODUCTION Sildenafil treatment has not been evaluated in a double-blind, placebo-controlled (DBPC) trial specific to men with mild erectile dysfunction (ED), defined by a 22-25 score on the International Index of Erectile Function-erectile function domain (IIEF-EF). AIM To assess sildenafil efficacy in sexually dissatisfied men with mild ED. MAIN OUTCOME MEASURES Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), IIEF, Quality of Erection Questionnaire (QEQ), Erection Hardness Score (EHS 4=completely hard/fully rigid), general efficacy questions (GEQs), event log questions (hardness sufficient for penetration, duration sufficient for successful intercourse, ejaculation/orgasm, and second erection within 24 hours), and analog scales (erection firmness, reliability, and maintenance, and general sexual performance). METHODS Eight-week DBPC flexible-dose (25, 50, or 100 mg) trial with 6-week, open-label (OL) extension. RESULTS One hundred and seventy-six men were randomized (mean±standard deviation: age, 50±12 year; ED duration, 3.5±3.2 year). Most had organic or mixed ED. For sildenafil vs. placebo, 66% vs. 89% titrated to 100 mg and efficacy at DBPC end was better, including the EDITS Index score (least squares mean [standard error], 80.3 [2.3] vs. 62.1 [2.5]; P<0.0001); treatment satisfaction (EDITS Index score >50 in 89% vs. 63%; P=0.0001); no ED (IIEF-EF ≥26 in 58% vs. 39%; P<0.05); GEQs (≥4.9-fold greater odds of improved erections and ability to have sexual intercourse); and EHS 4 (47.2% vs. 25.2% of occasions; P<0.0001). At OL end, 93% of men were satisfied (EDITS Index score>50), 77% had no ED, and ≥89% were GEQ responders; mean scores on IIEF domains, the QEQ, and analog scales were >80% of the maximum; 60% of occasions had EHS 4; and event log responses were positive on >80% of occasions, except for second erections (41.9%). Headache, nasal congestion, and flushing, mostly mild to moderate, were the most common adverse events. CONCLUSION Men with mild ED derive substantial benefit from sildenafil treatment.