René Yiou

Prospective evaluation of a 21-sample needle biopsy procedure designed to improve the prostate cancer detection rate.

OBJECTIVES To evaluate prospectively the diagnostic yield of a 21-sample ultrasound-guided needle biopsy procedure for prostate cancer in patients with elevated serum prostate-specific antigen and/or abnormal digital rectal examination findings. METHODS Between December 2000 and May 2002, 303 patients underwent 21-sample needle biopsy under local anesthesia, comprising sextant biopsies at a 45 degrees angle, 3 biopsies in each peripheral zone at an 80 degrees angle, 3 biopsies in each transition zone (TZ), and 3 biopsies in the midline peripheral zone. Morbidity was assessed clinically. A short questionnaire was filled out by 90 consecutive patients. RESULTS The cancer detection rate using 6 biopsy samples (sextant biopsies only), 12 samples (sextant plus lateral biopsies), 18 samples (sextant plus lateral plus TZ biopsies), and 21 samples (sextant plus lateral plus TZ, plus midline biopsies) was 22.7%, 28.3%, 30.7%, and 31.3%, respectively. The 21-sample procedure statistically improved the cancer detection rate by 37.9% relative to the 6-sample procedure. The improvement was most marked in patients with a prostate volume of more than 40 cm(3) (48.3%), patients with Stage T1c prostate disease (44.9%), patients undergoing repeat biopsy (66.2%), and patients with prostate-specific antigen levels greater than 10 ng/mL (38.5%). Adverse effects were infrequent (3%), consisting of prostatitis in 3 patients, acute urinary retention in 6 patients, and rectal bleeding requiring hospitalization in 1 patient taking aspirin. Using the questionnaire, 84% of patients reported macroscopic hematuria for an average of 3.4 days and hematospermia for 12.8 days, and 45% reported minor rectal bleeding lasting 1.1 days. The mean pain score, with a visual analog scale ranging between 0 (no pain) and 10 (intense pain), was 4.56. CONCLUSIONS A 21-sample needle biopsy procedure increased the prostate cancer detection rate relative to a 6-sample procedure, without increasing morbidity. Patients with elevated prostate-specific antigen values should undergo sextant biopsies and at least 6 additional biopsies in the peripheral zone and 6 in the TZ.

Restoration of functional motor units in a rat model of sphincter injury by muscle precursor cell autografts

Background. Urinary incontinence is a debilitating condition that affects primarily elderly individuals. One major mechanism results from chronic denervation of the striated urethral sphincter with associated fibrosis. The authors investigated the fate of muscle precursor cells (MPC) injected into a model of striated urethral sphincter injury that reproduces the histopathologic changes of sphincter insufficiency. Methods. The striated urethral sphincter of older male rats was damaged by electrocoagulation. MPC were isolated from limb myofiber explants, infected with an adenovirus carrying the transgene encoding &bgr;-galactosidase, and injected into the sphincter of the same animal 37 days after injury. Animals were killed 5 and 30 days after injection for assessment of sphincter function and the formation of motor units. Results. Electrocoagulation resulted in an irreversible destruction of both sphincteric myofibers and nerve endings, with a functional incapacity of the damaged sphincter to sustain an increase in bladder pressure; atrophy and fibrosis developed after 1 month. Injection of MPC resulted in the formation of &bgr;-galactosidase–expressing myotubes in the sphincter that persisted beyond 30 days. The regenerated myotubes carried acetylcholine receptors associated with a nerve ending and were thus considered to form anatomic motor units. Urodynamic studies confirmed the restoration of 41% of sphincter function 1 month after MPC injection. Conclusions. The authors showed that MPC isolated from limb muscles of an older animal can recapitulate a myogenic program when injected into an irreversibly injured sphincter. The maturation of MPC activates nerve regeneration and restores functional motor units.

Prostate Cancer Detection Rate in Patients with Repeated Extended 21-Sample Needle Biopsy

BACKGROUND Prevalence of prostate cancer (PCa) after a negative first extended prostate needle biopsy protocol is unknown. OBJECTIVE To evaluate the prevalence of significant PCa in patients who have had a negative first extended prostate biopsy protocol. DESIGN, SETTING, AND PARTICIPANTS Between March 2001 and May 2007, 2500 consecutive patients underwent an extended protocol of 21 biopsies. Of 953 patients who had a negative first extended prostate biopsy procedure, 231 patients underwent a second or more set of 21-core biopsies. Indications for repeated biopsies were persistently elevated prostate-specific antigen (PSA), PSA increase during the follow-up, or prior prostatic intraepithelial neoplasia (PIN), or atypical small acinar proliferation (ASAP). INTERVENTION All participants underwent at least two extended prostate needle biopsy protocols. MEASUREMENTS Clinical and pathologic factors (age, PSA, PSA doubling time, PIN, ASAP, digital rectal exam [DRE]) were analyzed for their ability to predict positive biopsy, and tumour parameters were assessed in patients undergoing radical prostatectomy. RESULTS AND LIMITATIONS Second, third, and fourth extended 21-sample biopsy procedures yielded a diagnosis of PCa in 18%, 17%, and 14% of patients respectively. Patients with prior PIN had 16% risk of prostate cancer; patients with ASAP had a 42% risk. The mean number of positive cores was 2.19. Prostate volume and PSA density were statistically significant predictors of positive biopsy (p<0.05). For the 43 patients who underwent radical prostatectomy, pathologic findings revealed mean Gleason score of 6.7 (6-8), pT2a-c in 72%, pT3a in16%, and pT4 in 7%. Mean cancer volume was 1.15 cc and 85.2% of tumours were clinically significant (tumour volume > 0.5 cc, Gleason > or = 7 and/or pT3). CONCLUSIONS Negative first extended biopsies should not reassure a patient of not having PCa. However, prostate cancers detected after two or more sets of extended procedures, appear to be localized (intracapsular disease) and well-differentiated prostate cancers, although they are still clinically significant.

Open versus laparoscopic radical prostatectomy: Part II.

notably the nodes were withdrawn in a protective bag [7]. In the largest series of node dissection in node-positive patients there were no cases of peritoneal, parietal or trocar port seeding, even in hormone-resistant patients [8]. Although the follow-up is short, prostate cancer does not appear to implant readily on the peritoneum or trocar track. The laparoscopic extraperitoneal approach avoids this potential risk of intraperitoneal dissemination [9–12].

Duloxetine for Mild to Moderate Postprostatectomy Incontinence: Preliminary Results of a Randomised, Placebo-Controlled Trial

BACKGROUND Duloxetine is effective in the management of stress urinary incontinence (SUI) in women but has been poorly evaluated in the treatment of SUI following radical prostatectomy (RP). OBJECTIVE To establish the superiority of duloxetine over placebo in SUI after RP. DESIGN, SETTING, AND PARTICIPANTS We conducted a prospective, randomised, placebo-controlled, double-blind, monocentric superiority trial. After a placebo run-in period of 2 wk, patients with SUI after RP were randomised to receive either 80mg of duloxetine daily or matching placebo for 3 mo. MEASUREMENTS The primary outcome measure was the relative variation in incontinence episodes frequency (IEF) at the end of study compared to baseline. Secondary outcomes included quality of life (QoL) measures (Incontinence Impact Questionnaire Short Form [IIQ-SF], Urogenital Distress Inventory Short Form [UDI-SF], Incontinence Quality of Life [I-QoL]), symptom scores (Urinary Symptom Profile [USP] questionnaire, International Consultation on Incontinence/World Health Organisation Short Form questionnaire [ICIQ-SF], the Beck Depression Inventory [BDI-II] questionnaire), 1-h pad test, and assessment of adverse events. RESULTS AND LIMITATIONS Thirty-one patients were randomised to either the treatment (n=16) or control group (n=15). Reduction in IEF was significant with duloxetine compared to placebo (mean±standard deviation [SD] variation: -52.2%±38.6 [range: -100 to +46] vs +19.0%±43.5 [range: -53 to +104]; mean difference: 71.2%; 95% confidence interval [CI] for the difference: 41.0-101.4; p<0.0001). IIQ-SF total score, UDI-SF total score, SUI subscore of the USP questionnaire, and question 3 of the ICIQ-SF questionnaire showed improvement in the duloxetine group (p=0.006, p=0.02, p=0.0004, and p=0.003, respectively). Both treatments were well tolerated throughout the study period. CONCLUSIONS Duloxetine is effective in the treatment of incontinence symptoms and improves QoL in patients with SUI after RP.

Laparoscopic Radical Prostatectomy After Transurethral Resection of the Prostate: Surgical and Functional Outcomes

OBJECTIVES To compare the morbidity and functional results after laparoscopic radical prostatectomy with and without previous transurethral resection of the prostate (TURP). METHODS From May 1998 to January 2005, 640 patients underwent laparoscopic radical prostatectomy, of whom 46 (7.2%) had previously undergone TURP. The perioperative and postoperative data were compared between group 1 (with previous TURP) and group 2 (without previous TURP). The functional results were assessed by self-administered questionnaires at 12 and 24 months after surgery. RESULTS In group 1, the operative time, hospital stay, and bladder catheterization duration was increased by 31 minutes, 1.9 days, and 2.9 days, respectively. The positive margin rate was not significantly different statistically between the two groups (P = .62). The 5-year actuarial freedom from biochemical recurrence rate was similar between the two groups (P = .86). Surgical complications occurred in 15.2% of group 1 and 5.7% of group 2 (P = .02). The risk of anastomotic stricture was 6.5% and 1.2% in groups 1 and 2, respectively (P = .02). Two years after surgery, the continence rate was 86.9% in group 1 and 95.8% in group 2 (P = .77), and the potency rate was 63.8% and 70.9%, respectively, after bilateral neurovascular bundle preservation (P = .61). However, neurovascular bundle preservation was performed after previous TURP in only 56.5% of group 1 vs 78.9% in group 2 (P = .02). The median follow-up was 50.8 months (range 30-107). CONCLUSIONS Laparoscopic radical prostatectomy can be performed after TURP without compromising the oncologic results. However, patients should be informed that the procedure is associated with worse intraoperative and postoperative outcomes. Although the urinary continence rate was not hampered by previous TURP, neurovascular bundle preservation is technically more difficult and compromises postoperative erectile function.

Relationship between penile thermal sensory threshold measurement and electrophysiologic tests to assess neurogenic impotence

OBJECTIVES Erectile function is usually assessed by neurophysiologic tests such as the bulbocavernosus reflex or pudendal nerve somatosensory evoked potentials. These tests investigate only large nerve fibers, although erection depends on autonomic nerve fibers, which are of small diameter. Warm and cold sensory fibers have similar calibers as the autonomic nerve fibers, and their integrity can be reliably evaluated by the measurement of thermal sensory thresholds. We studied penile thermal sensory testing in parallel with standard electrophysiologic tests to assess their sensitivity in the diagnosis of penile neuropathy. METHODS Twenty-five normal male subjects without erectile dysfunction or evidence of diffuse neuropathy (group 1) and 35 diabetic patients who complained of impotence (group 2) were studied. Erectile function was quantitated using the erectile dysfunction symptom score. Warm, cold, and vibratory sensory thresholds were assessed on the dorsal aspect of the penis. In addition, penile sympathetic skin responses and pudendal nerve somatosensory evoked potentials were recorded. RESULTS We found a significant difference between the two groups in the erectile dysfunction symptom score (P <0.0001), cold threshold (P = 0.0007), and warm threshold (P = 0.0025), but not for the other parameters. The erectile dysfunction symptom score correlated with the penile warm and cold thresholds (P = 0.0006 and 0.002, respectively). CONCLUSIONS Thermal thresholds assess small nerve fiber damage, which can indirectly reflect autonomic disturbances, particularly in the context of a diffuse neuropathy such as diabetic polyneuropathy. Penile thermal sensory testing correlated strongly with the clinical evaluation of erectile function and is a new and promising tool for the diagnosis of neurogenic impotence.

Pudendal nerve terminal motor latency: age effects and technical considerations

OBJECTIVES The measurement of the pudendal nerve terminal motor latency (PNTML) is used to assess anal sphincter innervation. In healthy subjects, we studied the influence of age on PNTML and the advantage of a new intra-rectal stimulator. METHODS PNTML was determined in a first series of 40 normal subjects, aged 21-75 years, using a standard St. Marks electrode, and in a second series of 20 normal subjects over 50 years, using a new intra-rectal monopolar stimulator that did not require finger insertion through the anal canal. RESULTS In the first series, PNTML ranged from 1.8 to 5.6 ms (mean+/-SD 2.94+/-0.8 ms) and correlated positively with the age of the subjects (P=0.01, Spearman test). In the second series, PNTML ranged from 2.2 to 5.4 ms (3.7+/-0.9 ms) and was similar to that of the subjects over 50 years of the first series (3.5+/-0.4 ms) (P=0.35, Mann-Whitney U test). CONCLUSIONS This study showed significant effects of age on PNTML. This should encourage every examiner to establish age-stratified reference values of PNTML for older age groups. In addition, we showed the advantage of using a new type of intra-rectal stimulator to reduce the patients discomfort by avoiding finger insertion to stimulate the pudendal nerve.

The pathophysiology of pelvic floor disorders: evidence from a histomorphologic study of the perineum and a mouse model of rectal prolapse

The muscle changes related to pelvic floor disorders are poorly understood. We conducted an anatomical and histological study of the perineum of the normal mouse and of a transgenic mouse strain deficient in urokinase‐type plasminogen activator (uPA−/−) that was previously reported to develop a high incidence of rectal prolapse. We could clearly identify the iliococcygeus (ILC) and pubococcygeus (PC) muscles and anal (SPA) and urethral (SPU) sphincters in male and female mice. The bulbocavernosus (BC), ischiocavernosus (ISC) and levator ani (LA) muscles could be found only in male mice. Histochemical analysis of the pelvic floor muscles revealed a majority of type IIA fibres. Rectal prolapses were observed only in male uPA−/− mice. The most obvious finding was an irreducible evagination of the rectal mucosa and a swelling of the entire perineal region corresponding to an irreducible hernia of the seminal vesicles through the pelvic outlet. The hernia caused stretching and thinning of the ISC, BC and LA. Myopathic damage, with degenerated and centronucleated myofibres, were observed in these muscles. The PC, ILC, SPA and SPU were not affected. This study provides an original description of a model of pelvic floor disorder and illustrates the differences existing between the perineum of humans and that of a quadruped species. In spite of these differences, the histopathologic changes observed in the pelvic floor muscles of uPA−/− mice with rectal prolapse suggest that prolonged muscular stretching causes a primary myopathic injury. This should be taken into account in the evaluation of pelvic floor disorders.

Safety of Intracavernous Bone Marrow-Mononuclear Cells for Postradical Prostatectomy Erectile Dysfunction: An Open Dose-Escalation Pilot Study

UNLABELLED Evidence from animal models replicating postradical prostatectomy erectile dysfunction (pRP-ED) suggests intracavernous injection of bone marrow-mononuclear cells (BM-MNCs) as a promising treatment approach for pRP-ED. We conducted a phase 1/2 pilot clinical trial of intracavernous autologous BM-MNC injection to treat pRP-ED (NCT01089387). Twelve patients with localized prostate cancer and vasculogenic pRP-ED refractory to maximal medical treatment were divided into four equal groups treated with escalating BM-MNC doses (2×10(7), 2×10(8), 1×10(9), 2×10(9)). Tolerance was the primary endpoint. Secondary endpoints were the effects on erectile function and penile vascularization at 6 mo, as assessed using the International Index of Erectile Function-15 and Erection Hardness Scale questionnaires, and color duplex Doppler ultrasound. We measured the peak systolic velocity in cavernous arteries and assessed endothelial function using the penile nitric oxide release test. No serious side effects occurred. At 6 mo versus baseline, significant improvements of intercourse satisfaction (6.8±3.6, 3.9±2.5, p=0.044) and erectile function (17.4±8.9, 7.3±4.5, p=0.006) domains of the International Index of Erectile Function-15 and Erection Hardness Scale (2.6±1.1, 1.3±0.8, p=0.008) were observed in the total population. Spontaneous erections showed significantly greater improvement with the higher doses. Clinical benefits were associated with improvement of peak systolic velocity and of % penile nitric oxide release test and sustained after 1 yr. Our results need to be confirmed by phase 2 clinical trials. PATIENT SUMMARY We report a phase 1/2 pilot clinical trial investigating cell therapy with injection of bone marrow mononucleated cells to treat postradical prostatectomy erectile dysfunction. No serious side effects occurred. Improvements of erectile function and penile vascularization were noted. Further studies are required to confirm these preliminary results.