Best of the 2006 AUA Annual Meeting

Meeting Review

RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 120 MEETING REVIEW Best of the 2006 AUA Annual Meeting Highlights from the 2006 Annual Meeting of the American Urological Association, May 20–25, 2006, Atlanta, GA [Rev Urol. 2006;8(3):120-164] © 2006 MedReviews, LLC Key words: Erectile dysfunction • Ejaculatory dysfunction • Peyronie’s disease • Infertility • Androgen replacement therapy • Chronic pelvic pain syndrome • Chronic prostatitis • Interstitial cystitis • Stress urinary incontinence • Overactive bladder • Neurogenic bladder • Spina bifida • Bladder exstrophy • Anorectal malformations • Renal stones • Lower urinary tract symptoms • Benign prostatic hyperplasia • Prostate cancer • Robotic-assisted radical prostatectomy • Tumor markers • Bladder cancer • Kidney cancer here is no better place to learn about the latest advances in urology than the annual meeting of the American Urological Association (AUA). This year’s meeting was held in Atlanta, GA, and was attended by more than 10,000 urologists and health care professionals. A total of 1725 abstracts were presented at the meeting. The editors of Reviews in Urology have culled through this enormous volume of data, and here they present the findings that are most noteworthy and most relevant to practicing urologists. T 120 VOL. 8 NO. 3 2006 Sexual Medicine Erectile Dysfunction Melman and colleagues1 reported on 11 patients who had undergone a single intracavernosal injection of a naked DNA plasmid vector containing the Maxi-K gene. Doses of hMaxi-K ranged from 500 to 7500
g, all of which are considerably lower than doses used in prior rat model studies. The Maxi-K gene was chosen because it is responsible for encoding the production of potassium channels in penile smooth muscle. Being a phase I trial, the primary outcome was safety. REVIEWS IN UROLOGY No transfer-related adverse events were noted in any treatment patient (including no changes on physical examination, electrocardiogram testing, hormones, or other blood testing). All patients were required to use condoms during the study, but no evidence of the plasmid getting into the semen was detected on careful screening. A secondary study outcome was efficacy of treatment, and 2 of 4 of the patients who had received the highest doses of hMaxi-K therapy noted a substantial positive clinical response, with normalization of their RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 121 AUA Annual Meeting International Index of Erectile Function (IIEF) scores. This small pilot study supports the safety of this novel approach and signals the inevitable progress of this strategy through phase II trials. The same research group presented an animal study looking at the effects of repeat weekly administration of intracavernosal Maxi-K in the rat model. Because the hMaxi-K gene is not integrated into the genome of the rat, its benefits are short lived and repeated dosing is required. Lowe and colleagues2 reported on the response of 10 Sprague-Dawley rats who were randomized to 4 weekly intracavernosal injections of Maxi-K or vector alone (controls) with end-of-treatment erectile function assessment (intracorporal pressure [ICP] measurement). The treatment group had statistically significant improvements in ICP responses compared with the controls. No significant changes in systemic blood pressure were noted between treatment and control animals. Also, no cases of priapism developed in the study animals. Thus, at least in an animal model, repeated dosing of intracavernosal Maxi-K injections seems to be safe and effects some benefit from an erectile function standpoint. Data regarding 2 novel phosphodiesterase type 5 (PDE-5) inhibitors were presented. Prince and colleagues3 presented early phase I and phase II trial data on SLx-2101 (Surface Logix, Brighton, MA). SLx-2101 is converted in the liver to an active metabolite, SLx-2081. The activity of the parent compound is responsible for the rapid onset of action, whereas the metabolite accounts for the long duration. With half-lives ranging from 8 to 14 hours for both parent and metabolite, SLx-2101 was shown to maintain significantly higher concentrations than the IC50 (inhibitory concentration of 50%) for PDE-5 for more than 48 hours. The investigators noted that headache was the most common side effect and that the compound was well tolerated, with no withdrawals secondary to adverse events. They then presented preliminary phase II data in a small cohort of men with ED, showing improvement in Rigiscan measurements (Dacomed, Minneapolis, MN) at 48 hours after administration. These data suggest that this agent might have both a rapid onset and long duration of ac- The effects of medications used to treat benign prostatic hyperplasia (BPH) on ejaculatory function were presented by Rosen and colleagues.5 Dr. Rosen shared the initial findings on a large ongoing registry database of men treated for BPH. He stressed that these were findings in a “realworld” clinical registry, as opposed to a trial. In the study, the investigators measured the effects of various blockers and 5-reductase inhibitors How many PDE-5 inhibitors will the erectile dysfunction market sustain? tion. Phase III studies are awaited. The real question, however, is how many PDE-5 inhibitors will the erectile dysfunction (ED) market sustain? Data on avanafil, another novel PDE-5 inhibitor, were presented in a paper by Kaufman and Dietrich.4 They reviewed the pharmacokinetics of avanafil, characterized by fast absorption and clearance, with a Tmax of approximately 30 minutes and a halflife of approximately 1.5 hours. They also pointed out that avanafil is more selective for PDE-5 than the other PDE-5 inhibitors, with no cross-reactivity with PDE-1, -6, or -11 in particular. The investigators then presented phase II trial data from 19 centers. On the key measures of ability to penetrate and successful completion of intercourse (questions 2 and 3 of the Sexual Encounter Profile), avanafil exhibited a dose-dependent response that was statistically significant compared with placebo. At the 200-mg dose, approximately 80% of men were able to achieve rigidity sufficient for penetration, and approximately 63% successfully completed intercourse. To define efficacy, however, a true phase III trial will need to be conducted, although the dose to be used has now been identified and the safety profile seems to be acceptable. on ejaculatory force and volume. They found that of the drugs tested, alfuzosin affected ejaculation the least, followed by other -blockers, including tamsulosin, and 5-reductase inhibitors. Combination therapy patients fared worse, with approximately two thirds reporting significant loss in ejaculatory force or volume. One caveat raised by the audience was that the open-label, nonrandomized nature of the registry opened it to treatment selection bias. In reply, Dr. Rosen reasserted that these data were for the enrollment questionnaire only and that the more interesting results would be obtained by the longitudinal progression of ejaculatory dysfunction with each therapy. Because enrollment for the registry has been completed, the urologic community can look forward to these results in the near future. McVary and associates6 presented data suggesting that sildenafil might improve lower urinary tract symptoms (LUTS) when given to patients with both ED and BPH. The investigators presented the effects of sildenafil versus placebo in 366 men treated for ED with concomitant LUTS. They reported that sildenafil taken daily at bedtime for 12 weeks resulted in an average drop of 6.3 points on the International VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 121 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 122 AUA Annual Meeting continued Prostate Symptom Score (IPSS), compared with only 1.9 for placebo. The mean baseline IPSS was 17. These data suggest that PDE-5 inhibitor use might benefit men with LUTS secondary to BPH. Ongoing analyses are aimed at assessing the other PDE-5 inhibitors for use in this area. Burnett and coworkers reported on the use of PDE-5 inhibitors for the treatment of recurrent priapism. The patient population was men with recurrent (stuttering) priapism secondary to sickle cell disease or an idiopathic cause and who had failed standard therapy. Although counterintuitive, the rationale for such treatment is that recurrent priapism is due to abnormally low PDE-5 activity in search showing positive effects using this approach in sickle cell mice, and although larger, randomized, controlled trials will be required to provide definitive data, the pilot data are intriguing. Mueller and colleagues7 evaluated a large database of men who had enrolled in a post–radical prostatectomy (RP) rehabilitation program. Typically men were started early after RP on oral PDE-5 inhibition. They were given at least 4 attempts to respond to PDE-5 inhibitors, and those who did not were then switched to intracavernosal injections. Patients receiving injection therapy were then re-challenged every 4 months with sildenafil; if they responded, the injections The rationale is that recurrent priapism is due to abnormally low PDE-5 activity in cavernosal smooth muscle and that chronic administration of a PDE-5 inhibitor might lead to normalization of PDE-5 levels. cavernosal smooth muscle and that chronic administration of a PDE-5 inhibitor might lead to normalization of PDE-5 levels. A PDE-5 inhibitor, initially sildenafil but later also tadalafil, was given daily in the morning, a timing chosen to coincide with a flaccid state and lack of sexual activity. Most patients responded to the therapy, as indicated by a decrease in the frequency of priapic episodes, usually after 2 to 3 weeks of therapy. Although reporting promising results, Dr. Burnett strongly cautioned that such off-label use of PDE-5 inhibitors must be within the context of a rigorous research protocol that includes careful patient selection and extensive patient education. In the subsequent question session, the lack of a placebo control and the fact that some patients might have been taking anti-androgen therapy were commented upon. The basis for this work is Dr. Burnett’s pioneering basic re- 122 VOL. 8 NO. 3 2006 were stopped. The goal for patients was to get 2 to 3 erections per week that were rigid enough for penetration. Ninety-two patients with an average age of 59 years were evaluated in this study, and 90% reported normal erections preoperatively. All patients had organ-confined disease and had started penile rehabilitation within 12 months after RP. Sixtyseven percent of patients had a bilateral nerve-sparing procedure, 11% unilateral nerve sparing, and 22% had non–nerve-sparing RP. At 18 months of follow-up, 56.5% reported rigid erections without the use of medications. On multivariate analysis, factors that predicted a failure to regain erections without the use of medications included nerve-sparing status, sildenafil use for less than 6 months after RP, 2 or more vascular risk factors, and age greater than 65 years. Montorsi and associates8 attempted to define whether the use of PDE-5 REVIEWS IN UROLOGY inhibitors for penile rehabilitation after RP had the same beneficial results when taken on a scheduled versus an on-demand basis. This retrospective study looked at 233 consecutive patients who had undergone bilateral nerve-sparing RP (80 patients had the minimal 12-month follow-up to be included in data analysis). Patients were placed into 1 of 4 groups: no post-RP penile rehabilitation, post-RP intracavernosal therapy only, post-RP scheduled PDE5 inhibitor daily (1⁄2 full-strength tablet nightly at bedtime), and ondemand post-RP PDE-5 inhibitor (full dose). Patients who took on-demand therapy took PDE-5 inhibitors an average of 1.8 times a week. At 12 months, the IIEF score for patients who took no treatment was 8.5 and for patients who had taken any therapy it was 19.6. There was no difference in mean IIEF scores for any of the 3 treatment groups, including between on-demand and scheduled PDE-5 inhibitors. Although emanating from a well-recognized research center, these data are flawed because the population was highly selected and no assessment of compliance was conducted (how many pills were “regular users” actually taking per week?). Thompson and colleagues9 used the Prostate Cancer Prevention Trial database, an 18,882-patient database comparing finasteride with placebo, to determine how cardiovascular disease (CVD) outcomes correlate with ED in the placebo arm of this study. Forty-seven percent had ED initially, increasing to 57% at 5 years, with 11% having a CVD event during that time frame. The relative risk of CVD events in men with ED was calculated at 1.46, similar to that seen with current smoking or familial history of myocardial infarction. The investigators believed this to be compelling evidence to consider incident ED as a risk factor in patients with precedent RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 123 AUA Annual Meeting vascular risk factors for a CVD event. This is a robust analysis supporting other preliminary analyses that ED might be a harbinger of occult coronary artery disease. Revision washout procedures for penile implants after mechanical failure has become a recommendation since the demonstration of biofilms on implants. Henry and coworkers10 presented data on a salvage irrigation protocol from 3 institutions. Of 148 patients with implants undergoing revision surgery, the percentage of patients having positive cultures on the swab of fluid around the pump and the capsule tissue around the pump space were 66% and 43%, respectively. This number dropped to 25% after a revision washout procedure was performed. Although prospective results are not available, washout protocols seem to decrease intracorporal bacterial density and thus, it is hoped, reduce secondary implant infection. Secin and colleagues11 examined cavernous nerve (CN) grafting in 44 patients undergoing bilateral CN resection. Overall 5-year recovery of any penetration ability with or without oral medications was 34%; consistent penetration was 11%. Sural grafts had better outcomes compared with genitofemoral or ilioinguinal nerve grafts. No patients undergoing salvage prostatectomy regained erectile function. These data lead to the recommendation of using sural nerve grafting in specific patient populations only. Donohue and colleagues12 at Memorial-Sloan Kettering Cancer Center and New York Hospital-Cornell Medical Center presented a study assessing optimal timing and dosing of sildenafil in a rat model. Bilateral CN crush injuries were induced in rats, which were divided into groups receiving no sildenafil or sildenafil. Each group was further subdivided into 3 different medication com- mencement regimens: 3 days before crush injury, 1 hour before crush injury, and 3 days after crush injury. Intracavernosal pressure/mean arterial pressure (ICP/MAP) ratios were measured in all rats 28 days after crush injury. After the rats were killed, whole-mount corporal bodies were evaluated using TUNEL assay and immunohistochemical staining. The rats treated with sildenafil starting 1 hour before crush injury had significantly higher ICP/MAP ratios compared with controls. The group treated with sildenafil beginning 3 days before crush injury exhibited a significantly higher ICP/MAP ratio than the groups that received sildenafil 1 hour before or 3 days after crush injury. If this rat model reflects human nerve injury after CN crush. At 28 days, only the high-dose (3.2 mg/kg) animals that had been treated on the day of CN crush and for 3 days after showed a significant improvement in ICP/MAP compared with controls. Pretreatment with FK506 did not seem to improve outcome parameters at 28 days. Ejaculatory Dysfunction Dapoxetine, a short-acting selective serotonin reuptake inhibitor developed specifically for the treatment of premature ejaculation (PE), was the topic of 2 papers. In a study presented by Hellstrom and coworkers,14 dapoxetine was found effective in men with the worst forms of PE, whereas in the work by Shabsigh and colleagues15 dapoxetine was shown to be effective If this rat model reflects human nerve injury sustained as a result of radical prostatectomy, it suggests that pre-injury initiation of sildenafil might better preserve erectile function. sustained as a result of radical prostatectomy, it suggests that pre-injury initiation of sildenafil might better preserve erectile function. The same group presented data on the immunophilin ligand FK506 (tacrolimus). FK506 is an immunosuppressant agent that has been shown to protect CN architecture and erectile function in rat CN injury models. In this study, Golijanin and colleagues13 sought to further define the optimal timing and dosing of FK506 in the rat model (which simulated CN injury by controlled crushing of the CN). Rats were randomized to receive no treatment (controls), low-dose FK506 (1 mg/kg), or highdose FK506 (3.2 mg/kg). The timing of treatment was either 3 days before and day of CN crush, day of and 3 days after CN crush, or 3 days before and after CN crush. Outcomes measured were ICP/MAP ratios measured when animals were killed 28 days in long-term use. Using subgroup analysis from previous trials, Dr. Hellstrom showed that dapoxetine taken on demand had a robust effect on the Intravaginal Ejaculatory Latency Time (IELT) in men with moderate to severe PE, with an average improvement of approximately 2 minutes. Similarly, approximately half of the patients who initially reported poor or very poor control over ejaculation improved to fair or better control. Both of these measures were statistically better than those seen with placebo. Dr. Shabsigh presented extension data on previous trials of dapoxetine. He showed that the beneficial effect of dapoxetine on IELT continued beyond the 12-week period used in previous trials, and there seemed to be no tachyphylaxis as far out as 1 year. On the other hand, he also reported that 11% of patients receiving the 60-mg dose adjusted their regimen down owing to side effects. VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 123 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 124 AUA Annual Meeting continued The US Food and Drug Administration initially rejected this medication; however, the sponsor (Ortho-Urology, Raritan, NJ) has plans to re-submit the application in first quarter 2007. Rosenberg and associates16 attempted to demonstrate the impact of PE on the female partner. One hundred twenty-nine general urology female patients completed an extensive survey querying their sexual satisfaction. normal controls. These results suggest that protein expression might serve as a biomarker to predict the progression of Peyronie’s disease. Further work in the identification of the most robust candidate protein and correlation of its level of expression is forthcoming. Greenfield and associates18 presented data from a double-blind, placebo-controlled trial evaluating the electromotive drug administra- Women who had partners with reported PE generally had decreased satisfaction with the duration of intercourse and generally had problems reaching orgasm, often feeling “rushed.” The women who had partners with reported PE generally had decreased satisfaction with the duration of intercourse and generally had problems reaching orgasm, often feeling “rushed.” Many of these women were bothered by this problem enough to confront their partners. Sixty-five percent of these women were interested in receiving counseling. Peyronie’s Disease Although the cause of Peyronie’s disease (PD) is unclear even after 250 years of study, Dr. Gerald Brock and colleagues17 from London, Ontario, Canada, provided data that a novel biomarker might predict the progression of PD. This group used surfaceenhanced laser desorption/ionization time-of-flight mass spectrometry to screen cell proteins from PD plaque samples and tunica albuginea samples. They reported a significant increase in protein expression of muscle -actin, -catenin, and HSP47, as well as a variety of other proteins (on CM10 array) as compared with the tunica albuginea controls. They also found a significant increase in transforming growth factor  1/3 receptors and fibronectin from cultured PD plaque fibroblasts compared with 124 VOL. 8 NO. 3 2006 tion, also known as iontophoresis, of verapamil versus saline for PD. Fortytwo men with PD were randomized to either verapamil or saline. Treatments were administered with a Physion Mini-Physionizer (Physion, Mirandola, Italy) (2 mA for 20 minutes) twice a week for 3 months. All patients received end-of-treatment duplex ultrasound by a blinded technician. Of the 23 patients receiving verapamil, 15 (65%) had improvement in curvature (mean 9°). Of the 19 men randomized to saline treatment, 11 (58%) measured improvement in curvature (mean 7°). The percentage of patients demonstrating improvement of 20° or more was 30% for verapamil compared with 21% for saline controls. This result showed a trend toward significance. The use of this technology for the treatment of Peyronie’s disease in a noninvasive fashion shows that modest improvements might be achieved. Definitive data would require a larger trial, but these results, although disappointing, suggest that the electrical energy itself might be of some benefit. Nelson and colleagues19 presented work from 2 studies evaluating demographic and mental health status of men with Peyronie’s disease. In this REVIEWS IN UROLOGY study, 434 patients completed a Webbased survey. Mean age was 51.4  12.4 years. Fifty-six percent of patients reported problems with erections since the onset of PD. Most interestingly, 12% of men surveyed stated that they became depressed after the onset of PD. This figure is 4 times greater than the incidence of depression in the general population. In the second analysis, 87 patients completed a number of questionnaires, including quality-of-life and depression scales. Patients with PD had reduced mental health sub-scale scores on the SF-36 questionnaire, and 52% had moderate to severe depression on the Center for Epidemiological Studies-Depression Scale questionnaire. These data confirm the clinical impression that men with PD have significant impairment of their mental health. [John P. Mulhall, MD] Infertility, Androgen Replacement Therapy In the areas of infertility and androgen replacement therapy, many interesting talks and research observations were presented at this year’s meeting of the AUA. Infertility One dilemma that urologists who perform vasectomy reversals face at the time of surgery is how to proceed once examination of the fluid in the proximal vas reveals sperm parts. Should a vaso-vasostomy be performed, or should a vaso-epididymostomy be performed? Previous data from the literature suggest that a simple vaso-vasostomy can be performed with high success rates in such patients. However, at the meeting of the Society for the Study of Male Reproduction, this was called into question by data presented by Thomas and colleagues from the Cleveland Clinic. They reported on RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 125 AUA Annual Meeting their results of vasectomy reversals and came to the conclusion that in many men with sperm parts present at the site of the vasectomy the success of the surgery was much lower than anticipated. They proposed that when this occurs serious consideration should be given to the performance of vaso-epididymostomy, now that the technique for this more difficult procedure has been refined. Androgen Replacement Therapy Aging and its effects on male quality of life is a hotly debated issue. There is no question that some agingrelated effects in men are androgen dependent, and logic would dictate that androgen replacement therapy should help in such situations. However, the long-term safety of androgens, particularly their effect on the prostate gland, continues to be a controversial subject. This was evident at the plenary session on Sunday, May 21, at which 2 non-urologists debated the issue. From this reviewer’s perspective, the data presented by Andre Guay, MD, from Boston, suggested that androgen replacement therapy in aging men seems to be safe, with no solid evidence to suggest that it “causes” prostate cancer or BPH. Glenn Cunningham, MD, from Houston provided the counterpoint to this argument, stating that cause-andeffect data are unavailable and that therefore caution should be exercised until a randomized, placebocontrolled study can be performed. In support of androgen replacement therapy in aged men, Marks and colleagues20 from the University of California, Los Angeles gave what this reviewer considered to be one of the most elegant talks about this topic. Marks, in collaboration with experts from all over the United States, gave middle-aged patients placebo or testosterone daily for 6 months and performed prostate biop- sies before and after cessation of testosterone therapy. No difference in the incidence of carcinoma of the prostate was found between the placebo and testosterone therapy groups, and levels of testosterone and dihydrotestosterone within the prostate tissue also were no different between the 2 groups. In addition, Mostaghel and colleagues21 found that the genes that promote or represent prostatic growth (eg, prostatespecific antigen [PSA]) were not stimulated more in the testosterone group than in the placebo group. The investigators suggested that the effects of exogenous androgens are “buffered” by the prostate and that the long-held belief that exogenous androgens are stimulatory when given to aged men needs to be re-examined. [Jacob Rajfer, MD] Advancing Our Understanding of Chronic Pelvic Pain Syndrome, “Chronic Prostatitis,” and “Interstitial Cystitis” The 2006 meeting of the AUA was an important forum for researchers to present their latest findings related to our evolving understanding of the 2 chronic pelvic pain syndromes that continue to frustrate urologists: chronic prostatitis/chronic pelvic pain syndrome (CPPS) in men and interstitial cystitis (IC) in women (and some men). A number of extremely important basic science studies attempting to unravel the mystery of these conditions were presented, but this review will cover only the most important, clinically relevant studies that will have the most impact on practicing urologists. Etiology and Epidemiology of CPPS Lee and colleagues22 and Yilmaz and colleagues23 independently showed that patients with CPPS had evidence of allostatic overload (altered autonomic nervous system response). These 2 independent studies provide insights into possible therapeutic avenues for the management of CPPS. Nickel and coworkers24 examined the relationship between prostatitislike symptoms (clinical prostatitis) and prostate inflammation (histological prostatitis) in more than 5000 patients enrolled in the REDUCE (Reduction by Dutasteride in Prostate Cancer Events) trial for whom baseline histological and chronic prostatitis symptom index data were available. The analyses of these data do not support a correlation between clinical prostatitis and histological prostatitis, although there was weak evidence for an association between chronic prostate inflammation and the urinary subscore of the Chronic Prostatitis Symptom Index (CPSI). Further analyses might show that there is a stronger association between histological prostatic inflammation and BPH symptoms and outcomes than clinical prostatitis. In a unique analysis, Tripp and colleagues25 assessed the impact of cohabitating with a CPPS partner suffering from pain, depression, voiding disturbances, and related sexual problems. The psychosocial functioning of spouses of CPPS patients had not been examined until this group compared CPPS couples with control couples. The investigators found that the problems in psychological functioning experienced by partners of CPPS patients might not be the direct result of being in a relationship with an individual who suffers chronic pain; instead it might be that the depression arising from being in a relationship with a chronic pain patient is of prime importance. This study suggests the need for patient partner inclusion in CPPS treatment programs. Clemens and coworkers26 showed conclusively that a physician diagnosis of prostatitis is associated with a significant increase in direct medical VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 125 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 126 AUA Annual Meeting continued Table 1 Medical Costs and Medication Use Associated With a Physician Diagnosis of Prostatitis Prescription Costs Prescription Fills Outpatient Costs Outpatient Visits Inpatient Costs Inpatient Stays Total Costs Cases $1201 16.6 $945 5.4 $3051 0.38 $4387 Controls $957 13.7 $677 4.0 $2944 0.37 $2689 1.3 1.2 1.4 1.4 1.0 1.0 1.6  .001  .001  .001 .001 NS NS .001 Value Mean Ratio P value Median Cases $416 9 $594 4 $0 0 $1506 Controls $268 7 $374 2 $0 0 $948 1.6 1.3 1.6 2.0 1 1 1.6 Cases $137,105 379 $14,039 70 $381,717 7 $383,527 Controls $66,788 318 $13,727 67 $75,260 4 $253,003 Ratio Maximum NS, nonsignificant. Reprinted from Clemens JQ et al,26 with permission from the American Urological Association. costs compared with the costs observed in similar individuals without prostatitis. The difference seemed to be entirely due to outpatient and pharmacy expenses (Table 1). Because prostatitis is a frequent diagnosis, these data imply that the cost to society is substantial. Treatment of CPPS Reports from a number of clinically relevant treatment trials were presented at this year’s meeting of the AUA. Anderson and colleagues27 treated 146 men with refractory CPPS with at least 1 month of trigger point release and paradoxical relaxation training, which resulted not only in a clinically meaningful relief of pelvic pain and urinary symptoms but also appreciable improvements in libido, ejaculatory pain, and erectile and ejaculatory symptoms in almost 50% of patients with these dysfunctions. 126 VOL. 8 NO. 3 2006 Shin and Park28 treated a total of 78 men with a clinical diagnosis of CPPS with low-dose botulinum toxin A (BTA). Patients with repeated and multiregional injections showed best results, with marked improvement of symptoms and improvement in quality of life in as many as 60% of patients. This trial provides further evidence that BTA should be further evaluated in a prospectively planned and ideally sham-controlled trial. Kim and coworkers29 determined the efficacy of alfuzosin in a prospective, randomized, single-blind trial with 57 young and middle-aged (to exclude BPH patients) men with CPPS. Patients all received antibiotics and were randomized to alfuzosin or placebo. Improvements in the National Institutes of Health (NIH)CPSI total score, particularly the voiding subscore, were demonstrated in the alfuzosin group compared with the placebo group. REVIEWS IN UROLOGY Schneider and colleagues30 evaluated the efficacy of Cernilton® (a ryepollen extract) (AB Cernelle, Ängelholm, Sweden) in patients with NIH IIIA CPPS in a randomized, prospective, double-blind, placebo-controlled study. This multicenter trial, which randomized 178 patients, demonstrated that Cernilton significantly improves pain symptoms and quality of life without severe side effects compared with placebo (Table 2). Etiology and Epidemiology of IC The most important clinical papers presented at this year’s AUA meeting concentrated on the epidemiology of IC. Clemens and coworkers31 attempted to determine the prevalence of IC/PBS (painful bladder syndrome) in a community-based sample in an attempt to determine whether the prevalence varied by age, gender, race/ethnicity, and socioeconomic status. Prevalence RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 127 AUA Annual Meeting Table 2 NIH-CPSI Scores After 12 Weeks’ Treatment With Cernilton Versus Placebo Before Therapy After 12 Weeks Score Cernilton Group (n = 59) Placebo Group (n = 63) Cernilton Group (n = 52) Placebo Group (n = 60) U Test Pain 10.07 10.29 5.08 7.47 P  .0031 Urinary Symptoms 2.68 3.57 1.73 2.37 P  .5367 Quality of Life 6.47 6.73 4.19 5.36 P  .0021 Data are median scores. NIH-CPSI, National Institutes of Health Chronic Prostatitis Symptom Index. Reprinted from Schneider H et al,30 with permission from the American Urological Association. estimates varied from less than 1% to 10%, depending on the definition of the condition used. Symptoms were more common in women, older individuals, and those with lower socioeconomic status, but no significant differences were seen between the different racial/ethnic groups. IC/PBS might be more common in racial/ethnic minorities than previously thought. Clemens and colleagues32 demonstrated that a diagnosis of IC is associated with direct medical costs that are 2- to 3-fold higher in women with a physician diagnosis of IC in a large managed care population compared with costs in similar individuals without IC (Table 3). The increased costs seemed to be entirely due to outpatient and pharmacy expenses. The re- ported cost is very high, but it really is an underestimate, given that indirect costs of treatment, such as missed work, lost productivity, and poor quality of life, were not included. Carrico and coworkers33 attempted to estimate the prevalence of abuse in women with IC in pelvic floor dysfunction. Fifty-five percent of patients with pelvic floor dysfunction Table 3 Medical Costs and Medication Use Associated With a Physician Diagnosis of Interstitial Cystitis Value Prescription Costs Prescription Fills Outpatient Costs Outpatient Visits Inpatient Costs Inpatient Stays Total Costs Mean IC Cases $8834 148 $7435 Controls $4087 76 $2895 24 2.2 1.9 1.9 1.7 .001 .001 .001 .001 IC Cases $5266 107 $6243 Controls $1627 48 $2966 3.2 2.2 Ratio P value 41 $13,878 2 $30,899 78 1.6 $14,542 1.2 1.2 2.1 NS .005 .001 36 $8447 1 $22,342 19 $6660 1 $8027 2.1 1.9 1.3 1 2.8 Median Ratio Maximum IC Cases $102,900 933 $28,657 141 $89,841 15 $205,174 Controls $80,757 609 $19,787 114 $166,300 11 $207,427 IC, interstitial cystitis; NS, nonsignificant. Reprinted from Clemens JQ et al,32 with permission from the American Urological Association. VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 127 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 128 AUA Annual Meeting continued (patient-reported levator pain) had been abused physically, sexually, or emotionally. The mean number of years from the onset of abuse to the diagnosis of IC was 24 years. It seems that abuse is more common in women with IC who have pelvic floor pain than in the general IC population (55% vs 37%), and rates of abuse IC and 823 control women and noted that women with IC have significantly more pelvic surgeries than women without IC. The majority of these surgeries were performed before their diagnosis of IC; however, further studies are needed to evaluate whether these surgeries were done for pain that ultimately was proven to be Fifty-five percent of patients with pelvic floor dysfunction (patient-reported levator pain) had been abused physically, sexually, or emotionally. seem to be significantly higher in these women than in patients without IC. It might be helpful and even important to assess IC patients for abuse and offer appropriate referrals and treatment. This important research needs to be corroborated by other groups. Nickel and colleagues34 examined the interrelationships of IC symptoms and associated bother, employment, and sexual function on quality of life in a sample of 217 women with moderate to severe IC of long duration enrolled in an NIH treatment trial. This study identified sexual functioning as a strong predictor of both mental and physical quality of life. Sexual functioning, employment, and pain issues seem to be therapeutic targets in a multifaceted approach to the treatment of IC patients. Shorter and coworkers35 determined the effect of comestibles (ingested food and drink) on symptoms of IC, using a comprehensive questionnaire in 37 IC patients. The most frequently reported and the most bothersome comestibles included items containing caffeine, citrus fruits and juices, tomatoes and tomato products, items containing vinegar, and alcoholic beverages. Peters and colleagues36 compared the history of pelvic surgery in 215 women with a confirmed diagnosis of 128 VOL. 8 NO. 3 2006 from IC or whether these surgeries were involved in the etiology of the subsequent IC. Treatment of IC Bade and Smans37 have been using sacral neuromodulation since December 2001 in IC patients and presented longer-term data in 21 patients. Eighty-five percent of patients who had positive percutaneous test stimulation reported subjective improvement at 3 months; however, over time, this response rate dropped to 45% (at 25 months). The long-term benefits of this expensive, invasive intervention must be further evaluated in IC before it can be recommended as standard of care. [J. Curtis Nickel, MD, FRCSC] Incontinence Stem Cell Treatment for Stress Urinary Incontinence In the first clinical study of its kind in North America, women with stress urinary incontinence (SUI) were treated with muscle-derived stem cell injections to strengthen deficient sphincter muscles responsible for their SUI.38 Results of the study, led by researchers at the Sunnybrook Health Science Centre in Toronto and the University of Pittsburgh, School of Medicine, suggest that it is a safe approach for improving patients’ REVIEWS IN UROLOGY quality of life, with the potential to become an effective treatment for SUI. “The technique to achieve optimal efficacy is still in evolution, but we are pleased with what this study has shown,” said principal investigator Lesley Carr, MD, a urologist at Sunnybrook. “We now have evidence that stem cells are safe to use in humans and appear to improve female stress urinary incontinence.” Previous studies at the University of Pittsburgh School of Medicine using animal models with SUI have demonstrated that injecting stem cells into the urethral muscles not only increases leak point pressure but also restores the deficiency inflicting the muscles. “These findings are extremely encouraging to the 13 million people, most of them women, coping with stress urinary incontinence in the United States alone,” said Michael B. Chancellor, MD, the study’s senior author and professor of urology and gynecology at the University of Pittsburgh, School of Medicine. “These findings suggest, for the first time, that we may be able to offer people with SUI a long-term and minimally invasive treatment.” In the study, researchers took biopsies of skeletal muscle tissue from 7 female patients and isolated and expanded the stem cells from their cultured biopsy tissues. The patients then received injections of the musclederived stem cells into the area surrounding the urethra in an outpatient setting. Each patient received an equal dose of stem cell injections with 3 different injection techniques—a transurethral injection with either an 8-mm or a 10-mm needle or a periurethral injection. Of the 7 women who participated in the study, 5 reported an improvement in bladder control and quality of life, with no serious short- or long-term RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 129 AUA Annual Meeting adverse effects. These improvements were associated with the use of both the 10-mm needle injections and the periurethral injections, which allowed the investigators to deliver the stem cells close to the damaged sphincter muscles. A follow-up multiplesite study is currently being launched, which will allow researchers to determine the optimal dose of muscle stem cells needed to effectively treat SUI. Predicting Success With the Male Perineal Sling Procedure Victor W. Nitti, MD, and his group at New York University have been interested in the role of urodynamics and preoperative predictive factors for postoperative success in the sling operation. Dr. Nitti noted that urodynamic studies can be used to evaluate male patients with SUI before a perineal sling procedure. The implication of involuntary detrusor contractions (IDCs) preoperatively on patient outcome is not clear. Therefore, these investigators conducted a study to evaluate the association between preoperative IDCs and patient outcome after the male perineal sling procedure.39 At New York University Hospital, 51 men underwent a perineal sling procedure by Dr. Nitti for urodynamically proven SUI between April 2002 and June 2005. Prior therapy on these patients included radical prostatectomy (n  45), transurethral resection of the prostate (TURP) (n  4), and radiation therapy (n  9). Preoperatively, all the patients underwent urodynamic studies, and postoperative outcome was evaluated with the following self-assessment questionnaires: AUA Symptom Score (AUA-SS), Incontinence Impact Questionnaire–Short Form (IIQ-7), Urogenital Distress Inventory–Short Form (UDI-6), International Conference on Incontinence Questionnaire–Short Form (ICIQ), and the Patient Global Impression of Improvement Scale (PGII). Patients were divided into 2 groups on the basis of the presence (n  19) or absence (n  32) of IDCs on urodynamic studies. Postoperatively, 45, 34, 36, 37, and 47 patients completed the AUA-SS, IIQ-7, UDI-6, ICIQ, and PGII, respectively. With a 2-tailed t-test, it was determined that there was no significant difference between the 2 groups in terms of AUA-SS (P  .16), AUA storage score (P  .42), AUA voiding score (P  .10), IIQ-7 (P  .47), UDI-6 (P  .35), ICIQ (P  .59), and PGII (P  .45). although the mechanisms by which it works are unknown. However, because the drug is insoluble in water, its administration directly into the bladder is difficult. For the study, researchers at the University of Pittsburgh School of Medicine addressed the hydrophobic properties of IP-751 by introducing the drug into liposomes, which are advanced particulate drug carriers. Encapsulation of IP-751 into liposomes allowed it to be introduced directly into rat bladders induced with acute and subacute bladder inflammation. IP-751 significantly suppressed the bladder overactivity in Men with the overactive bladder syndrome and SUI are not at risk for postoperative failure with the sling. The investigators found no association between IDCs determined preoperatively and outcomes as measured by the AUA-SS, IIQ-7, UDI-6, ICIQ, and PGII. Further studies are warranted to clarify the prognostic value of preoperative IDCs and the effectiveness of tools currently used to evaluate outcome after the male perineal sling procedure. The conclusion from this study was that preoperative detrusor overactivity does not predict the outcome of the male sling operation. Men with the overactive bladder syndrome and SUI are not at risk for postoperative failure with the sling. Ajulemic Acid for Bladder Pain IP-751, a potent synthetic analogue of a metabolite of tetrahydrocannabinol— the principal active ingredient of marijuana—effectively suppresses pain in hypersensitive bladder disorders such as IC, according to results from an animal model study40 presented at the annual meeting of the AUA. IP-751 is a potent anti-inflammatory and a powerful analgesic, both animal models. Bladder overactivity is the underlying cause of irritation and pain in the bladder. “Interstitial cystitis is a difficult disease to treat, and not all treatments work well on all patients,” said Michael B. Chancellor, MD, one of the investigators. “Any new option we can give to our patients to alleviate their painful symptoms is very exciting.” According to the National Institute of Diabetes and Digestive and Kidney Diseases, 700,000 Americans have IC; 90% are women. IC is one of the chronic pelvic pain disorders, defined by recurring discomfort or pain in the bladder and surrounding pelvic region. Symptoms vary and can include any combination of mild to severe pain, pressure or tenderness in the bladder and pelvic area, and an urgent and/or frequent need to urinate. In IC, the bladder wall might become scarred or irritated, and pinpoint bleeding might appear on the bladder wall. This study was supported by the National Institutes of Health and the Fishbein Family Foundation CURE-IC VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 129 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 130 AUA Annual Meeting continued (Center of Urologic Research Excellence–Interstitial Cystitis) Project. IP751 was provided by Indevus Pharmaceuticals (Lexington, MA). IP-751 is currently being considered for development by Indevus for specialty disease states, including IC, with additional applications in the treatment of pain and inflammation. Distal Urethral Polypropylene Sling Procedure for SIU Investigators at the University of California, Los Angeles, reported on 5 years postoperatively, 72% of patients reported no symptoms of SUI, and 74% reported never being bothered by SUI. Patients reported an overall mean improvement of symptoms of 81% and ranked their satisfaction with quality of life as related to urinary symptoms between “pleased” and “mostly satisfied.” The investigators concluded that the distal urethral polypropylene sling procedure has low morbidity and excellent durability for the treatment of patients with SUI. This report signifi- The investigators concluded that the distal urethral polypropylene sling procedure has low morbidity and excellent durability for the treatment of patients with SUI. the long-term outcomes of the distal urethral polypropylene sling procedure.41 This procedure was developed by Shlomo Raz, MD, and numerous experts in the field were excited to see the long-term outcome of this minimally invasive and inexpensive technique for treatment of SUI. Consecutive women who underwent a distal urethral polypropylene sling procedure between November 1999 and April 2000 for treatment of SUI were included in this review. Surgical outcome was determined by patient self-assessment along with symptom, bother, and quality-of-life questionnaires. Physicians were blinded to patient responses. All patients had a minimum of 5years’ follow-up. Every treated patient was enrolled for reporting outcomes in the intent-to-treat analysis. In all, 69 patients were treated, and a minimum of 5-years’ follow-up was performed before the analysis. Treated patients lost during follow-up were defined as failures. At a minimum follow-up of 5 years the subjective success rate was determined in 88% of patients. More than 130 VOL. 8 NO. 3 2006 cantly augments the confidence of SUI experts performing synthetic sling procedures at the distal urethra. [Shachi Tyagi, MD, Michael B. Chancellor, MD] Neurourology: Basic Science Research The field of neurourology and basic science research in this area continues to expand, as evidenced by the number and quality of abstracts presented at this year’s annual meeting of the AUA. There were a number of basic science abstracts that might have significant implications for how we diagnose and treat patients with lower urinary tract dysfunction. Overactive Bladder Over the past decade there has been a growth in the diagnosis and treatment of overactive bladder (OAB). With newer antimuscarinic compounds and formulations, there has been an emphasis on differentiation by safety and side effect profiles because all available agents have similar efficacy. One such area of differentiation has been the impact of antimuscarinic REVIEWS IN UROLOGY agents on cognitive function, particularly in the elderly. This includes the impact on those patients with normal as well as impaired cognition. To date, much of the clinical work has focused on elderly patients without cognitive impairment. However, many patients who are treated with antimuscarinics do have cognitive dysfunction, such as those with Alzheimer’s disease. Sharma and associates42 investigated the effects of oxybutynin on behavior and amyloid plaque deposition in an Alzheimer’s rat model. Alzheimer’s disease is characterized by aggregates of -amyloid plaques and neurofibrillary tangles. Rats were treated for 5 to 8 months with daily oxybutynin. The investigators found an effect on behavior, but contrary to their hypothesis there was not an increase in plaque formation. Female, but not male, rats treated with oxybutynin showed reduced exploratory behavior, indicating an effect on cognition. Oxybutynin actually reduced amyloid plaque burden. The implication of this work is that in Alzheimer’s disease there might be an effect on behavior but not an acceleration of neurodegenerative changes. There has also been an increased interest in muscarinic receptor sensitivity and selectivity because some OAB agents are receptor-type nonselective, whereas others are receptortype selective (eg, darifenacin, which is M3 selective). To date, no efficacy advantages have been demonstrated for receptor-selective versus nonselective agents. Most of the clinical data are based on the idiopathic OAB population. Two presentations focused on the possible role of M2 receptors in neurogenic lower urinary tract dysfunction. Gevaert and colleagues43 used a spinal cord injury rat model and found that the M2-selective agonist arecaidine produced a significantly higher response (higher increase in baseline pressure, higher RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 131 AUA Annual Meeting rise in amplitude of macro-transients, more pressure spikes) in spinalized versus control rats. The effects of the nonselective M-agonist carbachol were similar in both groups. Tyagi and colleagues44 showed a 30-fold increase in M2 receptors in the urothelium of human bladder biopsies from neurogenic bladder patients compared with healthy bladder taken from organ donors. Interestingly, there was only a slightly higher expression of M2 receptors in the detrusor of neurogenic versus healthy bladder. The information obtained from these 2 studies supports the theory that there might be an up-regulation of M2 receptors in neurogenic detrusor overactivity. This has possible implications in terms of how neurogenic detrusor overactivity is treated and how future agents are developed. Pelvic Pain Disorders Many clinicians have observed an association between functional and pain disorders of the pelvic floor, lower genitourinary tract, and gastrointestinal system in the same patient. Through their work in an experimental rat model, Ustinova and associates45 offer a possible common mechanism for pelvic pain disorders. These investigators recorded single-unit afferent activity from fine filaments of the pelvic nerve in anesthetized rats 1 hour and 10 days after intracolonic administration of trinitrobenzenesulfonic acid (TNBS), a colonic irritant. They noted a significant increase in the resting firing rate of bladder afferents, an increased response to bladder distension, and an increased response to intravesical capsaicin administered acutely (after 1 hour) and chronically (after 10 days). Denervation of the bladder before TNBS administration greatly diminished the effects on bladder afferents. Thus, intrarectal irritation with THBS sensitized urinary bladder afferents to noxious and chemical stimuli, and interruption of efferent input minimized this effect. This finding suggests a local neurogenic pathway from the colon to the bladder and might help explain the association of disorders like interstitial cystitis and irritable bowel syndrome. Epigenetic Treatment for Neurogenic Bladder Hodges and associates46 presented the first evidence that epigenetic therapy might reverse abnormal gene function in neurogenic bladders. Histone iopathic detrusor overactivity. Traditionally, its mechanism of action has been thought to be based on the inhibition of acetylcholine from the efferent nerve terminal and subsequent decrease in detrusor activity. Recent research has shown that there might also be an effect on afferent nerves through inhibition of release of other neurotransmitters. Lucioni and coworkers47 showed that BTX-A partially inhibited the basal release of a calcitonin gene-related peptide from sensory neurons in the hydrochloric This finding suggests a local neurogenic pathway from the colon to the bladder and might help explain the association of disorders like interstitial cystitis and irritable bowel syndrome. deacetylase inhibitors trichostatin A (TSA) and valproic acid have been shown to reverse epigenetic effects on certain cells. The investigators first showed that there is a significant increase in collagen production from smooth muscle cells from human neurogenic bladders (myelomeningocele patients) when compared with smooth muscle cells from healthy human bladders. Treatment with TSA decreased the collagen level in neurogenic bladder muscle cells to almost normal. In addition, valproic acid decreased collagen types I and III gene expression as compared with controls in a dose-dependent manner up to its maximal effect at 300 mg/mL. This demonstration that epigenetic treatment with histone deacetylase inhibitors reverses abnormal collagen production in neurogenic bladder muscle cells has numerous implications for future treatment of neurogenic voiding dysfunction. Mechanism of Action of Botulinum Toxin Type A Botulinum toxin type A (BTX-A) has been reported to have significant effects on refractory neurogenic and id- acid–inflamed rat bladder. This work adds further to the experimental evidence that BTX-A might treat detrusor overactivity, at least in part, by blocking the release of sensory neurotransmitters from afferent neurons. All of the investigators mentioned above should be congratulated for their work. These highlighted abstracts have particular applicability to clinical practice and might lead to advances in the treatment of lower urinary tract dysfunction. [Victor W. Nitti, MD] Pediatric Urology: Quality of Life in Adults With Congenital Urologic Anomalies The pediatric urology sessions at this year’s meeting of the AUA were held on May 21 and 22. There were 3 poster sessions and a video session that highlighted new pediatric laparoscopic techniques. A series of 3 papers dealt with quality of life issues in adults with congenital urologic anomalies. Spina Bifida The first report was from investigators VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 131 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 132 AUA Annual Meeting continued at Children’s Hospital of Philadelphia.48 They examined the prevalence of urinary incontinence in adult spina bifida patients and its impact on quality of life. They studied 44 patients (19 female, 25 male; mean age, 24 years) with spina bifida who had medical records for review and had completed validated questionnaires, including the International Consultation on Incontinence Questionnaire (ICIQ) and the Medical Outcomes Study 36-Item Short Form, to assess urinary incontinence and quality of life issues. In addition, the subscales Physical (PH) and Mental Health (MH) were compared with age-matched national controls. The urinary tract was managed with clean intermittent catheterization (CIC) in 25 of 44 patients. Of the 25 patients on CIC, 12 had augmented bladders, with 10 of those 12 reporting a continence interval greater than 4 hours. Of the remaining 13 patients on CIC, 6 reported a continence interval of more than 4 hours. One patient in each of the 2 groups on CIC reported continuous incontinence. No significant difference was noted in the ICIQ scores of these 2 groups: 3.8  5.2 (augmented) versus 6.6  4.3 (non-augmented) (P  .1). Of the remaining 19 patients not on CIC, 10 voided through their urethra, and 9 had a vesicostomy. None of these patients had a desire to become continent, with ICIQ scores of 13.2  3.4 and 14.1  3.3, respectively (P  .5). The ICIQ scores of patients on CIC were significantly better than those not on CIC. The PH score was decreased when compared with age-matched controls, but interestingly the MH score was increased. No differences in the PH or MH scores were noted on the basis of CIC. The investigators concluded that almost half of the patients had urinary incontinence and had no interest in becoming continent. Patients on CIC had greater con- 132 VOL. 8 NO. 3 2006 tinence rates when compared with those not on catheterization. There was no difference in quality of life scores in the patients with increased continence. It was also of interest that despite their lower physical health status, adult spina bifida patients had higher mental health subscale results than age-matched national norms. Comment This study is important because surgery in the spina bifida patient can and voiding through their urethra. Renal insufficiency or failure occurred in 7, including 5 who required nephrectomy for chronic infection. Almost 20% of those who underwent primary cystectomy developed renal failure, compared with 6% of those who underwent primary reconstruction. Data on sexual function were available in 55 of 79 patients. Approximately 75% were sexually active. Six of forty-nine (12%) were continent, voided through the ure- Despite their lower physical health status, adult spina bifida patients had higher mental health subscale results than age-matched national norms. be complex, and it is imperative that a patient understand the implications of surgical reconstruction and the lifelong commitment to catheterization and urologic follow-up. Bladder Exstrophy Another very interesting study was a 30-year follow-up of a cohort of bladder exstrophy patients at the Johns Hopkins Hospital.49 Medical records were examined for surgical history and urinary, bowel, renal, and sexual function. These investigators identified 79 patients with bladder exstrophy who had at least 30 years of follow-up since birth or since their primary repair. The average age of the patients was 40.6 years. Only 16 of 79 (20.3%) voided normally through their urethra and were continent. Almost 10% catheterized through their urethra to empty their bladder, and 13.3% emptied their native bladder through a continent catheterizable stoma. Just over half were completely diverted. Methods of diversion included bowel loop diversion in 36%, ureterosigmoidostomy in 13.3%, and a continent pouch in 2.7%. Of the 24 patients who underwent a bladder neck reconstruction, 50% were dry REVIEWS IN UROLOGY thra, and were born before 1970, whereas 10 of 30 (33%) were continent, voided through the urethra, and were born after 1970. Comment This study is an important evaluation of long-term outcomes of exstrophy treatment. The surgical alternative of cystectomy is no longer routine, and osteotomy is more commonly used, yielding a higher percentage of individuals with continence and maintenance of a functioning, anatomical urinary tract. We will look forward to continued reports of surgical advancements in the care of this difficult group of patients from institutions with long-term follow-up. Anorectal Malformations A third group of investigators presented another important long-term outcomes study, of adults who have undergone surgery for anorectal malformations.50 Of the patients contacted, 75 of 117 (64%) responded to questionnaires that examined urinary and bowel continence and quality of life issues, including body image, sexual function, and fertility. Participants were also invited to undergo a RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 133 AUA Annual Meeting physical examination. The group had a mean age of 26 years (range, 18–60 years) and included 44 women and 30 men. Fifty-seven individuals spontaneously voided, 9 performed CIC, 7 patients catheterized through an appendiceal stoma, and 1 patient had an ileal conduit diversion. Only 1 patient credéd her bladder. The group had an overall urinary continence rate of 41% (31 of 75). In contrast, 59% (44 of 75) were able to defecate without additional measures. Approximately half of patients had perfect or good bowel continence, whereas almost 40% had moderate to severe fecal incontinence. Patients with permanent stomas were not included in the fecal continence questions. Twelve percent were not employed and were in the disabled category, whereas 66 of 75 were in full-time employment or in an educational program. Sixty percent of patients were in a relationship, and approximately 75% were cohabitating. There were 27 pregnancies, which resulted in 20 live births, and 50% were to the partners of male participants. Comment This important study denotes the significant level of morbidity in this select group of patients. Urinary and fecal incontinence rates were high. Nonetheless, most of the patients were employed or receiving formal education, and approximately two thirds were in relationships. This study is another important look at the long-term outcome in a group of adult patients with anorectal malformations. [Ellen Shapiro, MD, FACS, FAAP] Renal Stones A number of fine papers were presented at the 2006 AUA meeting about the pathophysiology of nephrolithiasis, advancements in treatment strategies, and technology used to treat afflicted patients. Pathophysiology Patients with cystinuria have been documented to be at risk for developing renal insufficiency. Evan and colleagues51 from Indianapolis and Chicago analyzed biopsies of renal papillae obtained at the time of percutaneous nephrolithotomy performed on cystinuric patients using light and electron microscopy, infrared spectroscopy and electron diffraction, and micro-computed tomography. They found that the ducts of Bellini were plugged with cystine crystals and that many of the inner medullary collecting ducts were dilated and contained apatite crystals. The latter were also seen in the loops of Henle. It is conceivable that “micro-obstruction” occurring within the nephron could be a causative factor for renal insufficiency in patients with cystinuria. There is a morbid obesity epidemic in the United States, a condition that is associated with an increased risk of developing kidney stones. This has been attributed to a number of factors, including increased excretion of calcium and oxalate and a reduction in urinary pH as compared with nonobese subjects. Insulin resistance is thought to play a role in the reduced urinary pH in obese individuals and the consequent uric acid stone risk. More than 100,000 gastric bypass procedures per year are now being performed in the United States to promote weight loss in this cohort. Asplin and Coe52 from Chicago reported on urinary stone risk metabolic parameters in patients who developed stones after contemporary bariatric surgery. The average time from the bariatric surgery to the initial stone event was 3.6 years. The mean 24hour urinary oxalate excretion in this group was 83 mg, as compared with 39 mg in stone formers not subjected to bariatric surgery. Severe hyperoxaluria ( 100 mg/d) was found in 23% of the subjects undergoing bariatric surgery. This approaches levels of oxalate excretion in patients with primary hyperoxalauria. Although the reduction or eradication of insulin resistance that occurs after bariatric surgery might reduce stone risk, the looming question is whether these procedures promote a widespread significant increase in oxalate excretion, promoting stone risk. Carefully performed, prospective studies are needed to address this question. Treatment Strategies The administration of -1 blockers has been demonstrated to facilitate spontaneous ureteral stone passage and fragment clearance after shock wave lithotripsy (SWL). This has been attributed to the presence of -1 receptors throughout the ureter. When these are blocked, basal ureteral tone, frequency, and the intensity of ureteral contractions are all thought to be decreased, thus facilitating stone transport. Razdan and Vasquez53 reported that the administration of tamsulosin facilitated stone clearance after ureteroscopic laser lithotripsy in patients harboring renal and ureteral stones 8 to 20 mm in size. Technological Insights SWL remains a viable treatment for patients with nephrolithiasis. Insights into shock wave physics and mechanisms of stone fragmentation can help improve results and the safety of SWL. It has clearly been demonstrated that a faster rate of shock wave delivery reduces stone fragmentation efficiency. This was previously attributed to the interference of incipient shock waves by cavitation bubble debris. However, Pishchalnikov and associates54 from Indianapolis demonstrated that this phenomenon is due to cavitation nuclei such as micro-bubbles associated with fine particles released VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 133 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 134 AUA Annual Meeting continued Table 4 Comparison of Ureteroscope Damage After Processing With 2 Different Cleaning Methods Sterilization Method Steris System 1 Cidex OPA Broken Fibers (30 cycles) Broken Fibers (100 cycles) Change in Contrast Discrimination (100 cycles) Change in Resolution (100 cycles) 12 297 14% 37% 4 10 None None 57 Reprinted from Borin JF et al, with permission from the American Urological Association. from stones interfering with shock wave propagation. There are more of these bubbles present at a fast rate. The size or width of a lithotripter’s focal zone is thought to be an important factor. Hematoma rates have been higher in patients with renal stones undergoing SWL with lithotripters having narrow focal zones, and fragmentation rates are no better. Bailey and colleagues55 reported that a broad focal zone enhances the synergism and the squeezing and shearing components of a shock wave, resulting in improved fragmentation efficiency in an in vitro model. Evan and colleagues56 from Indianapolis reported on the use of an electromagnetic lithotripter with a broad focal zone and a low pressure (Eisenmenger device) in a porcine stone model. There was minimal renal injury, and fragmentation efficiency was similar to that achieved with an unmodified Dornier HM3 device. The latter 2 reports suggest that the lithotripters of the future should have broad focal zones with lower pressures. Flexible ureteroscopes are commonly being used by urologists. Durability remains a problem with these instruments. Although improper use of the ureteroscope by the operating surgeon might play a role in its rather short life span, other factors are involved. Borin and associates57 from Orange, CA, assessed the impact 134 VOL. 8 NO. 3 2006 of the method of cleaning flexible ureteroscopes in a simulated model of 100 cases whereby the instruments were either bathed in Cidex OPA solution (Johnson & Johnson, Irvine, CA) or subjected to the Steris 1 system (Steris, Mentor, OH). The latter approach was associated with accelerated scope fiber breakage and reduction in the instrument’s contrast discrimination and resolution as compared with the Cidex OPA cleansing process (Table 4). [Dean G. Assimos, MD] Update on Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia At this year’s meeting of the AUA, as in years past, the topic of LUTS and BPH was of significant interest. Of the 1725 abstracts presented, approximately 5% were dedicated to this topic. The presentations were divided into poster sessions on basic research, epidemiology, and natural history, a poster and podium session on surgery and new technologies, and a podium session on medical and hormonal therapy. In addition, this year the Endocrine Forum was dedicated to the topic of LUTS and BPH, and a special forum was held featuring the baseline results of the Boston Area Community Health (BACH) study, an exciting new population-based study conducted by the New England Research Institute REVIEWS IN UROLOGY and supported by a grant from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK). Basic Research Among the several theories regarding the etiology of BPH, the hormonal hypothesis is by far the most appealing. It stipulates that the androgenic hormones, testosterone and its 5reduced form, dihydrotestosterone (DHT), generated by the activity of the 5-reductase enzymes, play an important role in the development of not only the normal but also the abnormal prostate in BPH and prostate cancer. Shapiro and associates58 studied the regional expression of the androgen receptor (AR), which is the target for testosterone and DHT, as well as the expression of 5-reductase type 2, which is the predominant of the 2 isoenzymes of 5-reductase in the prostate. The investigators demonstrated the presence of AR and 5reductase in the peripheral stroma and AR expression in luminal cells of the urogenital sinus by 7 weeks. The 5-reductase type 2 is expressed in a gradient fashion from the apex to the base of the prostate, with increasing expression as gestational age increases. These studies and other investigations suggest that DHT serves largely as a hormonal signal amplification during prostate development RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 135 AUA Annual Meeting and is directly associated with the target tissue distance from the testicular androgen source. Lucia and colleagues59 analyzed a subset of 198 patients from the placebo arm of the 5-year Medical Therapy of Prostate Symptoms (MTOPS) trial who underwent baseline prostate biopsies. The transition zone tissue was stained with modified trichrome and epithelial cytokeratin and subjected to quantitative image analysis. The investigators showed that the transition zone volume alone and the content of connective tissue, as well as stromal smooth muscle tissue, correlated well with age and baseline PSA level but not with baseline symptom severity or urinary flow rate. The most important observation was that the smooth muscle/transition zone volume index correlated strongly with the overall progression rate in the placebo group, with 11.1% of the patients with an index below the median experiencing progression, compared with 22.2% of those above the median (P  .036). This adds further evidence to the notion that the smooth muscle context is a major contributor to the progression of BPH. A similar effort was conducted by a group of researchers from Denver, who studied the association of stromal, epithelial, smooth muscle, and luminal composition to nodule size and symptom severity of BPH.60 Whole-mount sections of radical prostatectomy specimens were sampled and were stained similarly with trichrome and combined with immunohistochemistry of epithelial cytokeratin. BPH nodules of radical prostatectomy specimens with a low ( 8) versus a high ( 18) IPSS were compared. A distinct relationship between nodule composition, nodule size, and IPSS was found. Smaller nodules with a higher proportion of epithelial tissue were associated with low symptom scores, whereas larger nodules with less epithelial tissue were associated with higher symptom scores. As nodules increase in size over time, the contribution of cystic formation and/or stromal tissue becomes more pronounced in a progressive disproportion of stromal versus epithelial tissue, with increasing nodule size leading to the development of clinical and progressive BPH. As with the study by Lucia and colleagues, these findings suggest the importance of stromal and smooth muscle tissue as the main contributors to progressive BPH. JM-27 has been shown to be a prostate-specific marker, and Cannon and Getzenberg61 developed a serumbased enzyme-linked immunosorbent assay using monoclonal antibody techniques. The serum marker was tested in asymptomatic men with a an effect on obstruction-induced bladder detrusor muscle hypertrophy. Female Wistar rats underwent ligation of the urethra for approximately 6 weeks, after which they were given the -blocker alfuzosin at 3 or 10 mg/kg body weight/d for 7 days.62 Thereafter, urodynamics were performed and bladder weight assessed. The investigators reported a significant reduction in bladder weight in both the 3- and 10-mg groups, as well as a significant effect on urodynamics. In fact, the obstructed group given vehicle only had a significant increase in bladder capacity and bladder weight, whereas the group of animals given alfuzosin 10 mg had a bladder capacity similar to that of the sham-treated animals. This suggests that  receptors might not only exert their effect on the -adrenergic receptors in the blad- As the first serum test for LUTS and BPH ever to be developed, JM-27 deserves our attention. symptom score of less than 8 points compared with men with highly symptomatic BPH (IPSS  28); men with prostate cancer served as controls. The serum antibody test was found to have a sensitivity and specificity of 90% and 77%, respectively, to identify highly symptomatic men, and the area under the curve by receiver operating characteristic analysis was 0.86. These findings are of interest inasmuch as this is a first serum marker that is highly sensitive to identify men with BPH and severe LUTS symptomatology. One must recognize that this is only a first step, and clearly the test will not perform as well in men with intermediate IPSS; however, as the first serum test for LUTS and BPH ever to be developed, it deserves our attention. It has been suggested in the past that  receptor blockade might have der neck and prostate area but might also have secondary effects on hypertrophy of the detrusor muscle, thereby also affecting obstructive and irritative LUTS symptomatology. Given our current uncertainty regarding the actual mechanism of action of -blocker therapy, this is potentially a very important insight into a different mechanism. During last year’s meeting of the AUA, data were presented suggesting that chronic inflammatory infiltrates in the prostate of men with BPH, also known as category IV prostatitis by the NIDDK classification, might play an important role as a predictor of an accelerated natural history, with more patients in the placebo group of the MTOPS trial progressing if such inflammatory infiltrates were present in the baseline biopsy. This year, 3 groups studied the role of inflammation in the VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 135 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 136 AUA Annual Meeting continued prostate and its impact on LUTS/BPH and its severity. The group from Vienna studied the T cell–derived lymphokine interleukin-17 (IL-17) and its importance during chronic inflammation in the aging prostates.63 IL-17 has been shown to stimulate local tissue damage and induce the production of cyclo-oxygenase II and the production of hematopoietic cytokines. Hrachowitz and colleagues studied the expression pattern of the proinflammatory IL-17 isoforms and their receptors in BPH and prostate cancer. They were able to show a close association between BPH/prostate cancer and chronic inflammation, leading to an altered microenvironment resulting in tissue damage and tumor growth. IL-17 and the various isoforms might serve as perpetuators of this state. The investigators suggest that this observation might lead to new therapeutic targets and that immunotherapeutic strategies might be developed to eliminate this vicious circle, thus impacting the natural history of BPH and perhaps also prostate cancer. Levitt and coworkers64 from the Baylor College of Medicine compared expression arrays using transition zone samples from very large BPH glands and very small prostates without BPH to identify molecular candidates associated with BPH. They found a family of genes that demonstrated a more than 2-fold up-regulation, namely members of the pro-inflammatory interferon-inducible CXC chemokines. Three of such chemokines were up-regulated 2- to 3-fold in enlarged prostates, and all signal through the same receptor and are known chemo-attractants for T cells. This finding also suggested an increasing importance for inflammation in the progression of BPH and opens the opportunity to study such molecules as potential diagnostic markers and later as therapeutic targets. 136 VOL. 8 NO. 3 2006 Finally, Penna and colleagues65 from Italy established primary human BPH cell cultures from surgical specimens and found that BPH cells might act as antigen-presenting cells and exacerbate antigen-specific CD4 T cells. BPH cells can produce chemokines able to recruit cells that are known to be key players in the inflammatory response. The investigators’ conclusion is that BPH cells might induce and sustain a chronic autoimmune inflammatory process. Again, these investigators speculate that this might represent a possible Information Services (IHCIS) National Medicare Benchmark Database, which includes more than 30 managed care plans and covers 25 million lives, were analyzed by Naslund and colleagues.66 Among 1,134,491 male patients aged greater than 50 years with a total of 963,425 years of follow-up, they found that BPH is the fourth most commonly treated disease, with a prevalence rate of 13.5%, following coronary artery disease and hyperlipidemia, hypertension, and type 2 diabetes mellitus. Incidentally, prostate cancer, at a 7.8% prevalence rate, BPH cells might induce and sustain a chronic autoimmune inflammatory process. therapeutic target to control the proliferative and inflammatory components of LUTS and BPH. It is clear that the presentation of the role of chronic inflammatory infiltrates at last year’s AUA meeting sparked a great deal of interest in various laboratories around the world. It seems that what is urgently needed is (1) to further characterize the chronic inflammatory infiltrates seen in approximately 40% to 60% of all BPH specimens; (2) to attempt to identify markers in body fluids (eg, expressed prostatic secretions, ejaculate) or in the serum for the presence of such inflammatory infiltrate; and (3) to ultimately develop new therapeutic strategies aimed against what seems to be either an autoimmune process or a self-sustaining inflammatory and proliferative process leading to the progression of LUTS and BPH. No doubt this is a fertile field for future basic, translational, and ultimately clinical research. Natural History, Epidemiology, and Evaluation Data from the Integrated Health Care REVIEWS IN UROLOGY ranks number 10 in this population. The investigators also analyzed the costs associated with the treatment for these 10 most common conditions and, in fact, both prostate cancer and BPH were 2 of the 10 most costly diseases treated in this database, with prostate cancer ranking first and BPH ranking eighth. This finding highlights the enormous socioeconomic importance of prostate diseases, both benign and malignant, to our society and health care delivery system. Recently, a topic of great interest in urology has been the association of male pelvic diseases such as LUTS and BPH, as well as erectile dysfunction, with the metabolic syndrome. Parsons and associates67 examined metabolic factors associated with BPH from the Baltimore Longitudinal Study of Aging. A total of 422 adult men underwent magnetic resonance imaging of the prostate and associations of body mass index (BMI), fasting glucose, and diabetes mellitus with prostate enlargement and AUA Symptom Score were determined while adjusting for age and serum testosterone level. The investigators defined RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 137 AUA Annual Meeting Table 5 Metabolic Factors Associated With Benign Prostatic Hyperplasia: The Baltimore Longitudinal Study of Aging Age-Adjusted Odds Ratio for MRI-Measured Prostate Volume 40 mL Metabolic Factor P Trend 2 Body Mass Index (kg/m )  25 1.00 25–29.9 1.41 30–34.9 1.27 35 3.52 .01 Fasting Glucose (mg/dL) 110 1.00  110 2.98 .001 Waist Circumference (cm) 102 1.00  102 1.26 .1 67 MRI, magnetic resonance imaging. Data from Parsons JK et al. sumption and measures of LUTS and BPH, as well as to study explanatory variables for sexual dysfunction in this group of men. The participants Figure 1. Relationship between alcohol consumption and mean total International Prostate Symptom Score (IPSS). SD, standard deviation. 17.0 *P  .001 vs no alcohol consumption 16.5 16.0 Mean total IPSS prostate enlargement as a prostate volume of greater than 40 mL at the first visit. They found that the odds ratio for having an enlarged prostate was significantly greater in men with a BMI greater than 35 kg/m2 but also for those with a fasting glucose level greater than 110 mg/dL compared with those with a fasting glucose of less than 110 mg/dL (Table 5). They conclude that obesity, elevated fasting plasma glucose, and diabetes mellitus (ie, those factors contributing to the metabolic syndrome) are all risk factors for BPH. This adds further information to our already existing knowledge base regarding the relationship between the metabolic syndrome and BPH.68,69 Roehrborn and colleagues70 used baseline data from 5 BPH trials and 1 prostate cancer prevention trial (Reduction by Dutasteride of Prostate Cancer Events [REDUCE]), involving more than 19,000 men, to analyze the relationship between alcohol con- were divided into 4 groups stratified by units of alcohol consumption per week, ranging from “never drink any alcohol” to “drinking more than 6 units per week.” Surprisingly, there were no differences regarding age or BMI among the 4 groups. Prostate size was slightly smaller in those with regular alcohol consumption compared with those who never drink alcohol, and serum PSA levels were slightly higher in those with regular alcohol consumption, leading to the fact that PSA density increased from 10.1 ng/mL in those who never drink alcohol to 11.5 ng/mL in those who drink more than 6 units per week. DHT and testosterone levels, however, were not significantly different between these 2 groups. All measures of LUTS severity were significantly worse in those claiming never to drink any alcohol compared with those who drank occasionally or regularly. This was true for the total symptom score and the irritative and obstructive scores, as well as for the maximum urinary flow rate (Figure 1). Men who never drink any 15.5 * 15.0 14.5 * * 14.0 13.5 13.0 12.5 0.0 n SD 6314 7.32 0.5–2.0 3.0–6.0 Alcohol consumption (U/wk) 4080 7.35 3055 7.23 VOL. 8 NO. 3 2006 6.0 5206 7.21 REVIEWS IN UROLOGY 137 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 138 AUA Annual Meeting continued Table 6 Statistical Significance of the Effect of Alcohol Consumption on Symptom Scores, Qmax, and Sexual Activity After Adjustment for Age, BMI, PSA, and PV Least-Square Means Adjusted for Age, BMI, PSA, and PV Non-consumers of Alcohol Consumers of Alcohol Statistical Significance 16.14 14.55 P  .0001 7.12 6.47 P  .0001 Total IPSS Irritative IPSS Obstructive IPSS Qmax (mL/s) Sexual activity 9.03 8.09 P  .0001 11.57 12.53 P  .0001 — — OR  1.406* (95% CI 1.306-1.513) Least square adjusted means for symptom scores and Qmax were calculated using a multiple regression model. BMI, body mass index; PSA, prostate-specific antigen level; PV, prostate volume; IPSS, International Prostate Symptom Scale. *A logistic regression model was applied to determine the odds ratio for sexual activity in consumers of alcohol vs non-consumers of alcohol. alcohol were significantly less likely to be sexually active compared with those who admitted to the consumption of alcohol either occasionally or regularly (odds ratio  1.406) (Table 6). In a second analysis by Roehrborn and associates,71 the relationship between age, BMI, and IPSS and sexual activity, erectile dysfunction, decreased libido, and an instrument that measures problems associated with sexual dysfunction was studied. Age, BMI, and LUTS symptom severity as measured by the IPSS were significantly related to all 4 measures of sexual function, whereas in general elderly men and men with an increased BMI had a deterioration of their sexual function. Although this is certainly expected, the surprising finding was that sexual inactivity, decreased libido, and erectile dysfunction all increased in prevalence with increasing IPSS, whereas the Problem Assessment Scale of the Sexual Function Inventory score decreased dra- 138 VOL. 8 NO. 3 2006 matically in the same direction (Figure 2). These findings corroborate several cross-sectional, populationbased studies also emphasizing a strong correlation between LUTS severity and measures of erectile function.72 Additional data supporting this relationship are expected from the BACH study. Although not implying a causal link, it seems quite clear that both conditions might result from a common pathophysiologic background, and further basic research is needed to better understand these mechanisms, perhaps involving the nitric oxide (NO) synthase/NO system, pelvic ischemia, or even inflammatory conditions in the male pelvis. Sanofi-Aventis is currently supporting a BPH registry and patient survey, which has enrolled more than 6900 men at 402 sites, with both primary care providers and urologists all across the United States. The objective of this BPH registry is to examine patient management practices and patient outcomes, including symptom REVIEWS IN UROLOGY amelioration and disease progression in a real-world setting. At this year’s AUA meeting, several abstracts were presented from the baseline data of the registry.5,73,74 One of the original research questions was the difference in management styles of primary care physicians as compared with urologists, and indeed, not only were there significant differences regarding the evaluation of men with LUTS and BPH, but also regarding the use of medication. Urologists were far more likely to use combination therapy and 5-reductase inhibitors and less likely to use non-selective -blockers compared with primary care providers (Figure 3). In a separate analysis from the BPH registry, a significant association was demonstrated between specific BPH medical therapies at baseline and various measures of ejaculatory dysfunction. The issue of ejaculatory disorders and the correlation of these with LUTS severity in men with BPH was also examined by Rosen and Fitzpatrick75 in 2442 sexually active men in Europe who were given the IPSS as well as the Male Sexual Health Questionnaire. Men with more severe LUTS symptomatology experienced worse ejaculatory function compared with those with mild or moderate symptoms. The extraordinarily high prevalence of reduced ability to ejaculate, delayed ejaculation, decreased force of ejaculation, and decreased amounts of semen was surprising. Particularly surprising was the fact that, overall, 25.9% of men claimed to experience pain and discomfort during ejaculation, a number that increased from 15.4% for those with mild LUTS to 43.2% for those with severe LUTS. Frequency-volume charts (FVC) or voiding diaries have been far more commonly used in Europe than in the United States. It seems logical to ask patients to fill in the frequency of their urination as well as the expelled RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 139 AUA Annual Meeting C 40 Decreased libido (%) Sexually inactive (%) A 30 20 10 0 8 8–12 12–16 16–20 20–24 24–28 40 30 20 10 0 8 28 8–12 12–16 16–20 20–24 24–28 IPSS n 3458 1973 4410 3930 2588 1481 948 n B 3444 1981 4151 3887 2430 1380 884 D 10 Mean PAS SFI score 50 Impotence (%) 28 IPSS 40 30 20 10 0 8 6 4 2 0 8 8–12 12–16 16–20 20–24 24–28 8 28 8–12 12–16 16–20 20–24 24–28 IPSS n 3443 1981 4153 3685 28 IPSS 2428 1357 865 n 3182 1713 1870 1489 685 446 256 Figure 2. Sexual inactivity, impotence, decreased libido, and PAS SFI score by IPSS baseline categories. PAS SFI, Problem Assessment Scale of the Sexual Function Inventory; IPSS, International Prostate Symptom Scale. Figure 3. Comparison of the use of specific medical treatments for lower urinary tract symptoms/benign prostatic hyperplasia by primary care physicians (PCPs) and urologists. P  .0001, urologists vs PCPs, based on 2 analysis. SAB, uroselective 1-blockers alfuzosin and tamsulosin; NSAB, all other 1-blockers; 5ARI, 5-reductase inhibitor; Combo, AB 5ARI; AC, anticholinergic. AC 2% AC 4% Combo 12% 5ARI 8% Combo 24% SAB 42% SAB 51% NSAB 27% 5ARI 14% NSAB 16% Urologists (n  2820) PCPs (n  1075) urine volume over a period of 48 to 72 hours before their visit with a health care provider because such data form an excellent basis for the discussion of drinking habits and fluid intake versus volume output and give objective data regarding actual frequency and nocturia. Why American health care providers have been reluctant to embrace this as a standard assessment tool is unclear. However, 3 groups reported their findings with FVCs in the section on epidemiology and evaluation of LUTS and BPH. Anneveld and colleagues76 demonstrated that the FVC has discriminatory value in analyzing micturition disorders and recommended its use as a first-time diagnostic test in evaluating men with LUTS and BPH. Yap and coworkers77 studied the relationship VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 139 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 140 AUA Annual Meeting continued between FVCs and IPSS and found no simple relationship between these data. There was no strong association between the self-rated IPSS measure of urinary symptoms and the measures of voiding behavior based on objective data. The investigators suggested that this is somewhat unexpected, given that several questions of the IPSS are similar to the variables assessed in an FVC. For example, the IPSS asks specifically about frequency of urination and nocturia, clearly items of co-information that are obtained in an FVC. This is not an entirely new finding; other investiga- inhibits only type 2 of the 5-reductase, dutasteride inhibits both types 1 and 2. Although one could argue whether the different selectivity of inhibition has a significant impact on clinical efficacy and safety, an unanswered question has been whether dutasteride induces a greater reduction of intraprostatic DHT. It is known that dutasteride at the prescribed dose of 0.5 mg daily reduces serum DHT by greater than 90%, whereas finasteride reduces it by approximately 70%. This is a result of the preponderance of the type 1 5-reductase in liver and skin, which is not affected by finasteride Patients’ perception of frequency and nocturia as reported on the IPSS does not necessarily match the actual frequency of urination or the episodes of nightly urination. tors have reported that the patients’ perception of frequency and nocturia as reported on the IPSS does not necessarily match the actual frequency of urination or the episodes of nightly urination. Finally, Kaplan and associates78 suggested that the FVC is actually a better measure of improvement of LUTS symptoms in men treated with medications for LUTS and BPH. In a treatment trial with an -blocker, the IPSS improved by 25.7% and the maximum flow rate by 15%; however, urinary frequency and nocturia on an FVC improved by 33.7% and 33%, a significantly greater margin of improvement. All of these observations together suggest that health care providers engaging in the counseling and treatment of men with LUTS and BPH should take more frequent advantage of this tool in their practice. Medical and Hormonal Therapy Two inhibitors of 5-reductase enzymes are currently available: finasteride and dutasteride. They differ by their selectivity. Whereas finasteride 140 VOL. 8 NO. 3 2006 but is effectively blocked by dutasteride. Wurzel and coworkers79 presented data on 39 patients who were given either dutasteride (0.5 mg daily) or placebo for 3 months before TURP. Tissue samples were then obtained and analyzed for intraprostatic DHT concentration. They found that intraprostatic DHT was suppressed by 94% after 3 months of dutasteride at 0.5 mg daily, whereas testosterone increased significantly owing to the blockage of the conversion. Despite the expected increase in intraprostatic testosterone, however, the overall androgen load was decreased in the dutasteride-treated patients because of the overall stronger affinity of DHT to the androgen receptor. The investigators also demonstrated that the DHT suppression in the prostate is near maximal at as early as 2 weeks (89%). It is known that finasteride also reduces intraprostatic DHT by approximately 90% or more. Thus there does not seem to be a significant difference in terms of intrapro- REVIEWS IN UROLOGY static DHT reduction, at least in men with LUTS and BPH. Whether the increase in type 1 5-reductase in men with prostate cancer leads to a different scenario and whether this will demonstrate an enhanced efficacy of dutasteride in terms of prostate cancer chemoprevention remains to be seen. It is expected that data from the ongoing REDUCE prostate cancer prevention trial, in comparison with the recently finished Prostate Cancer Prevention Trial using finasteride will address this remaining question. One of the peculiar aspects of medical therapy with -adrenergic receptor blockers is the observation that some of the compounds affect ejaculatory functions more than others. Tamsulosin, for example, is associated with a higher incidence of ejaculatory abnormalities compared with the other  blockers (terazosin, doxazosin, or alfuzosin). A trial was specifically designed to study the effect of tamsulosin versus alfuzosin versus placebo with regard to ejaculatory abnormalities.80 This trial showed that men receiving 0.8 mg of tamsulosin (twice the normal clinical dose) had a high likelihood of experiencing anejaculation rather than retrograde ejaculation, as determined by postclimatic urine sampling and analysis. In a further presentation of the data from this trial, it was demonstrated that compared with placebo and alfuzosin, tamsulosin also decreased the mean sperm count, the sperm count per milliliter of ejaculate, and the mean total sperm count. In addition, sperm viscosity, motility, and morphology were negatively affected by tamsulosin compared with alfuzosin. It is unclear what causes these differences, but physicians counseling younger men with LUTS and BPH might want to be aware of these phenomena. A topic that has received significant interest by urologists as well as ophthalmologists is the intraoperative RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 141 AUA Annual Meeting floppy iris syndrome. This refers to a relaxation of the iris dilator muscle (meiosis and billowing of the iris), which makes cataract surgery more difficult. Although the overall incidence is low, it is a real problem for cataract surgeons and has been shown to occur with the use of adrenergic receptor blockers. Although initially it had only been reported to occur in patients treated with tamsulosin, it is now clear that all  receptor antagonists cause pupil constrictions.81 It has also been shown that by 8 hours all effects of the blocker on the diameter of the pupil have disappeared. This has led to the suggestion that physicians should discontinue -blockers at least several days before cataract surgery, in collaboration between the urologist and the treating ophthalmologist. However, this is not a uniform opinion shared by all ophthalmologists, and it has been shown that in some cases, even after weeks or months of discontinuation of the -blockers, the floppy iris syndrome still exists. At this time, there is no universal recommendation regarding the discontinuation and/or the duration of discontinuation before cataract surgery, but rather it is suggested that ophthalmologists and urologists should be aware of the condition when undertaking cataract surgery. Ophthalmologists might adjust the technique of cataract surgery to overcome the problem of the floppy iris or the billowing of the iris. The US Food and Drug Administration views the floppy iris syndrome as a classic effect of all -blockers, and warnings have appropriately been updated on package inserts for all available -adrenergic receptor agonists. In a related presentation by Radomski and coworkers82 at this year’s AUA meeting, iris prolapse was found intra-operatively in 14.7% of all cataract surgical procedures at the Toronto General Hospital, based on a total number of 1298 patients and 1612 eyes operated upon by 2 surgeons. The investigators also recognized that floppy iris syndrome might be associated with other conditions, such as diabetes. A new concept in combination medical therapy for LUTS and BPH is the use of an -blocker together with an antimuscarinic agent to help those men suffering from mostly irritative voiding symptoms. Macdiarmid and colleagues83 conducted a multicenter, double-blind trial enrolling 418 men over the age of 45 years with an IPSS of 13 points or more and an irritative subscore of 8 points or more. These men received either tamsulosin (.4 mg daily) with placebo or with additional extended-release (ER) oxybutynin (10 mg) for 12 weeks. Patients had to have a maximum flow rate of greater than 8 mL/s and a residual urine volume of less than 150 mL on 2 occasions. The investigators found that tamsulosin combined with ER oxybutynin elicited a greater improvement in total as well as irritative IPSS and greater improvement in the Quality of Life Score compared with the tamsulosin-plus-placebo group. Certain safety criteria were established, and patients were considered to have reached an endpoint if they had a maximum flow rate of less than 5 mL/s or a postvoid residual volume of greater than 300 mL on any of the subsequent follow-up visits. Either or both of these endpoints occurred in 14 (6.7%) of the tamsulosin-plus-ER oxybutynin group, compared with 13 (6.2%) of the placebo group. Obviously, this difference was not statistically significant, and thus the investigators believe that the combination of an antimuscarinic agent with an blocker provides increased efficacy in terms of irritative symptoms while being safe at least over a 12-week period. Clearly, additional studies will need to demonstrate efficacy but also safety over a longer period of time and in patient populations stratified by risk factors for retention and surgery, such as age, prostate size, and serum PSA level. The Alfuzosin Long-Term Efficacy and Safety Study (ALTESS) is a 2year, double-blind, placebo-controlled, multicenter, randomized study comparing placebo with alfuzosin (10 mg once daily) in men at increased risk for progression of LUTS and BPH.84,85 The men in the ALTESS study had a serum PSA level of 3.5 ng/mL, compared with 2.4 ng/mL in the MTOPS trial, a symptom score of 19.2 points, compared with 16.9 points in the MTOPS trial. The distribution of clinical progression events was similar to that observed in the MTOPS trial. Sixty-seven percent of all progression events were worsening of the IPSS by 4 points or more, 7% acute urinary retention episodes, and 26% BPH-related surgery. Compared with placebo, overall BPH progression was reduced statistically significantly (by 26%) by alfuzosin (Figure 4). The incidence of surgery was reduced by 22% (nonsignificant), and the incidence of symptomatic worsening was reduced by 30% (P  .001). The incidence of acute urinary retention was not significantly impacted by alfuzosin. Over the 2-year period, alfuzosin induced a symptom improvement of 5.9 points, compared with placebo at 4.7 points, while being very well tolerated with a very low incidence of vasodilatory or sexually related adverse events. When comparing results from ALTESS with those of the MTOPS trial, it is striking how similarly the incidence of acute retention, symptomatic worsening, and BPH-related surgery is related to the baseline serum PSA levels (Figure 5). Overall, baseline serum PSA level and digital rectal examination (DRE)-estimated prostate size were the best VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 141 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 142 AUA Annual Meeting continued Placebo Log-rank test P  .0008 26% 2.0 Alfuzosin 1.5 1.0 0.5 0 0 90 180 270 360 450 Time (d) 540 630 720 Figure 4. Cumulative incidence of overall benign prostatic hyperplasia progression with alfuzosin versus placebo. 142 VOL. 8 NO. 3 2006 This year, 3 abstracts reported on 2 different drugs tested against placebo, as well as the combination of an blocker with sildenafil citrate in the treatment of men with LUTS and ED.88-90 Tadalafil was given in a double-blind, randomized, parallelgroup study after a 4-week placebo run-in over a period of 12 weeks (6 weeks at 5 mg and 6 weeks at Figure 5. ALTESS and MTOPS: incidence of benign prostatic hyperplasia–related surgery by prostate-specific antigen tertile. ALTESS, Alfuzosin Long-Term Efficacy and Safety Study; MTOPS, Medical Therapy of Prostate Symptoms. REVIEWS IN UROLOGY MTOPS (4 y) ALTESS (2 y) 12 AUR, cumulative incidence (%) predictors for both AUR and surgery, but similar to the MTOPS trial, postvoid residual volume was also predictive of symptomatic worsening over time (Figure 6). An exciting new development in the medical therapy of LUTS and BPH is the use of PDE inhibitors, specifically inhibitors of the PDE-5 isoenzyme. These drugs, currently approved for the treatment of erectile dysfunction, work by relaxation of the smooth muscle in the cavernous tissue of the penis. It is known that there is also a considerable abundance of PDE-5 in the prostate, presumably involved in smooth muscle tone regulation as well. It seemed plausible that inhibition of PDE-5 in the prostate might lead to smooth muscle relaxation by a mechanism not unlike that of the postulated mechanism for -receptor blockers, leading to an improvement in the signs and symptoms of LUTS associated with clinical BPH. Indeed, in addition to other studies, reports from non-controlled studies have emphasized the improvement in LUTS symptoms in men treated with sildenafil citrate for BPH.86,87 20 mg) and compared with placebo.88 From the screening visit to the endpoint, tadalafil improved the IPSS by 6.2 points (5 mg) and 7.1 points (20 mg) compared with the placebo effect of 3.9 and 4.5 points, respectively (Figure 7). Quality of life scores and BPH impact indices were equally improved. Surprisingly, however, there was no effect regarding maximum urinary flow rate or postvoid residual urine measures. Tadalafil was well tolerated and, in addition to its effect on LUTS, had a significant improvement on the IIEF score. In a very similar trial,89 sildenafil citrate was given daily at 50 and 100 mg at bedtime or before sexual activity to 366 men over the age of 45 years with an IIEF score of less than 25 and IPSS of greater than 12 points. The EF domain of the IIEF improved by 9.2 points in the sildenafil group compared with 1.9 points in the placebo group (P  .001), but the IPSS improved by 6.3 points versus 1.9 points with sildenafil versus placebo; all other measures, such as BPH Impact Index and Quality of Life Score, improved as well. In this study as in the 10 12 10.8 Placebo Doxazosin 8.7 8 6.6 5.7 6 4 2 3.2 2.1 0 AUR, cumulative incidence (%) Cumulative incidence (%) Overall progression events 2.5 10 11 Placebo Alfuzosin 8 7.0 5.9 6 5.4 4 2.8 2 2.1 0  1.4 1.4–3.9 PSA (ng/mL)  4.0  2.3 2.3–3.9 PSA (ng/mL)  3.9 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 143 AUA Annual Meeting Age PSA DRE IPSS Bother Qmax unexpected that some of these studies reported a nearly 50% decrease in prostate size, whereas other studies found a 10% to 20% decrease. It is not entirely clear how chemodenervation can, over a short period, lead to an approximately 50% reduction in prostate size. Investigators from Pittsburg91 provided an update of a study in which 40 men were treated with either 100 U or 200 U of BTX-A transperineally, depending on their prostate size ( 30 mL or  30 mL by transrectal ultrasound [TRUS]). The cohort of patients has now been followed for up to 1 year and, in both size groups, a substantial reduction in symptom score was noted (from 18.7 to 9.0 points and from 19.3 to 8.3 points in the 100-U and 200-U groups, respectively). Commensurate with this, improvement in flow rate, quality of life, and residual urine was noted. In this particular study the prostate size changed slightly, but not to the extent reported by other investigators. It remains to be seen whether BTX-A in a sham-controlled setting and over PVR IPSS worsening - Placebo - Alfuzosin AUR - Placebo - Alfuzosin BPH surgery - Placebo - Alfuzosin Higher baseline value associated with significantly higher risk (P ⬍ .10) Lower baseline value associated with significantly higher risk (P ⬍ .10) Figure 6. ALTESS: impact of baseline variables on the risk of benign prostatic hyperplasia (BPH) progression. ALTESS, Alfuzosin Long-Term Efficacy and Safety Study; PSA, prostate-specific antigen level; DRE, digital rectal examination–estimated prostate size; IPSS, International Prostate Symptom Score; PVR, postvoid residual volume; AUR, acute urinary retention. Minimally Invasive Treatments and New Technologies One of the emerging technologies and minimally invasive or office-based treatments for LUTS and BPH is the injection of BTX-A transperineally into the prostate. Injection of botulinum toxin essentially results in chemodenervation of the injected organ. BTX-A injection has been popular in cosmetic surgery and in several other areas of medicine (eg, the injection of vocal cords for spastic dysphonia). Several small, non-controlled studies have examined the role of BTX-A injections in the prostate, with results indicating a substantial decrease in IPSS and an equally substantial improvement in maximum urinary flow rate. It was somewhat Figure 7. Change in International Prostate Symptom Score (IPSS) at 6 and 12 weeks with tadalafil (5 and 20 mg) compared with placebo. LS, least square. *Tadalafil compared with placebo; one-sided P values from analysis of covariance models with terms for treatment group, geographic region, previous -blocker use, and baseline IPSS value; last observation carried forward (LOCF) analysis for weeks 0–12. Visit 2 to endpoint 0 135 135 Baseline (visit 3) to endpoint 137 136 1 Change in IPSS, LS mean tadalafil study, however, no effect was seen on maximum urinary flow rate. Last, Kaplan and colleagues90 studied 62 consecutive men with untreated LUTS and sexual dysfunction randomized to either alfuzosin (10 mg daily), sildenafil (25 mg daily), or a combination of both for 12 weeks. The results showed that the combination had the most significant effect on IPSS, peak maximum urinary flow rate, and IIEF score (Figure 8). The investigators concluded that the combination of an -blocker and a PDE-5 inhibitor is both safe and most effective to treat both voiding and sexual dysfunction in this population and suggested that larger-scale, placebocontrolled studies would be warranted. 136 135 1.2 2 3 4 138 136 Number of patients 1.7 2.8 3.9 5 3.8 4.5 6 7 8 6.2 7.1 P  .001* 6-week Placebo P  .001* P  .003* 12-week 6-week Tadalafil 5 mg P  .001* 12-week Endpoint Tadalafil 5/20 mg VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 143 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 144 AUA Annual Meeting continued A B 20 30 18 P  .03 P  .002 17.8 17.3 16.9 16 14.9 14.6 14 13.5 P  .11 Mean IIEF erectile function score Mean IPSS total score P  .01 12 P  .01 P  .002 25.7 25 21.4 20.3 20 17.4 16.2 15 14.3 10 Alfuzosin 10 mg Sildenafil Combination 25 mg Baseline Alfuzosin 10 mg Sildenafil Combination 25 mg Endpoint Figure 8. Effects of daily alfuzosin (10 mg), sildenafil (25 mg), or both on (A) lower urinary tract symptoms, according to International Prostate Symptom Score (IPSS), and (B) erectile dysfunction, according to the International Index of Erectile Function (IIEF) (higher scores indicate better function). longer periods in a multicenter study will hold up to its initial promise. One of the commonly held beliefs regarding transurethral microwave thermotherapy (TUMT) is that it is not suitable for men with smaller prostates (ie, a TRUS volume  30 mL). Larson and coworkers92 presented a database of 713 men from 6 studies using TUMT (all performed with the Urologix device [Minneapolis, MN]) and analyzed the improvement in IPSS and urinary flow rates stratified by prostate size in 4 categories ( 30 mL, 30–39 mL, 40–60 mL, and  60 mL). The improvement in symptoms was essentially the same in patients with smaller versus larger prostates, suggesting that the efficacy of TUMT is not limited to prostates above a certain size threshold. Another less well understood aspect of TUMT treatment is the rate of retreatment and factors that might predict the need for retreatment over time. A European, multicenter, pooled 144 VOL. 8 NO. 3 2006 analysis was performed focusing on 614 patients treated with high-energy TUMT and followed for 2 to 8 years.93 Just over 78% of patients experienced a 50% or greater improvement in IPSS at 2 years, 51.2% experienced the same threshold of improvement at 6 years, and 45.6% at 8 years. Retreatment was required in 33.2% at 8 years, and the need for retreatment was correlated with a transition zone volume of greater than 50 mL or less than 20 mL and a PSA level of less than 2 ng/mL, as well as the presence of an intravesical lobe. It should be noted that with this particular analysis surgery was considered as retreatment but additional drug treatment was not. In a subset of 188 patients, urodynamic parameters were also available at the 3-year follow-up. At this point, the detrusor pressure at peak urinary flow had decreased from 42.3 cm H2O to 29.5 cm H2O, a significant reduction in this parameter of subvesical obstruction. REVIEWS IN UROLOGY The issue of tolerability of in-office minimally invasive treatments for BPH remains controversial. Most practitioners believe that high-energy TUMT requires considerable local anesthetic enhanced by oral, intramuscular, or even intravenous pain medications or sedatives. Schelin and Richthoff 94 from Ljungby, Sweden, reported on the use of a new device, the Schelin Catheter™, which allows the physician to administer drugs transurethrally into and around the prostate. This device was used in 113 patients with BPH treated in 2 different centers in Sweden before treatment with the CoreTherm TUMT device (ProstaLund, Lund, Sweden). The highly significant finding from this trial was that the device resulted in significantly improved treatment comfort but also in significantly reduced treatment duration and energy consumption. The reason for this is presumably the vascular effect of the local anesthetic, leading to less perfusion and thereby to less of a “heat sink” effect in the prostate. Normally during TUMT treatment, vascularity in the prostate increases, and the flow in blood carries away the energy administered by convection. It is only later in the treatment when, owing to capillary and vascular collapse, the prostate acts as a heat sink and temperatures rise to affect tissue kill. The administration of these local anesthetics apparently alters the vascularity of the prostate to the point that the heat stays within the prostate, so that therapeutic temperatures are reached quickly and in a shorter period of time and with less energy consumed. Thus, a similar effect is achieved while the patient’s tolerability is greatly increased. Again, this device also will need to be examined and tested in a multicenter, sham-controlled study, but if proven effective, it would alter significantly how in-office minimally invasive treatments for BPH are administered. RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 145 AUA Annual Meeting Surgery Surgical therapy and new technologies were presented in 1 moderated poster and podium session, and several aspects of surgical treatment for BPH were critically examined. Most notably, there were several reports from trials of the use of the KTP laser or photoselective vaporization of the prostate (PVP) procedure, the use of the Holmium laser for resection or enucleation of the prostate, and the use of bipolar energy to perform standard electrocautery TURP—all newer surgical technologies becoming more and more established as equivalent to standard electrocautery TURP. The issue of incontinence as a result of surgical procedures for BPH has been controversial, and vastly different incidence rates have been reported. Han and colleagues95 examined the association between surgical procedures for BPH and incontinence using the IHCIS National Managed Care Benchmark Database. They found that overall, 18.3% of men who in the database were listed as having the diagnosis of incontinence had a surgical procedure for BPH, compared with only 2.9% in the control group. The most commonly specified type of postprocedural incontinence was urge incontinence (16.1%). Postoperative incontinence was highest for the transurethral needle ablation procedure (19.4%) and lowest for laser prostatectomy (11.3%). Overall, it seems that BPH-related postoperative incontinence is higher in this dataset than previously reported. Even when accounting for the problems associated with the examination of an administrative database such as the IHCIS, this data set does suggest that patients’ self-reported incontinence in their doctor’s office might be more common than we had previously assumed to occur with our surgical procedures. Part of the explanation clearly is the fact that peer-reviewed articles usually report data and com- plications from centers of excellence, whereas the IHCIS database provides a cross-section of a large number of providers. A randomized trial was presented comparing TURP by electrocautery with PVP using the KTP laser.96 The investigators observed similar improvements in the IPSS (13.2 vs 13.7 points, respectively, for the TURP vs PVP groups) and in maximum urinary flow rate but a significantly reduced average length of stay (3.4 days with TURP vs 1.1 days with PVP; P  .005). The results of this trial and several others suggest that the PVP laser, at least in the short to intermediate term, is as effective as TURP in improving the symptoms and urodynamic parameters of men with LUTS and BPH. in serum PSA from 7.85 to 1.06 ng/mL (mean), for a reduction of 86.5%, commensurate with that expected from TURP. These findings suggest that, with regard to volume reduction and PSA reduction, Holmium laser enucleation of the prostate is as effective as TURP. Last, a prospective, randomized study with 5-year follow-up was reported comparing TURP and transurethral vaporization of the prostate using plasma kinetic energy.98 Results from this study, which enrolled 51 patients in the plasma kinetic transurethral vaporization arm and 25 in the TURP arm, suggest a nearly equivalent reduction in symptom score (from 19.9 to 4.2 points at 5 years for the plasma kinetic group and from 19.0 to 5.4 in the TURP These findings suggest that, with regard to volume reduction and PSA reduction, Holmium laser enucleation of the prostate is as effective as TURP. With performance of a complete transurethral resection of the transition zone of the prostate to the level of the surgical capsule, the serum PSA level should, independent of the baseline level, drop to a level of approximately 1 to 2 ng/mL after an appropriate period of follow-up. This suggests a near complete resection of the transition zone, and independent of the actual volume removed, the surgical capsule left behind produces a relatively homogeneous amount of PSA. In some way, one could argue that the drop in serum PSA might be an indirect or proxy measure of completeness of tissue removal after various surgical interventions. Along this line, investigators from Indianapolis97 examined the drop in serum PSA in a group of 68 patients who had undergone Holmium laser enucleation of the prostate. They reported a decrease in prostate volume from 114 to 26 g, for a 77.2% reduction, and a decrease group). Improvements in maximum urinary flow rate were similar, reaching a level of 20.0 versus 20.4 mL/s in the plasma kinetic versus the TURP group, respectively. Summary and Conclusions The 2006 meeting of the AUA once again provided a forum for the presentation of new findings regarding basic research, epidemiology and natural history, and medical and surgical treatment for men with LUTS and BPH. It is clear that we still do not exactly understand the etiology of BPH, despite decades of research. However, the observation of chronic inflammatory infiltrates acting as a predictor of progression and natural history led several researchers to investigate this association closer. One might expect that in the future several pathways might be identified that are active in the benignly enlarged prostate, and it might be hoped that such insight will VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 145 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 146 AUA Annual Meeting continued eventually translate into either serum markers or new therapeutic targets for the treatment of this condition. Regarding medical therapy for BPH, it is clear that a glass ceiling has been reached in terms of efficacy of our standard therapies with  receptor blockers and 5-reductase inhibitors. For the first time this year, a trial was presented using a new form of combination therapy, namely the combination of an -adrenergic receptor blocker with an antimuscarinic agent, which in the past was considered a contraindication in men with BPH for fear of inducing retention episodes or at least increasing residual urine. The trial demonstrated superiority of the tamsulosin plus oxybutynin ER arm compared with the tamsulosin plus placebo arm in terms of the irritative and total symptom scores. Longer trials, with patients stratified by risk parameters for retention and surgical interventions, should be conducted to prove that such combination medical therapy is indeed not only efficacious but also safe over the long term. Regarding minimally invasive and surgical treatments for BPH, the various laser interventions seem to be all but established at the present time. Holmium laser ablation, resection, and enucleation have been demonstrated to be effective when compared with standard TURP, as has PVP using the KTP laser. Whether the widespread acceptance of the various hospital-based laser techniques will eliminate or reduce the need for the office-based procedure, which in the past held an intermediate position between medical and surgical treatment, remains to be seen. Part of this decision will depend on whether the minimally invasive office-based technologies can be shown to be well tolerated, effective, and associated with durable symptom improvement. It is hoped that many of the presenters at this year’s meeting will de- 146 VOL. 8 NO. 3 2006 velop and submit manuscripts of their research findings, such that the wealth of information presented will find its way into the peer-reviewed literature and thereby become available to a wider audience of health care providers worldwide. [Claus G. Roehrborn, MD, FACS] Prostate Cancer Oncologic Outcomes in RoboticAssisted Radical Prostatectomy: Learning Curves and Surgical Margins Regardless of the approach used to perform a prostatectomy for cancer, certain oncologic principles, such as achieving negative surgical margins (especially in patients with T2 disease), must be achieved to attain durable disease control. Compared with open radical retropubic prostatectomy (RRP), there has been little substantive data published to date (and by only a few groups) describing outcomes from robotic-assisted radical prostatectomy (RAP).99-102 Some of the earliest data from the initial series of Menon and colleagues100 described excellent results with regard to pathologic stage and margin status, as well as decreased blood loss and transfusion rates compared with RRP. Other investigators, such as Joseph Smith, MD,101 chose to wait for the maturation of their data before comparing surgical margins in patients undergoing robotic versus open prostatectomy because of the selection bias involved: men undergoing RAP usually have lower-stage disease than those undergoing RRP. At this year’s meeting of the AUA, a number of groups published data on their surgical margin rates and how these rates have evolved with increasing experience. Sarle and coworkers103 reviewed the first 1452 cases performed by Mani Menon, MD, and colleagues. The group reports excellent data on return of erectile function and continence, REVIEWS IN UROLOGY which they attribute to preservation of neurologic tissue along the anterior aspect of the prostate (“veil of Aphrodite” technique), as well as to precision of dissection afforded by the da Vinci surgical robot system (Intuitive Surgical, Sunnyvale, CA). Regarding their positive margin rate, overall they saw 11% of men with positive margins. Among men with pT2 disease, only 5% had a positive margin, compared with 30% of men with pT3 disease. Herrell and associates104 reported on 286 patients with pT2 disease (out of a total of 484) treated by RAP at Vanderbilt University Medical Center. Data were recorded prospectively. Prostates were analyzed as wholemount specimens, and tumor extending to an inked margin or to the site of a capsular incision was recorded as a positive margin, even if subsequent resection of additional tissue resulted in a negative margin. Data were analyzed by groups of 100 patients. Overall a 17% positive margin rate for T2 tumors was found; however, the rate declined from 30% in the first 100 cases to 13% in the next 100 to 9.3% in the final group. This represents a statistically significant trend in decreasing positive surgical margins. Patel and Arends105 also reported their evolving experience with positive surgical margins. In the first 500 patients, 78% had pT2 disease. The overall positive margin rate was 2.5% for pT2 disease and 31% for non–organ-confined disease. Examining the positive margin rate, not corrected for stage, by 100-patient groups demonstrated a decreasing incidence of positive surgical margins: 13% to 8% to 12% to 5% and finally to 8% in cases 401 to 500. Also noted was the finding that positive margins were more likely posterolateral (56%) than apical (8.5%). Although the investigators do not note this, this difference in comparison with RRP, RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 147 AUA Annual Meeting where positive margins are more common at the apex, might be explained by a combination of the superior visualization during apical dissection with the robot and the lack of tactile sensation with the robot during nerve sparing. Slawin and Guariguata106 also discussed the effects of increasing numbers of cases on surgical margin rates. In a retrospective analysis of 759 men treated with either RAP, RRP, or en bloc RRP (for higher-grade and higher-stage disease), the investigators demonstrated a 5.5% rate of pT2 positive surgical margins, regardless of technique. When analyzed by surgical technique, positive surgical margins in pT2 patients were 3.1%, 6.2%, and 5.5% for RRP, RAP, and en bloc RRP, respectively; these differences did not achieve statistical significance. Whereas positive margin rates for RRP and en bloc RRP remained constant through time, decreasing rates of positive margins were observed when RAP procedures were analyzed by year: 5.9% to 2.5% to 0% for pT2 disease and 0 (0 of 2 patients) to 35% to 14.3% in pT3a/b disease. These investigators also demonstrated, using Kaplan-Meier analysis, that there was no statistical difference in PSA recurrence-free survival between men undergoing RAP and RRP (the longest follow-up was 2500 days). Gong and colleagues107 demonstrated that the expertise necessary to perform a successful RAP can be acquired in a short period by a trained open surgeon, to rival the outcomes of a fellowship-trained laparoscopist performing RAP. In a nonrandomized study, 2 surgeons, one a skilled open prostatectomist and the other a fellowship-trained laparoscopist, performed 40 RAPs to overcome the initial learning curve and then reported their outcomes with the next 100 patients they each operated on. Neither surgeon had any open conversions, nor was there any statistically significant difference between the 2 surgeons with respect to operative time, hospital stay, estimated blood loss, transfusion rate, complication rate, and rate of positive margins. This study suggests that, given an adequate amount of practice, any urologist, regardless of formal training, can successfully perform RAP. However, this study and others have not evaluated the learning curve on the basis of functional (ie, continence and potency) outcomes, which would likely exceed the 30 to 40 cases routinely reported as the learning curve for RAP. Another interesting abstract discussed the vagaries of operating with merits and shortcomings of this approach, as well as to consider providing this technique for their patients. In the words of Ingolf Tuerk, MD, during his Take Home Messages talk on Laparoscopic Oncology, “It is never too late to learn the skills to perform laparoscopic or robotic surgery.” [Danil V. Makarov, MD, Li-Ming Su, MD, Alan W. Partin, MD, PhD] Prostate Cancer Markers Once again prostate serum markers were a major subject at the annual meeting of the AUA. Presti and associates109 studied the ability of PSA values to predict cancer during the era of extended biopsy. In this investigation, This report is particularly important because it was conducted at Stanford University, where a previous study raised the question of whether “the PSA era is over.” the da Vinci robot system. Kozlowski and associates108 reported that in the first 200 patients undergoing RAP at their institution, there were 8 equipment failures necessitating abandonment of the robotic approach. Malfunctions were related to joint setup (2), arm malfunction (2), software incompatibility (1), “power off” error (1), monocular monitor loss (1), and camera malfunction (1). The group wisely concludes that multiple contingency plans should be set in place, including additional da Vinci units, development of straight laparoscopic skills, and counseling of patients to determine their preference should the system fail. Overall, this year’s meeting included a great number of RAP-related abstracts demonstrating that, at least for the time being, this technology is here to stay and will likely continue to have a more prominent role in the armamentarium of urologists in the United States and abroad. Urologists should at least become familiar with RAP to better understand the true 999 first-time biopsy patients with total PSA levels between 4.0 and 10.0 ng/mL underwent a 12-core extended biopsy (standard sextant and lateral sextant). Among men aged 50 to 59 years with normal results on DRE, cancer was found in 36% of those with a PSA level between 4.0 and 5.9 ng/mL, 38% of those with a PSA level between 6.0 and 7.9 ng/mL, and 45% of those with a PSA level between 8.0 and 9.9 ng/mL. High-grade cancer was seen in 14% of patients in the lower PSA grouping and in 19% in the higher. In contrast, in the oldest cohort (70–79 years) cancer was found in 50% of those with a PSA level between 4.0 and 5.9 ng/mL and in 68% of those with a PSA level between 8.0 and 9.9 ng/mL. High-grade cancer was found in 26% of those in the lower PSA range and in 53% of those in the high range. The investigators concluded that “PSA is a good test for the detection of prostate cancer.” This report is particularly important because it was conducted at Stanford VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 147 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 148 AUA Annual Meeting continued Table 7 Initial PSA Level and Risk of Prostate Cancer Age (y) PSA Level (ng/mL)  50 50–59 60–69 70 0–0.99 0.03 (1.0) 0.23 (1.0) 0.44 (1.0) 1.23 (1.0) 1–1.99 0.13 (4.7†) 0.73 (3.2) 1.21 (2.7) 1.92 (1.6†) 2–2.99 0.69 (24.4) 1.52 (6.6) 2.46 (5.6) 2.34 (1.9) 3–3.99 3.93 (139.6) 3.59 (15.7) 5.49 (12.5) 3.63 (3.0) 4–4.99 4.38 (155.8) 9.72 (42.4) 11.2 (25.4) 8.24 (6.7) 10 9.48 (337.1) 45.1 (196.5) 54.8 (124.6) 66.5 (54.1) No. of Cancers 23 250 816 1733 No. of Patients 8323 13,924 19,091 26,274 Values are absolute risk of cancer per 1000 person-years (hazard ratio), unless otherwise noted. For all hazard ratios P  .01, except where marked (†). PSA, prostate-specific antigen. Reproduced from Connolly D et al,111 with permission from the American Urological Association. University, where a previous study raised the question of whether “the PSA era is over.”110 Connolly and colleagues111 studied the correlation between initial PSA level and the risk of prostate cancer. This study, conducted in Northern Ireland, used an established cancer registry. Men who had initial PSA tests between 1994 and 1998 were followed until 2003 for the detection of cancer. There were more than 68,000 men in the initial cohort. Of these, 4.1% were diagnosed with prostate cancer (Table 7). The investigators concluded that over a 5- to 10year period there is a low risk of the diagnosis of prostate cancer in men with a low initial PSA value; however, the risk of developing cancer correlates with PSA. For example, men younger than 50 years with a PSA level below 1.0 ng/mL had less than a 0.03/1000 man-year risk of cancer, compared with 9.48/1000 in those with a PSA level above 10 ng/mL. As expected, older men had a greater risk at a given PSA level, including 1.23/1000 man-years in those with a PSA level below 1.0 ng/mL, rising to 148 VOL. 8 NO. 3 2006 66.5/1000 in those with a PSA level above 10.0 ng/mL. Ian Thompson, MD, and coworkers112 capitalized on data derived from the Prostate Cancer Prevention Trial. They used area under the curve analysis comparing the placebo and finasteride cohorts to evaluate whether the performance characteristics of PSA were greater in higher-grade cancers. The investigators demonstrated that the PSA test accuracy in men with higher-grade carcinoma (Gleason score  7 or  8) was better in those men receiving finasteride than in those receiving placebo. These data confirm the suspicion that there was a bias toward a greater detection of prostate cancer and high-grade prostate cancer in the finasteride group. This might well generate considerable reassessment of the utility of 5-reductase inhibitors in the prevention of prostate cancer because it would serve to, at least in part, alleviate the concern that these agents somehow promote higher-grade malignancy. Loeb and associates113 evaluated different thresholds of PSA velocity (PSAV) for predicting prostate cancer REVIEWS IN UROLOGY in young men with a PSA level less than 4.0 ng/mL. They evaluated 6844 participants younger than 60 years from their large screening trial. Of these, 346 were subsequently diagnosed with prostate cancer. The investigators calculated PSAV during the year before diagnosis and observed that the median PSAV was significantly higher in the men later diagnosed with prostate cancer compared with those who were not (0.840 vs 0.094 ng/mL per year). On multivariate analysis, PSAV greater than 0.5 ng/mL per year was more predictive of prostate cancer than age, PSA level, family history, or race. Using this cutpoint, a sensitivity of 62%, a specificity of 85%, and an 18% positive predictive value were found. Makarov and colleagues114 compared men with a PSA level between 2.6 and 4.0 ng/mL with men with a PSA level between 4.1 and 6.0 ng/mL undergoing radical prostatectomy at Johns Hopkins. In a multivariate analysis, the investigators observed that the men with a lower PSA level had decreased odds of high-grade disease, positive surgical margins, or RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 149 AUA Annual Meeting extraprostatic extension. There was a trend for reduced risk of biochemical progression associated with a lower preoperative PSA level, but this did not achieve statistical significance. The investigators conclude that it remains controversial whether the degree of improved outcomes, particularly in the absence to date of definitive evidence of reduction of PSA progression, justifies the limitations associated with lowering the PSA cutpoint. Grubb and associates115 and Scales and associates116 studied the relationship between obesity and prostate cancer detection. Grubb’s group used data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. They demonstrated an inverse relationship between PSA level and BMI. Obese men (BMI  30) were 25% more likely to have a positive biopsy than men with a lower BMI. However, overall cancer detection rates were similar in both groups of men using the same PSA threshold for biopsy. Scales’s group noted that obese men were more likely than normal men to have had a PSA test in a study of the Behavioral Risk Factor Surveillance System evaluation of more than 57,000 men. Risk factors predicting PSA testing included an ongoing relationship with a physician, African American race, a household income greater than $35,000, increased education, and being married. These observations are significant because prior findings that obese men have worse rates of prostate cancer might be the result of a higher chance of detection. Hofer and colleagues117 analyzed prostate-specific membrane antigen (PSMA) expression using tissue microarray in 96 patients who underwent radical prostatectomy. One third of the men had 1 metastatic lymph node, and another third had more than 1 node involved. PSMA was significantly up-regulated in men with metastatic versus localized prostate cancer and localized prostate cancer versus benign tissue. PSMA levels were associated with a significant increase of PSA recurrence, along with the chance of lymph node positivity, extraprostatic extension, seminal vesicle invasion, and high Gleason score. The investigators concluded that PSMA might be used as a predictor of prostate cancer aggressiveness. Grubb and associates118 studied the relationship of PSAV and Gleason score in the PLCO Cancer Screening Trial. More than 38,000 men were studied with annual PSA tests and DRE. A total of 1694 men were diagnosed with cancer. The investigators evaluated the 2 PSA levels preceding diagnosis. The mean PSA level at the 1.8 ng/mL or greater per year (the upper quartile) had a higher likelihood of having Gleason 8 or greater carcinoma (9% vs 5% in all others). However, PSAV did not correlate with a Gleason score of 7 or less (the chance of a Gleason score of 7 or less increased only from 60% to 62% with this threshold). Loeb and associates120 examined PSAV after an isolated diagnosis of prostatic intraepithelial neoplasia (PIN) on biopsy. A total of 111 men from their screening study who had an initial finding of high-grade PIN were evaluated. The investigators observed that both the median and mean PSAV were significantly higher in men with high-grade PIN on initial biopsy who progressed to prostate cancer (n  24) as opposed to those who did not (n  87). PSAV of 0.75 ng/mL per year Prostate-specific membrane antigen was significantly up-regulated in men with metastatic versus localized prostate cancer. time of diagnosis was 6.55 ng/mL. The PSA level increased by more than 2 ng/mL in 23.5% of the men diagnosed with cancer, and 12.8% had an increase of more than 3.0 ng/mL in the year before diagnosis. Among those who had a greater than 2.0 ng/mL annual increase, 30.8% had Gleason scores of 7 and 12.9% had Gleason scores greater than 7, compared with 25.9% and 5.9%, respectively, of men whose PSA level increased less than 2.0 ng/mL. These data would seem to clearly indicate a significant predictive ability of a PSAV greater than 2.0 ng/mL. This report was somewhat refuted by that from D’Amico and colleagues,119 who studied 3512 consecutive prostate biopsies performed because of a PSA level greater than 4.0 ng/mL or palpable nodule. They demonstrated that those men who had a PSAV of provided a sensitivity of 42% and specificity of 86% for subsequent detection of cancer. Age and initial PSA value were not predictors. PCA3 gene expression is gaining increased interest. In a study by Van Gils and associates,121 PCA3 gene expression was evaluated in men undergoing radical prostatectomy. The investigators correlated the ratio of PCA3 to PSA ribonucleic acid (RNA) in the urine sediments after extended DRE to the findings of radical prostatectomy. A total of 114 men were studied. The ratio of PCA3 to PSA RNA selected was .000132. There was no difference in the ratio of PCA3 to PSA RNA in patients based on Gleason score or pathologic stage. Intriguingly, although there was no significant correlation between tumor volume and the PCA3 ratio, there was a significant difference in mean VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 149 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 150 AUA Annual Meeting continued tumor volume between patients with a negative versus a positive ratio. The investigators concluded that PCA3 test results might reflect access to the urine of the PCA3 RNA in largervolume malignancy. Fradet and colleagues122 reported on their advancements in the PCA3 urine test. Urine was collected after DRE from 355 men scheduled for biopsy and 62 about to undergo radical prostatectomy. In all, 180 biopsies were positive, and 138 of the 237 biopsy-negative patients had PIN or atypical small acinar proliferation (ASAP). The average PCA3/PSA messenger RNA ratios ( 1000) for negative, PIN or ASAP, and positive subjects were 20, 50, and 70, respectively. Test specificity of 76% and sensitivity of 50% in the biopsy population was observed. Total PSA had a specificity of only 22%, indicating the potential utility of the PCA3 assay. [Michael K. Brawer, MD] Bladder Cancer At the 2006 meeting of the AUA, many abstracts were presented in the field of bladder cancer covering a spectrum of topics, including bladder cancer detection and screening, superficial disease, and invasive disease. Of the many outstanding abstracts, some are highlighted below that have clinical relevance in the treatment of bladder cancer today. Superficial Disease Herr and Donat123 evaluated a total of 710 patients with superficial bladder tumors and determined whether pathology on restaging transurethral resection (TUR) predicted early progression of the disease. They found that only 5% of low-grade bladder tumors were upstaged on repeat TUR, and 15% of high-grade bladder tumors were upstaged. Stage progression occurred in none of the lowgrade tumors or those with no 150 VOL. 8 NO. 3 2006 evidence of tumor on repeat resection, in 20% of high-grade Ta tumors or those with carcinoma in situ (cis), and in 76% of patients with residual T1 tumors. In a multivariate analysis, the most significant factors for predicting early progression were repeat TUR pathology, response at first follow-up cystoscopy, presence of cis, and initial tumor stage and grade. The investigators concluded that repeat TUR is not necessary for patients with superficial low-grade bladder tumors but does identify those with high-grade superficial bladder cancer who are at risk for progression and might better select those for an early cystectomy. These patients with superficial bladder cancer who had not been previously treated with intravesical immunotherapy. Furthermore, the number of previous courses of intravesical BCG therapy in this group of patients did not seem to impact future response, and therefore they could be considered for future intravesical immunotherapy. Au and associates125 reported their findings with long-term follow-up on an international, randomized, phase III trial that was intended to optimize mitomycin C (MMC) treatment using 40 mg MMC together with several pharmacologic interventions to maxi- These findings underscore the growing body of evidence confirming the importance of repeat TUR in all patients with lamina propria–invasive tumors. findings underscore the growing body of evidence confirming the importance of repeat TUR in all patients with lamina propria–invasive tumors. Gallagher and associates124 evaluated the impact of the bacillus Calmette-Guérin (BCG) failure pattern in patients with superficial bladder cancer on their subsequent response to intravesical immunotherapy. A total of 536 BCG-naïve and 467 BCGfailure patients were evaluated. The BCG-naïve patients received full-dose BCG, whereas the BCG failures received a one-third dose of BCG. All patients received 50 million U of interferon . Response rates were evaluated, with a median follow-up of 24 months. When the response rates of BCG-naïve patients and BCG failures who failed after 12 and 24 months were compared, there were no significant differences. The investigators concluded that patients with recurrent superficial bladder cancer after 12 months of remission have a similar response to intravesical immunotherapy (BCG and interferon ) as those REVIEWS IN UROLOGY mize drug delivery before drug instillation, including ultrasound-guided bladder emptying, voluntary dehydration, and urine alkalinization. All patients had transitional cell carcinoma (TCC) and were considered at high risk for tumor recurrence. A total of 119 patients were randomized into the socalled optimized arm and received a 40-mg dose of MMC, whereas 111 patients were randomized into the standard arm and received 20 mg MMC without the manipulation. Both groups were treated for 6 weeks. The long-term findings were similar to those from the investigators’ initial report and demonstrated that the 40 mg MMC group with manipulation showed a longer median time to recurrence and a greater recurrence-free fraction. In addition, there seemed to be a survival benefit in the 40 mg MMC group as well. These data support the benefits of optimizing MMC treatment and might warrant future investigation of these concepts to other intravesical therapies in patients with superficial bladder cancer. RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 151 AUA Annual Meeting Sylvester and colleagues126 proposed a simple scoring system and risk assessment tables that would allow urologists to more easily calculate a patient’s probabilities of recurrence and progression after TUR, based on routinely assessed clinical and pathologic factors. The analysis was carried out using 2596 patients (stage Ta, T1) with superficial bladder cancer who were entered in 7 European Organisation for Research and Treatment of Cancer phase III trials comparing different prophylactic treatments after TUR. The time to first recurrence and the time to progression to muscle-invasive disease were assessed as endpoints. In this analysis, the investigators identified the most important prognostic factors for recurrence, including the number of tumors, prior recurrence rate, and tumor size. Factors important for tumor progression were concomitant cis, tumor grade, and T stage. A scoring system was proposed to provide risk assessment. Importantly, the investigators commented that the most important prognostic factor for tumor progression in patients with T1 grade 3 tumors is the presence of cis. It is clear that this group of patients is at significant risk for tumor progression and might warrant an early and aggressive treatment approach. Rischmann and coworkers127 evaluated the effect of ofloxacin prophylaxis to improve tolerance of intravesical BCG instillation in patients with TCC of the bladder. This was a randomized trial of 115 patients with primary or recurrent superficial bladder cancer (Ta, T1, cis, G1-3) who had not been previously treated with intravesical BCG therapy. All patients were treated with 6 3 weekly instillations of BCG and randomized to ofloxacin (200 mg) given 6 hours and 12 hours after BCG instillation or a placebo group after the BCG instillation. The investigators found that the use of ofloxacin significantly decreased the moderate to severe side effects and increased the compliance to full BCG treatment. In addition, ofloxacin did not seem to impair the oncologic efficacy of therapy at 1-year follow-up. Although confirmatory studies are important to verify these findings, this seems to be a very important and practical approach to reduce the side effects of intravesical BCG therapy without compromising the results. Dalbagni and associates128 performed a phase II study to determine the efficacy of gemcitabine as an intravesical agent in patients with TCC of the bladder who were either refractory or intolerant to previous BCG therapy and refusing a cystectomy. A total of 30 patients were eligible and included in the analysis, with a median gemcitabine alone eventually failed; however, 15 of the 27 patients with the addition of MMC were disease-free with short follow-up (median 7 months). The investigators comment that both treatments were well tolerated. This study confirms the relatively poor results with intravesical gemcitabine alone,6 but there might be some activity with the addition of MMC in high-risk patients with superficial bladder cancer who have failed previous intravesical therapies. Joudi and colleagues130 evaluated the influence of age on response to intravesical immunotherapy in patients with superficial bladder cancer. Data from a national phase II multicenter trial using BCG plus interferon were analyzed. Recurrence-free survival was analyzed by incremental decade The use of ofloxacin significantly decreased the moderate to severe side effects and increased the compliance to full BCG treatment. follow-up of 19 months. In brief, 50% of patients did not respond. Of the 14 patients who had a complete response, 12 recurred. Overall, 11 patients (37%) ultimately underwent cystectomy. Although the investigators state that gemcitabine has activity in high-risk patients, the majority of patients recur, and a significant number of patients will require cystectomy, which might be better performed sooner than later. These data call into question the efficacy of gemcitabine in refractory superficial bladder cancer. Maymi and colleagues129 investigated the efficacy of intravesical gemcitabine alone or in sequence with MMC as a salvage treatment for patients with refractory superficial bladder cancer. A total of 39 patients were treated with a gemcitabine-containing regimen, including 12 with gemcitabine alone and 27 with gemcitabine and MMC. All 12 patients treated with of age. In brief, the investigators found that aging seems to be associated with a decreased response to intravesical immunotherapy, and this finding is particularly apparent in patients older than 80 years. In fact, in a multivariate analysis, age was an independent risk factor for response. Joudi and colleagues hypothesize that depressed baseline immune status and consequently an inability to mount an immune response to BCG or interferon might be a potential explanation. In addition, it might be important to study alternative intravesical therapies in elderly patients ( 80 years). Parekh and coworkers131 prospectively evaluated the use of p53 as a prognostic marker for patients with T1 bladder cancer. All patients with the first diagnosis of a T1 tumor were enrolled, and the tumor was evaluated for p53 by immunohistochemical techniques. The surgeon and the patient VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 151 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 152 AUA Annual Meeting continued were blinded to the results to avoid any interference in the decision-making process. Overall, 60% of the patients were p53 positive (altered), and 14 patients underwent immediate cystectomy, whereas 75 patients were managed initially with TUR (with or without intravesical BCG). During the follow-up period, an additional 34 patients underwent cystectomy. The investigators found that the association of p53 as determined by immunohistochemistry and survival was not significant in this group of patients and did not seem to provide any clinical usefulness as a prognostic marker for overall survival. It is important to note that this study represents a small subgroup of bladder cancer patients (T1 disease) and that there are other ways (possibly more accurate) to measure p53 status than immunohistochemical means. Lambert and associates132 evaluated the increasing use of intravesical therapies for T1 bladder cancer patients and the subsequent impact on survival for patients ultimately proceeding to cystectomy at a single institution. A total of 94 patients with T1 bladder cancer who had undergone cystectomy were analyzed, including the date of diagnosis, intravesical therapies, and recurrences, as well as clinical and pathologic stage. Patients were then divided into 2 groups: those having cystectomy before 1998 and those after 1998. Before 1998, 71% of patients proceeded directly to cystectomy without the use of intravesical therapy, compared with 46% after 1998. The mean number of intravesical therapies delivered before 1998 was 0.68, compared with 1.17 after (P  .06). Patients having cystectomy before 1998 had a 74% disease-free survival rate, compared with 54% for those after. The investigators state that in the past 15 years, patients with T1 superficial bladder cancer are now more likely to receive 152 VOL. 8 NO. 3 2006 intravesical therapy and have a significantly worse rate of disease-free survival. They postulate that the decrease in survival might be related to the increased use and application of therapy. The findings from this study continue to add to the growing body of evidence suggesting that we are treating many patients with superficial invasive bladder cancer too conservatively and that they should be considered for earlier and more definitive forms of treatment. Detection and Screening Messing and colleagues133 analyzed the long-term outcomes and findings in men undergoing a home screening program for bladder cancer, to determine whether bladder cancer screen- the screened group of patients was significantly lower (43%) compared with the unscreened group (74%), primarily owing to the bladder cancer mortality. This important study strongly supports bladder cancer screening and suggests that screening shifts the diagnosis of high-grade tumors to pre-invasive stages, where treatment and bladder cancer outcomes are more favorable. Furthermore, these data from long-term follow-up suggest that a lead-time bias is not responsible for the outcome in mortality. These findings are very provocative, and large prospective randomized trials evaluating hematuria screening are needed to confirm these results. It will be these trials that will ultimately impact and This important study strongly supports bladder cancer screening and suggests that screening shifts the diagnosis of high-grade tumors to pre-invasive stages, where treatment and bladder cancer outcomes are more favorable. ing decreases mortality from the disease. A total of 1575 patients (aged  50 years) were recruited from well patient clinics and underwent home screening for hematuria. A positive test stimulated a routine hematuria workup. All diagnosed bladder cancers were reviewed by a designated central pathology laboratory, and clinical outcomes were reported regarding the bladder cancer. Although there were no differences in the incidence of low- and high-grade tumors between the screened and unscreened patients, there was a significantly higher incidence of muscle-invasive disease in the unscreened group (60%, compared with only 10% in the screened population). Importantly, 20% of the patients in the unscreened group had died from bladder cancer, compared with none in the screened group (median follow-up, 14 years). Furthermore, the overall mortality in REVIEWS IN UROLOGY improve survival in bladder cancer patients today. Lotan and associates134 evaluated the cost and life-years saved associated with bladder cancer screening in high-risk patients. A Markov model was created to estimate the 5-year cumulative cancer-related costs and efficacy of screening in a high-risk population group for bladder cancer using a urine-based marker. The investigators found that screening for bladder cancer in a population with an incidence of 4% resulted in a gain of 3.1 life-years per 1000 subjects, at a cost savings of $118,000 for the population, assuming a 50% downstaging in the screened population from muscle-invasive to non–muscleinvasive disease. Furthermore, the varying costs of therapy or disease states over a wide range did not affect the superiority of screening for bladder cancer. This study adds to a RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 153 AUA Annual Meeting growing body of evidence suggesting that screening for bladder cancer in a high-risk group of patients not only save lives but might also save money in the long run. Madeb and coworkers135 evaluated the long-term outcomes in a group of patients with hematuria and a negative workup. The previous recommendation for patients with asymptomatic microscopic hematuria has included serial cystoscopy for several years. The investigators looked to evaluate these guidelines in a group of patients (older than 50 years) who were screened and found to have microhematuria but a negative urologic workup. Only 2 of 234 men (0.85%) who had an initial workup negative for bladder cancer ultimately developed the disease over 6 and 11 years after the initial evaluation. Both patients had a history of smoking. The investigators commented that patients screened for hematuria who have a negative initial urologic workup have a small chance of developing bladder cancer. The previously recommended guidelines for asymptomatic microhematuria should be interpreted with these findings in mind and might require re-evaluation, particularly in nonsmoking (low-risk) patients. Boorjian and associates136 evaluated a large disease registry to determine the incidence of bladder cancer in patients with prostate cancer. In addition, the types of treatment for prostate cancer were evaluated to determine whether they subsequently increased or impacted the risk for bladder cancer. The CaPSURE database for men diagnosed with both prostate and bladder cancer was utilized from 1989 to 2003. Of 9780 patients in the database, a total of 143 patients (1.4%) had both malignancies. Several interesting findings were observed during the analysis of this registry, including an almost 2-fold likelihood of developing bladder cancer if treated with radiation therapy, as compared with those treated with radical prostatectomy for their prostate cancer. Patients who were smokers had an independent risk for developing bladder cancer, and smokers who were treated with radiation therapy had nearly a 4-fold risk of developing bladder cancer. The findings from this analysis confirm other reports in the literature that have identified smoking and radiation therapy as significant risk factors for bladder cancer. Johnson and colleagues137 evaluated gender disparities in urologic referral for hematuria, using a nonprofit health care organization to determine whether any differences exist between men and women with this entity. The episodes of hematuria, which could potentially contribute to a delay in the diagnosis of bladder cancer. This interesting analysis could clearly be highlighting 1 contributing factor in the gender disparities in bladder cancer stage at presentation and potential clinical outcomes. Grossman138 evaluated a point-ofcare proteomic test (NMP22 BladderChek Test; Matritech, Newton, MA) that measures the nuclear matrix protein NMP22 in voided urine specimens of bladder cancer patients, to determine whether this test could enhance detection of bladder cancer recurrence. A total of 23 academic, private practice, and veteran’s hospitals (in 9 states) enrolled a total of Primary care physicians are less likely to refer women for urologic evaluation of new and first recurrent episodes of hematuria, which could potentially contribute to a delay in the diagnosis of bladder cancer. investigators note that the increasing incidence of higher tumor stage at presentation in female bladder cancer patients has led to the speculation regarding the possibility of a delay in referral and subsequent diagnosis. Insurance records from a nonprofit health plan of 926 patients were retrospectively evaluated with the diagnosis code of hematuria, including 559 men (60%) and 367 women. Overall, 47% of men and 27% of women were referred for urologic evaluation of hematuria. Increased urologic referral was associated with increasing age, male gender, and repeat episodes of hematuria. In an adjusted multivariate analysis, it was demonstrated that men were 65% more likely to undergo a urologic evaluation for hematuria than women. The investigators concluded that primary care physicians are less likely to refer women for urologic evaluation of new and first recurrent 668 patients with a history of bladder cancer. Patients provided a voided urine sample for analysis of NMP22 and cytology before cystoscopy. Overall, 103 of 668 patients were found to have bladder cancer, including 94 (91%) seen on cystoscopy. The combination of cystoscopy and urine NMP22 assay together detected 102 of the 103 cancers (99%). It should be noted that 7 of the 9 cancers that were detected with the NMP22 alone were high grade, whereas urine cytology detected only 3 of these 9 socalled occult tumors not seen on cystoscopy. Grossman commented that the noninvasive point-of-care assay can significantly improve the detection of recurrent bladder cancer. In addition, it should be noted that the cost of the NMP22 assay is half that of voided urine cytology. There is clearly a growing body of data suggesting that urinary markers, other than cytology, might improve the VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 153 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 154 AUA Annual Meeting continued detection of bladder cancer and should be considered in the follow-up of patients with this disease. Karl and coworkers139 evaluated the efficacy of fluorescence cystoscopy (FC) in patients with positive results on cytology but negative (normal) results from white light cystoscopy and normal upper urinary tracts. A total of 63 patients in this study had normal results on cystoscopy and suspicious or abnormal results on urinary cytology. In 51 (81%) of these patients, FC was able to detect the precise site of malignancy within the bladder. Thus, Although a lymphadenectomy was performed in 91%, the extent was not mentioned; the mean number of lymph nodes removed was 9 (range, 2–36), and only 18% had node-positive disease. With a mean follow-up of 18 months, the investigators report overall and cancer-specific survival of 80% and 94%, respectively. It will clearly require longer follow-up before the true oncologic outcomes with this technique will be able to be determined. Importantly, if the laparoscopic approach of radical cystectomy in the treatment of invasive bladder Seven of the 9 cancers that were detected with the NMP22 alone were high grade, whereas urine cytology detected only 3 of these 9 so-called occult tumors not seen on cystoscopy. it seems that FC might be an effective tool in detecting recurrent disease in patients with normal upper urinary tracts, positive results on cytology, and normal results on routine cystoscopy and might become a valuable tool in the urologist’s armamentarium. Staging/Invasive/Metastatic Disease Haber and associates140 reported on the newly developed International Registry for Laparoscopic Radical Cystectomy, which provided collaborative data on 308 patients undergoing laparoscopic radical cystectomy. A database was developed from 9 international centers with published experience in this technique. From December 1999 to July 2005, a total of 308 patients reportedly underwent a laparoscopic radical cystectomy, with extracorporeal urinary diversion in 89% of patients (orthotopic diversion in 56% and ileal conduit in 38%). The mean operating room time was 6.3 hours, with an average hospital stay of 11 days. Complications occurred in 8% intraoperatively and in 40% postoperatively or in a delayed fashion. 154 VOL. 8 NO. 3 2006 cancer is to gain acceptance, it must be performed in a technical manner similar to the open approach with an appropriate lymphadenectomy, negative margins, and good long-term oncologic outcomes. In addition, all patients should be properly informed regarding the various forms of urinary diversion after cystectomy. In another study of laparoscopic radical cystectomy, Haber and colleagues141 evaluated the outcomes of a pure laparoscopic radical cystectomy and urinary diversion compared with a similar laparoscopic radical cystectomy with the urinary diversion performed extracorporeally through a mini-laparotomy abdominal incision. In brief, the data suggest that the morbidity of the laparoscopic procedure is primarily related to the urinary diversion. The investigators recommended that the bowel work and the ureterointestinal anastomosis be done extracorporeally, which will result in a quicker recovery profile with fewer complications. Akkad and coworkers142 evaluated the incidence and risk factors of sec- REVIEWS IN UROLOGY ondary TCC in the remnant urothelium in women after radical cystectomy for bladder cancer. A total of 85 women were followed (median followup, 50 months), including 46 women undergoing an orthotopic form of urinary diversion. All patients had intraoperative frozen section analysis of the urethral and the distal ureters with negative margins. Approximately 5% of women developed an upper tract tumor and approximately 4% developed a tumor in the retained urethra. The investigators identified recurrent or multifocal TCC as a risk factor for secondary tumor recurrence, which tended to occur late (after 3 years of follow-up). They appropriately concluded that urethra-sparing cystectomy and orthotopic diversion in women for TCC does not seem to compromise the oncologic outcomes in carefully selected women. Long-term follow-up is important in all patients, with continued evaluation of the remnant urothelium. Koppie and associates143 attempted to identify the minimum number of lymph nodes that should be removed at the time of radical cystectomy for bladder cancer. A total of 1121 patients underwent the surgery, with the extent of the lymphadenectomy determined by the operative surgeon (limited or extended). The median number of lymph nodes removed was 9. The dose–response curve for the effect of number of lymph nodes removed on the probability of survival at 3 years did not reach a plateau but instead continued to rise steadily as the number of lymph nodes removed increased. The study confirms the importance of a lymphadenectomy and suggests that an extended dissection might provide a benefit to patients with bladder cancer requiring cystectomy. Hollenbeck and colleagues144 noted that hospital and surgeon volume independently might explain variations in clinical outcomes in surgical RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 155 AUA Annual Meeting procedures such as radical cystectomy. In this study, they attempted to better explain these short-term outcome differences in radical cystectomy by evaluating the variations in the availability of selected consultative, diagnostic, and ancillary hospital services. After adjusting for differences in patient and hospital qualities, patients treated at low-volume centers (1–3 procedures annually) were 9.0 times more likely to die postoperatively and 2.4 times more likely to have a prolonged length of hospital stay compared with high-volume centers ( 37 procedures annually). The availability of specific health services could explain some of these outcome differences, but the investigators also suggested that hospital and or surgeon volume remain an important determinant in the outcomes of this disease and the surgical treatment with radical cystectomy. This might be a reasonable conclusion for those undergoing radical cystectomy, which is not only technically challenging but also requires significant ancillary involvement from physicians and other health care providers. Amiel and associates145 from the Bladder Cancer Research Consortium (BCRC) reported the gender-related differences in pathology and clinical outcomes after radical cystectomy in patients treated and evaluated from 3 referral centers in the United States. A total of 766 men and 189 women were included in the analysis. Multiple pathologic indices and clinical outcomes were determined. The only significant pathologic differences in this analysis were that women were less likely to have TCC (94% of men and 88% of women) and more likely to have squamous cell bladder tumors. In this study, no obvious differences in clinical outcomes were observed even when stratified for the histology between these men and women. Nielsen and colleagues146 and the BCRC evaluated the delay in radical cystectomy of 12 weeks and the outcomes associated with this delay. The investigators examined the association between the time interval from last TUR to radical cystectomy and bladder cancer–specific outcomes. The records of 592 patients with complete clinical information regarding the last TUR preceding cystectomy were reviewed. Overall, the interval to radical cystectomy, analyzed as a continuous or categorical variable, was not associated with advanced disease, disease recurrence, or bladder cancer–specific survival. Appropriately, the investigators commented that they see no reason to advocate anything less than a timely and serious consideration for definitive therapy. It must be noted that there are several well-studied, single-institution, peer-reviewed reports that have documented an association of worse clinical outcomes associated with a delay in cystectomy of 3 months, and all efforts should be made to avoid these lengthy delays. Weizer and coworkers147 evaluated the risk of cancer in the prostate adenoma and capsule in a cohort of patients undergoing radical cystectomy for bladder cancer, to determine the feasibility of a prostate capsule–sparing cystectomy. A total of 35 men who underwent radical cystectomy had the prostate capsule submitted separately from the adenoma and bladder at the time of surgery. These specimens were then pathologically evaluated. Overall, 57% of patients had either urothelial cancer or cancer involving the prostate. The investigators acknowledge that examination of the prostate adenoma alone and other preoperative characteristics did not identify all patients with cancer involving the prostate. Although the investigators recommend that transrectal ultrasound–guided prostate biopsy and transurethral prostate biopsy might be needed preoperatively to identify which patients might be appropriate for prostate capsule–sparing cystectomy, it is clear that we are currently unable to identify these patients with any certainty and that the risks from an oncologic perspective might be significant with this approach. Pettus and associates148 similarly evaluated the pathologic features of the prostate in 122 men undergoing radical cystectomy for bladder cancer. The prostates were evaluated with whole-mount sectioning. Overall, 47% of these men had prostate cancer, with the apex being involved in one third of these patients. Furthermore, urothelial tumor involving the prostate was seen in 32% of patients, with the majority of these being stromal-invasive tumors. These data confirm a growing body of pathologic evidence to support that both urothelial and prostate cancer are commonly present in radical cystectomy specimens, which should be considered when contemplating prostate-sparing cystectomy for bladder cancer. Josephson and colleagues149 evaluated the clinical and pathologic outcomes in a large group of women undergoing cystectomy for bladder cancer with various forms of urinary diversion, including ileal conduits, continent cutaneous, and orthotopic neobladders. Of 327 women who were followed for a median of 12 years, 35% underwent an orthotopic, 37% a continent cutaneous, and 28% an ileal conduit form of urinary diversion. There were no obvious differences in the pathologic characteristics, early complication rate, and perioperative mortality. Furthermore, there were no obvious differences in survival stratified by the form of urinary diversion. These data suggest that orthotopic urinary diversion in women is an appropriate form of reconstruction in properly selected women with bladder VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 155 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 156 AUA Annual Meeting continued cancer requiring cystectomy and does not obviously compromise the oncologic outcomes in these individuals. The investigators acknowledge that functional studies addressing quality of life issues, continence, and voiding pattern will be important in the future to validate these aforementioned clinical outcomes. Siefker-Radtke and coworkers150 reported their preliminary results from a phase II clinical trial evaluating systemic chemotherapy in small-cell urothelial tumors of the bladder. A total of 26 patients were enrolled into the study with chemotherapy that included ifosfamide, doxorubicin, etoposide, and cisplatin. Of those patients with surgically resectable disease, 4 cycles of chemotherapy were administered followed by cystectomy. Those patients with metastatic or un- 36%, respectively. Importantly, the survival was similar for those nodepositive patients with common iliac and sacral lymph node compared with the other node-positive patients (external iliac and obturator fossae area). Other risk factors included number of nodes involved, lymph node density, and pathologic subgroup of the primary tumor. These data underscore the importance of resecting nodepositive disease in the region of the common iliac vessels or presacral region, and that patients with regional nodal involvement might benefit from an extended LND. In addition, risk factors for node-positive patients in this series confirm previous reports with regard to risk assessment. Schumacher and colleagues152 evaluated the incidence of ureteral pathology at the time of cystectomy and as- These data provide a reasonable rationale to treat patients with surgically resectable small-cell tumors of the bladder with 4 cycles of neoadjuvant therapy before surgery. resectable disease received 2 cycles beyond maximal response. Compared with historical controls, those patients undergoing neoadjuvant chemotherapy then cystectomy demonstrated an improved survival. These data provide a reasonable rationale to treat patients with surgically resectable small-cell tumors of the bladder with 4 cycles of neoadjuvant therapy before surgery. Steven and associates151 evaluated their outcomes in patients with lymph node metastasis after radical cystectomy and an extended lymph node dissection (LND), which included the common iliac and presacral lymph nodes. Overall, 72 of 346 patients (21%) had nodal involvement and were followed for a median of 2.5 years. The overall and recurrence-free 5-year survival rates were 41% and 156 VOL. 8 NO. 3 2006 sessed the value of intraoperative frozen section analysis of the ureter in patients with TCC of the bladder. Frozen section of the distal ureter was performed on 805 patients, with severe atypia seen in 1.4%, cis in 3.7%, and TCC in 1.1%. Final pathologic analysis of the ureteral segment demonstrated cis or TCC in 4.6%. In the most proximal ureteral segment, tumor was found in 1.2%. The diagnostic accuracy of intraoperative frozen section and corresponding paraffin-embedded section was 92%. The investigators concluded that because only 1.2% of the patients had tumor (cis or TCC) in the proximal resected ureteral segment, division of the ureters at the level of the common iliac vessels during cystectomy for TCC of the bladder is safe and results in a 99% probability of a tumor-free ureteroileal anastomo- REVIEWS IN UROLOGY sis and that therefore the frozen section analysis can be omitted. Unfortunately, no follow-up data were presented regarding upper tract recurrence in these patients. Furthermore, it must be understood that 6.2% of patients in this study did have abnormal intraoperative frozen sections that might have alerted the surgeon to the situation, suggesting that a more proximal ureteral segment needed to be removed. Shabsigh and associates153 retrospectively evaluated the incidence and the risk factors for treatmentrelated morbidity in women undergoing radical cystectomy. All complications within 90 days of surgery were analyzed and graded I to V. A total of 429 female patients were analyzed, with 41% having no complications. Grade I and II minor complications were observed in 46% of patients. Major complications (grade III–V) were seen in 13% of patients. The most common complication was a prolonged ileus in 13% of patients. In a multivariate analysis, only younger age ( 70 years) and undergoing an ileal conduit diversion were associated with fewer early complications. Age greater than 70 years and lymph node involvement were associated with higher-grade complications; however, the form of urinary diversion was not associated with an increased risk of high-grade complications. Although there is a significant risk of complications after radical cystectomy, the incidence of high-grade complications in this series was only 13%. The potential for significant postoperative morbidity and mortality after radical cystectomy should not be underestimated and underscores the need for appropriate patient selection, attention to surgical and perioperative detail, and a multidisciplinary approach to patient care. Kassouf and coworkers154 evaluated the performance of the TNM staging RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 157 AUA Annual Meeting system and compared this with lymph node density in risk stratification of patients with node-positive bladder cancer after radical cystectomy. A total of 108 node-positive patients (median follow-up, 41 months) were evaluated without neoadjuvant chemotherapy. The median number of lymph nodes removed was 12, and the median number of lymph nodes involved was 2. Overall, 71% of patients received adjuvant chemotherapy. Although lymph node density of greater than 25% and pN3 were significant risk factors in univariate analysis for recurrence-free survival, in a multivariate analysis only pN status remained significant. The investigators suggested that the TNM staging system seems to be superior to lymph node density in this group of node-positive patients. This finding is in contrast to those of several previously reported cystectomy studies that have shown the prognostic significance of lymph node density. This might relate to the extent of the node dissection and the number of lymph nodes removed and/or analyzed. It is important to note that lymph node density incorporates both the tumor volume (number of lymph nodes involved) and the extent of the dissection (number of nodes removed) and conceptually should be prognostic. Levin and Jones155 sought to determine the impact of evaluating tissue slides from 114 bladder cancer patients whose bladder biopsies were performed at an outside facility. The investigators found that the institutional interpretation differed substantially from the outside (referral) report in approximately 35% of the patients. This was important because this difference changed management in 30% of patients. Most commonly, the difference involved the determination of whether muscle invasion had been established, requiring repeat TUR to establish the proper stag- ing. The investigators conclude that reinterpretation of biopsy slides for patients diagnosed elsewhere and subsequently receiving treatment for bladder cancer at a referral center identifies potential findings that could alter management in one third of patients. This study underscores the importance of and the need for careful pathologic evaluation of bladder cancer tumors in all patients, not only by tertiary and referral hospitals but all institutions managing these patients. Tal and associates156 retrospectively evaluated the utility of ureteral margins during radical cystectomy for TCC of the bladder, to determine the frozen section analysis of the ureter will have limited utility in reducing risk for an upper tract recurrence, this might simply be related to the length of follow-up and the small number of patients with an upper tract recurrence. Frozen section analysis of the ureter is highly sensitive and specific and might provide risk assessment that might ultimately alter follow-up evaluation and schedule in these patients. Sanderson and colleagues157 evaluated risk factors for upper tract recurrence after radical cystectomy in 1069 patients undergoing radical cystectomy for TCC of the bladder. With a median follow-up of more than 10 These findings confirm the notion that TCC is a pan-urothelial disease. whether ureteral involvement and margin status were risk factors for an upper tract recurrence. A total of 2055 ureteral margins in 1031 patients were histopathologically evaluated, including 1215 frozen section ureteral margins. On frozen section, 10% of the specimens were positive, and frozen section was noted to be 87% sensitive and 97% specific on permanent section analysis. Interestingly, only 28% of patients with frozen section–positive ureteral margins were converted to negative on frozen section. Furthermore, of the group with a positive frozen section ureteral margin, 61% of the ureters had a positive anastomotic margin on permanent section. The investigators note that ureteral involvement on frozen section or permanent section was significantly associated with upper tract recurrence. However, conversion of ureteral anastomotic margin from positive to negative on either frozen or permanent section was not associated with a decreased likelihood of upper tract recurrence. Although the investigators state that years, a total of 25 patients (2.5%) developed an upper tract recurrence, with a median time to recurrence of 3.6 years. More than three quarters of these patients presented symptomatically with gross hematuria, flank pain, or pyelonephritis. Only 23% of the patients were found to have an upper tract recurrence with routine follow-up radiographic imaging. Positive ureteral margins on either frozen section or permanent section were significant risk factors for an upper tract recurrence. Furthermore, men with non-stromal involvement of the prostatic urethra were also more likely to develop an upper tract recurrence. The presence of cis in the bladder did not increase the risk of an upper tract recurrence. These findings confirm the notion that TCC is a panurothelial disease and that those patients with risk factors associated with an upper tract recurrence should be carefully followed over the long term with imaging modalities directed to the upper tracts. [John P. Stein, MD, FACS] VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 157 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 158 AUA Annual Meeting continued Kidney Cancer The field of kidney cancer continues its dynamic growth with 2 new drugs, sorafenib and sunitinib, recently approved by the US Food and Drug Administration (FDA) for the treatment of advanced disease. These approvals follow an explosion of information regarding the biology of the disease, its molecular basis, and patient selection for the various therapies available. Because of the number of highquality abstracts presented at the AUA annual meeting, we have selected those reports that focus on the surgical management of kidney cancer, small renal tumors, tumor classification, and molecular markers. Finally, we include a brief summary of the upcoming drug therapies for this disease, as presented at the 2006 meeting of the American Society of Clinical Oncology (ASCO), also held in Atlanta. Surgical Management The value of LND during nephrectomy for renal cell carcinoma (RCC) was addressed at this year’s AUA meeting. Thompson and colleagues158 presented a list of pre-operative and intra-operative risk factors that can be used to identify patients who are at risk for lymph node metastasis. In their study of 1124 patients who underwent radical nephrectomy for unilateral, sporadic M0 RCC, the following pre-operative risk factors for lymph node metastasis were identified: lymphadenopathy on computed tomography scan (relative risk [RR] 9.7, P  .001), constitutional symptoms at diagnosis (RR 1.9, P  .04), Eastern Cooperative Oncology Group performance status greater than 0 (RR 2.4, P  .049), tumor size 10 cm or greater (RR 2.2, P  .014), and presence of tumor thrombus (RR 2.5, P  .006). When looking at both intra-operative and pre-operative features, they found that lymphadenopa- 158 VOL. 8 NO. 3 2006 thy (RR 8.3, P  .001), tumor size 10 cm or greater (RR 2.0, P  .03), fat invasion (RR 2.6, P  .004), and tumor necrosis (RR 4.3, P  .001) had significant association with positive regional lymph nodes. Only 3 of 583 patients (0.5%) with none of these features had positive lymph nodes, compared with 36 of 204 patients (17.7%) with 2 or more features. Leibovich and coworkers159 were able to demonstrate the significant benefit of formal LND from a study of 356 patients with M1 RCC. The median survival time of pN0 patients (n  69) was 1.8 years, compared with 1 year for pNx patients (n  232). Brassell and associates160 expanded upon this with a retrospective review of 422 patients who underwent cytoreductive P  .0001) and urinary fistula (12.1% vs 2.5%, P  .0001) were more frequent in patients receiving laparoscopic NSS. Finally, the investigators were able to demonstrate safety for NSS procedures in tumors greater than 4 cm. Small Renal Tumors Because of the increased use of abdominal imaging procedures related to nonspecific complaints, there has been an increase in the number of incidental findings of early-stage cancers. Kane and coworkers163 presented data from the National Cancer Database for 184,508 patients with RCC during the period of 1993 to 2003, showing a significant increase (from 42% to 55%) of stage I cancers upon Lymphadenopathy, tumor size 10 cm or greater, fat invasion, and tumor necrosis had significant association with positive regional lymph nodes. nephrectomy for metastatic clear cell RCC. They found that LND in nodepositive patients with M1 RCC increased survival time from 4.9 to 16.3 months. This would suggest the importance of acquiring a non-pNx pathology status to benefit postoperative clinical management. The issue of surgical approaches to nephron-sparing surgery (NSS) was also presented at this year’s meeting. Although NSS is considered to be standard treatment for surgical management of small renal tumors, the choice between open NSS and laparoscopic NSS remains an issue. Patard and associates161,162 showed in 2 multicenter studies that factors such as surgical complication rate, need for blood transfusion, positive surgical margin rates, and length of hospital stay were not significantly different between 91 laparoscopic NSS and 1018 open NSS procedures. Medical complications (12.1% vs 2.5%, REVIEWS IN UROLOGY diagnosis. The incidence of stage II, III, and IV cancers declined during the same period. Although partial nephrectomy is currently considered the standard form of treatment for small renal tumors, many other therapeutic procedures exist. Feldman and colleagues164 reported on a 7-year study of 222 patients, in which radiofrequency ablation (RFA) (n  95) was compared with both open partial nephrectomy (n  109) and laparoscopic partial nephrectomy (n  18) for rates of comorbidity, perioperative complications, and short-term cancer control. Patients who received RFA were significantly older, with more severe comorbidity, but had a reduced rate of blood transfusion and therapy-related complications when compared with the surgical group. The short-term cancer control rate was comparable between the RFA group and the surgical group. The investigators concluded RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 159 AUA Annual Meeting that patients older than 60 years with 3 or more medical comorbidities were better served by treatment with RFA. However, Stern and colleagues165 showed worse cancer control rates. In their study, 4 of 80 RFA patients had incomplete ablations, and 3 patients had recurrence after a mean follow-up of 1.4 years. Longer follow-up should resolve the ongoing debate about the efficiency of RFA. Hegarty and associates166 reported long-term follow-up of 44 patients who underwent laparoscopic cryoablation due to discovery of a small solitary sporadic renal lesion. Median follow-up was 72 months. Recurrence rates were low (n  3, 6.7%), and the 5-year cancer-specific survival rate was 100%. Enucleation procedures and active surveillance were also discussed at this year’s meeting. Kutikov and coworkers167 reported a retrospective study of 135 RCC patients who underwent enucleation combined with laser ablation of the tumor bed (n  55) or standard partial nephrectomy (n  80), showing no significant differences in rates of disease progression (P  .488). This study demonstrated the clinical importance of margin status rather than margin size. Enucleation in carefully selected patients with laser ablation of the tumor bed might enhance surgical versatility and maximize parenchyma preservation with no change to disease progression. Kunkle and colleagues168 reported a study of 89 patients in which 34% demonstrated enhancing renal masses that showed no tumor growth during a follow-up time of at least 1 year, reemphasizing the importance of active surveillance in lieu of surgical intervention in the current setting of increased incidental findings of stage I tumors. However, they were unable to show clinical or radiographic predictors for such patients. Improvements in Tumor Classification The question of whether the 2002 pT2 tumor classification can be improved upon was addressed during this year’s meeting by Lam and associates.169 They presented a multicenter study of 639 patients with pT2 RCC. Patients with tumors between 7 and 13 cm had a median survival of 208 months, compared with 145 months for those with tumors greater than 13 cm (P  .0373). These data suggested that subclassifying pT2 patients into 2 groups, those with tumors greater than 7 cm and less than 13 cm and those with tumors greater than 13 cm, would provide significant prognostic value for determining survival time. tumor-infiltrating lymphocytes expressing PD-1, a receptor for B7-H1, had a greater risk of cancer-specific death. Krambeck and coworkers173 showed that B7-H4 was associated with a significantly increased risk of RCC-related death. Patients with RCC tumors expressing both B7-H1 and B7-H4 showed a 3-fold increased risk of disease-related death. Weiss and colleagues174 demonstrated p21 as a new independent predictor of survival in patients with localized RCC disease (P  .015), with those having less than 32.5% expression having a worse survival. In addition, the subcellular localization of p21 seems to be of highest importance. A tissue microarray–based study by Lam and Enucleation in carefully selected patients with laser ablation of the tumor bed might enhance surgical versatility and maximize parenchyma preservation with no change to disease progression. Furthermore, those patients with tumors greater than 13 cm should now be considered at higher risk for disease progression, warranting their eligibility for adjuvant clinical trials. Molecular Markers Several molecular markers with the potential for use in determining clinical prognosis and targeting therapies were discussed at this year’s AUA meeting. Thompson and colleagues170,171 and Webster and colleagues172 presented studies that highlighted the importance of the B7 family as predictors of cancer progression and poor prognosis in patients with RCC. B7-H1 was reported as an independent prognostic variable predictive of cancer progression. In addition, the same group was able to demonstrate complete tumor regression of established murine RCC after CD4+ T cell depletion and B7-H1 blockade. Furthermore, patients with coworkers175 showed that there was a higher expression of vascular endothelial growth factor (VEGF)-A (57% vs 37%, P  .0001) and VEGFR2 (49% vs 37%, P  .0001) in papillary than in clear cell RCC. The investigators concluded that patients with papillary RCC should be considered for therapies targeting the VEGF pathway, which has traditionally been used for patients with clear cell RCC. Carmack and coworkers176 evaluated the expression of osteopontin, a secreted glycoprotein involved in bone remodeling, in primary RCC from patients with and without metastasis. Both were shown to have a significant osteopontin expression (66.7% and 46%, respectively). Staining intensity and positivity were directly associated with metastatic disease (P  .002). Several presentations also focused on the PI3K pathway. Hennenlotter and colleagues177 showed that PI3K and EGFR status were positively correlated VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 159 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 160 AUA Annual Meeting continued with an increased tendency toward tumor progression and reduced longterm survival (P  .03). In addition, Kuczyk and associates178 presented data supporting the prognostic relevance of decreased expression of p27 (P  .04) for predicting long-term survival in RCC patients. 2. 3. 4. New Drug Therapies Two important randomized phase III trials for metastatic kidney cancer were presented at the 2006 ASCO annual meeting. Motzer and colleagues179 presented a study of sunitinib, an inhibitor of VEGF and platelet-derived growth factor receptors. The study compared sunitinib with interferon- (IFN-) as first-line therapy in 750 patients with metastatic RCC. Median progression-free survival for the sunitinib arm was 11 months, compared with 5 months for the IFN- arm. Using RECIST (Response Evaluation Criteria in Solid Tumors) criteria, the objective response rate was 31% for the sunitinib arm, compared with 6% for the IFN- arm. Temsirolimus (CCI-779), a specific inhibitor of mTOR kinase, was compared with IFN- as both a combinatorial (dosage of CCI-779  15 mg) and alternative treatment (dosage of CCI779  25 mg) in poor-risk metastatic RCC patients according to Motzer criteria. The results of this randomized phase III trial of 626 patients were presented by Hudes and colleagues.180 Median overall survival was 10.9 months for the CCI-779 arm, 7.3 months for the IFN- arm, and 8.4 months for the combination arm. The investigators concluded that temsirolimus represents an effective first-line therapy. [Tobias Klatte, MD, Michael E. Aldridge, MD, Arie S. Belldegrun, MD, FACS] 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. References 1. 160 Melman A, Bar-Chama N, McCullough AR, et al. Results of the first human trial for genetransfer therapy for the treatment of erectile dysfunction VOL. 8 NO. 3 2006 16. REVIEWS IN UROLOGY [abstract 686]. J Urol. 2006;175(4 suppl):222. Lowe D, Hoffmann JD, Christ GJ, et al. Efficacy of weekly administration of hSlo (hMaxi-K) gene transfer for treatment of erectile dysfunction in aging rats [abstract 688]. J Urol. 2006;175(4 suppl):223. Prince W, Campbell AS, Tong W, et al. SLx-2101, a new long-acting PDE5 inhibitor: preliminary safety, tolerability, PK and endothelial function effects in healthy subjects [abstract 924]. J Urol. 2006;175(4 suppl):299. Kaufman J, Dietrich JW. Safety and efficacy of avanafil, a new phosphodiesterase type-5 inhibitor for treating erectile dysfunction [abstract 923]. J Urol. 2006;175(4 suppl):299. Rosen RC, Marks LS, McVary KT, et al. Association between ejaculatory dysfunction and therapy among men enrolled in the BPH registry and patient survey [abstract 921]. J Urol. 2006;175(4 suppl):298. McVary KT, Swierzewski MJ, Monnig WB, et al. Sildenafil improves erectile function and concomitant lower urinary tract symptoms in men [abstract 920]. J Urol. 2006;175(4 suppl):298. Mueller A, Parker M, Waters WB, et al. Analysis of predictors of erectile function outcomes with pharmacological penile rehabilitation following radical prostatectomy [abstract 694]. J Urol. 2006;175(4 suppl):225. Montorsi F, Salonia A, Gallina A, et al. There is no significant difference between on-demand PDE5-I vs PDE5-I as rehabilitative treatment in patients treated by bilateral nerve-sparing radical retropubic prostatectomy [abstract 695]. J Urol. 2006;175(4 suppl):225. Thompson IM Jr, Probstfield J, Tangen CM, et al. Association of erectile dysfunction and subsequent cardiovascular disease [abstract 1333]. J Urol. 2006;175(4 suppl):429. Henry GD, Carson CC, Wilson SK, et al. Revision washout reduces implant capsule tissue culture positivity: a multicenter study [abstract 1308]. J Urol. 2006;175(4 suppl):421. Secin FP, Koppie TM, Patel M, et al. Determinants of success of bilateral cavernous nerve interposition grafting during radical retropubic prostatectomy [abstract 1316]. J Urol. 2006;175 (4 suppl):423. Donohue JF, Tal R, Akin-Olugbade Y, et al. Sildenafil and cavernous nerve injury in the rat: defining the optimal dosing and timing regimen [abstract 1017]. J Urol. 2006;175(4 suppl):327. Golijanin D, Donohue JF, Tal R, et al. FK506 and erectile function preservation in the rat cavernous nerve injury model: defining optimal dosing and treatment regimens [abstract 689]. J Urol. 2006;175(4 suppl):223. Hellstrom WJG, Sharlip ID, Miloslavsky M. Efficacy of dapoxetine in men with self-rated very poor control over ejaculation [abstract 917]. J Urol. 2006;175(4 suppl):297. Shabsigh R, Broderick BA, Miloslavsky M, Bull S. Dapoxetine has long-term efficacy in the treatment of premature ejaculation [abstract 918]. J Urol. 2006;175(4 suppl):297. Rosenberg MT, Sailor N, Tallman CT, Ohl DA. Premature ejaculation as reported by female partners: prevalence and sexual satisfaction 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. survey results from a community practice [abstract 1332]. J Urol. 2006;175(4 suppl):428. Brock GB, Young LD, Gan BS, et al. The pathogenesis of Peyronie’s disease: can protein expression predict progression [abstract 1002]. J Urol. 2006;175(4 suppl):323. Greenfield JM, Shah SJ, Levine LA. Verapamil versus saline in electromotive drug administration (EMDA) for Peyronie’s disease: a doubleblind placebo-controlled trial [abstract 992]. J Urol. 2006;175(4 suppl):320. Nelson CJ, Hardin S, McKown M, et al. Demographics and mental health status of men with Peyronie’s disease: an association of Peyronie’s Disease Advocates (APDA) survey [abstract 997]. J Urol. 2006;175(4 suppl):321. Marks LS, Mazer N, Hess DL, et al. Effects of testosterone administration on prostate tissues in men with ADAM syndrome [abstract 691]. J Urol. 2006;175(4 suppl):224. Mostaghel EA, Marks LS, Mazer N, et al. Quantitative assessment of prostate gene expression changes following testosterone supplementation. [abstract 437]. J Urol. 2006;175(4 suppl):142. Lee J, Nickel JC, Downey J, et al. Chronic pelvic pain syndrome patients show evidence of allostatic overload [abstract 94]. J Urol. 2006;175 (4 suppl):30-31. Yilmaz U, Liu YW, Yang CC, Berger RE. Heart rate variability and sympathetic skin responses in men with chronic pelvic pain syndrome [abstract 96]. J Urol. 2006;175(4 suppl):31. Nickel JC, Bostwick DG, Allen G, et al. Lack of relationship between clinical prostatitis and prostate inflammation: baseline data from the REDUCE trial [abstract 97]. J Urol. 2006;175 (4 suppl):33-32. Tripp DA, Nickel JC, Soryal AK, et al. Depression mediates poor quality of life in partners of men with chronic prostatitis/chronic pelvic pain syndrome [abstract 101]. J Urol. 2006;175 (4 suppl):33. Clemens JQ, Mennan RT, Rossetti MCO, et al. Analysis of medical costs associated with prostatitis [abstract 98]. J Urol. 2006;175(4 suppl):32. Anderson RU, Wise D, Sawer T, Chan CA. Sexual dysfunction in men with chronic pelvic pain syndrome: improvements after trigger point release and paradoxical relaxation training [abstract 102]. J Urol. 2006;175(4 suppl):33. Shin SM, Park DS. Multi-regional injections of low-dose botulinum toxin A for men with chronic pelvic pain syndrome [abstract 104]. J Urol. 2006;175(4 suppl):34. Kim HJ, Sohm GI, Lee JU, et al. Efficacy of alfuzosin for chronic prostatitis/chronic pelvic pain syndrome in young and middle-aged patients: a prospective, randomized, controlled study [abstract 103]. J Urol. 2006;175(4 suppl):33-34. Schneider H, Ludwig M, Horstmann A, et al. The efficacy of Cernilton in patients with chronic pelvic pain syndrome (CP/CPPS) type NIH IIIa: a randomized, prospective, double-blind placebo controlled study [abstract 105]. J Urol. 2006; 175(4 suppl):34. Clemens JQ, Link CL, Eggers PW, et al. The effect of varying definitions on the prevalence of interstitial cystitis (IC)/painful bladder syndrome RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 161 AUA Annual Meeting 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. (PBS) in a racially and ethnically diverse sample [abstract 283]. J Urol. 2006;175(4 suppl):94. Clemens JQ, Meenan RT, Rosetti MCO, et al. Medical costs and medication used in women with interstitial cystitis [abstract 284]. J Urol. 2006;175(4 suppl):94-95. Carrico DJ, Diokno AC, Peters KM. The prevalence of abuse in women with interstitial cystitis in pelvic floor dysfunction [abstract 290]. J Urol. 2006;175(4 suppl):96-97. Nickel JC, Tripp DA, Fitzgerald MP, et al. Sexual functioning as a determinant of poor quality of life in interstitial cystitis [abstract 291]. J Urol. 2006;175(4 suppl):97. Shorter B, Kushner L, Moldwin RM. Effects of comestibles on symptoms of interstitial cystitis [abstract 292]. J Urol. 2006;175(4 suppl):97. Peters KM, Carrico DJ, Ibrahim IA, et al. Women with interstitial cystitis have significantly more pelvic surgeries than controls [abstract 296]. J Urol. 2006;175(4 suppl):98-99. Bade JJ, Smans AJ. Long-term efficacy of sacral neuro-modulation (Interstim) in patients with refractory interstitial cystitis (IC) shows tendency to decrease [abstract 295]. J Urol. 2006;175 (4 suppl):98. Carr LK, Steele D, Steele S, et al. Single institution clinical trial of muscle-derived cell injection to treat stress urinary incontinence [abstract 1284]. J Urol. 2006;175(4 suppl):414. Fischer MC, Twiss CO, Nitti VW. Association between involuntary detrusor contractions on preoperative urodynamics and postoperative outcomes in patients undergoing male perineal sling [abstract 1364]. J Urol. 2006;175(4 suppl):440. Ganabathi R, Tyagi P, de Miguel F, et al. Effect of IP-751, ajulemic acid, against acetic acid induced bladder pain responses in rats 24h after intravesical administraion [abstract 282]. J Urol. 2006;175(4 suppl):93. Rutman M, Itano N, Deng DY, et al. Long term durability of the distal urethral polypropylene sling (DUPS) procedure for stress urinary incontinence: minimum 5-year follow-up of surgical outcome and satisfaction determined by patient reported questionnaires [abstract 345]. J Urol. 2006;175(4 suppl):113. Sharma S, Klausner AP, Fletcher SG, et al. The effect of oxybutynin treatment on plaques, amyloid-beta peptides (ABP), and behavior in mouse and human cybrid models of Alzheimer’s disease [abstract 171]. J Urol. 2006;175(4 suppl):55. Gevaert T, Ost D, De Ridder D. Effects of muscarinic agonists on autonomous activity in normal and neurogenic rat bladders [abstract 1288]. J Urol. 2006;175(4 suppl):415. Tyagi S, Yoshimura N, Chancellor MB, De Miguel F. Quantitative expression of muscarinic receptors in urothelium and detrusor of healthy and neurogenic human bladder [abstract 1294]. J Urol. 2006;175(4 suppl):55. Ustinova EE, Pezzone MA, Fraser MO. Colonic irritation in the rat sensitizes urinary bladder afferents to mechanical and chemical stimuli: a role of local cross-organ afferent reflexes in the overlap of chronic pelvic pain disorders [abstract 196]. J Urol. 2006;175(4 suppl):64. Hodges S, Hipp J, Mishra N, et al. Reversal of 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. abnormal gene function in neurogenic bladders using epigenetic therapy [abstract 1272]. J Urol. 2006;175(4 suppl):409. Lucioni A, Rapp DE, Gong EM, et al. Botulinum toxin type A inhibits the release of calcitonin gene-related peptide in an acute inflammatory rat bladder model [abstract 1274]. J Urol. 2006; 175(4 suppl):410. Lassmann J, Gonzalez FG, Melchionni JB, et al. Prevalence of urinary incontinence in adult spina bifida patients and impact on quality of life [abstract 584]. J Urol. 2006;175(4 suppl):189. Nelson CP, King J, Gearhart JP. Thirty year follow-up of a cohort of bladder exstrophy patients: the Johns Hopkins experience [abstract 574]. J Urol. 2006;175(4 suppl):186. Davies MC, Wilcox DT, Woodhouse CR, Creighton SM. What are the adult outcomes after anorectal malformation repair? [abstract 585]. J Urol. 2006;175(4 suppl):190. Evan AP, Coe FL, Lingeman JE, et al. Renal crystal deposits and histopathology in patients with cystine stones [abstract 1541]. J Urol. 2006; 175(4 suppl):498. Asplin JR, Coe FL. Hyperoxaluria in bariatric surgery patients with urolithiasis [abstract 1040]. J Urol. 2006;175(4 suppl):334. Razdan S, Vasquez G. Adjunctive tamsulosin improves stone free rate after ureteroscopic lithotripsy of large renal and ureteric calculi: a prospective randomized study [abstract 1707]. J Urol. 2006;175(4 suppl):549. Pishchalnikov YA, VonDerHaar RJ, Pishchalnikova IV, et al. Why stones break better at slow shock wave rate in SWL [abstract 1706]. J Urol. 2006;175(4 suppl):548. Bailey MR, Maxwell AD, Macconaghy B, et al. Advantage of a broad focal zone in SWL: synergism between squeezing and shear [abstract 1667]. J Urol. 2006;175(4 suppl):538. Evan AP, Pishchalnikov YA, Williams JC Jr, et al. Minimal tissue injury and effective stone breakage in the pig model using the Eisenmenger broad focal zone, low-pressure lithotripter [abstract 1668]. J Urol. 2006;175(4 suppl):538. Borin JF, Abdelshehid CS, Jellison F, et al. Comparison of ureteroscope damage after processing with Steris System 1 vs Cidex OPA [abstract 1083]. J Urol. 2006;175(4 suppl):348. Shapiro E, Huang H, Masch RJ, et al. Regional expression of the androgen receptor and 5reductase type 2 in the human fetal prostate [abstract 1437]. J Urol. 2006;175(4 suppl):464. Lucia SM, Burrows PK, La Rosa FG, et al. Combining transition zone biopsy composition with transition zone volume to predict progression in the MTOPS trial [abstract 1439]. J Urol. 2006;175(4 suppl):465. Werahera PN, Van Bokhoven A, La Rosa FG, et al. Association of stromal, epithelial, smooth muscle, and luminal compositions to nodule size and symptom severity of benign prostatic hyperplasia [abstract 1440]. J Urol. 2006;175(4 suppl):465. Cannon GW, Getzenberg RH. A serum-based assay for JM-27 can identify men with symptomatic benign prostatic hyperplasia [abstract 1354]. J Urol. 2006;175(4 suppl):436. Lluel P, Méen M. Alfuzosin reverses bladder 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. hypertrophy induced by bladder outlet obstruction in rats [abstract 1455]. J Urol. 2006;175 (4 suppl):469. Hrachowitz K, Kramer G, Steiner G, et al. Expression of proinflammatory interleukin-17B, -C, -E and their receptors in prostatic tissue [abstract 1448]. J Urol. 2006;175(4 suppl):467. Levitt JM, Song W, Guariguata L, et al. Up-regulation of a family of interferon-inducible inflammatory chemokines in benign prostatic hyperplasia [abstract 1449]. J Urol. 2006;175(4 suppl):468. Penna G, Cossett C, Amuchastegui S, et al. Human prostate cells as inducers and targets of chronic autoimmune inflammation [abstract 1451]. J Urol. 2006;175(4 suppl):468. Naslund MJ, Issa MM, Fenter TC. The prevalence, costs, and burden of enlarged prostate (EP) in men 50 years of age [abstract 1345]. J Urol. 2006;175(4 suppl):433. Parsons JK, Carter HB, Partin AW, et al. Metabolic factors associated with benign prostatic hyperplasia: the Baltimore Longitudinal Study of Aging [abstract 1344]. J Urol. 2006;175(4 suppl):432. Hammarsten J, Hogstedt B. Hyperinsulinaemia as a risk factor for developing benign prostatic hyperplasia. Eur Urol. 2001;39:151-158. Rohrmann S, De Marzo AM, Smit E, et al. Serum C-reactive protein concentration and lower urinary tract symptoms in older men in the Third National Health and Nutrition Examination Survey (NHANES III). Prostate. 2005;62:27-33. Roehrborn CG, Marberger M, Wolford ET, Wilson TH. Relationships between alcohol use and measures of LUTS/BPH severity: baseline data from dutasteride studies involving a total of 18,914 subjects [abstract 1350]. J Urol. 2006;175(4 suppl):435. Roehrborn CG, Marberger M, Wolford ET, Wilson TH. Explanatory variables for measures of sexual dysfunction in LUTS/BPH and prostate cancer risk reduction studies: baseline data from dutasteride studies involving a total of 18,914 subjects [abstract 1348]. J Urol. 2006;175 (4 suppl):434. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol. 2003;44:637-649. Steers WD, Nuckolls J, Seftel AD, et al. Differences between PCPs and urologists in the evaluation of men with LUTS/BPH [abstract 6]. J Urol. 2006;175(4 suppl):2. Wei JT, Nuckolls J, Miner M, et al. Differences in medical management of LUTS-BPH between PCPs and urologists [abstract 7]. J Urol. 2006;175(4 suppl):3. Rosen RC, Fitzpatrick JM. All components of ejaculation are impaired in men with LUTS suggestive of BPH [abstract 1360]. J Urol. 2006;175(4 suppl):438. Anneveld M, van Haarst EP, Heldeweg EA. A comparison of frequency-volume-charts in men with and without voiding complaints [abstract 1351]. J Urol. 2006;175(4 suppl):435. Yap TL, Cromwell D, Van der Meulen J, et al. The relationship between frequency-volume chart VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 161 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 162 AUA Annual Meeting continued 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 162 data and the International Prostate Symptom Score (IPSS) in men with lower urinary tract symptoms [abstract 1355]. J Urol. 2006;175(4 suppl):437. Kaplan SA, Kaplan JD, Gonzalez RR, et al. The use of a voiding diary to evaluate urinary frequency and nocturia is a better indicator than the IPSS in assessing alpha blocker efficacy in men with lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BHP) [abstract 1359]. J Urol. 2006;175(4 suppl):438. Wurzel R, Ray P, Major-Walker KY, et al. Inhibition of type I and type II 5-reductase with dutasteride (0.5 mg) significantly reduces intraprostatic dihydrotestosterone in BPH patients [abstract 1635]. J Urol. 2006;175(4 suppl):526. Hellstrom WJG, Sikka SC. Alpha-blockers may adversely affect sperm parameters in healthy adult men [abstract 1422]. J Urol. 2006;175(4 suppl):459. Michel MC, Okutsu H, Noguchi Y, et al. In vivo studies on the effects of 1-adrenoceptor antagonists on pupil diameter and urethral tone in rabbits. Naunyn Schmiedebergs Arch Pharmacol. 2006;372:346-353. Radomski SB, Srinivasan S, Chung J, et al. Intraoperative iris prolapse during cataract surgery in men using alpha-blockers for lower urinary tract symptoms due to benign prostatic hypertrophy [abstract 1634]. J Urol. 2006;175(4 suppl):526. Macdiarmid S, Chen A, Tu N, et al. Effects of tamsulosin and extended-release oxybutynin on lower urinary tract symptoms in men [abstract 1639]. J Urol. 2006;175(4 suppl):528. Roehrborn CG. Alfuzosin 10mg once daily prevents BPH overall clinical progression but not the AUR occurrence: a 2-year placebo-controlled study [abstract 1633]. J Urol. 2006;175(4 suppl):526. Roehrborn CG. Impact of baseline variables on the risk of LUTS and BPH progression in placebo and alfuzosin treated patients: results of the 2 years ALTESS study [abstract 1641]. J Urol. 2006;175(4 suppl):529. Sairam K, Kulinskaya E, McNicholas TA, et al. Sildenafil influences lower urinary tract symptoms. BJU Int. 2002;90:836-839. Hopps CV, Mulhall JP. Assessment of the impact of sildenafil citrate on lower urinary tract symptoms (LUTS) in men with erectile dysfunction (ED). J Urol. 2003;169:375A. Roehrborn CG, McVary KT, Kaminetsky JC, et al. The efficacy and safety of tadalafil adminstered once a day for lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) [abstract 1636]. J Urol. 2006;175(4 suppl):527. McVary KT, Camps J, Henry GD, et al. Sildenafil improves erectile function and urinary symptoms in men with erectile dysfunction and concomitant lower urinary tract symptoms [abstract 1637]. J Urol. 2006;175(4 suppl):527. Kaplan SA, Gonzalez RR, Ogiste J, et al. Combination of an alpha blocker, alfuzosin SR and a PDE-5 inhibitor, sildenafil citrate is superior to monotherapy in treating lower urinary tract symptoms (LUTS) and sexual dysfunction [abstract 1638]. J Urol. 2006;175(4 suppl):528. VOL. 8 NO. 3 2006 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. REVIEWS IN UROLOGY Chuang YC, Chiang PH, Hsien K, et al. Beneficial effects of up to one year with intraprostatic botulinum toxin type A injection on LUTS and quality of life in BPH patients [abstract 1436]. J Urol. 2006;175(4 suppl):464. Larson BT, Mynderse LA, Ulchaker JC, et al. Dispelling myths of cooled transurethral microwave thermotherapy and small prostates [abstract 1525]. J Urol. 2006;175(4 suppl):492. Waldert M, Djavan B, Seitz C, et al. 8 year clinical and urodynamical outcome and retreatment rates of high energy transurethral microwave thermotherapy: multicenter European pooled analysis [abstract 1430]. J Urol. 2006;175(4 suppl):461. Schelin S, Richthoff J. Experiences of a new device for mediating intraprostatic injections of drugs via the urethra [abstract 1526]. J Urol. 2006;175(4 suppl):492. Han E, Black LK, Lavelle JP, et al. BPH-related surgical procedures in incontinent males with BPH [abstract 1426]. J Urol. 2006;175(4 suppl):460. Bouchier-Hayes DM, Anderson P, Van Appledorn S, et al. A randomized trial comparing photoselective vaporization of the prostate (PVP) and transurethral resection of the prostate (TURP) in treatment of LUTS [abstract 1433]. J Urol. 2006;175(4 suppl):463. Miller NL, Matlaga BR, Kim SC, et al. Holmium laser enucleation of the prostate: effect on prostate volume [abstract 1520]. J Urol. 2006;175(4 suppl):490. Chandrasekar P, Kapasi F, Virdi JS. A prospective randomised study between transurethral vaporisation using plasmakinetic energy and transurethral resection of prostate—five year results [abstract 1510]. J Urol. 2006;175(4 suppl):487. Abbou CC, Hoznek A, Salomon L, et al. Laparoscopic radical prostatectomy with a remote controlled robot. J Urol. 2001;165:1964-1966. Menon M, Tewari A, Baize B, et al. Prospective comparison of radical retropubic prostatectomy and robot-assisted anatomic prostatectomy: the Vattikuti Urology Institute experience. Urology. 2002;60:864-868. Smith JA Jr. Robotically assisted laparoscopic prostatectomy: an assessment of its contemporary role in the surgical management of localized prostate cancer. Am J Surg. 2004;188:63S-67S. Ahlering TE, Woo D, Eichel L, et al. Robotassisted versus open radical prostatectomy: a comparison of one surgeon’s outcomes. Urology. 2004;63:819-822. Sarle R, Bhandari A, Shah N, et al. The Vattikuti Institute prostatectomy: a single surgeon experience of 1452 cases [abstract 1154]. J Urol. 2006;175(4 suppl):370. Herrell DS, Schachter LR, Smith JA. Impact of learning curve for robotic-assisted laparoscopic prostatectomy: positive surgical margin rate [abstract 216]. J Urol. 2006;175(4 suppl):71. Patel VR, Arends D. The incidence and location of positive margins after robotic assisted radical prostatectomy [abstract 1080]. J Urol. 2006; 175(4 suppl):347. Slawin KM, Guariguata L. The influence of in- 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. creasing experience and surgical technique on surgical margin status in patients undergoing open and robotic prostatectomy by a single surgeon [abstract 1164]. J Urol. 2006;175(4 suppl):374. Gong EM, Mikhail AA, Lucioni A, et al. Learning curve for robotic assisted radical prostatectomy: comparison between an open and laparoscopic trained surgeon [abstract 1082]. J Urol. 2006; 175(4 suppl):348. Kozlowski PM, Porter CR, Corman JM. Mechanical failure of da Vinci robotic system: implications for pre-op patient counseling [abstract 1159]. J Urol. 2006;175(4 suppl):372. Presti JC, McNeal JE, Hsu TH, et al. Performance of PSA levels between 4 and 10 ng/mL in the era of extended biopsy schemes [abstract 468]. J Urol. 2006;175(4 suppl):151. Stamey TA, Caldwell M, McNeal JE, et al. The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J Urol. 2004;172(4 pt 1):1297-1301. Connolly D, Black A, Nambirajan T, et al. Initial PSA levels and the long-term risk of prostate cancer [abstract 469]. J Urol. 2006;175(4 suppl): 152. Thompson IM, Chi C, Goodman P, et al. Comparison of the operating characteristics of PSA for prostate cancer detection for finasteride and placebo in the Prostate Cancer Prevention Trial [abstract 470]. J Urol. 2006;175(4 suppl):152. Loeb S, Roehl KA, Graif T, et al. PSA velocity threshold for predicting prostate cancer in young men with PSA  4 ng/mL [abstract 471]. J Urol. 2006;175(4 suppl):153. Makarov DV, Humphreys EB, Mangold LA, et al. Pathologic outcomes and biochemical progression in men with T1c prostate cancer undergoing radical prostatectomy with PSA 2.6-4.0 ng/mL versus PSA 4.1-6.0 ng/mL [abstract 474]. J Urol. 2006;175(4 suppl):154. Grubb RL, Levin DL, Pinsky PF, et al. Body mass index and impact on PSA screening and prostate cancer detection in the PLCO trial [abstract 477]. J Urol. 2006;175(4 suppl):155. Scales CD, Curtis LH, Norris RD, et al. Relationship between obesity and prostate cancer screening in the United States [abstract 478]. J Urol. 2006;175(4 suppl):155. Hofer MD, Perner S, Li H, et al. Prostate-specific membrane antigen (PSMA) expression as a predictor of prostate cancer progression [abstract 479]. J Urol. 2006;175(4 suppl):155. Grubb RL, Levin DL, Pinsky PF, et al. Relationship of PSA velocity and Gleason score in the PLCO cancer screening trial [abstract 522]. J Urol. 2006;175(4 suppl):169. D’Amico AV, Cullen J, Chen Y, McLeod DG. Prostate-specific antigen velocity and the odds of identifying prostate cancer at biopsy [abstract 523]. J Urol. 2006;175(4 suppl):169. Loeb S, Roehl KA, Han M, et al. PSA velocity to follow patients with isolated high-grade PIN on prostate biopsy [abstract 524]. J Urol. 2006; 175(4 suppl):170. Van Gils MP, Hessels D, Hulsberger-Van De Kaa CA, et al. Detailed analysis of histopathological parameters and PCA3 test results [abstract 537]. J Urol. 2006;175(4 suppl):174. RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 163 AUA Annual Meeting 122. Fradet Y, Groskopf J, Walker S, et al. Prototype APTIMA® PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer [abstract 538]. J Urol. 2006; 175(4 suppl):174. 123. Herr HW, Donat MS. A restaging transurethral resection predicts early progression of superficial bladder cancer [abstract 829]. J Urol. 2006;175(4 suppl):267. 124. Gallagher BL, Joudi FN, O’Donnell MA. Response to intravesical immunotherapy in BCG naive and BCG treated patients [abstract 831]. J Urol. 2006;175(4 suppl):268. 125. Au JL, Badalament RA, Wientjes MG, et al. Optimized intravesical mitomycin C treatment for superficial bladder cancer: long-term follow-up [abstract 832]. J Urol. 2006;175(4 suppl):268. 126. Sylvester R, Van der Meijden APM, Oosterlinck W, et al. Predicting recurrence and progression in stage Ta T1 bladder cancer patients using EORTC risk tables [abstract 834]. J Urol. 2006; 175(4 suppl):269. 127. Rischmann P, Colombel M, Chopin DK, et al. Prophylactic ofloxacin to improve tolerance of BCG intravesical instillations: a randomised prospective, double blind, placebo-controlled, multicentre study in patients with mid to high risk superficial bladder tumors [abstract 835]. J Urol. 2006;175(4 suppl):269. 128. Dalbagni G, Russo P, Ben-Porat L, et al. Phase II trial of intravesical gemcitabine in BCG-refractory transitional cell carcinoma of the bladder [abstract 839]. J Urol. 2006;175(4 suppl):270. 129. Maymi JL, Saltsgaver N, O’Donnell MA. Intravesical sequential gemcitabine-mitomycin chemotherapy as salvage treatment for patients with refractory superficial bladder cancer [abstract 840]. J Urol. 2006;175(4 suppl):271. 130. Joudi FN, Smith BJ, O’Donnell MA, Konety BR. The impact of age on response of patients with superficial bladder cancer to intravesical immunotherapy [abstract 843]. J Urol. 2006;175(4 suppl):272. 131. Parekh DJ, Herr HW, Ben-Porat L, et al. Prospective evaluation of P53 as a prognostic marker in T1 transitional cell carcinoma (TCC) of the bladder [abstract 847]. J Urol. 2006;175(4 suppl):273. 132. Lambert EH, Pierorazio PM, Poon SA, et al. The increasing use of intravesical therapies for T1 bladder cancer coincides with decreasing survival after cystectomy [abstract 848]. J Urol. 2006;175(4 suppl):273. 133. Messing EM, Madeb RR, Golijanin D, et al. Longterm outcome of hematuria home screening for bladder cancer (BC) [abstract 881]. J Urol. 2006;175(4 suppl):284. 134. Lotan Y, Svatek RS, Sagalowsky AI. Screening high risk patients for bladder cancer is costeffective [abstract 882]. J Urol. 2006;175 (4 suppl):285. 135. Madeb RR, Golijanin D, Stephenson L, et al. Long-term outcome of patients with a negative work-up for asymptomatic microhematuria (MH) [abstract 883]. J Urol. 2006;175(4 suppl):285. 136. Boorjian SA, Cowan JE, Konety BR, et al. Bladder cancer incidence and risk factors among men with prostate cancer: results from CaPSURETM [abstract 886]. J Urol. 2006;175(4 suppl):286. 137. Johnson E, Daignault S, Zhang Y, et al. Gender disparities in urologic referral of hematuria [abstract 887]. J Urol. 2006;175(4 suppl):286. 138. Grossman HB. Surveillance of patients with a history of bladder cancer using a point-of-care proteomic assay [abstract 891]. J Urol. 2006;175(4 suppl):288. 139. Karl A, Reich O, Tritschler S, et al. Positive cytology, but negative white light endoscopy: an indication for fluorescence cystoscopy in bladder cancer? [abstract 892]. J Urol. 2006;175(4 suppl):288. 140. Haber GP, Gill IS, Rozet F, et al. International registry of laparoscopic radical cystectomy: first report on 308 patients [abstract 1224]. J Urol. 2006;175(4 suppl):394. 141. Haber GP, Colombo JR, Aron M, et al. Laparoscopic radical cystectomy with urinary diversion: pure laparoscopic versus laparoscopic assisted [abstract 1229]. J Urol. 2006;175(4 suppl):396. 142. Akkad T, Gozzi C, Deibl M, et al. Tumor recurrence in the remnant urothelium after radical cystectomy for transitional cell carcinoma of the bladder in females: long term results of a single center [abstract 1225]. J Urol. 2006;175(4 suppl):394. 143. Koppie TM, Vickers AJ, Vora KC, et al. Establishing a minimum number of lymph nodes to be removed during radical cystectomy: implications for the necessary extent of dissection [abstract 1226]. J Urol. 2006;175(4 suppl):394. 144. Hollenbeck BK, Miller DC, Daignault S, et al. Getting “under the hood” of the volume-outcome relationship for radical cystectomy [abstract 1228]. J Urol. 2006;175(4 suppl):395. 145. Amiel GE, Shariat SF, Shen S, et al. Evidence based gender related outcomes after radical cystectomy [abstract 1230]. J Urol. 2006;175(4 suppl):396. 146. Nielsen ME, Shariat SF, Karakiewicz PI, et al. Delay in radical cystectomy over 12 weeks is not associated with adverse outcome: results from the Bladder Cancer Research Consortium [abstract 1231]. J Urol. 2006;175(4 suppl):396. 147. Weizer AZ, Shah RB, Gilbert SB, et al. Presence, location and significance of prostate cancer in patients undergoing radical cystoprostatectomy: feasibility of prostate capsule sparing cystectomy [abstract 1234]. J Urol. 2006;175(4 suppl):397. 148. Pettus JA, Al-Ahmadie H, Barocas DA, et al. Prostate involvement by urothelial and prostatic carcinoma in radical cystoprostatectomy specimens [abstract 1235]. J Urol. 2006;175 (4 suppl):397. 149. Josephson DY, Buscarini M, Lee CC, et al. Urinary diversion in women following radical cystectomy: a single center comparison and update on outcomes [abstract 1239]. J Urol. 2006;175(4 suppl):399. 150. Siefker-Radtke AO, Kamat AM, Grossman HB, et al. Prospective evidence supporting the utility of neoadjuvant chemotherapy in small cell urothelial cancer: preliminary results from a phase II clinical trial at the M. D. Anderson Cancer Center [abstract 1240]. J Urol. 2006;175(4 suppl):399. 151. Steven K, Horn T, Poulsen AL. Radical cystec- 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. tomy with extended pelvic lymphadenectomy: survival for patients with lymph node metastasis treated by surgery only stratified according to the anatomical location of the metastasis [abstract 1241]. J Urol. 2006;175(4 suppl):399. Schumacher M, Scholz M, Thalmann GN, et al. Is there an indication for frozen section analysis of the ureteral margin during cystectomy for transitional cell carcinoma of the bladder? [abstract 1244]. J Urol. 2006;175(4 suppl):400. Shabsigh A, Raj GV, Korets R, et al. The incidence and risk factors of post-operative complications in female patients undergoing radical cystectomy [abstract 1245]. J Urol. 2006;175(4 suppl):400. Kassouf W, Spiess PE, Brown GA, et al. A comparison of performance of TNM staging versus lymph node density in risk stratification of patients undergoing cystectomy for urothelial carcinoma [abstract 1251]. J Urol. 2006;175(4 suppl):402. Levin H, Jones JS. Is there still a role for reinterpretation of outside biopsy slides when bladder cancer patients are referred for tertiary care? [abstract 1253]. J Urol. 2006;175(4 suppl):403. Tal R, Raj GV, Bochner BH, et al. Utility of assessment of ureteral margins during radical cystectomy for urothelial cancer [abstract 1258]. J Urol. 2006;175(4 suppl):404. Sanderson KM, Stein JP, Cai J, et al. Upper tract recurrence following radical cystectomy for transitional cell carcinoma: an analysis of 1069 patients with 10-year follow-up [abstract 1262]. J Urol. 2006;175(4 suppl):406. Thompson RH, Lohse CM, Frank I, et al. Preoperative and intraoperative features associated with positive lymph nodes during nephrectomy for renal cell carcinoma [abstract 73]. J Urol. 2006; 175(4 suppl):24. Leibovich BC, Thompson RH, Lohse CM, et al. The impact of lymphadenectomy at the time of nephrectomy for metastatic RCC [abstract 1115]. J Urol. 2006;175(4 suppl):359. Brassell S, Sanchez-Ortiz RF, Matin SF, et al. Resection of nodal disease in patients with metastatic conventional renal cell carcinoma improves survival [abstract 743]. J Urol. 2006;175 (4 suppl):241. Patard JJ, Pantuck AJ, Lam JS, et al. Morbidity and clinical outcome of nephron sparing surgery in relation to tumor size and indication [abstract 51]. J Urol. 2006;175(4 suppl):18. Patard JJ, Crepel M, Colombel M, et al. Comparison between open and laparoscopic nephron sparing surgery. Results from a multicenter experience [abstract 91]. J Urol. 2006;175(4 suppl):29. Kane CJ, Cooperberg MR, Richey J, et al. Stage migration in renal cell carcinoma patients demonstrated by analysis of the National Cancer Database, 1993-2003 [abstract 1105]. J Urol. 2006;175(4 suppl):355. Feldman AS, Gervais DA, Cutie CJ, et al. A comparison of nephron-sparing techniques: percutaneous radiofrequency ablation (RFA) vs. open and laparoscopic partial nephrectomy [abstract 1114]. J Urol. 2006;175(4 suppl):358. Stern JM, Svatek RS, Park S, et al. Intermediate follow-up comparison between partial nephrectomy and radio frequency ablation in T1A renal VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 163 RIU2006AUA_08-12.qxd 8/12/06 3:11 PM Page 164 AUA Annual Meeting continued tumors [abstract 46]. J Urol. 2006;175(4 suppl):16. 166. Hegarty NJ, Gill IS, Kaouk JH, et al. Renal cryoablation: 5 year outcomes [abstract 1091]. J Urol. 2006;175(4 suppl):351. 167. Kutikov A, Fossett LK, Guzzo TJ, et al. Enucleation of renal cell carcinoma with ablation of tumor base: is cancer control comparable to partial nephrectomy? [abstract 45]. J Urol. 2006;175(4 suppl):16. 168. Kunkle DA, Crispen PL, Chen DYT, et al. Characteristics of enhancing renal masses with zero net growth during active surveillance [abstract 720]. J Urol. 2006;175(4 suppl):233. 169. Lam JS, Patard JJ, Goel RH, et al. Can PT2 classification for renal cell carcinoma be improved? An International multicenter experience [abstract 740]. J Urol. 2006;175(4 suppl):240. 170. Thompson RH, Leibovich BC, Dong H, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long term follow-up [abstract 386]. J Urol. 2006;175(4 suppl):126. 171. Thompson RH, Dong H, Lohse CM, et al. PD-1 expression by tumor infiltrating lymphocytes is associated with poor prognosis in renal cell 164 VOL. 8 NO. 3 2006 172. 173. 174. 175. 176. REVIEWS IN UROLOGY carcinoma patients [abstract 385]. J Urol. 2006;175(4 suppl):126. Webster WS, Dong H, Thompson RH, et al. Complete tumor regression of established murine renal cell carcinoma following CD4+ T cell depletion and B7-H1 blockade [abstract 399]. J Urol. 2006;175(4 suppl):130. Krambeck AE, Parks E, Lohse CM, et al. The immunomodulatory protein B7-H4 expression in renal cell carcinoma patients: a strong predictor of cancer progression and survival [abstract 387]. J Urol. 2006;175(4 suppl):127. Weiss RH, Borowsky AD, Seligson DB, et al. The P21 growth and apoptosis regulatory protein is an independent predictor of survival in patients with clear cell renal cell carcinoma [abstract 718]. J Urol. 2006;175(4 suppl):232. Lam JS, Leppert JT, Yu H, et al. Expression analysis of the vascular endothelial growth factor (VEGF) family in renal cell carcinoma: targeting the VEGF pathway [abstract 372]. J Urol. 2006;175(4 suppl):122. Carmack AJK, Saenz D, Jorda M, et al. Osteopontin expression in metastatic renal cell carcinoma [abstract 392]. J Urol. 2006;175 (4 suppl):128. 177. Hennenlotter J, Merseburger AS, Kuehs U, et al. Activation combined biomarkers PI3K and p-AKT is associated with reduced survival in renal cell carcinoma [abstract 394]. J Urol. 2006;175(4 suppl):129. 178. Kuczyk M, Serth J, Mengel M, et al. Decreased P27KIP Protein Expression as Determined by Tissue Microarray Analysis (TMA) Predicts the Clinical Prognosis of Renal Cell Cancer Patients [abstract 395]. J Urol. 2006;175(4 suppl): 129. 179. Motzer RJ, Hutson TE, Tomczak P, et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alpha (IFN-alpha) as first-line systemic therapy for patients with metastatic renal cell carcinoma (RCC). J Clin Oncol. 2006;24(18S):LBA3. 180. Hudes G, Carducci M, Tomczak P, et al. A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of firstline, poor-risk patients with advanced renal cell carcinoma (adv RCC). J Clin Oncol. 2006; 24(18S):LBA4.