Overactive Bladder

Although many patients are not fully satisfied [Akino, H. et al., Abst 1871], antimuscarinic therapies have been the cornerstone for the treatment of overactive bladder and neurogenic detrusor overactivity, with the possibility of combining different drugs or adding a second drug with a different mechanism of action to improve outcomes in patients not fully responding to a single agent [Cameron, A.P. et al., Abst 953; Game, X. et al., Abst 954; Lim, I. et al., Abst 959]. In fact, although not the only drugs currently in use, antimuscarinic agents are the most commonly prescribed medications for overactive bladder, topped by tolterodine followed by oxybutynin, tricyclic antidepressants, solifenacin, darifenacin and hyoscyamine in a registry of over 3 million men from the U.S. [Helfand, B.T. et al., Abst 1939]. New trials on these agents were presented this year at the McCormick Convention Center, including notably a study that demonstrated significantly better tolerability with solifenacin than immediate-release oxybutynin, although both treatments were equieffective in improving symptoms of overactive bladder and patient-reported outcomes [Herschorn, S. et al., Abst LBA7] (Fig. 1); additional studies confirmed the safety and efficacy profiles of agents such as trospium [Chancellor, M.B. et al., Abst 1872] and oxybutynin [Dmochowski, R.R. et al., Abst 1636] (Fig. 2), although according to some evidence, switch from branded anticholinergic therapy to generic oxybutynin resulted in a loss of efficacy and safety [Kaplan, S.A. et al., Abst 1870]. In the experimental setting, fesoterodine lowered maximal and threshold pressure in animal models of partial outflow obstruction without significant urodynamic changes, whereas doxazosin increased bladder capacity and compliance and decreased frequency, abolishing the effects of fesoterodine. These results suggest potential for a combination of both agents [Fullhase, C. et al., Abst 1928]. Regarding safety issues, while in healthy control subjects tolterodine increased heart rate and decreased heart rate variability compared to darifenacin [Olhansky, B. et al., Abst LBA4] (Fig. 3), very low CNS exposure to fesoterodine was noted in experimental animals [Kay, G. et al., Abst 227]. Additional experimental findings revealed the potential of solifenacin to prevent detrusor changes and improve urodynamics in animals with bladder outlet obstruction [Kimm, S. et al., Abst 1918; Kimm, S. et al., Abst 1926]. Also of interest regarding anticholinergic therapies for overactive bladder, a PLGA-based trospium-carrying polymer formulation with sustained delivery over 24 hours was introduced that with single daily application may offer an intravesical alternative to oral therapy with reduced systemic exposure and improved tolerability [Grosse, J.O. et al., Abst 1590].

Fig. 1. Dry mouth rates in patients treated with solifenacin or oxybutynin [Herschorn, S. et al., Abst LBA7].

Fig. 2. Change in the daily urinary incontinence, micturition frequency and nocturia episodes after 12 weeks of treatment with topical oxybutynin gel or placebo [Dmochowski, R.R. et al., Abst 1636].

Fig. 3. Change in heart rate after treatment with extended-release tolterodine, darifenacin or placebo [Olshansky, B. et al., Abst LBA4].

While new studies and observations confirmed the feasibility and favorable impact on quality of life of botulinum toxin against overactive bladder/detrusor hyperreflexia in a number of settings and patient types [Laschke, S. et al., Abst 872; Petoru, S.P. et al., Abst 1532; Fowler, C. et al., Abst LBA8; Guggenbuehl-roy, S. et al., Abst 1591; Schmid, D.M. et al., Abst 1637], mechanistic experimental studies revealed an effect of the toxin in blocking L-type voltage-gated calcium currents and attenuating distension-evoked sensory afferent nerve firing without affecting bladder compliance [Collins, V.M. et al., Abst 223; Yunoki, T. et al., Abst 1510] which, along with a demonstration that botulinum toxin exclusively targets nerve fibers in the cholinergic system [Cruz, F.R. et al., Abst 417], confirms the selectivity of its use in the treatment of overactive bladder. Moreover, the feasibility of intravesical instillation of botulinum toxin-containing liposomes, along with immunohistochemical demonstration of its uptake by afferent nerve terminals and the resulting cystometric and urodynamic changes, suggested a new treatment modality for detrusor hyperactivity [Chuang, Y.C. et al., Abst 1638].

As an alternative to anticholinergic therapy, the neurokinin blocker serlopitant also improved overactive bladder outcomes, although not as effectively as tolterodine [Frenkl, T.L. et al., Abst 1873] (Fig. 4). In the experimental arena, studies in rodents confirmed the activity of the NK1 blocker netupitant in reversing acetic acid-induced bladder overactivity [Lluel, P. et al., Abst 1583] and suggested improvements in cyclophosphamide-induced nonvoiding bladder contractions by tamsulosin through suppression of central afferent/efferent activation of the lower urinary tract [Kim, K.H. et al., Abst 948], while in fact the agent has been effectively tested to improve subjective symptoms and urometric parameters in women with lower urinary tract symptoms [Kim, S.O. et al., Abst 1534]. Additional in vivo studies illustrated the efficacy of mirabegron [Noguchi, Y. et al., Abst 25] and cannabinor [Gratzke, C. et al., Abst 1579] in improving bladder outlet obstruction-induced nonmicturition contractions in animals, and that of soy isoflavones in improving detrusor overactivity in ovariectomized animals [Okada, S. et al., Abst 1588], suggesting efficacy in the treatment of storage symptoms in patients with overactive bladder. Further experimental models of neurogenic detrusor overactivity demonstrated improvements in cystometrogram parameters after treatment with pregabalin and lamotrigine [Campeau, L. et al., Abst 947]. Relief of detrusor overactivity secondary to middle cerebral artery occlusion were described in further studies with the cyclooxygenase inhibitors rofecoxib, FYO-750 and SC-560 [Tanaka, I. et al., Abst 224]. The relaxation of carbachol-precontracted bladder strips by sildenafil [Behr,Roussel, D. et al., Abst 1583] and vardenafil [Ückert, S. et al., Abst 423; Sandner, P. et al., Abst 949] and the bladder vasorelaxant effects of the latter, along with the detrusor-relaxing activity of udenafil and its synergy with oxybutinin [Oger, S. et al., Abst 1582] suggested further avenues to explore in the treatment of detrusor overactivity and hyperreflexia. (Although not related specifically to urinary incontinence, intravenous sildenafil was also reported to improve endothelial function and hemodynamics during experimental kidney ischemia/reperfusion injury [Lledo-Garcia, E. et al., Abst 2059].) Improvements in animal models of bladder overactivity were also reported with herpes simplex virus-mediated enkephalin gene therapy [Yokoyama, H. et al., Abst 55].

Fig. 4. Change in daily urinary episodes over 8 weeks of treatment with serlopitant, tolterodine or placebo [Frenkl, T.L. et al., Abst 1873].

Regarding nonpharmacological approaches, home-based cognitive therapy offered a simple but effective option for overactive bladder according to results in six patients [Abbasy, S.A. et al., Abst 1562], pudendal and tibial nerve stimulation effectively improved refractory urge incontinence [Comiter, C.V. et al., Abst 1875; MacDiarmid, S.A. et al., Abst 1876] and sacral neuromodulation, while also being effective [White, W.M. et al., Abst 1639; Leng, W.W. & Smith, K.J., Abst 1640], was associated with a high level of concomitant bowel dysfunction [Swartz, M.A. et al., Abst 1565]. Additionally, deep brain stimulation for Parkinson’s disease also improved voiding and storage dysfunction, but said effect was much less prominent in cases of essential tremor [Vishwajit, S. et al., Abst 1866].

Stress Urinary Incontinence

Judging from the number of presentations at this and other meetings on urology, surgery remains the most popular approach to the treatment of stress urinary incontinence, with trials and observations confirming the usefulness of sling [Swartz, M.A. et al., Abst 452; Pickens, R.B. et al., Abst 1521; Wilson, C. et al., Abst 1522; Yoost, T.R. et al., Abst 1523; Sohn, D.W. et al., Abst 1524; Sung, L.H. et al., Abst 1566; Jeonng, S.J. et al., Abst 1705; Goudelocke, C.M. et al., Abst 1706; Bae, J.H. et al., Abst 1707; Reddy, S.K. et al., Abst 1708; Gamble, T. et al., Abst 1710], tape [Hyun, C.H. et al., Abst 1519; Dmochowski, R.R. et al., Abst 1520; Kim, J.J. et al., Abst 1559; Jern, T.K. et al., Abst 1704], mesh [Ortiz Gorraiz, M.A. et al., Abst 1517] and balloon [Kocjanoncic, E. et al., Abst 1567] procedures for female patients, and sling [Sievert, K.D. et al., Abst V361; Wadie, B.S. et al., Abst 1035; Grise, P., Abst 1197; Christine, B. et al., Abst 1256; Webster, G.D. et al., Abst 1644; Bauer, R.M. et al., Abst 1645; Christine, B. et al., Abst 1714; Cornel, E.B. et al., Abst 1716; Rapoport, D. et al., Abst 1717; Bochove-Overgaauw, D. et al., Abst 1718; Hind, A. et al., Abst 1719; Styn, N.R. et al., Abst 1720] techniques for male patients, while a similar approach, an intraurethral variable tension ring, was described as being effective for the treatment of orgasm-associated incontinence [Deveci, S. et al., Abst 1482] and an adjustable balloon system was effective against intrinsic sphincteric deficiency [Carmel, M. et al., Abst 1518]. Other surgical options, including notably neobladder augmentation cystoplasty, have been effective against signs and symptoms of neurogenic bladder [Joseph, D. et al., Abst LBA2], while the use of bulking agents has been displaced towards more complex incontinence cases [Kumar, A. & Nitti, V.W., Abst 1711], although efficacy was still reported in a trial with dextranomer/hyaluronate in men with postprostatectomy stress urinary incontinence [Seibold, J. et al., Abst 1721]. Vaginal electrical stimulation [Bezerra, C.A. et al., Abst 1561] and a vaginal weight cone [Moreira, E. et al., Abst 1703], with or without pelvic floor muscle training, also offered improvements in stress urinary incontinence, and in males with postprostatectomy incontinence, feasibility was reported with periurethral constrictor devices [Simone, G. et al., Abst 1715]. However, pelvic floor muscle training and pelvic floor electrical stimulation, biofeedback and behavioral therapy were also reported effective in selected patients, including notably men who had undergone prostatectomy [Centemero, A. et al., Abst 1642; Goode, P.S. et al., Abst 1643; Ribeiro, L.S. et al., Abst 1882; Sciarra, A. et al., Abst 1883].

Further advances in this domain are illustrated by the demonstration that urine-derived stem cells can be isolated and expanded for safe, noninvasive, low-cost injection therapy [Zhang, Y. et al., Abst 1525], by the safety and activity against stress urinary incontinence already demonstrated with autologous muscle-derived cells [Carr, L.K. et al., Abst 1526] and by the myogenic differentiation and survival of human mesenchymal stem cells [Feil, G. et al., Abst 1885]. In a related way, human adipose tissue-derived stem cells improved vesical leak point pressure in animal models of stress urinary incontinence through an effect on the micturition center mediated by suppression of central afferent/efferent activation of the urinary tract [Kim, K.H. et al., Abst 124], offering putative new approaches to therapy. Neurogenic-like bladder dysfunction was also improved in further animal studies by skeletal muscle-derived and mesenchymal multipotent stem cells [Nitta, M. et al., Abst 127; Dayanc, M. et al., Abst 128]. Similarly, while bone marrow mesenchymal stromal cells were able to differentiate into a smooth muscle phenotype [Campeau, L. et al., Abst 125], modified monocyte-derived cells were also able to enhance urethral sphincter rehabilitation [Hamann, M.F. et al., Abst 126], providing further avenues to explore in the treatment of sphincteric incontinence and bladder wall defects.

Pharmacotherapies for stress urinary incontinence are not widely recommended or currently used, but news related to this area was also reported during the meeting, namely a study that demonstrated the reliability of fluoxetine in preventing sneeze-induced continence reflex in experimental animals [Miyazato, M. et al., Abst 1533].

Benign Prostatic Hyperplasia

Lower urinary tract symptoms secondary to benign prostatic hyperplasia are very common in older men, and may have a severe impact on subjects’ daily activities. Although many patients with benign prostatic hyperplasia refuse treatment because of lack of bother, lack of associated comorbidity or assumption that "it comes with age", effective therapies are available, and drugs such as tamsulosin, doxazosin, alfuzosin, terazosin, finasteride, dutasteride and anticholinergic drugs are frequently prescribed in the U.S. for improving lower urinary tract symptoms [Helfand, B.T. et al., Abst 1794]. Furthermore, despite high discontinuation rates (especially considering alpha 1 receptor blockers; less so with the 5 alpha reductase inhibitors), noncompliance or underuse of medications has been associated with an increased risk for surgical therapy, suggesting a need for extending use of and compliance with these medications [Sarma, A.V. et al., Abst 1797], with the added caution that, according to some investigations, generic substitutes are less safe and effective than branded products [Kaplan, S.A. et al., Abst 1870; Kaplan, S.A. et al., Abst 1799].

alpha1-Receptor blockers remain the most common approach to the symptomatic management of benign prostatic hyperplasia, providing fast symptom relief, with intermittent therapy remaining effective while leading to cost savings when patients are not bothered by symptoms [Bulbul, M.A., Abst 1804]. Benefits on lower urinary tract symptoms secondary to benign prostatic hyperplasia were reported with naftopidil, which was safe both as monotherapy and in combination with anticholinergic drugs such as propiverine, and was superior to the anticholinergic in improving the International Prostate Symptom Scale scores [Yokoyama, T. et al., Abst 1581], and also with silodosin, with benefits on both storage and voiding function, and with rapid benefits on irritative and obstructive symptoms [Matsukawa, Y. et al., Abst 1920; Marks, L.S. et al., Abst 1921] (Fig. 5), although with a risk of retrograde ejaculation resulting from relaxation of smooth muscle and directly related to urodynamic and symptomatic improvements [Roehrborn, C.G. et al., Abst 1922]. To note, silodosin was also demonstrated active in improving bothersome nocturia in patients resistant to tamsulosin and naftopidil [Kira, S. et al., Abst 1923]. New mechanistic data with some of these agents were analyzed, including regulation of cellular proliferation by naftopidil, which while improving lower urinary tract symptoms by relaxing the prostatic urethra smooth muscle, also inhibited prostate cell proliferation [Kojima, Y. et al., Abst 1418]. On the opposite scale of the balance, treatment with alpha-blockers was reported to be associated with increased risk for floppy iris syndrome and cataract surgery [Bakalian, S. et al., Abst 1803].

5 alpha-Reductase inhibitors are also a major asset in the drug armamentarium for benign prostatic hyperplasia. Mechanistic data with finasteride revealed promotion of molecular pathways associated with prostate cancer progression on epithelial cells, but induction of cell death in the presence of stromal cells, suggesting chemopreventive benefits when used in men with benign prostatic hyperplasia [Niu, Y. et al., Abst 1411].

With good tolerability, evidence of symptomatic improvements and benefits on the quality of life were also reported with PORxin-302, a prostate-specific antigen-activated protoxin [Pommerville, P.J. et al., Abst 1946]. Improvements in lower urinary tract symptoms secondary to benign prostatic hyperplasia were also safely obtained by intraprostatic botulinum toxin type A injection [Crawford, E.D. et al., Abst 1800; Silva, J.F. et al., Abst 1801; Roehrborn, C.G. et al., Abst 1802; de Kort, L.M. et al., Abst 1945]. In addition, intraprostatic injection of botulinum toxin improved ejaculatory but not erectile function in patients with benign prostatic hyperplasia [Bruskewitz, R., Abst 1477] and was associated with apoptosis and atrophic changes in experimental animals [Yokoyama, T. et al., Abst 1405].

Turning to experimental treatments, preclinical evidence of activity of the TRPM8 ion channel opener D-3263 [Duncan, D. et al., Abst 1408], the peptidic alpha1A-adrenoceptor blocker AdTx1 [Palea, S. et al., Abst 1416] and light-activated talaporfin [Marks, L.S. et al., Abst 1948] were presented.

Regarding putative adjuvant therapies, phosphodiesterase V inhibitor therapy was associated with improved lower urinary tract symptoms in men with benign prostatic hyperplasia [Seftel, A.D. et al., Abst 1795], and at least in the case of tadalafil, led to a favorable impact on obstruction and quality of life [Dmochowski, R.R. et al., Abst 1924; Broderick, G. et al., Abst 1925] (Fig. 6). Vardenafil was reported to increase bladder contractile force in both disease and normal conditions [Matsumoto, S. et al., Abst 422], while according to further experimental studies, elocalcitol reverted benign prostatic hyperplasia-associated inflammatory responses in the urethral smooth muscle cells through interaction with the vitamin D receptor [Fibbi, B. et al., Abst 219].

Fig. 6. Change in the International Prostatic Symptom Scale overall, bother and quality of life scores after treatment with tadalafil or placebo [Broderick, G. et al., Abst 1925].

Surgery still remains an option for the treatment of benign prostatic hyperplasia, with favorable results reported with prostatectomy [Cardin, A.L. et al., Abst V354; Childs, M.A. et al., Abst V355; Sotelo, R.J. et al., Abst V356; Patil, N.N. et al., Abst 497], single-port transvesical enucleation [Desai, M.M. et al., Abst V353; Desai, M.M. et al., Abst 1935], transurethral laser enucleation [Chung, D.E. et al., Abst V360; Krambeck, A.E. et al., Abst 2103; Lerner, L. et al., Abst 2104; Ahyai, S.A. et al., Abst 2105; Saito, K. et al., Abst 2106; Shibata, Y. et al., Abst 2107], laser vaporization [Erol, A. et al., Abst LBA6; Wezel, F. et al., Abst 2109; Hermanns, T. et al., Abst 2112; Goh, A. et al., Abst 2113; Rieken, M. et al., Abst 2114; Woo, H.H., Abst 2115; Ayres, B.E. et al., Abst 2116; Hermanns, T. et al., Abst 2117; Woo, H.H., Abst 2118; Spaliviero, M. et al., Abst 2119; Otsuki, H. et al., Abst 2110; Seki, N. et al., Abst 2121], plasma vaporization [Lucan, M. et al., Abst V359; Wezel, F. et al., Abst 2108; Chandrasekar, P. et al., Abst 2111] and cooled thermotherapy [Roehrborn, C.G. et al., Abst 2122].

Interstitial Cystitis

Intravesical botulinum toxin type A injection followed by hydrodistention was reported as significantly beneficial compared to hydrodistention alone in patents with refractory interstitial cystitis [Kuo, H.C. & Chancellor, M.B., Abst 47]; intratrigonal injection of the toxin was reported effective against bladder pain syndrome [Pinto, R.A. et al., Abst 54]. As an alternative, relief of pain in interstitial cystitis patients was reported with Chinese herbal medicines containing aconitine, Keisika-jutsu-buto and Mao-bushi-saisinto [Tsuchida, T. et al., Abst 64]. On the other hand, the use of sodium pentosan polysulfate was associated with worsened pain in women with painful bladder syndrome taking benzodiazepines, without adding benefit to treatment with antidepressants [Zaslau, S. et al., Abst 1483].

In the experimental arena, intravesical chondroitin sulfate restored damaged urothelial barrier after acid exposure [Sofinowski, T.M. et al., Abst 52], while locally delivered ketoprofen inhibited bladder overactivity and pain in models of acute inflammation, suggesting a role for intravesical ketoprofen [Herz, J.M. et al., Abst 416]. Benefits on bladder inflammation and resulting overactivity in further animal models of cystitis were also associated to treatment with parthenolide [Kiuchi, H. et al., Abst 658] and ISO-1 [Vera, P.L. et al., Abst 659], whereas intravesical instillation of LP08 liposomes offered protection against urothelial coating and chemical irritation [Kaufman, J. et al., Abst 1506]. In vitro results on cultured urothelial cells suggested potential for isotretinoin [Harris, C. et al., Abst 58] and the synthetic antiproliferative factor derivatives Gal-Gal-N-Ac-TV-(d-pipecolic acid)-AAVVVA and Gal-Gal-N-Ac-TV(d-proline)AAVVVA [Keay, S. et al., Abst 59]. On the other hand, success in the treatment of painful bladder syndrome was also reported with acupuncture [Reeves, F.A. et al., Abst 62].

Chronic Prostatitis/Pelvic Pain Syndrome

Two interesting studies demonstrated promise for pelvic floor radiofrequency therapy [Oh, M.M. et al., Abst 337] and extracorporeal shock wave treatment [Zeng, X. et al., Abst 338] as noninvasive options for the management of chronic prostatitis/chronic pelvic pain syndrome. However, pharmacotherapy could be a preferred approach, and benefits compared to placebo were demonstrated with memantine in a randomized study that also demonstrated the safety of such treatment [Dimitrakov, J.D. et al., Abst 339], and with pregabalin in another similar trial [Pontari, M.A. et al., Abst 340] (Fig. 7).

Fig. 7. Global Response Assessment rates in patients receiving memantine or pregabalin compared to placebo [Dimitrakov, J.D. et al., Abst 339; Pontari, M.A. et al., Abst 340].

Erectile Dysfunction

Besides new reports of the usefulness of vacuum erection devices [McCulloough, A.R. et al., Abst 1363], novel observations were discussed this year in the Windy City of Chicago on the use of phosphodiesterase inhibitors for the treatment of erectile dysfunction, including the preserving effect of sildenafil administered before bilateral cavernosal nerve injury [Tavukçu, H.H. et al., Abst 668] and also the effect of the agent in improving endothelial nitric oxide synthase expression and cyclic GMP responses to nitric oxide [Vela-Navarrete, R. et al., Abst 844]. On the other hand, nightly sildenafil was considered unnecessary for restoring erectile function after minimally invasive nerve-sparing radical prostatectomy [Pavlovich, C.P. et al., Abst 1361], while according to additional studies nightly intraurethral alprostadil was superior to sildenafil monotherapy for early sexual rehabilitation after radical, nerve-sparing prostatectomy [McCullough, A.R. et al., Abst 1362] (Fig. 8) (alprostadil also improved flaccid penile oxymetry which decreased during sildenafil therapy [McCullough, A.R. et al., Abst 1467]), although penile rehabilitation and pelvic floor biofeedback training also resulted effective for recovering postoperative erectile function [Mombet, A. et al., Abst 1465; Prota, C. et al., Abst 1466]. In the case of tadalafil, daily treatment was associated with improved erectile function in men with benign prostatic hyperplasia and erectile dysfunction regardless of the use of alpha-blockers or prostate volume [Porst, H. et al., Abst 1365] (Fig. 9). The efficacy of safety of a further oral phosphodiesterase V inhibitor, mirodenafil, in the treatment of erectile dysfunction in men with diabetes was demonstrated in a placebo-controlled trial [Park, N.C. et al., Abst 1476] (Fig. 10).

Fig. 8. Intercourse success rates after radical nerve-sparing prostatectomy in men receiving intraurethral alprostadil or oral sildenafil [McCullough, A.R. et al., Abst 1362].

Fig. 9. Change in the International Index of Erectile Function – erectile function domain scores after treatment with tadalafil or placebo in patients receiving or not α-blocker therapy [Porst, H. et al., Abst 1365].

Fig. 10. Change in the International Index of Erectile Function – erectile function domain scores after treatment with mirodenafil or placebo [Park, N.C. et al., Abst 1476].

New results from a phase I study in human males revealed the safety of human maxi-K gene therapy as potential treatment for erectile dysfunction [Melman, A. et al., Abst 1364]. In the experimental field, approaches reported effective in the management of some forms of erectile dysfunction included losartan for nerve injury-related erectile dysfunction [Canguven, O. et al., Abst 664], and imatinib [Gur, S. et al., Abst 833], telokin [Villegas, G.A. et al., Abst 670] and intracavernously delivered cartilage oligomeric matrix protein-angiopoietin-1 [Jin, H.R. et al., Abst 663] for diabetic erectile dysfunction. Further experimental observations reported during the meeting in the Windy City confirmed prior findings on the feasibility of cavernous nerve reconstitution with bone marrow- and adipose tissue-derived stem cells [Kaufmann, O.G. et al., Abst 121; Fandel, T.M. et al., Abst 122; Garcia, M.M. et al., Abst 123] and the potential of intracavernosal muscle-derived stem cell transplantation [Sohn, D.W. et al., Abst 680] as additional means of restoring erectile function in animals. Regarding purely mechanistic studies, a role of rosiglitazone in normalizing decreased caveolin-1 and increased ABCA-1 expression in the cavernous tissue during hyperlipidemia was demonstrated [Ozdemir, I. et al., Abst 846].

Other Male Sexual Disorders

While a metered-dose aerosol formulation of lidocaine/prilocaine was found safe and effective for the treatment of premature ejaculation compared to placebo [Wyllie, M.G. et al., Abst 1370], selective serotonin reuptake inhibitors remain the most effective approach to the treatment of the condition, with fluoxetine showing significant improvements in ejaculatory latency, self-reported ejaculatory control and partner distress [Tal, R. et al., Abst 1479]. Safety and efficacy were also demonstrated with the most recently launched drug within this family, dapoxetine [Sharlip, I. et al., Abst 1371; Brock, G.B. et al., Abst 1480] (Fig. 11), while observational data regarding paroxetine revealed that despite high self-reported stress and motivation for therapy, up to one-third of patients with lifelong premature ejaculation freely decided not to start therapy and another third discontinued treatment [Salonia, A. et al., Abst 1481]. Prolongation of ejaculation latency in animals was demonstrated with NH02D, a shorter-acting D-isomer of modafinil [Marson, L. & Farber, N.M., Abst 672].

Fig. 11. Intravaginal ejaculatory latency in patients with acquired or lifelong premature ejaculation treated with dapoxetine or placebo [Sharlip, I. et al., Abst 1371].

Regarding Peyronie’s disease, while clinical data confirmed the benefits of intralesional verapamil [Alex, B. et al., Abst 784], experimental data with pentoxifylline, a drug that had been previously reported effective to manage the disease, confirmed an effect in attenuating transforming growth factor-beta-stimulated elastogenesis in the tunica albuginea fibroblasts [Lin, G. et al., Abst 781].

Surgery remains the therapeutic approach for relieving priapism, and is able to preserve spontaneous erectile function with favorable outcomes [Chiou, R.K. et al., Abst 1254; Brant, W.O. et al., Abst 1255], but effective medical therapies are also available, including phosphodiesterase V inhibitors, which were able to prevent recurrences over the long term in an open follow-up [Nardozza, A. et al., Abs 1478].

Various formulations of testosterone have been effective in the management of hypogonadism, including long-acting intramuscular testosterone undecanoate [Permongkosol, S. et al., Abst 1369; Morgentaler, A. et al., Abst 1469], subcutaneous testosterone pellet implants [Cavender, R.K. et al., Abst 1366] and testosterone-containing adhesive matrix patch [Raynaud, J.P. et al., Abst 2012], although clomiphene may represent a viable, cost-effective option devoid of remarkable adverse events [Taylor, F.L. & Levine, L.A., Abst 1368]. Testosterone replacement using a gel formulation also offered an effective augmentation approach to the treatment of erectile dysfunction not responding to phosphodiesterase V inhibitors [Buvat, J. et al., Abst 1367]. Use of testosterone replacement in patients with Klinefelter’s syndrome also resulted in increases in bone mineral density and serum testosterone levels, confirming the effectiveness of the therapy in preventing compression vertebral fractures and femoral neck fractures [Seo, J.T. et al., Abst 1023].

Urinary Lithiasis

Besides surgery for calculus-related obstruction [Iwaszko, M.R. et al., Abst 1633; Bird, V.G. et al., Abst V2034], minimally invasive approaches to the treatment of urinary lithiasis reported effective in new studies presented during this year’s meeting included percutaneous nephrostolithotomy [Hyams, E.S. et al., Abst 550; Bagrodia, A. et al., Abst 1373; Patel, S.R. et al., Abst 1374; Chew, B.H. et al., Abst 1381; Yuruk, E. et al., Abst 1383; Tatman, P.J. et al., Abst 1722; Semins, M.J. et al., Abst 1723; Chi, T. et al., Abst 1724; Aslam, M.Z. et al., Abst 1725; Patel, S.R. et al., Abst 1726; Shah, H.N. et al., Abst 1727; Sofer, M. et al., Abst 1728; Antonelli, J. et al., Abst 1729; Kumar, R. et al., Abst 1731; Tomaszewski, J.J. et al., Abst 1733; Peterson, C.A. et al., Abst 1734; Kurtulus, F.O. et al., Abst 1736], shock wave lithrotripsy [Faragalla, Y. et al., Abst 1617; Sacco, D.E. et al., Abst 1618; Knopf, J.K. et al., Abst 1621; Neisius, A. et al., Abst 1622; Mobley, J.D. et al., Abst 1625; Pishchalnikov, Y.A. et al., Abst 1626; McAdams, S. et al., Abst 1627; Hung, S.F. et al., Abst 1268; Ray, A.A. et al., Abst 1629; Mucksavage, P. et al., Abst 1630; Hammad, F.T. et al., Abst 1631; Chew, B.H. et al., Abst 1632; Handa, R.K. et al., Abst 2001] and laser lithotripsy [Honeck, P.R. et al., Abst 1735; Schatloff, O. et al., Abst 1738; Uhmann, E.W. et al., Abst 1740; McAteer, J.A. et al., Abst 1845] (to note that laser lithotripsy for bladder calculi at the time of holmium laser enucleation of the prostate was demonstrated feasible and safe in a video presentation at the meeting [Krambeck, A.E. et al., Abst V358]). Additionally, periureteric botulinum toxin was reported to significantly decrease postoperative pain and narcotic requirements after ureteral stent placement [Patel, T. et al., Abst 1376]; pain and quality of life improvements after percutaneous nephrolithotomy were also obtained with intercostal blockade with bupivacaine and epinephrine [Pace, K.T. et al., Abst 1382]. Furthermore, in both clinical trial and experimental animal studies, a ketorolac-eluting ureteral stent offered improved comfort and reduced stent-associated pain [Chew, B.H. et al., Abst 1838; Lingeman, J.E. et al., Abst 2003].

Adjuvant therapies may be of value in patients undergoing nonpharmacological stone disease management, as exemplified by the reduced blood loss during percutaneous nephrolithotomy in patients receiving ethamsylate, although without benefit on hemoglobin levels, hematocrit or length of hospital stay [Negrete, O.R. et al., Abst 1732], or the potential of isoprenaline in lowering pressure:flow relationship during semirigid ureterenoscopy, at least in the experimental arena [Jakobsen, J.S. et al., Abst 2009]. Furthermore, medical expulsive therapy has been able to reduce adverse outcomes of urolithiasis and the total cost associated with management of the condition [Brede, C.M. et al., Abst 1454], and has been gaining popularity in recent years, although neither improved expulsion rates nor shortened time to stone expulsion were obtained with tamsulosin in a placebo-controlled study [Sauerman, P. et al., Abst 1455]. Furthermore, use of celecoxib was effective in preventing renal tubular injuries during shock wave lithotripsy [Park, H.K. et al., Abst 1616], while administration of losartan decreased deterioration and enhancer recovery of renal function upon relief of stone-related partial unilateral ureteral obstruction in experimental animals [Soliman, S.A. et al., Abst 1994]. On the other hand, pretreatment of the intraluminal ureteral surface with protamine sulfate significantly reduced nifedipine concentrations required for blocking peristaltism, increasing urothelial permeability [Shelkovnikov, S. et al., Abst 1830].

Regarding preventive approaches, alendronate was associated with reduced calcium stone formation in postmenopausal women [Yasui, T. et al., Abst 1456] (Fig. 12), while at least in the experimental arena, supplementation with Ammi visnaga (toothpick weed; Khella) increased urinary pH and citrate levels and reduced hyperoxaluria and calcium oxalate nephrolithiasis [Vanachayankul, P. et al., Abst 1463]. Also in experimental animal studies, prevention of calcium oxalate stone formation and hyperoxaluria was reported after treatment with recombinant Bacillus subtilis oxalate decarboxylase (YvrK) gene-expressing Escherichia coli [Jeong, B.C. et al., Abst 1829].

Fig. 12. Nephrolithiasis rates in postmenopausal women receiving or not alendronate [Yasui, T. et al., Abst 1456].

Kidney Cancer

Total or partial nephrectomy [Simone, G. et al., Abst 370; Berger, A. et al., Abst 375; Lipkin, M.E. & Stifelman, M.D., Abst V500; Benway, B.M. et al., Abst V501; Tsivian, A. et al., Abst V502; Wu, G. et al., Abst V504; Lee, B.R. et al., Abst V505; San Jose, L.E. et al., Abst V508; Tsuchiya, N. et al., Abst 699; Lifshitz, D.A. et al., Abst 601; Bertini, R. et al., Abst 603; Bertini, R. et al., Abst 613; Crouzet, S. et al., Abst 691; Simon, J. et al., Abst 767; Munver, R. et al., Abst 768; Teber, D. et al., Abst 769; Harraz, A. et al., Abst 772; Pouliot, F. et al., Abst 773; Kumazawa, T. et al., Abst 774; Nogueira, L. et al., Abst 775; Capitanio. U. et al., Abst 777; Shikanov, S. et al., Abst 888; Thompson, R.H. et al., Abst 898; Patard, J.J. et al., Abst 901; Lucas, S.M. et al., Abst 905; Mucksavage, P. et al., Abst 982; Patard, J.J. et al., Abst 983; Abouassaly, R. et al., Abst 987; Bagrodia, A. et al., Abst 988; Patel, N.S. et al., Abst 993; Ciancio, G. et al., Abst 997; Leppert, J.T. et al., Abst 1206; Breau, R.H. et al., Abst 1210; Roupret, M. et al., Abst 1221; Yokoyama, M. et al., Abst 1223; Hakimi, A.A. et al., Abst1225; Izuka, J. et al., Abst 1227; Mayo, K. et al., Abst 1228; La Rochelle, J.C. et al., Abst 1229; Chughtai, B. et al., Abst 1230; Mercado, M.A. et al., Abst 1231; Iida, S. et al., Abst 1235; Osawa, T. et al., Abst 1236; Li, Q.I. et al., Abst 1237; Kitrey, N.D. et al., Abst 1238; Halachmi, S. et al., Abst 1239; Routh, J.C. et al., Abst 1248; Duarte, R.J. et al., Abst 1249; Kawa, G. et al., Abst 1301; Shikanov, S. et al., Abst 1302; Hermanns, T. et al., Abst 1303; Porter, J.R., Abst 1306; Kamoi, K. et al., Abst 1308; Benoist, N.D. et al., Abst 1310; Kaye, D.R. et al., Abst 1313; Bellec, L. et al., Abst 1316; Mason, R.J. et al., Abst 1317; Deklaj, T. et al., Abst 1320; Simone, G. et al., Abst 1321; Bylund, J.R. et al., Abst 1322; Kava, B.R. et al., Abst 1323; Gabr, A.H. et al., Abst 1324; Sanchez-Salas, R. et al., Abst 1325; Imbeault, A. et al., Abst 1326; Luciani, L.G. et al., Abst 1387; Margulis, V. et al., Abst 1388; Kutikov, A. et al., Abst 1390; Zini, L. et al., Abst 1391; Rane, A. et al., Abst 1484; Steinway, M.L. et al., Abst 1488; White, W.M. et al., Abst 1489; Wang, A.J. et al., Abst 1492; Feder, M.T. et al., Abst 1494; Michel, M.S. et al., Abst 1495; Shikanov, S. et al., Abst 1496; Ho, H. et al., Abst 1497; Boris, R.S. et al., Abst 1498; Wheat, J. et al., Abst 1499; Parekattil, S.J. et al., Abst 1500; Viterbo, R. et al., Abst 1501; Hyams, E.S. et al., Abst 1502; Kroepfl, D. et al., Abst 1983; Naitoh, Y. et al., Abst 2278] with lymphadenectomy as required [Komatsu, T. et al., Abst 352; Marshall, J. et al., Abst 766; Patard, J.J. et al., Abst 899; Weight, C. et al., Abst 900; Culp, S.H. et al., Abst 1389; Alt, A.L. et al., Abst 1392; Staehler, M.D. et al., Abst 1395; Matveev, V. et al., Abst 1396; Gagne, S.B. et al., Abst 1397; Margulis, V. et al., Abst 1398] are major assets in the treatment of many kidney cancers, but less invasive approaches such as cryoablation [Ko, Y.H. et al., Abst 435; Haber, G.P. et al., Abst V509; Kelly, C.R. et al., Abst V513; Puri, I. et al., Abst 682; Fulmer, B.R. et al., Abst 690; Kutikov, A. et al., Abst 770; Crouzet, S. et al., Abst 1309; Shingleton, W.B. et al., Abst 1327; Dhar, N. et al., Abst 1975; Dhar, N. et al., Abst 1976; Levy, D.A. et al., Abst 1977; Levy, D.A. et al., Abst 1981], radiofrequency ablation [Storey, B.B. et al., Abst V510] and high intensity focused ultrasound ablation [Ritchie, R.W. et al., Abst 1311; Hempel, C.R. et al., Abst 1945; Dotan, Z.A. et al., Abst 1949; Proano, J.M. et al., Abst 1951; Haddad, R.L. & Woo, H.H., Abst 1973; Pinthus, J.H. et al., Abst 1974; Mallick, S. et al., Abst 1978; Mallick, S. et al., Abst 1980] are gaining popularity.

Turning to pharmacotherapies for metastatic kidney cancer, new studies supporting the use of sequential sorafenib and sunitinib [Heuer, R. et al., Abst 1402] or interferon alfa/sorafenib [Eto, M. et al., Abst 429] were reported. New interventions are expected in the coming years, with current preclinical, experimental data suggesting an effect of resveratrol in inhibiting CXCR4-mediated tumor growth and migration [Yoon, S.J. et al., Abst 428], induction of tumor cell apoptosis by curcumin [Hwa, J.S. et al., Abst 439], blockade of renal cell carcinoma cell adhesion to the endothelium and extracellular matrix by valproate [Jones, J. et al., Abst 4432] and inhibition of renal cell cancer cell proliferation by suberoylanilide combined with ritonavir [Sato, A. et al., Abst 441].

Advances in immuno- and gene therapy for kidney cancer announced during AUA meeting in Chicago included a report on the effect of adenovirus-delivered granulocyte colony-stimulating factor/carbonic anhydrase IX gene on dendritic cell immune function [Li, Z. et al., Abst 424] and reports on oncolytic herpes simplex virus containing interleukin-12 [Fukuhara, H. et al., Abst 427] and encephalomyocarditis virus [Roos, F.C. et al., Abst 436], supporting further research into vaccination and virus-vectored strategies.

Bladder/Urothelial Cancer

Surgery remains a valid option for localized upper urothelial and bladder carcinoma [Novara, G. et al., Abst 346; Capiutanio, U. et al., Abst 347; Ng, C.K. et al., Abst 349; Reich, O. et al., Abst 350; Abouassaly, R. et al., Abst 365; Isbarn, H. et al., Abst 367; Hubosky, S.G. et al., Abst 377; Shariat, S.F. et al., Abst 383; Wu, G. & Rashid, H., Abst V506; Scoll, B.J. et al., Abst 507; Lee, R. et al., Abst 553; Jonsson, M. et al., Abst 796; Nix, J. et al., Abst 1015; Coward, M. et al., Abst 1020; Bagrodia, A. et al., Abst 1021; Yali, F.A. et al., Abst 1051; Nix, J. et al., Abst 1052; Kamdar, C. et al., Abst 1208; Martin, A.D. et al., Abst 1211; Moinzadeh, A. et al., Abst V1670; Wang, G.HJ. et al., Abst V1679; Shrivastava, A. et al., Abst V1681; Umbreit, E.C. et al., Abst 1743; Svatek, R.S. et al., Abst 1744; Shariat, S.F. et al., Abst 1745; Brausi, M. et al., Abst 1746; Jankowski, J.T. et al., Abst 1748; Stimson, C.J. et al., Abst 1749; Isbarn, H. et al., Abst 1751; Schnoeller, T. et al., Abst 1752; Tollefson, M.K. et al., Abst 1753; Addla, S.K. et al., Abst 1754; Siegrist, T.C. et al., Abst 1755; Fairey, A.S. et al., Abst 1759; Jayram, G.T. et al., Abst 1760; Jeldres, C. et al., Abst 1761; Cechini, L. et al., Abst 1770; Guzzo, T.J. et al., Abst 1780; Berdijs, N. et al., Abst 1781; Schumacher, M.C. et al., Abst 1906], including cases with lymph node involvement requiring lymphadenectomy [Roscigno, M. et al., Abst 341; Tiemann, A. et al., Abst 342; Hellenthal, N.J. et al., Abst 343; Nunez, C. et al., Abst 345; Kondo, T. et al., Abst 372; Abe, T. et al., Abst 373; Bochner, B.H., Abst V1674; Lerner, S.P. et al., Abst 1747; Roth, B. et al., Abst 1750] or complementary or salvage radiotherapy [Krause, S. & Wullich, B., Abst 1756], but besides the risk of complications, in the case of upper urothelial carcinoma may result in chronic kidney disease affecting administration of any subsequent chemotherapy required [Lane, B.R. et al., Abst 380], and alternative chemotherapeutic approaches have been effectively used for very localized disease, or as adjuvant/neoadjuvant therapy for more extensive tumors [Khurana, K.K. et al., Abst 1757]. Less invasive surgical techniques have also been implemented with success for localized, small bladder tumors, including notably cystodiathermy [Chandrasekar, P. et al., Abst 1773].

Intravesical therapy with bacillus Calmette-Guérin alone [Kohjimoto, Y. et al., Abst 1764; Takeda, T. et al., Abst 1768; Lampe, M. et al., Abst 1771; Gofrit, O.N. et al., Abst 1776; Alkhateeb, S.S. et al., Abst 1915], combined with interferon alfa-2b [Rastinehad, A.R. et al., Abst 376] or gemcitabine [Horinaga, M. et al., Abst 1145] or alternating with epirubicin [Barakat, T.S. et al., Abst 1778], gemcitabine [Böhle, A. et al., Abst 1908] and mitomycin [O’Brien, T.S. et al., Abst 378; Halachmi, S. et al., Abst 1765] continue to be reported effective in new clinical studies and observations [Prasad, S.M. et al., Abst 196], and the safety and feasibility of adenoviral-mediated interferon alfa were confirmed in a phase I trial [Fisher, M.B. et al., Abst 1907]. In addition, experimental studies also suggested efficacy for intravesical treatment with paclitaxel nanoparticles [Au, J.L.S. et al., Abst 1762], recombinant, pertussis toxin-expressing bacillus Calmette-Guérin [Chade, D.C. et al., Abst 1158], superantigen staphylococcal enterotoxin B [Reis, L.O. et al., Abst 1157] and Grifola frondosa mushroom-derived D-fraction combined with interferon alfa-2b [Louie, B. et al., Abst 1159]. Considering further options, celecoxib effectively and safely reduced recurrence rates in patients with recurring non-muscle invasive transitional-cell urothelial bladder cancer, but the results were only marginally significant [Lerner, S.P. et al., Abst 194] (Fig. 13), and mistletoe extract offered a well-tolerated, safe adjuvant approach for preventing local recurrences [Ibrahiem, E.I. et al., Abst 1775]. Regarding experimental findings, sunitinib proved active against experimental orthotopic bladder cancer [Patel, A.R. et al., Abst 1148] and cancer targeting by annexin A1-binding IF7 peptide conjugated with geldanamycin was reported feasible, resulting in tumor cell apoptosis [Hatemayama, S. et al., Abst 195]. The feasibility of R11 in targeting drugs to the bladder was confirmed in a further in vivo animal model [Zhou, J. et al., Abst 404], and sorafenib [Rose, A. et al., Abst 1150] and the spindle inhibitor AZD-4866 [Shah, J.B. et al., Abst 1151] showed activity in in vitro studies.

Fig. 13. Recurrence-free survival at 1 and 2 years in patients on celecoxib or placebo [Lerner, S.P. et al., Abst 194].

Vaccinations for bladder cancer have been developed, and phase I trial evidence of tolerability and feasibility was reported in Chicago with a M-phase phosphoprotein-1 (MPHOSPH1) and DEP domain containing-1 (DEPDC1) epitope-based peptide vaccine [Obara, W. et al., Abst 980].

In addition to the above information, bacillus Calmette-Guérin-induced toxicity in patients with non-muscle-invasive bladder cancer was effectively prevented by a short cycle of prulifloxacin [Autorino, R. et al., Abst 1913], while alkalinization of the urine was associated with improved efficacy of intravesical mitomycin [Maeda, T. et al., Abst 1914].

Prostate Cancer

Radical prostatectomy [Suardi, N. et al., Abst 154; Dakwar, G. et al., Abst 546; Jayachandran, J. et al., Abst 577; Desmukh, S.M. & Mohler, J.L., Abst 585; Mucksavage, P. et al., Abst 586; Stackhouse, D.A. et al., Abst 590; Briganti, A. et al., Abst 813; Moreira, D.M. et al., Abst 815; Ahlering, T.E. et al., Abst 882; Vickers, A.J. et al., Abst 892; Lindner, U. et al., Abst 893; Kural, A. et al., Abst V930; Carlucci, J.R. et al., Abst V932; Mason, B.M. et al., Abst V933; Lux, M.M. et al., Abst V934; Humphreys, M.R. et al., Abst V936; Atalla, M.A. et al., Abst V937; Kalisvaart, J.F. et al., Abst 1004; Chauhan, S. et al., Abst 1005; Golijanin, D.J. et al., Abst 1006; Nunez, R.N. et al., Abst 1008; Tan, G.Y. et al., Abst 1009; Satyanarayana, R.K. et al., Abst 1010; Krane, L.S. et al., Abst 1011; Kaul, S. et al., Abst 1012; Blatt, A.M. et al., Abst 1013; Cheetham, P.J. et al., Abst 1014; Sethi, K. et al., Abst 1016; Patel, M.B. et al., Abst 1017; Davis, J.W., Abst 1018; Nelson, C. et al., Abst 1034; Choi, Y.D. et al., Abst 1209; Patil, N.N. et al., Abst 1210; Siddiqui, S. et al., Abst 1212; Cheetham, P.J. et al., Abst 1213; Dusseault, B. et al., Abst 1214; Braasch, M.R. et al., Abst 1215; Smith, A. et al., Abst 1216; Patel, S.R. et al., Abst 1217; Smith, A. et al., Abst 1218; Guru, K.A. et al., Abst 1219; Cooperberg, M.R. et al., Abst 1276; Katz, D.J. et al., Abst 1277; Barocas, D.A. et al., Abst 1278; Spahn, M. et al., Abst 1279; Satyanarayana, R.K. et al., Abst 1280; Suardi, N. et al., Abst 1281; Lack, B.D. et al., Abst 1282; Chiong, E. et al., Abst 1284; Skolarus, T.A. et al., Abst 1289; Kibel, A.S. et al., Abst 1594; Joniau, S. et al., Abst 1599: Gallina, A. et al., Abst 1601; Gontero, P. et al., Abst 1602; Rabbani, F. et al., Abst 1603; Zwergel, U.E. et al., Abst 1604; Choueiri, T.K. et al., Abst 1605; Lasser, M.S. et al., Abst 1607; Potdevin, L. et al., Abst 1608; Mufarrij, P.W. et al., Abst 1685; Martin, G.L. et al., Abst 1846; Sciarra, A. et al., Abst 1848; Netto, G.J. et al., Abst 1849; Rabbani, F. et al., Abst 1850; Salomon, L. et al., Abst 1851; Shikanov, S. et al., Abst 1852; Kordan, Y. et al., Abst 1853; Choi, Y.D. et al., Abst 1854; Yoo, C. et al., Abst 1856; Abraham, N. et al., Abst 1857; Yadav, R. et al., Abst 1858; Gallina, A. et al., Abst 1859; Pettus, J.A. et al., Abst 1864; Griffin, C.R. et al., Abst 1865; Hampel, C. et al., Abst 1930; Chung, J.I. et al., Abst 1931; Bertolotto, F. et al., Abst 1932; Schulze, M. et al., Abst 1933; Ozden, C. et al., Abst 1937; Koontz, B.F. et al., Abst 1970; Roberts, W.B. et al., Abst 1986; Lerner, M.A. et al., Abst 1989; Cestari, A. et al., Abst 2089; Stranne, J. et al., Abst 2090; Lack, B.D. et al., Abst 2095; Patel, N.D. et al., Abst 2097; Vallancien, G. et al., Abst 2099; Ta, K. et al., Abst 2100; Hoekstra, R.J. et al., Abst 2110; Jin, D.H. et al., Abst 2230; Secin, F.P. et al., Abst 2269; Matsumoto, E. et al., Abst 2270], with extended lymph node dissection as required [Briganti, A. et al., Abst 810; Briganti, A. et al., Abst 811; Ghazi, A. & Janetschek, G., Abst V935; Katz, D.J. et al., Abst V938; Budäus, L.H. et al., Abst V939; Desai, M.M. et al., Abst V940; Martinez-Salamanca, J.I. et al., Abst V941; Kasraeian, A. et al., Abst 1002; Chapin, B.F. et al., Abst 1003; Bastian, P.J. et al., Abst 1595; Pinochet, R. et al., Abst 1609; tranne, J. et al., Abst 1611; Gacci, M. et al., Abst 1612; Zbrun, S. et al., Abst 1847; Hinev, A.I., Abst 1855; Briganti, A. et al., Abst 2087] can be effectively used in the management of prostate cancer, but such approach is not devoid of risk for complications, including postoperative erectile dysfunction [Lux, M.M. et al., Abst 1880; Krane, L.S. et al., Abst 1881], and carries a negative impact on the urinary quality of life [Liss, M.A. et al., Abst 1878]. Thus less invasive nonpharmacological approaches such as radiotherapy [Boorjian, S.A. et al., Abst 764; Moreira, D.M. et al., Abst 816; Margel, D. et al., Abst 1699; Moreira, D.M. et al., Abst 1700; Obedian, E. et al., Abst 2101; Elliott, S.P. et al., Abst 2102], high-intensity focused ultrasound therapy [Sumitomo, M. et al., Abst 140; Blana, A. et al., Abst 635; Ward, J.F. et al., Abst 636; Uchida, T. et al., Abst 637], cryoablation [Dhar, N. et al., Abst 631; Witzsch, U. et al., Abst 632; Dhar, N. et al., Abst 633; Dineen, M.K. et al., Abst 634] and brachytherapy [Shapiro, E.Y. et al., Abst 589; Ballek, N.K. et al., Abst 627; Thomas, K.R. et al., Abst 628; Cho, J.S. et al., Abst 629; Davits, R.J.A.M. et al., Abst 630; Heinrich, E. et al., Abst 1693; Inagaki, T. et al., Abst 1694; Stone, N.N. et al., Abst 1697; Lee, H.K. et al., Abst 1698] continue to be reported effective in the management of many forms of prostate cancer, although failures, recurrences and relapses are common, and salvage and adjuvant/neoadjuvant therapies have been developed.

Although when used as primary therapeutic approach it resulted in a higher risk of death compared to prostatectomy [Miyaji, Y. et al., Abst 1696], androgen deprivation is the mainstay in pharmaco- and salvage therapy for prostate cancer [Bañez, L.L. et al., Abst 818; Trock, B.J. et al., Abst 1285], with the use of gonadotropin-releasing hormone agonists and/or androgen receptor blockers being the approach preferred by most urologists against metastatic disease [Malaeb B. & Slaton, J.W., Abst 765; Georges, C.E. et al., Abst 829] and delayed therapy resulting in worse outcomes [Golijanin, D.J. et al., Abst 755]. In addition, at least in the case of ozarelix, a favorable effect in relaxing the prostate was demonstrated in in vitro studies [Giuliano, F. et al., Abst 1919]. However, preoperative treatment with leuprorelin was not able to reduce the pathological tumor stage, and tended to worsen postoperative recovery of erectile function [Helfand, B.T. et al., Abst 1788] and preoperative hormonal therapy did not prevent biochemical recurrences, local recurrences or metastases after radical prostatectomy [Yee, D.S. et al., Abst 1985]. Hormonal therapy also results in a number of complications, including notably decreased bone mineral density and increased risk of fractures [Ginger, V.A.T. et al., Abst 475]. Furthermore, use of luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer brought about increases in visceral fat and LDL-cholesterol [Torimoto, K. et al., Abst 255] and increased likelihood of dementia [Capitanio, U. et al., Abst 828]. On the other hand, independent observations suggested reduced failure rates with testosterone level- rather than calendar-based dosing of such agents [Blumberg, J.M. et al., Abst 261], although pretreatment testosterone levels were associated with resistance to androgens in patients starting luteinizing hormone-releasing hormone agonist therapy [Blumberg, J.M. et al., Abst 266].

Hormonal therapies carry a risk of hormone-dependent adverse events such as bone mineral density loss (see below) and hot flushes. The latter, however, were effectively improved by cyproterone, medroxyprogesterone or, with reduced efficacy, venlafaxine according to a trial in men receiving leuprorelin therapy [Irani, J. et al., Abst 643] (Fig. 14).

Fig. 14. Change in hot flush scores after treatment with venlafaxine, cyproterone or medroxyprogesterone [Irani, J. et al., Abst 643]

A different approach to prevent adverse effects of hormonal therapy is the use of intermittent rather than continuous androgen blockade. In that respect, both approaches were equieffective according to a trial in patients with metastatic disease, but maximal intermittent blockade was safer, although without an impact on the quality of life [Mottet, N.A. et al., Abst 645] (Fig. 15). In other studies, intermittent blockade seemed to offer higher efficacy, with fewer patients presenting with symptomatic relapse or increases in prostate-specific antigen levels [Calais da Silva, F.E. et al., Abst 646].

Fig. 15. Median overall and progression-free survival in patients on intermittent or continuous maximal androgen blockade [Mottet, N.A. et al., Abst 645].

Alternatives to direct hormonal therapies include inhibition of 5 alpha-reductase to prevent activation of testosterone to the dihydro-metabolite, or the use of androgen receptor blockers. Regarding the first approach, a follow-up of 146 men undergoing 3-dimensional mapping biopsies demonstrated reduction of prostatic volume during treatment with dutasteride [Tandberg, D.J. et al., Abst 160], an inhibitor with activity against both isoforms 1 and 2 of 5 alpha-reductase [Vicentini, C. et al., Abst 1114]. Moreover, a combination of dutasteride and extended-release tolterodine offered a successful approach to the management of symptoms secondary to overactive bladder in patients with enlarged prostate [Chung, D.E. et al., Abst 1927]. Furthermore, results of the REDUCE trial reported during this year’s AUA meeting in Chicago confirmed the benefit of dutasteride in reducing the incidence of prostate cancer in men at risk [Andriole, G. et al., Abst 2207; Andriole, G. et al., Abst LBA1] (Fig 16). On the other hand, at least in experimental animals, by activating hypoxia-inducible factor-1alpha in the prostate, treatment with finasteride increased the chances for more aggressive prostate tumors [Srivastava, J.K. et al., Abst 256].

Fig. 16. Detection of prostate cancer during the first two and second two years of the 4-year REDUCE study period [Andriole, G. et al., Abst 2207].

Among androgen receptor modulator therapies, a clinical study with the blocker MDV-3100 demonstrated activity against progressive, castration-resistant prostate cancer, with encouraging results in terms of prostate-specific antigen level declines, imaging and circulating tumor cell counts [Scher, H.I. et al., Abst 641].

Chemotherapies for hormone-refractory or -independent prostate cancer reported effective during this year’s meeting included docetaxel [Kumazawa, T. et al., Abst 263; Akdogan, B. et al., Abst 649], paclitaxel [Ploussard, G. et al., Abst 821], docetaxel/ketoconazole [Womble, P.R. et al., Abst 1862] and docetaxel/estramustine/carboplatin [Narita, S. et al., Abst 820], and in the experimental arena everolimus [Chiong, E. et al., Abst 1140], cisplatin nanoparticles [Singh, R. et al., Abst 1102], apaziquone [Arentsen, H.C. et al., Abst 1142], the hedgehog pathway inhibitor cyclopamine [Matsui, Y. et al., Abst 1141], the chemokine CXCR4 receptor blocker CTCE-9908 [Sakamoto, N.B. et al., Abst 1108], the heat shock protein-27 inhibitor OGX-427 [Zoubeidi, A. et al., Abst 1437], the natural polyphenolic flavone luteolin [Tsui, K.H. et al., Abst 1110], Phellodendron amurense bark extract [Robson, C.H. et al., Abst 1342] and S-1/docetaxel [Hasegawa, M. et al., Abst 1103] and vorinostat/docetaxel [Kwon, T. et al., Abst 1338] combinations. Targeted biological therapies were also reported effective, including notably bevacizumab, with a radiosensitizing effect [Kang, T.W. et al., Abst 1101], bortezomib, which in in vitro studies enhanced radiation sensitivity of androgen-independent prostate cancer cells [Goktas, S. et al., Abst 265], a saporin toxin-conjugated monoclonal anti-prostate-specific membrane antigen antibody [Kuroda, K. et al., Abst 1105], and the clusterin expression inhibitor antisense nucleotide custirsen, with activity demonstrated against castrate-resistant prostate cancer relapsing on or shortly after first-line docetaxel [Saad, F. et al., Abst 640].

Further clinical observations in patients with prostate cancer were the prolongation of prostate-specific antigen doubling time obtained with nitroglycerin patches [Siemens, D.R. et al., Abst 644] or pomegranate juice [Pantuck, A.J. et al., Abst 826] after surgery and/or radiotherapy, but also the activity of resveratrol in reversing metastases and improving or worsening survival in different types of prostate cancer xenografts in experimental animals through effects on angiogenesis, metastasis-associated protein-1-dependent mechanisms and alterations of the insulin-like growth factor axis [Klink, J.C. et al., Abst 724; Samuel, S.K. et al., Abst 1441] and the lack of effect of vitamin E, selenium and soy protein supplementation in preventing the progression of high-grade prostatic intraepithelial neoplasia to prostate cancer [Fleshner, N.E. et al., Abst 736] (experimental data confirmed an effect of soy protein in altering protein expression and modulating cell apoptosis and proliferation [Rebello, S.A. et al., Abst 1337]. The safety of supplementation was demonstrated in men at high risk for biochemical failure after radical prostatectomy [Bosland, M.C. et al., Abst 1861]).

In the experimental setting, in vitro results confirmed inhibition of prostate cancer cell growth by a combination of ritonavir and suberoylanilide hydroxamic acid [Sato, A. et al., Abst 144], capsaicin with lycopene, selenium and/or vitamin E [Venier, N.A. et al., Abst 148], the geranylgeranyl transferase inhibitor GGTI-2147 [Fujimoto, N. et al., Abst 142] and the Src kinase inhibitor saracatinib [Yang, J.C. et al., Abst 725].

In the context of immunotherapy, a description of the cytotoxic T-cell response-inducing effect of CpG-DNA oligonucleotide/prostatic-specific antigen peptide65-73 vaccination was presented [Maurer, T. et al., Abst 519].

Regarding additional issues, use of statins was associated with lower prostate-specific antigen levels [Krane, L.S. et al., Abst 1783] and a reduced risk for and reduced aggressiveness of prostate cancer [Breau, R.H. et al., Abst 574; Bañez, L.L. et al., Abst 575; Loeb, S. et al., Abst 576], whereas further observations confirmed the chemopreventive potential of lycopene taken in the form of whole tomato products or as dietary supplements [Konijeti, R. et al., Abst 1440] and in vitro observations suggested potential for vitamin D-dependent chemoprevention [Ting, H.J. & Lee, Y.F., Abst 1442]. Furthermore, while regular intake of nonsteroidal antiinflammatory drugs was related to slower prostate growth rates [Jacobsen, S.J. et al., Abst 1655], synergistic activity of NSAIDs and statins in preventing adverse urologic outcomes such as lower urinary tract symptoms and benign prostatic hyperplasia was noted in a study including 2,447 men aged 40-79 years [St. Sauver, J.L. et al., Abst 1646]. On the contrary, no clear impact of aspirin or ibuprofen on the risk of prostate cancer was noted in a large surveillance study, although the risk was reduced in selected subgroups of men receiving aspirin, including younger subjects with a history of cardiovascular disease or arthritis [Sakoda, L.C. et al., Abst 465]. To close this chapter, thromboprophylaxis with dalteparin was confirmed safe and effective in patients undergoing transurethral prostatectomy in a placebo-controlled trial [Maurer, P.F. et al., Abst 1938], whilst piperacillin/tazobactam was a feasible prophylactic regimen for febrile complications of prostate biopsy [Aguilar-Davidov, B. et al., Abst 2211].

Bone disease in prostate cancer

Prostate cancer itself, and many of the hormonal therapies used in its treatment, are associated with bone abnormalities, including osteolytic metastases and reduced bone mineral density.

Therapies for improving bone mineral density in hormone-treated prostate cancer include zoledronate, with preventive activity in hormone-naïve prostate cancer patients starting androgen deprivation therapy [Satoh, T. et al., Abst 642] (Fig. 17), denosumab, which according to trials reported this year consistently increased bone mineral density at all skeletal sites regardless of age, baseline BMD, duration of prior androgen-deprivation therapy and the presence of prevalent vertebral fractures [Smith, M.R. et al., Abst 638], and toremifene, which by improving bone mineral density also reduced the incidence of new vertebral fractures [Lin, D.W. et al., Abst 639]. In patients with established bone metastases, zoledronate was also deemed cost-effective for preventing skeletal-related events [Meijboom, M. et al., Abst 825] (Fig. 18), an extent that was also demonstrated in case of bone metastases from renal cell carcinoma [Botteman, M.F. et al., Abst 1400]. Benefits on bone mineral density in patients on androgen deprivation therapy for prostate cancer were also obtained with denosumab [Egerdie, B. et al., Abst 1695] (Fig. 19).

Fig. 17. Change in posteroanterior lumbar spine bone mineral density at 6 months in patients receiving or not zoledronate while starting first-line androgen deprivation therapy [Satoh, T. et al., Abst 642].

Fig. 18. Projected per-patient incidence of skeletal-related events during 15 months of treatment with zoledronate or placebo [Meijboom, M. et al., Abst 825].

Fig. 19. Percent of patients with a >6% increase in bone mineral density during 36 months of treatment with denosumab or placebo [Egerdie, B. et al., Abst 1695].

Other Genitourinary Tract Cancers

While testicular cancers are susceptible to retroperitoneal surgical excision, with lymph node dissection as required [Nicolai, N. et al., Abst 906; Kakiashvili, D. et al., Abst 911; Heidenreich, A. et al., Abst 912; Large, M.C. et al., Abst 913; Campero, J.M.M. et al., Abst 1290; Correa, J. et al., Abst V1676], methotrexate/actinomycin/etoposide was reported effective as salvage chemotherapy for advanced germ cell tumors [Terakawa, T. et al., Abst 556] and carboplatin in that of stage I seminoma [Steiner, H. et al., Abst 910]. In addition, the known activity of cisplatin against testicular cancer was accompanied by an effect in regulating transferrin and interleukin expression in Sertoli cells [Yamaguchi, K. et al., Abst 1894]. High-risk penile cancer can and should be managed by radical excision [Heyns, C.F. et al., Abst V1675], including inguinal lymphadenectomy [Hsiao, W. et al., Abst V1680].

Urinary Tract Infections

Scattered information related to urinary tract infection was discussed this year in Chicago. An in vitro assessment of uropathogen samples from children with documented infections suggested no increase in the antibacterial activity of trimethoprim upon addition of sulfamethoxazole [Nguyen, H.T. et al., Abst 1056]. In addition, ciprofloxacin/acetylcysteine-impregnated catheters offered enhanced protection against microbial adherence [Abolyosr, A. et al., Abst 1272] (acetylcysteine attenuating oxidative stress in additional studies [Danilovic, A. et al., Abst 2044]), while oral therapy with the agents, also in combination, resulted in increased protection against biofilm-associated urinary tract infections [Abolyosr, A. et al., Abst 1273]. On the other hand, NU14deltawaal, a live-attenuated vaccine for the treatment of uropathogenic Escherichia coli urinary tract infections, was developed and reported effective [Billips, B.K. et al., Abst 656].

Miscellaneous

Glutamate supplementation prevented radiotherapy-damaged collagen expression in experimental animals [Ramos, C.F. et al., Abst 226].

Use of bupivacaine for dorsal penile blockade in pediatric urology surgery was associated with a high risk for cardiac toxicity, calling for caution and monitorization [Yu, R.N. et al., Abst 320].

Use of low-dose finasteride in the treatment of androgenic alopecia resulted in an effect on prostate-specific antigen levels comparable to that noted in patients with benign prostatic hyperplasia in subjects younger than 50 years with normal prostate [Ito, K. et al., Abst 591].

Repeat injections of dextranomer/hyaluronate remained effective in the treatment of vesicoureteral reflux in children [Higuchi, T.T. et al., Abst 620]; hyaluronate/poly-(lactic-co-glycolic) acid was successfully used to regenerate the bladder using small intestinal submucosa [Roth, C.C. et al., Abst 808]. In a similar way, transurethral injection of carbon-coated beads also improved vesicoureteral reflux and prevented recurrent pyelonephritis in kidney allografts [Antonopoulos, I.M. et al., Abst 2046].

Subthalamic stimulation for Parkinson’s disease resulted in transient urgency, lower urinary volumes at voiding sensation and lower maximum cystometric capacity [Pinto, R.A. et al., Abst 960].

Many urological disease conditions are subject to surgical repair, and it should be mentioned that continuing antiplatelet therapy for cardiovascular risk control was feasible and safe during surgery, especially in the case of robotic radical prostatectomy [Choi, Y.D. et al., Abst 1299]. Also regarding adjuvant pharmacotherapy in surgery, ketorolac brought about improvements in the quality of life in the immediate postoperative period in subjects undergoing laparoscopic donor nephrectomy [Pace, K.T. et al., Abst 2060].

Enalapril prevented deterioration of renal function after partial unilateral ureteral obstruction in experimental animals [Soliman, S.A. et al., Abst 1836]. In a related manner, the protein kinase C inhibitor chelerythrine prevented renal apoptosis and fibrosis after partial ureteral obstruction [Zhou, G. et al., Abst 653].