Ex Vivo Model of Human Penile Transplantation and Rejection: Implications for Erectile Tissue Physiology

Ex Vivo Model of Human Penile Transplantation and Rejection: Implications for Erectile Tissue Physiology

BACKGROUND: Penile transplantation is a potential treatment option for severe penile tissue loss. Models of human penile rejection are lacking.

OBJECTIVE: Evaluate effects of rejection and immunosuppression on cavernous tissue using a novel ex vivo mixed lymphocyte reaction (MLR) model.

DESIGN, SETTING, AND PARTICIPANTS: Cavernous tissue and peripheral blood mononuclear cells (PBMCs) from 10 patients undergoing penile prosthesis operations and PBMCs from a healthy volunteer were obtained. Ex vivo MLRs were prepared by culturing cavernous tissue for 48h in media alone, in media with autologous PBMCs, or in media with allogenic PBMCs to simulate control, autotransplant, and allogenic transplant conditions with or without 1μM cyclosporine A (CsA) or 20nM tacrolimus (FK506) treatment.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Rejection was characterized by PBMC flow cytometry and gene expression transplant array. Cavernous tissues were evaluated by histomorphology and myography to assess contraction and relaxation. Data were analyzed using two-way analysis of variance and unpaired Student t test.

RESULTS AND LIMITATIONS: Flow cytometry and tissue array demonstrated allogenic PBMC activation consistent with rejection. Rejection impaired cavernous tissue physiology and was associated with cellular infiltration and apoptosis. CsA prevented rejection but did not improve tissue relaxation. CsA treatment impaired relaxation in tissues cultured without PBMCs compared with media and FK506. Study limitations included the use of penile tissue with erectile dysfunction and lack of cross-matching data.

CONCLUSIONS: This model could be used to investigate the effects of penile rejection and immunosuppression. Additional studies are needed to optimize immunosuppression to prevent rejection and maximize corporal tissue physiology.

Erectile dysfunction following prostatectomy: prevention and treatment

Erectile dysfunction following prostatectomy: prevention and treatment

Radical prostatectomy (RP) remains the standard treatment for men with clinically localized prostate cancer, despite the range of alternative treatment modalities. Even with significant advances in surgical technique and superb results for cancer control and preservation of urinary function, erectile dysfunction (ED) following RP is a common complication. This is mainly attributed to temporary cavernous nerve damage (neuropraxia) resulting in penile hypoxia, smooth muscle apoptosis, fibrosis and veno-occlusive dysfunction. One of the most promising new approaches is the concept of early penile rehabilitation, which is thought to prevent ED after RP by countering post-RP pathophysiological changes during the period of neural recovery. Various treatments, such as vacuum constriction devices, intraurethral and intracorporal alprostadil, and phosphodiesterase type 5 (PDE5) inhibitors, might serve to facilitate recovery of erectile function. PDE5 inhibitors are considered as the first-line treatment for early penile rehabilitation, with superior erectile function outcomes compared to placebo. Definitive conclusions regarding the success of penile rehabilitation cannot be drawn at this time because of differences in study design, data acquisition, and definitions of potency. Continued prospective, rigorous study is needed to develop and bring forward this important field and to establish the best evidence basis for counseling and treating patients suffering from ED after RP.

Ex Vivo Model of Human Penile Transplantation and Rejection: Implications for Erectile Tissue Physiology

Phosphodiesterase Type 5 Inhibitors in Postprostatectomy Erectile Dysfunction: A Critical Analysis of the Basic Science Rationale and Clinical Application

CONTEXT: Erectile dysfunction (ED) after radical prostatectomy (RP) has a significant negative impact on a patient’s health-related quality of life. Phosphodiesterase type 5 inhibitors (PDE5-Is) have recently been utilized not only as a treatment of ED in this population but also as a preventive strategy in penile rehabilitation programs.

OBJECTIVE: To elucidate the pathophysiologic mechanisms of post-RP ED, to assess the need for rehabilitation following surgery, and to analyze the basic scientific evidence and clinical applications of PDE5-Is for the prevention and treatment of ED.

EVIDENCE ACQUISITION: A systematic review of the literature using Medline, Cancerlit, and the Cochrane Library was conducted for the period between January 1997 and June 2008 using the keywords erectile dysfunction, radical prostatectomy, and phosphodiesterase inhibitors. Efficacy and safety of PDE5-Is in the randomized, placebo-controlled trials are evaluated in this review, and the limitations of the remaining studies are also discussed.

EVIDENCE SYNTHESIS: Post-RP ED has many factors. Cavernosal nerve injury induces pro-apoptotic factors (ie, loss of smooth muscle) and pro-fibrotic factors (ie, an increase in collagen) within the corpora cavernosa. Cavernosal changes may also be attributed to poor oxygenation due to hemodynamic changes. Experimental data support the concept of cavernosal damage and suggest a protective role for daily dosage of a PDE5-I; however, similar data have not yet been replicated in humans. Penile rehabilitation programs are common in clinical practice, but there is no definitive evidence to support their use or the best treatment strategy. PDE5-Is are efficacious and safe in young patients with normal preoperative erectile function who have undergone bilateral nerve-sparing radical prostatectomy. On-demand use of a PDE5-I may be at least as efficacious as daily use. PDE5-I use in penile rehabilitation programs is not supported by rigorous level 1 evidence-based medicine.

CONCLUSIONS: PDE5-Is are an efficacious and safe treatment for post-RP ED in properly selected patients. The experimental results on the protective role of daily dosages of PDE5-Is, while robust, have not been replicated in humans. With current human data, the role of a PDE5-I alone as a rehabilitation strategy is unclear and deserves further investigation.

Ex Vivo Model of Human Penile Transplantation and Rejection: Implications for Erectile Tissue Physiology

Radical Prostatectomy in 2007: Oncologic Control and Preservation of Functional Integrity

Stolzenburg et al [1] report on their first experience with regard to intrafascial nerve-sparing endoscopic extraperitoneal radical prostatectomy (nsEERPE) in a series of 150 consecutive patients with clinically organ-confined prostate cancer (PCa). The most important results for the practising urologist are the demonstration of excellent oncologic control documented by the low frequency of positive surgical margins and the excellent preservation of erectile function and continence in 80% and 94% of patients, respectively. The authors are to be congratulated for their perfect surgical technique of anatomic radical prostatectomy (RPE), which will have a future impact on both laparoscopic and open RPE.

Erectile Function Outcome Reporting After Clinically Localized Prostate Cancer Treatment

Erectile Function Outcome Reporting After Clinically Localized Prostate Cancer Treatment

PURPOSE: In conjunction with the assignment to update the Guidelines for Management of Clinically Localized Prostate Cancer, the American Urological Association Prostate Cancer Guideline Update Panel performed a side analysis of the reporting of erectile function outcomes in this clinical context as published in the medical literature.

MATERIALS AND METHODS: Four National Library of Medicine PubMed(R) Services literature searches targeting articles published from 1991 through early 2004 were done to derive outcome reporting (efficacy or side effects) for the treatment of clinical stage T1 or T2 N0M0 prostate cancer. A database was constructed containing descriptions relating to erectile function as well as numerical frequency rates of complete erectile dysfunction, and partial and intact erectile function for various treatments. A literature review was also done, consisting of a PubMed Services search of current measures and protocols used for assessing erectile function outcomes and a survey of consensus opinion sources on the management of male sexual dysfunctions.

RESULTS: Based on inclusion criteria 436 articles were selected. Of these articles database extraction from 100 pertaining to radical prostatectomy garnered various characterizations of erectile function, including qualitative descriptions, generic terminology and rating systems. Database extraction from 31 articles, in which results for at least 50 patients were reported, yielded ranges of rates for complete erectile dysfunction, partial erectile function and intact erectile function that were 26% to 100%, 16% to 48% and 9% to 86% for radical prostatectomy, 8% to 85%, 21% to 47% and 36% to 63% for external beam radiation, and 14% to 61%, 21% and 18% for interstitial radiation, respectively. The literature review showed an evolution in standards for studying and reporting erectile function outcomes.

CONCLUSIONS: Clinical studies reporting erectile function outcomes after localized prostate cancer treatment often demonstrate poorly interpretable and inconsistent manners of assessment as well as widely disparate rates of erectile dysfunction and erectile function. Future studies must apply scientifically rigorous methodology and standard outcomes measures to advance this field of study.

Early combination therapy: intracavernosal injections and sildenafil following radical prostatectomy increases sexual activity and the return of natural erections

Early combination therapy: intracavernosal injections and sildenafil following radical prostatectomy increases sexual activity and the return of natural erections

Early pharmacological prophylaxis has been reported to increase the return of spontaneous erections following radical prostatectomy (RP). In this study, we evaluated the role of intracavernosal alprostadil (PGE1) combined with sildenafil in stimulating early recovery of spontaneous erections following RP. In this prospective study, we included 22 patients who underwent bilateral nerve-sparing RP after October 2004. Sildenafil dose of 50 mg/day was started at the time of hospital discharge. Of 22 patients, 18 started on PGE1-4 microg (1-8) and four started on low-dose Trimix (20 U) 2-3 times/week. These patients are followed up at regular intervals (3, 6, 9 and 12 months) with abridged version of the International Index for Erectile Function-5 questionnaire. Patient compliance, return of sexual activity and return of natural erection, adverse effects and reasons for discontinuation were recorded. Penile doppler studies were performed during followup visits to assess the vascular status. After a mean followup of 6 months (3-8 months), 11/22 (50%) patients had return of spontaneous partial erections. Of the 18 PGE1 users, six continued 4 microg PGE1, four increased the dose to 8 microg, six decreased the dose to 2 microg and two patients further reduced the dose to 1 microg. Of four low-dose Trimix users, three increased the dose to 30 U and one reduced the dose to 15 U. Of 22 patients, 21 were sexually active: 12/21 (57%) with the injections alone and 9/21 (42.9%) with combination therapy (injections (PGE1) and sildenafil). Penile doppler studies revealed arterial insufficiency in 77% (17/22) patients and venous insufficiency in one patient. Early intracavernosal injections following RP facilitated early sexual intercourse, patient satisfaction and potentially earlier return of natural erections. Early combination therapy with sildenafil allowed a lower dose of intracavernous injections, minimizing the penile discomfort.