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Phillip M Pierorazio,
Jeffrey K Mullins,
John B Eifler,
Kipp Voth,
Elias S Hyams,
Misop Han,
Christian P Pavlovich, Trinity J Bivalacqua,
Alan W Partin,
Mohamad E Allaf,
Edward M Schaeffer
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ABSTRACT: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The ideal treatment for men with high-risk prostate cancer is controversial, although most physicians agree that a multimodal approach, including radiation and hormone therapy with or without surgery, offers the best chance of cancer control. Minimally-invasive radical prostatectomy has emerged as a treatment option for clinically localized cancer; however, critics argue that the open approach may afford advantages of tactile feedback and a better lymph node dissection. The present study demonstrates that open and minimally-invasive radical prostatectomy offer equivalent short-term outcomes for men with high-risk prostate cancer at a highly experienced centre. OBJECTIVES: To analyze pathological and short-term oncological outcomes in men undergoing open and minimally-invasive radical prostatectomy (MIRP) for high-risk prostate cancer (HRPC; prostate-specific antigen level [PSA] >20 ng/mL, ≥ cT2c, Gleason score 8-10) in a contemporaneous series. PATIENTS AND METHODS: In total, 913 patients with HRPC were identified in the Johns Hopkins Radical Prostatectomy Database subsequent to the inception of MIRP at this institution (2002-2011) Of these, 743 (81.4%) underwent open radical retropubic prostatectomy (ORRP), 105 (11.5%) underwent robot-assisted laparoscopic radical prostatectomy (RALRP) and 65 (7.1%) underwent laparoscopic radical prostatectomy (LRP) for HRPC. Appropriate comparative tests were used to evaluate patient and prostate cancer characteristics. Proportional hazards regression models were used to predict biochemical recurrence. RESULTS: Age, race, body mass index, preoperative PSA level, clinical stage, number of positive cores and Gleason score at final pathology were similar between ORRP and MIRP. On average, men undergoing MIRP had smaller prostates and more organ-confined (pT2) disease (P = 0.02). The number of surgeons and surgeon experience were greatest for the ORRP cohort. Overall surgical margin rate was 29.4%, 34.3% and 27.7% (P = 0.52) and 1.9%, 2.9% and 6.2% (P = 0.39) for pT2 disease in men undergoing ORRP, RALRP and LRP, respectively. Biochemical recurrence-free survival among ORRP, RALRP and LRP was 56.3%, 67.8% and 41.1%, respectively, at 3 years (P = 0.6) and the approach employed did not predict biochemical recurrence in regression models. CONCLUSIONS: At an experienced centre, MIRP is comparable to open radical prostatectomy for HRPC with respect to surgical margin status and biochemical recurrence.
BJU International 01/2013; · 2.84 Impact Factor
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ABSTRACT: Introduction. Radical cystectomy with urinary diversion is the treatment of choice for muscle-invasive, and certain populations with non-invasive, urothelial carcinoma of the bladder. There have not been any reports to date on patients undergoing this surgery who have had previous placement of an inflatable penile prosthesis. Aim. To present the outcomes of four patients with pre-existing inflatable penile prostheses (IPP) with reservoirs within the space of Retzius who were subsequently treated with radical cystectomy for bladder cancer management. Methods. After obtaining institutional review board approval, the demographic, clinical, and pathologic data were reviewed in the Johns Hopkins Cystectomy Database for patients who underwent radical cystectomy for bladder cancer from 1994 to 2012. A case series of four patients is presented who had a preexisting IPP and their post-operative course and long-term outcomes are reviewed. Results. All four patients had radical cystectomy and ileal conduit urinary diversion with no intra-operative or post-operative complications. One patient was not sexually active and therefore had the reservoir explanted and not replaced. The other three patients had the reservoir removed prior to bladder extirpation and the tubing capped, with reservoir replacement in the pseudocapsule at the termination of the procedure. In one patient an omental flap was used to ensure separation between the reservoir and ileal conduit. The devices were all functional intra-operatively and on follow-up. Conclusions. As erectile dysfunction is more commonly being diagnosed and treated with IPP insertion at younger ages, surgeons will increasingly encounter pre-placed abdominal reservoirs when performing pelvic surgery. This case series of four patients undergoing radical cystectomy with prior-placed IPPs reveals that the functionality of the IPP can be preserved while still performing oncologically sound extirpative procedures. Segal RL, Readal N, Pieororazio PM, Kutlu O, Schoenberg M, and Bivalacqua TJ. Radical cystectomy in patients with preexisting three-piece inflatable penile prosthesis. J Sex Med **;**:**-**.
Journal of Sexual Medicine 10/2012; · 3.55 Impact Factor
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ABSTRACT: PURPOSE: Bilateral cavernous nerve injury (BCNI) results in upregulation of Rho-associated protein kinase (ROCK) signaling in the penis which is linked to erectile dysfunction (ED) in an animal model of post-prostatectomy ED. To evaluate whether daily treatment with Y-27632, a ROCK-inhibitor, prevents ED in a rat model of BCNI. MATERIALS AND METHODS: Sprague-Dawley rats underwent sham (n=14) or BCNI (n=27) surgery. In the BCNI group, 13 rats received treatment (Y-27632, 5mg/kg, twice daily) and 14 rats received vehicle. Fourteen days after BCNI, rats underwent cavernous nerve stimulation to determine erectile function. Penes were assessed for levels of neuronal nitric oxide synthase (nNOS), membrane-endothelial NOS (m-eNOS), and ROCK2 by western blot, and cGMP by ELISA. Cavernosal homogenates were tested for ROCK and protein kinase G (PKG) enzymatic activity. Penile apoptosis was evaluated using the apostain technique. Data were analyzed Rho-associated protein kinase using ANOVA and t-test. RESULTS: While erectile function was reduced in BCNI rats, daily administration of Y-27632 improved erectile responses. BCNI decreased nNOS and m-eNOS whereas ROCK2 was significantly increased. Y-27632 treatment restored nNOS, m-eNOS, and cGMP levels and PKG activity. Treatment significantly decreased ROCK2 protein levels and ROCK activity. Apoptotic cells were significantly lower after treatment compared to injured controls. CONCLUSIONS: These results provide evidence for upregulation of the RhoA/ROCK signaling pathway with detrimental effects on erectile function following BCNI. ROCK inhibition improved ED associated with BCNI by preserving penile NO bioavailability and diminished penile apoptosis.
The Journal of urology 09/2012; · 4.02 Impact Factor
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ABSTRACT: PURPOSE: To provide long-term follow-up on a modification of the Al-Ghorab distal penile corporoglandular shunt surgery for treating ischemic priapism. MATERIAL & METHODS: Retrospective review of patients surgically treated for ischemic priapism at the Johns Hopkins Hospital from January 2008 to April 2012 with the Burnett "Snake" maneuver of the Al-Ghorab shunt. Electronic medical records were reviewed to collect demographic information, and telephone follow-up was carried out to verify treatment outcomes. Patients completed the Sexual Health Inventory for Men (SHIM) to assess current erectile function. RESULTS: Ten patients were analyzed (age range 31-59 years). Mean follow-up time was 6.7 months (range 0.5-17). Priapism etiologies were: idiopathic (3); trazodone (2); trazodone & cocaine (3); intracavernosal injection of trimix (1); spinal cord injury (1). 6 patients had previously undergone unsuccessful surgical attempts at priapism decompression, and mean priapism duration was 75 hours (range 24-288). 8/10 men achieved successful resolution of priapism with no recurrences. 2 men with recurrent priapism refractory to all management were definitively treated with insertion of an inflatable penile prosthesis. 6/9 men had normal erectile function pre-operatively of which 2 achieved at least partial erectile function post-operatively. 2 men sustained complications, one having developed a wound infection with skin necrosis and the other an intra-operative urethral injury, with subsequent urethrocutaneous fistula formation and wound infection with skin necrosis. CONCLUSION: The modified Al-Ghorab corporoglanular shunt employing the Burnett "Snake" maneuver is successful in resolving ischemic priapism, particularly for cases refractory to first-line management, with prevention of further priapism episodes.
The Journal of urology 09/2012; · 4.02 Impact Factor
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ABSTRACT: Introduction. Experimental studies investigating physiology of erectile function and pathophysiology erectile dysfunction employ several in vitro and in vivo techniques. As the field of sexual medicine expanding, the proper conduct of such techniques is becoming an even more important necessity than before. Aim. This review article aims to guide scientists, particularly young researchers and new comers in the field, toward employment of these techniques in an appropriate, timely, and competent fashion. Methods. The authors reviewed the existing available published articles on the following topics: intracavernosal pressure measurements, cavernous nerve injury models, nitric oxide-cyclic guanosine monophosphate pathway, hypertension- and smoking-induced erectile dysfunction models, and stem cells. Results. The authors present a consensus on how to best perform these models and techniques and also highlight the pitfalls. Conclusions. The authors hope that this article will assist and encourage young scientists in the field and that similar articles covering other important models will be also available to them soon. Cellek S, Bivalacqua TJ, Burnett AL, Chitaley K, and Lin CS. Common pitfalls in some of the experimental studies in erectile function and dysfunction: A consensus article. J Sex Med **;**:**-**.
Journal of Sexual Medicine 09/2012; · 3.55 Impact Factor
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ABSTRACT: Priapism refers to the nonwillful persistence of penile erection in the absence of sexual excitation, and thus it constitutes
a true sexual dysfunction. At present, the precise pathophysiologic basis for the disorder remains largely misunderstood,
particularly with respect to its recurrent or “stuttering” clinical presentations. New concepts in this field of study suggest
that priapism often results from altered vascular homeostatic actions in the penis and is associated with deficient erection
control mechanisms on a molecular level. A leading proposal is that aberrant signaling of the nitric oxide signal transduction
pathway in the penis is a principal mechanism. Additionally, dysfunctional regulatory control of signal transduction systems
that interact with this pathway may contribute to the display of priapism. These advances have paved the way for understanding
this disorder as having a molecular pathogenesis. As the molecular science underlying priapism further emerges, increasingly
effective therapeutics for priapism are certain to follow.
Current Sexual Health Reports 04/2012; 4(1):9-14.
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ABSTRACT: Arginase expression and activity has been noted to be heightened in conditions associated with erectile dysfunction, including aging. Previously, arginase inhibition by chronic administration of the arginase inhibitor 2-S-amino-6-boronohexanoic acid (ABH) has been shown to improve endothelial dysfunction in aged rats. The objective of this study was to assess whether chronic oral ABH administration affects cavernosal erectile function. Rats were divided into 4 groups: young control, young treated with arginase inhibitor, aged control, and aged treated with arginase inhibitor. Arginase activity was measured and presented as a proportion of young untreated rats. In vivo erectile responses to cavernous nerve stimulation (CNS) were measured in all cohorts. The cavernous nerve (CN) was stimulated with a graded electrical stimulus, and the intracavernosal/mean arterial pressure (ICP/MAP) ratios and total ICP were recorded. Arginase activity was elevated in the aged rats compared to young controls; however, arginase activity was significantly decreased in aged rats treated with ABH. With the addition of ABH, erectile responses improved in the aged rats (P < 0.05). Oral inhibition of arginase with ABH results in improved erectile function in aged rats, resulting in erectile hemodynamics similar to young rats. This represents the first documentation of systemic arginase inhibition positively affecting corporal cavernosal function.
Journal of Andrology 04/2012; · 2.97 Impact Factor
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ABSTRACT: Study Type - Therapy (retrospective cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Erectile dysfunction following radical prostatectomy (RP) is among the most common and dreaded adverse effects of the surgery. Multiple studies confirm the potential benefit of various drug classes to accelerate the return of erectile function (EF) after RP. There is pre-clinical evidence supporting the use of angiotensin-receptor blockers (ARBs) for this purpose, although this has not been studied in humans. The present study shows that there may be a benefit in the recovery of EF post-RRP in patients taking a daily dose of irbesartan, an ARB, following RRP. In addition, the use of irbesartan may curb the loss of stretched penile length which occurs postoperatively. Further study in the form of prospective, randomized, placebo-controlled clinical trials are necessary to confirm these findings. OBJECTIVE: • To evaluate retrospectively the potential benefit of administering irbesartan, an angiotensin-receptor blocker, to improve erectile function (EF) recovery after nerve-sparing radical retropubic prostatectomy (RRP). PATIENTS AND METHODS: • Before surgery potent patients who underwent nerve-sparing RRP between April and December 2009 elected to start daily oral irbesartan 300 mg on postoperative day 1 (n= 17). A contemporaneously clinically matched cohort consisting of patients who declined irbesartan use served as the control group (n= 12). • Postoperative 'on demand' use of erectile aids (phosphodiesterase type 5 [PDE5] inhibitors and intracavernous injections) was adopted. • Potency was monitored by the administration of International Index of Erectile Function-5 (IIEF-5) questionnaires before surgery and at early (3 months) and long-term (12 and 24 months) postoperative intervals. • Stretched penile length (SPL) was measured both immediately and 3 months after surgery. RESULTS: • EF status was no different between groups at baseline (P > 0.05). • While the IIEF-5 scores at 24 months after surgery were statistically similar between the two groups (control = 15.2 ± 2.0, irbesartan = 14.1 ± 3.1, P= 0.77), at 12 months the IIEF-5 scores of the irbesartan group were significantly higher than those of the control group (14 ± 2.6 vs. 7.2 ± 1.6, P < 0.05). • The proportional loss of SPL after RRP was less in the irbesartan than in the control group at 3 months (-0.9 ± 1.5% vs -5.6 ± 1.5, P < 0.05). CONCLUSION: • Regular irbesartan use after nerve-sparing RRP in patients with normal preoperative erectile function could improve EF recovery after surgery and mitigate early loss of SPL.
BJU International 03/2012; · 2.84 Impact Factor
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ABSTRACT: What's known on the subject? and What does the study add? With the present study, we aimed to provide a global picture of the molecular processes that are activated by CN injury. The present study used genomic expression profiling to identify candidate genes that might be useful targets in the CN recovery process and, thus, the ultimate preservation of penile erection. Regeneration of the CN and axonal outgrowth clearly involve changes in multiple biochemical pathways that have never been investigated by microarray analysis. We analyzed global gene expression in the major pelvic ganglion at early stages (48 h and 14 days) after CN injury and focused on the detection of changes in genes related to nervous tissue repair and proliferation. The findings of the present study provide important insight into the molecular systems affected by CN injury and identify candidate genes that may be utilized for novel molecular-based therapies for the preservation and protection of the CN during RP.
To to examine the complexity of the many molecular systems involved in supporting cavernous nerve (CN) repair and regeneration in a rat model of bilateral crush injury utilizing a microarray analysis approach. Erectile dysfunction (ED) is a common clinical complication after prostate cancer treatment by radical prostatectomy, and recovery of erectile function can take as long as 2 years. There are gaps in our understanding of the autonomic pelvic innervation of the penis that still need to be addressed for the development of an adequate treatment strategy for post-prostatectomy ED. The molecular mechanisms of the intrinsic ability of CN to regenerate after an injury have not been elucidated.
We analyzed global gene expression in the major pelvic ganglion 48 h and 14 days after CN injury. Overall, a comparative analysis showed that 325 genes changed at the 48-h time point and 114 genes changed at 14 days. There were 60 changed genes in common with both time points. Using the Ingenuity Pathway Analysis® system (Ingenuity Systems, Inc., Redwood City, CA, USA), we were able to analyze the significantly changed genes that were unique and common to each time point by biological function. We focused on the detection of changes related to nervous tissue repair and proliferation, molecular networks of neurotrophic factors, stem cell regulation and synaptic transmission.
There was strong evidence of the early mobilization of genes involved in repair and neuroprotection mechanisms (SERPINF1, IGF1, PLAU/PLAUR, ARG1). Genes related to nervous system development (ATF3 GJA1, PLAU, SERPINE1), nerve regeneration (SERPINE2, IGF1, ATF3, ARG1) and synaptic transmission (GJC1, GAL) were changed. Several genes related to proliferation as well as apoptosis (A2M, ATF3, C3, EGR4, FN1, GJA1, GAL) were also changed, possibly as part of a protective mechanism or the initiation of remodelling.
The results obtained show that multiple biological processes are associated with injury and repair of the CN and provide a systematic genome-wide screen for neurotrophic and/or inhibitory pathways of nerve regeneration. These data identify the candidate genes that may be utilized in novel molecular-based therapies for the preservation and protection of the CN during radical prostatectomy.
BJU International 02/2012; 109(10):1552-64. · 2.84 Impact Factor
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ABSTRACT: What's known on the subject? and What does the study add? In the present study the mechanisms regulating EFS-evoked neurogenic contraction in the human corpus cavernosum (HCC) were investigated. Overall, our data adds to current knowledge that the NO-independent heme dependent activation of sGC and the RhoA/Rho-kinase signaling pathways play an important role in the regulation of neurogenic contractile activity in HCC tissue.
To investigate the mechanisms of adrenergically mediated smooth muscle contraction in the human corpus cavernosum (HCC) using an organ bath approach.
Human corpus cavernosum specimens were obtained from patients (aged 59-72 years) with erectile dysfunction (ED), undergoing penile prosthesis implantation surgery. Isolated HCC strips (1 × 1 × 6 mm) were suspended in tissue bath chambers for isometric tension recording. The effects of various drugs on neurogenic contractions evoked by electrical field stimulation (EFS) were investigated. The drugs included nitric oxide (NO) donors, phosphodiesterase 5 (PDE5) inhibitor, Rho kinase (ROCK) inhibitor, NO-independent stimulator, L-type Ca2+ channel blocker and α-receptor antagonist.
Pre-incubation with the NO donor sodium nitroprusside (SNP; 10(4) M) significantly reduced the initial peak increase in tension evoked by EFS (by 71%, P < 0.05). The PDE5 inhibitor sildenafil (10(-4) M) reduced the increase in tension by 69%, while a combination of sildenafil and ROCK inhibitor, fasudil, inhibited tension by 81%. The EFS-induced contractile response at 80 Hz was decreased by 65% with fasudil and by 70% with isradipine (P < 0.001), while a combination of these drugs decreased the response by 88%. An NO-independent stimulator soluble guanylate cyclase (sGC), BAY 41-8543, significantly reduced the response (by 82%, P < 0.001) Phentolamine, an α-receptor antagonist, nearly eliminated the contractile response (98%, P < 0.001).
These data suggest that neurogenic contractions are mediated by an increase in Ca(2+) influx via L-type voltage-gated Ca(2+) channels and that an increase in Ca(2+) sensitivity is mediated by the ROCK pathway and the PDE5 enzyme system as well as by the inhibitory NO/sGC/cGMP pathway. The neurogenic contractile response in HCC is mediated by several intracellular pathways, including adrenergic receptors, Ca(2+) entry, Ca(2+) sensitization and activation of the PDE5 enzyme. The Rho-kinase (ROCK) inhibitor fasudil, L-type Ca(2+) channel antagonist isradipine, and PDE5 inhibitor sildenafil, as well as a NO-independent stimulator of sGC, had similar inhibitory effects, suggesting parallel mechanisms in the HCC.
BJU International 01/2012; 110(6):856-62. · 2.84 Impact Factor
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ABSTRACT: Muscle invasive and recurrent nonmuscle invasive bladder cancers have been traditionally treated with a radical cystectomy and urinary diversion. The urinary diversion is generally accomplished through the creation of an incontinent ileal conduit, continent catheterizable reservoir, or orthotopic neobladder utilizing small or large intestine. While radical extirpation of the bladder is often successful from an oncological perspective, there is a significant morbidity associated with enteric interposition within the genitourinary tract. Therefore, there is a great opportunity to decrease the morbidity of the surgical management of bladder cancer through utilization of novel technologies for creating a urinary diversion without the use of intestine. Clinical trials using neourinary conduits (NUC) seeded with autologous smooth muscle cells are currently in progress and may represent a significant surgical advance, potentially eliminating the complications associated with the use of gastrointestinal segments in the urinary reconstruction, simplifying the surgical procedure, and greatly facilitating recovery from cystectomy.
Advances in Urology 01/2012; 2012:653652.
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ABSTRACT: To determine the impact of stenting ureteroenteric anastomoses on postoperative stricture rate and gastrointestinal recovery in continent and noncontinent urinary diversions (UDs).
We retrospectively reviewed the clinical and pathologic data on 192 consecutive patients who underwent a radical cystectomy and UD. Patients received either a continent or noncontinent UD with or without stent placement through the ureteroenteric anastomoses. Stricture rate, gastrointestinal recovery, length of hospital stay, and stricture characteristics were analyzed. Study endpoints were compared between four groups--stented and nonstented continent and stented and nonstented noncontinent UDs.
36% of patients were stented and 64% were nonstented at the time of UD. Total ureteral stricture rate was 9.9%. There was no statistically significant difference in stricture rate (p = 0.11) or length of hospital stay (p = 0.081) in stented compared to nonstented patients. There was a significantly (p = 0.014) greater rate of ileus in patients who were nonstented in both continent and noncontinent UDs.
Stenting of ureteroenteric anastomoses in both continent and noncontinent UD has no effect on postoperative stricture rate, but is associated with lower rates of postoperative ileus.
Urologia Internationalis 01/2012; 88(1):66-70. · 0.99 Impact Factor
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ABSTRACT: To determine the knowledge level of patients with bladder cancer (BC) regarding smoking risks. We also sought to determine the role of their urologists in initiating smoking cessation at the diagnosis. Smoking is the leading risk factor for BC in industrialized nations. However, little information is available regarding patients' knowledge of the risks of smoking and the role of their urologists in initiating smoking cessation at diagnosis.
A smoking knowledge and cessation questionnaire was administered to 71 patients referred to the Johns Hopkins Hospital for BC from April 2008 to June 2009. The questionnaire captured data on demographics, BC history, smoking status and history, risk factor knowledge, and cessation patterns.
The mean age of the cohort was 65.1 years (range 42-86) and 72% were men. At the referral, all 71 patients (100%) knew smoking was a risk factor for lung cancer compared with 61 (86%) who knew it was for BC. Only 36 patients (51%) knew smoking was the leading risk factor for BC. Of the 17 patients (24%) who were smokers at their BC diagnosis, 12 (71%) were counseled by their referring urologist to quit smoking; however, the significant majority (76%) was not offered any specific intervention.
The association between smoking and BC was not as well known as that of lung cancer in our cohort of patients. Most current smokers were advised to stop smoking by their primary urologist; however, few were offered any intervention to aid in cessation. Urologists should assume a more active role both in educating patients regarding smoking's link to BC and in initiating smoking cessation.
Urology 01/2012; 79(1):166-71. · 2.43 Impact Factor
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ABSTRACT: Priapism is defined as a prolonged and persistent erection of the penis without sexual stimulation. This is a poorly understood disease process with little information on the pathophysiology of this erectile disorder. Complications from this disorder are devastating due to the irreversible erectile damage and resultant erectile dysfunction (ED). Stuttering priapism, though relatively rare, affects a high prevalence of men with sickle-cell disease (SCD) and presents a challenging problem with guidelines for treatment lacking or resulting in permanent ED. The mechanisms involved in the development of priapism in this cohort are poorly characterized; therefore, medical management of priapism represents a therapeutic challenge to urologists. Additional research is warranted, so we can effectively target treatments for these patients with prevention as the goal. This review gives an introduction to stuttering priapism and its clinical significance, specifically with regards to the patient with SCD. Additionally, the proposed mechanisms behind its pathophysiology and a summary of the current and future targets for medical management are discussed.
Asian Journal of Andrology 11/2011; 14(1):156-63. · 1.52 Impact Factor
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Urology 09/2011; 78(6):1229-31. · 2.43 Impact Factor
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ABSTRACT: With the increased diagnosis of low grade, low volume, potentially non-lethal disease, active surveillance (AS) has become an increasingly popular alternative for select men with low-risk prostate cancer. The absence of precise clinical staging modalities currently makes it difficult to predict which patients are most appropriate for AS. The goal of our study was to evaluate the ability of endorectal MRI (eMRI) to predict adverse pathologic features in patients who would otherwise qualify for an AS program.
We retrospectively reviewed our institution's radical prostatectomy (RP) database from 1991 to 2007 and identified 172 patients who would have qualified for AS and underwent preoperative staging eMRI with T2-weighted (T2W) sequences. MRI findings were correlated to final pathology in order to assess the ability of staging eMRI to predict adverse pathologic features in patients suitable for AS.
The mean age of our cohort was 59.8 ± 6.2 years. The mean PSA at the time of diagnosis was 5.2 ± 2.2 ng/ml. In 51% of patients, no discrete tumor was visualized on eMRI and in 49% of patients a discrete tumor was detected. At the time of RP, Gleason score upgrading, extracapsular extension, and a positive surgical margin occurred in 17%, 6%, and 5% of cases, respectively. Patients with documented tumor on eMRI did not have an increased incidence of adverse pathologic findings with regard to tumor volume (P = 0.31), extra-capsular extension (P = 0.82), Gleason upgrading (P = 0.92), seminal vesicle invasion (P = 0.97), or positive surgical margin rate (P = 0.95) compared with those in whom no tumor was seen.
Discrete tumor identification on eMRI is not predictive of adverse pathologic features in patients who would otherwise qualify for AS. eMRI likely does not provide additional information when prospectively evaluating patients for AS protocols.
Urologic Oncology 08/2011; 30(3):301-5. · 3.22 Impact Factor
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ABSTRACT: Priapism is defined as an erectile disorder, in which erection persists uncontrollably without sexual purpose. The precise mechanisms involved in the development of sickle cell disease-associated priapism are ill defined.
To summarize the recent developments that increase our understanding of the molecular mechanisms of priapism.
This article reviews the literature (Medline search 2000-2010) that relates the key molecular signaling pathways that contribute to the development of priapism associated with sickle-cell disease. It focuses on basic science investigations using multiple animal models.
The reader will be informed of the most current research regarding the role of endothelial nitric oxide synthase, phosphodiesterase type 5 (PDE5), adenosine, RhoA/Rho-kinase (ROCK), and opiorphins in the pathophysiology of priapism.
New concepts in the field of priapism research suggest that priapism often results from altered vascular homeostatic actions in the penis and is associated with deficient erection control mechanisms on a molecular level. A leading proposal in this regard is the notion of aberrant signaling of the endothelium-derived nitric oxide and PDE5 signal transduction pathway in the penis. Additionally, dysfunctional regulatory control of signal transduction systems which interact with this pathway such as adenosine and RhoA/Rho-kinase may contribute to the development of priapism. Recent investigations of opiorphins also demonstrate a role in regulating corporal smooth muscle tone and thereby dysregulation of erection physiology in priapism. These advances have paved the way for understanding this disorder as having a molecular pathogenesis.
As the science underlying priapism further emerges, increasingly effective therapeutics for sickle cell disease-associated priapism is certain to follow.
Journal of Sexual Medicine 05/2011; 9(1):79-87. · 3.55 Impact Factor
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ABSTRACT: Advances have recently been made in both medical and surgical management of priapism, and these offer improvements in the level of care afforded such patients. Further developments can be expected based on ongoing progress, particularly in the area of molecular science, which is the primary source for driving novel therapeutic approaches. Continued action to address the health care administrative concerns of those most commonly affected by priapism, specifically individuals with sickle cell disease, is also appropriate. All successes in these arenas ensure that afflicted individuals avoid the health burdens of priapism and preserve sexual function.
Urologic Clinics of North America 05/2011; 38(2):185-94. · 1.82 Impact Factor
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Milena A Gebska,
Blake K Stevenson,
Anna R Hemnes, Trinity J Bivalacqua,
Azeb Haile,
Geoffrey G Hesketh,
Christopher I Murray,
Ari L Zaiman,
Marc K Halushka,
Nispa Krongkaew,
Travis D Strong,
Carol A Cooke,
Hazim El-Haddad,
Rubin M Tuder,
Dan E Berkowitz,
Hunter C Champion
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ABSTRACT: It has been well demonstrated that phosphodiesterase-5A (PDE5A) is expressed in smooth muscle cells and plays an important role in regulation of vascular tone. The role of endothelial PDE5A, however, has not been yet characterized. The present study was undertaken to determine the presence, localization, and potential physiologic significance of PDE5A within vascular endothelial cells.
We demonstrate primary location of human, mouse, and bovine endothelial PDE5A at or near caveolae. We found that the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3). Treatment of human endothelium with PDE5A inhibitors resulted in a significant increase in NOS3 activity, whereas overexpression of PDE5A using an adenoviral vector, both in vivo and in cell culture, resulted in decreased NOS3 activity and endothelium-dependent vasodilation. The molecular mechanism responsible for these interactions is primarily regulated by cGMP-dependent second messenger. PDE5A overexpression also resulted in a significant decrease in protein kinase 1 (PKG1) activity. Overexpression of PKG1 rapidly activated NOS3, whereas silencing of the PKG1 gene with siRNA inhibited both NOS3 phosphorylation (S1179) and activity, indicating a novel role for PKG1 in direct regulation of NOS3.
Our data collectively suggest another target for PDE5A inhibition in endothelial dysfunction and provide another physiologic significance for PDE5A in the modulation of endothelial-dependent flow-mediated vasodilation. Using both in vitro and in vivo models, as well as human data, we show that inhibition of endothelial PDE5A improves endothelial function.
Cardiovascular research 03/2011; 90(2):353-63. · 5.80 Impact Factor
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ABSTRACT: Sickle cell disease (SCD)-associated priapism is characterized by endothelial nitric oxide synthase (eNOS) dysfunction in the penis. However, the mechanism of decreased eNOS function/activation in the penis in association with SCD is not known.
Our hypothesis in the present study was that eNOS is functionally inactivated in the SCD penis in association with impairments in eNOS post-translational phosphorylation and the enzyme's interactions with its regulatory proteins.
Sickle cell transgenic (sickle) mice were used as an animal model of SCD. Wild-type (WT) mice served as controls. Penes were excised at baseline for molecular studies. eNOS phosphorylation on Ser-1177 (positive regulatory site) and Thr-495 (negative regulatory site), total eNOS, and phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177) expressions, and eNOS interactions with heat-shock protein 90 (HSP90) and caveolin-1 were measured by Western blot. Constitutive NOS catalytic activity was measured by conversion of L-[14C]arginine-to-L-[14C]citrulline in the presence of calcium.
Molecular mechanisms of eNOS dysfunction in the sickle mouse penis.
eNOS phosphorylated on Ser-1177, an active portion of eNOS, was decreased in the sickle mouse penis compared with WT penis. eNOS interaction with its positive protein regulator HSP90, but not with its negative protein regulator caveolin-1, and phosphorylated AKT expression, as well as constitutive NOS activity, were also decreased in the sickle mouse penis compared with WT penis. eNOS phosphorylated on Thr-495, total eNOS, HSP90, and caveolin-1 protein expressions in the penis were not affected by SCD.
These findings provide a molecular basis for chronically reduced eNOS function in the penis by SCD, which involves decreased eNOS phosphorylation on Ser-1177 and decreased eNOS-HSP90 interaction.
Journal of Sexual Medicine 02/2011; 8(2):419-26. · 3.55 Impact Factor
