Anthony J Bella

Erectile Function Rehabilitation in the Radical Prostatectomy Patient

INTRODUCTION Prostate cancer is common and is being diagnosed in younger men now compared with two decades ago. Long-term functional outcomes are of significant importance to patient and impact upon the patient decision-making process regarding choice of therapy. Erectile function preservation (rehabilitation) has gained significant traction worldwide despite the absence of definitive evidence in its favor. AIM To define the role of rehabilitation in the prostate cancer patient who has undergone radical prostatectomy (RP). METHODS A committee of five experts in the field from three countries was convened, and using a thorough analysis of the literature and the Delphi approach to expert opinion, recommendations were arrived at for clinicians treating men with prostate cancer before and after definitive surgical management. RESULTS Recommendations arrived at included: that clinicians should discuss prevalence rates, the pathophysiology of erectile dysfunction after RP and the predictors of erectile function recovery, that validated instruments should be used using the published cut-offs for normalcy, that rehabilitation be discussed with patients, and that they be informed that significant potential benefits may be associated with rehabilitation. CONCLUSIONS The International Consensus of Sexual Medicine (ICSM) 2001 committee on rehabilitation after radical prostatectomy recommended that a discussion occur regarding rehabilitation in all patients undergoing or who have undergone RP. However, the committee recognized the absence of definitive data to date and could not comment on the optimal approach to rehabilitation at this time.

Brain‐Derived Neurotrophic Factor (BDNF) Acts Primarily via the JAK/STAT Pathway to Promote Neurite Growth in the Major Pelvic Ganglion of the Rat: Part 2

INTRODUCTION Identification of the molecular mechanism of cavernous nerve regeneration is essential for future development of neuroprotective and regenerative strategies. AIM To identify specific signal transduction pathway(s) associated with brain-derived neurotrophic factor (BDNF) enhanced cavernous nerve regeneration in an in vitro model. MATERIALS AND METHODS Using 6-month-old male Fisher rats, inhibitors of four candidate signaling pathways were added to BDNF-treated explant cultures of major pelvic ganglia with attached cavernous nerve fragments. Study groups comprised of controls, BDNF alone at 50 ng/mL, or BDNF 50 ng/mL and inhibitors against MEK, PI3-K, PKA, and JAK/STAT pathways at increasing concentrations. MAIN OUTCOME MEASURE The maximal neurite length for each tissue culture was measured and the mean maximal length +/- standard deviation was determined for all groups at 24, 36, and 48 hours. RESULTS The JAK/STAT specific inhibitor AG490 significantly reduced BDNF-enhanced neurite growth. Maximum neurite lengths at 24, 36, and 48 hours for BDNF 50 ng/mL treated groups were 182.3, 348.1, and 528.1 microm, compared with AG490 at 25 microM (86.4, 165.1, 278.3 microm), 50 microM (78.8, 151.7, 235.3 microm), and 100 microM (71.83, 107.0, 219.6 microm) (P < 0.05). Neurite measures for BDNF with 25 and 50 microM U0126 (MEK pathway) were reduced to 402.0 and 424.3 microm at 48 hours, respectively (P < 0.05), likely reflecting an accessory molecular pathway. A similar observation was made for 100 uM LY294002 (PI3-K). No difference was observed for PKA inhibition. CONCLUSION The JAK/STAT pathway is the major signal-transduction pathway of BDNF-enhanced cavernous nerve growth in an in vitro rat model.

T-Shaped Shunt and Intracavernous Tunneling for Prolonged Ischemic Priapism

PURPOSE Conservative management of prolonged ischemic priapism is rarely effective. Interventions include corporal aspiration/irrigation, injection of vasoconstrictive agents or surgical procedures. We describe a technique that fulfills several important criteria in the surgical management of ischemic priapism in that immediate resolution of ischemic pain is achieved, a wide area, reliably patent shunt is created, the procedure is technically simple and it may be performed with the patient under a local anesthetic. MATERIALS AND METHODS We reviewed the records of 13 patients treated with the T-shunt for whom followup, including erectile function, was available. RESULTS Records were available for review for 13 men who underwent the T-shunt procedure from April 2006 to January 2008. In most cases priapism had lasted for more than 24 hours and previous irrigation/intracorporal administration of sympathomimetics had been unsuccessful. Of these 13 men 6 had undergone unsuccessful distal or proximal shunt procedures before presentation to our service. All procedures were performed using local anesthetic only. Cavernous blood flow was restored in all but 1 patient and another required a second procedure. T-shunts resulted in resolution of penile pain in all patients and all but 2 had recovery of erectile function. CONCLUSIONS The T-shunt technique results in immediate resolution of ischemic penile pain and rigidity. Ultrasonography confirms that blood flow is usually restored to the previously ischemic corpora cavernosa after the procedure. The T-shaped shunt is simple and reliable, and access also allows for proximal trans-shunt dilation. We observed surprisingly excellent recovery of erectile function. This procedure may facilitate recanalization of corporal circulation and could make proximal shunts obsolete.

Potential of adipose-derived stem cells for treatment of erectile dysfunction.

INTRODUCTION Adipose-derived stem cells (ADSCs) are a somatic stem cell population contained in fat tissue that possess the ability for self-renewal, differentiation into one or more phenotypes, and functional regeneration of damaged tissue, which may benefit the recovery of erectile function by using a stem cell-based therapy. AIM To review available evidence concerning ADSCs availability, differentiation into functional cells, and the potential of these cells for the treatment of erectile dysfunction (ED). METHODS We examined the current data (from 1964 to 2008) associated with the definition, characterization, differentiation, and application of ADSCs, as well as other kinds of stem cells for the cell-based therapies of ED. MAIN OUTCOME MEASURES There is strong evidence supporting the concept that ADSCs may be a potential stem cell therapy source in treating ED. RESULTS The ADSCs are paravascularly localized in the adipose tissue. Under specific induction medium conditions, these cells differentiated into neuron-like cells, smooth muscle cells, and endothelium in vitro. The insulin-like growth factor/insulin-like growth factor receptor (IGF/IGFR) pathway participates in neuronal differentiation while the fibroblast growth factor 2 (FGF2) pathway is involved in endothelium differentiation. In a preliminary in vivo experiment, the ADSCs functionally recovered the damaged erectile function. However, the underlying mechanism needs to be further examined. CONCLUSION The ADSCs are a potential source for stem cell-based therapies, which imply the possibility of an effective clinical therapy for ED in the near future.

Penile Prosthesis Surgery: Current Recommendations From the International Consultation on Sexual Medicine

INTRODUCTION Penile prosthesis implantation has emerged as a definitive treatment to restore sexual function to the motivated man with erectile dysfunction. Substantial improvements in the design of inflatable devices have been made since they first became available more than four decades ago. AIM To review the history of the penile prosthesis, the indications, preoperative evaluation, and patient and partner satisfaction. The current approaches to addressing intra- and postoperative complications, provide an understanding of prosthesis infection, and placement of these devices will be reviewed. METHODS A committee of worldwide experts in this field was assembled during the 2015 International Consultation on Sexual Medicine (ICSM) and performed a systematic review of the peer-reviewed published medical literature pertaining to penile prosthesis. Particular attention was given to higher level trials when available. Recommendations are based upon the Oxford Criteria. MAIN OUTCOME MEASURES Unfortunately there is limited level 1 and 2 evidence, and where expert opinion was utilized, the decision was unanimous within the committee with a goal of presenting a clinically relevant guideline pertaining to penile prostheses. RESULTS Penile prosthesis has undergone an evolution over the past 40 years resulting in a more effective and reliable treatment for advanced erectile dysfunction not responding to less invasive methods including oral treatment with PDE5 inhibitors, vacuum erection device, and intracorporal injection therapy. It should be considered an appropriate treatment option for the man who wishes to restore erectile function and who understands the potential risk of mechanical failure and infection, both of which are less common now as a result of improvements made in device design as well as surgical protocols adhered to in the operating room. Patients must be clearly informed of the risks associated with penile prosthesis including mechanical failure, infection, shortening of the penis, change in sensation and configuration of the penis, as well as injury to local structures. Intraoperative complications are unusual but do occur and can usually be addressed intraoperatively to allow placement of the device at the time of initial surgery. Postoperative complications may also be addressed when they occur but may require more advanced reconstructive surgical techniques. Men with Peyronies disease, corporal fibrosis due to infection, trauma, prior prosthesis explantation, priapism, and men who have undergone construction of a neophallus may require additional advanced maneuvers to obtain optimum results with a penile prosthesis. CONCLUSION Penile prosthesis remains as an important, viable, and effective treatment for male erectile dysfunction that does not respond to other less invasive approaches or when these approaches are contraindicated or not acceptable to the patient. These devices provide the patient with the ability to engage in penetrative sexual activity without interfering with urination, ejaculation, sensation, or orgasm. Although mechanical failure can occur, the current devices are more reliable as a result of design modifications. Infection remains the most dreaded complication but since the introduction of antibiotic and hydrophilic coatings, infection is less common. Overall, patient and partner satisfaction appear to be reasonably high when a penile prosthesis is used to restore erectile function.

Nerve Growth Factor Modulation of the Cavernous Nerve Response to Injury

INTRODUCTION Surgical therapies for prostate cancer and other pelvic malignancies often result in neuronal damage and debilitating loss of sexual function due to cavernous nerve (CN) trauma. Advances in the neurobiology of growth factors have heightened clinical interest in the development of protective and regenerative neuromodulatory strategies targeting CN recovery following injury. AIM The aim of this review was to offer an examination of current and future nerve growth factor (NGF) modulation of the CN response to injury with a focus on brain-derived nerve growth factor (BDNF), growth differentiation factor-5 (GDF-5), and neurturin (NTN). METHODS Information for this presentation was derived from a current literature search using the National Library of Medicine PubMed Services producing publications relevant to this topic. Search terms included neuroprotection, nerve regeneration, NGFs, neurotrophic factors, BDNF, GDF-5, NTN, and CNs. MAIN OUTCOME MEASURES Basic science studies satisfying the search inclusion criteria were reviewed. RESULTS In this session, BDNF, atypical growth factors GDF-5 and NTN, and their potential influence upon CN recovery after injury are reviewed, as are the molecular pathways by which their influence is exerted. CONCLUSIONS Compromised CN function is a significant cause of erectile dysfunction development following prostatectomy and serves as the primary target for potential neuroprotective or regenerative strategies utilizing NGFs such as BDNF, GDF-5, and NTN, and/or targeted novel therapeutics modulating signaling pathways.

Intracavernous Growth Differentiation Factor‐5 Therapy Enhances the Recovery of Erectile Function in a Rat Model of Cavernous Nerve Injury

INTRODUCTION Neurogenic erectile dysfunction remains a serious complication in the postprostatectomy population. Effective protective and regenerative neuromodulatory strategies are needed. AIM To determine the effect of growth differentiation factor-5 (GDF-5) on erectile function and its mechanism in a rat model of cavernous nerve (CN) injury. MAIN OUTCOME MEASURES Erectile function was assessed by CN electrostimulation at 4 weeks. Penile tissues were examined by real-time polymerase chain reaction (PCR) and immunohistochemical analyses. METHODS Forty-eight male Sprague-Dawley rats were randomly divided into six equal groups: one group underwent sham operation (uninjured controls), while five groups underwent bilateral CN crush. Crush-injury groups were treated at the time of injury with intracavernous injection of a slow-release suspension of liquid microparticles containing no GDF-5 (vehicle), 0.4 microg (low concentration), 2 microg (intermediate concentration), or 10 microg GDF-5 (high concentration). One untreated group served as injured controls. RESULTS GDF-5 enhanced erectile recovery and significantly increased intracavernous pressure in the low and intermediate-concentration groups vs. injured controls. Low-concentration GDF-5 demonstrated the best functional preservation, as the intracavernous pressure increase in this group did not differ significantly from uninjured controls. A dose-response relationship was confirmed for the effects of GDF-5 in penile tissue. Low-concentration GDF-5 showed better preservation of the penile dorsal nerves and antiapoptotic effects in the corpus cavernosum (P < 0.05 vs. injured controls). Although high concentration GDF-5 did not confer meaningful erectile recovery, this dose was more effective at decreasing transforming growth factor-beta than low-concentration GDF-5. CONCLUSIONS Intracavernous injection of low (0.4 microg) or intermediate-concentration GDF-5 (2 microg) was effective in preserving erectile function in a rat model of neurogenic erectile dysfunction. The underlying mechanism appears to involve neuron preservation and antiapoptosis.

The Prognostic Significance of Capsular Incision Into Tumor During Radical Prostatectomy

BACKGROUND The prognostic significance of capsular incision (CapI) into tumor during radical prostatectomy (RP) with otherwise organ-confined disease remains uncertain. OBJECTIVE To evaluate the impact of CapI into tumor on oncologic outcome. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of 8110 consecutive patients with prostate cancer treated at Ottawa Hospital and at Memorial Sloan-Kettering Cancer Center, both tertiary academic centers, between 1985 and 2008. INTERVENTION All patients underwent an open, laparoscopic or robotic RP. MEASUREMENTS Patients were divided into four pathologic categories: group 1 (CapI group), positive surgical margins (PSMs) without extraprostatic extension (EPE); group 2, negative surgical margins (NSMs) without EPE; group 3, NSM with EPE; group 4, PSMs with EPE. Estimates of recurrence-free survival were generated with the Kaplan-Meier method. Recurrence was defined as a prostate-specific antigen (PSA) >0.2 ng/ml and rising. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for recurrence controlling for pretreatment PSA, RP date, RP Gleason sum, seminal vesicle invasion, and lymph node involvement. Pathologic categories were defined in the model by including the variables EPE and surgical margins (SMs) as well as their interaction. RESULTS AND LIMITATIONS Median follow-up was 37.3 mo. The 5-yr recurrence-free probability after RP for the CapI group was 77% (95% confidence interval [CI], 72-83). This was not only inferior to patients with NSMs and no EPE (log rank p<0.0001) but also to those with NSMs and EPE (log rank p=0.0002). In multivariate analysis the interaction between EPE and SM was not significant (p=0.26). In the adjusted model excluding the interaction term, patients with EPE had an increased risk for recurrence (HR: 1.80; 95% CI, 1.49-2.17; p<0.0001) as did those with positive margins (HR: 1.81; 95% CI, 1.51-2.15; p<0.0001). This was a retrospective study. CONCLUSIONS CapI into tumor has a significant impact on patient outcome following RP. Patients, who otherwise would have organ-confined disease, will now have a higher probability of recurrence than those with completely resected extraprostatic disease.

Focal segmental glomerular sclerosis in renal transplant recipients: predicting early disease recurrence may prolong allograft function.

Abstract:  Recurrence of focal segmental glomerular sclerosis (FSGS) in the allograft following renal transplantation can be graft threatening. To assess risk factors associated with FSGS recurrence, we analyzed 22 patients with FSGS who underwent transplantation between 1996 and 2004. Five patients (Group I, 23%) developed FSGS post‐transplantation. Of these patients, 60% had undergone bilateral nephrectomy (BN) for progressive disease compared with none of the patients that were free of recurrence (Group II) (p = 0.0006). Other factors linked with recurrent FSGS were time to first dialysis (Group I: 3.1 ± 1.1 yr vs. Group II: 11.9 ± 1.9 yr; p = 0.03), pre‐transplant proteinuria (Group I: 7.0 ± 1.8 g/d vs. Group II: 2.5 ± 0.7 g/d; p = 0.02), young age at transplantation (p = 0.09) and female sex (Group I: 80% vs. Group II: 24%; p = 0.021). Eighty percent of Group I patients received a living related transplant vs. 24% in Group II (p = 0.021). All grafts continue to function at last follow‐up with comparable serum creatinines. Overall, post‐transplant FSGS recurrence may be associated with BN, severity of pre‐transplant FSGS, female gender, and living donation. These patients should be monitored closely for early recurrence and may benefit from early plasmapheresis to restore and facilitate long‐term graft function.

Impact of cannabis use on male sexual health.

INTRODUCTION Cannabis (marijuana) is the most widely used illicit drug globally. Given the prevalence of nonprescription illicit drug abuse, there is a growing interest in the study of its potential effects on male sexual health. In this review, we discuss the effects of cannabis on male sexual health. OBJECTIVE In this review, we discuss the effects of cannabis on male sexual health. METHODS AND MAIN OUTCOME MEASURE: Critical review of scientific literature examining the impact of cannabis use on male sexual health. RESULTS Studies examining the effects of cannabis use on male sexual function have been limited in both quality and quantity. Most results of these studies are conflicting and contradictory. While some did outline the beneficial effects of cannabis in enhancing erectile function, others did not. However, recent animal and in vitro studies have identified potential links between cannabis and sexual health. It appears that cannabis may actually have peripheral antagonizing effects on erectile function by stimulating specific receptors in the cavernous tissue. CONCLUSIONS Given the prevalence of cannabis use, and the potential relationships between use and the development of potentially hazardous effects on male sexual function, we encourage renewed use of research resources to determine in-depth mechanistic knowledge, and new clinically oriented studies examining the effect of cannabis on male sexual function.