Emmanuel Weyne

Landmarks in erectile function recovery after radical prostatectomy.

The description of the nerve-sparing technique of radical prostatectomy by Walsh was one of the major breakthroughs in the surgical treatment of prostate cancer in the 20th century. However, despite this advance and consequent technological refinements to nerve-sparing surgery, a large proportion of men still suffer from erectile dysfunction (ED) as a complication of prostatectomy. A plethora of therapeutic approaches have been proposed to optimize erectile function recovery in these patients. Several preclinical and translational studies have shown benefits of therapies including PDE5 inhibitor (PDE5I) treatment, immunomodulation, neurotrophic factor administration, and regenerative techniques, such as stem cell therapy, in animal models. However, most of these approaches have either failed to translate to clinical use or have yet to be studied in human subjects. Penile rehabilitation with PDE5Is is currently the most commonly used clinical strategy, in spite of the absence of solid clinical evidence to support its use.

Caspase-3 dependent nitrergic neuronal apoptosis following cavernous nerve injury is mediated via RhoA and ROCK activation in major pelvic ganglion

Axonal injury due to prostatectomy leads to Wallerian degeneration of the cavernous nerve (CN) and erectile dysfunction (ED). Return of potency is dependent on axonal regeneration and reinnervation of the penis. Following CN injury (CNI), RhoA and Rho-associated protein kinase (ROCK) increase in penile endothelial and smooth muscle cells. Previous studies indicate that nerve regeneration is hampered by activation of RhoA/ROCK pathway. We evaluated the role of RhoA/ROCK pathway in CN regulation following CNI using a validated rat model. CNI upregulated gene and protein expression of RhoA/ROCK and caspase-3 mediated apoptosis in the major pelvic ganglion (MPG). ROCK inhibitor (ROCK-I) prevented upregulation of RhoA/ROCK pathway as well as activation of caspase-3 in the MPG. Following CNI, there was decrease in the dimer to monomer ratio of neuronal nitric oxide synthase (nNOS) protein and lowered NOS activity in the MPG, which were prevented by ROCK-I. CNI lowered intracavernous pressure and impaired non-adrenergic non-cholinergic-mediated relaxation in the penis, consistent with ED. ROCK-I maintained the intracavernous pressure and non-adrenergic non-cholinergic-mediated relaxation in the penis following CNI. These results suggest that activation of RhoA/ROCK pathway mediates caspase-3 dependent apoptosis of nitrergic neurons in the MPG following CNI and that ROCK-I can prevent post-prostatectomy ED.

Stem Cell Therapy for Erectile Dysfunction: Progress and Future Directions

INTRODUCTION Erectile dysfunction (ED) is the most common sexual disorder reported by men to their health-care providers and the most investigated male sexual dysfunction. Currently, the treatment of ED focuses on symptomatic relief of ED and therefore tends to provide temporary relief rather than providing a cure or reversing the underlying cause. Recently, stem cell-based therapies have received increasing attention regarding their potential for the recovery of erectile function. Preclinical studies have shown that these cells may reverse pathophysiological changes leading to ED rather than treating the symptom ED. AIM To review available evidence on the efficacy and mechanisms of action of stem cell application for the treatment of ED. METHODS A nonsystematic review was conducted on the available English literature between 1966 and 2013 on the search engines SciVerse-sciencedirect, SciVerse-scopus, Google Scholar, and PubMed. RESULTS Several preclinical studies have addressed stem cell-based therapies for the recovery of erectile function following cavernous nerve injury and in Peyronies disease, diabetes, aging, and hyperlipidemia. Overall, these studies have shown beneficial effects of stem cell therapy, while evidence on the mechanisms of action of stem cell therapy still varies between studies. While many authors propose engraftment and differentiation of stem cells, a recent paradigm shift toward paracrine mechanisms of action is observed. One clinical study investigated stem cell therapy in diabetic patients, and two more clinical trials are currently recruiting patients. CONCLUSIONS The development of methods to deliver stem cells to the penis has kindled a keen interest in understanding stem cell biology as it related to restoration of normal penile vascular and neuronal homeostasis. The use of stem cells for the treatment of ED represents an exciting new field, which still requires extensive basic research and human trials in diverse ED patient populations in order to define its role in the treatment of ED. Albersen M, Weyne E, and Bivalacqua TJ. Stem cell therapy for erectile dysfunction: Progress and future directions. Sex Med Rev 2013;1:50-64.

Advances in stem cell research for the treatment of male sexual dysfunctions

Purpose of review To summarize recent literature on basic stem cell research in erectile dysfunction in cavernous nerve injury, aging, diabetes, and Peyronies disease and to provide a perspective on clinical translation of these cellular therapies. Recent findings Stem cell research has been concentrated on mesenchymal stem (stromal) cells from bone marrow and adipose tissue. Application of both cell types has produced positive effects on erectile function in various animal models of erectile dysfunction. In acute animal models, such as cavernous nerve injury-induced erectile dysfunction and chemically induced Peyronies disease, engraftment and differentiation have not been observed, and stem cells are believed to interact with the host tissue in a paracrine fashion, whereas in chronic disease models some evidence suggests both engraftment and paracrine factors may support improved function. Clinical trials are now investigating therapeutic efficacy of cellular therapy, whereas the first safety studies in humans have recently been published. Summary Evidence from preclinical studies has established stem cells as a potential curative treatment for erectile dysfunction and early phase clinical trials are currently performed.

Stem Cells in Male Sexual Dysfunction: Are We Getting Somewhere?

INTRODUCTION Stem cells for sexual disorders are steadily being introduced into clinical trials. Two conditions of importance are the main target for this line of treatment, especially when regarding the wide array of translational and basic science highlighting the potential advantages of regenerative therapy: erectile dysfunction (ED) and more recently Peyronie disease (PD). Cellular therapy offers a treatment modality that might reverse disease progression. It would be used in a curative setting, in contrast to other pharmaceutical agents that are currently available. AIM To review basic preclinical studies and recent clinical trials of stem cells on ED and PD. METHODS A search of the medical literature for the following terms was performed using PubMed: stem cells, cellular therapy, erectile dysfunction, Peyronies disease, and clinical trial. MAIN OUTCOME MEASURES A non-systematic narrative review and critical reflection on preclinical and clinical studies administering stem cells for ED and PD in animal models and human subjects. RESULTS Numerous studies have confirmed the beneficial functional effects of stem cell injection in established animal models on ED and PD. Various stem cell types have been adopted, from embryonic to adult mesenchymal cell types. Each cell type offers distinctive advantages and disadvantages. Diverse administrations of stem cells were investigated, with insignificant variability in the ultimate results. Stem cells appear to have a pronounced paracrine effect, rather than the classic engraftment and differentiation hypothesis. Phase 1 clinical trials using stem cells have not reported any severe adverse events in animals. However, these results cannot be extrapolated to draw any conclusions about efficacy in human patients. CONCLUSION Stem cells have an established efficacy in preclinical studies and early clinical trials. Studies are currently being published demonstrating the safety of intrapenile injection of autologous bone marrow- and adipose tissue-derived stem cells. Soebadi MA, Milenkovic U, Weyne E, et al. Stem Cells in Male Sexual Dysfunction: Are We Getting Somewhere? Sex Med Rev 2017;5:222-235.

Adipose-derived Stem Cells Counteract Urethral Stricture Formation in Rats

BACKGROUND A medical treatment for urethral stricture (US) is not yet available. OBJECTIVE To evaluate if local injection of human adipose tissue-derived stem cells (hADSC) prevents urethral fibrosis in a rat model of US. DESIGN, SETTING, AND PARTICIPANTS Male rats were divided into three groups: sham, US, and hADSC (n=12 each). Sham rats received a vehicle injection in the urethral wall. US and hADSCs were incised and injected with the fibrosis-inducer transforming growth factor-β1 in the urethral wall. INTERVENTION One day later, hADSCs were injected in the urethral wall of hADSC rats whereas sham and US rats were injected with the vehicle. After 4 wk, the rats underwent cystometries and tissues were then harvested for functional and molecular analyses. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cystometry, microultrasound, histochemistry, organ bath studies, reverse transcription polymerase chain reaction, and western blot. RESULTS AND LIMITATIONS US rats exhibited 49-51% shorter micturition intervals, 35-51% smaller micturition volumes and bladder capacity, 33-62% higher threshold pressures and flow pressures, and 35-37% lower bladder filling compliance compared with hADSC-treated rats and sham rats (p<0.05). By ultrasound, US rats had hyperechogenic and thick urethral walls with narrowed lumen compared with sham rats, whereas hADSC rats displayed less extensive urethral changes. Isolated detrusor from US rats exhibited 34-55% smaller contractions than detrusor from sham rats (p<0.05). Corresponding values were 11-35% for isolated detrusors from hADSC rats. Collagen and elastin protein expression were increased in the penile urethras of US rats compared with sham and hADSC groups (p<0.05). Endothelial and inducible nitric oxide synthase expressions were higher (p<0.05) in the hADSC group. Compared with US rats, hADSC rats demonstrated decreased expression of several fibrosis-related genes. Administration of hADSCs was performed at an early stage of US development, which we consider a limitation of the study. CONCLUSIONS Local injection of hADSCs prevents stricture formation and urodynamic complications in a new rat model for US. PATIENT SUMMARY Stem cell therapy is effective for preventing urethral stricture in an experimental setting.

Increased Expression of the Neuroregenerative Peptide Galanin in the Major Pelvic Ganglion Following Cavernous Nerve Injury

INTRODUCTION Erectile dysfunction (ED) remains a frequent complication of radical prostatectomy due to injury to the cavernous nerves (CNs). A recent microarray showed the neuropeptide galanin to be one of the most strikingly upregulated genes in the rat major pelvic ganglion (MPG) after bilateral CN crush injury (BCNI). AIM The aim of this study is to evaluate the temporal regulation of galanin in the MPG after BCNI and its relationship to functional nerve regeneration. METHODS Changes in galanin, galanin receptor (galR), and c-JUN mRNA expression were assessed in Sprague-Dawley rats after sham operation (n = 10) and at 48 hours (n = 10), 7 (n = 10), 14 (n = 5), 21 (n = 5), 30 (n = 5), and 60 (n = 5) days after BCNI using quantitative PCR. Erectile function was assessed by measuring intracavernous pressure (ICP) divided by mean arterial pressure (MAP) during CN electrostimulation. Immunohistochemistry was performed on the MPG in sham-operated animals and 5 days after BCNI. MAIN OUTCOME MEASURES ICP/MAP upon CN stimulation; galanin, galR1, -2, -3, and c-JUN mRNA expression at various time points after BCNI; and nNOS, galanin, and galR distribution in the MPG of sham-operated rats and after BCNI. RESULTS After BCNI, ICP/MAP values quickly deteriorate, while after 60 days, spontaneous restoration of erectile responses to CN stimulation is observed, reflecting CN regeneration. Galanin mRNA in the MPG is up to 186-fold upregulated compared with sham-operated rats at 48 hours and 7 days after BCNI and gradually declines with increasing time from injury, whereas galanin receptor expressions decrease and c-JUN gradually increases. Galanin expression shows a strong inverse correlation with erectile responses to CN stimulation with time from injury. Injured MPGs show a colocalization between galanin- and nNOS-positive neuronal cell population in the MPG. CONCLUSIONS Galanin is upregulated in the MPG in the early phase after CN injury after which it gradually decreases and is present in nNOS-positive neurons of the ganglion. We hypothesize that galanin upregulation is an important factor in the endogenous neuroregenerative response to CN injury.

Idiopathic Partial Thrombosis (IPT) of the Corpus Cavernosum: A Hypothesis-Generating Case Series and Review of the Literature

INTRODUCTION Idiopathic partial thrombosis (IPT) of the corpus cavernosum is a rare condition. The etiology is not fully understood; however, the presence of an either or not congenital web in these patients may contribute to the development of IPT. AIM The aim of this study was to describe 18 new IPT cases and compare these with 38 cases found in the literature. METHODS A multicenter retrospective analysis was performed. Descriptive statistics are given. MAIN OUTCOME MEASURES The main outcome measures used were clinical presentation, clinical and radiographical diagnostics, treatment and resolution of symptoms. RESULTS Patients most frequently presented with perineal swelling (10/18; 56%) and pain (13/18; 72%), unilateral (12/18; 67%) or bilateral (4/18; 22%), and pain during erection (10/18; 72%). Penile curvature, dysuria or fever (each 1/18; 6%) were uncommon presenting symptoms. In our series, magnetic resonance imaging demonstrated a fibrous web in the corpus cavernosum in 100% of cases and was more bilaterally (11/18; 61%) than unilaterally (7/18; 39%) diagnosed. Cycling was found to be a provocative factor for IPT occurrence in patients at risk as 61% (11/18) of patients reported being a frequent cyclist with the episode of IPT occurring immediately after or during cycling activity in 8 out of 18 patients (8/18; 44%). In five centers, 15 patients were treated conservatively, the majority being treated with therapeutic doses of low molecular weight heparin and simultaneous anti-aggregant therapy. In one center, all three patients were treated with a surgical approach. Complete resolution of symptoms was noted in only 50% of cases. CONCLUSION IPT is a condition that presents typically with perineal pain and swelling. Cycling is often seen as a provocative factor, while the presence of a fibrous web at the level of the crurocavernosal junction is the underlying disorder allowing for entrapment of blood in the crura. Conservative treatment provides a reasonably good outcome in most cases. For therapy resistant cases, surgery can be considered.

Immunosympathectomy for Preservation of Erectile Function Following Cavernous Nerve Injury

Several prospective randomized trials have not been able to show a benefit with daily administration of phosphodiesterase type 5 inhibitors for recovery of erectile function following radical prostatectomy (RP) [1]. Consequently, both basic and translational researchers are continuing to search for effective strategies to preserve erectile function following RP. Despite the discovery of autonomic (sympathetic and parasympathetic) innervation and neurovascular bundles by Walsh and Donker in 1982 [2] and the advent of nervesparing surgical techniques, erectile dysfunction remains a common complication following RP. This is believed to be caused by traction, crushing, and coagulation on or in proximity to the neurovascular bundles, resulting in nerve injury (neuropraxia) that triggers wallerian degeneration, resulting in denervation of the corpora cavernosa and erectile failure. Neurodegeneration is potentially reversible, as the peripheral nervous system has an intrinsic neuroregenerative capacity in which the endogenous production of neurotrophic factors is believed to be a key component in the neuroprotective response to nerve injury [3]. This concept has been confirmed in several preclinical studies in which neuromodulatory or neurotrophic factor therapies led to improved erectile function in rodents after cavernous nerve injury (CNI) [4]. Several authors have suggested that sympathetic hyperinnervation may play a role in the impairment of erectile function following RP by potentially activating pathways leading to apoptosis and hypercontractility of cavernosal smooth muscle fibers such as the RhoA/Rho-associated kinase (ROCK) pathway. Martinez-Salamanca et al showed

Decade in review—sexual dysfunction: Post-RP erectile dysfunction—therapies for the next decade

Erectile dysfunction remains a frequent sequela of radical prostatectomy, owing to injury to the cavernous nerves that innervate the penile erectile tissue. Over the last decade, many strategies have been proposed to minimize the duration of denervation and prevent irreversible structural changes from occurring in the corpora cavernosa.