What role do pharmaceuticals play in the treatment of Peyronie's disease and is there a need for new emerging drugs?

INTRODUCTION: Finding novel medical treatment for Peyronie's disease (PD) has suffered from similar limitations and difficulties as other fibrotic diseases.Areas covered: Underlying fibrosis, there is a vastly complex intertwining of several pathways. Focusing on a single target during antifibrotic drug development has not led to the development of many efficacious drugs, especially in PD. Inhibiting one cog in this large machinery usually leads to activation of compensatory mechanisms.Expert opinion: Novel strategies in drug discovery such as phenotypical drug screening and gene expression profiling technologies could provide a solution for this impasse.

An update on emerging drugs for the treatment of erectile dysfunction.

Introduction: Erectile dysfunction is an extremely frequent and extensively studied condition, currently affecting the lives of tens of millions of men around the globe. The extensive knowledge of its pathophysiology has led to the development of phosphodiesterase 5-inhibitors, which can facilitate sexual intercourse in a large number of patients. However, an ever-increasing number of patients is unresponsive to these drugs due to underlying comorbidities or previous surgery. Different molecular pathways need to be addressed to provide treatment for a larger patient population. Areas covered: In this paper, we will review the underlying molecular pathways, discuss already available treatment options and their limitations and provide an overview of the newest therapeutics in development. Centrally and peripherally acting agents will be discussed separately. Additionally, newest advances in regenerative medicine options will be discussed. Expert opinion: Even though novel drugs have not been tested in a phase III setting, several phase II clinical trial results are eagerly awaited. These newest therapeutics could be applied as monotherapy or combination therapy in the subset of patients unresponsive to traditional treatment options.

Pelvic nerve injury negatively impacts female genital blood flow and induces vaginal fibrosis-implications for human nerve-sparing radical hysterectomy.

OBJECTIVE: This study sought to develop a novel animal model to study the impact of nerve-sparing radical hysterectomy (NSRH) on female genital blood flow. DESIGN: In vivo animal study. POPULATION: Thirty Sprague-Dawley female rats. MATERIALS AND METHODS: Female rats underwent either unilateral pelvic nerve (PN) crush (PNC; n = 9), or crush of both the PNs and all efferent nerves in the pelvic plexus ('clock-nerve crush', CNC; n = 9). Under anaesthesia, we electrically stimulated the crushed PN at 3 and 10 days after crush while monitoring blood pressure and recording clitoral and vaginal blood flows by laser Doppler. Uninjured PNs were stimulated as an internal control. Twelve additional rats were assigned either to bilateral PNC or sham surgery, and genital tissues were processed 10 days after injury for in vitro analysis. MAIN OUTCOME MEASURES: Genital blood flow, nNOS, eNOS, collagen I-III. RESULTS: Stimulation of the crushed PN in both groups subjected to PNC and CNC induced significantly lower peak genital blood flow at 3 and 10 days (P < 0.05) compared to stimulation of the non-crushed control PN. The immunofluorescence and Western blot analyses revealed that all injured rats exhibited more vaginal collagen III and collagen I than rats did that ad undergone sham surgeries (P < 0.05). PCN reduced nNOS expression in both clitoral and vaginal tissue. CONCLUSIONS: Based on our study it may be hypothesised that NSRH might cause reductions of genital blood flow and vaginal fibrosis due to neurapraxia of the pelvic nerve and reductions of nNOS nerve fibres in clitoral and distal vaginal tissue. TWEETABLE ABSTRACT: Pelvic nerve neurapraxia during nerve-sparing radical hysterectomy could lead to sexual arousal dysfunction.

Graft-related complications and biaxial tensiometry following experimental vaginal implantation of flat mesh of variable dimensions.

OBJECTIVE: To compare the occurrence of graft-related complications (GRCs) and biomechanical properties of meshes implanted vaginally and abdominally. DESIGN: In vivo animal experiment. SETTING: Centre for Surgical Technologies, Medical Faculty, KU Leuven, Belgium. POPULATION: Twenty adult parous Texel ewes. METHODS: Sheep were implanted with Gynemesh M, a 28-g/m² polypropylene mesh reinforced with polyglecaprone fibres, under general anaesthesia. Dissection into the rectovaginal septum was performed to accommodate a flat 50 × 50 mm (n = 10) or 35 × 35 mm (n = 10) mesh, which was sutured to the underlying tissues. A 50 × 50 mm mesh was laid over a primarily sutured, full-thickness, 40-mm longitudinal abdominal wall incision. Sacrifice was at 60 days (n = 10) or 90 days (n = 5). MAIN OUTCOME MEASURES: The occurrence of exposure, the degree of contraction and examination of the biomechanical properties of explants with a minimum radius of 32 mm via biaxial tensiometry. RESULTS: Insertion of a 50 × 50 mm mesh led to exposures in 30% (3/10) of cases, and the average contraction rate was 52 ± 14%. In the 35 × 35 mm implants, there were no exposures, and the contraction rate was 25 ± 26.3%. Vaginal explants with no GRCs and of sufficient size had biomechanical properties that were comparable with those of abdominal explants. CONCLUSION: Vaginal mesh insertion is associated with GRCs, such as exposure and contraction. Although other factors probably play a role, this study illustrates that mesh size may also induce these complications. In a vaginal surgery model, clinically occurring GRCs can be reproduced. In addition, biomechanics of uncomplicated vaginal explants are comparable with those measured on abdominal explants.

Adjuvant Radiotherapy After Radical Cystectomy for Patients with High-risk Muscle-invasive Bladder Cancer: Results of a Multicentric Phase II Trial.

BACKGROUND: High-risk muscle-invasive bladder cancer (MIBC) has a poor prognosis. Old trials showed that external beam radiotherapy (EBRT) after radical cystectomy (RC) decreases the incidence of local recurrences but induces severe toxicity. OBJECTIVE: To evaluate the toxicity and local control rate after adjuvant EBRT after RC delivered with volumetric arc radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: This is a multicentric phase 2 trial. From August 2014 till October 2020, we treated 72 high-risk MIBC patients with adjuvant EBRT after RC. High-risk MIBC is defined as ≥pT3-MIBC ± lymphovascular invasion, fewer than ten lymph nodes removed, pathological positive lymph nodes, or positive surgical margins. INTERVENTION: Patients received 50 Gy in 25 fractions with intensity-modulated radiotherapy to the pelvic lymph nodes ± cystectomy bed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome is acute toxicity. We report on local relapse-free rate (LRFR), clinical relapse-free survival (CRFS), overall survival (OS), and bladder cancer-specific survival (BCSS). RESULTS AND LIMITATIONS: The median follow-up is 18 mo. Forty-two patients (61%) developed acute grade 2 gastrointestinal (GI) toxicity. Four patients (6%) had acute grade 3 GI toxicity. One patient had grade 5 diarrhea and vomiting due to obstruction at 1 mo. Two-year probabilities of developing grade ≥3 and ≥2 GI toxicity were 17% and 76%, respectively. Urinary toxicity, assessed in 17 patients with a neobladder, was acceptable with acute grade 2 and 3 urinary toxicity reported in 53% (N = 9) and 18% (N = 3) of the patients, respectively. The 2-yr LRFR is 83% ± 5% and the 2-yr CRFS rate is 43% with a median CRFS time of 12 mo (95% confidence interval: 3-21 mo). Two-year OS and BCSS are 52% ± 7% and 62% ± 7%, respectively. Shortcomings are the nonrandomized study design and limited follow-up. CONCLUSIONS: Adjuvant EBRT after RC can be administered without excessive severe toxicity. PATIENT SUMMARY: In this report, we looked at the incidence of toxicity and local control after adjuvant external beam radiotherapy (EBRT) following radical cystectomy (RC) in high-risk muscle-invasive bladder cancer patients. We found that adjuvant EBRT was feasible and resulted in good local control. We conclude that these data support further enrollment of patients in ongoing trials to evaluate the place of adjuvant EBRT after RC.

Treatment of intraurethral condylomata acuminata with surgery and cidofovir instillations in two immunocompromised patients and review of the literature.

Condylomata acuminata (CA) or anogenital warts are benign proliferative lesions caused by low-risk human papillomaviruses (HPV). Treating CA can be very frustrating for patients and clinicians due to the high recurrence rates. Immunosuppression is associated with larger size of CA that are more frequently resistant to treatment. Surgical approaches tend to be poorly effective in the long-term because of high recurrence rates related to the persistence of HPV-infected cells. In our search to find an agent to treat intraurethral CA with minor or no side effects, we evaluated intraurethral cidofovir in two male patients, who were under immunosuppressing therapy due to organ transplantation and suffered from extensive urethral HPV lesions. Both patients underwent biopsy of the lesions and initial transurethral resection. In our first case, intraurethral cidofovir instillations were started after 2 months due to recurrence after surgical treatment. In our second case, intraurethral cidofovir was administered after surgery because of incomplete resection of extensive lesions. Because of persistent or rapidly recurrent lesions despite intraurethral cidofovir instillations, the first patient needed two additional surgical interventions while the second patient underwent one additional surgical intervention. After surgical intervention, both patients received again adjuvant cidofovir instillations without side effects. Over a period of 56 weeks, both patients received each a total of 28 instillations with cidofovir. Following 3.5 years (patient 1) of the last cidofovir instillation, no recurrences were observed in our first patient. Following 6 months of the last cidofovir instillation (patient 2), two very small recurrent lesions in the most distal part of the urethra were observed in our second patient for which he will receive a cycle of 6 cidofovir instillations in the near future. Intraurethral cidofovir is a safe, easy-to-use, well-tolerated and an effective adjuvant to surgery for extensive intraurethral CA in immunocompromised patients.

Grafts for Peyronie's disease: a comprehensive review.

The difficulty implicit in combining all the characteristics that an ideal patch to treat Peyronie's disease with a lengthening procedure should have, together with the challenges of comparing results from different series, means that the ideal patch has yet to be determined. Our objective with this review was to determine whether any given patch type is preferable to the others based on the evaluation of the results of published studies. A systematic search of the literature was conducted from PubMed until December 2016. Articles reporting basic research, animal research, reviews or meta-analyses and studies in children were eliminated. Series with patients undergoing some kind of other surgical intervention were only included if results were reported separately. Case reports and series of five patients were excluded. Five variables were selected to evaluate the results: number of patients, follow-up period, straightening rate, shortening rate and post-operative ED rate. For this purpose, 69 papers were included for review, and the outcomes of the use of autologous dermis, tunica vaginalis, dura mater, fascia, saphenous vein, tunica albuginea, buccal mucosa, porcine intestinal submucosa, pericardium, TachoSil® and synthetic materials were presented and analysed separately. The different series published are extremely variable and heterogeneous in terms of the number of patients included, patient selection, follow-up periods, and in the measurement and interpretation of the outcomes analysed. Given these facts, it is not possible to draw any definitive conclusion, homogeneous, prospective studies using validated tools are required to determine which the ideal graft is.

[Urethral centralization and pseudo-glans formation after partial penectomy]. / Zentralisierung der Harnröhre und Pseudoglansbildung nach partieller Penektomie.

The management of penile cancer has altered dramatically over the last decade. Confidence to excise lesions safely with smaller margins has led to the adoption of penile-preserving techniques and in turn improved the functional and cosmetic results. Patients undergoing partial penectomy (PP) find that the urethral meatus is located in an abnormal ventral position. In addition, there is a high risk of meatal stenosis. We describe our novel technique that allows the urethral meatus to be centralised after PP and creation of a pseudo-glans and wide meatus and therefore maintain the cosmetic appearance of the penis after split thickness skin grafting. The UCAPP technique allows the restoration of the normal meatal location and creation of a pseudo-glans in case of partial penectomy and therefore can improve the overall cosmetic appearance and reduce the psychological morbidity.

The survival impact of neoadjuvant hormonal therapy before radical prostatectomy for treatment of high-risk prostate cancer.

BACKGROUND: Several randomized controlled trials assessed the outcomes of patients treated with neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP). The majority of them included mainly low and intermediate risk prostate cancer (PCa) without specifically assessing PCa-related death (PCRD). Thus, there is a lack of knowledge regarding a possible effect of NHT on PCRD in the high-risk PCa population. We aimed to analyze the effect of NHT on PCRD in a multicenter high-risk PCa population treated with RP, using a propensity-score adjustment. METHODS: This is a retrospective multi-institutional study including patients with high-risk PCa defined as: clinical stage T3-4, PSA >20 ng ml-1 or biopsy Gleason score 8-10. We compared PCRD between RP and NHT+RP using competing risks analysis. Correction for group differences was performed by propensity-score adjustment. RESULTS: After application of the inclusion/exclusion criteria, 1573 patients remained for analysis; 1170 patients received RP and 403 NHT+RP. Median follow-up was 56 months (interquartile range 29-88). Eighty-six patients died of PCa and 106 of other causes. NHT decreased the risk of PCRD (hazard ratio (HR) 0.5; 95% confidence interval (CI) 0.32-0.80; P=0.0014). An interaction effect between NHT and radiotherapy (RT) was observed (HR 0.3; 95% CI 0.21-0.43; P<0.0008). More specifically, of patients who received adjuvant RT, those who underwent NHT+RP had decreased PCRD rates (2.3% at 5 year) compared to RP (7.5% at 5 year). The retrospective design and lack of specific information about NHT are possible limitations. CONCLUSIONS: In this propensity-score adjusted analysis from a large high-risk PCa population, NHT before surgery significantly decreased PCRD. This effect appeared to be mainly driven by the early addition of RT post-surgery. The specific sequence of NHT+RP and adjuvant RT merits further study in the high-risk PCa population.

Feasibility and safety of conservative surgery for the treatment of spermatic cord leiomyosarcoma.

OBJECTIVES: To assess the feasibility and the safety of conservative surgery to treat spermatic cord leiomyosarcoma. METHODS: Patients undergoing inguinoscrotal exploration in 10 different Urological Centers with diagnosis of leiomyosarcoma were enrolled. Preoperative evaluation included physical examination, Scrotal US, Abdominal CT and Scrotal MRI in selected cases. Patients underwent organ sparing surgery or orchiectomy in case of intraoperative FSE was positive for a local infiltration. Data collected were: age, presence of infiltration, length of the lesion, number of lesions, definitive histological outcome, pre and postoperative testosterone level. Follow up was performed with abdomen CT scan and scrotal US. RESULTS: From January 2007 to December 2013, 23 patients (mean age: 64.7 yrs) were diagnosed with spermatic cord leiomyosarcoma. Each patients underwent scrotal US. 10 patients underwent radical orchiectomy and 13 patients underwent conservative surgery. Mean follow up was 36.5 months. 5 patients (21.7%) developed a recurrent disease, 18 patients (78.3%) had a negative follow up (mean time: 40.8 months). Statistical analysis reveals that there is a significant correlation between number of lesions, length of the lesions and recurrent disease. CONCLUSIONS: Spermatic cord leiomyosarcoma is a rare disease. Conservative surgical treatment of spermatic cord leiomyosarcoma is a feasible therapeutic option for small, single and not infiltrating lesion.

Direct androgen regulation of PDE5 gene or the lack thereof.

Inhibition of phosphodiesterase-5 (PDE5) is a well-known mechanism for the effective treatment of erectile dysfunction (ED). Androgen supplementation has also been prescribed for treating ED. However, it has been widely accepted that androgen can upregulate PDE5 expression, and thus creating a paradox in which a positive regulator of erectile function (androgen) could possibly increase the level of a negative regulator (PDE5). To solve this paradox, we conducted a systematic search of the PubMed and a non-systematic search of the Internet using PDE5, erectile, penis, testosterone and androgen as keywords. The retrieved papers were analyzed for data concerning the expression and regulation of PDE5 by androgens. Human and rat PDE5A gene sequences were retrieved from GenBank and computer-analyzed. The results showed that a putative androgen-response element (ARE) was reported in a study of human PDE5A gene promoter, and this prompted a separate study on whether androgen regulates PDE5 expression. The positive outcome in the latter study has since been cited in 17 review and editorial articles as the underlying mechanism for androgen's therapeutic effects on ED. In addition, five other research studies also reached the same conclusion. On the other hand, two independent studies on the genome-wide searches for androgen-regulated genes did not find PDE5A as a candidate. Sequence analysis conducted in this study also failed to find ARE in rat PDE5A gene. Two independent studies on Leydig cells also failed to find positive regulation of PDE5 expression by androgen. Two other studies found concomitant reduction of cavernous smooth muscle and PDE5 expression in castrated rats. One of these studies also found no effect of androgen on PDE5 expression in cultured cavernous smooth muscle cells. Thus, it appears that reduced PDE5 expression in castrated animals is due to reduced smooth muscle content and that PDE5A gene is not directly regulated by androgens.

Quantification of vitamin B6 vitamers in human cerebrospinal fluid by ultra performance liquid chromatography-tandem mass spectrometry.

Since vitamin B6 is essential for normal functioning of the central nervous system, there is growing need for sensitive analysis of B6 vitamers in cerebrospinal fluid (CSF). This manuscript describes the development and validation of a rapid, sensitive and accurate method for quantification of the vitamin B6 vitamers pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), pyridoxic acid (PA), pyridoxal 5'-phosphate (PLP), pyridoxamine 5'-phosphate (PMP) and pyridoxine 5'-phosphate (PNP) in human CSF. The method is based on ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with a simple sample preparation procedure of protein precipitation using 50 g L(-1) trichloroacetic acid containing stable isotope labeled internal standards: PL-D(3) for PL and PM, PN-(13)C(4) for PN, PA-D(2) for PA and PLP-D(3) for the phosphorylated vitamers. B6 vitamers were separated (Acquity HSS-T3 UPLC column) with a buffer containing acetic acid, heptafluorobutyric acid and acetonitrile. Positive electrospray ionization was used to monitor transitions m/z 168.1→150.1 (PL), 169.1→134.1 (PM), 170.1→134.1 (PN), 184.1→148.1 (PA), 248.1→150.1 (PLP), 249.1→232.1 (PMP) and 250.1→134.1 (PNP). The method was validated at three concentration levels for each B6 vitamer in CSF. Recoveries of the internal standards were between 93% and 96%. Intra- and inter-assay variations were below 20%. Accuracy tests showed deviations from 3% (PN) to 39% (PMP). Limits of quantification were in the range of 0.03-5.37 nM. Poor results were obtained for quantification of PNP. The method was applied to CSF samples of 20 subjects and two patients on pyridoxine supplementation. Using minimal CSF volumes this method is suitable for implementation in a routine diagnostic setting.

Association of lower urinary tract symptoms and erectile dysfunction: pathophysiological aspects and implications for clinical management.

There is strong evidence from multiple epidemological studies that lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are correlated, independent of age or comorbidities as diabetes or hypertension. Although a direct causal relationship is not established yet, four pathophysiological mechanisms can explain the relationship. These include alteration in nitric oxide bioavailability, α1-adrenergic receptor hyperactivity, pelvic atherosclerosis and sex hormones. This association has different clinical implications on the management of both disorders. Men seeking care for one condition should always be screened for complaints of the other condition. Sexual function should be assessed and discussed with the patient when choosing the appropriate management strategy for LUTS, as well as when evaluating the patient's response to treatment. Multiple large clinical trials have shown an improvement in LUTS after phosphodiesterase-5 (PDE5)-inhibitor treatment. PDE5 inhibitors show promise as a future treatment for LUTS, either in conjunction with existing therapies or as a primary treatment. There may be a potential therapeutic role for testosterone in LUTS treatment in cases of testosterone deficiency that needs to be investigated. Much further investigation is required, but it is evident that the association between LUTS and ED is fundamental for future therapies and possible preventative strategies.

The influence of pregnancy on the recurrence of cutaneous malignant melanoma in women.

Objective. The aim of this study was to determine whether pregnancy increases the recurrence risk of cutaneous malignant melanoma (CMM) in women with a history of stage I CMM. Methods. The electronic medical databases of Medline and Embase were explored. All 1084 obtained articles were screened on title and abstract using predetermined inclusion and exclusion criteria. A critical appraisal of relevance and validity was conducted on the remaining full text available articles. Results. Two studies were selected. Both studies revealed no significant difference in disease-free survival between women with stage I CMM and the control population. Conclusion. Pregnancy does not increase the recurrence risk of CMM in women with a history of stage I CMM.

Preclinical evidence for the benefits of penile rehabilitation therapy following nerve-sparing radical prostatectomy.

Erectile dysfunction following radical prostatectomy remains a frequent problem despite the development of nerve-sparing techniques. This erectile dysfunction is believed to be neurogenic, enhanced by hypoxia-induced structural changes which result in additional veno-occlusive dysfunction. Recently, daily use of intracavernous vasoactive substances and oral use of PDE5-inhibitors have been clinically studied for treatment of postprostatectomy erectile dysfunction. Since these studies showed benefits of "penile rehabilitation therapy," these effects have been studied in a preclinical setting. We reviewed experimental literature on erectile tissue preserving and neuroregenerative treatment strategies, and found that preservation of the erectile tissue by the use of intracavernous nitric oxide donors or vasoactive substances, oral PDE5-inhibitors, and hyperbaric oxygen therapy improved erectile function by antifibrotic effects and preservation of smooth muscle. Furthermore, neuroregenerative strategies using neuroimmunophilin ligands, neurotrophins, growth factors, and stem cell therapy show improved erectile function by preservation of NOS-containing nerve fibers.