Multi-Institutional Outcomes of Dorsal Onlay Buccal Mucosal Graft Urethroplasty in Patients With Postprostatectomy, Postradiation Anastomotic Stenosis.

PURPOSE: The treatment of urethral stenosis after a combination of prostatectomy and radiation therapy for prostate cancer is understudied. We evaluate the clinical and patient-related outcomes after dorsal onlay buccal mucosal graft urethroplasty (D-BMGU) in men who underwent prostatectomy and radiation therapy. MATERIALS AND METHODS: A multi-institutional, retrospective review of men with vesicourethral anastomotic stenosis or bulbomembranous urethral stricture disease after radical prostatectomy and radiation therapy from 8 institutions between 2013 to 2021 was performed. The primary outcomes were stenosis recurrence and development of de novo stress urinary incontinence. Secondary outcomes were surgical complications, changes in voiding, and patient-reported satisfaction. RESULTS: Forty-five men were treated with D-BMGU for stenosis following prostatectomy and radiation. There was a total of 7 recurrences. Median follow-up in patients without recurrence was 21 months (IQR 12-24). There were no incidents of de novo incontinence, 28 patients were incontinent pre- and postoperatively, and of the 6 patients managed with suprapubic catheter preoperatively, 4 were continent after repair. Following repair, men had significant improvement in postvoid residual, uroflow, International Prostate Symptom Score, and International Prostate Symptom Score quality-of-life domain. Overall satisfaction was +2 or better in 86.6% of men on the Global Response Assessment. CONCLUSIONS: D-BMGU is a safe, feasible, and effective technique in patients with urethral stenosis after a combination of prostatectomy and radiation therapy. Although our findings suggest this technique may result in lower rates of de novo urinary incontinence compared to conventional urethral transection and excision techniques, head-to-head comparisons are needed.

PKC Inhibition Improves Human Penile Vascular Function and the NO/cGMP Pathway in Diabetic Erectile Dysfunction: The Role of NADPH Oxidase.

Erectile dysfunction (ED) is a frequent and difficult-to-treat condition in diabetic men. Protein kinase C (PKC) is involved in diabetes-related vascular and cavernosal alterations. We aimed to evaluate the role of PKC in endothelial dysfunction and NO/cGMP impairment associated with diabetic ED in the human corpus cavernosum (CC) and penile resistance arteries (PRAs) and the potential mechanisms involved. Functional responses were determined in the CC and PRAs in patients with non-diabetic ED and diabetic ED undergoing penile prosthesis insertion. PKC activator 12,13-phorbol-dibutyrate (PDBu) impaired endothelial relaxations and cGMP generation in response to acetylcholine in the CC from non-diabetic ED. PDBu also impaired responses to a PDE5 inhibitor, sildenafil, in non-diabetic ED patients. Conversely, a PKC inhibitor, GF109203X, improved endothelial, neurogenic, and PDE5-inhibitor-induced relaxations and cGMP generation only in the CC in diabetic ED patients. Endothelial and PDE5-inhibitor-induced vasodilations of PRAs were potentiated only in diabetes. Improvements in endothelial function in diabetes were also achieved with a specific inhibitor of the PKCß2 isoform or an NADPH-oxidase inhibitor, apocynin, which prevented PDBu-induced impairment in non-diabetic patients. PKC inhibition counteracted NO/cGMP impairment and endothelial dysfunction in diabetes-related ED, potentially improving response to PDE5 inhibition.

The Expression of Alamandine Receptor MrgD in Clear Cell Renal Cell Carcinoma Is Associated with a Worse Prognosis and Unfavorable Response to Antiangiogenic Therapy.

Renal cell carcinoma (RCC) ranks among the most prevalent malignancies in Western countries, marked by its notable heterogeneity, which contributes to an unpredictable clinical trajectory. The insufficiency of dependable biomarkers adds complexity to assessing this tumor progression. Imbalances of several components of the intrarenal renin-angiotensin system (iRAS) significantly impact patient prognoses and responses to first-line immunotherapies. In this study, we analyzed the immunohistochemical expression of the Mas-related G-protein-coupled receptor D (MrgD), which recognizes the novel RAS peptide alamandine (ALA), in a series of 87 clear cell renal cell (CCRCCs), 19 papillary (PRCC), 7 chromophobe (ChRCC) renal cell carcinomas, and 11 renal oncocytomas (RO). MrgD was expressed in all the renal tumor subtypes, with a higher mean staining intensity in the PRCCs, ChRCCs, and ROs. A high expression of MrgD at the tumor center and at the infiltrative front of CCRCC tissues was significantly associated with a high histological grade, large tumor diameter, local invasion, and locoregional node and distant metastasis. Patients with worse 5-year cancer-specific survival and a poorer response to antiangiogenic tyrosine-kinase inhibitors (TKIs) showed higher MrgD expression at the center of their primary tumors. These findings suggest a possible role of MrgD in renal carcinogenetic processes. Further studies are necessary to unveil its potential as a novel biomarker for CCRCC prognosis and response to frontline therapies.

Identification of miRNAs and Their Target Genes Associated with Sunitinib Resistance in Clear Cell Renal Cell Carcinoma Patients.

Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20-30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (miR-223, miR-155, miR-200b, miR-130b) and target genes (FLT1, PRDM1 and SAV1) in 35 ccRCC patients. High levels of miR-223 and low levels of FLT1, SAV1 and PRDM1 were associated with worse overall survival (OS), and combined miR-223 + SAV1 levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (FLT1) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (PRDM1) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect miR-155 we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation.

Upregulation of Orai Channels Contributes to Aging-Related Vascular Alterations in Rat Coronary Arteries.

Vascular territories display heterogeneous sensitivity to the impacts of aging. The relevance of the STIM/Orai system to vascular function depends on the vascular bed. We aimed to evaluate the contribution of the STIM/Orai system to aging-related vascular dysfunction in rat coronary circulation. Vascular function was evaluated according to myography in coronary arteries from young (three-month-old) and older (twenty-month-old) rats. The effects of aging and STIM/Orai inhibition on the contraction and relaxation of the coronary arteries and on the protein expression of STIM-1, Orai1, and Orai3 in these vessels were determined. Aging-related hypercontractility to serotonin and endothelin-1 in arteries from male rats was reversed by STIM/Orai inhibition with YM-58483 or by specifically blocking the Orai1 channel with Synta66. The inhibitory effects of Synta66 on coronary vasoconstriction were also observed in older female rats. YM-58483 relaxed serotonin- but not KCl-contracted arteries from males. STIM/Orai inhibition improved defective endothelial vasodilations in aged arteries, even in the presence of NO synthase and cyclooxygenase inhibitors, but not in KCl-contracted segments. YM-58483 significantly enhanced relaxations to calcium-activated potassium channel stimulation in aged vessels. Increased protein expression of Orai1 and Orai3 was detected in arterial homogenates and sections from older rats. Upregulation of the Orai channel contributes to aging-related coronary dysfunction, revealing a potential target in reducing CVD risk.

Claudin-3 Loss of Expression Is a Prognostic Marker in Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) development is the foremost concern after treatment of patients with high risk with locally advanced or metastatic prostate cancer. Androgen receptor (AR) is the main driver of CRPC development, through its interaction with epigenetic modifier genes, placing epigenetics modifications in the forefront of CRPC development. Comparing the DNA methylation and expression profile of androgen-sensitive and -refractory prostate cancer cells, we describe the epigenetic silencing of claudin-3 (CLDN3) in AR positive cells resistant to androgen deprivation (LNCaP-abl). CLDN3 silencing was associated with DNA methylation, loss of histone acetylation and H3K27 methylation, and was re-expressed by the combined treatment with the epigenetic modulators Aza and SAHA. From a functional point of view, CLDN3 loss was associated with increased cellular invasion. Immunohistochemical analysis showed decreased CLDN3 expression in samples from CRPC patients. Interestingly, CLDN3 expression was significantly decreased in samples from patients with high total Gleason score (≥8) and locally advanced tumors. Finally, CLDN3 loss of expression was associated with worse disease-free survival and time to clinical progression. In conclusion, our findings strongly indicate that epigenetic silencing of CLDN3 is a common event in CRPC that could be useful as a molecular marker for the prognosis of prostate cancer patients and to discriminate aggressive from indolent prostate tumors.

A buccal mucosal graft subcoronal resurfacing technique to treat recurrent penile adhesions: the buccal belt.

OBJECTIVE: To outline our step-by-step surgical technique using a subcoronal buccal mucosal graft (BMG) resurfacing technique for the treatment of recurrent penile adhesions. METHODS: To perform the 'buccal belt' procedure a subcoronal circumferential segment of diseased skin was excised. An appropriately sized BMG was circumferentially secured subcoronally with a proximal and distal anastomosis to the edges of the wound. Quilting stitches were also placed to allow proper graft fixation. A petroleum jelly bolster was secured as a tie-over dressing. Patients were discharged with a Foley catheter and the bolster dressing in place. The bolster and Foley catheter were removed 7 days postoperatively. The patients were then seen for follow-up at 4- to 6-month intervals. A retrospective, international multi-institutional review was conducted to include all patients who underwent this procedure. Surgical complications, evidence of recurrence, and patient-reported outcome measures including visual analogue scale (VAS) and global response assessment (GRA) questionnaires were reviewed. RESULTS: Thirty-one men underwent the procedure across six institutions between March 2014 and September 2020. The mean (range) surgical time was 59 (25-95) min. At the mean (range) follow-up of 27 (4-79) months all patients reported resolution of presenting symptoms and no recurrence of adhesions. The mean VAS score was 8.9 and 9.0 for aesthetics and functional outcomes, respectively. On GRA, overall improvement was reported by all patients (61%, +3; 25%, +2; 14%, +1). CONCLUSION: There are limited options for the treatment of recurrent penile adhesions. A subcoronal BMG resurfacing is feasible, with no recurrence and overall high satisfaction seen in an initial patient cohort.

Cardiometabolic Diseases and Female Sexual Dysfunction: Animal Studies.

BACKGROUND: The association between erectile dysfunction and cardiometabolic disease is well characterized; men are often diagnosed with cardiovascular disease 2-5 years following the incidence of erectile dysfunction. There is evidence that this relationship may also exist for cardiometabolic diseases and female sexual dysfunction (FSD) - particularly sexual arousal disorders. AIM: To provide a summary of the preclinical literature related to the evidence of FSD in animal models of cardiometabolic diseases and indicate where further research is needed. METHODS: A detailed Medline search of peer-reviewed publications was performed on the associations between animal models of cardiometabolic diseases, FSD and underlying mechanisms. OUTCOMES: A summary of the preclinical evidence of FSD in animal models of cardiometabolic diseases. RESULTS: Common methods for assessing female sexual arousal and physiology in animal models include: 1) behavioral assessments (apomorphine-induced genital vasocongestive arousal; hormone-dependent lordosis), 2) nerve-mediated vaginal and clitoral blood flow, 3) pudendal artery, vaginal and clitoral smooth muscle physiology (vasoreactivity and molecular biology), 4) morphology of genital tissues. Twenty-eight studies examined female animal models of atherosclerosis, hypertension, diabetes (type 1 and 2) and obesity. They showed functional alterations, including decreased lordosis, lubrication, or vaginal and clitoral blood flow, and structural impairments, such as increased clitoral and vaginal fibrosis. Several possible mechanisms have been described including increased TGF-ß, renin angiotensin system and endothelin/rho-kinase signaling, increased reactive oxygen species, and decreased nitric oxide/cGMP signaling. CLINICAL TRANSLATION: In line with existing clinical studies, preclinical evidence supports that cardiometabolic diseases alter female genital tissue's function and structure leading to impaired sexual arousal. STRENGTHS AND LIMITATIONS: This masterclass paper gives an overview of the preclinical research assessing FSD in cardiometabolic disease. Limitations include the small number of studies that have assessed sexual function and arousal in female cardiometabolic animal models. CONCLUSION: Preclinical evidence exists showing cardiometabolic diseases alter the structure and function of female genital tissues. However, similar to clinical studies, there are few studies to draw from, particularly in models of type 2 diabetes, obesity and metabolic syndrome. More studies are required using optimized animal models and methodology to confirm the mechanisms underlying cardiometabolic disease-induced FSD. Angulo J, Hannan JL. Cardiometabolic Diseases and Female Sexual Dysfunction: Animal Studies. J Sex Med 2022;19:408-420.

STIM/Orai Inhibition as a Strategy for Alleviating Diabetic Erectile Dysfunction Through Modulation of Rat and Human Penile Tissue Contractility and in vivo Potentiation of Erectile Responses.

BACKGROUND: Stromal interaction molecule (STIM)/Orai calcium entry system appears to have a role in erectile dysfunction (ED) pathophysiology but its specific contribution to diabetic ED was not elucidated. AIM: To evaluate STIM/Orai inhibition on functional alterations associated with diabetic ED in rat and human penile tissues and on in vivo erectile responses in diabetic rats. METHODS: Rat corpus cavernosum (RCC) strips from nondiabetic (No DM) and streptozotocin-induced diabetic (DM) rats and human penile resistance arteries (HPRA) and corpus cavernosum (HCC) from ED patients undergoing penile prosthesis insertion were functionally evaluated in organ chambers and wire myographs. Erectile function in vivo in rats was assessed by intracavernosal pressure (ICP) responses to cavernous nerve electrical stimulation (CNES). Expression of STIM/Orai elements in HCC was determined by immunofluorescence and immunoblot. MAIN OUTCOME MEASURES: Functional responses in RCC, HCC and HPRA and STIM/Orai protein expression in HCC. In vivo erectile responses to CNES. RESULTS: Inhibition of Orai channels with YM-58483 (20 µM) significantly reduced adrenergic contractions in RCC but more effectively in DM. Thromboxane-induced and neurogenic contractions were reduced by STIM/Orai inhibition while defective endothelial, neurogenic and PDE5 inhibitor-induced relaxations were enhanced by YM-58483 (10 µM) in RCC from DM rats. In vivo, YM-58483 caused erections and attenuated diabetes-related impairment of erectile responses. YM-58483 potentiated the effects of PDE5 inhibition. In human tissues, STIM/Orai inhibition depressed adrenergic and thromboxane-induced contractions in ED patients more effectively in those with type 2 diabetes. Diabetes was associated with increased expression of Orai1 and Orai3 in ED patients. CLINICAL TRANSLATION: Targeting STIM/Orai to alleviate diabetes-related functional alterations of penile vascular tissue could improve erectile function and potentiate therapeutic effects of PDE5 inhibitors in diabetic ED. STRENGTHS AND LIMITATIONS: Improving effects of STIM/Orai inhibition on diabetes-related functional impairment was evidenced in vitro and in vivo in an animal model and validated in human tissues from ED patients. Functional findings were complemented with expression results. Main limitation was low numbers of human experiments due to limited human tissue availability. CONCLUSIONS: STIM/Orai inhibition alleviated alterations of functional responses in vitro and improved erectile responses in vivo in diabetic rats, potentiating the effects of PDE5 inhibition. STIM/Orai inhibition was validated as a target to modulate functional alterations of human penile vascular tissue in diabetic ED where Orai1 and Orai3 channels were upregulated. STIM/Orai inhibition could be a potential therapeutic strategy to overcome poor response to conventional ED therapy in diabetic patients. Sevilleja-Ortiz A, El Assar M, García-Gómez B, et al. STIM/Orai Inhibition as a Strategy for Alleviating Diabetic Erectile Dysfunction Through Modulation of Rat and Human Penile Tissue Contractility and in vivo Potentiation of Erectile Responses. J Sex Med 2022;19:1733-1749.

Influence of ATOMS implant on the voiding phase of patients with post-prostatectomy urinary incontinence.

OBJECTIVE: To assess changes in voiding phase, especially urethral resistance after post-prostatectomy urinary incontinence (PPI) treatment with the Adjustable TransObturator Male System (ATOMS). MATERIAL AND METHODS: A longitudinal prospective study was performed on 45 men treated with ATOMS for PPI, with the intention to evaluate the changes produced by the implant on the voiding phase. Patients with preoperative urodynamic study were offered postoperative urodynamic evaluation, and both studies were compared. The following urodynamic date were evaluated: maximum voiding detrusor pressure, detrusor pressure at maximum flow rate, maximum flow rate (Qmax), voiding volume, post-void residue, bladder outlet obstruction index (BOOI), urethral resistance factor (URA), and bladder contractility index (BCI). The statistical analysis used were the mean comparison test for dependent groups (Student's t test) for parametric variables and the Wilcoxon test for non-parametric variables. The signification level was set at 95% bilateral. RESULTS: A total of 37 patients (82.2%) used zero pads/day at the time of urodynamic postoperative evaluation and pad-test evolved from 592 ± 289 ml baseline to 25 ± 40 ml (p = 0.0001). Significant differences were observed in Qmax (15 ± 8.3 before and 11 ± 8.3 after surgery; p = 0.008), voiding volume (282 ± 130.7 before and 184 ± 99.92 after surgery). BOOI (-12 ± 23.9 before and -2 ± 21.4 after surgery; p = 0.025) and BCI (93 ± 46.4 before and 76 ± 46.0 after surgery; p = 0.044). In no case did we observe postoperative bladder outlet obstruction, according to URA parameter below 29 cm H2 O in all cases. There was not a significant variation either in post-void urinary residual volume (15 ± 47.4 before and 14 ± 24.2 after surgery, p = 0.867). CONCLUSIONS: The ATOMS implant induces a decrease of Qmax, voided volume, and bladder contractility and an increase of BOOI. However, our findings suggest that ATOMS device does not cause bladder outlet obstruction.

Effect of LHRH analogs on lower urinary tract symptoms associated with advanced prostate cancer in real clinical practice: ANALUTS study.

AIMS: To estimate the prevalence of lower urinary tract symptoms (LUTS) in patients with prostate cancer scheduled to receive LHRH analogs, and to assess the effectiveness of LHRH analogs on LUTS in patients presenting moderate/severe symptoms. METHODS: Prospective, noninterventional, multicenter study conducted at 28 centers in Spain and Portugal. LUTS were evaluated using the International Prostate Symptom Score (IPSS) at baseline, 24 and 48 weeks after initiation of treatment. Subanalyses were performed according to age and concomitant treatment (radiotherapy, alpha-blockers, and antiandrogens). RESULTS: A total of 354 patients were treated with LHRH analogs for 48 weeks. The percentage of patients with moderate/severe LUTS (IPSS > 7) decreased from 60.2% (n = 213/354) at baseline to 52.8% (n = 187/354) at Week 48. Among patients with moderate/severe LUTS at baseline: 73.7% (n = 157/213) still had moderate/severe LUTS at Week 48; percentage reductions of patients with LUTS at Week 48 were statistically significant (p < 0.05) overall and by age or concomitant treatment, except for alpha-blockers (84.2% patients receiving them still had moderate/severe LUTS at Week 48). All IPSS items, including quality of life for urinary symptoms, improved throughout the study. The only predictor of response to treatment with LHRH analogs that improved IPSS by 3 points after 48 weeks was baseline testosterone levels. Lower baseline testosterone levels were associated with greater improvement in IPSS after treatment with LHRH analogs (odds ratio 0.998, 95% confidence interval 0.996-1.000, p = 0.0277). CONCLUSION: LHRH analogs have a positive effect in patients with locally advanced or metastatic prostate cancer presenting moderate/severe LUTS regardless of age or concomitant treatment received (radiotherapy, antiandrogens, or alpha-blockers).

Clear Cell Renal Cell Carcinomas with Aggressive Behavior Display Low Intratumor Heterogeneity at the Histological Level.

PURPOSE OF REVIEW: Intratumor heterogeneity (ITH) is an inherent characteristic of most tumors and its detection remains a key task for pathologists. However, the clinical significance of the degree of development of this feature is still poorly understood. RECENT FINDINGS: A series of 28 clear cell renal cell carcinomas (CCRCC) have been exhaustively analyzed with two different sampling protocols [multisite tumor sampling (MSTS) and total sampling] to evaluate to what point the level (low vs. high) of histological ITH detected in routine practice influences tumor behavior and patients' survival. All CCRCC (n = 14) pursuing an aggressive clinical course presented low levels of ITH. A significant worse survival was detected in CCRCC with low ITH (p < 0.001). The simple quantification of the level of ITH using extensive sampling protocol may be of help in predicting tumor evolution, since all CCRCC with aggressive behavior demonstrated low levels of histological ITH.

Multi-institutional review of non-hypospadiac penile urethral stricture management and outcomes.

OBJECTIVES: Penile urethral stricture disease not associated with hypospadias is rare, and there is a wide range of commonly used surgical repair techniques for this disease. We sought to compile a multi-institutional database of patients who had surgical correction of strictures in the penile urethra not limited to the meatus, and who had no history of hypospadias, for analysis using the Trauma and Urologic Reconstructive Network of Surgeons length, urethral segment and etiology classification system. METHODS: A retrospective database from 13 institutions was compiled of patients who had undergone surgical correction of Trauma and Urologic Reconstructive Network of Surgeons length, urethral segment and etiology urethral stricture segments S2b/S2c and excluding E5, with a minimum follow-up time of 4 months. Failure was defined as cystoscopically confirmed recurrence of a stricture measuring less than 16-Fr. RESULTS: We analyzed 222 patients with a median age of 57 years and a follow-up of 49 months. The overall surgical success rate was 80.2%. On multivariate analysis, the two variables identified that were predictive of surgical success were stricture length ≤2 cm as well as use of a buccal mucosa graft as compared to use of a fasciocutaneous flap, which had success rates of 83% and 52%, respectively (P = 0.0004). No statistically significant differences were found based on incisional approach or surgical technique, nor were outcomes different based on etiology or preoperative patient demographics. CONCLUSIONS: Surgical repair of penile urethral strictures of non-hypospadiac origin have a favorable overall success rate, at 80.2%. Regardless of incisional approach or surgical technique, all operations appear to have similar outcomes other than repairs using fasciocutaneous flap, which were statistically less successful than those using buccal mucosa graft.

Effect of Physical Activity/Exercise on Oxidative Stress and Inflammation in Muscle and Vascular Aging.

Functional status is considered the main determinant of healthy aging. Impairment in skeletal muscle and the cardiovascular system, two interrelated systems, results in compromised functional status in aging. Increased oxidative stress and inflammation in older subjects constitute the background for skeletal muscle and cardiovascular system alterations. Aged skeletal muscle mass and strength impairment is related to anabolic resistance, mitochondrial dysfunction, increased oxidative stress and inflammation as well as a reduced antioxidant response and myokine profile. Arterial stiffness and endothelial function stand out as the main cardiovascular alterations related to aging, where increased systemic and vascular oxidative stress and inflammation play a key role. Physical activity and exercise training arise as modifiable determinants of functional outcomes in older persons. Exercise enhances antioxidant response, decreases age-related oxidative stress and pro-inflammatory signals, and promotes the activation of anabolic and mitochondrial biogenesis pathways in skeletal muscle. Additionally, exercise improves endothelial function and arterial stiffness by reducing inflammatory and oxidative damage signaling in vascular tissue together with an increase in antioxidant enzymes and nitric oxide availability, globally promoting functional performance and healthy aging. This review focuses on the role of oxidative stress and inflammation in aged musculoskeletal and vascular systems and how physical activity/exercise influences functional status in the elderly.

Systematic review and meta-analysis comparing Adjustable Transobturator Male System (ATOMS) and male Readjustment Mechanical External (REMEEX) system for post-prostatectomy incontinence.

OBJECTIVE: To assess the efficacy and safety of Adjustable Transobturator Male System (ATOMS) compared to male Readjustment Mechanical External (REMEEX) system for post-prostatectomy incontinence (PPI). MATERIAL AND METHODS: A systematic review and meta-analysis on adjustable device ATOMS compared to male REMEEX is presented. Studies on female or neurogenic incontinence were excluded. Primary objectives were evaluation of dryness (the proportion of patients with no-pad or one safety pad/day after device adjustment) and improvement between devices. Secondary objectives were complications and explant rate. They were estimated using a random-effect model. Statistical heterogeneity among studies was assessed using Cochran's Q test, Higgins's I2 statistics and tau2. RESULTS: Combined data of 29 observational studies with 1919 patients showed an equivalent proportion of patients treated with radical prostatectomy (p = .125) and previous radiation (p = .126). Dryness rate was 69.3% for ATOMS and 53.4% for male REEMEX (p = .008). Improvement rate was 90.8% for ATOMS and 80.2% for REMEEX (p = .007). Complication rate was 18.9% for ATOMS and 35.8% for REMEEX (p = .096) and explant rate was 5.5% for ATOMS and 13.9% for REMEEX (p = .027). Significant heterogeneity was evidenced, due to absence of randomized studies, variable incontinence severity baseline, difficulties for a common reporting of complications and difference in the follow-up. Differences observed between devices remained statistically significant when only studies with silicone-covered scrotal port (SSP) ATOMS and male REMEEX system II were considered. CONCLUSIONS: Despite the absence of direct comparison and the limitations observed ATOMS appears more effective than male REMEEX to treat PPI, and with less explant rate as reported in the literature.

A multi-institutional critical assessment of dorsal onlay urethroplasty for post-radiation urethral stenosis.

PURPOSE: To critically evaluate a multi-institutional patient cohort undergoing Dorsal-Onlay Buccal Mucosal Graft Urethroplasty (D-BMGU) for recurrent post-radiation posterior urethral stenosis. METHODS: Retrospective multi-institutional review of patients with posterior urethral stenosis from 10 institutions between 2010-2019 was performed. Patients with at least 1-year follow-up were assessed. Patient demographics, stenosis characteristics, peri-operative outcomes, and post-operative clinical and patient-reported outcomes were analyzed. The primary outcomes were stenosis recurrence and de-novo stress urinary incontinence (SUI). Secondary outcomes were changes in voiding, sexual function, and patient-reported satisfaction. RESULTS: Seventy-nine men with post-radiation urethral stenosis treated with D-BMGU met inclusion criteria. Median age and stenosis length were 72 years, (IQR 66-75), and 3.0 cm (IQR 2.5-4 cm), respectively. Radiation modalities included: 36 (45.6%) external beam radiotherapy (EBRT), 13 (16.5%) brachytherapy (BT), 10 (12.7%) combination EBRT/BT, and 20 (25.3%) EBRT/radical prostatectomy. At a median follow-up of 21 months (IQR 13-40), 14 patients (17.7%) had stenosis recurrence. Among 37 preoperatively-continent patients, 3 men (8.1%) developed de-novo SUI following dorsal onlay urethroplasty. Of 29 patients with preoperative SUI all but one remained incontinent post-operatively (96.6%). Following repair, patients experienced significant improvement in PVR (92.5 to 26 cc, p = 0.001) and Uroflow (4.6 to 15.9 cc/s, p = 0.001), and high overall satisfaction, with 91.9% reporting a GRA of + 2 or better). CONCLUSION: Dorsal onlay buccal mucosa graft urethroplasty is a safe and feasible technique in patients with post-radiation posterior urethral stenosis. This non-transecting approach may confer low rates of de-novo SUI. Further research is needed to compare this technique with excisional urethroplasty.

Artificial urinary sphincter or a second adjustable transobturator male system offer equivalent outcomes in patients whom required revision on the initial ATOMS device: An international multi-institutional experience.

AIM: To evaluate treatment options after surgical revision of adjustable transobturator male system (ATOMS) and the results of further incontinence implantation. MATERIALS AND METHODS: A retrospective multicenter study evaluating patients with surgical revision of ATOMS in academic institutions. Causes and factors affecting revision-free interval were studied and also the frequency of device explant and placement of second ATOMS or artificial urinary sphincter (AUS) at surgeon discretion. Operative results, complications (Clavien-Dindo), and efficacy (postoperative pad-test, pad-count, patient satisfaction, and patient global impression of improvement [PGI-I scale]) of each treatment option were compared. RESULTS: Seventy-eight out of 902 patients (8.65%) with ATOMS underwent surgical revision at 4.1 ± 2.4 years mean follow-up and 75 (8.3%) were explanted. The main causes for revision included persistence of incontinence (35.9%) and scrotal port erosion (34.6%). Independent risk factors of the shortened revision-free interval were previous anti-incontinence surgery (HR, 1.83; 95% CI, 1.06-3.16; p = 0.007) and port erosion (HR, 1.83; 95% CI, 1.06-3.16; p = 0.0027). Fifty-eight (6.4%) received a second implant: 31 repeated ATOMS and 27 AUS. Operative time was longer for AUS (p = .003). The visual analog scale of pain at hospital discharge (p = 0.837) and postoperative complications (p = 0.154) were equivalent. The predominant cuff size for AUS was 4.5 cm (59.3%). Mean follow-up after the second implant was 29.1 ± 25.8 months. Postoperative efficacy of secondary treatment results favored ATOMS based on pad-test (p = 0.016), pad-count (p = 0.029), patient satisfaction (p = 0.04), and PGI-I (p = 0.025). CONCLUSIONS: ATOMS surgical revision due to different reasons generally leads to device explant. Rescue treatment is possible with ATOMS or AUS. No difference in postoperative complications was detected between secondary devices, but efficacy favors repeating ATOMS implantation.

Urorectal fistula repair using different approaches: operative results and quality of life issues.

PURPOSE: To evaluate efficacy of urorectal fistula (URF) repair using different approaches and the clinical factor determinant of success, and also the morbidity associated to the procedure and health-related quality of life (HRQoL) in male survivors of pelvic malignancies. MATERIAL AND METHODS: Retrospective evaluation of 39 patients with URF primarily intervened in three institutions using different surgical approaches. Success was defined as effective fistula closure. Variables evaluated included demographics, previous treatments, surgical approach, ancillary surgeries, complications and HRQoL by using a standardized non-validated specific questionnaire. Median follow-up from surgery to interview was 55 months (interquartile range 49, range 4-112). Factors determinant of success were investigated using logistic regression. Safety of the procedure was evaluated by Clavien-Dindo scale. Deterioration of continence and erectile function and other HRQoL issues were evaluated. RESULTS: Prostate cancer treatment was the predominant etiology. The success rate for fistula repair was 89.5%. The surgical approach was not related to failed repair (p=0.35) or complications (p=0.29). Factors associated with failure were complications (p=0.025), radiotherapy (p=0.03), fistula location (p=0.04) and fistula size (p=0.007). Multivariate analysis revealed fistula size was the only independent determinant of failure (OR 6.904, 1.01-47.75). Complications occurred in 46.2% and severe complications in 12.8%. The mortality related to the procedure was 2.6%. Urinary incontinence was present before repair in 26.3% and erectile dysfunction in 89.5%. Fistula repair caused de novo urinary incontinence in 7.9% and deterioration of erectile status in 44.7%. Globally 79% were satisfied after repair and only 7.9% rated HRQoL as unhappy. Trans-sphincteric approach was related to less deterioration of erectile function (p=0.003), and higher perceived satisfaction in QoL (p=0.04). CONCLUSIONS: The surgical approach elected to correct URF is not determinant of success nor of complications. Fistula size appears as independent determinant for failure. Trans-sphincteric approach could be advantageous over other procedures regarding HRQoL issues.

Enhanced Contribution of Orai Channels to Contractility of Human Penile Smooth Muscle in Erectile Dysfunction.

BACKGROUND: Store-operated calcium entry and its key players, stromal interaction molecule (STIM) and Orai calcium channels, have been proposed as emergent therapeutic targets in cardiovascular pathophysiology. We hypothesize alteration of STIM/Orai signaling in erectile dysfunction (ED). AIM: To evaluate the contribution of STIM/Orai to human penile tissue contraction and to analyze the influence of ED on STIM/Orai signaling at functional and expression levels in human penile vascular tissues. METHODS: Human penile resistance arteries (HPRA) and human corpus cavernosum (HCC) were dissected from cavernosal specimens from 30 organ donors without history of ED (No ED) and from 48 patients with ED undergoing penile prosthesis insertion and functionally evaluated in wire myographs and organ chambers, respectively. Expression of STIM-1, Orai1, and Orai3 in HCC was localized and quantified by immunofluorescence. MAIN OUTCOME MEASURES: The main outcome measures are functional responses in HCC and HPRA and STIM/Orai channel protein expression in human cavernosal tissue. RESULTS: Inhibition of Orai channels with YM-58483 (20 µM) significantly reduced norepinephrine-induced contractions in both HCC and HPRA from either No ED or ED subjects, but the effects were more marked in ED (-20.1 ± 5.9% vs -45.5 ± 13.2% and -15.9 ± 4.0% vs -31.4 ± 6.9% reduction in Emax to norepinephrine in HCC and HPRA, respectively). Thromboxane-induced contractions were reduced and neurogenic contractile and relaxant responses modulated by Orai inhibition in penile tissues from patients with ED. In fact, addition of YM-58483 concentration dependently relaxed precontracted HPRA and HCC. These relaxations were significantly more pronounced in tissues from patients with ED (EC50 7.5 vs 1.3 µM and 10.5 vs 1.3 µM, for HCC and HPRA, respectively). All HCC specimens displayed expression of STIM-1, Orai1, and Orai3. Significantly increased expression of Orai1 and Orai3 but not STIM-1 was observed in patients with ED. CLINICAL TRANSLATION: Inhibition of enhanced Orai activity in human penile vascular tissue could facilitate erectile responses, alleviating ED. STRENGTHS AND LIMITATIONS: Enhanced STIM/Orai activity contribution to penile smooth muscle tone in ED is demonstrated at functional and structural levels in human tissues from a representative sample of patients with ED and in comparison with healthy tissue. We cannot differentiate the specific contribution of risk factors associated with ED to hyperactivity of the Orai system. CONCLUSIONS: Orai channels significantly contribute to human penile smooth muscle contraction. Orai contribution to penile smooth muscle tone is functionally enhanced in ED accompanied by increased expression of Orai channels in cavernosal tissue. Orai inhibition could be a potential therapeutic strategy to reduce penile smooth muscle contraction in ED. Sevilleja-Ortiz A, El Assar M, García-Rojo E, et al. Enhanced Contribution of Orai Channels to Contractility of Human Penile Smooth Muscle in Erectile Dysfunction. J Sex Med 2020;17:881-891.

Complications of the urinary incontinence system ATOMS: description of risk factors and how to prevent these pitfalls.

BACKGROUND: We report on our multicentre evaluation of the occurrence and management of complications with the ATOMS device (A.M.I., Austria). PATIENTS AND METHODS: Between 10/09 and 09/18, a total of 187 patients with persistent postoperative stress urinary incontinence received an ATOMS device in Madrid (n = 101) or Halle (n = 86). This prospective evaluation was carried out consecutively. In addition to complications, patient age, BMI, comorbidities and previous treatments for prostate cancer and urinary incontinence were examined. Statistical analysis was performed with GraphPad Prism 7® (GraphPad Software, Inc., La Jolla, USA); p < 0.05 was considered significant. RESULTS: The average age of the overall population was 69.4 years, with a mean CCI of 4.3. In total, 18.2% of the patients had diabetes mellitus, 21.9% were irradiated, and 14.1% and 22.9% underwent previous surgery for urinary incontinence and urethral stricture, respectively. The overall success rate of the device was 80.2%. A total of 51 postoperative complications (51/187, 27.3%) were observed, with 18 grade I (9.6%), 1 grade II (0.5%), 3 grade IIIa (1.6%) and 29 grade IIIb (15.5%) complications. The most serious postoperative complications were primary wound infection (8/187, 4.3%) and long-term cutaneous erosion with subsequent infection (15/187, 8.02%). The main risk factors for complications were previous radiotherapy (p = 0.003) and surgery for urethral stricture (p = 0.017). No other parameters were significant in bivariate analysis (p > 0.05). CONCLUSION: The most severe complications of ATOMS implantation were primary wound infection and cutaneous erosion, especially in the presence of previous radiotherapy. Particular focus on performing hygienic and accurate implantation techniques is recommended.