Antifibrotic synergy between phosphodiesterase type 5 inhibitors and selective oestrogen receptor modulators in Peyronie’s disease models

Background: Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option. Objective: To identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD. Design, setting, and participants: We have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD. Results and limitations: The new assay was able to detect transforming growth factor-β1–induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy. Conclusions: This is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models. Patient summary: This report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase

Fate of mesoangioblasts in a vaginal birth injury model: influence of the route of administration

Currently cell therapy is considered as an experimental strategy to assist the healing process following simulated vaginal birth injury in rats, boosting the functional and morphologic recovery of pelvic floor muscles and nerves. However, the optimal administration route and dose still need to be determined. Mesangioblasts theoretically have the advantage that they can differentiate in skeletal and smooth muscle. We investigated the fate of mesoangioblasts transduced with luciferase and green fluorescent protein reporter genes (rMABseGFP/fLUC) using bioluminescence, immunofluorescence and RT-PCR in rats undergoing simulated birth injury. rMABseGFP/fLUC were injected locally, intravenously and intra-arterially (common iliacs and aorta). Intra-arterial delivery resulted in the highest amount of rMABseGFP/fLUC in the pelvic organs region and in a more homogeneous distribution over all relevant pelvic organs. Sham controls showed that the presence of the injury is important for recruitment of intra-arterially injected rMABseGFP/fLUC. Injection through the aorta or bilaterally in the common iliac arteries resulted in comparable numbers of rMABseGFP/fLUC in the pelvic organs, yet aortic injection was faster and gave less complications

The use of local therapy in preventing urethral strictures: A systematic review

BACKGROUND: Urethral stricture disease is a common problem amongst men in Western countries often leading to a decreased quality of life. Current endoscopic treatment procedure shows an unsatisfying stricture recurrence rate which could be improved by addition of local therapies. OBJECTIVES: To provide an overview of both preclinical and clinical studies in order to investigate current level of evidence on the addition of local therapy to improve urethral stricture recurrence rates after endoscopic procedures. METHODS: We performed a literature search in December 2020 and August 2021 using Cochrane, Embase, PubMed, Scopus and Web of Science and identified articles through combinations of search terms for 'urethral stricture disease', 'stricture formation' and 'local interventions'. We used the SYRCLE, RoB-2 and ROBINS-I tools to assess risk of bias across included studies. We did not perform a meta-analysis due to methodological differences between studies. RESULTS: We included 32 articles in the qualitative analysis, 20 of which were preclinical studies and 12 clinical studies. Regarding preclinical articles using an animal model, nearly all interventions showed to have a positive effect on either urethral fibrosis, urethral stricture formation and/or fibrotic protein expression levels. Here, immunosuppressants and chemotherapeutics seemed most promising for possible clinical purposes. Regarding clinical studies, mitomycin-C and hyaluronic acid and carboxymethylcellulose showed positive effects on urethral stricture recurrence rates with low to intermediate risk of bias across studies. However, the positive clinical effects of mitomycin-C and steroids seemed to decrease in studies with a longer follow-up time. CONCLUSION: Although local adjuvant use of mitomycin-C or hyaluronic acid and carboxymethylcellulose may carry clinical potential to improve urethral structure recurrence rates after endoscopic procedures, we believe that a large, well-designed RCT with a yearlong follow-up time is necessary to identify the true clinical value

Human and animal fertility studies in cystinosis reveal signs of obstructive azoospermia, an altered blood-testis barrier and a subtherapeutic effect of cysteamine in testis

Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the CTNS gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease-modifying treatment. We aimed at unraveling the origin of azoospermia in cysteamine-treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the Ctns−/− mouse model compared with wild type. Azoospermia was present in the vast majority of infantile type cystinosis patients. While spermatogenesis was intact, an enlarged caput epididymis and reduced levels of seminal markers for obstruction neutral α-glucosidase (NAG) and extracellular matrix protein 1 (ECM1) pointed towards an epididymal obstruction. Histopathological examination in human and mouse testis revealed a disturbed blood-testis barrier characterized by an altered zonula occludens-1 (ZO-1) protein expression. Animal studies ruled out a negative effect of cysteamine on fertility, but showed that cystine accumulation in the testis is irresponsive to regular cysteamine treatment. We conclude that the azoospermia in infantile cystinosis is due to an obstruction related to epididymal dysfunction, irrespective of the severity of an evolving primary hypogonadism. Regular cysteamine treatment does not affect fertility but has subtherapeutic effects on cystine accumulation in testis

Comparison of functional outcome after extended versus super-extended pelvic lymph node dissection during radical prostatectomy in high-risk localized prostate cancer

Background: Urinary continence and erectile function (EF) are best preserved whenmeticulous dissection of prostate and nerve sparing technique are used during radicalprostatectomy (RP). However, extent of lymph node dissection (LND) may also adverselyaffect functional results.Objective: To determine whether performing a super-extended LND (seLND) has asignificant effect on recovery of urinary continence and EF after RP.Design, setting, and participants: All patients who underwent RP from January 2007until December 2013 were handed questionnaires assessing continence and EF. Allpatients in whom at least an extended LND (eLND) was performed were selected. Thissearch yielded 526 patients. 172 of these patients had filed out 2 or more questionnairesand were included in our analysis.Outcome measurements and statistical analysis: All questionnaires were reviewed.We used Kaplan–Meier analyses and multivariate Cox analysis to assess the differencein recovery of continence and EF over time for eLND/seLND. Primary endpoints were fullrecovery of continence (no loss of urine) and full recovery of EF (successful intercoursepossible). Patients who did not reach the endpoint when the last questionnaire was filledout were censored at that time. Median follow-up was 12.43 months for continence, and18.97 months for EF.results and limitations: Patients undergoing seLND have a lower chance of regainingboth urinary continence [hazard ratio (HR) 0.59, 95% CI 0.39–0.90, p = 0.026] and EF(HR 0.28, 95% CI 0.13–0.57, p = 0.009). Age at surgery had a significant influence onboth continence and EF in multivariate analysis. Major limitation of the study was that noformal preoperative assessment of continence and potency was done.conclusion: Extending the LND template beyond the eLND template may cause atleast a significant delay in recovery of urinary continence and leads to less recovery of EF.</p

Preoperative Risk-Stratification of High-Risk Prostate Cancer: A Multicenter Analysis

Background: Cancer-specific survival (CSS) within high-risk non-metastatic prostate cancer varies dramatically. It is likely that within this heterogenous population there are subgroup(s) at extraordinary risk, burdened with an exaptational poor prognosis. Establishing the characteristics of these group(s) would have significant clinical implications since high quality preoperative risk stratification remains the cornerstone of therapeutic decision making to date. Objective: To stratify high-risk prostate cancer based on preoperative characteristics and evaluate cancer specific survival after radical prostatectomy. Method: The EMPaCT multi-center database offers an international population of non-metastatic high-risk prostate cancer. Preoperative characteristics such as age, biopsy Gleason score, PSA and clinical stage were subcategorized. A multivariate analysis was performed using predictors showing significant survival heterogeneity after stratification, as observed by a univariate analysis. Based upon the hazard ratios of this multivariate analysis, a proportional score system was created. The most ideal group distribution was evaluated trough different score cut-off's. The predictive value was tested by the herald C index. Results: An overall 5-years CSS of 94% was noted within the entire high-risk cohort (n = 4,879). Except for age, all preoperative risk factors showed a significantly differing CSS. Multivariate analysis indicated, T4 stage as being the strongest predictor of CSS (HR: 3.31), followed by ISUP grade 5 group (HR 3,05). A score system was created by doubling the hazard ratios of this multivariate analysis and rounding off to the nearest complete number. Multivariate analysis suggested 0, 4, 8, and 12 pts as being the most optimal group distribution (p-value: 0.0015). Five-years CSS of these groups were 97, 93, 87, and 70%, respectively. The calculated Herald C-index of the model was 0.77. Conclusion: An easy-to-use pre-operative model for risk stratification of newly diagnosed high-risk prostate cancer is presented. The heterogeneous CSS of high-risk non-metastatic prostate cancer after radical prostatectomy is illustrated. The model is clinically accessible through an online calculator, presenting cancer specific survival based on individualized patient characteristics

Intratunical injection of autologous adipose stromal vascular fraction reduces collagen III expression in a rat model of chronic penile fibrosis

Previous studies have shown that the injection of adipose stem cells and stromal vascular fraction(SVF) into the tunica albuginea (TA) during the inflammatory phase in a rat model of Peyronie’s disease(PD) prevented the development of TA fibrosis. Our aim was to investigate whether local injection of SVF can reduce established fibrosis in a rat model of chronic phase of PD. Eighteen-male 12-wk-old Sprague-Dawley rats were divided in three equal groups: sham, PD without treatment (PD) and PD treated with SVF(PD-SVF). Sham rats underwent 2 injections of vehicle into the TA one month apart. PD rats underwent TGF-β1 injection and injection of vehicle one month later. PD-SVF rats underwent TGF-β1 injection followed by SVF (1-million cells) one month later. One month after the last treatment, the animals, n = 6 rats per group, underwent measurement of intracorporal and mean arterial pressure during electrostimulation of the cavernous nerve. Following euthanasia, penises were harvested for in-vitro study. Erectile function was not statistically significantly different between groups. PD animals developed subtunical areas of fibrosis and elastosis with upregulation of collagen III protein. These fibrotic changes were reversed after injection of SVF. We provide evidence that local injection of SVF reverses TA fibrosis in a rat model of chronic phase of PD

Rates and Predictors of Perioperative Complications in Cytoreductive Nephrectomy: Analysis of the Registry for Metastatic Renal Cell Carcinoma

Background: Cytoreductive nephrectomy (CN) plays an important role in the treatment of a subgroup of metastatic renal cell carcinoma (mRCC) patients. Objective: We aimed to evaluate morbidity associated with this procedure and identify potential predictors thereof to aid patient selection for this procedure and potentially improve patient outcomes. Design, setting, and participants: Data from 736 mRCC patients undergoing CN at 14 institutions were retrospectively recorded in the Registry for Metastatic RCC (REMARCC). Outcome measurements and statistical analysis: Logistic regression analysis was used to identify predictors for intraoperative, any-grade (AGCs), low-grade, and high-grade (HGCs) postoperative complications (according to the Clavien-Dindo classification) as well as 30-d readmission rates. Results and limitations: Intraoperative complications were observed in 69 patients (10.9%). Thrombectomy (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.08-1.75, p = 0.009) and adjacent organ removal (OR 2.7, 95% CI 1.38-5.30) were significant predictors of intraoperative complications at multivariable analysis. Two hundred seventeen patients (29.5%) encountered AGCs, while 45 (6.1%) encountered an HGC, of whom 10 (1.4%) died. Twenty-four (3.3%) patients had multiple postoperative complications. Estimated blood loss (EBL; OR 1.49, 95% CI 1.08-2.05, p = 0.01) was a significant predictor of AGCs at multivariable analysis. CN case load (OR 0.13, 95% CI 0.03-0.59, p = 0.009) and EBL (OR 2.93, 95% CI 1.20-7.15, p = 0.02) were significant predictors solely for HGCs at multivariable analysis. Forty-one patients (11.5%) were readmitted within 30 d of surgery. No significant predictors were identified. Results were confirmed in a subanalysis focusing solely on patients treated in the contemporary targeted therapy era. Conclusions: Morbidity associated with CN is not negligible. Predictors of high-grade postoperative morbidity are predominantly indicators of complex surgery. EBL is a strong predictor of postoperative complications. CN case load correlates with lower high-grade morbidity and highlights the benefit of centralization of complex surgery. However, risks and benefits should be balanced when considering CN in mRCC patients. Patient summary: We studied patients with metastatic renal cancer to evaluate the outcomes associated with the surgical removal of the primary kidney tumor. We found that this procedure is often complex and adverse events are not uncommon. High intraoperative blood loss and a small number of cases performed at the treating center are associated with a higher rate of postoperative complications

Assessment of PI3K/mTOR/AKT Pathway Elements to Serve as Biomarkers and Therapeutic Targets in Penile Cancer

The PI3K/mTOR/AKT pathway might represent an intriguing option for treatment of penile cancer (PeCa). We aimed to assess whether members of this pathway might serve as biomarkers and targets for systemic therapy. Tissue of primary cancer from treatment-naïve PeCa patients was used for tissue microarray analysis. Immunohistochemical staining was performed with antibodies against AKT, pAKT, mTOR, pmTOR, pS6, pPRAS, p4EBP1, S6K1 and pp70S6K. Protein expression was correlated with clinicopathological characteristics as well as overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and metastasis-free survival (MFS). AKT inhibition was tested in two primarily established, treatment-naïve PeCa cell lines by treatment with capivasertib and analysis of cell viability and chemotaxis. A total of 76 patients surgically treated for invasive PeCa were included. Higher expression of AKT was significantly more prevalent in high-grade tumors and predictive of DSS and OS in the Kaplan–Meier analysis, and an independent predictor of worse OS and DSS in the multivariate regression analysis. Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one

Value of c-MET and Associated Signaling Elements for Predicting Outcomes and Targeted Therapy in Penile Cancer

Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis. Immunohistochemical staining was performed to determine the expression of the proteins c-MET, PPARg, β-catenin, snail, survivin, and n-MYC. In total, 94 PeCa patients with available tumor tissue were included. The median age was 64.9 years. High-grade tumors were present in 23.4%, and high-risk HPV was detected in 25.5%. The median follow-up was 32.5 months. High expression of snail was associated with HPV-positive tumors. Expression of β-catenin was inversely associated with grading. In both univariate COX regression analysis and the log-rank test, an increased expression of PPARg and c-MET was predictive of inferior disease-specific survival (DSS). Moreover, in multivariate analysis, a higher expression of c-MET was independently associated with worse DSS. Blocking c-MET with cabozantinib and tivantinib induced a significant decrease in viability in the primary PeCa cell line UKF-PeC3 isolated from the tumor tissue as well as in cisplatin- and osimertinib-resistant sublines. Strikingly, a higher sensitivity to tivantinib could be detected in the latter, pointing to the promising option of utilizing this agent in the second-line treatment setting