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

Management of non-visualization following dynamic sentinel lymph node biopsy for squamous cell carcinoma of the penis

Objectives: To review the management and clinical outcomes of uni- or bilateral non-visualization of inguinal lymph nodes during dynamic sentinel lymph node biopsy (DSNB) in patients diagnosed with penile cancer and clinically impalpable inguinal lymph nodes (cN0), and to develop an algorithm for the management of patients in which non-visualization occurs. Patients and Methods: This is a retrospective observational study over a period of 4 years, comprising 166 patients with penile squamous cell carcinoma undergoing DSNB and followed up for a minimum of 6 months. All cases diagnosed with uni- or bilateral non-visualization of sentinel nodes in this cohort were identified from a penile cancer database. The management of the inguinal lymph nodes after non-visualization and the oncological outcomes including local and regional recurrence rates were documented. Results: Out of 166 consecutive patients undergoing DSNB, 20 patients (12%) had unilateral non-visualization after injection of intradermal 99mTc. Of these 20 patients, seven underwent repeat DSNB at a later date, with six having successful visualization. One patient had persistent non-visualization and proceeded to a superficial modified inguinal lymphadenectomy (SML). None of these patients experienced recurrence at follow-up. A further seven patients underwent modified SML with on-table frozen-section analysis of the lymph node packet; none of these patients were found to have micrometastatic disease in the inguinal lymph nodes, although one patient developed metastatic inguinal node disease at a later date. Six patients elected to undergo clinical surveillance and have remained disease-free. Conclusion: Patients with impalpable inguinal lymph nodes undergoing DSNB with ≥G2 T1 disease should ideally have bilateral visualization of the sentinel lymph nodes, reflecting the drainage pattern from the primary tumour. In the present series, 12% of patients were found to have unilateral non-visualization after DSNB. Among patients offered a repeat DSNB at a later date, localizing the sentinel node was successful in 86% of cases. Patients with favourable histological characteristics can be placed on clinical surveillance. Those with high-risk disease can be offered a repeat DSNB procedure on the proviso that SML may be carried out if there is repeated non-visualization. Larger cohorts are required to validate this proposed algorithm

Acute In Vivo Response to an Alternative Implant for Urogynecology

Purpose. To investigate in vivo the acute host response to an alternative implant designed for the treatment of stress urinary incontinence (SUI) and pelvic organ prolapse (POP). Methods. A biodegradable scaffold was produced from poly-L-lactic acid (PLA) using the electrospinning technique. Human and rat adipose-derived stem cells (ADSCs) were isolated and characterized by fluorescence-activated cell sorting and differentiation assays. PLA scaffolds were seeded and cultured for 2 weeks with human or rat ADSCs. Scaffolds with and without human or rat ADSCs were implanted subcutaneously on the abdominal wall of rats. After 3 and 7 days, 6 animals from each group were sacrificed. Sections from each sample were analyzed by Haematoxylin and Eosin staining, Sirius red staining, and immunohistochemistry for CD68, PECAM-1, and collagen I and III. Results. Animals responded to the scaffolds with an acute macrophage response. After 7 days of implantation, there was extensive host cell penetration, new blood vessel formation, and new collagen deposition throughout the full thickness of the samples without obvious differences between cell-containing and cell-free scaffolds. Conclusions. The acute in vivo response to an alternative implant (both with and without cells) for the treatment of SUI and POP showed good acute integration into the host tissues

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

Practice Patterns Among Penile Cancer Surgeons Performing Dynamic Sentinel Lymph Node Biopsy and Radical Inguinal Lymph Node Dissection in Men with Penile Cancer: A eUROGEN Survey.

Dynamic sentinel lymph node biopsy (DSNB) and radical inguinal lymph node dissection (ILND) are important in the management of penile cancer patients, but high-level evidence for preoperative, perioperative, and postoperative management remains scarce. According to an online survey of 35 surgeons from ten European countries, 57% perform >10 ILND procedures per year and 86% offer DSNB. Furthermore, management differs substantially for dye injection site, use of lymphoscintigraphy, preferred incision sites, techniques for lymphatic control, duration of empiric antibiotic therapy, perioperative thromboprophylaxis, time points for drain removal, and definition of the ILND dissection floor. Consensus was observed for the use of perioperative antibiotics (although not duration and type) and the borders for ILND template definitions. We conclude that there is significant variation in patient management among eUROGEN penile cancer surgeons. This heterogeneity may confound multicentre studies; therefore, a consensus to standardise inguinal node management in penile cancer across European penile cancer centres is warranted. PATIENT SUMMARY: Our survey reveals that preferences and surgical techniques for inguinal lymph node sampling and removal varies significantly between European penile cancer surgeons. Consensus is needed to standardise the management approach for penile cancer

Clinicopathologic predictors of finding additional inguinal lymph node metastases in penile cancer patients following positive dynamic sentinel node biopsy:a European multicentre evaluation

OBJECTIVES: Following tumour positive sentinel lymph node biopsy (+DSNB), completion inguinal lymph node dissection (ILND) is negative in 84-89% of basins. Thus, ILND after +DSNB may be considered overtreatment resulting in substantial morbidity. This study aimed to develop a predictive model for additional inguinal lymph node metastases (LNM) at ILND following +DSNB using DSNB characteristics to identify a patient group in which ILND might be omitted. PATIENTS AND METHODS: A retrospective study of 407 inguinal basins with a +DSNB of penile cancer patients who underwent subsequent ILND from seven European centres. From the histopathology reports, the number of positive and negative lymph nodes, extranodal extension and size of the metastasis were recorded. Using bootstrapped logistic regression, variables were selected for the clinical prediction model based on the optimisation of Akaike's information criterion. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was calculated for the resulting model. Decision curve analysis (DCA) was used to evaluate the clinical utility of the model. RESULTS: 64 (16%) of +DSNB harboured additional LNM at ILND. The number of positive nodes at +DSNB (odds ratio (OR) 2.19; 95% confidence interval (CI) 1.17-4.00; p=0.01) and the largest metastasis size in mm (OR 1.06; 95%CI 1.03-1.10; p=0.001) were selected for the clinical prediction model. The AUC was 0.67 (95%CI 0.60-0.74). The DCA showed no clinical benefit of using the clinical prediction model. CONCLUSION: A small but clinically important group of basins harbour additional LNM at completion ILND following +DSNB. While DSNB characteristics were associated with additional LNM, they did not improve the selection of basins in which ILND could be omitted. Thus, completion ILND remains necessary in all basins with a +DSNB

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

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