Anterior Urethral Strictures in Children: Disease Etiology and Comparative Effectiveness of Endoscopic Treatment vs. Open Surgical Reconstruction

Pediatric anterior urethral strictures are rare and recommendations regarding treatment strategies derive from small monocentric case series. In 2014, a collaborative effort of the Société Internationale d'Urologie and the International Consultation on Urological Diseases drafted the first systematic and evidence-based guideline for diagnosis and treatment of urethral strictures in children. Against this backdrop, we performed an updated literature review to provide a comprehensive summary of the available evidence and contemporary outcomes with a focus on comparative effectiveness of endoscopic treatment (dilation or urethrotomy) vs. open surgical reconstruction. Overall, 22 articles reporting on children with anterior urethral strictures were included into the review. Most strictures were iatrogenic (48%) and traumatic (34%), whereas congenital (13%), inflammatory (4%), or postinfectious strictures (1%) were rather rare. The cumulative success rate of endoscopic treatment and urethroplasty was 46% (range: 21–75; N = 334) and 84% (range: 25–100; N = 347), respectively. After stratifying patients according to urethroplasty technique, success rates were 82% (range: 25–100; N = 206) for excision and primary anastomosis, 94% (range: 75–100; N = 40) for graft augmentation, 97% (range: 87–100; N = 30) for flap urethroplasty, and 70% (one study; N = 20) for pull-through urethroplasty. In conclusion, endoscopic approaches are rather ineffective in the long-term and open surgical reconstruction via urethroplasty should be preferred to avoid multiple, repetitive interventions. Future research may involve multi-institutional, collaborative, and prospective studies, incorporating well-defined outcome criteria and assessing objective surgical endpoints as well as patient-reported functional outcomes

Urethral management after artificial urinary sphincter explantation due to cuff erosion

Introduction: The artificial urethral sphincter (AUS) is the gold standard treatment in cases of moderate-to-severe stress urinary incontinence in males. Cuff erosions are one of the most important distant complications of AUS implantation. The optimal urethral management has still not been established. Material and methods: Search terms related to 'urethral stricture', 'artificial urinary sphincter', and 'cuff erosion' were used in the PubMed database to identify relevant articles. Results: In this mini review we identified 6 original articles that assessed the urethral management after AUS explantation due to cuff erosion and included urinary diversion by transurethral and/or suprapubic catheterization, urethrorrhaphy, and in situ urethroplasty. We summarized the results of different management methods and their efficacy in terms of preventing urethral stricture formation. We highlight the need for better-quality evidence on this topic. Conclusions: The available data do not provide a clear answer to the question of optimal urethral management during AUS explantation. There is a great need to provide higher-quality evidence on this topic

Advancing Intraoperative Assessment of Urethral Stricture Anatomic Variation: a Prospective Proof-of-concept Study

INTRODUCTION Urethral strictures, particularly those refractory to endoscopic interventions, are commonly treated through open urethroplasty. However, predicting recurrence in homogeneous patient populations remains challenging. METHODS To address this, we developed an intraoperative urethral stricture assessment tool aiming to identify comprehensive risk predictors. The assessment includes detailed parameters on stricture location, length, urethral bed width, spongiosum thickness, obliteration grade, and spongiofibrosis extension. The tool was prospectively implemented in 106 men with anterior one-stage augmentation urethroplasty 04/2020 to 10/2021. RESULTS An intraoperative granular assessment of intricate stricture characteristics is feasible. Comparative analyses revealed significant differences between bulbar and penile strictures. Bulbar strictures exhibited wider urethral beds and thicker spongiosum compared to penile strictures (all P<0.001). The assessment showed marked variations in the degree of obliteration and spongiofibrosis extension. CONCLUSION Our tool aligns with efforts to standardize urethral surgery, providing insights into subtle disease intricacies and enabling comparisons between institutions. Notably, intraoperative assessment may surpass the limitations of preoperative imaging, emphasizing the necessity of intraoperative evaluation. While limitations include a single-institution study and limited sample size, future research aims to refine this tool and determine its impact on treatment strategies, potentially improving long-term outcomes for urethral strictures

Ultrasound imaging of male urethral stricture disease: a narrative review of the available evidence, focusing on selected prospective studies

Purpose: To synthetize the current scientific knowledge on the use of ultrasound of the male urethra for evaluation of urethral stricture disease. This review aims to provide a detailed description of the technical aspects of ultrasonography, and provides some indications on clinical applications of it, based on the evidence available from the selected prospective studies. Advantages and limitations of the technique are also provided. Methods: A comprehensive literature search was performed using the Medline and Cochrane databases on October 2022. The articles were searched using the keywords "sonourethrography", "urethral ultrasound", "urethral stricture" and "SUG". Only human studies and articles in English were included. Articles were screened by two reviewers (M.F. and K.M.). Results: Our literature search reporting on the role of sonourethrography in evaluating urethral strictures resulted in selection of 17 studies, all prospective, even if of limited quality due to the small patients' number (varied from 28 to 113). Nine studies included patients with urethral stricture located in anterior urethra and eight studies included patients regardless of the stricture location. Final analysis was based on selected prospective studies, whose power was limited by the small patients' groups. Conclusion: Sonourethrography is a cost-effective and safe technique allowing for a dynamic and three-dimensional urethra assessment. Yet, because of its limited value in detecting posterior urethral strictures, the standard urethrography should remain the basic 'road-map' prior to surgery. It is an operator-dependent technique, which can provide detailed information on the length, location, and extent of spongiofibrosis without risks of exposure to ionizing radiation.Open Access funding enabled and organized by Projekt DEAL

Outcomes and Complication Rates of Cuff Downsizing in the Treatment of Worsening or Persistent Incontinence After Artificial Urinary Sphincter Implantation

Purpose This study investigated the functional outcomes and complication rates of cuff downsizing for the treatment of recurrent or persistent stress urinary incontinence (SUI) in men after the implantation of an artificial urinary sphincter (AUS). Methods Data from our institutional AUS database spanning the period from 2009 to 2020 were retrospectively analyzed. The number of pads per day was determined, a standardized quality of life (QoL) questionnaire and the International Consultation on Incontinence Questionnaire (ICIQ) were administered, and postoperative complications according to the Clavien-Dindo classification were analyzed. Results Out of 477 patients who received AUS implantation during the study period, 25 (5.2%) underwent cuff downsizing (median age, 77 years; interquartile range [IQR], 74–81 years; median follow-up, 4.4 years; IQR, 3–6.9 years). Before downsizing, SUI was very severe (ICIQ score 19–21) or severe (ICQ score 13–18) in 80% of patients, moderate (ICIQ score 6–12) in 12%, and slight (ICIQ score 1–5) in 8%. After downsizing, 52% showed an improvement of >5 out of 21 points. However, 28% still had very severe or severe SUI, 48% had moderate SUI, and 20% had slight SUI. One patient no longer had SUI. In 52% of patients, the use of pads per day was reduced by ≥50%. QoL improved by >2 out of 6 points in 56% of patients. Complications (infections/urethral erosions) requiring device explantation occurred in 36% of patients, with a median time to event of 14.5 months. Conclusions Although cuff downsizing carries a risk of AUS explantation, it can be a valuable treatment option for selected patients with persistent or recurrent SUI after AUS implantation. Over half of patients experienced improvements in symptoms, satisfaction, ICIQ scores, and pad use. It is important to inform patients about the potential risks and benefits of AUS to manage their expectations and assess individual risks

Awareness and perception of multidrug-resistant organisms and antimicrobial therapy among internists vs. surgeons of different specialties: Results from the German MR2 Survey

Background: Recently, antibiotic resistance rates have risen substantially and care for patients infected with multidrug-resistant organisms (MDRO) has become a common problem in most in &#8211; and outpatient settings. The objectives of the study were to compare the awareness, perception, and knowledge of MDRO and rational antibiotic use between physicians from different medical specialties in German hospitals. Methods: A 35-item questionnaire was sent to specialists in internal medicine (internists), gynecologists, urologists, and general surgeons (non-internists) in 18 German hospitals. Likert-scales were used to evaluate awareness and perception of personal performance regarding care for patients infected with MDRO and rational use of antibiotics. Additionally, two items assessing specific knowledge in antibiotic therapy were included. The impact of medical specialty on four predetermined endpoints was assessed by multivariate logistic regression. Results: 43.0 (456/1061) of recipients responded. Both internists and non-internists had low rates of training in antibiotic stewardship. 50.8 of internists and 58.6 of non-internists had attended special training in rational antibiotic use or care for patients infected with MDRO in the 12 months prior to the study. Internists deemed themselves more confidently to choose the indications for screening patients for colonization with methicillin-resistant Staphylococcus aureus (P=0.004) and to initiate adequate infection control measures (P=0.002) than other specialties. However, there was no significant difference between internists and other specialists regarding the two items assessing specific knowledge in antibiotic therapy and infection control. Conclusion: Among the study participants, a considerable need for advanced training in the study subjects was seen, regardless of the medical specialty

Upregulated Heat Shock Proteins After Hyperthermic Chemotherapy Point to Induced Cell Survival Mechanisms in Affected Tumor Cells From Peritoneal Carcinomatosis

In patients with peritoneal carcinomatosis cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment strategy. Here, we studied the role of hyperthermic chemotherapy on heat shock protein (HSP) expression and induction of tumor cell death and survival. HSP27, HSP70, and HSP90 combined with effects on tumor cell proliferation and chemosensitivity were analyzed in human colon cancer. Hyperthermic chemotherapy resulted in significant HSP27/HSP70 and HSP90 gene/protein overexpression in analyzed HT-29/SW480/SW620 colon cancer cells and peritoneal metastases from patients displaying amplified expression of proliferation markers, proliferating cell nuclear antigen and antiapoptotic protein Bcl-xL. Moreover, functionally increased chemoresistance against 5-fluorouracil/mitomycin C and oxaliplatin after hyperthermic chemotherapy points to induced survival mechanisms in cancer cells. In conclusion, the results indicate that intracellular HSP-associated antiapoptotic and proliferative effects after hyperthermic chemotherapy negatively influence beneficial effects of hyperthermic chemotherapy-induced cell death. Therefore, blocking HSPs could be a promising strategy to further improve the rate of tumor cell death and outcome of patients undergoing HIPEC therapy

Molecular Heat Shock Protein-induced Repair Mechanisms After Hyperthermic Intraperitoneal Chemoperfusion for Peritoneal Carcinomatosis

Die hypertherme Chemoperfusion der Bauchhöhle (HIPEC) in Kombination mit einer vorangestellten, ausgedehnten, zytoreduktiven chirurgischen Therapie stellt eine vielversprechende Methode der Krebsbehandlung für Patienten dar, die an einer Peritonealkarzinose auf dem Boden gastroenterologischer oder gynäkologischer Primärtumore erkrankt sind. Da bislang wenige Standards bezüglich der angewendeten klinischen Bedingungen im Rahmen der HIPEC existieren und um jene zu optimieren, wurden ex vivo und in vitro Untersuchungen mit Tumorzellen durchgeführt. Ziel dieser Experimente war die Identifizierung von zellulären Schutzmechanismen in Reaktion auf Hyperthermie als externen Stressor sowie deren Auswirkung auf prognostisch relevante tumorphysiologische Vorgänge wie Zellproliferation und Apoptose. Um die zellulären Vorgänge während einer HIPEC-Therapie vollends zu verstehen, müssen die beiden einflussnehmenden Größen Hyperthermie und Zytostase getrennt voneinander untersucht werden, um die therapeutischen Konsequenzen zu verbessern und gezielte Pharmaka einsetzen zu können. In Voruntersuchungen konnten an repräsentativen Tumorgeweben im Vergleich vor und nach HIPEC deutliche Veränderungen der Expression von onkologisch relevanten Heat Shock Proteinen HSP27, HSP70 und HSP90 dargestellt werden. Diese Veränderungen zeigten sich in dieser Form erstmalig entitätsübergreifend sowohl auf mRNA-Ebene in der real time quantitativen Polymerase-Kettenreaktion als auch in der Proteinexpression in Western Blot Analysen. Auf Basis dieser Beobachtungen wurden in einem neu etablierten Hyperthermie in vitro Modell humane HT-29 Kolonkarzinomzellen unter HIPEC-ähnlichen Bedingungen für 60 min verschiedenen Temperaturen ausgesetzt. Nach Regenerationszeiten von 30 min bzw. 12 h wurden anschließend Protein- und Genexpressionsanalysen mit Hilfe von Western Blot, Immunhistochemie und RT-qPCR durchgeführt. Veränderungen im Tumorwachstum wurden 30 min sowie 12 h nach der Hyperthermieeinwirkung mittels MTS- und AnnexinV-Apoptose-Tests detektiert. Ziel des in vitro Modells war die isolierte Betrachtung des Einflusses von Hyperthermie auf die zellulären Reparaturmechanismen vermittelt durch HSP sowie deren Auswirkung auf Zellproliferation und Apoptose. Der isolierte Einfluss der Hyperthermie auf die humanen HT-29 Kolonkarzinomzellen verursachte eine kurzfristige Hochregulierung der Gen- und Proteinexpression von HSP27 und HSP72, auch HSP90 zeigte sich kurzfristig erhöht, wenngleich in geringerem Ausmaße. Bereits nach 12 h war eine Schwächung der Hochregulierung bei allen drei HSP zu beobachten, lediglich HSP27 zeigte nach wie vor eine deutliche Expressionssteigerung mit Erhöhung der einwirkenden Temperaturen. Der für die Tumortherapie essenzielle Apoptose-induzierende und antiproliferative Effekt auf die Tumorzellen war nach kurzer und längerfristiger Zellregeneration in einem Temperaturfenster von 39-41 °C zu beobachten. Assoziiert man die Ergebnisse der unterschiedlichen HSP-Expressionen mit den Proliferations- und Apoptoseraten der Tumorzellen, so liegt die Schlussfolgerung nahe, dass bei hohen Temperaturen (43 °C) die Initiierung der intrazellulären Zellschutzmechanismen, repräsentiert durch die HSP, für eine erhebliche Abschwächung der gewünschten Tumorzellapoptose und Proliferationsminimierung verantwortlich sein könnten. Die eigenständigen Effekte einer Hyperthermie in der Malignomtherapie wie die Zytotoxizität, Veränderungen im Tumormikromilieu und die steigende Sensibilität der Tumorzellen auf chemotherapeutische Agenzien sollten folglich hinsichtlich der zielorientierten therapeutischen Betrachtung streng von den Mechanismen des induzierten Zellschutzes separiert werden. Die vorliegenden Ergebnisse zeigten ausgeprägte Heat Shock Protein-Antworten in der Tumorzelle, die gewünschte antiproliferative und apoptotische Effekte beeinträchtigen und Tumorzellschutzmechanismen induzieren könnten. Ferner legen die Ergebnisse nahe, dass die Effekte der HIPEC-Therapie unter Umständen in Bezug auf die Höhe der Temperatur der induzierten Hyperthermie bei den Patienten mit Peritonealkarzinose aufgrund der relevanten HSP-Überexpression gegebenenfalls einer Reevaluierung bedürfen. Der nächste Schritt der Untersuchungen führt zwangsläufig zum Einbezug verschiedener Chemotherapeutika in die in vitro Experimente, um die Rolle der Chemotherapie und Zytostase in Kombination mit der Hyperthermie zu klären. Die im Rahmen dieser Arbeit beschriebenen Ergebnisse stellen erstmalig eine klinisch potentiell hochrelevante Ergänzung zur Optimierung der vorhandenen HIPEC-Protokolle vor. Sowohl die Temperaturanpassung des applizierten Chemotherapeutikums als auch der additive Einsatz von HSP-Inhibitoren könnte einen vielversprechenden Ansatz zur langfristigen Verbesserung des tumorbedingten Überlebens für Peritonealkarzinose-Patienten bedeuten und sollte Gegenstand weiterführender Untersuchungen in Zellkultur, Mausmodell und klinischen Studien darstellen.Hyperthermic intraperitoneal chemoperfusion (HIPEC) after previous cytoreductive peritonectomy represents a promising approach for cancer therapy in patients with peritoneal carcinomatosis arising from primary gastrointestinal or gynecological malignancies. Given that the evidence of standardization for the HIPEC procedure is scarce, we performed ex vivo and in vitro analyses using tumor cells. Aim of these experiments was the identification of cell mechanisms to protect the tumor from external stressors, such as hyperthermia, and to depict the impact on prognostically relevant mechanisms such as proliferation and apoptosis. To understand these cellular events during HIPEC and to improve therapeutic consequences by implementing targeting drugs, both influencing factors hyperthermia and cytostasis have to be evaluated separately. In preliminary analyses, evaluating protein expression in representative biopsies before and after HIPEC, we demonstrated distinct changes in oncologically relevant heat shock proteins HSP27, HSP70, and HSP90. These changes were observed for different tumor entities on both mRNA and protein level using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. Against the backdrop of these observations, we established a hyperthermia in vitro model to create HIPEC-like conditions and to expose human HT-29 colon cancer cells to different temperatures for 60 minutes. Following a regeneration interval of 30 minutes or 12 hours at 37°C, we performed gene and protein expression analyses by using RT-qPCR, western blotting, and immunocytochemistry. Changes in tumor cell growth after hyperthermia and both regeneration intervals were detected by using an MTS proliferation assay and the Annexin V affinity assay. Aim of the hyperthermia in vitro model was the evaluation of a heat shock protein-mediated effect on cellular repair mechanisms in response to hyperthermic stress and to depict its impact on cell proliferation and apoptosis. The isolated hyperthermic effect induced a short-term upregulation of HSP27 and HSP70 gene and protein expression in human HT-29 colon cancer cells. Similar results were seen for HSP90. Of note, the intensity of upregulation was lower. Just after 12 hours, a certain mitigation of upregulation was observed in all heat shock proteins. However, a certain upregulation was still seen for HSP27 with increasing temperatures. The carcinogenic anti-proliferative and apoptosis-inducing effect on tumor cells was maximized at temperatures between 39 and 41°C, both after 30 minutes and 12 hours regeneration. The association of heat shock protein upregulation with tumor cell proliferation and apoptosis suggests that high temperatures (43°C) may induce cell repair mechanisms, which ensure a significant impairment of favored tumor cell apoptosis and anti-proliferative effects. Consequently, isolated hyperthermic effects in cancer therapy, such as cytotoxicity, alterations of the tumor microenvironment, and an increased chemosensitivity may be strictly distinguished from mechanisms of hyperthermia-induced cell repair. Our results show distinct heat shock protein responses in the tumor cell, which may interfere with favored anti-proliferative and apoptosis-inducing effects by triggering cellular repair and protection. Furthermore, our results suggest a thorough reconsideration of the applied temperature during HIPEC in patients with peritoneal carcinomatosis, given a relevant heat shock protein upregulation at highest temperatures. Future research necessarily should include cytotoxic agents into the in vitro experiments to evaluate the role of the combined hyperthermia and chemotherapy effect. In conclusion, our findings illustrate a clinically relevant addition towards the optimization of existing HIPEC protocols. Altering target temperature levels and the additional administration of heat shock protein inhibitors may both represent promising approaches to improve oncological outcomes in patients with peritoneal carcinomatosis and may be subject of further research by employing cell culture experiments, animal models, and clinical studies