Targeting cancer-derived extracellular vesicles by combining CD147 inhibition with tissue factor pathway inhibitor for the management of urothelial cancer cells.

BACKGROUND: Extracellular vesicles (EVs), including microvesicles, hold promise for the management of bladder urothelial carcinoma (BLCA), particularly because of their utility in identifying therapeutic targets and their diagnostic potential using easily accessible urine samples. Among the transmembrane glycoproteins highly enriched in cancer-derived EVs, tissue factor (TF) and CD147 have been implicated in promoting tumor progression. In this in vitro study, we explored a novel approach to impede cancer cell migration and metastasis by simultaneously targeting these molecules on urothelial cancer-derived EVs. METHODS: Cell culture supernatants from invasive and non-invasive bladder cancer cell lines and urine samples from patients with BLCA were collected. Large, microvesicle-like EVs were isolated using sequential centrifugation and characterized by electron microscopy, nanoparticle tracking analysis, and flow cytometry. The impact of urinary or cell supernatant-derived EVs on cellular phenotypes was evaluated using cell-based assays following combined treatment with a specific CD147 inhibitor alone or in combination with a tissue factor pathway inhibitor (TFPI), an endogenous anticoagulant protein that can be released by low-molecular-weight heparins. RESULTS: We observed that EVs obtained from the urine samples of patients with muscle-invasive BLCA and from the aggressive bladder cancer cell line J82 exhibited higher TF activity and CD147 expression levels than did their non-invasive counterparts. The shedding of GFP-tagged CD147 into isolated vesicles demonstrated that the vesicles originated from plasma cell membranes. EVs originating from invasive cancer cells were found to trigger migration, secretion of matrix metalloproteinases (MMPs), and invasion. The same induction of MMP activity was replicated using EVs obtained from urine samples of patients with invasive BLCA. EVs derived from cancer cell clones overexpressing TF and CD147 were produced in higher quantities and exhibited a higher invasive potential than those from control cancer cells. TFPI interfered with the effect when used in conjunction with the CD147 inhibitor, further suppressing homotypic EV-induced migration, MMP production, and invasion. CONCLUSIONS: Our findings suggest that combining a CD147 inhibitor with low molecular weight heparins to induce TFPI release may be a promising therapeutic approach for urothelial cancer management. This combination can potentially suppress the tumor-promoting actions of cancer-derived microvesicle-like EVs, including collective matrix invasion.

Small particles or vesicles released by cancer cells into their surroundings have the potential to stimulate the spread and growth of cancer cells. In this study, we focused on two specific molecules presented by these cancer cell-derived vesicles that could play a role in promoting the dissemination of cancer cells: a protein related to blood clotting and a protein on the cell surface.We found that large vesicles from bladder cancer cells that have the ability to spread had higher levels of these proteins than vesicles from nonspreading cancer cells. We also found that the former could make cancer cells move about more, produce more of a substance that helps cancer cells spread, and invade other tissues.To counteract the cancer-promoting actions of these vesicles, we examined the impact of combining a naturally occurring anticlotting protein that can be released by medications derived from heparin with an inhibitor targeting the cancer cell surface protein. We found that this combination stopped the vesicles from helping cancer cells move about more, produce more of the spreading substance, and invade other tissues.This approach of simultaneously targeting the two protein molecules present on cancer cell-derived vesicles might be a new way to treat bladder cancer.

An international multicentre randomised controlled trial of en bloc resection of bladder tumour vs conventional transurethral resection of bladder tumour: first results of the en bloc resection of urothelium carcinoma of the bladder (EBRUC) II trial.

OBJECTIVES: To determine the safety and oncological advantages of en bloc resection of bladder tumour (ERBT) vs conventional transurethral resection of bladder tumour (cTURBT) in terms of resection quality, staging quality, and safety. PATIENTS AND METHODS: We conducted a single-blinded randomised controlled trial at seven European hospitals with the following inclusion criteria: first diagnosis of non-muscle-invasive bladder cancer, no singular carcinoma in situ, and tumour size >4.3 mm. Patients were randomised intraoperatively in a 1:1 ratio to either the ERBT or cTURBT group. Outcome analysis was performed using the chi-square test, t-test, and multivariate regression analysis. RESULTS: A total of 97 patients were randomised into the study (cTURBT = 40, ERBT = 57). A switch to cTURBT was necessary in two patients (3.5%) and 11.5% of the screened patients were preoperatively excluded for ERBT. There was no difference in the specimen presence of detrusor muscle with 73.7% in cTURBT and 67.3% in ERBT specimens (P = 0.69). There were no significant differences in mean operative time (ERBT 27.6 vs cTURBT 25.4 min, P = 0.450) or mean resection time (ERBT 16.3 vs cTURBT 15.5 min, P = 0.732). Overall the complication rate did not differ significantly (ERBT 18.2% vs cTURBT 7.5%, P = 0.142). Bladder perforations occurred significantly more often in the ERBT group (ERBT seven vs cTURBT none, P = 0.020). R0 status was reported more often after ERBT, whilst a second resection was significantly less frequent after ERBT (P = 0.018). Recurrence rates were comparable for both techniques after 6 months of follow-up. CONCLUSION: The feasibility of ERBT is higher than previously reported. Whereas other perioperative and safety parameters are comparable to cTURBT, bladder perforations occurred significantly more often in the ERBT group and raised safety concerns. This is why this trial was terminated.

Experts' recommendations in laser use for the treatment of bladder cancer: a comprehensive guide by the European Section of Uro-Technology (ESUT) and Training and Research in Urological Surgery and Technology (TRUST)-Group.

PURPOSE: To identify laser settings and limits applied by experts during laser vaporization (vapBT) and laser en-bloc resection of bladder tumors (ERBT) and to identify preventive measures to reduce complications. METHODS: After a focused literature search to identify relevant questions, we conducted a survey (57 questions) which was sent to laser experts. The expert selection was based on clinical experience and scientific contribution. Participants were asked for used laser types, typical laser settings during specific scenarios, and preventive measures applied during surgery. Settings for a maximum of 2 different lasers for each scenario were possible. Responses and settings were compared among the reported laser types. RESULTS: Twenty-three of 29 (79.3%) invited experts completed the survey. Thulium fiber laser (TFL) is the most common laser (57%), followed by Holmium:Yttrium-Aluminium-Garnet (Ho:YAG) (48%), continuous wave (cw) Thulium:Yttrium-Aluminium-Garnet (Tm:YAG) (26%), and pulsed Tm:YAG (13%). Experts prefer ERBT (91.3%) to vapBT (8.7%); however, relevant limitations such as tumor size, number, and anatomical tumor location exist. Laser settings were generally comparable; however, we could find significant differences between the laser sources for lateral wall ERBT (p = 0.028) and standard ERBT (p = 0.033), with cwTm:YAG and pulsed Tm:YAG being operated in higher power modes when compared to TFL and Ho:YAG. Experts prefer long pulse modes for Ho:YAG and short pulse modes for TFL lasers. CONCLUSION: TFL seems to have replaced Ho:YAG and Tm:YAG. Most laser settings do not differ significantly among laser sources. For experts, continuous flow irrigation is the most commonly applied measure to reduce complications.

En bloc resection of bladder tumour: the rebirth of past through reminiscence.

PURPOSE: To learn about the history and development of en bloc resection of bladder tumour (ERBT), and to discuss its future directions in managing bladder cancer. METHODS: In this narrative review, we summarised the history and early development of ERBT, previous attempts in overcoming the tumour size limitation, consolidative effort in standardising the ERBT procedure, emerging evidence in ERBT, evolving concepts in treating large bladder tumours, and the future directions of ERBT. RESULTS: Since the first report on ERBT in 1980, there has been tremendous advancement in terms of its technique, energy modalities and tumour retrieval methods. In 2020, the international consensus statement on ERBT has been developed and it serves as a standard reference for urologists to practise ERBT. Recently, high-quality evidence on ERBT has been emerging. Of note, the EB-StaR study showed that ERBT led to a reduction in 1-year recurrence rate from 38.1 to 28.5%. An individual patient data meta-analysis is currently underway, and it will be instrumental in defining the true value of ERBT in treating non-muscle-invasive bladder cancer. For large bladder tumours, modified approaches of ERBT should be accepted, as the quality of resection is more important than a mere removal of tumour in one piece. The global ERBT registry has been launched to study the value of ERBT in a real-world setting. CONCLUSION: ERBT is a promising surgical technique in treating bladder cancer and it has gained increasing interest globally. It is about time for us to embrace this technique in our clinical practice.

The alternative renin-angiotensin-system (RAS) signalling pathway in prostate cancer and its link to the current COVID-19 pandemic.

BACKGROUND: The renin-angiotensin system is known to maintain blood pressure and body fluids. However, it has been found to consist of at least two major constituents, the classic and the alternative pathway, balancing and supporting each other's signalling in a very intricate way. Current research has shown that the renin-angiotensin system is involved in a broad range of biological processes and diseases, such as cancer and infectious diseases. METHODS AND RESULTS: We conducted a literature review on the interaction of the renin-angiotensin system and prostate cancer and explored the research on the possible impact of the SARS-CoV-2 virus in this context. This review provides an update on contemporary knowledge into the alternative renin-angiotensin system, its role in cancer, specifically prostate cancer, and the implications of the current COVID-19 pandemic on cancer and cancer care. CONCLUSION: In this work, we aim to demonstrate how shifting the RAS signalling pathway from the classic to the alternative axis seems to be a viable option in supporting treatment of specific cancers and at the same time demonstrating beneficial properties in supportive care. It however seems to be the case that the infection with SARS-CoV-2 and subsequent impairment of the renin-angiotensin-system could exhibit serious deleterious long-term effects even in oncology.

The Role of Urine and Washing Cytology in Primary Transurethral Resection of Bladder Tumours.

INTRODUCTION: Urine cytology (UC) is a recommended tool for the diagnosis of urothelial malignancies. Thus far, no specific recommendations regarding the role of washing cytology (WC) have been included in the guidelines. The goal of our study was to analyse the relationship between the histology of transurethrally (transurethral resection of the bladder [TURBT]) resected bladder tumours (BCa) and intraoperative UC or WC findings. MATERIALS AND METHODS: Five hundred consecutive primary TURBT cases conducted between November 2010 and 2015 at our department of the University Hospital Luebeck were retrospectively analysed. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of UC and WC were evaluated to detect BCa. Multivariate logistic regression models were fit to further examine associations between patient- and tumour-related factors and a bladder UC or WC positive for BCa. RESULTS: UC was performed in 297 patients, WC in 294 patients, and both in 261 patients. Sensitivity was 50.7% in UC, 58.1% in WC, and 62.1% for both tests combined. Specificity was 97.8% for UC, 98.0% for WC, and 96.4% for the combined tests. PPV was 98.0% for UC, 98.1% for WC, and 97.2% for combined tests. NPV was 47.8% for UC, 54.5% for WC, and 55.9% for the combined tests. The multivariate analyses revealed no association between positive UC or WC results and subsequent radical cystectomy (UC OR 1.35, 95% CI: 0.3-5.7; WC OR 2.0, 95% CI: 0.4-11.4). Neither UC nor WC was significantly correlated with local recurrence. CONCLUSIONS: Cytologic testing is an important diagnostic tool in BCa detection, showing acceptable sensitivity of around 60% and excellent specificity of over 90%. UC and WC present similar sensitivity. Our results advocate, however, against cytologic testing during primary TURBT, especially with regard to the lack of value in assessing the risk of recurrence. The clinical benefit of taking both types of samples at once is minimal. Furthermore, intraoperative WC collection does not reliably predict subsequent cystectomies.

Discrepancy between German S3 Guideline Recommendations and Daily Urologic Practice in the Management of Nonmuscle Invasive Bladder Cancer: Results of a Binational Survey.

INTRODUCTION: Guideline recommendations are meant to help minimize morbidity and to improve the care of nonmuscle invasive bladder cancer (NMIBC) patients but studies have suggested an underuse of guideline-recommended care. The aim of this study was to evaluate the level of adherence of German and Austrian urologists to German guideline recommendations. METHODS: A survey of 27 items evaluating diagnostic and therapeutic recommendations (15 cases of strong consensus and 6 cases of consensus) for NMIBC was administered among 14 urologic training courses. Survey construction and realization followed the checklist for reporting results of internet e-surveys and was approved by an internal review board. RESULTS: Between January 2018 and June 2019, a total of 307 urologists responded to the questionnaire, with a mean response rate of 71%. The data showed a weak role of urine cytology (54%) for initial diagnostics although it is strongly recommended by the guideline. The most frequently used supporting diagnostic tool during transurethral resection of the bladder was hexaminolevulinate (95%). Contrary to the guideline recommendation, 38% of the participants performed a second resection in the case of pTa low-grade NMIBC. Correct monitoring of Bacille Calmette-Guérin (BCG) response with cystoscopy and cytology was performed by only 34% of the urologists. CONCLUSIONS: We found a discrepancy between certain guideline recommendations and daily routine practice concerning the use of urine cytology for initial diagnostics, instillation therapy with a low monitoring rate of BCG response, and follow-up care with unnecessary second resection after pTa low-grade NMIBC in particular. Our survey showed a moderate overall adherence rate of 73%. These results demonstrate the need for sharpening awareness of German guideline recommendations by promoting more intense education of urologists to optimize NMIBC care thus decreasing morbidity and mortality rates.

Nomograms including the UBC® Rapid test to detect primary bladder cancer based on a multicentre dataset.

OBJECTIVES: To evaluate the clinical utility of the urinary bladder cancer antigen test UBC® Rapid for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high risk of primary BC. PATIENTS AND METHODS: Data from 1787 patients from 13 participating centres, who were tested between 2012 and 2020, including 763 patients with BC, were analysed. Urine samples were analysed with the UBC® Rapid test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid test was evaluated using receiver-operating characteristic curve analysis. Brier scores and calibration curves were chosen for the validation. Biopsy-proven BC was predicted using multivariate logistic regression. RESULTS: The sensitivity, specificity, and area under the curve for the UBC® Rapid test were 46.4%, 75.5% and 0.61 (95% confidence interval [CI] 0.58-0.64) for low-grade (LG) BC, and 70.5%, 75.5% and 0.73 (95% CI 0.70-0.76) for high-grade (HG) BC, respectively. Age, UBC® Rapid test results, smoking status and haematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in areas under the curve of 0.79 (95% CI 0.72-0.87) and 0.95 (95% CI: 0.92-0.98) for predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid test alone for low and medium risk levels in decision curve analysis. The R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. CONCLUSION: The UBC® Rapid test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status and haematuria provides a fast, highly accurate and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

Impact of COVID-19 crisis on medical care of patients with metastasized uro-oncologic disease under systemic cancer therapy: a multicenter study in German university hospitals.

PURPOSE: To date, over 4.2 million Germans and over 235 million people worldwide have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Uro-oncology (UO) patients are particularly vulnerable but in urgent need of life-saving systemic treatments. Our multicentric study examined the impact of the COVID-19 crisis on the medical care of UO patients in German university hospitals receiving ongoing systemic anti-cancer treatment and to detect the delay of medical care, defined as deferred medical treatment or deviation of the pre-defined follow-up assessment. METHODS: Data of 162 UO patients with metastatic disease undergoing systemic cancer treatment at five university hospitals in Germany were included in our analyses. The focus of interest was any delay or change in treatment between February 2020 and May 2020 (first wave of the COVID-19 crisis in Germany). Statistical analysis of contingency tables were performed using Pearson's chi-squared and Fisher's exact tests, respectively. Effect size was determined using Cramér's V (V). RESULTS: Twenty-four of the 162 patients (14.8%) experienced a delay in systemic treatment of more than 2 weeks. Most of these received immuno-oncologic (IO) treatments (13/24, 54.2%, p = 0.746). Blood tests were delayed or canceled significantly more often in IO patients but with a small effect size (21.1%, p = 0.042, V = 0.230). Treatment of patients with renal cell carcinoma (12/73, 16.4%) and urothelial carcinoma (7/32, 21.9%) was affected the most. CONCLUSIONS: Our data show that the COVID-19 pandemic impacted the medical care of UO patients, but deferment remained modest. There was a tendency towards delays in IO and ADT treatments in particular.

The dilemma of 12/14F ureteral access sheath (UAS) usage: a case control study.

BACKGROUND: The insertion of a ureteral access sheath (UAS) is a frequent procedure during flexible ureteroscopy (fURS) to facilitate kidney stone treatment. The aim of this study was to investigate the influence of 12/14 French (F) UAS on fURS outcomes. METHODS: We performed a retrospective monocentric analysis of fURS procedures conducted at the Department of Urology (University Hospital Schleswig-Holstein, Lübeck, Germany) for kidney stone treatment via lithotripsy or basket stone retrieval between September 2013 and June 2017. Uni- and multivariate analyses were done with the help of RStudio (Version 1.0.136) software. RESULTS: In total, 283 consecutive fURS were analyzed. UAS was applied in 98 cases (34.63%). The insertion of UAS was preferred in cases with multiple kidney stones and larger median maximal stone diameter (p < 0.05). UAS usage correlated with elevated radiation exposure in seconds (94 vs. 61; p < 0.0001), prolonged operation time in minutes (99 vs. 66, p < 0.0001), length of hospital stay over 48 h (LOS, 22.49% vs. 10.81%; p = 0.015), more frequent postoperative systemic inflammatory response syndrome (SIRS, 13.27% vs. 4.32%; p = 0.013) and lower postoperative stone-free rates (60.20% vs. 78.92%; p = 0.0013). Moreover, we conducted uni- and multivariate subgroup analysis for cases with multiple kidney stones (≥ 2) and comparable stone burden; UAS was inserted in 48.3% of these cases (71/147). On multivariate logistic regression, UAS insertion was statistically associated with prolonged operation time in minutes (101 vs. 77; p = 0.004). No statistical differences regarding radiation exposure, stone-free rates, postoperative SIRS rates or LOS were noted between UAS and non-UAS patients with multiple kidney stones of similar size (p > 0.05). CONCLUSIONS: 12/14F UAS does not seem to improve overall outcomes in fURS for kidney stones. In patients with multiple kidney stones it may be associated with elevated operation time without a clear benefit in terms of improved stone-free status or reduced perioperative complication rate. Further prospective randomized studies to specify the indications for UAS usage are urgently needed.

New computed tomographic predictors of complicated perioperative course of 17.5F mini-percutaneous nephrolithotomy (mini-PNL).

PURPOSE: Radiological parameters predicting a postoperative stone-free status (SFS) or a complicated perioperative course of mini-PNL, are scarce. Our aim was to identify such factors for prone 17.5F mini-PNL. METHODS: A monocentric cohort of 103 cases was retrospectively analysed for factors predicting SFS and relevant complications, i.e. Clavien-Dindo (CD) ≥ 2. Parameters measured on preoperative supine CT included maximal stone diameter, skin-to-stone distance (SSD), ideal tract length (ITL), access angle, minimal T12-Lower Kidney Pole distance (T12LP) and minimal Iliac Crest-Lower Kidney Pole distance (ICLP). Infundibulopelvic angle (IPA) was measured on intraoperative pyelography. RESULTS: The median maximal stone diameter was lower in cases with postoperative SFS [16 mm (Min. 10; Max. 35) vs. 20 mm (Min. 6; Max. 85), p = 0.0052]. CD ≥ 2 was more frequent in cases with a bigger stone burden [19 mm (Min. 13; Max. 85) vs. 16 mm (Min. 6; Max. 49), p = 0.0056] and with the ribs in the access angle [7/23 (30.43%) vs. 8/76 (10.53%); p = 0.0454]. T12LP significantly differed in cases with and without CD ≥ 2 [80.48 mm (± 21.31) vs. 90.43 mm (± 19.42), p = 0.0397]; however, it had no influence on SFS (p > 0.05). SSD, ITL, IPA and ICLP were significant regarding neither SFS nor CD ≥ 2 prevalence (p > 0.05). Using multivariate logistic regression, T12LP was confirmed as an independent predictor on CD ≥ 2 prevalence. CONCLUSIONS: Preoperative computed tomographic factors indicating elevated kidney position influence perioperative course of mini-PNL. T12LP and the presence of ribs in the access angle are, apart from stone diameter, the most useful indicators for cases at risk of CD ≥ 2.

Risk Factors for a Complicated Postoperative Course in Flexible Ureteroscopy.

INTRODUCTION: The goal was to determine risk factors for Clavien-Dindo (CD) grade ≥2 complications, with special focus on early postoperative systemic inflammatory response syndrome (SIRS), for flexible ureteroscopy (fURS). MATERIALS AND METHODS: A retrospective monocentric statistical analysis relating to 32 factors was performed with the χ2 test, Mann-Whitney U tests, and multivariate logistic regression. RESULTS: In total, 416 consecutive fURS performed between September 2013 and June 2017 were analyzed; 283 (68.03%) of these were for stone surgery and 133 (31.97%) for diagnostic purposes. In 43 cases (10.34%), CD ≥2 occurred; 31 cases (72.09%) of these were SIRS. On multivariate logistic regression, positive preoperative urine culture and steep pyelographic and CT-based infundibulopelvic angle (IPA) have been confirmed as independent risk factors for both CD ≥2 and SIRS. Greater maximal median stone diameter and female gender were significantly associated only with a higher CD ≥2 prevalence, but not with SIRS. The influence of ureteral access sheath (UAS) on CD ≥ 2 or SIRS occurrence could not be confirmed on multivariate analysis. Perioperative antibiotic prophylaxis for patients with negative urine culture showed no difference regarding SIRS prevalence. CONCLUSION: Steep CT-based IPA can be considered as a new radiologic predictor of complicated postoperative course and SIRS. The role of UAS as well as indications for perioperative antibiotic prophylaxis should be determined in prospective studies.

Impact of double J stenting or nephrostomy placement during transurethral resection of bladder tumour on the incidence of metachronous upper urinary tract urothelial cancer.

BACKGROUND: Whether or not double J (DJ) stenting during transurethral resection of a bladder tumour (TURBT) harms patients with regard to possible metachronous upper urinary tract urothelial cancer (UUTUC) development remains controversial. This study evaluated the impact of DJ compared to nephrostomy placement during TURBT for bladder cancer (BCa) on the incidence of metachronous UUTUCs. METHODS: We retrospectively analysed 637 patients who underwent TURBT in our department between 2008 and 2016. BCa, UUTUC and urinary drainage data (retrograde/anterograde DJ and percutaneous nephrostomy) were assessed, along with the prevalence of hydronephrosis, and mortality. Chi-square and Fisher's exact test was performed for univariate analyses. Survival analysis was performed by the Kaplan-Meier method and log-rank tests. RESULTS: UUTUC was noted in 28 out of 637 patients (4.4%), whereas only eight (1.3%) developed it metachronously to BCa. Out of these, four patients received DJ stents, while four patients received no urinary drainage of the upper urinary tract. Placement of urinary drainage significantly correlated with UUTUC (50.0% vs. 17.9%; p = 0.041). DJ stenting significantly correlated with UUTUC (50.0% vs. 11%; p <  0.01), while no patient with a nephrostomy tube developed UUTUC. UUTUC-free survival rates were significantly lower for patients with DJ stents than for all other patients (p = 0.001). Patients with or without DJ stents had similar overall survival (OS) rates (p = 0.73), whereas patients with nephrostomy tubes had significantly lower OS rates than all other patients (p <  0.001). CONCLUSIONS: Patients with DJ stenting during TURBT for BCa might have an increased risk of developing metachronous UUTUC. This study indicated advantages in placing nephrostomy tubes rather than DJ stents; however, confirmation requires investigation of a larger cohort. Even so, the increased mortality rate in the nephrostomy group reflected hydronephrosis as an unfavourable prognostic factor.

Laser fibre, rather than the stone, may harm the scope: retrospective monocentric analysis of 26 pre- and intraoperative factors of flexible ureteroscope (fURS) damage.

PURPOSE: The increasing number of flexible ureteroscopy procedures, the fragility of devices and their repair costs are a burden for urological departments worldwide. The objective was to investigate the impact of 26 pre- and intraoperative factors on reusable flexible ureteroscope (fURS) damage. METHODS: All procedures were conducted with reusable fURS: Karl Storz Flex-X2 or Olympus URF-V. Statistical analysis was performed in RStudio (1.0.136) with Chi-square test and Mann-Whitney U tests (MWU). RESULTS: In total, 416 flexible ureteroscopies, performed between September 2013 and June 2017, were analysed. 283 (68.03%) of these were for kidney stone surgery, and 133 (31.97%) for diagnostic purposes. In total, 39 (9.38%) devices were postoperatively deemed defective. The application of reusable laser fibre through fURS was more common in cases with documented defects [17/39 (43.59%) vs. 102/377 (27.06%), p = 0.047]. Other factors such as application of nitinol basket, biopsy via fURS, insertion of access sheath (UAS), as well as stone burden [median kidney stone maximal diameter: 6 mm (min 2.0; max 30.0) vs. 6 mm (min 1.0 vs. max 30.0)] showed no influence on fURS damage rate (p > 0.05). The infundibulopelvic angle (IPA) was steeper in cases with fURS damage as compared to cases without damage [median 44.0° (min 20.0; max 81.0) vs. 55.0 (min 7.0; max 122.0), p < 0.001]. CONCLUSIONS: Application of laser fibre via fURS can be considered as a risk factor of fURS damage. Stone burden, as well as the usage of not-sharp ended devices as nitinol baskets or forceps, is primarily not responsible for fURS damage.

The Impact of Endourological Experience on Flexible Ureteroscopy Outcomes and Performance at Different Levels of Expertise: Retrospective Multifactorial Analysis.

INTRODUCTION: The aim of this study was to analyze the influence of residents' participation in flexible ureteroscopy (fURS) on intra- and postoperative outcomes. MATERIALS AND METHODS: Intra- and postoperative parameters were compared in a retrospective monocentric setting between 3 groups: "resident group" (47 cases) for surgeries performed by experienced residents alone, "consultant group" (245 cases) for surgeries performed by consultants alone, "resident plus consultant group" (124 cases) for training surgeries between September 2013 and June 2017. RESULTS: Patients operated by residents alone had a significantly smaller median kidney stone diameter (5.0 vs. 7.0 mm for "consultant group" and 6.0 mm for "resident plus consultant group," p = 0.011), shorter operating time (median 47.0 vs. 63.0 and 77.0 min, p < 0.001) and fluoroscopy time (median 39.0 vs. 69.5 and 89.0 s, p < 0.001), as well as shorter postoperative hospital stay (p = 0.013). The laser application rate was the smallest in the "resident group" (10.64 vs. 31.43 and 29.84%, p = 0.009). Univariate analysis revealed no relevant differences regarding flexible ureteroscope defect rate, postoperative stone-free rate, or ≥2 Clavien-Dindo classification complications between the groups (p > 0.05). CONCLUSION: A proper case selection of less complicated cases, especially without laser application, could balance the experience deficit of the residents. fURS can be incorporated as a part of residents' training without an impact on fURS device defect rate or clinical outcomes.

Extended Techniques of Minimally Invasive Surgery in the Retroperitoneum: Practice Pattern in German Urology Departments.

INTRODUCTION: Laparoendoscopic single-site surgery (LESS), robot-assisted (RA), and retroperitoneoscopic (R) surgery expand the armamentarium of minimally invasive surgery (MIS). As information on the use of these surgical approaches in daily routine is limited, we conducted a survey among German urologists. MATERIALS AND METHODS: In 2017, all urology departments in Germany received a questionnaire evaluating practice patterns of MIS in the retroperitoneum. Chi-Square test was performed for statistical analyses. The response rate was 51.1% (162/311) including 23 universities. RESULTS: R adrenalectomy and (partial) nephrectomy are performed by 32.7-40.1% of all departments. Transperitoneal LESS adrenalectomy and nephrectomy are performed by 8.6-11.7%. Retroperitoneal RA adrenalectomy and (partial) nephrectomy are performed by 6.2-13.0%. There was no difference in the R and LESS approach between (non)-university departments. Retroperitoneal RA access is more frequently used in university hospitals (all p < 0.01). If performed, mean counts within the last 12 months were < 5 for R, LESS, and RA adrenalectomy; and < 20 for R, LESS, and RA (partial) nephrectomy. CONCLUSION: Our survey provides a detailed insight into MIS in the retroperitoneum in German urology departments. Numbers of adrenalectomies as well as R, transperitoneal LESS and retroperitoneal RA procedures are low. Retroperitoneal RA surgery is more common in universities. Comprehensively, our survey proves that these approaches are not standard approaches yet.

Acceptance of Adjuvant and Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer in Germany: A Survey of Current Practice.

BACKGROUND: Guidelines support the use of neoadjuvant (NAC) and adjuvant (AC) chemotherapy in muscle-invasive bladder cancer. However, data from North America reported the underutilization of NAC in favor of AC despite the lower level of scientific evidence supporting AC. We aimed to assess current practice patterns of NAC and AC in -Germany. METHODS: A 15-question online survey was developed and sent via email newsletters to members of the -German Association of Urology and of the German Society of Residents in Urology in October 2016 to analyze current practice patterns. RESULTS: The survey yielded 141 individual responses from 61 different German urology departments. Eighty-nine (69.0%) and 119 (93.0%) participants were stated to regularly use NAC and AC respectively. The number of participants who were stated to use NAC and AC regularly was not associated with the type of institution (academic vs. nonacademic), number of hospital beds, and number of cystectomies performed annually. Gemcitabine/cisplatin combination chemotherapy was named as the primarily used NAC regimen by 80 (95%) respondents. The median number of administered cycles was 3 for NAC and 4 for AC. In the case of cisplatin ineligibility, combination chemotherapy with gemcitabine/carboplatin was the most common regimen. Respondents stated that chemotherapy was generally administered by urologists (81% for NAC and 85% for AC). CONCLUSIONS: Our survey of current practice shows a high acceptance rate of NAC in Germany, which was independent of the type of institution. Although the scientific level of evidence for AC is lower, it still seems to be more widely accepted than NAC. NAC and AC were generally administered by urologists.

Hyaluronic acid family in bladder cancer: potential prognostic biomarkers and therapeutic targets.

BACKGROUND: Molecular markers of clinical outcome may aid in designing targeted treatments for bladder cancer. However, only a few bladder cancer biomarkers have been examined as therapeutic targets. METHODS: Data from The Cancer Genome Atlas (TCGA) and bladder specimens were evaluated to determine the biomarker potential of the hyaluronic acid (HA) family of molecules - HA synthases, HA receptors and hyaluronidase. The therapeutic efficacy of 4-methylumbelliferone (4MU), a HA synthesis inhibitor, was evaluated in vitro and in xenograft models. RESULTS: In clinical specimens and TCGA data sets, HA synthases and hyaluronidase-1 levels significantly predicted metastasis and poor survival. 4-Methylumbelliferone inhibited proliferation and motility/invasion and induced apoptosis in bladder cancer cells. Oral administration of 4MU both prevented and inhibited tumour growth, without dose-related toxicity. Effects of 4MU were mediated through the inhibition of CD44/RHAMM and phosphatidylinositol 3-kinase/AKT axis, and of epithelial-mesenchymal transition determinants. These were attenuated by HA, suggesting that 4MU targets oncogenic HA signalling. In tumour specimens and the TCGA data set, HA family expression correlated positively with ß-catenin, Twist and Snail expression, but negatively with E-cadherin expression. CONCLUSIONS: This study demonstrates that the HA family can be exploited for developing a biomarker-driven, targeted treatment for bladder cancer, and 4MU, a non-toxic oral HA synthesis inhibitor, is one such candidate.

Transurethral en bloc resection of nonmuscle invasive bladder cancer: trend or hype.

PURPOSE OF REVIEW: Inherent limitations of conventional transurethral resection of bladder tumors as the standard approach for diagnosis and treatment of bladder cancer are well know: staging error because of insufficient assessment of resection depth as well as intravesical tumor fragmentation that complicates histopathological evaluation. The purpose of this review is to present recent clinical data on en bloc resection of bladder tumor (ERBT) that has been demonstrated to offer high potential to overcome these limitations. RECENT FINDINGS: The recently published studies confirm the results our previous reviews for laser ERBT and current-based ERBT from 2014. ERBT provides a better resection quality with up to 95% presence lamina muscularis propria as surrogate marker for quality. It can be performed using all energy sources. Available data demonstrate with all due limitations of reporting quality no relevant difference with regard to perioperative morbidity compared with conventional transurethral resection of bladder tumors. No conclusions can be drawn regarding the impact of ERBT on recurrence as data are controversial. SUMMARY: ERBT has gained momentum in the past years. The hypothesized advantages over conventional TURBT seem to manifestate for tumors up to 3 or 4 cm in size with regard to staging, specimen quality, and analyzability in pathological evaluation in general. The impact on recurrence remains to be defined by further studies.

Long-term bowel disorders following radial cystectomy: an underestimated issue?

PURPOSE: Patients after radical cystectomy (RC) frequently complain about bowel disorders (BDs). Reports addressing related long-term complications are sparse. This cross-sectional study assessed changes in bowel habits (BH) after RC. METHODS: A total of 89 patients with a minimum follow-up ≥1 year after surgery were evaluated with a questionnaire. Patients with BD prior to surgery were excluded. Symptoms such as diarrhea, constipation, bloating/flatulence, incomplete defecation, uncontrolled stool loss, and impact on quality of life (QoL) were assessed. RESULTS: A total of 46.1 % of patients reported changes in BH; however, only 25.8 % reported experiencing related dissatisfaction. Primary causes of dissatisfaction were diarrhea and uncontrolled stool loss. The most common complaints were bloating/flatulence and the feeling of incomplete defecation, but these symptoms did not necessarily lead to dissatisfaction or impairment in quality of life. No difference was identified between an orthotopic neobladder and ileal conduit, and even patients without bowel surgery were affected. QoL, health status, and energy level were significantly decreased in unsatisfied patients. CONCLUSIONS: About 25 % of patients complain about BDs after RC. More prospective studies assessing symptoms, comorbidities, and dietary habits are necessary to address this issue and to identify strategies for follow-up recommendations.