Salvage Robotic-assisted Laparoscopic Radical Prostatectomy Following Focal High-Intensity Focused Ultrasound for ISUP 2/3 Cancer.

OBJECTIVE: To report feasibility and outcome of salvage robotic-assisted laparoscopic radical prostatectomy (S-RALP) after focal therapy using high-intensity focused ultrasound (HIFU) treatment compared to primary robotic-assisted laparoscopic radical prostatectomy (pRALP). METHODS: In this bicentric trial patients undergoing S-RALP for detection of WHO2016/ISUP Grade Group 2 or 3 prostate cancer were previously treated in prospective focal HIFU trials. Perioperative data, complications, oncological and functional outcome were analysed. Patients who underwent pRALP were matched in a ratio 2(pRALP):1(S-RALP) according to preoperatively functional, oncological and clinical parameters. RESULTS: A total of 39 patients were included in the study (13S-RALP, 26pRALP). Median operative time in the S-RALP group was 260minutes (pRALP: 257minutes), blood loss was 230ml (pRALP: 300ml). Complications occurred in 46.2% (6/13) of S-RALP patients (pRALP: 26.9%), including four Clavien-Dindo III complications (pRALP: 2/26). In S-RALP adverse histological outcome (≥pT3a, pN+ or R1) was detected in 23.1% (3/13) (pRALP: 26.9%). There was one patient with PSA-persistence (pRALP: 2/26). Regarding functional outcomes there was no difference between the two groups observed (incontinence P=.71, erectile function P=.21). CONCLUSION: S-RALP should be offered to patients with an early relapse after focal HIFU. The early oncological outcome is satisfactory and functional outcome one year postoperatively is similar to pRALP. However, S-RALP is associated with a higher rate of Clavien-Dindo III complications (mainly, placement of a drainage), of which patients should be informed beforehand.

Peritoneal flap for lymphocele prophylaxis following robotic-assisted laparoscopic radical prostatectomy with pelvic lymph node dissection: study protocol and trial update for the randomized controlled PELYCAN study.

BACKGROUND: Data from interventional studies suggest that a peritoneal flap after pelvic lymph node dissection (LND) during laparoscopic, robotic-assisted radical prostatectomy (RARP) may reduce the rate of symptomatic lymphoceles in transperitoneal approach. However, most of these studies are not conducted in a randomized controlled fashion, thus limiting their scientific value. A recent prospective, randomized, controlled trial (RCT) did not show superiority of a peritoneal flap while further trials are lacking. Therefore, the aim of the presented RCT will be to show that creating a peritoneal flap decreases the rate of symptomatic lymphoceles compared to the current standard procedure without creation of a flap. METHODS/DESIGN: PELYCAN is a parallel-group, patient- and assessor-blinded, phase III, adaptive randomized controlled superiority trial. Men with histologically confirmed prostate cancer who undergo transperitoneal RARP with pelvic LND will be randomly assigned in a 1:1 ratio to two groups-either with creating a peritoneal flap (PELYCAN) or without creating a peritoneal flap (control). Sample size calculation yielded a sample size of 300 with a planned interim analysis after 120 patients, which will be performed by an independent statistician. This provides a possibility for early stopping or sample size recalculation. Patients will be stratified for contributing factors for the development of postoperative lymphoceles. The primary outcome measure will be the rate of symptomatic lymphoceles in both groups within 6 months postoperatively. Patients and assessors will be blinded for the intervention until the end of the follow-up period of 6 months. The surgeon will be informed about the randomization result after performance of vesicourethral anastomosis. Secondary outcome measures include asymptomatic lymphoceles at the time of discharge and within 6 months of follow-up, postoperative complications, mortality, re-admission rate, and quality of life assessed by the EORTC QLQ-C30 questionnaire. DISCUSSION: The PELYCAN study is designed to assess whether the application of a peritoneal flap during RARP reduces the rate of symptomatic lymphoceles, as compared with the standard operation technique. In case of superiority of the intervention, this peritoneal flap may be suggested as a new standard of care. TRIAL REGISTRATION: German Clinical Trials Register DRKS00016794 . Registered on 14 May 2019.

Vesico-urethral anastomotic stenosis following radical prostatectomy: a multi-institutional outcome analysis with a focus on endoscopic approach, surgical sequence, and the impact of radiation therapy.

OBJECTIVES: To investigate the predictors of recurrence and of de novo incontinence in patients treated by transurethral incision or resection for vesico-urethral anastomotic stenosis (VUAS) after radical prostatectomy. MATERIAL AND METHODS: All patients undergoing endoscopic treatment for VUAS between March 2009 and October 2016 were identified in our multi-institutional database. Digital chart reviews were performed and patients contacted for follow-up. Recurrence was defined as any need for further instrumentation or surgery, and de-novo-incontinence as patient-reported outcome. RESULTS: Of 103 patients undergoing endoscopic VUAS treatment, 67 (65%) underwent transurethral resection (TR) and 36 (35%) transurethral incision (TI). TI was performed more frequently as primary treatment compared to TR (58% vs. 37%; p = 0.041). Primary and repeated treatment was performed in 46 (45%) and 57 patients (55%), respectively. Overall, 38 patients (37%) had a history of radiation therapy. There was no difference in time to recurrence for primary vs repeat VUAS treatment, previous vs no radiation, TR compared to TI (all p > 0.08). Regarding treatment success, no difference was found for primary vs. repeat VUAS treatment (50% vs. 37%), previous radiation vs. no radiation (42% vs. 43%), and TR vs. TI (37% vs. 53%; all p ≥ 0.1). Postoperative de novo incontinence was more common after TI vs. TR (31% vs. 12%; p = 0.032), no difference was observed for previous radiation therapy vs. no radiation therapy (18% vs. 18%; p > 0.9) or primary vs. repeat VUAS treatment (22% vs. 16%; p = 0.5). CONCLUSION: VUAS recurrence after endoscopic treatment is not predictable. Endoscopic treatment with TI showed a higher risk for de novo incontinence than TR, and previous irradiation and the number of treatments do not influence incontinence.

The comprehensive complication index (CCI): proposal of a new reporting standard for complications in major urological surgery.

PURPOSE: The comprehensive complication index (CCI) is a new tool for reporting the cumulative burden of postoperative complications on a continuous scale. This study validates the CCI for urological surgery and its benefits over the Clavien-Dindo-Classification (Clavien). MATERIAL AND METHODS: Data from a prospectively maintained data base of all consecutive patients at a university care-center was analyzed. Complications after radical cystectomy (RC), radical prostatectomy (RP), and partial nephrectomy (PN) were classified using the CCI and Clavien system. Differences in complications between the CCI and the Clavien were assessed and correlation analyses performed. Sample size calculations for hypothetical clinical trials were compared between CCI and Clavien to evaluate whether the CCI would reduce the number of required patients in a clinical trial. RESULTS: 682 patients (172 RC, 297 RP, 213 PN) were analyzed. Overall, 9.4-46.6% of patients had > 1 complication cumulatively assessed with the CCI resulting in an upgrading in the Clavien classification for 2.4-32.4% of patients. Therefore, scores between the systems differed for RC: CCI (mean ± standard deviation) 26.3 ± 20.8 vs. Clavien 20.4 ± 16.7, p < 0.001; PN: CCI 8.4 ± 14.7 vs. Clavien 7.0 ± 11.8, p < 0.001 and RP: CCI 5.8 ± 11.7 vs. Clavien 5.3 ± 10.6, p = 0.102. The CCI was more accurate in predicting LOS after RC than Clavien (p < 0.001). Sample size calculations based in the CCI (for future hypothetical trials) resulted in a reduction of required patients for all procedures (- 25% RC, - 74% PN, - 80% RP). CONCLUSION: The CCI is more accurate to assess surgical complications and reduces required sample sizes that will facilitate the conduction of clinical trials.

[Urological research in Germany : A retrospective, longitudinal observational study]. / Urologische Forschung in Deutschland : Eine retrospektive, longitudinale Beobachtungsstudie.

BACKGROUND AND OBJECTIVES: The congress of the German Society of Urology reflects urologic research in German-speaking countries. The objective was to identify trends by analyzing the congress' abstracts and following full publications longitudinally. MATERIALS AND METHODS: The abstracts of the 2016 congress were systematically analyzed regarding content, study design, cooperation, following full publications and journals which they were published in. Thereafter, the 2016 congress was compared to the 2002 and 2009 congresses. Statistical analysis included χ2-, Mann-Whitney U-, Cochran-Armitage-, and Kruskal-Wallis test. RESULTS: A total of 1073 abstracts were presented at the 2002, 2009, and 2016 congresses. We found an increase in abstracts regarding prostate disease (24.2%, 29.7%, and 34.0%; p = 0.0043), oncological abstracts (50.6%, 57.9%, and 61.7%; p = 0.003), multicenter studies (18.3, 28.6, and 34.3%; p < 0.0001) and cooperation (55.6%, 62.9%, and 70.5%, p < 0.0001). Experimental (29.0%, 33.2%, and 22.8%; p = 0.009) and prospective studies (62.1%, 42.0%, and 36.0%; p < 0.0001) declined. Abstracts including statistical analysis (18.4%, 14.7%, and 41.2%; p < 0.0001) and the impact factor of following full publications (2.08, 3.42, 4.42; p < 0.0001) rose. In 2016, 11.2% of those full publications were published Open Access. The publication rates of the presented abstracts were 49.1%, 56.3%, and 52.3%, respectively (p = 0.15). CONCLUSIONS: National and international networking of the urological research community has increased. Presentation of prospective studies has declined. The rate of peer-reviewed full publications following the DGU abstracts remains at a stable high level over the three congresses. The publication rate in Open Access journals is low.

Clinical relevance of gene expression in localized and metastatic prostate cancer exemplified by FABP5.

PURPOSE: Fatty acid-binding protein 5 (FABP5), a transport protein for lipophilic molecules, has been proposed as protein marker in prostate cancer (PCa). The role of FABP5 gene expression is merely unknown. METHODS: In two cohorts of PCa patients who underwent radical prostatectomy (n = 40 and n = 57) and one cohort of patients treated with palliative transurethral resection of the prostate (pTUR-P; n = 50) FABP5 mRNA expression was analyzed with qRT-PCR. Expression was correlated with clinical parameters. BPH tissue samples served as control. To independently validate findings on FABP5 expression, three microarray and sequencing datasets were reanalyzed (MSKCC 2010 n = 216; TCGA 2015 n = 333; mCRPC, Nature Medicine 2016 n = 114). FABP5 expression was correlated with ERG-fusion status, TCGA subtypes, cancer driver mutations and the expression of druggable downstream pathway components. RESULTS: FABP5 was overexpressed in PCa compared to BPH in the cohorts analyzed by qRT-PCR (radical prostatectomy p = 0.003, p = 0.010; pTUR-P p = 0.002). FABP5 expression was independent of T stage, Gleason Score, nodal status and PSA level. FABP5 overexpression was associated with the absence of TMPRSS2:ERG fusion (p < 0.001 in TCGA and MSKCC). Correlation with TCGA subtypes revealed FABP5 overexpression to be associated with SPOP and FOXA1 mutations. FABP5 was positively correlated with potential drug targets located downstream of FABP5 in the PPAR-signaling pathway. CONCLUSION: FABP5 overexpression is frequent in PCa, but seems to be restricted to TMPRESS2:ERG fusion-negative tumors and is associated with SPOP and FOXA1 mutations. FABP5 overexpression appears to be indicative for increased activity in PPAR signaling, which is potentially druggable.

Prognostic Value of Molecular Breast Cancer Subtypes based on Her2, ESR1, PGR and Ki67 mRNA-Expression in Muscle Invasive Bladder Cancer.

INTRODUCTION: Gene expression analyses have identified similarities between bladder and breast cancer, where clinical risk stratification is based on Her2, ESR1, PGR and Ki67 expression. The aim of the study was to assess the respective marker gene expression in patients treated with radical cystectomy for muscle-invasive bladder cancer (MIBC) and to evaluate the applicability of breast cancer subtypes for MIBC risk stratification. MATERIALS & METHODS: 102 patients treated with radical cystectomy for MIBC were assessed. Using routine FFPE tissue and an IVD validated kit, mRNA expression was measured by single step RT-qPCR. Partition test were employed to define cut-off values for high or low marker gene expression. Association of expression with outcome was assessed using Kaplan-Meier analysis and multivariate cox regression analysis. Finally, we performed validation of our results in the MD-Anderson cohort (n=57). RESULTS: Cancer specific survival (CSS) was impaired in patients with high gene expression of Her2 (P=0.0009) and ESR1 (P=0.04). In the multivariate regression model Her2 expression remained significant for the prediction of CSS (HR=2.11, CI 1.11-4.21, P=0.024). Furthermore, molecular stratification by breast cancer subgroups was significant (P=0.023) for CSS prediction. Especially the differentiation between Her2-positive and Luminal A (HR=4.41, CI 1.53-18.71, P=0.004) and Luminal B (HR=1.96, CI 0.99-4.08, P=0.053) respectively was an independent prognostic parameter for CSS. External validation resulted in comparable risk stratification with differences in fractional subgroups distribution. CONCLUSION: Gene expression of Her2, ESR1, PGR, Ki67 and corresponding breast cancer subtypes allow a risk-stratification in MIBC, whereby Her2 overexpressing tumors reveal a particularly poor prognosis.

Novel insights into a reputably irreversible process: combined mRNA and miRNA profiling of tissue from vesicourethral anastomotic stenosis after radical prostatectomy.

PURPOSE: Until recently, tissue fibrosis-ultimately leading to permanent scaring-has been considered an irreversible process. However, recent findings indicate that it may be reversible after all. Vesicourethral anastomotic stenosis (VUAS) as fibrous narrowing is a frequent complication after radical prostatectomy with high recurrence rates and requires invasive treatment. The pathophysiology is poorly understood. Therefore, a combined mRNA and miRNA transcription profiling in tissue from VUAS was performed using nCounter technology. METHODS: To assess tissue morphology and fiber composition, histochemical staining was performed. RNA expression of healthy and fibrotic tissue of twelve patients was analyzed using the human miRNA panel v3 and mRNA PanCancer pathway panel on the nCounter gene1 system and qRT-PCR. Differential expression data analysis was performed using the nSolver software implementing the R-based advanced pathway analysis tool. miRWalk2.0 was used for miRNA target prediction. RESULTS: More linearized tissue architecture, increased collagens, and decreased elastic fibers were observed in VUAS samples. 23 miRNAs and 118 protein coding genes were differentially expressed (p < 0.01) in fibrotic tissue. miRNA target prediction and overlap analysis indicated an interaction of the strongest deregulated miRNAs with 29 deregulated mRNAs. Pathway analysis revealed alterations in DNA repair, cell cycle regulation, and TGF-beta signaling. qRT-PCR confirmed differential expression of top deregulated miRNAs and mRNAs. CONCLUSIONS: In VUAS tissue, severe alterations on mRNA and miRNA level are found. These consistent changes give insights into the pathogenesis of VUAS after radical prostatectomy and point to future options for transcriptomics-based risk stratification and targeted therapies.

[Modern networks : Topics in the working group "Bladder cancer research" of the GeSRU Academics]. / Modernes Netzwerken : Thematische Ausrichtungen in der Arbeitsgruppe "Blasenkarzinom Experimentell" der GeSRU Academics.

In January 2015, the research group "bladder cancer research" was founded as part of the GeSRU Academics research initiative. A general challenge to work successfully in a novel network structure is to identify common scientific topics and technical expertise in the group. Thus, one of the first tasks was to learn about current research projects from members within the group in order to address a project that suits the group's expertise. The following review summarizes three different directions that are key projects in Urologic Departments at German Universities that will be the basis to start fruitful collaborations.

[Abstracts at congresses of the German Society of Urology. Trends and quality]. / Beiträge des Kongresses der Deutschen Gesellschaft für Urologie. Trends und Qualität.

BACKGROUND: The congress of the German Society of Urology is the third biggest urology congress worldwide and reflects the scientific landscape of urology in Germany. In the congress abstracts, detailed data regarding study design, current trends in urologic research and the cooperation of authors are lacking. We wanted to identify factors contributing to the likelihood of an abstract being followed by a publication in a peer-reviewed journal. MATERIAL AND METHODS: The two congresses of the years 2002 and 2009 were exemplarily analyzed. Various aspects regarding study design and cooperations were retrieved from the abstracts and trends were determined. Subsequent publications in peer-reviewed journals were searched for in MEDLINE and potential factors influencing publication success were identified. Significance was tested for using the χ (2) and Mann-Whitney-U statistical tests. RESULTS: A total of 732 abstracts (2002: 352, 2009: 380) were analyzed, one third of which contained prospective, retrospective or preclinical/experimental studies. Internal (28.7 %) and national (27.6 %) cooperations were most frequent. Significant trends towards more retrospective studies (p=0.008) and national cooperations (p=0.019) were found. Of the abstracts 49.2 % (2002) and 56.3% (2009) were followed by publication in peer-reviewed journals (median 15.1 months) with a significantly higher mean impact factor in 2009 (3.4 vs. 2.1, respectively p>0.0001). Therapeutic studies and those including statistics or national cooperations were significantly more likely to be published. CONCLUSION: In the future urologic research should focus on prospective studies. Many abstracts are not followed by a publication in a peer-reviewed journal. This is especially true for abstracts containing no statistics. As national collaborations are correlated with successful publication, an early national networking of young researching urologists should be promoted.

The pharmacodynamic characterization of an antisense oligonucleotide against monoamine oxidase-B (MAO-B) in rat brain striatal tissue.

1. The aim of our work was to pharmacodynamically characterize an antisense oligonucleotide sequence (5'-GCC AAA CTT TTG CAT GAC-3') against MAO-B, using qualitative and quantitative analyses as assessment measures. 2. Qualitative analysis using histochemical staining revealed that intracerebroventricular (ICV) administered antisense (100 picomoles twice daily x 3.5 days) eliminated all visibly detectable histochemical staining for MAO-B throughout the striatum 1, 12, and 24 h after the last antisense treatment. 3. Qualitative analysis using RT-PCR of the time course of MAO-B mRNA expression in the rat striatum following ICV administration of the antisense sequence showed that 12-24 h after the last administration there was a dramatic reduction in MAO-B mRNA expression in the striatum. The reverse and scrambled sequences generated no change in MAO-B mRNA at 1 or 24 h after the last treatment. 4. Quantitative analysis using the MAO-B selective substrate 4-dimethylamino-phenethylamine (DMAPEA) showed that the antisense sequence reduced MAO-B activity by more than 40%, which was comparable to a single 2 mg/kg, ip dose of L-deprenyl. 5. Quantitative analysis of neurotransmitter levels 24 h after the last treatment suggested that the antisense sequence did not produce any significant changes in neurotransmitter levels. 6. Potential mechanisms for enhancing the antisense response and the speculated potential of an antisense against MAO-B for studying neurotoxicity, Parkinson's disease, and the aging process are also discussed.