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Josef Mang,1 Linda Hennig,1 lutz Liefeldt,2 Michael Duerr,2 Lukas J Lehner,2 Anna Bichmann,3 Bernhard Ralla,1 Hannes Cash,4 Martin Christopher Kanne,5 Robert Peters,1 Andreas Maxeiner,1,* Frank Friedersdorff1,5,* 1Department of Urology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 2Department of Nephrology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 3Department of Anesthesiology and Operative Intensive Care Medicine, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 4PROURO, Berlin, Germany; 5Department of Urology, Evangelisches Krankenhaus Königin Elisabeth Herzberge, Berlin, Germany*These authors contributed equally to this workCorrespondence: Linda HennigDepartment of Urology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, Berlin, 10117, GermanyEmail linda.hennig@charite.dePurpose: Focal segmental glomerulosclerosis (FSGS) is a common cause for end-stage renal disease that can recur in the graft after kidney transplantation. The incidence of FSGS recurrence is reported in up to 47% of patients, predisposing those to possible poorer transplantation outcomes. Hence, we examined the incidence of FSGS recurrence and the effect on graft outcome in our patient cohort of living donor kidney transplantations (LDKT).Patients and Methods: We analyzed 194 adult patients who received a LDKT between 2011 and 2017 of which 22 (11%) had FSGS as underlying disease. Demographic data and clinical outcomes, especially regarding recurrence of FSGS, were evaluated.Results: FSGS recurrence was identified in three (14%) patients within three months after transplantation, of whom two patients (9%) lost their graft. There was no significant difference in graft survival comparing FSGS to other reasons for end-stage renal disease.Conclusion: Incidence of FSGS recurrence in the present patient cohort was within the range reported in the literature and comparatively low. Our data support LDKT as a treatment option in patients with end-stage renal disease due to FSGS.Keywords: FSGS, living donor nephrectomy, recurrence

Nora Köhler, Nasrin El-Bandar, Andreas Maxeiner, Bernhard Ralla, Kurt Miller, Jonas Busch,* Frank Friedersdorff* Department of Urology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humbold-Universität Zu Berlin, and Berlin Institute of Health, Berlin 10117, Germany*These authors contributed equally to this workCorrespondence: Frank Friedersdorff Tel +49 30 450615219Fax +49 30 450515910Email frank.friedersdorff@charite.dePurpose: To compare running suture (RS) and interrupted suture (IS) of vesicourethral anastomosis (VUA) during open retropubic radical prostatectomy (RRP) on early urinary continence and extravasation.Patients and Methods: Single center analysis of 211 patients who underwent RRP performed by a single surgeon during 2008 to 2017 was retrospectively analyzed. For VUA, we used the standard interrupted suture technique (n=100) with a 3– 0 PDS suture. The RS (n=111) was performed with 12-bite suture using 3– 0 PDS. The primary endpoints were extravasation and early continence. Demographic and peri-operative data were collected and analyzed using Pearson’s chi-square, t-Test and Mann–Whitney U-test. A binary logistic regression analysis was carried out to explore predictors that affected early continence after catheter removal.Results: The rates of early urinary incontinence (UI) were 7.7% vs 42.2% (p< 0.001). The duration of catheterization and hospitalization was significantly shorter in the interrupted group (4 days vs 5 days, p< 0.001 and 5 days vs 6 days, p< 0.001). The groups did not differ significantly in body mass index or prostate volume. There were older patients and higher PSA levels in the group with RS technique. No significant difference was found in the postoperative extravasation rates between both groups (13.5% vs 12%, p=0.742).Conclusion: Running vesicourethral anastomosis increased the rate of early urinary incontinence. Both anastomosis techniques provided a similar rate of postoperative urine extravasation. VUA should only be one of the many criteria that must be considered for the preservation of urinary continence of patients after RRP.Keywords: retropubic prostatectomy, vesicourethral anastomosis, suturing technique, continence, tightness

Purpose: To compare running suture (RS) and interrupted suture (IS) of vesicourethral anastomosis (VUA) during open retropubic radical prostatectomy (RRP) on early urinary continence and extravasation. Patients and methods: Single center analysis of 211 patients who underwent RRP performed by a single surgeon during 2008 to 2017 was retrospectively analyzed. For VUA, we used the standard interrupted suture technique (n=100) with a 3-0 PDS suture. The RS (n=111) was performed with 12-bite suture using 3-0 PDS. The primary endpoints were extravasation and early continence. Demographic and peri-operative data were collected and analyzed using Pearson's chi-square, t-Test and Mann-Whitney U-test. A binary logistic regression analysis was carried out to explore predictors that affected early continence after catheter removal. Results: The rates of early urinary incontinence (UI) were 7.7% vs 42.2% (p

Background: Circular RNAs (circRNAs) are a new class of RNAs with medical significance. Compared to that of linear mRNA transcripts, the stability of circRNAs against degradation owing to their circular structure is considered advantageous for their use as biomarkers. As systematic studies on the stability of circRNAs depending on the RNA integrity, determined as RNA integrity number (RIN), in clinical tissue samples are lacking, we have investigated this aspect in the present study under model and clinical conditions. Methods: Total RNA isolated from kidney cancer tissue and cell lines (A-498 and HEK-293) with different RIN after thermal degradation was used in model experiments. Further, RNA isolated from kidney cancer and prostate cancer tissue collected under routine surgical conditions, representing clinical samples with RIN ranging from 2 to 9, were examined. Quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR) analysis of several circRNAs (circEGLN3, circRHOBTB3, circCSNK1G3, circRNA4, and circRNA9), their corresponding linear counterparts, tissue-specific reference genes, and three microRNAs (as controls) was performed. The quantification cycles were converted into relative quantities and normalized to the expression of specific reference genes for the corresponding tissue. The effect of RIN on the expression of different RNA entities was determined using linear regression analysis, and clinical samples were classified into two groups based on RIN greater or lesser than 6. Results: The results of model experiments and clinical sample analyses showed that all relative circRNA expression gradually decreased with reduction in RIN values. The adverse effect of RIN was partially compensated after normalizing the data and limiting the samples to only those with RIN values > 6. Conclusions: Our results suggested that circRNAs are not stable in clinical tissue samples, but are subjected to degradative processes similar to mRNAs. This has not been investigated extensively in circRNA expression studies, and hence must be considered in future for obtaining reliable circRNA expression data. This can be achieved by applying the principles commonly used in mRNA expression studies.

Das Nierenzellkarzinom (NZK) stellt weltweit die dritthäufigste bösartige Erkrankung in der Urologie dar. Es werden das lokal begrenzte, das lokal fortgeschrittene und das metastasierte Krankheitsstadium unterschieden für die jeweils unterschiedliche Prognosen und Therapiestrategien bestehen. Eine Besonderheit beim lokal fortgeschrittenen NZK stellt das Tumorwachstum per continuitatem in die Vena renalis oder Vena cava inferior (VCI) dar, das bei 4-10% aller neudiagnostizierten NZK-Erkrankungen vorliegt. Trotz kurativer Therapie bei Patienten mit lokal begrenztem oder lokal fortgeschrittenem NZK erleiden zwischen 15-30% der Patienten im Verlauf ein Rezidiv oder Metastasen. Um den Patienten eine individualisierte Therapie- und Nachsorgestrategie anbieten zu können, besteht daher ein großer Bedarf an prognostischen Markern, insbesondere Biomarkern. Ziel der vorliegenden Arbeit war es, verschiedene Prognosefaktoren und die unterschiedliche Effektivität von Therapiestrategien bei Patienten mit lokal fortgeschrittenem oder metastasiertem NZK, die an der Klinik für Urologie der Charité – Universitätsmedizin Berlin behandelt wurden, zu untersuchen. In der ersten Studie dieser Arbeit wurden hierzu Patienten mit radiologischen Nachweis eines NZK und fortgeschrittenem Tumorthrombus in die VCI (Level II-IV nach der Mayo-Klassifikation) die durch eine radikale Nephrektomie mit Tumorthrombektomie behandelt wurden, untersucht. Nur das Vorliegen einer primären Metastasierung war ein statistisch signifikant unabhängiger Prädiktor für das Gesamtüberleben. Das Tumorthrombuslevel, Alter des Patienten, Komorbiditäten, OP-Technik bzw. -Dauer stellten keine statistisch signifikanten Prädiktoren dar. Eine radikale Nephrektomie mit Tumorthrombektomie stellt trotz hohen peri- und postoperativen Risikos eine anspruchsvolle, aber effektive Therapiestrategie dar. Ziel der zweiten Studie dieser Arbeit war es das Potenzial von piwi-interacting RNA (piRNA), als prognostische Biomarker für die Entwicklung eines Rezidivs bzw. für das Gesamtüberleben (OS) zu untersuchen. Es konnte gezeigt werden, dass alle drei ausgewählten piRNA in metastasiertem Tumorgewebe und Gewebe aus Knochenmetastasen verschiedene Expressionsprofile aufwiesen und statistisch signifikante Prädiktoren für OS bei Patienten mit lokal begrenzten und metastasierten NZK waren, obwohl in nicht metastasiertem Tumorgewebe alle drei piRNA im Vergleich zu Normalgewebe signifikant heruntergeregelt waren. Zusammen mit der histologischen Tumordifferenzierung war pRNA-38756 bei nicht metastasierten NZK-Patienten ein unabhängiger prognostischer Faktor für die Vorhersage des rezidivfreien Überlebens (RFS) und des OS. Weiter konnte gezeigt werden, dass piRNA als zusätzliche Biomarker konventionelle Prognosemodelle signifikant verbessern. Ziel der dritten Studie dieser Arbeit war es miRNA-Expressionsprofile aus Tumorgewebe als prädiktive Biomarker für eine primäre Resistenz einer systemischen Therapie bei Patienten mit mNZK zu identifizieren. Hierfür wurden Patienten mit mNZK eingeschlossen, die in Erstlinientherapie mit einem TKI behandelt wurden und je nach Therapieansprechen in „Responder“ und „Non-Responder“ eingeteilt wurden. Es konnte gezeigt werden, dass miR-9-5p und miR-489-3p in der Lage waren, zwischen beiden Gruppen zu differenzieren und miR-9-5p das Potenzial als prädiktiver Biomarker bzgl. des Ansprechens einer TKI-Therapie und des progressionsfreien Überlebens (PFS) unter Therapie besitzt. Ziel der vierten und fünften Studie dieser Arbeit war die Untersuchung der Effektivität einer systemischen Therapie bei metastasierten NZK-Patienten, die bereits mindestens drei Therapielinien als Sequenztherapie erhielten. Zusätzlich wurden Prädiktoren bzgl. des PFS und OS exploriert. Sowohl in Viert- als auch in Fünftlinientherapie lag die Krankheits-kontrollrate (DCR) bei 35,7% bzw. 20%. Das mediane OS von Beginn einer Viert- bzw. Fünftlinientherapie betrug 10,5 Monate bzw. 6,2 Monate mit einem PFS von 3,2 Monaten bzw. 4,1 Monaten. Sowohl in Viert- als auch in Fünftlinientherapie zeigten Patienten mitunter eine partielle Remission als bestes Therapieansprechen. Prädiktive Faktoren für ein kürzeres OS bei Patienten in Viertlinientherapie waren eine primäre Resistenz in der Erstlinientherapie, eine synchrone Metastasierung bei Diagnosestellung und ein intermediäres MSKCC-Risikoprofil.

Circular RNAs (circRNAs) may act as novel cancer biomarkers. However, a genome-wide evaluation of circRNAs in clear cell renal cell carcinoma (ccRCC) has yet to be conducted. Therefore, the objective of this study was to identify and validate circRNAs in ccRCC tissue with a focus to evaluate their potential as prognostic biomarkers. A genome-wide identification of circRNAs in total RNA extracted from ccRCC tissue samples was performed using microarray analysis. Three relevant differentially expressed circRNAs were selected (circEGLN3, circNOX4, and circRHOBTB3), their circular nature was experimentally confirmed, and their expression—along with that of their linear counterparts—was measured in 99 malignant and 85 adjacent normal tissue samples using specifically established RT-qPCR assays. The capacity of circRNAs to discriminate between malignant and adjacent normal tissue samples and their prognostic potential (with the endpoints cancer-specific, recurrence-free, and overall survival) after surgery were estimated by C-statistics, Kaplan-Meier method, univariate and multivariate Cox regression analysis, decision curve analysis, and Akaike and Bayesian information criteria. CircEGLN3 discriminated malignant from normal tissue with 97% accuracy. We generated a prognostic for the three endpoints by multivariate Cox regression analysis that included circEGLN3, circRHOBT3 and linRHOBTB3. The predictive outcome accuracy of the clinical models based on clinicopathological factors was improved in combination with this circRNA-based signature. Bootstrapping as well as Akaike and Bayesian information criteria confirmed the statistical significance and robustness of the combined models. Limitations of this study include its retrospective nature and the lack of external validation. The study demonstrated the promising potential of circRNAs as diagnostic and particularly prognostic biomarkers in ccRCC patients.

Approximately 20&ndash, 30% of patients with metastatic renal cell carcinoma (mRCC) in first-line treatment with tyrosine kinase inhibitors (TKIs) do not respond due to primary resistance to this drug. At present, suitable robust biomarkers for prediction of a response are not available. Therefore, the aim of this study was to evaluate a panel of microRNAs (miRNAs) in nephrectomy specimens for use as predictive biomarkers for TKI resistance. Archived formalin-fixed, paraffin embedded nephrectomy samples from 60 mRCC patients treated with first-line TKIs (sunitinib, n = 51, pazopanib, n = 6, sorafenib, n = 3) were categorized into responders and non-responders. Using the standard Response Evaluation Criteria in Solid Tumors, patients with progressive disease within 3 months after the start of treatment with TKI were considered as non-responders and those patients with stable disease and complete or partial response under the TKI treatment for at least 6 months as responders. Based on a miRNA microarray expression profile in the two stratified groups of patients, seven differentially expressed miRNAs were validated using droplet digital reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) assays in the two groups. Receiver operating characteristic curve analysis and binary logistic regression of response prediction were performed. MiR-9-5p and miR-489-3p were able to discriminate between the two groups. MiR-9-5p, as the most significant miRNA, improved the correct prediction of primary resistance against TKIs in comparison to that of conventional clinicopathological variables. The results of the decision curve analyses, Kaplan-Meier analyses and Cox regression analyses confirmed the potential of miR-9-5p in the prediction of response to TKIs and the prediction of progression-free survival after the initiation of TKI treatment.