Publications by authors named "Steffen Rausch"

79 Publications

Receptor Activator of NF Kappa B (RANK) Expression Indicates Favorable Prognosis in Patients with Muscle-invasive Bladder Cancer.

Eur Urol Focus 2021 May 4. Epub 2021 May 4.

Department of Urology, University Hospital, Tübingen, Germany; Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; Clinical Trials Unit, Studienpraxis Urologie, Nürtingen, Germany. Electronic address:

Background: Receptor activator of NF kappa B (RANK) and its ligand have an essential role in T-cell regulation and the development of bone metastases. The role of RANK expression in muscle-invasive bladder cancer (MIBC) is unknown.

Objective: To assess the relevance of RANK expression in patients with MIBC.

Design, Setting, And Participants: Expression of RANK was assessed via immunohistochemistry of benign urothelium, MIBC tissue, and lymph node metastases from 153 patients undergoing radical cystectomy. Expression data from The Cancer Genome Atlas (TCGA) cohort were analyzed for potential associations with molecular subtypes and outcome.

Outcome Measurements And Statistical Analysis: RANK expression was correlated with clinical and pathological parameters and to individual data for the clinical course of MIBC.

Results And Limitations: Expression of RANK was significantly higher in both primary tumors (p = 0.02) and lymph node metastases (p = 0.01) compared to normal urothelium. In tumor tissue, RANK expression was significantly lower in patients with locally advanced disease and lymph node involvement compared to those with organ-confined disease (p = 0.0009) and node-negative MIBC (p = 0.0002). In univariable and multivariable analyses, high expression of RANK was associated with a longer time to recurrence (p = 0.0005 and 0.01) and better cancer-specific (p = 0.0004 and 0.007) and overall survival (p = 0.002 and 0.04). High expression of RANK was associated with better outcome for patients with luminal infiltrated tumors in the TCGA cohort.

Conclusions: RANK expression is increased in bladder cancer tissue compared to benign urothelium, with higher expression in organ-defined compared to locally advanced disease. High RANK expression indicates a favorable prognosis in MIBC. The prognostic role differs in tumors of different molecular subtypes.

Patient Summary: Expression of a protein involved in bone turnover regulation (RANK) is higher in bladder cancer tissue than in benign bladder tissue. However, high levels of RANK on tumor cells indicate favorable prognosis for patients with bladder cancer that invades the muscle layer of the bladder.
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http://dx.doi.org/10.1016/j.euf.2021.04.015DOI Listing
May 2021

Utility of pT3 substaging in lymph node-negative urothelial carcinoma of the bladder: do pathologic parameters add to prognostic sub-stratification?

World J Urol 2021 Apr 21. Epub 2021 Apr 21.

Department of Urology, University Hospital, Tübingen, Germany.

Purpose: The value of bladder cancer (BC) substaging into macroscopic (pT3b) and microscopic (pT3a) perivesical fat extension in lymph node (Ln)-negative patients is controversially discussed and limited evidence for prognostic relevance of additional histopathological factors in pT3 BC exists. We evaluated the prognostic value of pT3 substaging and established pathological and clinical parameters with focus on tumor invasive front (TIF) and tumor size.

Methods: Specimens of 52 patients treated with radical cystectomy (RC) for pT3 a/b muscle-invasive BC were reviewed and re-evaluated by a pathologist specialized in uropathology. Clinical variables and standard histopathologic characteristics were assessed including TIF and tumor size. Their value as prognosticators for overall survival (OS) and recurrence-free survival (RFS) was evaluated.

Results: Mean age of patients was 67.55 years. Tumors were staged pT3a in 28 patients (53.8%) and pT3b in 24 (46.8%). Median OS was 34.51 months. Median tumor size was 3.2 cm, median TIF was 11.0 mm. Differences in OS between pT3a and pT3b were not significant (p = 0.45). Carcinoma in situ (CIS) and lymphovascular invasion (LVI) were significantly associated with pT3b tumors. Univariate analysis could not identify pathological prognosticators like TIF or tumor size for OS and RFS (p for all > 0.05).

Conclusion: No significant differences in OS or RFS were observed comparing Ln-negative pT3 BC following radical cystectomy. Additional pathologic variables like TIF could not be identified as prognosticator. Relevance of pT3 BC substaging needs reevaluation in larger prospective cohorts.
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http://dx.doi.org/10.1007/s00345-021-03697-3DOI Listing
April 2021

Minimal-invasive management of urological complications after kidney transplantation.

Int Urol Nephrol 2021 Mar 2. Epub 2021 Mar 2.

Department of Urology, University Hospital Tübingen, Eberhard Karls University, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

Kidney transplantation represents the gold standard treatment option for patients with end-stage renal disease. Improvements in surgical technique and pharmacologic treatment have continuously prolonged allograft survival in recent years. However, urological complications are frequently observed, leading to both postoperative morbidity and putative deterioration of allograft function. While open redo surgery in these patients is often accompanied by elevated surgical risk, endoscopic management of urological complications is an alternative, minimal-invasive option. In the present article, we reviewed the literature on relevant urological postoperative complications after kidney transplantation and describe preventive approaches during the pre-transplantation assessment and their management using minimal-invasive approaches.
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http://dx.doi.org/10.1007/s11255-021-02825-7DOI Listing
March 2021

The prognostic value of fat invasion and tumor expansion in the hilar veins in pT3a renal cell carcinoma.

World J Urol 2021 Feb 27. Epub 2021 Feb 27.

Department of Urology, University of Tuebingen, Tübingen, Germany.

Purpose: The 7th TNM classification summarizes renal cell carcinoma (RCC) with perirenal (PFI) and/or sinus fat invasion (SFI) as well as hilar vein involvement (RVI) as pT3a tumors. In this study, we aimed to determine the prognostic value of fat invasion (FI) in the different compartments and RVI for medium-term cancer-specific-survival (CSS) in pT3a RCC.

Materials And Methods: Patients with pT3a RCC were identified using an institutional database. All original pathological reports were reclassified according to the 7th TNM edition. The prognostic value of FI as well as divided into PFI, SFI, combined PFI + SFI, and RVI for CSS was assessed using univariate and multivariate Cox-regression analysis. Survival was estimated using the Kaplan-Meier method.

Results: Median follow-up in 184 pT3a tumors was 38 months. FI was detectable in 153 patients (32.7% PFI, 45.1% SFI, 22.2% PFI + SFI), 31 patients showed RVI alone. Combined PFI + SFI increased the risk of cancer-related death compared to PFI (HR 3.11, p < 0.01), SFI (HR 1.84, p = 0.023) or sole RVI (HR 2.12, p = 0.025). In multivariate analysis, a combined PFI + SFI vs. PFI or SFI as the only compartment involved was confirmed as independent prognostic factor (HR 1.83, p = 0.029). Patients with FI and simultaneous RVI had significantly shorter CSS (HR 2.63, p < 0.01). In an unweighted model, the difference between patients with combined PFI + SFI and RVI and those with PFI alone was highest (HR 4.01, p = 0.029).

Conclusions: These results underline the subdivision of pT3a RCC depending on the location of FI and RVI for patient stratification.
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http://dx.doi.org/10.1007/s00345-021-03638-0DOI Listing
February 2021

Versatility and clinical effectiveness of a synthetic sealing hemostatic patch as alternative to parenchyma suturing in laparoscopic partial nephrectomy.

Surg Endosc 2021 Feb 16. Epub 2021 Feb 16.

Department of Urology, Medical Faculty and University Hospital, Eberhard-Karls-University Tuebingen, Tübingen, Germany.

Background: Improvements in laparoscopic partial nephrectomy (LPN) in order to minimize perioperative warm ischemia time (WIT), complications, and consequently patient outcome are desirable. Veriset™ is a ready-to-use hemostatic patch of absorbable oxidized cellulose and hydrogel components that has earlier been implemented in vascular and hepatic surgery. We report our experience using this device in LPN.

Methods: Patients with a solitary malignant renal mass suspicious for renal cancer underwent LPN with either the use of Veriset™ hemostatic patch (n = 40) or conventional suture technique (n = 40). Patient characteristics, operation time and WIT, postoperative course and complications were recorded retrospectively. Tumor complexity was calculated according to the R.E.N.A.L. score. Outcome was determined according to the "trifecta" criteria (negative surgical margin, WIT < 25 min, no complications within 30 days).

Results: No significant differences with regard to clinical parameters and median R.E.N.A.L. score (6) were observed between both groups. Operation time (mean 127.1 min vs. 162. 8 min; p = 0.001) and WIT were both lower in the Veriset™ group (14.6 min vs. 20.6 min; p = 0.01). No differences in surgical margins (p = 0.602) and overall complication rates at 30 (p = 0.599) and 90 days (p = 0.611) postoperatively were noticed. The surgical outcome according to "trifecta" was achieved in 65% of patients using Veriset™ and in 57.5% of patients by suture closure, respectively.

Conclusion: The hemostatic Veriset™ patch can successfully be implemented in LPN. Handling and application appear favorable, thereby reducing operation time and WIT. The present results suggest that the device may represent an alternative to parenchyma suturing in LPN.
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http://dx.doi.org/10.1007/s00464-021-08333-0DOI Listing
February 2021

Combination of immune checkpoint inhibitors and tyrosine kinase inhibitors for the treatment of renal cell carcinoma.

Expert Opin Biol Ther 2021 Feb 27:1-12. Epub 2021 Feb 27.

Department of Urology, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Tübingen, Germany.

Introduction: We have experienced several paradigm shifts and substantial changes in the treatment of metastatic renal cell carcinoma (mRCC) over the last two decades. Combination therapy with immune checkpoint inhibitors (ICI) as a dual combination (ICI-ICI) or with VEGFR-tyrosine kinase inhibitors (VEGF-TKI) has shown remarkable efficacy in mRCC patients and has become the standard of care in first-line therapy.

Areas Covered: In this review, we will discuss the background as well as the benefits of combining ICI with TKI compared to ICI-ICI combination therapy for mRCC treatment and will also briefly highlight biomarkers for patient selection on therapies to improve patient outcomes and limit toxicities.

Expert Opinion: Due to the mediated additional anti-tumor effects, there is a strong rationale to combine ICIs and TKIs for mRCC therapy. When comparing first-line therapy options, the exceptionally higher ORR and PFS for the ICI-TKI combinations should be highlighted, whereas, nevertheless, the complete response rate is slightly higher for the ICI-ICI combination. In terms of an individualized therapeutic approach, biomarkers predicting the success or failure of an anti-VEGF-based regimen or ICI therapy as a corresponding mono - or combination therapy are lacking so far, however, gene expression signatures can be a landmark in this field.
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http://dx.doi.org/10.1080/14712598.2021.1890713DOI Listing
February 2021

Increased Expressions of Matrix Metalloproteinases (MMPs) in Prostate Cancer Tissues of Men with Type 2 Diabetes.

Biomedicines 2020 Nov 16;8(11). Epub 2020 Nov 16.

Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Type 2 diabetes (T2D) is associated with worse prognosis of prostate cancer (PCa). The molecular mechanisms behind this association are still not fully understood. The aim of this study was to identify key factors, which contribute to the more aggressive PCa phenotype in patients with concurrent T2D. Therefore, we investigated benign and PCa tissue of PCa patients with and without diabetes using real time qPCR. Compared to patients without diabetes, patients with T2D showed a decreased E-cadherin/N-cadherin (CDH1/CDH2) ratio in prostate tissue, indicating a switch of epithelial-mesenchymal transition (EMT), which is a pivotal process in carcinogenesis. In addition, the gene expression levels of matrix metalloproteinases () and CC chemokine ligands () were higher in prostate samples of T2D patients. Next, prostate adenocarcinoma PC3 cells were treated with increasing glucose concentrations to replicate hyperglycemia in vitro. In these cells, high glucose induced expressions of and , which showed significant positive associations with the proliferation marker proliferating cell nuclear antigen (). These results indicate that in prostate tissue of men with T2D, hyperglycemia may induce EMT, increase and gene expressions, which in turn activate invasion and inflammatory processes accelerating the progression of PCa.
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http://dx.doi.org/10.3390/biomedicines8110507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696165PMC
November 2020

A Modified Neobladder Technique: The "I-Pouch" - Illustration of Surgical Approach and Tricks.

Urology 2021 Jan 26;147:318. Epub 2020 Oct 26.

Department of Urology, Eberhard-Karls-University Tübingen, Tübingen, Germany. Electronic address:

Objective: Various techniques for orthotopic neobladder (ONB) are currently used and have shown satisfactory oncological and functional outcomes. Among the relevant oncological and functional aspects for long-term follow up is the easy accessibility of the upper urinary tract in urinary diversion for endoscopic monitoring. In addition, variety exists in the amount of ileum needed to create a urinary reservoir. Depending on the ONB technique, up to 60 cm of ileum are required, and bowel dysfunction may be a consequence especially when the ileocecal valve is used for the urinary diversion. We previously reported the technique, functional and oncologic results of the I-pouch, a modified ONB made of 40 cm of ileum, combining an antirefluxive ureter implantation technique with easy access to the uretero-intestinal anastomosis. The present video is intended to illustrate key surgical steps and pitfalls during the procedure.

Methods: The technique, surgical tips, and functional results in a as compared to a institutional control group receiving conventional Studer -Pouch-procedure are outlined.

Results: In a follow up series of 33 I-pouch and 23 S-pouch patients, there were no differences according to ONB type for 30-day major- (P = .33) and minor (P = 0.96) complication rates although 90-day major (P = 0.08) and minor (P = 0.08) complication rates tended to be associated with less complications in I-pouch patients.

Conclusion: The I-pouch can be used for neobladder substitution providing easy access to the upper urinary tract, reduced demand of ileum length along with a complication profile not distinct from Studer neobladder formation.
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http://dx.doi.org/10.1016/j.urology.2020.10.017DOI Listing
January 2021

Treatment and resistance mechanisms in castration-resistant prostate cancer: new implications for clinical decision making?

Expert Rev Anticancer Ther 2021 Feb 16;21(2):149-163. Epub 2020 Nov 16.

Department of Urology, Eberhard-Karls-University Tuebingen, Tuebingen, Germany.

: The armamentarium of treatment options in metastatic and non-metastatic CRPC is rapidly evolving. However, the question of how individual treatment decisions should be balanced by available predictive clinical parameters, pharmacogenetic and drug interaction profiles, or compound-associated molecular biomarkers is a major challenge for clinical practice.: We discuss treatment and resistance mechanisms in PC with regard to their association to drug efficacy and tolerability. Current efforts of combination treatment and putative predictive biomarkers of available and upcoming compounds are highlighted with regard to their implication on clinical decision-making.: Several treatment approaches are delineated, where identification of resistance mechanisms in CRPC may guide treatment selection. To date, most of these candidate biomarkers will however be found only in a small subset of patients. While current approaches of combination treatment in CRPC are proving synergistic effects on cancer biology, higher complexity with regard to biomarker analysis and interaction profiles of the respective compounds may be expected. Among other aspects of personalized treatment, consideration of drug-drug interaction and pharmacogenetics is an underrepresented issue. However, the non-metastatic castration resistant prostate cancer situation may be an example for treatment selection based on drug interaction profiles in the future.
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http://dx.doi.org/10.1080/14737140.2021.1843430DOI Listing
February 2021

Relationship between GFR, intact PTH, oxidized PTH, non-oxidized PTH as well as FGF23 in patients with CKD.

FASEB J 2020 11 22;34(11):15269-15281. Epub 2020 Sep 22.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.

Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are regulators of renal phosphate excretion and vitamin D metabolism. In chronic kidney disease (CKD), circulating FGF23 and PTH concentrations progressively increase as renal function declines. Oxidation of PTH at two methionine residues (positions 8 and 18) causes a loss of function. The impact of n-oxPTH and oxPTH on FGF23 synthesis, however, and how n-oxPTH and oxPTH concentrations are affected by CKD, is yet unknown. The effects of oxidized and non-oxidized PTH 1-34 on Fgf23 gene expression were analyzed in UMR106 osteoblast-like cells. Furthermore, we investigated the relationship between n-oxPTH and oxPTH, respectively, with FGF23 in two independent patients' cohorts (620 children with CKD and 600 kidney transplant recipients). While n-oxPTH stimulated Fgf23 mRNA synthesis in vitro, oxidation of PTH in particular at Met8 led to a markedly weaker stimulation of Fgf23. The effect was even stronger when both Met8 and Met18 were oxidized. In both clinical cohorts, n-oxPTH-but not oxPTH-was significantly associated with FGF23 concentrations, independent of known confounding factors. Moreover, with progressive deterioration of kidney function, intact PTH (iPTH) and oxPTH increased substantially, whereas n-oxPTH increased only moderately. In conclusion, n-oxPTH, but not oxPTH, stimulates Fgf23 gene expression. The increase in PTH with decreasing GFR is mainly due to an increase in oxPTH in more advanced stages of CKD.
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http://dx.doi.org/10.1096/fj.202000596RDOI Listing
November 2020

Vitamin A regulates fibroblast growth factor 23 (FGF23).

Nutrition 2020 Nov - Dec;79-80:110988. Epub 2020 Aug 28.

Department of Physiology, University of Hohenheim, Stuttgart, Germany. Electronic address:

Objectives: Renal phosphate and vitamin D metabolism are regulated by proteohormone fibroblast growth factor 23 (FGF23), which is secreted by bone cells. FGF23 inhibits phosphate reabsorption and the production of calcitriol, active vitamin D (1,25(OH)D). FGF23 generated by other cells exerts further paracrine effects in the liver, heart, and immune system. The FGF23 plasma concentration is positively associated with the onset and progression of kidney and cardiovascular diseases, disclosing FGF23 as a potential disease biomarker. The effects of vitamin A on the expression of FGF23 are controversial. Vitamin A components, retinoids, are mainly effective through nuclear retinoic acid receptors (RAR) and exert different effects on bone. The aim of this study was to clarify whether vitamin A modulates the production of FGF23.

Methods: We studied the relevance of vitamin A for FGF23 production. Fgf23 transcripts were determined by real-time quantitative polymerase chain reaction in UMR106 osteoblast-like cells and IDG-SW3 osteocytes. FGF23 protein in the cell culture supernatant was measured by enzyme-linked immunosorbent assay.

Results: All-trans-retinoic acid, retinyl acetate, RAR agonist TTNPB (4-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid), and 13-cis-retinoic acid downregulated the expression of the Fgf23 gene in a dose-dependent manner. This effect was significantly attenuated by RAR antagonist AGN193109 (4-[2-[5,6-Dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl]ethynyl]benzoic acid).

Conclusion: The present study demonstrated that vitamin A is a potent suppressor of FGF23 production through RAR.
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http://dx.doi.org/10.1016/j.nut.2020.110988DOI Listing
August 2020

Transcript Levels of Aldo-Keto Reductase Family 1 Subfamily C (AKR1C) Are Increased in Prostate Tissue of Patients with Type 2 Diabetes.

J Pers Med 2020 Sep 12;10(3). Epub 2020 Sep 12.

Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Aldo-keto reductase family 1 (AKR1) enzymes play a crucial role in diabetic complications. Since type 2 diabetes (T2D) is associated with cancer progression, we investigated the impact of diabetes on gene expression in the context of prostate cancer (PCa) development. In this study, we analyzed benign (BEN) prostate and PCa tissue of patients with and without T2D. Furthermore, to replicate hyperglycemia in vitro, we treated the prostate adenocarcinoma cell line PC3 with increasing glucose concentrations. Gene expression was quantified using real-time qPCR. In the prostate tissue of patients with T2D, and transcripts were higher compared to samples of patients without diabetes. In PC3 cells, high glucose treatment induced the gene expression levels of , and . Furthermore, both in human tissue and in PC3 cells, the transcript levels of and showed positive associations with oncogenes, which are involved in proliferation processes and HIF1α and NFκB pathways. These results indicate that in the prostate glands of patients with T2D, hyperglycemia could play a pivotal role by inducing the expression of and . The higher transcript level of was furthermore associated with upregulated HIF1α and NFκB pathways, which are major drivers of PCa carcinogenesis.
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http://dx.doi.org/10.3390/jpm10030124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564141PMC
September 2020

Enzalutamide plus androgen-deprivation therapy in hormone-sensitive prostate cancer: new perspectives from a current Phase III clinical trial.

Future Oncol 2020 Jul 24;16(21):1511-1524. Epub 2020 Jun 24.

Department of Urology, Eberhard-Karls-University Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.

Prostate cancer is a major health issue with an incidence of 1,100,000 worldwide. Eventually, 20-40% of curatively treated patients will face a biochemical recurrence. Lately, the treatment options in metastasized hormone sensitive prostate cancer (mHSPC) were rapidly evolving after years of stagnation. Encouraging results in clinical trials of combination treatment of androgen deprivation therapy with either chemotherapy or second-generation hormonal treatment indicate a paradigm shift in this clinical scenario. In the light of this, the current review is focusing on the concept and initial results of the Phase III (ARCHES) trial investigating enzalutamide plus androgen deprivation therapy in mHSPC. Moreover, a comprehensive appraisal of the expanding landscape of systemic therapies for mHSPC is provided.
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http://dx.doi.org/10.2217/fon-2019-0509DOI Listing
July 2020

Impact of Histopathological Prostate Inflammation on Urine-Based Prostate Cancer Prediction Using the Prostate Cancer Gene 3 Score.

Urol Int 2020 8;104(5-6):483-488. Epub 2020 May 8.

Department of Urology, Eberhard Karls University of Tübingen, Tübingen, Germany.

Introduction: The Prostate Cancer gene 3 (PCA3) urine test has gained importance in the diagnostic workup of prostate cancer (PC). Limited evidence suggests that PCA3 is not altered in the presence of inflammation.

Objective: To assess the impact of histological inflammation on PCA3.

Methods: PCA3 was evaluated in patients prior to prostate biopsy (n = 193) and to radical prostatectomy (n = 197). In patients without PC, inflammation was assessed and quantified by individual scores integrating grade and extent. Uni- and multivariate analyses were performed to assess the impact of inflammation grade on PCA3.

Results: The PCA3 scores prior to prostatectomy were lower (median 45) than those before positive biopsy (57; p = 0.008). Of 101 negative biopsies, 78% showed inflammation. The median PCA3 scores in the groups with no inflammation and with maximum grade 1 (n = 22), 2 (n = 38), and 3 (n = 19) inflammation were 45, 38, 27, and 25 (p = 0.016). The multivariate models revealed a decrease in PCA3 proportional to the grade and extent of inflammation (p < 0.04 each).

Conclusions: The present data imply that the PCA3 score decreases in the presence of inflammation, which is relevant, for instance, to testing after a recently performed biopsy. In general, inflammation should be regarded as a factor putatively influencing PCA3 and other available and upcoming PC tests.
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http://dx.doi.org/10.1159/000506885DOI Listing
March 2021

Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy.

Genome Med 2020 03 30;12(1):32. Epub 2020 Mar 30.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

Background: Clear cell renal cell carcinoma (ccRCC) is the dominant subtype of renal cancer. With currently available therapies, cure of advanced and metastatic ccRCC is achieved only in rare cases. Here, we developed a workflow integrating different -omics technologies to identify ccRCC-specific HLA-presented peptides as potential drug targets for ccRCC immunotherapy.

Methods: We analyzed HLA-presented peptides by MS-based ligandomics of 55 ccRCC tumors (cohort 1), paired non-tumor renal tissues, and 158 benign tissues from other organs. Pathways enriched in ccRCC compared to its cell type of origin were identified by transcriptome and gene set enrichment analyses in 51 tumor tissues of the same cohort. To retrieve a list of candidate targets with involvement in ccRCC pathogenesis, ccRCC-specific pathway genes were intersected with the source genes of tumor-exclusive peptides. The candidates were validated in an independent cohort from The Cancer Genome Atlas (TCGA KIRC, n = 452). DNA methylation (TCGA KIRC, n = 273), somatic mutations (TCGA KIRC, n = 392), and gene ontology (GO) and correlations with tumor metabolites (cohort 1, n = 30) and immune-oncological markers (cohort 1, n = 37) were analyzed to characterize regulatory and functional involvements. CD8 T cell priming assays were used to identify immunogenic peptides. The candidate gene EGLN3 was functionally investigated in cell culture.

Results: A total of 34,226 HLA class I- and 19,325 class II-presented peptides were identified in ccRCC tissue, of which 443 class I and 203 class II peptides were ccRCC-specific and presented in ≥ 3 tumors. One hundred eighty-five of the 499 corresponding source genes were involved in pathways activated by ccRCC tumors. After validation in the independent cohort from TCGA, 113 final candidate genes remained. Candidates were involved in extracellular matrix organization, hypoxic signaling, immune processes, and others. Nine of the 12 peptides assessed by immunogenicity analysis were able to activate naïve CD8 T cells, including peptides derived from EGLN3. Functional analysis of EGLN3 revealed possible tumor-promoting functions.

Conclusions: Integration of HLA ligandomics, transcriptomics, genetic, and epigenetic data leads to the identification of novel functionally relevant therapeutic targets for ccRCC immunotherapy. Validation of the identified targets is recommended to expand the treatment landscape of ccRCC.
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http://dx.doi.org/10.1186/s13073-020-00731-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106651PMC
March 2020

Age-Adapted Prostate Cancer Gene 3 Score Interpretation - Suggestions for Clinical Use.

Clin Lab 2020 Mar;66(3)

Background: The prostate cancer antigen 3 (PCA3) gene urine assay is established for biopsy decision in case of prostate cancer (PC) suspicion. Recent findings pointed to an age dependence of PCA3, with putative impact on test interpretation. However, to date no experience has been reported with regard to the extent age might modify the score in certain age ranges. Therefore, the aim of the present study was to re-evaluate the age dependency and, moreover, give suggestions for interpretation of the PCA3 score in dependence of patient's age in daily routine.

Methods: The study comprised 684 patients before prostate biopsy or prostatectomy. Post-massage voided urine samples were assessed by PCA3 measurement. PCA3 scores were correlated to patient's age. The collective was divided into four subcollectives by quartiles of age distribution. For every subcollective the cutoff value at specificity of ≥ 60 was determined. Results were classified by age-class specific cutoff values and test qualities were compared at different cutoffs.

Results: In the collective, 59.1% of patients had a positive biopsy. PCA3 correlated to patient's age in univariate and multivariate analysis (p < 0.001 each). The division into age subcollectives revealed groups < 60, 60 - 65, 66 - 69 and > 69 years. Median PCA3 values of patients without/with PC were 17/32, 27/42, 34/55 and 52/68 in the four age classes. Cutoff values for which specificity was determined with ≥ 60 were 23, 39, 42, and 65. Constant cutoff values showed lower sensitivities in younger and lower specificities in older patients. Only the age adjusted values revealed an improved performance with PPV 68.7, accuracy 59.5 and sensitivity 57.7 at specificity of 62.1% in the whole cohort.

Conclusions: The study confirms that the PCA3 score increases with age. The recommended cutoff score of 35 is suitable especially for patients aged in their sixties. Lower reference values between 20 and 30 have to be taken into account in patients aged < 60 years and higher values around 40 to 50 may point to suspicion for PC in patients > 69 years. These results may further improve the diagnostic performance of the PCA3 test and keep the PCA3 test as a significant test in PC diagnostics along with new upcoming urine markers.
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http://dx.doi.org/10.7754/Clin.Lab.2019.190714DOI Listing
March 2020

Immune checkpoint inhibition for the treatment of renal cell carcinoma.

Expert Opin Biol Ther 2020 01 13;20(1):83-94. Epub 2019 Oct 13.

Department of Urology, University of Tübingen, Tübingen, Germany.

: The systemic therapy in metastatic renal cell carcinoma (mRCC) is moving from tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors to immune checkpoint inhibitors and its combination with TKIs.: This review provides a general overview using immune checkpoint inhibition for the treatment of RCC. Clinical results from conducted and ongoing clinical trials are summarized and checkpoint inhibition is reviewed in the context to other available systemic therapies such as TKIs for mRCC based on the different International Metastastic RCC Database Consortium (IMCD) risk groups. Furthermore, prospects for the use of predictive biomarkers in the decision-making process of chosen therapy will be given.: Using checkpoint inhibition in mRCC has demonstrated a superior efficacy for patients with IMDC intermediate and poor risk for ipilimumab combined with nivolumab. Furthermore, therapeutic regimes with tyrosine kinase inhibition plus immune checkpoint-inhibition were recently presented and demonstrated superiority in all risk groups for axitinib plus pembrolizumab in overall survival and progression-free survival (PFS) and axitinib plus avelumab in PFS compared to sunitinib monotherapy. Novel biomarkers of response to further optimize therapeutic selection and patient outcomes are ongoing medical objectives.
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http://dx.doi.org/10.1080/14712598.2020.1677601DOI Listing
January 2020

Assessment of concomitant non-oncologic medication in patients with surgically treated renal cell carcinoma: impact on prognosis, cell-cycle progression and proliferation.

J Cancer Res Clin Oncol 2019 Jul 22;145(7):1835-1843. Epub 2019 Apr 22.

Department of Urology, Eberhard Karls University, Hoppe-Seyler- Strasse 3, 72076, Tuebingen, Germany.

Introduction: Based on the observation of beneficial effects on cancer metabolism, microenvironment, or VEGF-signaling, several non-anticancer drugs have been discussed as useful in renal cell carcinoma (RCC). In the present study, we investigated the prognostic impact of concomitant medication in RCC and correlated comedication with cell-cycle and proliferation activity in corresponding surgical specimen.

Methods: A total of 388 patients who underwent surgery for localized RCC were included. The individual medication was evaluated according to substance classes. Tissue microarrays from corresponding tumor specimen were immunohistochemically (IHC) stained for Cyclin D1 and Ki67 and semi-quantitatively evaluated. Uni- and multivariate analyses were used to compare survival outcomes. For the comparison of IHC expression according to medication subgroups, Kruskal-Wallis analysis was performed.

Results: Median follow-up was 57.93 months (95% CI 53.27-69.43) and median OS accounted for 181.12 months (129.72-237.17). Univariate analysis identified pathological standard variables (T-stage > T2, Grading > G2, L1, N1, M1, sarcomatoid subtype, necrosis) as significant determinants of OS. Moreover, statin use (p = 0.009) and sartan use (p = 0.032) were significantly associated with improved OS. Multivariate analysis identified M1-stage (p < 0.001), statin and sartan use (p = 0.003 and p = 0.033, respectively) as independent prognosticators of survival. Expression of Ki67 was significantly reduced in patients with statin use (p = 0.013), while Cyclin D1 expression showed no correlation with comedication.

Conclusions: Concomitant intake of statins and sartans identifies as an independent predictor of OS in RCC, and reduced Ki67 expression was significantly associated with statin use. Further evaluation of drug repurposing approaches with these substances in RCC appear warranted.
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http://dx.doi.org/10.1007/s00432-019-02914-2DOI Listing
July 2019

Determination of Free-PSA (fPSA) and fPSA/PSA-Ratio Using A Point-of-Care Device.

Clin Lab 2019 Jan;65(1)

Background: Prostate specific antigen (PSA) and free PSA (fPSA) are important tools for diagnosing prostate cancer (PC). Efforts are continuously undertaken to provide more patient-centered healthcare. The application of point-of-care (POC) systems for laboratory analyses represents a step in this direction. Previous investigations on total PSA measurements using a POC system (concile® Ω100 POC reader) showed good concordance with standard laboratory measurements. For the same POC reader a novel system for fPSA was developed. In the current study, we prospectively evaluated the quality of the POC system for fPSA.

Methods: Sixty-four patients undergoing PSA measurements in our outpatient clinic between 06/2015 and 09/2015 were enrolled in the study. We measured total PSA (tPSA) and fPSA with a POC reader system (concile® Ω100) and a standard laboratory system (Siemens Immulite 2000®) and compared the respective results using linear regression analyses for PSA, fPSA, and fPSA/tPSA ratio (%fPSA).

Results: The coefficients of determination (r²) for fPSA and %fPSA were 0.85 (p < 0.001) and 0.82 (p < 0.001) in the subgroup with total PSA between 4 and 10 ng/mL. In the subgroup with tPSA ≤ 4 ng/mL, r² for fPSA concile® was 0.55 (p < 0.001) and 0.10 (p = 0.088) for %fPSA. In the subgroup of tPSA > 10 ng/mL the r² for fPSA and %fPSA was 0.50 (p = 0.022) and 0.50 (p = 0.022), respectively.

Conclusions: The POC fPSA values correlated well with the laboratory analyses, specifically in the clinically relevant diagnostic range of tPSA 4 - 10 ng/mL. These results complement the tPSA data obtained previously and indicate the reliability of the fPSA method and the resulting %fPSA score.
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http://dx.doi.org/10.7754/Clin.Lab.2018.180710DOI Listing
January 2019

mTOR and mTOR phosphorylation status in primary and metastatic renal cell carcinoma tissue: differential expression and clinical relevance.

J Cancer Res Clin Oncol 2019 Jan 27;145(1):153-163. Epub 2018 Oct 27.

Department of Urology, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

Purpose: Impaired regulation of the Akt/mammalian target of rapamycin (mTOR) pathway has been implicated in mechanisms related to neoplastic transformation in renal cell cancer (RCC) through enhancement of cell proliferation and survival and mTOR activation has been reported to occur due to phosphorylation of mTOR. To further determine the relevance of mTOR expression and activation and to analyze their putative role as a biomarker for systemic treatment in metastatic RCC, we investigated the expression of mTOR and phospho(p)-mTOR in primary RCC and metastases and correlated levels with pathological variables and clinical outcome.

Methods: Tissue microarrays (TMA) from paraffin-embedded tissue from 342 patients with primary clear cell renal cell carcinoma and 90 patients undergoing surgical resection for metastases were immunohistochemically stained for mTOR and p-mTOR and expression was quantified with immunoreactivity scores. Clinical patient characteristics and follow-up were recorded. Comparative evaluation of protein expression levels and association of expression with clinical variables and survival was performed.

Results: mTOR staining revealed differential expression in benign, primary and RCC metastasis (average staining score: 1.64, 0.78, and 1.44, respectively). Average staining of p-mTOR was 0.99 in benign kidney tissue, 0.73 in primary RCC and 1.14 in RCC metastasis tissue. Elevated mTOR expression in primary RCC tissue was associated with the presence of tumor necrosis, while a high level of p-mTOR was significantly correlated with advanced T-stage, high Fuhrman grade, the presence of tumor necrosis and sarcomatoid features. An elevated ratio of p-mTOR/mTOR was significantly correlated with advanced stage and sarcomatoid histology. mTOR expression was not predictive of overall survival (OS), while high p-mTOR levels were associated with impaired OS (p = 0.0046) and cancer-specific survival (p = 0.0067). In univariate analysis, advanced stage (HR 3.78), high Fuhrman grade (HR 4.0), the presence of tumor necrosis (HR 1.99), and sarcomatoid features (HR 5.12) were significant predictors of OS. Moreover, elevated levels of p-mTOR (HR 1.67) and an elevated ratio of p-mTOR/mTOR ratio (HR 1.73) were significantly predictive of OS. In the multivariate regression model only the presence of locally advanced tumors (HR 2.44) was of independent prognostic value for OS, while there was a trend for impaired OS for patients with a high p-mTOR (HR 1.27, p = 0.21).

Conclusions: Phosphorylated mTOR is differentially expressed in localized RCC and metastasis. Elevated phosphorylation of mTOR is associated with aggressive pathologic features and unfavorable outcome. Whether these findings portend to relevance for mTOR inhibition treatment for metastatic RCC should be objective of further investigations.
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http://dx.doi.org/10.1007/s00432-018-2775-5DOI Listing
January 2019

Trimodal therapy for muscle-invasive bladder cancer.

Expert Rev Anticancer Ther 2018 12 17;18(12):1219-1229. Epub 2018 Oct 17.

a Department of Urology , University of Tübingen , Tübingen , Germany.

Introduction: Radical cystectomy is the standard therapy for patients with muscle-invasive bladder cancer. Organ-preserving surgical procedures have been established as alternatives to radical surgery for localized malignancies in other anatomic sites. Trimodal therapy consisting of radiation therapy, chemotherapy, and either transurethral resection of the bladder or partial cystectomy is an effective treatment for selected patients with muscle-invasive bladder cancer that allows for preservation of the urinary bladder. Areas covered: This review provides an overview of the value of trimodal therapy in the treatment of muscle-invasive bladder cancer. Expert commentary: Prerequisites for trimodal therapy for bladder cancer include: good bladder function, unifocal cT2 urothelial carcinoma of the bladder, and absence of hydronephrosis. Careful selection of patients and accurate assessment of the anatomic extent of the tumor is important for patient safety. The basis for successful trimodal therapy is complete transurethral resection of the tumor, followed by radiation therapy with concurrent radiosensitizing chemotherapy. Cystoscopic controls and follow-up biopsies should be performed at completion of adjuvant therapy or shortly after induction of trimodal therapy to identify nonresponders for whom salvage radical cystectomy may be indicated.
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http://dx.doi.org/10.1080/14737140.2018.1535314DOI Listing
December 2018

Systemic Alterations of Wnt Inhibitors in Patients with Prostate Cancer and Bone Metastases.

Dis Markers 2018 18;2018:1874598. Epub 2018 Jul 18.

Department of Urology, Eberhard Karls University of Tübingen, Tübingen, Germany.

Purpose: Dickkopf-1 (DKK-1) and sclerostin seem to inhibit osteoblast activity by blocking the Wnt pathway, which leads to progression of metastatic prostate cancer (PC). However, it is unknown whether serum levels of these proteins are altered in PC patients with or without metastasis. The aim of this study was to assess DKK-1 and sclerostin serum levels in PC patients, including patients with bone metastases.

Methods: The study cohort ( = 143) consisted of 53 controls with benign prostatic hyperplasia (BPH), 43 with localized PC (PC cM0), and 47 had PC with metastasis (PC cM1). Serum levels of DKK-1 and sclerostin were measured by enzyme-linked immunosorbent assay. Results were compared using the Kruskal-Wallis tests; post hoc analysis was performed using the Tukey-Kramer test.

Results: Mean DKK-1 levels in patients with BPH (2809.4 pg/ml) ( < 0.001) as well as PC cM1 (2575.5 pg/ml) ( = 0.001) were significantly higher than in patients with PC cN0 cM0 (1551.8 pg/ml). Among PC cM1 patients, median DKK-1 levels were significantly lower in patients with castration-resistant disease compared to those with hormone-sensitive PC ( = 0.02); in contrast, sclerostin concentrations were elevated ( = 0.04). DKK-1 correlated with PSA in the cM1 group ( = 0.03) and sclerostin correlated with PSA in the PC group (0.01).

Conclusions: DKK-1 is involved in the progression of PC. DKK-1-mediated inhibition of osteoblasts, which contributes to tumor progression and osteolytic metastases, may also play a role in the development of metastases with osteoblastic features. The use of DKK-1 antibodies should be considered for studies including metastatic PC patients.
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http://dx.doi.org/10.1155/2018/1874598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079590PMC
December 2018

Simultaneous Extraction of RNA and Metabolites from Single Kidney Tissue Specimens for Combined Transcriptomic and Metabolomic Profiling.

J Proteome Res 2018 09 23;17(9):3039-3049. Epub 2018 Aug 23.

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology , Stuttgart , Germany and University of Tübingen, Tübingen, Germany.

Tissue analysis represents a powerful tool for the investigation of disease pathophysiology. However, the heterogeneous nature of tissue samples, in particular of neoplastic, may affect the outcome of such analysis and hence obscure interpretation of results. Thus, comprehensive isolation and extraction of transcripts and metabolites from an identical tissue specimen would minimize variations and enable the economic use of biopsy material which is usually available in limited amounts. Here we demonstrate a fast and simple protocol for combined transcriptomics and metabolomics analysis in homogenates prepared from one single tissue sample. Metabolites were recovered by protein precipitation from lysates originally prepared for RNA isolation and were analyzed by LC-QTOF-MS after HILIC and RPLC separation, respectively. Strikingly, although ion suppression was observed, over 80% of the 2885 detected metabolic features could be extracted and analyzed with high reproducibility (CV ≤ 20%). Moreover fold changes of different tumor and nontumor kidney tissues were correlated to an established metabolomics protocol and revealed a strong correlation ( r ≥ 0.75). In order to demonstrate the feasibility of the combined analysis of RNA and metabolites, the protocol was applied to kidney tissue of metformin treated mice to investigate drug induced alterations.
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http://dx.doi.org/10.1021/acs.jproteome.8b00199DOI Listing
September 2018

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma.

Int J Cancer 2018 12 25;143(12):3181-3193. Epub 2018 Sep 25.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

The efflux transporter breast cancer resistance protein BCRP/ABCG2 is well-known for its contribution to multi-drug resistance in cancer. Its relevance in cancer biology independent from drug efflux remains largely elusive. Our study aimed at elucidating the biological relevance and regulatory mechanisms of BCRP/ABCG2 in clear cell renal cell carcinoma (ccRCC) and disease progression. Two independent ccRCC-cohorts [Cohort 1 (KIRC/TCGA): n = 453, Cohort 2: n = 64] were investigated to elucidate BCRP/ABCG2 mRNA and protein expression and their association with survival. The impact of BCRP/ABCG2 on response to sunitinib treatment was investigated in two independent sunitinib-treated ccRCC-cohorts based on mRNA levels. Moreover, underlying regulatory mechanisms for interindividual variability of BCRP/ABCG2 expression were systematically assessed. Owing to redundant functional properties, mRNA and protein expression of the multidrug resistance protein MDR1/ABCB1 were additionally evaluated in these cohorts. In independent ccRCC-cohorts, low BCRP/ABCG2 and MDR1/ABCB1 mRNA and protein expression were associated with severity (e.g., tumor stage) of ccRCC and poor cancer-specific survival. BCRP/ABCG2 and MDR1/ABCB1 mRNA expression were linked to decreased progression-free survival after sunitinib treatment. Germline and somatic variants influenced interindividual variability of BCRP/ABCG2 expression only moderately. miR-212-3p and miR-132-3p were identified to regulate BCRP/ABCG2 posttranscriptionally by interaction with the ABCG2 3'UTR as confirmed through reporter gene assays in RCC cell lines. In summary, BCRP/ABCG2 expression in ccRCC underlies considerable interindividual variability with impact on patient survival and response to sunitinib treatment. While germline or somatic genetic variants and DNA methylation cannot explain aberrant BCRP/ABCG2 expression, miR-212-3p and miR-132-3p were identified to contribute to posttranscriptional regulation of BCRP/ABCG2.
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http://dx.doi.org/10.1002/ijc.31741DOI Listing
December 2018

Clinical utility of the S3-score for molecular prediction of outcome in non-metastatic and metastatic clear cell renal cell carcinoma.

BMC Med 2018 07 5;16(1):108. Epub 2018 Jul 5.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.

Background: Stratification of cancer patients to identify those with worse prognosis is increasingly important. Through in silico analyses, we recently developed a gene expression-based prognostic score (S3-score) for clear cell renal cell carcinoma (ccRCC), using the cell type-specific expression of 97 genes within the human nephron. Herein, we verified the score using whole-transcriptome data of independent cohorts and extend its application for patients with metastatic disease receiving tyrosine kinase inhibitor treatment. Finally, we sought to improve the signature for clinical application using qRT-PCR.

Methods: A 97 gene-based S3-score (S3) was evaluated in a set of 52 primary non-metastatic and metastatic ccRCC patients as well as in 53 primary metastatic tumors of sunitinib-treated patients. Gene expression data of The Cancer Genome Atlas (n = 463) was used for platform transfer and development of a simplified qRT-PCR-based 15-gene S3-score (S3). This S3-score was validated in 108 metastatic and non-metastatic ccRCC patients and ccRCC-derived metastases including in part several regions from one metastasis. Univariate and multivariate Cox regression stratified by T, N, M, and G were performed with cancer-specific and progression-free survival as primary endpoints.

Results: The S3-score was significantly associated with cancer-specific survival (CSS) in 52 ccRCC patients (HR 2.9, 95% Cl 1.0-8.0, P = 3.3 × 10) as well as progression-free survival in sunitinib-treated patients (2.1, 1.1-4.2, P = 2.2 × 10). The qRT-PCR based S3-score performed similarly to the S3-score, and was significantly associated with CSS in our extended cohort of 108 patients (5.0, 2.1-11.7, P = 5.1 × 10) including metastatic (9.3, 1.8-50.0, P = 2.3 × 10) and non-metastatic patients (4.4, 1.2-16.3, P = 1.6 × 10), even in multivariate Cox regression, including clinicopathological parameters (7.3, 2.5-21.5, P = 3.3 × 10). Matched primary tumors and metastases revealed similar S3-scores, thus allowing prediction of outcome from metastatic tissue. The molecular-based qRT-PCR S3-score significantly improved prediction of CSS by the established clinicopathological-based SSIGN score (P = 1.6 × 10).

Conclusion: The S3-score offers a new clinical avenue for ccRCC risk stratification in the non-metastatic, metastatic, and sunitinib-treated setting.
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http://dx.doi.org/10.1186/s12916-018-1088-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033218PMC
July 2018

Single-use versus reusable ureterorenoscopes for retrograde intrarenal surgery (RIRS): systematic comparative analysis of physical and optical properties in three different devices.

World J Urol 2018 Dec 5;36(12):2059-2063. Epub 2018 Jun 5.

Department of Urology, Eberhard-Karls-University Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.

Introduction: Retrograde intrarenal surgery (RIRS) represents a standard option for kidney stone removal. However, RIRS is considered a cost-intensive procedure. Single-use flexible ureterorenoscopes have been introduced to improve budget predictability in RIRS. We assessed differences in physical and optical properties of single-use devices compared to standard reusable endoscopes.

Methods: In two single-use (LithoVue™, Boston Scientific; Pusen Uscope UE3011™), and one reusable ureterorenoscope (Flex-Xc™, Karl Storz), we investigated flow rates, deflection, illuminance, and intrapelvic pressure in a porcine kidney model. Subjective image quality was assessed using a standardized questionnaire. Common insertable devices were applied to investigate additional influence on physical properties.

Results: Significant variability in maximum flow rates was observed (Flex-Xc™: 25.8 ml/min, LithoVue™: 30.3 ml/min, Pusen™: 33.4 ml/min, p < 0.05). Insertion of a guide wire resulted in the highest reduction of flow rates in all endoscopes. Flection led to a reduction of absolute flow rates up to 9.4% (Flex-Xc™). Light intensity at 20/50 mm distance was 9090 lx/1857 lx (Flex-Xc™) and 5733 lx/1032 lx (LithoVue™) and 2160 lx/428 lx (Pusen™), respectively (p < 0.05). Subjective image quality score was highest using the Flex-Xc™ endoscope. During manipulation, maximum intrarenal pressure up to 66 mmHg (Pusen™) was measured.

Conclusions: Significant differences in physical and optical properties of single-use or reusable flexible ureterorenoscopes are present, with putative influence on surgical efficacy and complications. Further comparative evaluation of single-use and reusable endoscopes in a clinical scenario is useful. Moreover, utilization of ureteral access sheaths may be considered to avoid renal damage.
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http://dx.doi.org/10.1007/s00345-018-2365-9DOI Listing
December 2018

Transurethral Resection of Bladder Tumors: Next-generation Virtual Reality Training for Surgeons.

Eur Urol Focus 2019 Sep 22;5(5):906-911. Epub 2018 May 22.

University Tuebingen, Dept. of Urology, Tuebingen, Germany. Electronic address:

Background: The number of virtual reality (VR) simulators is increasing. The aim of this prospective trial was to determine the benefit of VR cystoscopy (UC) and transurethral bladder tumor resection (TURBT) training in students.

Design, Setting, And Participants: Medical students without endoscopic experience (n=51, median age=25 yr, median 4th academic year) were prospectively randomized into groups A and B. After an initial VR-UC and VR-TURBT task, group A (n=25) underwent a video-based tutorial by a skilled expert. Group B (n=26) was trained using a VR training program (Uro-Trainer). Following the training, every participant performed a final VR-UC and VR-TURBT task. Performance indicators were recorded via the simulator. Data was analyzed by Mann-Whitney U test.

Intervention: VR cystoscopy and TURBT.

Results And Limitations: No baseline and post-training differences were found for VR-UC between groups. During baseline, VR-TURBT group A showed higher inspected bladder surface than group B (56% vs 73%, p=0.03). Subgroup analysis detected differences related to sex before training (male: 31.2% decreased procedure time; 38.1% decreased resectoscope movement; p=0.02). After training, significant differences in procedure time (3.9min vs 2.7min, p=0.007), resectoscope movement (857mm vs 529mm, p=0.005), and accidental bladder injury (n=3.0 vs n=0.88, p=0.003) were found. Male participants showed reduced blood loss (males: 3.92ml vs females: 10.12ml; p=0.03) after training.

Conclusions: Measuring endoscopic skills within a virtual environment can be done easily. Short training improved efficacy and safety of VR-TURBT. Nevertheless, transfer of improved VR performance into real world surgery needs further clarification.

Patient Summary: We investigated how students without endoscopic experience profit from simulation-based training. The safe environment and repeated simulations can improve the surgical training. It may be possible to enhance patient's safety and the training of surgeons in long term.
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http://dx.doi.org/10.1016/j.euf.2018.04.011DOI Listing
September 2019

Molecular markers in disease detection and follow-up of patients with non-muscle invasive bladder cancer.

Expert Rev Mol Diagn 2018 05;18(5):443-455

a Department of Urolo`gy , University Hospital Tuebingen , Tuebingen , Germany.

Introduction: Diagnosis and surveillance of non-muscle invasive bladder cancer (NMIBC) is mainly based on endoscopic bladder evaluation and urine cytology. Several assays for determining additional molecular markers (urine-, tissue- or blood-based) have been developed in recent years but have not been included in clinical guidelines so far. Areas covered: This review gives an update on different molecular markers in the urine and evaluates their role in patients with NMIBC in disease detection and surveillance. Moreover, the potential of recent approaches such as DNA methylation assays, multi-panel RNA gene expression assays and cell-free DNA analysis is assessed. Expert commentary: Most studies on various molecular urine markers have mainly focused on a potential replacement of cystoscopy. New developments in high throughput technologies and urine markers may offer further advantages as they may represent a non-invasive approach for molecular characterization of the disease. This opens new options for individualized surveillance strategies and may help to choose the best therapeutic option. The implementation of these technologies in well-designed clinical trials is essential to further promote the use of urine diagnostics in the management of patients with NMIBC.
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http://dx.doi.org/10.1080/14737159.2018.1469979DOI Listing
May 2018

Optical improvements in the diagnosis of bladder cancer: implications for clinical practice.

Ther Adv Urol 2017 Nov 4;9(11):251-260. Epub 2017 Sep 4.

Department of Urology, University Hospital Tübingen, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.

Background: For over 100 years white-light cystoscopy has remained the gold-standard technique for the detection of bladder cancer (BCa). Some limitations in the detection of flat lesions (CIS), the differentiation between inflammation and malignancy, the inaccurate determination of the tumor margin status as well as the tumor depth, have led to a variety of technological improvements. The aim of this review is to evaluate the impact of these improvements in the diagnosis of BCa and their effectiveness in clinical practice.

Methods: A systematic literature search was conducted according to the PRISMA statement to identify studies reporting on imaging modalities in the diagnosis of NMIBC between 2000 and 2017. A two-stage selection process was utilized to determine eligible studies. A total of 74 studies were considered for final analysis.

Results: Optical imaging technologies have emerged as an adjunct to white-light cystoscopy and can be classified according to their scope as macroscopic, microscopic and molecular. Macroscopic techniques including photodynamic diagnosis (PDD), narrow-band imaging (NBI) and the Storz Professional Image Enhancement System (IMAGE1 S, formerly known as SPIES) are similar to white-light cystoscopy, but are superior in the detection of bladder tumors by means of contrast enhancement. Especially the detection rate of very mute lesions in the bladder mucosa (CIS) could be significantly increased by the use of these methods. Microscopic imaging techniques like confocal laser endomicroscopy and optical coherence tomography permit a real-time high-resolution assessment of the bladder mucosa at a cellular and sub-cellular level with spatial resolutions similar to histology, enabling the surgeon to perform an 'optical biopsy'. Molecular techniques are based on the combination of optical imaging technologies with fluorescence labeling of cancer-specific molecular agents like antibodies. This labeling is intended to favor an optical distinction between benign and malignant tissue.

Conclusions: Optical improvements of the standard white-light cystoscopy have proven their benefit in the detection of BCa and have found their way into clinical practice. Especially the combination of macroscopic and microscopic techniques may improve diagnostic accuracy. Nevertheless, HAL-PDD guided cystoscopy is the only approach approved for routine use in the diagnosis of BCa by most urological associations in the EU and USA to date.
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http://dx.doi.org/10.1177/1756287217720401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896854PMC
November 2017

Performance of Urinary Markers for Detection of Upper Tract Urothelial Carcinoma: Is Upper Tract Urine More Accurate than Urine from the Bladder?

Dis Markers 2018 30;2018:5823870. Epub 2018 Jan 30.

Department of Urology, Eberhard Karls University, Tuebingen, Germany.

Objectives: To assess the performance of urine markers determined in urine samples from the bladder compared to samples collected from the upper urinary tract (UUT) for diagnosis of UUT urothelial carcinoma (UC).

Patients And Methods: The study comprised 758 urine samples either collected from the bladder ( = 373) or UUT ( = 385). All patients underwent urethrocystoscopy and UUT imaging or ureterorenoscopy. Cytology, fluorescence in situ hybridization (FISH), immunocytology (uCyt+), and nuclear matrix protein 22 (NMP22) were performed.

Results: UUT UC was diagnosed in 59 patients (19.1%) (UUT urine) and 27 patients (7.2%) (bladder-derived urine). For UUT-derived samples, sensitivities for cytology, FISH, NMP22, and uCyt+ were 74.6, 79.0, 100.0, and 100.0, while specificities were 66.6, 50.7, 5.9, and 66.7%, respectively. In bladder-derived samples, sensitivities were 59.3, 52.9, 62.5, and 50.0% whereas specificities were 82.9, 85.0, 31.3, and 69.8%. In UUT-derived samples, concomitant bladder cancer led to increased false-positive rates of cytology and FISH.

Conclusions: Urine markers determined in urine collected from the UUT exhibit better sensitivity but lower specificity compared to markers determined in bladder-derived urine. Concomitant or recent diagnosis of UC of the bladder can further influence markers determined in UUT urine.
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http://dx.doi.org/10.1155/2018/5823870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831978PMC
September 2018