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Limited nutrient availability in the tumor microenvironment can cause the rewiring of signaling and metabolic networks to confer cancer cells with survival advantages. We show here that the limitation of glucose, glutamine and serum from the culture medium resulted in the survival of a population of cancer cells with high viability and capacity to form tumors in vivo. These cells also displayed a remarkable increase in the abundance and size of lysosomes. Moreover, lysosomes were located mainly in the perinuclear region in nutrient-limited cells; this translocation was mediated by a rapid post-transcriptional increase in the key endolysosomal trafficking protein Rab7a. The acidic lysosomes in nutrient-limited cells could trap weakly basic drugs such as doxorubicin, mediating resistance of the cells to the drug, which could be partially reversed with the lysosomal inhibitor bafilomycin A1. An in vivo chorioallantoic membrane (CAM) assay indicated a remarkable decrease in microtumor volume when nutrient-limited cells were treated with 5-Fluorouracil (5-FU) and bafilomycin A1 compared to cells treated with either agent alone. Overall, our data indicate the activation of complementary pathways with nutrient limitation that can enable cancer cells to survive, proliferate and acquire drug resistance., (© 2024 The Author(s). Traffic published by John Wiley & Sons Ltd.)

Following a description of the historic evolution of botulinum toxin A detrusor injections for neurogenic and nonneurogenic bladder overactivity, which was mainly driven by German-speaking countries, the terminological revolution of 2002 and the influence on design and outcomes of upcoming approval studies for the indication overactive bladder (OAB) are examined. OnabotulinumtoxinA (100 IU) for second-line treatment of OAB received European approval in 2013. Phase IV observational studies concerning therapeutic persistence and adherence with onabotulinumtoxinA are analyzed and compared with therapeutic alternatives. Predictors of treatment success and complications are identified and compared to the required preinterventional diagnostic effort. Since onabotulinumtoxinA and sacral neuromodulation (SNM) are competing for second-line OAB treatment, both options are compared with regard to differential indications, effectivity, durability and patient adherence. Gender-specific causes of urgency and urge incontinence in women are differentiated from the diagnosis of OAB and require priority treatment. On the basis of diagnostic examination results, an algorithm for invasive second-line treatment of OAB is presented, since overly liberal utilization of onabotulinumtoxinA in therapy-naive OAB patients has not proven superiority over oral antimuscarinergic standard therapy, which can only be explained by improper patient selection., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Pancreatic cancer is a malignant tumor of the digestive system. It is highly aggressive, easily metastasizes, and extremely difficult to treat. This study aimed to analyze the genes that might regulate pancreatic cancer migration to provide an essential basis for the prognostic assessment of pancreatic cancer and individualized treatment. A CRISPR knockout library directed against 915 murine genes was transfected into TB 32047 cell line to screen which gene loss promoted cell migration. Next-generation sequencing and PinAPL.py- analysis was performed to identify candidate genes. We then assessed the effect of serine/threonine kinase 11 (STK11) knockout on pancreatic cancer by wound-healing assay, chick agnosia (CAM) assay, and orthotopic mouse pancreatic cancer model. We performed RNA sequence and Western blotting for mechanistic studies to identify and verify the pathways. After accelerated Transwell migration screening, STK11 was identified as one of the top candidate genes. Further experiments showed that targeted knockout of STK11 promoted the cell migration and increased liver metastasis in mice. Mechanistic analyses revealed that STK11 knockout influences blood vessel morphogenesis and is closely associated with the enhanced expression of phosphodiesterases (PDEs), especially PDE4D, PDE4B, and PDE10A. PDE4 inhibitor Roflumilast inhibited STK11-KO cell migration and tumor size, further demonstrating that PDEs are essential for STK11-deficient cell migration. Our findings support the adoption of therapeutic strategies, including Roflumilast, for patients with STK11-mutated pancreatic cancer in order to improve treatment efficacy and ultimately prolong survival., (© 2024. The Author(s).)

Partial epithelial-mesenchymal transition (p-EMT) has recently been identified as a hybrid state consisting of cells with both epithelial and mesenchymal characteristics and is associated with the migration, metastasis, and chemoresistance of cancer cells. Here, we describe the induction of p-EMT in starved colorectal cancer (CRC) cells and identify a p-EMT gene signature that can predict prognosis. Functional characterisation of starvation-induced p-EMT in HCT116, DLD1, and HT29 cells showed changes in proliferation, morphology, and drug sensitivity, supported by in vivo studies using the chorioallantoic membrane model. An EMT-specific quantitative polymerase chain reaction (qPCR) array was used to screen for deregulated genes, leading to the establishment of an in silico gene signature that was correlated with poor disease-free survival in CRC patients along with the CRC consensus molecular subtype CMS4. Among the significantly deregulated p-EMT genes, a triple-gene signature consisting of SERPINE1, SOX10, and epidermal growth factor receptor (EGFR) was identified. Starvation-induced p-EMT was characterised by increased migratory potential and chemoresistance, as well as E-cadherin processing and internalisation. Both gene signature and E-cadherin alterations could be reversed by the proteasomal inhibitor MG132. Spatially resolving EGFR expression with high-resolution immunofluorescence imaging identified a proliferation stop in starved CRC cells caused by EGFR internalisation. In conclusion, we have gained insight into a previously undiscovered EMT mechanism that may become relevant when tumour cells are under nutrient stress, as seen in early stages of metastasis. Targeting this process of tumour cell dissemination might help to prevent EMT and overcome drug resistance. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Context: The complications of synthetic midurethral slings (MUSs) in women with stress urinary incontinence (SUI) have become a globally debated issue., Objective: To systematically review the short- and long-term complications of mesh slings reported in observational data compared with clinical trial data, to determine whether the complication rates from clinical trials reflects "real-world" observational data., Evidence Acquisition: PubMed and Cochrane Library were searched. Methods as detailed in Preferred Reporting Items for Systematic Reviews and Meta-analyses and Cochrane Handbook for Systematic Reviews of Interventions were followed., Evidence Synthesis: Thirty registries/databases including 709 335 MUS procedures (1-22 yr of follow-up) were identified. MUS procedures were associated with intraoperative bladder perforation in 0.86-3.6%, urethral perforation in 0-0.1%, vascular injury in 0.04-0.1%, voiding lower urinary tract symptoms (LUTS) in 1.47-3.5%, vaginal exposure in 0.2-1.9%, and reoperation in up to 9% of cases. Forty-three randomised clinical trials were identified, including 6284 women who underwent MUS procedures and 2177 women who underwent other interventions (1-10 yr of follow-up). MUS procedures were associated with urinary tract perforation in 2.58%, vaginal injury in 1.43%, de novo voiding LUTS in 4.37%, de novo storage LUTS in 5.41%, mesh extrusion/exposure (vaginal/urinary tract) in 2.54%, dyspareunia in 2.26%, pain (pelvic/suprapubic/perineal) in 2.83%, and reoperation for complications required in 1.82% of cases. Meta-analyses of the randomised controlled trials revealed that retropubic MUSs were associated with more events of urinary tract perforation (risk ratio [RR] 9.81, 95% confidence interval [CI] 5.05-19.04, high certainty of evidence [COE]) and voiding LUTS (RR 1.57, 95% CI 1.19-2.07, high COE) than transobturator MUSs. MUSs were associated with more events of pain than mini-slings (RR 1.72, 95% CI 1.04-2.87, moderate COE)., Conclusions: Short- and long-term data on complications of polypropylene mesh used for female SUI are fairly comparable when using outcome data from well-designed clinical trials or from less structured prospective or retrospective registries. Comparisons have to be made with caution since the two systems of data collection are inherently incomparable. This knowledge should be incorporated in the discussion on how to implement polypropylene mesh for female stress incontinence., Patient Summary: In order to know whether mesh tapes used for treating stress incontinence work well and are safe, high-quality information is important. It appears that well-designed clinical studies give similar results to large registration databases. These data should be interpreted with caution in view of the different ways the information was collected. These results will help physicians and patients understand the risks of mesh tapes., (Copyright © 2023. Published by Elsevier B.V.)

Background: The role of ATF2 in colon cancer (CC) is controversial. Recently, we reported that low ATF2 expression is characteristic of highly invasive tumors, suggesting that ATF2 might also be involved in therapy resistance. 5-Fluorouracil (5-FU) is the best-known chemotherapeutic drug for CC, but drug resistance affects its curative effect. To date, the role of ATF2 in the 5-FU response remains elusive., Methods/results: For our study, we had available HCT116 cells (wild-type p53) and HT29 colon tumor cells (mutant p53) and their corresponding CRISPR‒Cas9-generated ATF2-KO clones. We observed that loss of ATF2 triggered dose- and time-dependent 5-FU resistance in HCT116 cells by activating the DNA damage response (DDR) pathway with high p-ATR Thr1989 and p-Chk1 Ser317 levels accompanied by an increase in the DNA damage marker γ-H2AX in vitro and in vivo using the chicken chorioallantoic membrane (CAM) model. Chk1 inhibitor studies causally displayed the link between DDR and drug resistance. There were contradictory findings in HT29 ATF2-KO cells upon 5-FU exposure with low p-Chk1 Ser317 levels, strong apoptosis induction, but no effects on DNA damage. In ATF2-silenced HCT116 p53 -/- cells, 5-FU did not activate the DDR pathway. Co-immunoprecipitation and proximity ligation assays revealed that upon 5-FU treatment, ATF2 binds to ATR to prevent Chk1 phosphorylation. Indeed, in silico modelling showed reduced ATR-Chk1 binding when ATF2 was docked into the complex., Conclusions: We demonstrated a novel ATF2 scaffold function involved in the DDR pathway. ATF2-negative cells are highly resistant due to effective ATR/Chk1 DNA damage repair. Mutant p53 seems to overwrite the tumor suppressor function of ATF2., (© 2023. The Author(s).)

Background: Pelvic floor disorders are common, especially in pregnancy and after delivery, in the postmenopausal period, and old age, and they can significantly impact on the patient's quality of life., Methods: This narrative review is based on publications retrieved by a selective search of the literature, with special consideration to original articles and AWMF guidelines., Results: Pelvic floor physiotherapy (evidence level [EL] 1), the use of pessaries (EL2), and local estrogen therapy can help alleviate stress/urge urinary incontinence and other symptoms of urogenital prolapse. Physiotherapy can reduce urinary incontinence by 62% during pregnancy and by 29% 3-6 months post partum. Anticholinergic and β-sympathomimetic drugs are indicated for the treatment of an overactive bladder with or without urinary urge incontinence (EL1). For patients with stress urinary incontinence, selective serotonin-noradrenaline reuptake inhibitors can be prescribed (EL1). The tension-free tape is the current standard of surgical treatment (EL1); in an observational follow-up study, 87.2% of patients were satisfied with the outcome 17 years after surgery. Fascial reconstruction techniques are indicated for the treatment of primary pelvic organ prolapse, and mesh-based surgical procedures for recurrences and severe prolapse (EL1)., Conclusion: Urogynecological symptoms should be specifically asked about by physicians of all relevant specialties; if present, they should be treated conservatively at first. Structured surgical techniques with and without mesh are available for the treatment of urinary incontinence and pelvic organ prolapse. Preventive measures against pelvic floor dysfunction should be offered during pregnancy and post partum.

The current guideline "Female Urinary Incontinence" of the working group of scientific medical professional associations (AWMF) comprises a recommendation about the optional use of vaginal laser therapy in patients with mild to moderate stress urinary incontinence (SUI). Since to date there is no corresponding recommendation within the European Association of Urology (EAU) guidelines, the scientific evidence of the AWMF recommendation is evaluated. On the basis of limited data, both available laser systems (Erbium:YAG and CO 2 ) seem to work equivalently in patients with mild SUI. The problematic comparability of studies with different definitions of incontinence, severity classifications, outcome parameters, and consideration of diverse etiological aspects is addressed. After thorough consideration of the available prognosticator research, a profile of an ideal laser candidate is developed for proper patient selection. This profile includes younger age, normal body mass index, sufficient estrogenization status, pure stress urinary incontinence due to urethral hypermobility, and urine loss of < 8 g during a 1 h pad test., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Aim This completely revised interdisciplinary S2k-guideline on the diagnosis, therapy, and follow-up care of female patients with urinary incontinence (AWMF registry number: 015-091) was published in December 2021. This guideline combines and summarizes earlier guidelines such as "Female stress urinary incontinence," "Female urge incontinence" and "Use of Ultrasonography in Urogynecological Diagnostics" for the first time. The guideline was coordinated by the German Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the Working Group for Urogynecology and Plastic Pelvic Floor Reconstruction (Arbeitsgemeinschaft für Urogynäkologie und plastische Beckenbodenrekonstruktion e. V., AGUB). Methods This S2k-guideline was developed using a structured consensus process involving representative members from different medical specialties and was commissioned by the Guidelines Commission of the DGGG, OEGGG and SGGG. The guideline is based on the current version of the guideline "Urinary Incontinence in Adults" published by the European Association of Urology (EAU). Country-specific items associated with the respective healthcare systems in Germany, Austria and Switzerland were also incorporated. Recommendations The short version of this guideline consists of recommendations and statements on the surgical treatment of female patients with stress urinary incontinence and urge incontinence. Specific solutions for the diagnostic workup and treatment of uncomplicated and complicated urinary incontinence are discussed. The diagnostics and surgical treatment of iatrogenic urogenital fistula are presented., Competing Interests: Conflict of Interest The conflicts of interest of the authors are listed in the long version of the guideline ( https://register.awmf.org/de/leitlinien/detail/015-091 )./ Die Interessenkonflikte der Autoren sind in der Langfassung der Leitlinie ( https://register.awmf.org/de/leitlinien/detail/015-091 ) aufgelistet., (Thieme. All rights reserved.)

Aim This completely revised interdisciplinary S2k-guideline on the diagnosis, therapy, and follow-up care of female patients with urinary incontinence (AWMF registry number: 015-091) was published in December 2021. This guideline combines and summarizes earlier guidelines such as "Female stress urinary incontinence," "Female urge incontinence" and "Use of Ultrasonography in Urogynecological Diagnostics" for the first time. The guideline was coordinated by the German Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the Working Group for Urogynecology and Plastic Pelvic Floor Reconstruction (Arbeitsgemeinschaft für Urogynäkologie und plastische Beckenbodenrekonstruktion e. V., AGUB). Methods This S2k-guideline was developed using a structured consensus process involving representative members from different medical specialties and was commissioned by the Guidelines Commission of the DGGG, OEGGG and SGGG. The guideline is based on the current version of the guideline "Urinary Incontinence in Adults" published by the European Association of Urology (EAU). Country-specific items associated with the respective healthcare systems in Germany, Austria and Switzerland were also incorporated. Recommendations The short version of this guideline consists of recommendations and statements on the epidemiology, etiology, classification, symptoms, diagnostics, and treatment of female patients with urinary incontinence. Specific solutions for the diagnostic workup and appropriate conservative and medical therapies for uncomplicated and complication urinary incontinence are discussed., Competing Interests: Conflict of Interest The conflicts of interest of all the authors are listed in the long version of the guideline ( https://register.awmf.org/de/leitlinien/detail/015-091 )./ Die Interessenkonflikte der Autoren sind in der Langfassung der Leitlinie ( https://register.awmf.org/de/leitlinien/detail/015-091 ) aufgelistet., (Thieme. All rights reserved.)

Purpose: To investigate the differences in maximal (isometric and concentric peak torque) and explosive (rate of torque development (RTD)) hamstring and quadriceps strength symmetry between males and females during early- and late-phase rehabilitation after anterior cruciate ligament reconstruction (ACLR) using hamstring tendon (HT) autografts and to determine the interaction of time and sex on maximal and explosive strength symmetry., Methods: A total of 38 female and 51 male participants were assessed during early (3-6 months post-operative) and late (7-12 months post-operative) phases of rehabilitation following ACLR. Maximal (concentric and isometric peak torque) and explosive (isometric RTD) hamstring and quadriceps strength were assessed and presented as limb symmetry index (LSI)., Results: Maximal concentric hamstrings asymmetry (Early: 86 ± 14; Late 92 ± 13; p = 0.005) as well as maximal concentric (Early, 73 ± 15; Late 91 ± 12; p < 0.001) and explosive (Early: 82 ± 30; Late: 92 ± 25; p = 0.03) quadriceps asymmetry decreased from early to late rehabilitation. However, there were no significant changes in maximal isometric quadriceps strength and explosive isometric hamstring strength in the same time period. Females had a larger asymmetry in maximal concentric (Females: 75 ± 17; Males: 81 ± 15; p = 0.001) and explosive (Females: 81 ± 32; Males: 89 ± 25; p = 0.01) quadriceps strength than males throughout rehabilitation. There were no sex differences in maximal and explosive hamstring strength. There were no sex by time interactions for any variables., Conclusion: Explosive hamstring strength asymmetry did not improve despite recovery of maximal hamstring strength during rehabilitation following ACLR with HT autografts. While sex did not influence strength recovery, females had larger maximal and explosive quadriceps strength asymmetry compared to males throughout rehabilitation following ACLR., Level of Evidence: Level III., (© 2022. The Author(s).)

In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2 KO /TROP2 high status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2 low /TROP2 high expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells., (© 2022. The Author(s).)

The epithelial-mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.

As a consequence of the demographic change, the prevalence of female and male bladder and bowel dysfunction, functional pelvic floor disorders and pelvic organ prolapse are steadily increasing. Continence and pelvic floor centers are interdisciplinary facilities that focus on these functional disorders, including malformations, tumors and functional disorders resulting from neurogenic diseases, injuries or surgery. The affected patient clientele includes children, women, and men of all ages. The certification is carried out by the accredited certification company CERT iQ Certification Services. In addition to structural requirements, personal quality criteria are also implemented in the novel harmonized and standardized certification system. The assessment of treatment quality is also a component of the procedure, although it is currently limited to the midurethral sling tracer procedure for the treatment of female stress urinary incontinence. Regarding the other conservative and surgical treatment options for pelvic floor, bladder and bowel functional disorders, no quality of outcome has so far been recorded. Internationally recognized and validated questionnaires to assess preoperative and postoperative quality of life would be valuable tools to define the quality of treatment and outcome. Similarly, supplementary thresholds should be established for complication rates and quality of the success of treatment to identify centers with high expertise. In this context, it is crucial to consider the individual complexity of the patient groups and to distinguish between primary and recurrent interventions., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial-mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.

Due to a safety alert issued by the US Food and Drug Administration (FDA) in 2011 for transvaginal mesh implants to treat female prolapse as a result of numerous reports of complications such as infection, chronic pain, dyspareunia, vaginal erosion, shrinkage and erosion into other organs nearly all industrial products have been withdrawn from the market in the meantime. The United Kingdom, Australia, and New Zealand extended warnings and prohibitions even on the implantation of midurethral slings (TVT, TOT). In view of these current international controversies regarding the use of implanted materials for the treatment of stress incontinence and prolapse and the lack of clear guidelines for the use of biomaterials, the opinion of the Working Group on Urological Functional Diagnostics and Female Urology should provide clarity. The Opinion is based on the SCENIHR Report of the "European Commission's Scientific Committee on Emerging and Newly Identified Health Risks", the "Consensus Statement of the European Urology Association and the European Urogynaecological Association on the Use of Implanted Materials for Treating Pelvic Organ Prolapse and Stress Urinary Incontinence" and in compliance with relevant EAU and national guidelines and the opinion of the Association for Urogynaecology and Plastic Pelvic Floor Reconstruction (AGUB eV). In addition, recommendations are given for the future handling of implants of slings and meshes for the treatment of stress incontinence and prolapse from a urologic viewpoint.

Colorectal cancer (CRC) is one of the leading cancer-related causes of death worldwide. Despite the improvement of surgical and chemotherapeutic treatments, as of yet, the disease has not been overcome due to metastasis to distant organs. Hence, it is of great relevance to understand the mechanisms responsible for metastasis initiation and progression and to identify novel metastatic markers for a higher chance of preventing the metastatic disease. The Death-associated protein kinase 1 (DAPK1), recently, has been shown to be a potential candidate for regulating metastasis in CRC. Hence, the aim of the study was to investigate the impact of DAPK1 protein on CRC aggressiveness. Using CRISPR/Cas9 technology, we generated DAPK1-deficient HCT116 monoclonal cell lines and characterized their knockout phenotype in vitro and in vivo. We show that loss of DAPK1 implemented changes in growth pattern and enhanced tumor budding in vivo in the chorioallantoic membrane (CAM) model. Further, we observed more tumor cell dissemination into chicken embryo organs and increased invasion capacity using rat brain 3D in vitro model. The novel identified DAPK1-loss gene expression signature showed a stroma typical pattern and was associated with a gained ability for remodeling the extracellular matrix. Finally, we suggest the DAPK1-ERK1 signaling axis being involved in metastatic progression of CRC. Our results highlight DAPK1 as an anti-metastatic player in CRC and suggest DAPK1 as a potential predictive biomarker for this cancer type.

Objective: To compare open simple prostatectomy, endoscopic enucleation and laparoscopic, robot-assisted enucleation of high-volume prostate in terms of operation time, blood loss, transfusion and complication rates and early continence rates., Material and Methods: Patients with BPH treated endoscopically (ThuVEP, Hamburg and Hannover) or robotically (Mainz) were evaluated prospectively for prostate size, free flow and validated questionnaires (IPSS, QoL). 35 patients were matched to patients after open prostatectomy (Mainz) for age, prostate size, IPSS and QoL scores. Operation time was noted from the first cut to the last suture; blood loss was estimated by the drop of haemoglobin preoperatively and one day after surgery. Transfusion rates were documented. Early continence was estimated by pad use over the first 24 h after catheter removal. Statistical analysis was performed with SPSS 22.0., Results: No significant differences in prostate size, age and preoperative questionnaires were found (p > 0.3). Postoperative flow and the results of the questionnaires were significantly improved (all p < 0.05), without difference between the approaches (p > 0.8). Endoscopic surgery showed superiority in operation time (both p < 0.05); blood loss and transfusion rates were significantly lower compared to open surgery (both p < 0.01) and lower than in robotic surgery without reaching significance (p = 0.18, p = 0.36). Similar results were seen in early continence rates., Conclusion: Due to our results, endoscopic surgery should be considered as first-line therapy unless there are comorbidities like diverticula and/or bladder calculi that can be easily treated simultaneously by robotic surgery. Against the background of these findings, indications favouring open surgery are getting sparse.

Proper indication, preoperative diagnostics and final choice of surgical technique in the operative management of female stress urinary incontinence are subject to somewhat irrational, trend-based changes. For various reasons (insufficient reimbursement, poor expertise, limited therapeutic spectrum) preoperative urodynamic tests are increasingly thought to be unnecessary and are progressively replaced by perineal ultrasound despite lack of evidence. Since the AWMF guidelines (AWMF: Association of the Scientific Medical Societies in Germany) for the diagnosis and treatment of stress urinary incontinence in women were published, individualized planning of therapy is "out". Unconditional guideline adherence in certified pelvic floor centers, which have become very popular in Germany, has furthermore restricted the spread of therapeutic options due to minimum procedure number requirements. With regard to suburethral tension-free alloplastic slings, the retropubic version, which was temporarily unfashionable, has been experiencing a renaissance at the cost of the transobturator alternative. Single-incision slings were developed for the outpatient US market and have never become established in Germany due to lack of proof of superiority. In the setting of a limited spectrum of surgical procedures, adjustable sling systems offer promising treatment options for risk groups with acceptance of higher infection and erosion rates, thus gaining popularity. Reliable and comprehensive preoperative patient information comprising the whole spectrum of therapeutic options with individual risks and opportunities is key to prevent the impending ban of alloplastic implants in female stress incontinence surgery.

Introduction: Urinary incontinence in men after radical prostatectomy affects strongly quality of life. If conservative treatment fails, surgical treatment consists of implantable devices. If the requirement of manual dexterity in the artificial sphincter is to be avoided, the ProACT system offers a readjustable system, which shows good continence, but also high revision rates. Aim of our single-centre, single-surgeon study was to evaluate the success and revision rates of ProACT over long-term follow-up and if repeat ProACT implantation after failure would be a reasonable strategy., Materials and Methods: In May 2017, follow-up of all patients who underwent ProACT implantation between 2003 and 2013 was obtained. Parameters were numbers of pads used, filling volume of balloons, and patient-reported satisfaction. Furthermore, revisions were noted., Results: Between 2003 and 2013, 134 patients were implanted a ProACT system. Median age was 71 years; median follow-up was 118 months. 112 implantations were successful (82.6%) and the number of pads used decreased significantly (p < 0.005). 63 patients were revised and 49 were successful (77.8%). No differences in success rate, pads used, or filling volume were seen (all p > 0.8). In a second revision, again, no differences in success rate or pads used were noted (all p > 0.7). Patients' personal satisfaction was high despite the high revision rate., Conclusion: In the hands of an experienced surgeon, ProACT is a safe and effective therapy for post-prostatectomy incontinence especially if mayor surgery is to be avoided. Revision rates are high, but the results of ProACT reimplantation are comparable to the results after the first implantation.

Alloplastic transvaginal meshes have become very popular in the surgery of pelvic organ prolapse (POP) as did alloplastic suburethral slings in female stress incontinence surgery, but without adequate supporting data. The simplicity of the mesh procedure facilitates its propagation with acceptance of higher revision and complication rates. Since attending physicians do more and more prolapse surgeries without practicing or teaching alternative techniques, expertise in these alternatives, which might be very useful in cases of recurrence, persistence or complications, is permanently lost. It is doubtful that proper and detailed information about alternatives, risks, and benefits of transvaginal alloplastic meshes is provided to every single prolapse patient according to the recommendations of the German POP guidelines, since the number of implanted meshes exceeds the number of properly indicated mesh candidates by far. Although there is no dissent internationally about the available mesh data, thousands of lawsuits in the USA, insolvency of companies due to claims for compensation and unambiguous warnings from foreign urological societies leave German urogynecologists still unimpressed. The existing literature in pelvic organ prolapse exclusively focusses on POP stage and improvement of that stage with surgical therapy. Instead, typical prolapse symptoms should trigger therapy and improvement of these symptoms should be the utmost treatment goal. It is strongly recommended for liability reasons to obtain specific written informed consent.

Objective: To evaluate the long-term outcomes in patients with classic bladder exstrophy and continent anal urinary diversion (CAD) for continence, upper urinary tract status, secondary malignancies, and sexual function., Patients and Methods: The medical records of 82 exstrophy patients having undergone CAD in our department between 1970 and 2015 were reviewed. Patients were invited for follow-up examinations and asked to complete validated questionnaires relating to sexual function., Results: Thirty-two of 57 eligible patients with a median follow-up of 23.9 years were included in the study. Ninety-seven percent of patients were fully continent during daytime. Upper urinary tract and renal function remained stable in 75% and 87%, respectively. Five patients developed secondary malignancies originating from the rectal reservoir. Forty-one percent received prophylactic alkaline substitution. Sexual function as measured by the Female Sexual Function Index and the International Index on Erectile Function was negatively affected in all domains in both genders. Eighty-six percent of patients had a stable relationship and 35% were married. Five women conceived a total of 6 healthy children. Paternity rate was 40%., Conclusion: CAD constitutes an effective treatment option with acceptable long-term outcomes in exstrophy patients in whom all attempts at restoring the lower urinary tract have failed. Long-term follow-up of the upper urinary tract, assessment of acid-base balance, and endoscopy of the rectosigmoid reservoir are paramount for the safety of this type of management. Evaluation of sexual dysfunction should be an active part of follow-up., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: The study aimed to evaluate the efficacy and safety of solifenacin in older patients with overactive bladder (OAB)., Materials and Methods: Observational data on patients aged ≥70 years and the prescribed flexible dose of solifenacin for OAB were collected at 294 offices of German general practitioners. Baseline and week 12 data included type and severity of OAB symptoms, adverse events, quality of life, and change in cognitive function per Mini Mental State Examination (MMSE)., Results: Mean age of 774 patients was 78 ± 6 years. A decrease was observed in all OAB symptoms including a reduction of urinary urgency and micturition, each by 4 episodes per 24 h. No change in mean MMSE scores was apparent at week 12. Adverse events and treatment discontinuations were low at 5.8 and 0.5%, respectively., Conclusion: Solifenacin was well-tolerated while OAB symptoms declined at week 12. No relevant effect of solifenacin on cognitive function was observed in this elderly population., (© 2017 S. Karger AG, Basel.)

Objectives: The aim of this study was to evaluate the role of bone scintigraphy (BS) in early prediction of clinically asymptomatic bisphosphonate (BP)-related osteonecrosis of the jaws (BRONJ) in patients with metastatic castration-resistant prostate cancer (mCRPC)., Material and Methods: BS of mCRPC patients treated with BP was evaluated for pathologic tracer uptake of the jaws in BS suspicious for BRONJ. Results were compared to development of clinically evident BRONJ. Sensitivity, specificity and predictive values of BS for the detection of BRONJ as well as time from beginning of BP therapy to pathologic tracer uptake in BS and time from pathologic tracer uptake in BS to clinically evident BRONJ were determined., Results: Thirty BP-treated patients were included. Nine patients (30%) had pathologic BS lesions of the jaws. Six patients (20%) developed BRONJ. Sensitivity and specificity of BS for BRONJ prediction were 67 and 79%. Median time from the start of BP treatment to pathologic tracer uptake in BS was 28 months (range 10-33) and from pathologic tracer uptake in BS to clinically evident BRONJ 6.5 months (range 2-19). Pathologic tracer uptake in BS was significantly more often observed in patients who developed BRONJ compared to patients who did not (p = 0.049; OR 7.6)., Conclusions: Patients with pathologic tracer uptake in the jaws in BS significantly more often develop BRONJ. An unsuspicious BS is predictive for absence of BRONJ in the future., Clinical Relevance: We conclude that when BS has been performed, it should not only be used to assess tumour stage and treatment response but also to check for pathologic tracer uptake in the jaws in BS to detect BRONJ at an early stage in mCRPC patients receiving bisphosphonates.

Introduction: The study aimed to compare the incidence of cardiovascular events (CVEs) after donor nephrectomy (DN) and radical tumor nephrectomy (RN), according to an estimated glomerular filtration rate (eGFR), were evaluated over time., Materials and Methods: Follow-up was collected for DN who underwent surgery from 1998 to 2007 for CVE and renal function. All DN were matched for age to patients treated by RN or adenoma enucleation (control group), who were eligible for DN. eGFR was estimated using the Cockgroft-Gould formula. Patients with preoperative comorbidities were excluded., Results: Thirty DN (median age 48.9 years) were included with a median follow-up of 138.5 months (interquartile range 119-159). No significant differences in patients' characteristics were found preoperatively (p > 0.5). Four out of 30 DN developed a CVE (3 myocardial infarctions (MI), 1 stroke), 2 of 30 patients in the control group (both MI) and 8 of 30 RN patients (6 MI, 2 strokes, p > 0.05). Arterial hypertension developed in 14 DN (46.7%), in 12 (40%) after RN and in 15 controls. The CVE occurred after a median time of 68 months (5-231) and were related to a drop of ∼30% in the eGFR irrespective of the group., Conclusion: Decline of renal function after nephrectomy is the main risk factor for CVE. Close monitoring of renal function and new onset hypertension is warranted., (© 2016 S. Karger AG, Basel.)

Objective: To identify clinical parameters influencing German urologists treating cT1a renal tumours, we performed a nationwide survey among members of the German urological associations (DGU and BDU)., Material and Methods: In spring 2012, DGU and BDU members were invited to complete our survey. For 8 cases and 3 index patients, participants were asked about their preferred treatment. Multivariate analyses were used to identify significant parameters leading the responders to favour radical nephrectomy (RN) over nephron sparing surgery (NSS) as well as active surveillance (AS) over invasive treatment., Results: Three hundred six (7.4%) forms were included in our analysis. In patients with larger tumours (4 vs. 2 cm, OR 3.16), endophytic growth (endophytic vs. exophytic, OR 2.70), hilar tumour location (perihilar vs. polar, OR 14.37), normal renal function (normal vs. decreased, OR 1.92) and elderly patients (elderly vs. young, OR 2.14) RN was preferred. Based on decreased renal function (decreased vs. normal, OR 12.74), elderly (elderly vs. young, OR 14.31) and hilar tumour location (perihilar vs. polar, OR 2.14), 77.2% of respondents recommended AS for selected patients. Treating physician factors had no influence on the treatment preference., Conclusions: Elderly patients with small tumours and impaired renal function were candidates for AS. Younger patients mainly underwent NSS. However, when the tumours' location was endophytic or hilar, RN was recommended., (© 2016 S. Karger AG, Basel.)

Background: Certified Prostate Centers proclaim congruent process and outcome quality results for treatment of prostate carcinoma. Therapy in accordance with the guidelines after presentation of the patient in an interdisciplinary conference and regular documented follow up are not in themselves a guarantee for good quality results (complication free, continence, erectile function, negative surgical margins, biochemical recurrence free), and are significantly influenced by factors not contained within the certification framework., Discussion: An association between exceeding the minimum number of operations and quality assurance exists, if at all, only vaguely and on no account justifies the absolute numbers necessary for certification. Although good measuring instruments for a Pentafecta analysis are available, the gathering of quality results for a center are limited to questionnaires for functional quality results and in the non-differentiated request for a pT2R1 rate of under 10 % for oncological quality results., Conclusions: The reasons for this systematic ignoring of the for the patient so important quality results with a simultaneous excessive regard for standardizing organizational procedure processes are manifold. They comprise valid verifiability of process quality, the unclear effects of standardized treatment pathways on actual operation quality and the capitulation to statistical and patient determined problems with sufficient acquisition of comparable functional OP results. Whereas the outcome quality is more important than the process quality for patients with prostate carcinoma, the certified centers conduct themselves in exactly the opposite manner, thus creating a virtually insoluble dilemma.

Background: In contrast to conventional laparoscopic partial nephrectomy, the approach of robot-assisted partial nephrectomy (RAPN) shows a steep learning curve with shorter warm ischaemia times (WIT) and comparable postoperative outcomes. Therefore RAPN is considered a good minimally-invasive surgical procedure for patients presenting with a renal cell carcinoma in clinical stage cT1a. The aim of the presented study was to evaluate the perioperative outcomes of our patients after RAPN and to illustrate the learning curve based on characteristic perioperative parameters such as WIT., Material and Methods: The data of 109 patients treated by RAPN in our clinic between January 2010 and April 2015 were retrospectively analysed regarding perioperative, laboratory and oncological outcomes. Postoperative complications until 30 days after surgery were documented. We analysed the data of the largest patient population treated by a single urologist, comparing WIT, operating time, blood loss and decline of the glomerular filtration rate between the first and the second 30 consecutive cases., Results: Mean WIT was 18.4 min (SD±10.2), mean operating time was 199 min (SD±20), and mean estimated blood loss was 657 millilitres (SD±715 ml). Mean loss of GFR was reported to be 4.99 mg/dl/1.73 m (2) (SD±15.44). 83 (76%) malignant lesions were removed. 11 patients (10%) had a R1 resection, one patient had a R2 resection and in 2 cases the resection status was Rx. 22% of patients developed postoperative complications. Intraoperative complications were documented in 2 cases. According to the Clavien-Dindo Classification, 6% of patients had grade 1 and 2 complications and 13% developed grade 3 and 4 complications. WIT was significantly lower after 30 consecutive cases treated by one urologist. Regarding operating time, GFR or blood loss no significant correlation was found., Conclusion: Our data is in line with the surgical outcomes described in the literature. RAPN is a safe surgical technique with a steep learning curve. In our experience, 30 surgical cases provide a urologist with sufficient expertise to achieve good perioperative results. Weaknesses of this report include the retrospective design and insufficient documentation in some cases., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: In bladder cancer (BCa) patients undergoing radical cystoprostatectomy (RCPx), concomitant prostate cancer (PCa) is a common finding. Up to now there is no clear evidence to suggest that concomitant PCa is a predictor of outcome in these patients. Aim of this study was to assess incidence and clinicopathologic characteristics of concomitant PCa in RCPx specimen and correlate it to survival parameters from a single-centre material over two decades., Methods: All men who had undergone RCPx for BCa at our institution between 1994 and 2013 were included in this study. Clinicopathologic parameters for BCa and PCa were evaluated and correlated with outcome parameters. Survival analysis was performed for the subgroup of nonmetastatic organ-confined BCa to evaluate the role of concomitant Gleason Score (GS) ≥7 PCa., Results: Of 945 men who had undergone RCPx for BCa, concomitant PCa was present in 237 patients (25.1 %). There was a significant increase in PCa incidence from 18.9 to 32.3 % between 1994 and 2013 (p = 0.009). Concomitant PCa represented a more aggressive phenotype at the end of the study (p = 0.037). In nonmetastatic organ-confined BCa, concomitant GS ≥7 PCa (HR 3.09; p = 0.0001) and age > 68 (HR 1.80; p = 0.0004) were independent negative predictors for overall survival., Conclusions: Concomitant PCa in RCPx specimen of BCa patients is a common finding. The incidence of concomitant PCa has significantly increased within 2 decades, presenting a more aggressive phenotype. Age and in particular concomitant GS ≥7 PCa are independent prognosticators for poor survival in patients with nonmetastatic organ-confined BCa.

The prevalence of kidney stones is increasing worldwide. Asymptomatic non-obstructing kidney stones are increasingly detected as an incidental finding on radiologic imaging, which has been performed more frequently over the last decades. Beside the current interventional treatment modalities such as extracorporeal shockwave lithotripsy (ESWL), ureterorenoscopy (URS) and percutaneous nephrolithotomy (PNL), active surveillance of asymptomatic kidney stones has been a focus of discussion lately, not only for attending physicians, but even more so for patients. The current German and European guidelines recommend active surveillance for patients with asymptomatic kidney stones if no interventional therapy is mandatory because of pain or medical factors. Herein we review the current literature on risks and benefits of active surveillance of asymptomatic non-obstructing kidney stones., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Bone metastasis develops in 30% of all patients with renal cell carcinoma. We elucidated the mechanisms that lead to and predict bone metastasis of renal cell carcinoma., Materials and Methods: Nine renal cell carcinoma primary cell lines and 30 renal cell carcinoma tissue specimens (normal and tumor tissue) were collected from 3 patients with no metastasis and 10 with lung or bone metastasis within 5 years after nephrectomy. Cell migration was analyzed in a Boyden chamber and proliferation was assessed by bromodeoxyuridine incorporation. Adhesion to fibronectin, and collagen I and IV was determined after cell staining. The expression and/or activity of cellular signaling molecules was quantified by Western blot., Results: Compared to renal cell carcinoma cells from patients without metastasis, the migration of cells from patients with bone metastasis was enhanced 13.5-fold (p = 0.034), and adhesion to fibronectin and collagen I was enhanced 5.8-fold and 6.1-fold (p = 0.002 and 0.014, respectively). In general proliferation was decreased in metastasizing cells. In accordance with these results we detected higher activity of AKT (p = 0.011) and FAK (p = 0.054), higher integrin α5 expression (p = 0.052) and lower PTEN expression in primary cells from patients with bone metastasis compared to nonmetastasizing cells. An almost similarly altered expression pattern was also observed in the renal cell carcinoma tissue specimens and the normal renal tissue of patients with bone metastasis., Conclusions: We describe evidence that molecular predispositions determine the potential for bone metastasis to develop in renal cell carcinoma, which may serve as prognostic markers after initial tumor detection., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer., Methods: 44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3-6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose. The primary endpoint was safety and tolerability, the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17., Results: The most frequent adverse events were grade 1/2 injection site erythema, injection site reactions, fatigue, pyrexia, chills and influenza-like illness. Possibly treatment related urinary retention occurred in 3 patients. The recommended dose was 1280 μg. A total of 26/33 evaluable patients treated at 1280 μg developed an immune response, directed against multiple antigens in 15 out of 33 patients. One patient showed a confirmed PSA response. In the subgroup of 36 metastatic patients, the Kaplan-Meier estimate of median overall survival was 31.4 months [95 % CI: 21.2; n.a]., Conclusions: The self-adjuvanted RNActive® vaccine CV9103 was well tolerated and immunogenic. The technology is a versatile, fast and cost-effective platform allowing for creation of vaccines. The follow-up vaccine CV9104 including the additional antigens prostatic acid phosphatase (PAP) and Muc1 is currently being tested in a randomized phase IIb trial to assess the clinical benefit induced by this new vaccination approach., Trial Registration: EU Clinical Trials Register: EudraCT number 2008-003967-37, registered 27 Jan 2009.

Background: Vesicovaginal fistulae are much more common in developing countries along the equatorial fistula belt than in industrialized countries. However, although the classical obstetric fistula caused by lack of medical support through pregnancy and delivery in adolescent primiparae has almost vanished in Germany, we are now facing new and predominantly iatrogenic variants. Increasing frequency of gynecological surgery as well as pelvic radiation, forgotten vaginal foreign bodies, or uninhibited cancer growth are the modern causes for vesicovaginal fistula in elderly patients. Comorbidities and genital atrophy impair surgical therapy in view of a limited success rate of conservative transient transurethral catheterization., Methods: Diagnostics should start early and should be initially limited to vaginal inspection, cystourethroscopy, and the blue dye test. Radiological investigations including CT and MRI are only indicated in patients suspicious for ureterovaginal fistula or with inconclusive findings or malignant fistula. The surgical armamentarium comprises vaginal, abdominal, and combined approaches, which all underlie basic principles of fistula repair: protection of the ureteral orifices, complete excision of the fistula canal, accurate separation of the organs connected to the fistula, sufficient tissue mobilization for tension-free suturing, interposition of padding material for prevention of recurrency., Conclusion: Depending on the degree of sphincter damage, stress urinary incontinence might persist despite successful fistula repair, requiring further incontinence surgery or ultimate urinary diversion in recurrent cases that are hopeless.

Sacrocolpopexy has remained standard procedure for correction of pelvic organ prolapse regardless of the affected compartment. Assuming the appropriate indication, it is characterized by an excellent long-term cure rate. Asymptomatic pelvic organ prolapse is no indication for surgery and should not be corrected in view of possible complications. This article summarizes general and method-specific complications of sacrocolpopexy, identifies causes, and allows error management to be tailored to each individual patient to increase treatment and outcome quality.

Background: Robot-assisted laparoscopic radical prostatectomy (RALP) has been rapidly adopted as a standard approach for surgical treatment of organ-confined prostate cancer. Despite additional costs, RALP seems to provide better functional and oncological outcomes and less blood loss compared to open radical prostatectomy (ORP). However, prospective randomized studies are still missing., Purpose: Based on the current literature, this review reports about the role of RALP in prostate cancer treatment. Its functional and oncologic outcomes as well as complication rates are compared to ORP. Particularly, the role of RALP in nonorgan-confined tumors will be discussed., Results: Based on the current literature, RALP provides better continence and potency rates as compared to ORP. Moreover, the incidence of positive surgical margins seems to be reduced. However, there is conflicting data regarding the role of RALP in nonorgan-confined prostate cancer. Regarding long-term oncologic outcomes, RALP seems to be comparable to ORP.

Background: In recent years, small renal masses (SRM) have been increasingly detected as an incidental finding of radiological or ultrasound studies for other indications. Organ-sparing renal tumor resection as open partial nephrectomy (OPN) is the international standard for renal tumors <7 cm., Results: Due to technical developments, minimally invasive procedures have emerged as an alternative to OPN. In experienced hands, conventional laparoscopic partial nephrectomy (LPN) has achieved good functional and oncological results comparable to OPN. Robot-assisted laparoscopic partial nephrectomy (RAPN) has been performed since 2004. Compared to LPN, RAPN provides a faster learning curve, better visualization and more versatile instrumentation due to the degrees of freedom of the articulated instruments. After about 30 procedures, a level of experience is reached, which is characterized by good functional results, less blood loss, and shorter warm ischemia time of the kidney as compared to LPN. This can relate to a shorter hospital stay and faster recovery. Complications according to the Clavien classification are mostly grade I and II and are mainly treated conservatively., Conclusion: Oncological long-term results are not available yet; so that RAPN cannot be considered as an equivalent treatment to LPN and OPN. Until long-term evidence is available, decisions regarding the surgical technique for organ-sparing renal tumor resection will be determined by patient's wishes and surgeon's preference.

Unlabelled: In patients with metastasized, castration resistant prostate cancer (mCRPC) treatment with radium-223 (Xofigo) is an attractive therapeutic option. In particular, patients with high tumour load seem to profit from this treatment in regard of survival and quality of live. Aim of this study was to stratify mCRPC patients according to a quantitative imaging marker derived from routine bone scans (EXINI bone) and analyze haematopoietic toxicity of Xofigo in these patients., Patients, Methods: Toxicity and oncologic outcome were investigated in a cohort of 14 patients with high tumour load. Additionally, based on a web survey, experience of toxicity in 41 high tumour load patients in Germany in 2014 was collected., Results: In patients with a bone scan index (BSI) greater than 5, significant toxicity occurred in more patients than expected from the ALSYMPCA trial. This was associated with application of fewer cycles. Similar experiences have been made in other centers in Germany. Approximately 7% of these patients will need very long time or will not recover from grade ≥ 3 toxicity., Conclusion: Close follow-up of haematopoietic indices and, in case of toxicity, early termination of therapy is in particular necessary in late stage disease where limited bone marrow reserve is likely.

Introduction: To evaluate incidence, symptoms and management of postoperative pancreatic fistula (POPF) after urologic surgery based on our experience., Material and Methods: Database was searched for clinically evident POPF after urologic surgery between 1998 and 2014. Fistulae were graded using the POPF classification. Clinical course of every POPF patient was evaluated., Results: During this time, 3,200 surgeries for renal, adrenal and retroperitoneal pathologies were performed. Twelve POPF occurred postoperatively in this series. Eight fistulae were POPF grade A, 3 POPF grade B and one POPF grade C. POPF became clinically evident after a median of 3 days (IQR 2-3). In all POPF grade A/B patients, secretion from the pancreatic fistula completely subsided under conservative therapy. In one POPF grade C patient with positive surgical margins of urothelial cancer, conservative treatment failed and the patient died due to POPF-related sepsis., Conclusions: POPF is a rare complication after urologic surgery. Conservative therapy is the first choice of treatment and will be successful in the majority of cases. Pancreatic fistula after surgery of recurrent malignancy may have a poor outcome., (© 2015 S. Karger AG, Basel.)

Purpose: To evaluate the efficacy and safety of solifenacin for the treatment of OAB in men., Methods: This prospective observational study, reflective of actual practice patterns, was conducted in men older than 18 years who were prescribed solifenacin for the treatment of OAB symptoms. Men with suspected bladder outlet obstruction were excluded. The primary efficacy measure was change in OAB symptoms after 12 weeks of solifenacin. Also assessed were changes in severity of urinary urgency, IPSS, quality of life, cognitive function, and adverse events. Data were analyzed using descriptive methods., Results: A total of 799 men recruited at 251 centers, average age 67 years (range 27-92), received solifenacin 5 mg or 10 mg/day. Mean episodes of urinary urgency, frequency, and nocturia decreased by 4.4, 3.6, and 1.4 episodes/24 h, respectively. As per IPSS, severe urinary symptoms were reported by 20.4 % at baseline versus by 2.3 % at week 12. Both voiding and storage symptoms showed improvement. Patient-reported general health condition was excellent/good for 39 % at baseline increasing to 76 % at week 12. Adverse event rate was 5.5 %, and discontinuation of solifenacin due to an event was 1.6 %. No change in post-void residual urine volume was experienced in 80%, while an increase of ≥50 mL was observed in 2.2 %; no cases of acute urinary retention occurred. Baseline mean MMSE was 27.5 points versus 27.9 points at week 12., Conclusions: Solifenacin reduced all OAB symptoms, was well tolerated, and had no apparent effect on post-void residual urine volume. Cognitive function was unaltered in this population of older men with OAB.

Tension-free alloplastic slings (TFAS) have revolutionized surgery for female stress urinary incontinence for more than 20 years. The procedure is easy to perform, minimally invasive with a short operating time in an outpatient setting and has proven efficacy comparable to retropubic colposuspension. The frequency of surgery for female stress incontinence has tripled within one decade which has to have an impact on the number of complications. In contrast, sacrocolpopexy has remained the gold standard in urological prolapse surgery as none of the new techniques has reached similar efficacy or safety; however, possible complications have to be named and their causes have to be understood to maintain the highest quality of care in the future. Possible complications of TFAS are potentially underestimated with respect to prevalence and manageability. Possible complications of prolapse and incontinence surgery are presented and the underlying causes are identified. Knowledge of the pathophysiology and the cause of complications together with the results of a postoperative diagnostic work-up, allow complication management to be tailored to each individual patient. To prevent complications all conservative treatment options should have been tried preoperatively and a complete evaluation (including urodynamics) should have been carried out for every patient. Postoperative urodynamics may help to document treatment success and to identify and quantify complications.

Today, for the surgical treatment of postprostatectomy incontinence, several treatment options are available, e.g., adjustable and functional sling systems, artificial sphincter, bulking agents, and balloons. However, no recommendations in terms of specific diagnostic tools and differentiated treatment options for everyday life are available. Our aim is to provide some clinically relevant recommendations for the necessary diagnostic workup and different treatment options of postprostatetectomy incontinence to support clinical decisions in everyday life. Treatment selection should be based on contraindications. However, there is a broad overlap of the various surgical options.

Introduction: Open simple prostatectomy is a well-established and effective operation for prostate volumes greater than 80 gm but also associated with bleeding and urinary incontinence. To benefit from the advances of laparoscopy, robot-assisted simple prostatectomy was established. We determined the learning curve of this minimally invasive surgery by evaluating the first procedures by an experienced robotic surgeon., Methods: Patients presenting for surgical therapy with prostate volumes greater than 80 gm were considered for the study. Evaluation included validated questionnaires preoperatively, and at 6 and 12 weeks postoperatively. Blood loss, transfusions, operation time and pad use after catheter removal were documented. The experience based on the results from 18 cases treated with robot-assisted simple prostatectomy by one of us (JWT) is presented., Results: Mean age of the 18 patients was 71.2 years, mean enucleated prostate volume was 91 gm and mean preoperative flow was 9.0 ml/second. I-PSS and QoL values improved significantly from 25 to 6.1 (p <0.005) and from 5 to 1.1 (p <0.005), respectively, and flow rate increased to 28.2 ml/second (p <0.005) postoperatively. There were no significant changes in sexual performance based on IIEF (p = 0.73). Of the 18 patients 14 had complete continence immediately after catheter removal, and at 6 weeks postoperatively 17 were completely continent. Decreases in operation time from 250 to 150 minutes and blood loss from 400 to 200 ml were noted after 5 procedures. Only minor complications occurred and 1 patient required transfusion postoperatively (Clavien-Dindo II)., Conclusions: Robot-assisted simple prostatectomy is a safe and effective operation for benign prostatic hyperplasia, which can be learned with good results in a rather short time.

Cadherin-11 (CDH11), associated with epithelial to mesenchymal transformation in development, poor prognosis malignancies and cancer stem cells, is also a major therapeutic target in rheumatoid arthritis (RA). CDH11 expressing basal-like breast carcinomas and other CDH11 expressing malignancies exhibit poor prognosis. We show that CDH11 is increased early in breast cancer and ductal carcinoma in-situ. CDH11 knockdown and antibodies effective in RA slowed the growth of basal-like breast tumors and decreased proliferation and colony formation of breast, glioblastoma and prostate cancer cells. The repurposed arthritis drug celecoxib, which binds to CDH11, and other small molecules designed to bind CDH11 without inhibiting COX-2 preferentially affect the growth of CDH11 positive cancer cells in vitro and in animals. These data suggest that CDH11 is important for malignant progression, and is a therapeutic target in arthritis and cancer with the potential for rapid clinical translation.

Background: The prognosis for renal cell carcinoma (RCC) is related to a high rate of metastasis, including 30% of bone metastasis. Characteristic for bone tissue is a high concentration of calcium ions. In this study, we show a promoting effect of an enhanced extracellular calcium concentration on mechanisms of bone metastasis via the calcium-sensing receptor (CaSR) and its downstream signaling molecules., Methods: Our analyses were performed using 33 (11/category) matched specimens of normal and tumor tissue and 9 (3/category) primary cells derived from RCC patients of the 3 categories: non-metastasized, metastasized into the lung and metastasized into bones during a five-year period after nephrectomy. Expression of CaSR was determined by RT-PCR, Western blot analyses and flow cytometry, respectively. Cells were treated by calcium and the CaSR inhibitor NPS 2143. Cell migration was measured in a Boyden chamber with calcium (10 μM) as chemotaxin and proliferation by BrdU incorporation. The activity of intracellular signaling mediators was quantified by a phospho-kinase array and Western blot., Results: The expression of CaSR was highest in specimens and cells of patients with bone metastases. Calcium treatment induced an increased migration (19-fold) and proliferation (2.3-fold) exclusively in RCC cells from patients with bone metastases. The CaSR inhibitor NPS 2143 elucidated the role of CaSR on the calcium-dependent effects. After treatment with calcium, the activity of AKT, PLCγ-1, p38α and JNK was clearly enhanced and PTEN expression was almost completely abolished in bone metastasizing RCC cells., Conclusions: Our results indicate a promoting effect of extracellular calcium on cell migration and proliferation of bone metastasizing RCC cells via highly expressed CaSR and its downstream signaling pathways. Consequently, CaSR may be regarded as a new prognostic marker predicting RCC bone metastasis.

Objectives: To evaluate the clinical efficiency of a third generation electromagnetic shock wave lithotripter, the Lithoskop(®) (Siemens, Erlangen, Germany), regarding outcomes, stone disintegration, retreatment and complication rates. To compare the results of the Lithoskop with other currently available systems and the reference standard lithotripter, the HM-3 (Dornier MedTech Europe GmbH, Wessling, Germany)., Patients and Methods: We analysed the data from 183 patients, including 13 children, undergoing extracorporeal shock wave lithotripsy (ESWL) for renal and ureteric calculi collected from a prospectively populated database. Outcomes were assessed by plain abdominal film of kidney, ureter and bladder and renal ultrasonography for radiopaque and computerized tomography for radiolucent stones 1 day after treatment and after 3 months. We analysed stone size and location before and after treatment, stone disintegration rate, retreatment rate, stone-free and residual fragment rates after 3 months, along with auxiliary procedures and complications., Results: The mean (range) patient age was 48.6 (1.3-81.4) years, including 13 children with a mean (range) age of 8.4 (1.3-16.7) years, and 77% of the patients were male. In all, 46% of the calculi were localized in the kidney and 54% in the ureter. Renal stones were localized in the upper, middle and lower calyx and in the renal pelvis in 9, 29, 30 and 32% of patients, respectively. Ureteric stones were localized in the upper, mid- and distal ureter in 29, 19 and 52% of patients, respectively. The median (range) stone size before ESWL was 10 (4-25) mm in the kidney and 8 (4-28) mm in the ureteric calculi. The overall stone-free rate after 3 months was 91% (88% for renal and 93% for ureteric calculi); the mean number of sessions to achieve these rates was 1.3. Stone-free rates and the required number of sessions were determined only by stone size. In 7.1% of the patients (n = 13) post-interventional auxiliary procedures were necessary. We observed one perirenal haematoma as a major complication (0.5%), but this did not require any further therapy., Conclusions: Clinical stone-free rates with the Lithoskop are high and similar to those of other available systems, including the reference standard HM-3 lithotripter. Retreatment and complication rates are low, supporting the use of ESWL as first-line therapy for urinary calculi <10 mm, independent of stone location., (© 2013 The Authors. BJU International © 2013 BJU International.)

Background: The objective was to investigate whether two-dimensional intraoperative neuromonitoring (IONM) of pelvic autonomic nerves has the potential to predict erectile function (EF) following surgery for rectal cancer., Methods: A consecutive series of 17 sexually active male rectal cancer patients undergoing IONM-based nerve-sparing low anterior rectal resection were evaluated prospectively. IONM was performed by electric stimulation of the pelvic splanchnic nerves with concomitant electromyography of the internal anal sphincter and cystomanometry. Sexual function was assessed using a validated questionnaire., Results: The degree of agreement between electromyography-based and cystomanometry-based IONM with postoperative EF was moderate and good (κ = 0.43 and κ = 0.66). Combined assessment yielded the best agreement (κ = 0.76) with sensitivity of 90%, specificity of 86%, positive predictive value of 90%, negative predictive value of 86%, and overall accuracy of 88%, respectively, in terms of prediction of postoperative EF., Conclusion: The method may be suitable to predict male EF following rectal resection., (2014 S. Karger AG, Basel.)