[Life-threatening bleeding from ileal conduit venous varices in a patient with portal hypertension]. / Vitalitätsgefährdende Blutungen aus einem Ileumconduit bei Varikosis im Rahmen einer portalen Hypertension.

Life-threatening bleeding from portosystemic varices is a feared complication of portal hypertension. Particularly, varices in atypical locations-so-called ectopic varices-pose a challenge for diagnosis and therapy. In the present article, we describe the case of a patient with liver cirrhosis and recurrent bleeding from an ileal conduit resulting from peristomal varicosis. The difficult and hence delayed diagnosis led to a life-threatening hemorrhage that was successfully treated with interventional radiological variceal embolization and TIPS (transjugular intrahepatic portosystemic shunt) implantation.

[Lutetium-177-PSMA radioligand therapy : Consensus within the framework of GKV-funded care between the university hospitals in Aachen, Bonn, Düsseldorf, Essen, and Cologne and the MDK Nordrhein]. / Lutetium-177-PSMA-Radioligandentherapie : Konsensus im Rahmen der GKV-finanzierten Versorgung zwischen den Hochschulkliniken in Aachen, Bonn, Düsseldorf, Essen und Köln und dem MDK Nordrhein.

In the last 3 years, Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA-RLT) has received increasing attention in nuclear medicine as a new form of treatment for castration-resistant metastatic prostate cancer. This therapy combines the radionuclide Lutetium-177, which has been therapeutically used in nuclear medicine for many years, with a molecular target of the transmembrane prostate-specific membrane antigen expressed by prostate cancer cells. Since there are no prospective randomized studies on Lu-177-PSMA-RLT and the question of reimbursement has repeatedly been the subject of review by the MDK Nordrhein (Medischenische Dienst der Krankenversicherung), there was a desire because of the increasing number of patients being treated to clarify under which circumstances Lu-177-PSMA-RLT can be reimbursed by German statutory health insurance. The goals of this article are to help treating physicians understand how this new therapy option works, to integrate it in the overall therapy concept for castration-resistant metastatic prostate cancer, and, above all, to use Lu-177-PSMA-RLT-based on the current data-at the right place in the therapy sequence of castration-resistant metastatic prostate cancer.

[When is surgical resection of the primary tumor indicated in metastatic urothelial carcinoma of the bladder and what is the scientific rationale?] / Wann ist bei eingetretener Metastasierung des Harnblasenkarzinoms die operative Entfernung des Primärtumors angezeigt und gibt es eine wissenschaftliche Grundlage dafür?

Cisplatin-based polychemotherapy is still the standard therapy for metastatic urothelial carcinoma, although disease progression is often noted at an early time point even in patients with response. In recent years, cytoreductive surgery has been gaining increasing interest in many tumor entities in the setting of metastatic disease to improve patients outcome, but urothelial carcinoma is not regarded as a candidate for such a multimodal therapy approach. However, several retrospective studies suggest a survival benefit of radical cystectomy and/or metastasectomy for well-selected patients with metastatic urothelial carcinoma. Prognostically relevant parameters for consolidative cystectomy/metastasectomy after chemotherapy seem to be a distinct response to inductive chemotherapy and limited metastatic spread (regional lymph node, single lung metastasis).

Towards standardized automated immunomonitoring: an automated ELISpot assay for safe and parallelized functionality analysis of immune cells.

The ELISpot assay is used for the detection of T cell responses in clinical trials and vaccine evaluations. Standardization and reproducibility are necessary to compare the results worldwide, inter- and intra-assay variability being critical factors. To assure operator safety as well as high-quality experiment performance, the ELISpot assay was implemented on an automated liquid handling platform, a Tecan Freedom EVO. After validation of the liquid handling, automated loading of plates with cells and reagents was investigated. With step by step implementation of the manual procedure and liquid dispensing optimization on the robot platform, a fully automated ELISpot assay was accomplished with plates remaining in the system from the plate blocking step to spot development. The mean delta difference amounted to a maximum of 6%, and the mean dispersion was smaller than in the manual assay. Taken together, we achieved with this system not only a lower personnel attendance but also higher throughput and a more precise and parallelized analysis. This platform has the potential to guarantee validated, safe, fast, reproducible and cost-efficient immunological and toxicological assays in the future.

Low-noise humidity controller for imaging water mediated processes in atomic force microscopy.

We demonstrate the construction of a novel low-noise continuous flow humidity controller and its integration with a commercial variable-temperature atomic force microscope fluid cell, allowing precise control of humidity and temperature at the sample during nanoscale measurements. Based on wet and dry gas mixing, the design allows a high mechanical stability to be achieved by means of an ultrasonic atomiser for the generation of water-saturated gas, improving upon previous bubbler-based architectures. Water content in the flow is measured both at the inflow and outflow of the fluid cell, enabling the monitoring of water condensation and icing, and allowing controlled variation of the sample temperature independently of the humidity. To benchmark the performance of the controller, the results of detailed noise studies and time-based imaging of the formation of ice layers on highly oriented pyrolytic graphite are shown.

[Magnetic urethral closure device. Negative outcome after implantation for the treatment of female urinary incontinence]. / Magnetisches Harnröhrenverschlusssystem. Desaströser Verlauf nach Implantation zur Behandlung der weiblichen Belastungsinkontinenz.

We report on a negative outcome after implantation of a magnetic urethral closure device, consisting of one part screwed into the pubic bone and one part as a vaginal cone, for the treatment of urinary stress incontinence grade III. Continence was never achieved for the patient. The urethra narrowed over time due to erosion and scarring and the patient started intermittent catheterization, because spontaneous micturition was not possible. The magnet was broken, the bladder neck was eroded, several fragments were found in the bladder, and numerous fragments were scattered throughout the small pelvis. Surgery consisted of removing most of the fragments, followed by bladder neck closure and suprapubic diversion.

[Detection of cell-free lncRNA in serum of cancer patients]. / Nachweis von zellfreier lncRNA im Serum von Tumorpatienten.

BACKGROUND: The analysis of circulating RNA molecules is of increasing interest since tumor-specific RNA expression patterns could be a useful cancer biomarker. A new entity of RNA molecules, the so-called long non-coding RNAs (lncRNA), are of particular interest because of its high tissue- and tumor-specificity. The importance of analytical factors in the quantification of lncRNAs is largely unclear and should therefore be investigated in the present study. PATIENTS AND METHODS: Serum RNA was isolated from patients with bladder, prostate and kidney cancer as well as patients with non-malignant disease. Analytical variables like different RNA isolation procedures, cDNA synthesis and preamplification were studied with respect to quantification of MALAT1 and ACTB via real-time PCR. RESULTS: The quantification of cell-free serum RNA is feasible although the levels of ACTB and MALAT1 were often only slightly above the detection limit. RNA isolation with a combined phenol-based column purification (Ambion mirVana PARIS miRNA Isolation Kit; Qiagen miRNeasy Serum/Plasma Kit) was most effective. The elimination of DNA contamination was most successful during cDNA synthesis with (Takara-Bio PrimeScript RT Reagent Kit with gDNA Eraser). Preamplification with the Applied Biosystems TaqMan PreAmp Master Mix Kit improved sensitivity. Serum ACTB and MALAT1 levels were not significantly increased in patients with urological tumors compared to patients with non-malignant diseases. CONCLUSION: An optimized protocol for the analysis of circulating lncRNAs is described in the present study.

[Complications and their management after urinary diversion]. / Komplikationen und deren Management nach Harnableitung.

BACKGROUND: Bladder cancer is a common disease. It is predicted that 11,900 men and 4,500 women in Germany will be diagnosed with invasive bladder cancer in 2014. The cystectomy, which is standard treatment in muscle-invasive bladder cancer, requires urinary diversion. PURPOSE: The goal of this article is to present the complications associated with urinary diversions and their management. METHODS: Based on a selective literature search in PubMed and our own clinical experience, the options for urinary diversion and their management are discussed. RESULTS: In patients treated with curative intent, orthotopic bladder replacement is preferred. In patients with palliative intent, incontinent cutaneous urinary diversion is commonly used. The present work shows the variety of early and late complications, peri-/postoperative mortality, and the management of these patients. CONCLUSION: After cystectomy, various methods for urinary diversion are available, which can be used in curative and/or palliative intent. Crucial to the success and the long-term satisfaction of the patients is selection of the right urinary diversion method.

Clinical and pathological nodal staging score for urothelial carcinoma of the bladder: an external validation.

PURPOSE: Radical cystectomy (RC) and pelvic lymph node dissection (LND) are standard treatments for muscle-invasive urothelial carcinoma of the bladder. Lymph node staging is a prerequisite for clinical decision-making regarding adjuvant chemotherapy and follow-up regimens. Recently, the clinical and pathological nodal staging scores (cNSS and pNSS) were developed. Prior to RC, cNSS determines the minimum number of lymph nodes required to be dissected; pNSS quantifies the accuracy of negative nodal staging based on pT stage and dissected LNs. cNSS and pNSS have not been externally validated, and their relevance for prediction of cancer-specific mortality (CSM) has not been assessed. METHODS: In this retrospective study of 2,483 RC patients from eight German centers, we externally validated cNSS and pNSS and determined their prediction of CSM. All patients underwent RC and LND. Median follow-up was 44 months. cNSS and pNSS sensitivities were evaluated using the original beta-binominal models. Adjusted proportional hazards models were calculated for pN0 patients to assess the predictive value of cNSS and pNSS for CSM. RESULTS: cNSS and pNSS both pass external validation. Adjusted for other clinical parameters, cNSS can predict outcome after RC. pNSS has no independent impact on prediction of CSM. The retrospective design is the major limitation of the study. CONCLUSIONS: In the present external validation, we confirm the validity of both cNSS and pNSS. cNSS is an independent predictor of CSM, thus rendering it useful as a tool for planning the extent of LND.

Prediction of outcome in patients with urothelial carcinoma of the bladder following radical cystectomy using artificial neural networks.

AIM: The outcome of patients with urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC) shows remarkable variability. We evaluated the ability of artificial neural networks (ANN) to perform risk stratification in UCB patients based on common parameters available at the time of RC. METHODS: Data from 2111 UCB patients that underwent RC in eight centers were analysed; the median follow-up was 30 months (IQR: 12-60). Age, gender, tumour stage and grade (TURB/RC), carcinoma in situ (TURB/RC), lymph node status, and lymphovascular invasion were used as input data for the ANN. Endpoints were tumour recurrence, cancer-specific mortality (CSM) and all-cause death (ACD). Additionally, the predictive accuracies (PA) of the ANNs were compared with the PA of Cox proportional hazards regression models. RESULTS: The recurrence-, CSM-, and ACD- rates after 5 years were 36%, 33%, and 46%, respectively. The best ANN had 74%, 76% and 69% accuracy for tumour recurrence, CSM and ACD, respectively. Lymph node status was one of the most important factors for the network's decision. The PA of the ANNs for recurrence, CSM and ACD were improved by 1.6% (p = 0.247), 4.7% (p < 0.001) and 3.5% (p = 0.007), respectively, in comparison to the Cox models. CONCLUSIONS: ANN predicted tumour recurrence, CSM, and ACD in UCB patients after RC with reasonable accuracy. In this study, ANN significantly outperformed the Cox models regarding prediction of CSM and ACD using the same patients and variables. ANNs are a promising approach for individual risk stratification and may optimize individual treatment planning.

Endogenous BTG2 expression stimulates migration of bladder cancer cells and correlates with poor clinical prognosis for bladder cancer patients.

BACKGROUND: The B-cell translocation gene 2 (BTG2) is considered to act as a tumour-suppressor gene because of its antiproliferative and antimigratory activities. Higher levels of BTG2 expression in tumour cells have been linked to a better clinical outcome for several cancer entities. Here, we investigated the expression and function of BTG2 in bladder cancer. METHODS: The expression of BTG2 in bladder cancer cells was silenced by RNA interference. Cell motility was investigated by wound healing and Boyden chamber assays. The protein expression of BTG2 in bladder cancer was studied by immunohistochemistry. RESULTS: We observed that targeted suppression of BTG2 by RNA interference did not result in growth stimulation but led to a substantial inhibition of bladder cancer cell motility. Tissue microarray analyses of bladder cancer cystectomy specimens revealed that higher BTG2 expression levels within the tumours correlated strongly with a decreased cancer-specific survival for bladder cancer patients. CONCLUSION: These results indicate that endogenous BTG2 expression contributes to the migratory potential of bladder cancer cells. Moreover, high levels of BTG2 in bladder cancers are linked to decreased cancer-specific survival. These findings question the conception that BTG2 generally acts as a tumour suppressor and typically represents a favourable clinical marker for cancer patients.

[Quality and objectifiability of training and advanced training in urology]. / Qualität und Objektivierbarkeit der Aus- und Weiterbildung in der Urologie.

The attraction to study medicine has not changed, however we are facing a lack of trainees especially in surgical subspecialties like urology. Possible explanations are a 70% proportion of female students and different views on the work-life balance in the future. A high burden of theory and unrealistic multiple choice examinations support those who can learn but there are no objective and reproducible criteria to recognize the competence of a good physician early in the career. This problem continues during residency, especially in surgical subspecialities. The different medical boards in Germany responsible for the training programs have no concepts. Many attempts in other countries to objectively measure surgical skills have so far been ignored. If we do not want to lose our traditionally high competence in medicine we should join those who attempt to improve teaching and to use methods for selecting suitable candidates for surgery as soon and as objectively as possible.

[Educating transurethral electroresection of the prostate is safe and efficient: is training a risk factor for patients and hospitals?]. / Die transurethrale Elektroresektion der Prostata durch Weiterbildungsassistenten : Ausbildung als Risiko für Patient und Klinik?

BACKGROUND: German residents are becoming increasingly more discontent with their situation. Besides unfriendly working hours and growing bureaucracy the lack of surgical education is considered as causative. Surgical education is assumed to be time-consuming and might impair operative results. Moreover, a number of patients refuse to be misused as a teaching tool. AIM OF THE STUDY: The aim of this study was to compare operative procedures (transurethral resection of the prostate) performed by residents and consultants. PATIENTS AND METHODS: All patients underwent monopolar transurethral electroresection of the prostate for symptomatic benign enlargement. All data were collected retrospectively. Mean follow-up to collect functional results and late complications was 70 months. RESULTS: Both groups did not differ significantly in perioperative and postoperative results except for the weight of resected tissue in favor of the consultants group. Functional results and late complications were comparable in both groups. CONCLUSIONS: Transurethral resection of the prostate performed by residents is a safe and effective procedure.

[Guidelines: reality and quality]. / Leitlinien: Realität und Qualität.

The aim of guidelines is to increase the quality of care in clinical practice. Any influence or financial support by the pharmaceutical industry must be excluded. In urology only two S3 guidelines have been published in German and all others are more or less recommendations (S1). The example of the second opinion project on testicular germ cell tumors shows that a reduction of recurrence, morbidity and mortality can be achieved by the consistent application of guidelines. Oncological guidelines are often focused on the unidirectional parameter overall survival but do not include other important aspects, such as long-term morbidity or quality of life.

[Catheterizable continence mechanisms for various urinary diversion reservoirs: serosa lined and tapered ileum]. / Katheterisierbarer Kontinenzmechanismus für verschiedene Harnableitungsreservoire : Getapertes, seroserös eingebettetes Ileum.

In a retrospective multicenter study of four clinics perioperative complications as well as incontinence and stoma stenosis of serosa-lined tapered ileum as catheterizable continence mechanisms for different urinary diversions were analyzed. Between 2008 and 2012 a total of 40 patients received a continent catheterizablestoma, 15 (37.5%) in combination with continent vesicostomy and closure of the bladder neck due to postoperative incontinence and recurrent stenosis including radical prostatectomy, transurethral resection (TUR) of the prostate, bladder neck incision (n=11), neurogenic bladder with reduced capacity and incontinence (n=2), interstitial cystitis (n=1) and recurrent urethral tumor following ileal neobladder (n=1). Of the patients 25 (62.5%) received this continence mechanism in combination with a modified Mainz pouch I, in 19 patients as primary and in 6 patients as secondary efferent segment for trouble shooting. The complications were subdivided according the Clavien classification. In 29 patients information concerning continence and stenosis were obtained, the median follow-up was 25 months (range 1-111 months). In patients with continent vesicostomy (n=11) the incontinence rate was 9.1% (1/11) and the stenosis rate 18.2% (2/11). In 18 patients with an ileocecal pouch, incontinence and stenosis rates were 0% and 11.1% (2/18), respectively. The presented technique is a safe continence mechanism for various catheterizable continent urinary diversions for both primary and secondary indications.

[Secondary malignancies in urinary diversions]. / Sekundärmalignome in Harnableitungen.

In contrast to ureterosigmoidostomy no reliable clinical data exist for tumor risk in different forms of urinary diversion using isolated intestinal segments.In 44 German urological departments, operation frequencies, indications, patient age, and operation dates of the different forms of urinary diversion, operated between 1970 and 2007, could be registered. The secondary tumors up to 2009 were registered as well and related to the numbers of the different forms of urinary diversions resulting in tumor prevalences.In 17,758 urinary diversions 32 secondary tumors occurred. The tumor risk in ureterosigmoidostomy (22-fold) and cystoplasty (13-fold) is significantly higher than in other continent forms of urinary diversion such as neobladders or pouches (p<0.0001). The difference between ureterosigmoidostomy and cystoplasty is not significant, nor is the difference between ileocecal pouches (0.14%) and ileal neobladders (0.05%) (p=0.46). The tumor risk in ileocecal (1.26%) and colonic neobladders (1.43%) is significantly higher (p=0.0001) than in ileal neobladders (0.5%). Of the 16 tumors that occurred following ureterosigmoidostomy, 16 (94%) developed directly at the ureterocolonic borderline in contrast to only 50% following urinary diversions via isolated intestinal segments.From postoperative year 5 regular endoscopic controls of ureterosigmoidostomies, cystoplasties, and orthotopic (ileo-)colonic neobladders are necessary. In ileocecal pouches, regular endoscopy is necessary at least in the presence of symptoms or should be performed routinely at greater intervals. Following neobladders or conduits, only urethroscopies for urethral recurrence are necessary.

External validation of disease-free survival at 2 or 3 years as a surrogate and new primary endpoint for patients undergoing radical cystectomy for urothelial carcinoma of the bladder.

PURPOSE: To perform the first external validation of a recently identified association between disease-free survival at two years (DFS2) or three years (DFS3) and overall survival at five years (OS5) in patients after radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB). METHODS AND METHODS: Records of 2483 patients who underwent RC for UCB at eight European centers between 1989 and 2008 were reviewed. The cohort included 1738 patients with pT2-4a tumors and negative soft tissue surgical margins (STSM) according to the selection criteria of the previous study (study group (SG)). In addition, 745 patients with positive STSM or other tumor stages (pT0-T1, pT4b) that were excluded from the previous study (excluded patient group (EPG)) were evaluated. Kappa statistic was used to measure the agreement between DFS2 or DFS3 and OS5. RESULTS: The overall agreement between DFS2 and OS5 was 86.5% (EPG: 88.7%) and 90.1% (EPG: 92.1%) between DFS3 and OS5. The kappa values for comparison of DFS2 or DFS3 with OS5 were 0.73 (SE: 0.016) and 0.80 (SE: 0.014) respectively for the SG, and 0.67 (SE: 0.033) and 0.78 (SE: 0.027) for the EPG (all p-values <0.001). CONCLUSIONS: We externally validated a correlation between DFS2 or DFS3 and OS5 for patients with pT2-4a UCB with negative STSM that underwent RC. Furthermore, this correlation was found in patients with other tumor stages regardless of STSM status. These findings indicate DFS2 and DFS3 as valid surrogate markers for survival outcome with RC.

[Urogynecology, overactive bladder, and neurourology]. / Urogynäkologie, "overactive bladder" und Neurourologie.

This overview presents new results regarding urogynecology, overactive bladder, and neurourology. The importance of interdisciplinary pelvic floor centers and Burch colposuspension are discussed.