[Urinary incontinence after radical prostatectomy for prostate cancer-data from 17,149 patients from 125 certified centers]. / Harninkontinenz nach radikaler Prostatektomie beim Prostatakarzinom ­ aktuelle Daten von 17.149 Patienten aus 125 zertifizierten Zentren.

BACKGROUND: In addition to erectile dysfunction, urinary incontinence is the most common functional limitation after radical prostatectomy (RPE) for prostate cancer (PCa). The German S3 guideline recommends informing patients about possible effects of the therapy options, including incontinence. However, only little data on continence from routine care in German-speaking countries after RPE are currently available, which makes it difficult to inform patients. OBJECTIVE: The aim of this work is to present data on the frequency and severity of urinary incontinence after RPE from routine care. MATERIALS AND METHODS: Information from the PCO (Prostate Cancer Outcomes) study is used, which was collected between 2016 and 2022 in 125 German Cancer Society (DKG)-certified prostate cancer centers in 17,149 patients using the Expanded Prostate Cancer Index Composite Short Form (EPIC-26). Changes in the "incontinence" score before (T0) and 12 months after RPE (T1) and the proportion of patients who used pads, stratified by age and risk group, are reported. RESULTS: The average score for urinary incontinence (value range: 0-worst possible to 100-best possible) was 93 points at T0 and 73 points 12 months later. At T0, 97% of the patients did not use a pad, compared to 56% at T1. 43% of the patients who did not use a pad before surgery used at least one pad a day 12 months later, while 13% use two or more. The proportion of patients using pads differs by age and risk classification. CONCLUSION: The results provide a comprehensive insight into functional outcome 12 months after RPE and can be taken into account when informing patients.

Prediction models of incontinence and sexual function one year after radical prostatectomy based on data from 20 164 prostate cancer patients.

BACKGROUND: Incontinence and sexual dysfunction are long-lasting side effects after surgical treatment (radical prostatectomy, RP) of prostate cancer (PC). For an informed treatment decision, physicians and patients should discuss expected impairments. Therefore, this paper firstly aims to develop and validate prognostic models that predict incontinence and sexual function of PC patients one year after RP and secondly to provide an online decision making tool. METHODS: Observational cohorts of PC patients treated between July 2016 and March 2021 in Germany were used. Models to predict functional outcomes one year after RP measured by the EPIC-26 questionnaire were developed using lasso regression, 80-20 splitting of the data set and 10-fold cross validation. To assess performance, R2, RMSE, analysis of residuals and calibration-in-the-large were applied. Final models were externally temporally validated. Additionally, percentages of functional impairment (pad use for incontinence and firmness of erection for sexual score) per score decile were calculated to be used together with the prediction models. RESULTS: For model development and internal as well as external validation, samples of 11 355 and 8 809 patients were analysed. Results from the internal validation (incontinence: R2 = 0.12, RMSE = 25.40, sexual function: R2 = 0.23, RMSE = 21.44) were comparable with those of the external validation. Residual analysis and calibration-in-the-large showed good results. The prediction tool is freely accessible: https://nora-tabea.shinyapps.io/EPIC-26-Prediction/. CONCLUSION: The final models showed appropriate predictive properties and can be used together with the calculated risks for specific functional impairments. Main strengths are the large study sample (> 20 000) and the inclusion of an external validation. The models incorporate meaningful and clinically available predictors ensuring an easy implementation. All predictions are displayed together with risks of frequent impairments such as pad use or erectile dysfunction such that the developed online tool provides a detailed and informative overview for clinicians as well as patients.

Serum DNA hypermethylation in patients with bladder cancer: results of a prospective multicenter study.

BACKGROUND: Cell-free serum DNA levels are increased in patients with cancer, and at least partially, these DNA fragments are derived from cancer cells. A few reports indicated that methylated serum DNA in patients with bladder cancer (BCA) is a useful non-invasive biomarker. The purpose of this prospective multicenter study was to validate earlier studies. MATERIALS AND METHODS: In total, 227 consecutive participants (non-muscle invasive BCA, n=75; muscle-invasive BCA, n=20; transurethral bladder resection (TURB) without BCA, n=48; benign disease, n=31; healthy individuals, n=53), were recruited for this study. Cell-free serum DNA was isolated and digested with methylation-sensitive restriction-enzymes (Bsh1236I, HpaII and HinP1I) to quantify the amount of methylated (TIMP3, APC, RARB, TIG1, GSTP1, p14, p16, PTGS2 and RASSF1A) DNA fragments. RESULTS: The amount of methylated DNA was usually small (<10%), and the methylation frequencies varied for different genes (e.g. frequent: TIMP3; moderate: APC, RARB, TIG1; infrequent: p16, PTGS2, p14, RASSF1A, GSTP1). Methylation levels at each gene site and the number of methylated genes were increased in BCA compared to healthy individuals, but were similar in BCA and patients with non-malignant disease. The number of methylated genes allowed for discrimination (62% sensitivity, 89% specificity) of BCA patients from healthy individuals. DNA hypermethylation was not correlated with advanced stage or grade in patients with BCA. CONCLUSION: The detection of hypermethylated DNA in serum allows for discrimination of patients with BCA and healthy individuals, but there is no difference between patients with BCA and those with non-malignant disease, thereby limiting its value as a non-invasive biomarker.

Cell-free serum DNA in patients with bladder cancer: results of a prospective multicenter study.

BACKGROUND/AIM: Cell-free DNA may serve as a biomarker for patients with cancer; we designed our study to determine its potential in patients with bladder cancer (BCA). MATERIALS AND METHODS: Short ß-actin (ACTB)-106 and large ACTB-384 fragments were quantified using real time PCR (RT-PCR); the ratio of ACTB-384/ACTB-106 was defined as DNA integrity. We analyzed the serum from 95 patients with and from 132 without BCA. RESULTS: Patients with BCA had increased ACTB-106 levels and lower DNA integrity compared to patients without cancer. However, patients undergoing transurethral bladder resection (TURB) with histological exclusion of BCA had a similar ACTB-106 level and DNA integrity, as patients with BCA. Cell-free DNA was not correlated with smoker status, pT stage, grade or lymph node metastasis, or DNA integrity. There was a weak inverse correlation of age with DNA integrity in patients with BCA. CONCLUSION: Analysis of serum cell-free DNA levels and fragmentation patterns are of limited value regarding the identification of patients with BCA.

Inhibition of Rho-kinase abrogates migration of human transitional cell carcinoma cells: results of an in vitro study.

INTRODUCTION: Migration of cells involves a complex signaling network. The aim of the present study was to elucidate the impact of Rho-kinase (ROK) on G protein-coupled receptor-induced migration of human transitional cell carcinoma cells in an in vitro experimental setting. MATERIALS AND METHODS: Intracellular calcium concentration ([Ca(2+)](i)) was measured with the indicator dye Fura-2 in response to lysophosphatidic acid, thrombin and sphingosine-1-phosphate. Phospholipase C activity was determined in myo-[(3)H]inositol- (0.5 µCi/ml) labeled cells. Migration was performed using a Boyden chamber. Transient transfection of a dominant-negative mutant of ROK was done with calcium phosphate. For staining of actin filaments, tetramethylrhodamine isothiocyanate-conjugated phalloidin was used. RESULTS: Lysophosphatidic acid, thrombin and sphingosine-1-phosphate cause increases in [Ca(2+)](i), cellular responses being accompanied by an enhancement of phospholipase C activity and sensitive to the G(i) inhibitor pertussis toxin. Agonists potently stimulated migration of T24 and J82 cells. Inhibition of Rho proteins by Clostridium difficile toxin B abrogated cell migration. Inhibition of ROK using HA1077 and Y-27632 mimicked the properties of toxin B. Expression of a ROK mutant drastically reduced migration. CONCLUSIONS: G protein-coupled receptors potently stimulated cell migration in T24 and J82 cells. Rho proteins and ROK play a pivotal role in this signaling cascade. Rho and ROK may be putative targets for new therapy options in bladder cancer.

The GNAS1 T393C polymorphism predicts survival in patients with clear cell renal cell carcinoma.

PURPOSE: G proteins mediate signaling from cell surface receptors to specific intracellular proteins. In vitro cancer cell line studies revealed a link between the Galphas protein and proapoptotic processes. We have recently shown that TT genotypes of the GNAS1 T393C polymorphism display increased transcription of Galphas and a more favorable clinical course in bladder and colorectal cancer patients compared both with TC or CC genotypes. EXPERIMENTAL DESIGN: In the present study, 150 patients with clear cell renal cell carcinoma surgically treated by nephrectomy with curative intent were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome. RESULTS: The C-allele frequency in the renal cell carcinoma patient group was 0.51, which is not significantly different from that of a healthy blood donor group. Kaplan-Meier curves for tumor progression, development of metastasis, and tumor-related death showed a significant association of the T393C polymorphism with outcome (5-year cancer-specific survival rates: TT, 91%; TC, 81%; CC, 69%; P = 0.015). Multivariate Cox proportional analysis of a 10-year follow-up confirmed the T393C polymorphism as an independent prognostic factor in clear cell renal cell carcinoma. Homozygous CC patients were at highest risk for progression (hazard ratio, 2.48; P = 0.009) or tumor-related death (hazard ratio, 3.15; P = 0.018) compared with T-allele carriers. CONCLUSION: Our results show that besides tumor stage, lymph node status, and tumor grade, the GNAS1 T393C status is a novel independent host factor for disease progression in patients with clear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a general prognostic tumor marker.

Association study of the G-protein beta3 subunit C825T polymorphism with disease progression in patients with bladder cancer.

The T-allele in the GNB3 C825T polymorphism has been associated with increased cell migration, a prerequisite for metastasis. In this study we investigated a potential association of the C825T-allele status and disease progression in patients with transitional cell carcinoma of the bladder (TCC). Genotyping of the GNB3 C825T polymorphism was performed in 389 patients with transitional cell carcinoma of the bladder and in 104 control subjects and clinical follow-up was worked up in 339 patients. Genotype distribution in 389 patients with bladder cancer was comparable to genotype distribution of the control group. There was no association of GNB3 C825T genotype with tumor stage or grade, but follow-up analysis in the subgroup of non-smokers revealed a shorter time to metastasis in 825T-allele carriers compared to individuals homozygous CC. The genotype of the GNB3 C825T polymorphism appears to influence the biological behavior of tumor disease in non-smoking TCC patients.

The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer.

The G protein G(alpha)s pathway is linked to proapoptotic signaling in cancer cell lines. To assess the role of the GNAS1 locus encoding G(alpha)s as a genetic factor for disease progression of transitional cell carcinoma (TCC) of the bladder, we genotyped the synonymous T393C polymorphism in 254 patients with TCC (minor allele frequency: 0.43) to examine a potential association between genotypes and disease progression. Using Kaplan-Meier estimates to calculate 5-year probabilities of follow-up, we could show that progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. Real-time PCR analysis of urothelial tumor tissue as well as adipose and heart tissue revealed that G(alpha)s mRNA expression was highest in TT genotypes, indicating a proapoptotic effect in these genotypes. In conclusion, the GNAS1 T393C status associated with differential G(alpha)s mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of G(alpha)s in bladder cancer progression.

Expression analysis and potential functional role of the CXCR4 chemokine receptor in bladder cancer.

OBJECTIVE: Recent analysis gave evidence for the fact that the chemokine receptor CXCR4 is of functional significance in the multistep procedure of metastasis directing tumor cells to their metastatic target organs. In our study we investigated the expression of the CXCR4 receptor on bladder cancer cells and the functional activation of the CXCR4 receptor in bladder cancer cell lines regarding signal transduction pathways, which are involved in metastasis. METHODS: Receptor transcript expression was analysed and quantified by reverse transcription PCR with RNA extracted from different samples of native human bladder cancer tissue, normal urothelium and the bladder cancer cell lines J82 and T24. Measurement of intracellular [Ca(++)](i) and analysis of intracellular stress fiber formation, chemotaxis, Matrigel invasion and proliferation were performed in the bladder cancer cell lines J82 and T24 upon stimulation with the specific agonist SDF-1. RESULTS: Specific CXCR4 receptor transcripts were detected in normal urothelium, the bladder cancer cell lines J82 and T24 and in all bladder carcinoma specimens. We did not observe a quantitative correlation of transcript expression and tumor stage. While SDF-1 did not evoke increases in [Ca(++)](i) in bladder cancer cell lines, we observed a distinct rise in intracellular stress fiber formation, chemotactic activity, invasion through Matrigel coated membranes and cell growth upon stimulation with SDF-1, which was blocked in the presence of a specific CXCR4 receptor antibody. CONCLUSION: Our results support that the chemokine receptor CXCR4 is an interesting candidate for the future investigation of metastasis of bladder cancer in vivo.

[New treatment options for erectile dysfunction. Pharmacologic and nonpharmacologic options]. / Neue Therapieoptionen zur Behandlung der erektilen Dysfunktion. Medikamentöse und nichtmedikamentöse Möglichkeiten.

Erectile dysfunction is a medical condition that influences the sexual life of millions of men and women worldwide. Due to a large number of currently available drugs, the therapy of erectile dysfunction has changed profoundly during the last decades. The pharmacologic options are divided into initiators versus conditioners and central- or peripheral-acting drugs. Besides intraurethral and intracavernous application of prostaglandin E(1) (PGE(1), peripheral initiator)--a transdermal application is still in clinical testing--there are drugs for oral application. PGE(1), the vasoactive drug mainly used, was replaced by sildenafil in first-line-therapy. PGE(1), administered intracavernosally or intraurethrally, is highly effective with success rates up to 90%, but the attrition rate due to personal inconvenience remains significant. Yohimbine is known as a central amplifier of erection and is useful in psychogenic and mild organic erectile dysfunction. Apomorphine, a central initiator of erection, amplifies erectile response as a central dopamine agonist in mild and moderate erectile dysfunction and starts acting 15-20 min after sublingual application. The phosphodiesterase type 5 (PDE-5) inhibitors sildenafil, vardenafil, and taldalafil are peripheral conditioners. Sildenafil, the most distributed oral agent worldwide, should be taken orally 60 min before sexual intercourse in combination with sexual stimulation. Sildenafil shows a high efficacy-safety profile with success rates for all etiologies between 50-80%. Paralleling nitrate-containing medication is an absolute contraindication. Vardenafil, another selective PDE-5 inhibitor with potentially higher selectivity and efficacy compared to sildenafil was just approved. The data from the clinical trials show the same adverse events and success rates as sildenafil. Tadalafil, just launched as well, amplifies erectile function for up to 24 h, allowing the patient to engage in sexual activity for this period. Adverse events and success rates resemble those of the other two substances. If medical treatment fails, there are nonpharmacologic options such as the vacuum constriction device and penile implants. The vacuum device is a safe and effective option for well-selected patients. Penile implants, especially the inflatable ones, completely imitate the physiologic erection. Due to recent research, infection rates and mechanical failures were minimized. Therefore penile implant surgery is well accepted by the patients and their partners. Despite this wide variety of options, therapy of erectile dysfunction should be performed in an individually adapted way. The patient's exact history, physical examination, collaboration of medical disciplines and choice of therapy will offer all patients the possibility to achieve or regain a satisfying sexual life.

Influence of pertussis toxin on superficial bladder carcinoma in rats.

The proliferation and migration of cells is a fundamental process for the metastasis of malignant tumour cells. In several in vitro studies, pertussis toxin (PTX) inhibited cell proliferation and cell motility in the human transitional cell carcinoma cell line J82. The present study investigated the effect of the intravesical application of PTX on the development of superficial bladder cancer in rats. We used the model of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, 0.05% via drinking water x10 weeks) to induce superficial bladder carcinomas in 40 female rats. After 16 weeks the rats were treated in two groups with 0.4 ml PTX (1 microg/ml) or 0.4 ml phosphate buffered saline (PBS) by intravesical application (once a week for 10 weeks). In the 25th week urine cytology was determined and all rats were killed at week 26 followed by histological evaluation. In the control group, the urine cytology was positive for G2/G3 cells in ten of 17 rats. In the PTX group G2/G3 cells were determined in five of 20 rats ( P two tailed <0.05). Histopathologically 12 rats (71%) of the control group and 11 rats (55%) of the PTX group developed T1-T2 transitional-cell carcinomas. No local or systemic side effects were disclosed. PTX treatment reduces the development of G3 transitional cell carcinomas in rats and may represent a new approach for local therapy in superficial bladder cancer.