Dynamic phenotypic shifts and M2 receptor downregulation in bladder smooth muscle cells induced by mirabegron.

Introduction: Mirabegron is available for treatment of overactive bladder (OAB). However, mechanisms underlying symptom improvements and long-term effects on bladder smooth muscle cells are uncertain. Contractility and growth of bladder smooth muscle contribute to OAB, and depend on smooth muscle phenotypes, and on muscarinic receptor expression. Here, we examined prolonged exposure to mirabegron (20-48 h) on phenotype markers, muscarinic receptor expression, and phenotype-dependent functions in human bladder smooth muscle cells (hBSMC). Methods: Expression of markers for contractile (calponin, MYH11) and proliferative (MYH10, vimentin) phenotypes, proliferation (Ki-67), and of muscarinic receptors were assessed by RT-PCR. Proliferation, viability, actin organization and contractions in cultured hBSMC were examined by EdU, CCK-8, phalloidin staining and matrix contraction assays. Results: Calponin-1 mRNA decreased with 100 nM and 150 nM mirabegron applied for 20 h (0.56-0.6 fold of controls). Decreases were resistant to the ß3-AR antagonist L-748,337 (0.34-0.55 fold, 100-150 nM, 20 h). After 40 h, decreases occured in the presence of L-748,337, but not without L-748,337. MYH11 mRNA increased with 150 nM mirabegron (40 h, 1.9 fold). This was partly preserved with L-748,337, but not observed after 20 h mirabegron exposure. Vimentin mRNA reduced with 150 nM mirabegron after 20 h, but not after 40 h, with and without L-748,337 (0.71-0.63 fold). MYH10 mRNA expression remained unaffected by mirabegron. Exposure to 150 nM mirabegron increased Ki-67 mRNA after 20 h in the presence of, but not without L-748,337, and after 40 h without, but not with L-748,337. Proliferation rates and actin organization were stable with 50-150 nM mirabegron (24 h, 48 h). Viability increased significantly after mirabegron exposure for 20 h, and by trend after 40 h, which was fully sensitive to L-748,337. M2 mRNA was reduced by 20 h mirabegron, which was resistant to L-748,337. Carbachol (3 µM) enhanced time-dependent contractions of hBSMC, which was inhibited by mirabegron (150 nM) in late phases (24 h), but not in early phases of contractions. Conclusion: Mirabegron induces dynamic phenotype alterations and M2 downregulation in hBSMC, which is paralleled by time-shifted anticontractile effects. Phenotype transitions may be involved in improvements of storage symptoms in OAB by mirabegron.

[Urinary diversion for acute epididymitis : Transurethral or suprapubic catheter?] / Harnableitung bei akuter Epididymitis : Transurethraler oder suprapubischer Katheter?

Acute infective epididymitis is the most common cause for scrotal pain in adults. The severe course of the disease requires immediate antimicrobial management, comprised antibiotic treatment and supportive measures. Patients with chronic indwelling catheters and developing epididymitis show a more severe clinical course compared to patients without a catheter. Although it is common clinical practice to place a catheter for the treatment of a systemic infectious condition of the genitourinary tract, there is only limited evidence of support due to the absence of clinical trials.

Polyethylene glycol-coated collagen patch (hemopatch®) in open partial nephrectomy.

PURPOSE: To describe the results of a polyethylene glycol-coated collagen patch, Hemopatch® on blood loss, surgical time and renal function in partial nephrectomy (PN) for renal cell carcinoma (RCC). METHODS: Out of a single surgeon cohort of n = 565 patients undergoing conventional open PN (CPN) between 01/2015 and 12/2017 at the University of Munich a consecutive subgroup (n = 42) was operated on using a polyethylene glycol-coated collagen-based sealant Hemopatch® (Baxter International Inc., Deerfield, IL, USA) (HPN). RESULTS: Median age was 65.2 years (range 12.7-95.2) with median follow-up of 9.43 months (0.03-49.15). Baseline renal function (CKD-EPI) was 78.56 ml/min/1.73 m2 (range 20.38-143.09) with a non-significant decline to 74.78 ml/min/1.73 m2 (range 3.75-167.74) at follow-up. In CPN 46% had low complexity, 33% moderate complexity and 20% high complexity lesions with 33% low, 40% moderate and 27% high complexity masses in HPN. Median tumor size was 4.3 cm (range 1-38 cm) in CPN with 4.8 cm (range 3.8-18.3 cm) with HPN, p = 0.293. Median blood loss and duration of surgery was significantly lower in the HPN group vs. CPN (146 ml ± 195 vs. 114 ml ± 159 ml; p = 0.021; 43 min ± 27 for HPN vs. 53 min ± 49; p = 0.035) with no difference in clamping time (12.6 min ± 8.6 for HPN vs. 12.0 min ± 9.5; p = 0.701). CONCLUSIONS: Hemopatch® supported renoraphy shows promising results compared to standard renoraphy in PN. No side effects were seen. Further studies should evaluate the prevention of arterio-venous or urinary fistulas. In complex partial nephrectomies Hemopatch® supported renoraphy should be considered.

[Enhanced Recovery After Surgery (ERAS®) after radical cystectomy-current data]. / Aktuelle Studienlage der Enhanced Recovery After Surgery (ERAS®) nach radikaler Zystektomie.

BACKGROUND: Radical cystectomy is associated with considerable morbidity and mortality. Based on the solid evidence in colorectal surgery, fast-track/ERAS® (Enhanced Recovery After Surgery) protocols have been developed to improve the perioperative management of patients undergoing radical cystectomy. OBJECTIVES: To review the literature and guidelines and evaluate the evidence regarding the different components of ERAS® protocols. MATERIALS AND METHODS: Systemic literature search and evaluation of relevant guidelines. RESULTS: The majority of ERAS® recommendations for radical cystectomy are based on extrapolations of abdominal surgery studies. Four randomized, controlled trials and one ERAS® guideline were published for radical cystectomy. ERAS® seems to shorten length of stay without increasing the complication rate. Key elements are no bowel preparation, no nasogastric tube, optimized fluid substitution, multimodal pain management, early mobilization, and oral diet. CONCLUSIONS: Implementation of ERAS® requires multidisciplinary collaboration. Individualization of an ERAS® program, identification of the most important components and adaption to the specific needs of radical cystectomy patients are future goals.

Postoperative change in Gleason score of prostate cancer in fusion targeted biopsy: a matched pair analysis.

OBJECTIVE: To evaluate if MRI/ultrasound fusion based targeted biopsy (FBx) leads to a reduced rate of change in Gleason score (GS) compared to prostatectomy specimen. METHODS: The histopathological findings of the biopsy of the prostate and the radical prostatectomy (RP) specimen of 210 patients who were referred to our hospital between 2012 and 2017 were compared retrospectively in this study. One hundred and five patients who underwent FBx combined with ultrasound-guided 12-core biopsy of the prostate (SBx) were matched with 105 patients who underwent SBx only. This study evaluated the rate of up- or downgrading in the RP specimen in both groups and compared the results via matched pair analysis. RESULTS: Concordance in Gleason grade group (GGG) was found in 52/105 patients (49.5%) in SBx and in 49/105 patients (46.7%) with FBx (p = 0.679). The rate of downgrading was statistically significant (p = 0.014) and was higher in the FBx group (14/105 patients, 13.3%) than in the SBx group (4/105 patients, 3.8%). A higher rate of upgrading was seen in SBx (49/105 patients; 46.7%) compared to FBx (42/105 patients; 40%), with no statistical significance (p = 0.331). The change in GGG from biopsy to final pathology in patients with GGG 1 and 2 at biopsy level was not statistically significant (p = 0.168). CONCLUSION: FBx does not decrease the rate of upgrading between biopsy and final pathology in RP specimens. Our results indicate that FBx tends to overestimate the final GGG compared to SBx.

18F-PSMA-1007 PET/CT for response assessment in patients with metastatic renal cell carcinoma undergoing tyrosine kinase or checkpoint inhibitor therapy: preliminary results.

INTRODUCTION: Tyrosine kinase (TKI) and checkpoint inhibitors (CI) prolonged overall survival in metastatic renal cell carcinoma (mRCC). Early prediction of treatment response is highly desirable for the individualization of patient management and improvement of therapeutic outcome; however, serum biochemistry is unable to predict therapeutic efficacy. Therefore, we compared 18F-PSMA-1007 PET imaging for response assessment in mRCC patients undergoing TKI or CI therapy compared to CT-based response assessment as the current imaging reference standard. METHODS: 18F-PSMA-1007 PET/CT was performed in mRCC patients prior to initiation of systemic treatment and 8 weeks after therapy initiation. Treatment response was evaluated separately on 18F-PSMA-PET and CT. Changes on PSMA-PET (SUVmean) were assessed on a per patient basis using a modified PERCIST scoring system. Complete response (CRPET) was defined as absence of any uptake in all target lesions on posttreatment PET. Partial response (PRPET) was defined as decrease in summed SUVmean of > 30%. The appearance of new, PET-positive lesions or an increase in summed SUVmean of > 30% was defined as progressive disease (PDPET). A change in summed SUVmean of ± 30% defined stable disease (SDPET). RECIST 1.1 criteria were used for response assessment on CT. Results of radiographic response assessment on PSMA-PET and CT were compared. RESULTS: Overall, 11 mRCC patients undergoing systemic treatment were included. At baseline PSMA-PET1, all mRCC patients showed at least one PSMA-avid lesion. On follow-up PET2, 3 patients showed CRPET, 3 PRPET, 4 SDPET, and 1 PDPET. According to RECIST 1.1, 1 patient showed PRCT, 9 SDCT, and 1 PDCT. Overall, concordant classifications were found in only 2 cases (2 SDCT + PET). Patients with CRPET on PET were classified as 3 SDCT on CT using RECIST 1.1. By contrast, the patient classified as PRCT on CT showed PSMA uptake without major changes during therapy (SDPET). However, among 9 patients with SDCT on CT, 3 were classified as CRPET, 3 as PRPET, 1 as PDPET, and only 2 as SDPET on PSMA-PET. CONCLUSION: On PSMA-PET, heterogeneous courses were observed during systemic treatment in mRCC patients with highly diverging results compared to RECIST 1.1. In the light of missing biomarkers for early response assessment, PSMA-PET might allow more precise response assessment to systemic treatment, especially in patients classified as SD on CT.

[The role of the microbiome in urology]. / Die Rolle des Mikrobioms in der Urologie.

With the advent of novel high throughput-sequencing technologies we gained greater insights into the complex and diverse interactions of the microbiome for health and disease in the human body. The concept of urinary sterility has long been dismissed and now we strive for deciphering various microbial signatures associated with a disease. A dysbalance of the microbiome appears to have a substantial impact on the pathogenesis of both malignant and benign conditions. Novel preventive and therapeutic approaches and biomarker systems have been proposed for prostate cancer, renal cell carcinoma and bladder cancer based on microbiome analyses. The exclusion of a microbial origin was always part of the diagnosis of benign disorders such as interstitial cystitis, urinary urge incontinence or chronic prostatitis/chronic pelvic pain syndrome. Now we are certain that an imbalanced microbial profile plays an essential role for the pathogenesis and disease management of these challenging conditions.

[The microbiome in benign prostatic hyperplasia]. / Das Mikrobiom beim benignen Prostatasyndrom.

The advent of new high throughput sequencing technologies has paved the way for microbiome research, opening up entirely new perspectives on the complex and diverse ecosystems of the human body. One of the main findings was that it became clear that in contrast to the widely held dogma the urinary tract is not a sterile environment. As for all niches of the human body, a well-balanced microbiome is an essential part for the physiological functioning of the urinary tract and therefore it must be considered a prerequisite for health. The dysbalance of the microbiome is now seen as having a considerable impact on the pathogenesis of a plethora of diseases. Its role in benign disorders, such as interstitial cystitis, urinary urge incontinence and chronic prostatitis/chronic pelvic pain syndrome as well as participation in malignant conditions, such as prostate cancer has recently been revealed. The contribution of the urinary microbiome to the pathogenesis and progression of lower urinary tract symptoms due to benign prostatic obstruction are currently under investigation.

[Chronic prostatitis/chronic pelvic pain syndrome]. / Chronische Prostatitis/chronisches Beckenschmerzsyndrom.

Chronic prostatitis (CP, or chronic pelvic pain syndrome, CPPS) is defined as chronic pain or discomfort in the pelvic region for at least 3 of the past 6 months, often accompanied by lower urinary tract symptoms, psychosocial impairments and sexual dysfunction. Currently, no biomarkers or clinical test procedures for a definitive diagnosis are available. The main objectives for the diagnostic assessment are to exclude differential diagnoses of pelvic pain and to determine the individual symptom profile of the patient. The UPOINTS classification identifies the individual clinical profile of the patient, provides guidance for the necessary diagnostic steps and is the foundation for a tailored multimodal, symptom-oriented and personalized treatment concept. Regular follow-up controls are needed to monitor the treatment response with the option to modify if necessary.

Heteroresistant Bacteria Detected by an Extended Raman-Based Antibiotic Susceptibility Test.

Worldwide, multiresistant bacterial strains are emerging at unprecedented rates. This development seriously threatens the ability of humanity to treat even common infections, resulting in disability and death. Furthermore, this development endangers all medical achievements including cancer therapy or organ transplantations. Therefore, the World Health Organization has endorsed antimicrobial resistance as a great threat to humanity. To still allow effective treatment of patients, rapid, automated, and reliable antibiotic susceptibility testing (AST) of bacterial pathogens is essential. Thereby, speed and sensitivity of the AST results are crucial for improving patient care. Here, Raman spectroscopy as a nondestructive technique providing chemical-specific information is employed to monitor the deuterium uptake of metabolically active bacteria during antibiotic treatment, enabling fast and reliable AST. For this purpose, a bulk sample-preparation method was developed, allowing a high-throughput analysis of a significant number of cells. A protocol was developed for Gram-positive (Enterococcus faecalis) and Gram-negative (Escherichia coli) reference strains and was tested on 51 clinical isolates with well-characterized resistance phenotypes against ampicillin, ciprofloxacin, meropenem, and vancomycin. Borderline resistant and heteroresistant phenotypes were observed and further investigated. This is of critical importance as the sensitive detection of low-frequency heteroresistance in bacterial populations is a huge challenge. Such isolates seem susceptible but are resistant to treatment in vivo. Automatable analysis detects strong phenotypes within 3 h. On the basis of experimental and modeled data, heteroresistance is estimated to be detectable down to frequencies of 10-6 and investigated on clinical isolates as a proof-of-concept study, but requiring longer incubation time.

Advanced Molecular Imaging in Histologically Verified Metanephric Adenoma.

Metanephric adenoma (MA) describes a rare renal tumor and is generally considered a benign lesion. However, there are cases with regional lymphogenic and distant metastases. Noninvasive diagnosis of MA using conventional imaging remains challenging. Here, we describe a case of histologically verified MA with additional advanced molecular imaging consisting of 18F-PSMA-1007 PET/CT, 99mTc-Sestamibi SPECT and contrast-enhanced ultrasound.

Correction to: The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence.

In multivariate analysis, GS of the regular prostatectomy specimen was the only statistically significant parameter for pT2R1 prostate cancer.

Prospective evaluation of 4-D contrast-enhanced-ultrasound (CEUS) imaging in bladder tumors.

PURPOSE: The evaluation of the potential clinical benefit of four-dimensional ultrasound (4D-US) in the assessment of bladder cancer (BC). MATERIAL AND METHODS: 20 patients with indication for cystoscopy for suspicion of bladder cancer were prospectively included in this study. All patients underwent two-dimensional ultrasound (2D-US), contrast enhanced ultrasound (CEUS) and real-time four-dimensional ultrasound (4D-US). All acquisitions were compared to each other in regard to image quality. This assessment was done using a 6 point scale (1 = best). All patients underwent subsequently cystoscopy with resection of the tumor (TURB), due a histopathological analysis was possible. RESULTS: All examinations were performed successfully and no patient had to be excluded from the study. Patients acceptance of 4D-US was consistently good. No adverse events occurred. Image quality of real time 4D-US (score: 1.27±0.46) was significantly superior (p < 0.001) to both, conventional 2D-US (score: 2.33±0.62) and also to 2D-CEUS (score: 2.00±0.53). In terms of tumor detection no superiority was evident for 4D-US compared to 2D-US or in utilization of CEUS (sensitivity = 0.89; specificity = 1.00; positive predictive value = 1.00; negative predictive value = 0.50; AUC = 0.944; (95% CI: 07.43-0.998)). CONCLUSION: The assessment of bladder cancer using real time 4D-US is feasible and improves the image quality and therefore also the precise anatomical consistency of intravesical tumor masses.

Detection of Gleason 6 prostate cancer in patients with clinically significant prostate cancer on multiparametric magnetic resonance imaging.

INTRODUCTION: Multiparametric-Magnetic Resonance Imaging (mpMRI)-Ultrasound fusion guided biopsy (Fbx) has emerged as the new standard of risk stratification for prostate cancer (PCa) with superior detection rates of clinically significant PCa than randomized biopsy. In the present study, we evaluated patients with suspicion of clinically significant PCa on mpMRI, but histopathologically proven Gleason 6 PCa in Fbx. MATERIAL AND METHODS: Between 2015 and 2019, 849 patients underwent Fbx and concurrent systematic 12-core biopsy at our department. 234 patients were diagnosed with Gleason 6 PCa in either mpMRI-targeted and/or concurrent systematic biopsy. Patients were analyzed regarding PSA, mpMRI findings according to PI-RADS classification, histopathological results of Fbx and systematic 12-core biopsy. 99/234 patients were also analyzed in regards of histopathology of the whole-mount specimen of subsequent radical prostatectomy (RP). RESULTS: In 131/234 patients (56%), Gleason 6 PCa was detected in the mpMRI target. In 103/234 patients (44%), Gleason 6 PCa was detected in the concurrent systematic 12-core biopsy with negative mpMRI-targeted biopsy. Men with evidence of Gleason 6 in the mpMRI target had significantly higher amounts of overall positive biopsies (median 4 vs. 2, p < 0.001) and higher maximum tumor infiltration per biopsy core (30% vs. 20%, p < 0.001) compared to men with negative mpMRI-targeted biopsy. Detection of Gleason 6 in mpMRI Target lesions correlated significantly with the PI-RADS score (p < 0.001). Patients with positive mpMRI-target had significantly higher tumor infiltration in whole-mount specimen after prostatectomy (20% vs. 15%, p = 0.0026) compared to men without detection of Gleason 6 in mpMRI-targeted biopsy but in additional systematic biopsy. CONCLUSION: Detection of Gleason 6 PCa in mpMRI-targeted biopsy indicates higher tumor burden compared to detection of Gleason 6 PCa in concurrent systematic biopsy and negative mpMRI-targeted biopsy.

Follow-up after focal therapy of the prostate with high intensity focused ultrasound (HIFU) using contrast enhanced ultrasound (CEUS) in combination with MRI image fusion.

INTRODUCTION: Focal therapy (FT) of the prostate for low risk prostate cancer (PCa) is an alternative to traditional definite treatment options like external beam radiotherapy or radical prostatectomy. However, follow up after FT is still challenging and is subject to current studies. Significance of imaging after FT such as multiparametric MRI (mpMRI) is currently not well established. In this study, we aimed to evaluate the efficacy of alternative imaging during the follow up of low risk PCa treated with focal HIFU therapy using CEUS and image fusion. MATERIALS AND METHODS: Retrospective single arm study in patients with uni- or bilateral, low or intermediate risk prostate cancer treated with HIFU at our institution between October 2016 and January 2018. CEUS in combination with image fusion using an axial T2-weighted MRI sequence was performed during follow up 3, 6, 9 and 12 months after the therapy. RESULTS: 4 consecutive patients with Gleason score (GS) 6 and 4 patients with GS 7a prostate cancer were included in the study. Hemiablation was performed in 7 patients with unilateral tumor. One patient underwent whole gland treatment due to histological proven bilateral PCa. Mean patient age at time of therapy was 70.3 (54-83) years and mean Prostate-specific antigen (PSA) level prior treatment was 7.8 ng/ml (2.1-14.4), after 3 months mean PSA level was 3.9 ng/ml (0.1-7.2), after 6 months 3.5 ng/ml (0.2-6.0), after 9 months 3.1 ng/ml (0.2-6.8) and 3.3 ng/ml (0.2-6.1) after 12 months. CEUS showed no signs of microvascularisation after 3, 6, 9 and 12 months in the ablated zone. 3 months posttreatment the necrotic tissue was still visible in the B-mode scan, although with no signs of vascularization performing CEUS. After 6 months the ablated side of the prostate was almost completely atrophic. And after 9 months the necrotic tissue was completely resolved. Between 9 and 12 months no changes in microvascularisation and perfusion could be shown. CONCLUSIONS: MpMRI/CEUS image fusion is a cost-effective and feasible technique to monitor the perfusion of the ablation zone after focal therapy of the prostate.

[Follow-up surveillance of muscle-invasive urinary bladder cancer after curative treatment]. / Nachsorge des muskelinvasiven Harnblasenkarzinoms nach kurativer Therapie.

Follow-up care of patients with muscle-invasive bladder cancer is subdivided into oncological and functional surveillance. More than 80% of local relapses and distant metastases occur within the first 2 years. Recurrences in the remnant urothelium also occur several years after radical cystectomy. Urinary cytology and a computed tomography (CT) scan of the abdomen and thorax including a urography phase are the standard diagnostics for tumor follow-up. There is no clear evidence for a survival benefit for the detection of asymptomatic vs. symptomatic recurrences. After partial cystectomy or trimodal treatment, there is no established follow-up schedule; however, the relatively high incidence of intravesical recurrences should be considered as there are curative treatment approaches including salvage cystectomy. Functional surveillance, which should be carried out lifelong, encompasses prevention and diagnostics of metabolic complications, urethral/ureteral strictures, problems with the urinary stoma, urinary incontinence, sexual dysfunction and urinary tract infections.

Anesthesia for Open Radical Retropubic Prostatectomy: A Comparison between Combined Spinal Epidural Anesthesia and Combined General Epidural Anesthesia.

BACKGROUND: Several anesthesiologic regimens can be used for open radical retropubic prostatectomy. The aim of this retrospective analysis was to compare the combined general epidural anesthesia and the combined spinal epidural anesthesia with regard to availability, efficacy, side effects, and perioperative time consumption in a high-volume center. METHODS: A retrospective analysis was performed by querying the electronic medical records of 1207 consecutive patients from the database of our online documentation software. All patients underwent open radical retropubic prostatectomy from 01/2008 to 08/2011 and met the study criteria. Linear and multivariate regression analyses were performed to identify differences in parameters such as time consumption in the operating unit, hemodynamic parameters, volume replacement, and catecholamine therapy. RESULTS: 698 (57.8%) patients have been undergoing open radical retropubic prostatectomy under combined spinal epidural anesthesia and 509 (42.2%) patients by combined general epidural anesthesia. Operating unit (p <0.0001) and post-anesthesia care unit stay (p <0.0001) as well as total hospital stay (p <0.0001) were significantly shorter in the combined spinal epidural anesthesia group. In addition, this group had reduced intraoperative volume need (p <0.0001) as well as lower need of catecholamines (p <0.0001). CONCLUSIONS: This retrospective study suggests that the combined spinal epidural anesthesia seems to be a suitable and efficient anesthesia technique for patients undergoing open radical retropubic prostatectomy. This specific approach reduces time in the operation unit and length of hospital stay.

[Aftercare of non-muscle invasive bladder cancer]. / Nachsorge des nicht muskelinvasiven Harnblasenkarzinoms.

Tumor follow-up in patients with non-muscle invasive bladder cancer (NMIBC) is a weighing up between the morbidity associated with invasive diagnostics and the risk of tumor recurrence and especially progression. The risk stratification into low, intermediate, and high-risk tumors enables a risk-adapted follow-up. For individual estimation of the risk of progression and recurrence, risk calculators should be used. Follow-up is still based on cystoscopy, which is recommended lifelong for high and intermediate-risk tumors and for up to 5 tumor-free years for low-risk tumors. Urine cytology has a high sensitivity and specificity for high-risk tumors and is recommended in the follow-up care. There is currently no recommendation for any commercially available urinary marker due to inadequate evidence. For the clarification of synchronous and metachronous tumors of the upper urinary tract computed tomography (CT) urography or alternatively magnetic resonance (MR) urography is recommended.