The Vanishing Clinical Value of PD-L1 Status as a Predictive Biomarker in the First-Line Treatment of Urothelial Carcinoma of the Bladder.

BACKGROUND: Our study endeavors to elucidate the clinical implications of PD-L1 positivity in individuals afflicted with advanced urothelial carcinoma of the bladder (UCB). METHODS: Patients with advanced UCB were prospectively enrolled following a radical cystectomy (RC) performed within January 2017 to December 2022 at our tertiary referral center. The clinical outcome, defined as the progression-free survival (PFS) and overall survival (OS) on systemic treatment, was analyzed using an χ2-test, Mann-Whitney U-test, the Kaplan-Meier method, and a log-rank test. RESULTS: A total of 648 patients were included following an RC performed within January 2017 to December 2022. Their PD-L1 status was analyzed with the primary PD-L1-specific antibody (clone SP263, Ventana) and defined both by the CPS and IC-score in 282 patients (43.5%) with a high risk (pT3-pT4 and/or lymph node involvement) or metastatic UCB. While the median PFS was significantly prolonged 5-fold in PD-L1+ patients, we found no difference in OS, regardless of PD-L1 status, or treatment regimen. CONCLUSIONS: While PD-L1 positivity indicates prolonged PFS, the presence of PD-L1 does not influence OS rates, suggesting its limited usefulness as a prognostic biomarker in bladder cancer. However, the positive correlation between an PD-L1 status and a sustained response to ICI treatments indicates its potential role as a predictive biomarker. Further research is required to understand how the predictive value of PD-L1 positivity may extend to the use of ICIs in combination with antibody-drug conjugates.

Isoform-independent promotion of contractility and proliferation, and suppression of survival by with no lysine/K kinases in prostate stromal cells.

With no lysine/K kinases (WNKs) promote vasocontraction and vascular smooth muscle cell proliferation. In the prostate, smooth muscle contraction and growth may be critical for the development and medical treatment of voiding symptoms in benign prostatic hyperplasia. Here, we examined the effects of isoform-specific WNK silencing and of the WNK inhibitor WNK463 on growth-related functions and contraction in prostate stromal cells, and in human prostate tissues. Impacts of WNK silencing by transfection of cultured stromal cells with isoform-specific siRNAs were qualitatively and quantitatively similar for each WNK isoform. Effects of silencing were largest on cell death (3-5 fold increase in annexin V-positive/7-AAD-positive cells), on proliferation rate, Ki-67 mRNA expression and actin organization (reduced around two-thirds). Contraction in matrix contraction assays and viability were reduced to a lower degree (approximately half), but again to a similar extent for each WNK isoform. Effects of silencing were quantitatively and qualitatively reproduced by 10 µM WNK463, while 1 µM still induced cell death and breakdown in actin organization, without affecting proliferation or viability. Using 500 nM and 10 µM, WNK463 partly inhibited neurogenic and U46619-induced contractions of human prostate tissues (around half), while inhibition of α1-adrenergic contractions (around half) was limited to 10 µM. All four WNK isoforms suppress cell death and promote proliferation in prostate stromal cells. WNK-driven contraction of stromal cells appears possible, even though to a limited extent. Outcomes of isoform-specific WNK silencing can be fully reproduced by WNK463, including inhibition of smooth muscle contraction in human prostate tissues, but require high concentrations.

Propensity score-matched evaluation of palliative transurethral resection and holmium laser enucleation of the prostate for bladder outlet obstruction in patients with prostate cancer.

BACKGROUND: While transurethral resection of the prostate (TURP) is the standard-of-care, Holmium laser enucleation of the prostate (HoLEP) is widely accepted as a size-independent method for surgical treatment of patients with lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction (BOO). However, in an ageing society an increasing number of patients presents with BOO due to locally advanced prostate cancer. There is currently no guidelines recommendation as to the enucleation or resection technique. Therefore, we compared intraoperative performance, postoperative outcomes, and safety for palliative (p)TURP and (p)HoLEP. METHODS: We conducted a retrospective, propensity score-matched analysis of 1373 and 2705 men who underwent TURP or HoLEP for LUTS/BOO between 2014 and 2021, respectively. Patients were matched for age, prostate size and preoperative international prostate symptom score (IPSS). Patients were stratified by technique and groups were compared for perioperative parameters, safety, and functional outcomes. RESULTS: While postoperative symptoms and urodynamic parameters improved irrespective of technique, we report significantly increased resection and enucleation times for palliative indication. For corresponding efficiency parameters, we observed a two-fold higher surgical performance (g/min) for both techniques in patients without prostate cancer. While adverse events were comparable between groups, we found a two-fold higher hemoglobin drop in palliative patients. CONCLUSIONS: Currently, there is no standard-of-care for patients with BOO and locally advanced prostate cancer. Our data show that both TURP and HoLEP offer adequate symptom improvement and comparable safety profiles. While HoLEP is feasible even in larger prostates, both procedures become more difficult in patients with prostate cancer. Taken together, this study covers an important gap in current literature, helping urological surgeons to make evidence-based decisions for the benefit of their patients.

Organ-specific off-target effects of Pim/ZIP kinase inhibitors suggest lack of contractile Pim kinase activity in prostate, bladder, and vascular smooth muscle.

Smooth muscle contraction by Pim kinases and ZIPK has been suggested, but evidence for lower urinary tract organs or using Pim-selective inhibitor concentrations is not yet available. Here, we assessed effects of the Pim inhibitors AZD1208 and TCS PIM-1 and the dual ZIPK/Pim inhibitor HS38 on contractions of human prostate and bladder tissues and of porcine interlobar arteries. Human tissues were obtained from radical prostatectomy and radical cystectomy and renal interlobar arteries from pigs. Contractions were studied in an organ bath. Noradrenaline-, phenylephrine- and methoxamine-induced contractions were reduced (up to > 50%) with 500-nM AZD1208 in prostate tissues and to lesser degree and not consistently with all agonists in interlobar arteries. A total of 100-nM AZD1208 or 500-nM TCS PIM-1 did not affect agonist-induced contractions in prostate tissues. Decreases in agonist-induced contractions with 3-µM HS38 in prostate tissues and interlobar arteries were of small extent and did not occur with each agonist. Carbachol-induced contractions in detrusor tissues were unchanged with AZD1208 (500 nM) or HS38. Electric field stimulation-induced contractions were not affected with AZD1208 or HS38 in any tissue, but slightly reduced with 500-nM TCS PIM-1 in prostate tissues. Concentration-dependent effects of Pim inhibitors suggest lacking Pim-driven smooth muscle contraction in the prostate, bladder, and interlobar arteries but point to organ-specific functions of off-targets. Procontractile functions of ZIPK in the prostate and interlobar arteries may be limited and are lacking in the detrusor.

Selective inhibition of neurogenic, but not agonist-induced contractions by phospholipase A2 inhibitors points to presynaptic phospholipase A2 functions in contractile neurotransmission to human prostate smooth muscle.

BACKGROUND: Phospholipases A2 (PLA2 ) may be involved in α1 -adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1 -adrenergic contractions of the prostate, is still unknown. While α1 -adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2 . Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1 -adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls. RESULTS: Frequency-dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3 and 1 µM) neither affected EFS-induced contractions, nor contractions by α1 -adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM). CONCLUSIONS: Our findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1 -adrenergic agonists occur PLA2 -independent. Lacking sensitivity to montelukast excludes an involvement of PLA2 -derived leukotrienes in promotion of contractile neurotransmission.

Silencing of CDC42 inhibits contraction and growth-related functions in prostate stromal cells, which is mimicked by ML141.

BACKGROUND: Prostate smooth muscle contraction and stromal growth may contribute to lower urinary tract symptoms suggestive of benign prostatic hyperplasia, but are incompletely understood. A role of the monomeric GTPase CDC42 for smooth muscle contraction and proliferation appears possible, but is unknown for the prostate. Here, we silenced CDC42 expression in prostate stromal cells (WPMY-1), and examined contractility, growth-related functions and responses to the presumed CDC42 inhibitor, ML141. METHODS: WPMY-1 cells were transfected with scrambled or CDC42-specific siRNA, and characterized for GTPase activities, contraction, proliferation, colony formation, apoptosis, cell death and viability. Effects of ML141 were examined in cells with and without silencing. RESULTS: CDC42 silencing was confirmed by reduced mRNA and protein expression, and reduced CDC42 activity. Silencing impaired contraction (23-47 %), actin organization (25 %), proliferation (17-63 %), colony formation and viability (64-89 %), and increased the percentage of dead cells (2.6-fold). ML141 mimicked the phenotype of silencing in scrambled siRNA-transfected controls, and in non-transfected WPMY-1 cells, including inhibition of contraction, proliferation, colony formation and viability, breakdown of actin organization and increased cell death. In CDC42-silenced cells, ML141 still affected phalloiding organization, proliferation and cell death, with effect sizes resembling controls without silencing. ML141 inhibited RhoA activity in CDC42-silenced cells, but not in cells without silencing. CONCLUSIONS: CDC42 promotes contraction of prostate stromal cells, and drives stromal growth by CDC42-mediated proliferation and suppression of apoptosis-independent cell death. ML141 mimicks all effects of CDC42 silencing, but its specificity may be limited and depends on GTPase phenotypes of cells.

Inhibition of growth and contraction in human prostate stromal cells by silencing of NUAK1 and -2, and by the presumed NUAK inhibitors HTH01-015 and WZ4003.

Background: NUAKs promote myosin light chain phosphorlyation, actin organization, proliferation and suppression of cell death in non-muscle cells, which are critical for smooth muscle contraction and growth. In benign prostatic hyperplasia (BPH), contraction and growth in the prostate drive urethral obstruction and voiding symptoms. However, a role of NUAKs in smooth muscle contraction or prostate functions are unknown. Here, we examined effects of NUAK silencing and the presumed NUAK inhibitors, HTH01-015 and WZ4003 on contraction and growth-related functions in prostate stromal cells (WPMY-1) and in human prostate tissues. Methods: Effects of NUAK1 and -2 silencing, HTH01-015 and WZ4003 on matrix plug contraction, proliferation (EdU assay, Ki-67 mRNA), apoptosis and cell death (flowcytometry), viability (CCK-8) and actin organization (phalloidin staining) were examined in cultured WPMY-1 cells. Effects of HTH01-015 and WZ4003 on smooth muscle contraction were assessed in organ bath experirments with human prostate tissues. Results: Effects of silencing were most pronounced on proliferation and cell death, resulting in decreases of proliferation rate by 60% and 70% by silencing of NUAK1 and NUAK2 (compared to scramble siRNA-transfected controls), decreases in Ki-67 by 75% and 77%, while numbers of dead cells after silencing of NUAK1 and NUAK2 amounted to 2.8 and 4.9 fold of scramble-transfected controls. Silencing of each isoform was paralleled by reduced viability, breakdown in actin polymerization, and partial decreases in contractility (maximally 45% by NUAK1 silencing, 58% by NUAK2 silencing). Effects of silencing were mimicked by HTH01-015 and WZ4003, with numbers of dead cells amounting up to 16.1 fold or 7.8 fold with HTH01-015 or WZ4003, compared to solvent-treated controls. Using concentrations of 500 nM, neurogenic contractions of prostate tissues were inhibited partly by HTH01-015 and U46619-induced contractions were inhibited partly by HTH01-015 and WZ4003, while α1-adrenergic and endothelin-1-induced contractions remained unaffected. Using 10 µM, inhibition of endothelin-1-induced contractions by both inhibitors and inhibition of α1-adrenergic contractions by HTH01-015 added to effects seen by 500 nM. Conclusion: NUAK1 and -2 suppress cell death and promote proliferation in prostate stromal cells. A role in stromal hyperplasia appears possible in BPH. Effects of NUAK silencing are mimicked by HTH01-015 and WZ4003.

[Laser Techniques in the Treatment of Benign Prostatic Syndrome]. / Lasertechniken in der Behandlung des benignen Prostatasyndroms.

Laser Techniques in the Treatment of Benign Prostatic Syndrome Abstract: Lasers have a wide range of applications in endourological therapy. Not only in the treatment of stones, but also in the treatment of benign prostatic syndrome (BPS), their importance continues to grow. The endourological treatment of BPH with different laser techniques will be discussed in more detail in the following. The physical differences between the individual lasers will be explained first, followed by the treatment options that can be performed with a laser. The main focus will be on the concrete comparison of the treatment methods, especially in clinical contexts. In particular, the duration of surgery, length of hospitalisation, risk of post-operative bleeding, catheterisation duration, risk of urinary retention and risk of post-operative complications such as retrograde ejaculation, bladder neck sclerosis, urethra stricture and adenoma recurrence will be listed and compared for the most important methods. Nevertheless, the distribution of TURP to laser is still 30:1 in favour for TURP [1].

[Benign Prostate Hyperplasia - Current Medical Therapy, New Developments, and Side Effects]. / Benigne Prostatahyperplasie.

Benign Prostate Hyperplasia - Current Medical Therapy, New Developments, and Side Effects Abstract: Lower urinary tract symptoms (LUTS) consist of both voiding and storage symptoms. Urethral obstruction leading to voiding symptoms is most commonly attributed to benign prostatic hyperplasia (BPH), where hyperplastic growth and increased smooth muscle tone in the hyperplastic prostate may lead to benign prostate obstruction (BPO). Spontaneous contractions of the detrusor muscle may cause storage symptoms, which are referred to as overactive bladder (OAB). With a considerable proportion of patients suffering from "mixed LUTS", a combination of voiding and storage symptoms, LUTS affect a large portion of the population worldwide, with major impact on quality of life (QoL). A demographic shift in society, will lead to higher incidence and prevalence of LUTS, with a growing economic burden. Standard-of-care medical treatment for LUTS/BPO includes α1-adrenoceptor antagonists and phosphodiesterase-5 (PDE-5) inhibitors, for reduction of prostate smooth muscle tone, and 5α-reductase inhibitors (5-ARI) to slow down disease progression. Medical therapy for LUTS/OAB includes muscarinic receptor antagonists, and ß3-agonists for relief of spontaneous bladder contractions. When left untreated, LUTS may cause considerable adverse events, ranging from acute urinary retention with kidney failure, and recurring infections, to social withdrawal, and depression.

Efficacy, Efficiency, and Safety of En-bloc vs Three-lobe Enucleation of the Prostate: A Propensity Score-matched Analysis.

OBJECTIVE: To assess efficacy, efficiency, and safety in holmium laser enucleation of the prostate (HoLEP), we directly compared intraoperative performance, postoperative outcomes, and safety in the original 3-lobe enucleation technique with the more recent en-bloc method. As HoLEP is widely accepted as a size-independent method for surgical treatment of patients with lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO), detailed understanding of its benefits is mandatory. METHODS: We conducted a retrospective, propensity score-matched analysis of 1,396 men who underwent HoLEP for LUTS/BPO between 2017 and 2020. We included 606 patients in the final analysis (en-bloc n = 303; 3-lobe n = 303), who were matched for prostate size (50 cc), age, body mass index, and preoperative international prostate symptom score. Patients were then stratified by technique, and groups were compared for perioperative parameters, safety, and short-term functional outcomes. RESULTS: While postoperative symptoms and urodynamic parameters improved irrespective of technique, we report significantly less adverse events (Clavien-Dindo classification ≥II vs

Inhibition of α1-Adrenergic, Non-Adrenergic and Neurogenic Human Prostate Smooth Muscle Contraction and of Stromal Cell Growth by the Isoflavones Genistein and Daidzein.

Isoflavone-rich legumes, including soy, are used for food production, as dietary supplements and in traditional medicine. Soy consumption correlates negatively with benign prostatic hyperplasia (BPH) and voiding symptoms. However, isoflavone effects on the prostate are hardly known. Here, we examined the effects on human prostate smooth muscle contractions and stromal cell growth, which are driving factors of voiding symptoms in BPH. Smooth muscle contractions were induced in prostate tissues from radical prostatectomy. Growth-related functions were studied in cultured stromal cells (WPMY-1). Neurogenic, α1-adrenergic and non-adrenergic contractions were strongly inhibited with 50 µM and by around 50% with 10 µM genistein. Daidzein inhibited neurogenic contractions using 10 and 100 µM. Agonist-induced contractions were inhibited by 100 µM but not 10 µM daidzein. A combination of 6 µM genistein with 5 µM daidzein still inhibited neurogenic and agonist-induced contractions. Proliferation of WPMY-1 cells was inhibited by genistein (>50%) and daidzein (<50%). Genistein induced apoptosis and cell death (by seven-fold relative to controls), while daidzein induced cell death (6.4-fold) without apoptosis. Viability was reduced by genistein (maximum: 87%) and daidzein (62%). In conclusion, soy isoflavones exert sustained effects on prostate smooth muscle contractions and stromal cell growth, which may explain the inverse relationships between soy-rich nutrition, BPH and voiding symptoms.

Gender Bias in Urology: How Do Patients Really Choose Their Urologist?

Purpose: The present study aimed to investigate the influence of patients' and urologists' gender when choosing a urologist. With rising population diversity through immigration and generational differences, patient-centered healthcare has recently moved to the focus of European healthcare systems. As healthcare in urology often concentrates on sensitive topics, and often involves gender-specific diseases, research on the influence of gender on decision-making processes is of high importance. Understanding influence of gender on patients' choices in real life would provide patients, and physicians alike, with the means to provide better resources to achieve greater satisfaction from visits to a urologist. Patients and Methods: A questionnaire was prepared, and patients at our tertiary referral center were given the opportunity to voluntarily participate in our survey. We collected questionnaires from 1012 patients during their visits from June 2021 to October 2021. Results: Patients were divided into groups according to their gender: male (n=763), female (n=246), and non-binary (n=3). Our patient cohort consisted of more men than women (75% vs 24%), with only three patients identifying as non-binary. Irrespective of the patients' own gender, patients preferred a male urologist when problems were considered embarrassing, limiting daily activities, or when worrisome. When problems were considered painful, all patients preferred a female urologist. When patients had had a previous positive experience with a female or male urologist, they preferred to be treated by a female or male urologist, respectively. Overall, 65% of patients stated a gender preference for at least one given situation, or consultation scenario. Conclusion: As the majority of our patients stated a gender preference, urological departments should be considerate of potential patients' preferences for urologist gender that may be based on the individual patient's history, taking a comprehensive approach to fulfill the patients' need for same gender urologists in educational hospitals and health care services.

Permixon®, hexane-extracted Serenoa repens, inhibits human prostate and bladder smooth muscle contraction and exerts growth-related functions in human prostate stromal cells.

AIMS: Recently, the European Association of Urology recommended hexane-extracted fruit of Serenoa repens (HESr) in their guidelines on management of non-neurogenic male lower urinary tracts symptoms (LUTS). Despite previously lacking recommendations, Permixon® is the most investigated HESr in clinical trials, where it proved effective for male LUTS. In contrast, underlying mechanisms were rarely addressed and are only marginally understood. We therefore investigated effects of Permixon® on human prostate and detrusor smooth muscle contraction and on growth-related functions in prostate stromal cells. MAIN METHODS: Permixon® capsules were dissolved using n-hexane. Contractions of human prostate and detrusor tissues were induced in organ bath. Proliferation (EdU assay), growth (colony formation), apoptosis and cell death (flow cytometry), viability (CCK-8) and actin organization (phalloidin staining) were studied in cultured human prostate stromal cells (WPMY-1). KEY FINDINGS: Permixon® inhibited α1-adrenergic and thromboxane-induced contractions in prostate tissues, and methacholine-and thromboxane-induced contractions in detrusor tissues. Endothelin-1-induced contractions were not inhibited. Neurogenic contractions were inhibited in both tissues in a concentration-dependent manner. In WPMY-1 cells, Permixon® caused concentration-dependent breakdown of actin polymerization, inhibited colony formation, reduced cell viability, and proliferation, without showing cytotoxic or pro-apoptotic effects. SIGNIFICANCE: Our results provide a novel basis that allows, for the first time, to fully explain the ubiquitous beneficial effects of HESr in clinical trials. HESr may inhibit at least neurogenic, α1-adrenergic and thromboxane-induced smooth muscle contraction in the prostate and detrusor, and in parallel, prostate stromal cell growth. Together, this may explain symptom improvements by Permixon® in previous clinical trials.

Inhibition of Human Prostate and Bladder Smooth Muscle Contraction, Vasoconstriction of Porcine Renal and Coronary Arteries, and Growth-Related Functions of Prostate Stromal Cells by Presumed Small Molecule Gαq/11 Inhibitor, YM-254890.

Introduction: Lower urinary tract symptoms (LUTS) involve benign prostatic hyperplasia (BPH) and overactive bladder (OAB). Standard-of-care medical treatment includes α1-blockers and antimuscarinics for reduction of prostate and detrusor smooth muscle tone, respectively, and 5α-reductase inhibitors (5-ARI) to prevent prostate growth. Current medications are marked by high discontinuation rates due to unfavourable balance between efficacy and treatment-limiting side effects, ranging from dry mouth for antimuscarinics to cardiovascular dysregulation and a tendency to fall for α1-blockers, which results from hypotension, due to vasorelaxation. Agonist-induced smooth muscle contractions are caused by activation of receptor-coupled G-proteins. However, little is known about receptor- and organ-specific differences in coupling to G-proteins. With YM-254890, a small molecule inhibitor with presumed specificity for Gαq/11 became recently available. Here, we investigated effects of YM-254890 on prostate, bladder and vascular smooth muscle contraction, and on growth-related functions in prostate stromal cells. Methods: Contractions of human prostate and detrusor tissues, porcine renal and coronary arteries were induced in an organ bath. Proliferation (EdU assay), growth (colony formation), apoptosis and cell death (flow cytometry), viability (CCK-8) and actin organization (phalloidin staining) were studied in cultured human prostate stromal cells (WPMY-1). Results: Contractions by α1-adrenergic agonists, U46619, endothelin-1, and neurogenic contractions were nearly completely inhibited by YM-254890 (30 nM) in prostate tissues. Contractions by cholinergic agonists, U46619, endothelin-1, and neurogenic contractions were only partly inhibited in detrusor tissues. Contractions by α1-adrenergic agonists, U46619, endothelin-1, and neurogenic contractions were strongly, but not fully inhibited in renal arteries. Contractions by cholinergic agonists were completely, but by U46619 and endothelin-1 only strongly inhibited, and neurogenic contractions reduced by half in coronary arteries. YM-254890 had no effect on agonist-independent contractions induced by highmolar (80 mM) potassium chloride (KCl). Neurogenic detrusor contractions were fully sensitive to tetrodotoxin. In WPMY-1 cells, YM-254890 caused breakdown of actin polymerization and organization, and obvious, but clearly limited decreases of proliferation rate, colony formation and viability, and slightly increased apoptosis. Conclusion: Intracellular post-receptor signaling pathways are shared by Gαq-coupled contractile receptors in multiple smooth muscle-rich organs, but to different extent. While inhibition of Gαq/11 causes actin breakdown, anti-proliferative effects were detectable but clearly limited. Together this may aid in developing future pharmaceutical targets for LUTS and antihypertensive medication.

Antagonism of α1-adrenoceptors by ß3-adrenergic agonists: Structure-function relations of different agonists in prostate smooth muscle contraction.

Effects of ß3-adrenergic agonists on prostate smooth muscle contraction are poorly characterized, although mirabegron is used for treatment of lower urinary tract symptoms. Off-target effects of several ß3-adrenergic agonists include antagonism of α1-adrenoceptors. Proposed, but unconfirmed explanations include phenylethanolamine backbones, found in some ß3-adrenergic agonists and imparting interaction with catecholamine binding pockets of adrenoceptors. Here, we examined effects of ß3-adrenergic agonists on contractions of human prostate tissues, including ZD7114 (without phenylethanolamine moiety), ZD2079 (phenylethanolamine backbone), BRL37344 and CL316243 (chloride-substituted phenylethanolamine deriatives). Prostate tissues were obtained from radical prostatectomy. Contractions by α1-adrenergic agonists and electric field stimulation (EFS) were studied in an organ bath. ZD7114 (10 µM) right-shifted concentration responses curves for α1-adrenergic agonists, resulting in increased EC50 values for phenylephrine, methoxamine and noradrenaline up to one magnitude, without affecting Emax values. ZD7114 (10 µM) inhibited EFS-induced contractions, resulting in reduced Emax values. All effects of ZD7114 were resistant to the ß3-adrenergic antagonist L-748337, including increases in EC50 values for α1-adrenergic agonists, up to more than two magnitudes. Using 10 µM, neither ZD2079, BRL37344 or CL316243 affected α1-adrenergic or EFS-induced contractions. At escalated concentrations, BRL37344 (200 µM) right-shifted concentration response curves for phenylephrine, increased EC50 values for phenylephrine, and inhibited EFS-induced contractions, while CL316243 (300 µM) did not affect phenylephrine- or EFS-induced contractions. In conclusion, phenylethanolamine backbones are not decisive to impart α1-adrenoceptor antagonism to ß3-agonists. Effects of ß3-adrenergic agonists on prostate smooth muscle contraction are limited to off-target effects, including α1-adrenoceptor antagonism by ZD7114 and BRL37344.

Propensity Score-Matched Analysis of Single Fraction Robotic Radiosurgery Versus Open Partial Nephrectomy in Renal Cell Carcinoma: Oncological Outcomes.

Introduction High-dose local stereotactic robotic radiosurgery (RRS) is a non-invasive alternative to surgery in renal masses and selected patients. We have, so far, limited its use to the elderly and patients at high risk from surgery. In this study, we matched patients with renal tumors who were treated with single fraction RRS to patients who underwent open partial nephrectomy (OPN). Methods Between January 2009 and December 2017, we included 571 consecutive patients undergoing OPN and 99 patients who underwent RRS in this retrospective analysis. Patients had to have a follow-up of at least six months and we were able to match 35 with a propensity score. Matching criteria were Eastern Cooperative Oncology Group (ECOG) status, age, clinical tumor, nodes, and metastases (TNM), and tumor diameter. Tumor response, renal function, survival, and adverse events were evaluated every three months until progression or death. Results Median age was 65 years for RRS (range 58-75) and 71 (range 56-76) for OPN (p=0.131). Median diameter of renal tumors was 2.8 cm (range 2.4-3.9) for RRS and 3.5 cm (2.8-4.5) for OPN, p=0.104. Median follow-up was 28.1 months (range 6.0-78.3 months). Local tumor control nine months after RRS and OPN was 98% (95% CI: 89-99%). Renal function remained stable with a median creatinine clearance (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) at baseline of 76.8mlmin/1.73m2 (range 25.3-126.3) and 70.3ml/min/1.73m2 (range 18.6-127.3) at follow-up (p=0.89). Median overall survival was not reached. No difference in overall survival (OS) was seen in RRS compared to OPN (p=0.459). Conclusions Single fraction RRS is an alternative to OPN in patients unfit for surgery. Oncological and functional results are comparable to those of OPN. Further studies are needed to determine long-term results and limits of RRS in this setting and in younger patients.

Strategies to successfully prevent COVID-19 outbreak in vulnerable uro-oncology patient population.

PURPOSE: As COVID-19 pandemic persists with variants, and despite effective vaccination campaigns, breakthrough infections surge. We implemented strategies to protect vulnerable patients of the uro-oncologic outpatient clinic. We adopted proactive non-symptomatic risk reduction measures, which include non-symptomatic testing requirements for both patients and health care professionals (HCP), intensified patient tracing and contact reduction by implementation of digital health options. Here, we present our best practice example to safely guide oncology professionals and patients with metastasized genitourinary cancers through the current and future pandemics. METHODS: Solely for this purpose, we created a registry of collected data (current telephone numbers, e-mail addresses, vaccination status). We collected a nasopharyngeal swab from every patient upon presentation for treatment. We implemented bi-weekly RNA-PCR assay tests for HCP with patient contact, and limited personal contact at our facility through digital patient consultations. RESULTS: We started implementing our COVID prevention model at the beginning of the second wave in September 2020 and included 128 patients with urologic malignancies requiring systemic treatment. After COVID vaccination became available in December 2020, all of our HCP were fully vaccinated within 6 weeks and 97% of our patients (125/128) within 9 months. We performed 1410 nasopharyngeal swabs during in-house visits, thereby detecting two COVID-19 infections among our patients, who both survived and successfully continued treatment. To further reduce personal contact, half of our consultations were fully operated digitally, with 76% (97/128) of our patients participating in our digital health offers. CONCLUSION: The willingness of patients and HCPs to participate in the study allowed us to implement strict standards to prepare for the ongoing and future pandemics in outpatient cancer units. Next to general preventive measures such as frequent hand disinfection, wearing facial masks, and keeping distance, an important measure to protect vulnerable uro-oncology patients is the capability to perform virus genome sequencing to trace transmission chains.