Cost-Effectiveness Analysis of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer poses a therapeutic challenge with poor prognosis. The VISION trial showed prolonged progression-free and overall survival in patients treated with lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) radioligand therapy compared with using the standard of care (SoC) alone. The objective of this study was to determine the cost-effectiveness of 177Lu-PSMA-617 treatment compared with SoC therapy. METHODS: A partitioned survival model was developed using data from the VISION trial, which included overall and progression-free survival and treatment regimens for 177Lu-PSMA-617 and SoC. Treatment costs, utilities for health states, and adverse events were derived from public databases and the literature. Because 177Lu-PSMA-617 was only recently approved, costs for treatment were extrapolated from 177Lu-DOTATATE. Outcome measurements included the incremental cost, effectiveness, and cost-effectiveness ratio. The analysis was performed in a US setting from a healthcare system perspective over the lifetime horizon of 60 months. The willingness-to-pay threshold was set to $50,000, $100,000, and $200,000 per quality-adjusted life years (QALYs). RESULTS: The 177Lu-PSMA-617 group was estimated to gain 0.42 incremental QALYs. Treatment using 177Lu-PSMA-617 led to an increase in costs compared with SoC ($169,110 vs $85,398). The incremental cost, effectiveness, and cost-effectiveness ratio for 177Lu-PSMA-617 therapy was $200,708/QALYs. Sensitivity analysis showed robustness of the model regarding various parameters, which remained cost-effective at all lower and upper parameter bounds. In probabilistic sensitivity analysis using Monte Carlo simulation with 10,000 iterations, therapy using 177Lu-PSMA-617 was determined as the cost-effective strategy in 37.14% of all iterations at a willingness-to-pay threshold of $200,000/QALYs. CONCLUSIONS: Treatment using 177Lu-PSMA-617 was estimated to add a notable clinical benefit over SoC alone. Based on the model results, radioligand therapy represents a treatment strategy for patients with metastatic castration-resistant prostate cancer with cost-effectiveness in certain scenarios.

Current perceptions and working time models of female urologists in Germany: results of a large-scale survey.

PURPOSE: Female urologists are distinctly underrepresented in leading positions. The reasons behind this inequity remain unclear, with some suggesting factors such as family responsibilities, part-time work and insufficient mentorship. This study aimed to explore and characterize the working conditions of female urologists in Germany, with a focus on factors influencing the working time model. METHODS: A questionnaire was developed and distributed to 1343 female members of the German Society of Urology between February and March 2022. The survey consisted of 43 questions covering the categories demographics, occupation situation, satisfaction at work, family situation, career aspects and research activity. RESULTS: Of the 487 female German urologists who participated in the survey, 167 (34.3%) worked part-time. Doctors in training were significantly less likely to work part-time than colleagues who had completed their specialist training (p < 0.001). Only 10% of female doctors in training reported working part-time. Similarly, having children (p < 0.001) and engaging in scientific activities (p = 0.03) were independent factors influencing part-time work, with children increasing the likelihood of working part-time as expected, while scientifically active female urologists were more likely to work full-time. CONCLUSION: This study provides the largest survey on the situation of female urologists in German-speaking countries to date. Part-time work during specialist training is rare, while more than 50% of female urologists with children work part-time. With the projected decline in the number of practicing physicians and the increasing demand for medical attention, it is crucial to find ways to retain and support healthcare professionals, particularly female urologists.

RAS-NOTECHS: validity and reliability of a tool for measuring non-technical skills in robotic-assisted surgery settings.

BACKGROUND: Non-technical skills (NTS) are essential for safe surgical practice as they impact workflow and patient outcomes. Observational tools to measure operating room (OR) teams' NTS have been introduced. However, there are none that account for the specific teamwork challenges introduced by robotic-assisted surgery (RAS). We set out to develop and content-validate a tool to assess multidisciplinary NTS in RAS. METHODOLOGY: Stepwise, multi-method procedure. Observations in different surgical departments and a scoping literature review were first used to compile a set of RAS-specific teamwork behaviours. This list was refined and expert validated using a Delphi consensus approach consisting of qualitative interviews and a quantitative survey. Then, RAS-specific behaviours were merged with a well-established assessment tool on OR teamwork (NOTECHS II). Finally, the new tool-RAS-NOTECHS-was applied in standardized observations of real-world procedures to test its reliability (inter-rater agreement via intra-class correlations). RESULTS: Our scoping review revealed 5242 articles, of which 21 were included based on pre-established inclusion criteria. We elicited 16 RAS-specific behaviours from the literature base. These were synthesized with further 18 behavioural markers (obtained from 12 OR-observations) into a list of 26 behavioural markers. This list was reviewed by seven RAS experts and condensed to 15 expert-validated RAS-specific behavioural markers which were then merged into NOTECHS II. For five observations of urologic RAS procedures (duration: 13 h and 41 min), inter-rater agreement for identification of behavioural markers was strong. Agreement of RAS-NOTECHS scores indicated moderate to strong agreement. CONCLUSIONS: RAS-NOTECHS is the first observational tool for multidisciplinary NTS in RAS. In preliminary application, it has been shown to be reliable. Since RAS is rapidly increasing and challenges for effective and safe teamwork remain at the forefront of quality and safety of surgical care, RAS-NOTECHS may contribute to training and improvement efforts in technology-facilitated surgeries.

Influence of pelvic lymph node dissection and node-positive disease on biochemical recurrence, secondary treatment, and survival after radical prostatectomy in men with prostate cancer.

BACKGROUND: The benefit of pelvic lymph node dissection (PLND) at radical prostatectomy (RP) remains unclear given the low prevalence of known nodal disease (pN1) and concerns about its therapeutic utility. OBJECTIVE: To characterize the impact of PLND and secondary treatment on oncologic outcomes. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of men who underwent primary RP with PLND for prostate cancer (PCa) at our institution since 2003. Men stratified by nodal status. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Outcomes include biochemical recurrence-free survival (bRFS), overall survival, and PCa-specific mortality (PCSM). Multivariable Cox regression models used for each outcome. RESULTS AND LIMITATIONS: Of 1,543 men who underwent primary RP, 174 (11%) had pN1 disease. Median follow-up was 34 months (interquartile range, 15-62). Seven-year outcomes were similar whether less than or ≥14 LNs dissected. Among node-positive patients, 29% had undetectable (UDT) prostate-specific antigen (PSA), 11% had UDT PSA + adjuvant therapy, and 60% had detectable PSA, and 7-year bRFS differed (75% for UDT PSA, 90% for UDT + adjuvant therapy, 38% for detectable PSA, p < .01). Survival outcomes did not differ. In multivariable analysis, detectable PSA (vs. UDT, HR 5.2, 95% CI 2.0-13.3) associated with worse bRFS. After salvage treatment, 7-year outcomes did not differ between groups. Study limited by retrospective review.

A NAV2729-sensitive mechanism promotes adrenergic smooth muscle contraction and growth of stromal cells in the human prostate.

Voiding symptoms in benign prostatic hyperplasia (BPH) are driven by prostate smooth muscle contraction and prostate growth. Smooth muscle contraction in the prostate and other organs critically depends on activation of the small monomeric GTPase RhoA and probably Rac1. A role of another GTPase, ADP-ribosylation factor 6 (ARF6), for smooth muscle contraction has been recently suggested by indirect evidence but remains to be proven for any organ. Here, we report effects of NAV2729, an inhibitor with assumed specificity for ARF6, in human prostate tissues and cultured prostate stromal cells (WPMY-1). NAV2729 (5 µm) inhibited neurogenic and α1-adrenergic contractions of human prostate tissues. Contractions induced by endothelin-1, by the thromboxane A2 agonist U46619, or by high molar KCl were not inhibited. Correlation analyses suggested up-regulation of prostatic ARF6 expression with increasing degree of BPH, as ARF6 expression increased with the content of prostate-specific antigen (PSA) of prostate tissues. NAV2729 inhibited ARF6 activity but not other GTPases (ARF1, RhoA, Rac1) in prostate tissues and in WPMY-1 cells. Proliferation of WPMY-1 cells was inhibited concentration-dependently by NAV2726, as reflected by decreased viability, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, and expression of Ki-67. Silencing of ARF6 expression mimicked effects of NAV2729 on viability and in the EdU assay. Effects of NAV2729 on viability and proliferation were attenuated in cells with silenced ARF6 expression. Our findings suggest that a NAV2729-sensitive mechanism promotes adrenergic contraction and stromal cell growth in the human prostate, which is probably ARF6-mediated. Similar actions in other organs and urodynamic effects of NAV2729 appear possible.

Inhibition of neurogenic and thromboxane A2 -induced human prostate smooth muscle contraction by the integrin α2ß1 inhibitor BTT-3033 and the integrin-linked kinase inhibitor Cpd22.

INTRODUCTION: Prostate smooth muscle contraction is critical for etiology and treatment of lower urinary tract symptoms in benign prostatic hyperplasia (BPH). Integrins connect the cytoskeleton to membranes and cells to extracellular matrix, what is essential for force generation in smooth muscle contraction. Integrins are composed of different subunits and may cooperate with integrin-linked kinase (ILK). Here, we examined effects of inhibitors for different integrin heterodimers and ILK on contraction of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Integrins and ILK were detected by Western blot, real-time polymerase chain reaction (RT-PCR), and double fluorescence staining. Smooth muscle contractions of prostate strips were studied in an organ bath. Contractions were compared after application of solvent (controls), the ILK inhibitor Cpd22 (N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide), the integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide), or the integrin α4ß1/α9ß1 inhibitor BOP (N-(benzenesulfonyl)- l-prolyl- l-O-(1-pyrrolidinylcarbonyl)tyrosine sodium salt). RESULTS: Western blot analyses of prostate tissues using antibodies raised against integrins α2b, α4, α9, ß1, and ILK revealed bands matching the expected sizes of corresponding antigens. Expression of integrins and ILK was confirmed by RT-PCR. Individual variations of expression levels occurred independently from divergent degree of BPH, reflected by different contents of prostate-specific antigen. Double fluorescence staining of prostate sections using antibodies raised against integrins α2 and ß1, or against ILK resulted in immunoreactivity colocalizing with calponin, suggesting localization in prostate smooth muscle cells. Electric field stimulation (EFS) induced frequency-dependent contractions, which were inhibited by Cpd22 (3 µM) and BTT-3033 (1 µM) (inhibition around 37% by Cpd22 and 46% by BTT-3033 at 32 Hz). The thromboxane A2 analog U46619-induced concentration-dependent contractions, which were inhibited by Cpd22 and BTT-3033 (around 67% by Cpd22 and 39% by BTT-3033 at 30 µM U46619). Endothelin-1 induced concentration-dependent contractions, which were not affected by Cpd22 or BTT-3033. Noradrenaline and the α1 -adrenergic agonists methoxamine and phenylephrine-induced concentration-dependent contractions, which were not or very slightly inhibited by Cpd22 and BTT-3033. BOP did not change EFS- or agonist-induced contraction. CONCLUSIONS: Integrin α2ß1 and ILK inhibitors inhibit neurogenic and thromboxane A2 -induced prostate smooth muscle contraction in human BPH. A role for these targets for prostate smooth muscle contraction may appear possible.

New strategies for inhibition of non-adrenergic prostate smooth muscle contraction by pharmacologic intervention.

BACKGROUND: Inhibition of prostate smooth muscle contraction by α1 -adrenoceptor antagonists (α1 -blockers) is a first-line medical treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Increased smooth muscle tone in the hyperplastic prostate may drive urethral obstruction, resulting in bladder outlet obstruction and voiding symptoms. However, efficacy of α1 -blockers is limited, as non-adrenergic mediators including endothelin-1 and thromboxane A2 (TXA2 ) increase prostate smooth muscle tension in parallel to α1 -adrenoceptors. This may maintain urethral obstruction despite therapy with α1 -blockers. Consequently, future treatment options with higher efficacy need to target α1 -adrenergic and non-adrenergic contractions simultaneouly. Recently, several compounds were reported to inhibit adrenergic or neurogenic prostate contractions, however, their effects on non-adrenergic contraction are unknown. Here, we examined effects of inhibitors for Rac-GTPase, Src family kinases (SFKs), and p21-activated kinases (PAKs) on non-adrenergic prostate contractions. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath. Viability of cultured stromal cells was assessed by CCK-8 assay. RESULTS: Inhibition of α1 -adrenergic contractions by Rac inhibitors EHT1864 (100 µM) and NSC23766 (100 µM), and SFK inhibitors AZM475721 (10 µM) and PP2 (10 µM) was confirmed by inhibition of methoxamine-induced contractions. No effects of the PAK inhibitors FRAX486 (30 µM) and IPA3 (300 µM) on α1 -adrenergic contraction were confirmed by absent effects on methoxamine-inuced contractions. EHT1864 caused inhibition of endothelin-1- and U46619-induced contractions. EHT1864 reduced the viability of stromal cells concentration- and time-dependently. EHT1864 attenuated KCl-induced contractions of prostate strips only slightly, so that toxic effects may not account alone for inhibition of agonist-induced contractions. NSC23766 inhibited U46619-induced contractions, but not endothelin-1-induced contractions. AZM475271 had no effects on endothelin-1- or U46619-induced contractions, while PP2 inhibited U46619- but not endothelin-1-induced contractions. FRAX486 caused inhibition of U46619-induced contractions. IPA3 inhibited U46619-, but not endothelin-1-induced contractions. CONCLUSIONS: Of all six inhibitors, EHT1864 seems to be most promising from a translational point of view, as it inhibited TXA2 - and endothelin-1-induced besides α1 -adrenergic prostate contractions. This reflects divergent pharmacologic profiles of EHT1864 and NSC23766, although both are Rac-GTPase inhibitors. In vivo, urodynamic effects of EHT1864 and possibly of FRAX486 may exceed those of α1 -blockers.

The increase of stage, grading, and metastases in patients undergoing radical prostatectomy during the last decade.

PURPOSE: To investigate changes in clinical data and pathological features of prostatectomy specimens of prostate cancer (PCa) patients in a large tertiary care center over the last 12 years as potential consequence of reduced acceptance of prostate-specific antigen (PSA)-based screening and implementation of active surveillance as a therapeutic option in PCa. METHODS: We retrospectively identified all patients with PCa who underwent radical prostatectomy at our institution between 2004 and 2016 from our clinical database. We reviewed clinical and pathological data including patient age, PSA level, number of positive cores and Gleason score in prostate biopsy, and pathologic N- and T-stage, and Gleason score in radical prostatectomy specimen. RESULTS: Data of 5497 consecutive patients were analyzed. Median PSA increased from 7 (IQR 4.8-10.5) to 9 ng/ml (IQR 5.8-16.1; p < 0.001), and median number of positive biopsy cores increased from 3 (IQR 2-5) to 5 (IQR 3-7; p < 0.001). The proportion of patients with Gleason score ≥ 7 in biopsy and prostatectomy specimens increased from 40 to 78% and 49 to 89% (p < 0.001), respectively. The rate of locally advanced (≥ pT3a) and lymph node-positive tumors increased from 28 to 43% and 5 to 16% (p < 0.001), respectively. CONCLUSIONS: We observed a significant change in clinical and pathological findings in our prostatectomy series with a significantly higher proportion of aggressive and locally advanced PCa in recent years. These findings may be related to a reduced acceptance of PSA-based screening and the use of active surveillance as management strategy and have significant impact on daily patient care.

Minimally invasive prostatic urethral lift (PUL) efficacious in TURP candidates: a multicenter German evaluation after 2 years.

INTRODUCTION: Successful outcomes have been reported for the treatment of lower urinary tract symptoms (LUTS) with the prostatic urethral lift (PUL) in a number of clinical investigations. Our aim was to investigate PUL outcomes in patients treated in a day-to-day clinical setting without the rigid exclusion criteria of clinical studies. MATERIALS AND METHODS: We investigated the outcome of the PUL procedure at five German departments during the initial period when PUL was approved for the clinic (10/2012-06/2014). All candidates for transurethral resection of the prostate (TURP) received PUL information and were given the choice of procedures. The only exclusion criterion was an obstructive median lobe. No patients were excluded because of high post-void residual volume (PVR), prostate size, retention history or LUTS oral therapy. Maximum urinary flow (Qmax), PVR, International Prostate Symptom Score (IPSS) and Quality of Life (QOL) were assessed at baseline, 1, 6, 12, and 24 months after surgery. RESULTS: Of 212 TURP candidates, 86 choose PUL. A mean of 3.8 (2-7) UroLift implants were implanted in patients of 38-85 years with a prostate size of 17-111 ml over 57 (42-90) min under general or local anesthesia. Thirty-eight (38.4%) patients had severe BPH obstruction and would have been denied PUL utilizing previously reported study criteria. Within 1 month 74 (86%) reported substantial symptom relief with significant improvements in Qmax, PVR, IPSS, and QOL (p < 0.001) that was maintained within the follow-up. Sexual function including ejaculation was unchanged or improved. No Clavien-Dindo Grad ≥ 2 was reported postoperatively. Eleven (12.8%) patients were retreated over 2 years. Twelve (86%) of 14 patients presenting with chronic urinary retention were catheter free at last follow-up. CONCLUSION: PUL is a promising surgical technique that may alleviate LUTS, even in patients with severe obstruction.

Active surveillance for intermediate-risk prostate cancer: yes, but for whom?

PURPOSE OF REVIEW: Active surveillance is becoming more widely accepted as an initial management option for carefully selected men with favorable intermediate-risk prostate cancer (PCa). As prospective active surveillance cohorts mature sufficiently to begin evaluating longer-term outcomes, consensus on more precise evidence-based guidelines is needed to identify the patient cohorts who may be safely managed with active surveillance and what the ideal surveillance protocol entails. RECENT FINDINGS: Long-term outcomes updates have suggested a trend toward worse 15-year survival outcomes for intermediate-risk patients on active surveillance compared with definitive treatment, but 'intermediate-risk' is a broad category and there is a subset of favorable intermediate-risk patients for whom survival outcomes remain equivalent. Promising updates to current risk stratification include consideration of genomic classifiers, advanced imaging and more nuanced interpretation of biopsy results. SUMMARY: Despite widespread acknowledgement of the pitfalls of overtreatment in clinically localized PCa, utilization of active surveillance in the intermediate-risk population remains marginal, in part due to the absence of easily interpretable consensus recommendations. As more long-term outcomes data become available for this subgroup, the field is now poised to refine the definition of favorable intermediate-risk patients for whom active surveillance is a safe, evidence-based first-line management option.

Inhibition of smooth muscle contraction and ARF6 activity by the inhibitor for cytohesin GEFs, secinH3, in the human prostate.

Prostate smooth muscle contraction is critical for etiology and treatment of male lower urinary tract symptoms (LUTS) and is promoted by small monomeric GTPases (RhoA and Rac). GTPases may be activated by guanosine nucleotide exchange factors (GEFs). GEFs of the cytohesin family may indirectly activate Rac, or ADP ribosylation factor (ARF) GTPases directly. Here we investigated the expression of cytohesin family GEFs and effects of the cytohesin inhibitor Sec7 inhibitor H3 (secinH3) on smooth muscle contraction and GTPase activities in human prostate tissues. Of all four cytohesin isoforms, cytohesin-1 and -2 showed the highest expression in real-time PCR. Western blot and fluorescence staining suggested that cytohesin-2 may be the predominant isoform in prostate smooth muscle cells. Contractions induced by norepinephrine, the α1-adrenoceptor agonist phenylephrine, the thromboxane A2 analog U-46619 , and endothelin-1 and -3, as well as neurogenic contractions induced by electric field stimulation (EFS), were reduced by secinH3 (30 µM). Inhibition of EFS-induced contractions appeared to have efficacy similar to that of inhibition by the α1-adrenoceptor antagonist tamsulosin (300 nM). Combined application of secinH3 plus tamsulosin caused larger inhibition of EFS-induced contractions than tamsulosin alone. Pull-down assays demonstrated inhibition of the small monomeric GTPase ARF6 by secinH3, but no inhibition of RhoA or Rac1. In conclusion, we suggest that a cytohesin-ARF6 pathway takes part in smooth muscle contraction. This may open attractive new possibilities in medical treatment of male LUTS.

Non-Adrenergic, Tamsulosin-Insensitive Smooth Muscle Contraction is Sufficient to Replace α1 -Adrenergic Tension in the Human Prostate.

BACKGROUND: Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia may be caused by prostate smooth muscle contraction. Although α1 -blockers may improve symptoms by prostate smooth muscle relaxation, their efficacy is limited. This may be explained by non-adrenergic mediators causing contraction in parallel to α1 -adrenoceptors. However, little is known about the relevance and cooperative actions of non-adrenergic mediators in the prostate. METHODS: Prostate tissues were obtained from radical prostatectomy (n = 127 patients). Contractile responses were studied in an organ bath. RESULTS: Endothelin-1 and noradrenaline induced contractions of similar magnitude (116 ± 23 and 117 ± 18% of KCl-induced contractions). Endothelin-2- and -3-induced maximum contractions of 63 ± 8.6 and 71 ± 19% of KCl, while contractions by the thromboxane analog U46619 amounted up to 63 ± 9.4%. Dopamine-induced contractions averaged to 22 ± 4.5% of KCl, while maximum contractions by serotonin, histamine, and carbachol stayed below 10% of KCl-induced. While noradrenaline-induced contractions were inhibited by tamsulosin (300 nM), endothelin-1-, -2-, or -3-induced contraction were not. No additive effects were observed if endothelins and noradrenaline were applied consecutively to the same samples. If endothelin-1 was applied after U46619, resulting tension (172 ± 43% of KCl) significantly exceeded noradrenaline-induced contraction. Tensions following combined application of endothelin-2 or -3 with U46619 stayed below noradrenaline-induced contractions. Tension following combined application of all three endothelins with U46619 resembled maximum noradrenaline-induced tone. CONCLUSIONS: Contractions following concomitant confrontation of human prostate tissue with noradrenaline and endothelin-1 are not additive. Endothelin-1 is sufficient to induce a smooth muscle tone resembling that of noradrenaline. This may replace lacking α1 -adrenergic tone under therapy with α1 -blockers, explaining the limited efficacy of α1 -blockers in LUTS treatment. Contractions by thromboxane and endothelin-1 may be additive, and may exceed α1 -adrenergic tone. Prostate 77:697-707, 2017. © 2017 Wiley Periodicals, Inc.

Postoperative upgrading of prostate cancer in men ≥75 years: a propensity score-matched analysis.

PURPOSE: Gleason score upgrading should be considered when indicating surgery in prostate cancer (PCa) patients. In elderly patients, definitive treatment of low-risk PCa must be weighed with the risks of overtreatment. Our aim was to evaluate rates of Gleason score upgrading in patients ≥75 years undergoing radical prostatectomy (RP) for localized PCa and to identify predictors associated with upgrading. METHODS: 3296 patients undergoing RP were retrospectively evaluated and categorized into age groups: <70 years (n = 2971) vs. ≥75 years (n = 325). We analyzed prostate-specific antigen (PSA), biopsy counts, Gleason score, pathologic T- and N-stage, and surgical margin. Propensity score matching was performed to compare rates of up- and downgrading on surgical specimen using the new five-tier pathologic grading system. Logistic regression was used to identify independent predictors of upgrading. RESULTS: Preoperatively, patients ≥75 years had higher PSA (8.8 vs. 7.3 ng/mL) and lower proportion of grade group 1 (Gleason score 6) at biopsy (29.2 vs. 47.9%; both p < 0.001) compared to patients <70 years. At RP, patients ≥75 years were more likely to have extraprostatic disease (50 vs. 30%) and lower rates of grade group 1 (14.1 vs. 34.8%; both p < 0.001). Postoperative downgrading was similar (15.1 vs. 19.5%). However, patients ≥75 years had higher rates of postoperative upgrading (46.6 vs. 27.9%; p < 0.001). Age ≥75 years, higher PSA levels at RP, and an increased number of positive biopsy cores were associated with upgrading. CONCLUSIONS: Patients ≥75 years not only demonstrated higher rates of advanced disease but more frequent upgrading on RP specimen. Age ≥75 years, higher PSA levels at RP, and an increased number of positive biopsy cores were predictive for upgrading. The increased risk of upgrading should be taken into consideration when discussing optimal treatment for this specific cohort.

"Finding the needle in a haystack": oncologic evaluation of patients treated for LUTS with holmium laser enucleation of the prostate (HoLEP) versus transurethral resection of the prostate (TURP).

PURPOSE: To evaluate oncologic parameters of men with bothersome LUTS undergoing surgical treatment with HoLEP or TURP. METHODS: Five hundred and eighteen patients undergoing HoLEP (n = 289) or TURP (n = 229) were retrospectively analyzed for total PSA, prostate volume, PSA density, history of prostate biopsy, resected prostate weight, and histopathological features. Univariate and multivariate logistic regression models were used to identify independent predictors of incidental PCa (iPCa). RESULTS: Men undergoing HoLEP had a significantly higher total PSA (median 5.5 vs. 2.3 ng/mL) and prostate volume (median 80 vs. 41 cc), and displayed a greater reduction of prostate volume after surgery compared to TURP patients (median 71 vs. 50%; all p < 0.001). With a prevalence of incidental PCa (iPCa) of 15 and 17% for HoLEP and TURP, respectively, the choice of procedure had no influence on the detection of iPCa (p = 0.593). However, a higher rate of false-negative preoperative prostate biopsies was noted among iPCa patients in the HoLEP arm (40 vs. 8%, p = 0.007). In multivariate logistic regression, we identified patient age (OR 1.04; 95% CI 1.01-1.07, p = 0.013) and PSA density (OR 2.13; 95% CI 1.09-4.18, p = 0.028) as independent predictors for the detection of iPCa. CONCLUSIONS: Despite differences in oncologic parameters, the choice of technique had no influence on the detection of iPCa. Increased patient age and higher PSA density were associated with iPCa. A higher rate of false-negative preoperative prostate biopsies was noted in HoLEP patients. Therefore, diagnostic assessment of LUTS patients requires a more adapted approach to exclude malignancy, especially in those with larger prostates.

Perioperative patient education improves long-term satisfaction rates of low-risk prostate cancer patients after radical prostatectomy.

PURPOSE: To evaluate patient-reported functional outcomes after radical prostatectomy (RP) and to analyse the effect of perioperative patient education on satisfaction rates among low-risk prostate cancer patients. METHODS: Inclusion criteria encompassed low-risk prostate cancer patients as defined by the D'Amico criteria, undergoing nerve-sparing RP without pelvic lymph node dissection. Patient-centred functional outcomes, subjective evaluation of perioperative counselling, and patient satisfaction rates were documented. Stress urinary incontinence (SUI) was assessed by daily pad usage. Erectile dysfunction (ED) was assessed using IIEF5 score. Patients' histories were attained from the electronic medical records. The effect of pre-defined predictive features for satisfaction rates was analysed in low-risk patients. Statistical analyses included Fisher's exact test, Mann-Whitney-U test, and binary logistic regression models (p < 0.05). RESULTS: 266 patients met the inclusion criteria. Median follow-up was 94 months (68-118). The global satisfaction rate was 75.1%. Regarding SUI, 69.5% of patients required no pads. 67.1% felt very well informed, while 11.7% felt poorly educated about postoperative SUI. Regarding ED, an IIEF score of ≥18 was reached by 33.7%. 59.6% felt very well educated, while 13.0% felt poorly informed. Poor patient counselling regarding SUI and ED led to significantly decreased long-term satisfaction rates [40.7, 33.3% (p < 0.001)]. In multivariate analysis, poor ED patient counselling [OR 0.190, 95% CI 0.055-0.652 (p = 0.008)], and postoperative IIEF5 score [OR 3.061, 95% CI 1.013-3.111 (p = 0.013)] could be confirmed as independent predictors for patient satisfaction. CONCLUSIONS: Patient-centred functional outcome analysis has illustrated the importance of perioperative patient education on long-term patient satisfaction rates after RP in low-risk prostate cancer patients.

Impact of the United States Preventive Services Task Force 'D' recommendation on prostate cancer screening and staging.

PURPOSE OF REVIEW: In 2012, the United States Preventive Services Task Force (USPSTF) issued a grade 'D' recommendation against the use of routine prostate-specific antigen (PSA)-based screening for any men. This recommendation reflects critical misinterpretations of the available evidence base regarding benefits and harms of PSA screening and has influenced the nationwide landscape of prostate cancer screening, diagnosis, and treatment. RECENT FINDINGS: Following the USPSTF recommendation, a substantial decline in PSA screening was noted for all age groups. Similarly, overall rates of prostate biopsy and prostate cancer incidence have significantly decreased with a shift toward higher grade and stage disease upon diagnosis. Concurrently, the incidence of metastatic prostate cancer has significantly risen in the United States. These trends are concerning particularly for the younger men with occult high-grade disease who are expected to benefit the most from early detection and definitive prostate cancer treatment. SUMMARY: These emerging trends in PSA screening and prostate cancer incidence following the USPSTF recommendation may have significant public health implications. Due to the long natural history of the disease, a long-term follow-up is needed to provide a better understanding on the implications of such recommendations on disease progression and mortality rates in prostate cancer patients. The future of US screening policy should reflect a targeted 'smarter' screening strategy rather than dichotomizing the decision between 'screen all' or 'screen none'.

Inhibition of Adrenergic and Non-Adrenergic Smooth Muscle Contraction in the Human Prostate by the Phosphodiesterase 10-Selective Inhibitor TC-E 5005.

BACKGROUND: The phosphodiesterase (PDE) 5 inhibitor tadalafil is available for treatment of male lower urinary tract symptoms (LUTS), while the role of other PDE isoforms for prostate smooth muscle tone is still unknown. Here, we examined effects of the PDE10-selective inhibitor TC-E 5005 on smooth muscle contraction in human prostate tissue. METHODS: Prostate samples were obtained from patients undergoing radical prostatectomy. Expression of PDE10 was addressed by RT-PCR, Western blot, and fluorescence staining with different markers. Effects of TC-E 5005 and tadalafil on contraction, and relaxation of prostate strips were studied via organ bath. RESULTS: PDE10A was detectable by RT-PCR, Western blot, and fluorescence staining in prostate tissues. Colocalization with markers suggested expression of PDE10A in smooth muscle cells and catecholaminergic nerves. Norepinephrine, the α1 -adrenergic agonist phenylephrine, the thromboxane A2 analogue U46619, and endothelins 1-3 induced concentration-dependent contractions of prostate strips, while electric field stimulation (EFS) induced frequence-dependent contractions. Application of TC-E 5005 (500 nM) caused significant inhibition of norepinephrine-, phenylephrine-, and endothelin-3-induced contractions. Inhibition of EFS-induced contractions by TC-E 5005 ranged around 50%, resembling inhibition of EFS-induced contractions by tadalafil (10 µM). The prostacyclin analog treprostinil and the nitric oxide donor DEA NONOate induced relaxations of precontracted prostate strips, which were significantly amplified by TCE 5005. CONCLUSIONS: The PDE10-selective inhibitor TC-E 5005 inhibits adrenergic and neurogenic smooth muscle contractions in the human prostate. TC-E 5005 inhibits neurogenic contractions with similar efficacy than tadalafil, so that urodynamic effects in vivo appear possible. Prostate 76:1364-1374, 2016. © 2016 Wiley Periodicals, Inc.

Platelet Derived Growth Factor Has a Role in Pressure Induced Bladder Smooth Muscle Cell Hyperplasia and Acts in a Paracrine Way.

PURPOSE: Bladder outlet obstruction is a finding in many urological disorders, leading to bladder wall hyperplasia. We investigated platelet derived growth factor and its receptor in human bladder smooth muscle cells and urothelial cells exposed to hydrostatic pressure or PDGF in vitro. MATERIALS AND METHODS: Bladder smooth muscle cells and urothelial cells were exposed to elevated hydrostatic pressure for 1 hour. The expression of PDGF and PDGFR was evaluated using reverse transcriptase-polymerase chain reaction and Western blot analysis. Pressure or PDGF induced proliferation of bladder smooth muscle cells with or without pretreatment with lovastatin or imatinib was measured by enzyme-linked immunosorbent assay. PDGFRα was knocked down with siRNA. RESULTS: After hydrostatic pressure bladder smooth muscle cells showed increased PDGFRα and ß expression. PDGF was not expressed in bladder smooth muscle cells. Urothelial cells showed no expression of PDGFR but PDGF expression was noted. Western blot analysis of bladder smooth muscle cells revealed a pressure induced increase in PDGFR in the membrane fraction. Phosphorylation of PDGFR occurred with pressure induction. Bladder smooth muscle cell proliferation was increased in pressure and PDGF mediated fashion. Pretreatment with lovastatin or imatinib prevented proliferation. There was no cell proliferation after PDGFRα knockdown. CONCLUSIONS: Increased expression and phosphorylation of PDGFR in bladder smooth muscle cells after hydrostatic pressure suggests a pivotal role of the PDGF pathway in pressure induced hyperplasia of bladder smooth muscle cells. PDGF expressed in urothelial cells may act in a paracrine way. Cholesterol depletion, inhibition of receptor tyrosine kinase activity and knockdown of PDGFRα in bladder smooth muscle cells prevent pressure and PDGF mediated cell proliferation. Targeting PDGFR seems a promising way to influence pressure induced bladder wall hyperplasia.

Long-Term Follow-Up in Patients Undergoing Renal Mass Biopsy: Seeding is not Anecdotal.

INTRODUCTION: Renal biopsy is recommended if the outcome might alter therapeutic decisions for patients who present with renal masses of unclear etiology. However, little is known about long-term risks related to this procedure. PATIENTS AND METHODS: We performed a retrospective analysis of an institutional database maintained by a tertiary referral center that included patients who underwent renal biopsies between 2003 and 2005 with a follow-up of at least 15 years. Renal biopsies were taken percutaneously with a coaxial technique according to guideline recommendations and included off-line ultrasound guidance. RESULTS: We identified 106 patients who underwent biopsies for a renal mass of unclear etiology. The median age was 58.7 years (43.7-66.2). A median of 4.2 (3-6) biopsies were collected from each patient. Tumor seeding leading to local growth was identified in 6 patients (5,7%) after a median follow-up of 8.2 years. Four of these lesions that were resected exhibited the same histology as the original biopsy result; these patients experienced no further recurrence. In 45 patients (42%), the biopsy results led to a therapy other than surgery (n = 28 lymphoma, n = 6 metastasis from other malignancies, n = 11 oncocytoma). The remaining 61 patients (58%) were diagnosed with renal cell carcinoma treated either surgically or with ablation. None of the patients developed metastatic spread related to tumor seeding. CONCLUSION: Tumor seeding after renal mass biopsy is a rare, but relevant risk associated with this procedure. As indications for renal mass biopsy increase, longer-term follow-up and improved biopsy techniques should be considered to address this complication.