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.

[68Ga]Ga-FAPI-46 PET/CT for penile cancer - a feasibility study.

PURPOSE: Penile cancer is a rare entity and has a good prognosis in localized stage. Delayed surgical treatment of lymphatic disease is associated with poor overall survival but conventional imaging cannot detect occult lymph node metastasis sufficiently. Imaging cancer related fibroblasts has shown promising results as non-invasive staging tool in various tumor entities but has not yet been evaluated in penile cancer. METHODS: In this single-center pilot study, patients planned for surgical treatment for penile cancer underwent preoperatively [68Ga]Ga-FAPI-46 PET/CT. Post-operative histopathology was compared to [68Ga]Ga-FAPI-46 PET/CT results. RESULTS: From January 2022 to June 2022, a total number 11 patients with histopathologically proven penile cancer underwent surgery and received [68Ga]Ga-FAPI-46 PET/CT prior therapy. 8 primary tumor sites and 4 lymph node regions were analyzed. FAPI uptake was increased on primary tumor site (SUVmax 16.2 (9.1 - 25.8)). Histopathological proven lymph node regions showed highly increased FAPI uptakes (SUVmax 17.9 (16.4 - 23.5) on [68Ga]Ga-FAPI-46 PET/CT. CONCLUSION: In this first pilot cohort, there were no false-positive FAPI uptake which might allow the detection of occult lymph node metastasis by [68Ga]Ga-FAPI-46 PET/CT and might consequently lead to omitting lymph node regions during surgery that had no increased FAPI uptake pre-operatively.

[68 Ga]Ga-FAPI-46 PET/CT for locoregional lymph node staging in urothelial carcinoma of the bladder prior to cystectomy: initial experiences from a pilot analysis.

INTRODUCTION: [68 Ga]Ga-FAPI-46 PET/CT is a novel hybrid imaging method that previously showed additional diagnostic value in the assessment of distant urothelial carcinoma lesions. We hypothesized that patients with bladder cancer benefit from [68 Ga]Ga-FAPI-46 PET/CT prior to radical cystectomy for locoregional lymph node staging. MATERIALS AND METHODS: Eighteen patients underwent [68 Ga]Ga-FAPI-46 PET/CT for evaluation of lymph node (LN) status in predefined LN regions. Two hundred twenty-nine intraoperatively removed LN served as histopathological reference standard. RESULTS: Urothelial carcinoma (UC) spread was found in ten LN in seven different regions (14.3%). Hereby, [68 Ga]Ga-FAPI-46 PET/CT was positive in four out of seven regions (57.1%) and showed significantly increased FAPI uptake compared to non-pathological regions. In the remaining three out of seven (42.9%) regions, [68 Ga]Ga-FAPI-46 PET/CT was rated negative since no pathological increased FAPI uptake was detected or the proximity of the urinary tract prevented a differentiation from physiological uptake. CT was inconspicuous in these three regions. In total, two FAP-positive LN regions were found without histopathological counterpart. Overall, sensitivity, specificity, positive predictive value, and negative predictive value were 57.1%, 95.2%, 66.7%, and 93.0% for PET imaging. CONCLUSION: In summary, this innovative [68 Ga]Ga-FAPI-46 PET/CT method showed high specificity and negative predictive value in patients with bladder UC with a future potential to optimize therapy planning.

Oncological impact of perioperative blood transfusion in bladder cancer patients undergoing radical cystectomy: Do we need to consider storage time of blood units, donor age, or gender matching?

BACKGROUND: The oncological impact of perioperative blood transfusions (PBTs) of patients undergoing radical cystectomy (RC) because of bladder cancer (BCa) has been a controversial topic discussed in recent years. The main cause for the contradictory findings of existing studies might be the missing consideration of the storage time of red blood cell units (BUs), donor age, and gender matching. STUDY DESIGN AND METHODS: We retrospectively analyzed BCa patients who underwent RC in our department between 2004 and 2021. We excluded patients receiving BUs before RC, >10 BUs, or RC in a palliative setting. We assessed the effect of blood donor characteristics and storage time on overall survival (OS) and cancer-specific survival (CSS) through univariate and multivariable Cox regression analysis. We also performed a propensity score matching with patients who received BUs and patients who did not on a 1:1 ratio. RESULTS: We screened 1692 patients and included 676 patients for the propensity score matching. In the multivariable analysis, PBT was independently associated with worse OS and CSS (p < .001). Postoperative transfusions were associated with better OS (p = .004) and CSS (p = .008) compared to intraoperative or mixed transfusions. However, there was no influence of blood donor age, storage time, or gender matching on prognosis. DISCUSSION: In our study of BCa patients undergoing RC, we demonstrate that PBT, especially if administered intraoperatively, is an independent risk factor for a worse prognosis. However, storage time, donor age, or gender matching did not negatively affect oncological outcomes. Therefore, the specific selection of blood products does not promise any benefits.

The effect of hospital caseload on perioperative mortality, morbidity and costs in bladder cancer patients undergoing radical cystectomy: results of the German nationwide inpatient data.

OBJECTIVES: To determine a data-based optimal annual radical cystectomy (RC) hospital volume threshold and evaluate its clinical significance regarding perioperative mortality, complications, length of hospital stay, and hospital revenues. MATERIAL AND METHODS: We used the German Nationwide inpatient Data, provided by the Research Data Center of the Federal Bureau of Statistics (2005-2020). 95,841 patients undergoing RC were included. Based on ROC analyses, the optimal RC threshold to reduce mortality, ileus, sepsis, transfusion, hospital stay, and costs is 54, 50, 44, 44, 71 and 76 cases/year, respectively. Therefore, we defined an optimal annual hospital threshold of 50 RCs/year, and we also used the threshold of 20 RCs/year proposed by the EAU guidelines to perform multiple patient-level analyses. RESULTS: 28,291 (29.5%) patients were operated in low- (< 20 RC/year), 49,616 (51.8%) in intermediate- (20-49 RC/year), and 17,934 (18.7%) in high-volume (≥ 50 RC/year) centers. After adjusting for major risk factors, high-volume centers were associated with lower inpatient mortality (OR 0.72, 95% CI 0.64-0.8, p < 0.001), shorter length of hospital stay (2.7 days, 95% CI 2.4-2.9, p < 0.001) and lower costs (457 Euros, 95% CI 207-707, p < 0.001) compared to low-volume centers. Patients operated in low-volume centers developed more perioperative complications such as transfusion, sepsis, and ileus. CONCLUSIONS: Centralization of RC not only improves inpatient morbidity and mortality but also reduces hospital stay and costs. We propose a threshold of 50 RCs/year for optimal outcomes.

The impact of health care on outcomes of suspected testicular torsion: results from the GRAND study.

BACKGROUND: Suspicion of testicular torsion represents a urological emergency, necessitating immediate surgery. Comprehensive data on the current trends and perioperative outcomes regarding surgical exploration are sparse. Therefore, we utilized nationwide data on the prevalence and results of this surgery, aiming to provide evidence on this matter. METHODS: We assessed the GeRmAn Nationwide inpatient Data (GRAND) from 2005 to 2021, provided by the Research Data Center of the Federal Bureau of Statistics. We performed multiple regression analyses to evaluate the perioperative outcomes (length of hospital stay, transfusion, and surgical wound infection) after surgical exploration due to suspected testicular torsion based on both the outcome of surgery (orchiectomy, detorsion with preservation of the testicle, and no testicular torsion) and on the department of operation (urological versus non-urological). RESULTS: A total of 81,899 males underwent surgical exploration due to suspected testicular torsion in Germany from 2005 to 2021. Of them, 11,725 (14%) underwent orchiectomy, 30,765 (38%) detorsion with preservation of the testicle and subsequent orchidopexy, and 39,409 (48%) presented no testicular torsion. Orchiectomy was significantly associated with longer length of hospital stay (day difference of 1.4 days, 95%CI: 1.3-1.4, p < 0.001), higher odds of transfusion (1.8, 95% CI: 1.2-2.6, p = 0.002) and surgical wound infections (1.8, 95%CI: 1.4-2.3, p < 0.001) compared to no testicular torsion. The proportion of patients undergoing orchiectomy was significantly lower in urological departments (14%) versus non-urological departments (16%) and the proportion of patients undergoing preservation of testicle after detorsion was significantly higher in urological departments (38%) versus non-urological departments (37%), p < 0.001. Patients undergoing treatment in a urological department were discharged earlier and presented lower odds of transfusion and surgical wound infection (p < 0.001) compared to patients undergoing treatment in a non-urological department. CONCLUSIONS: Nearly half of patients who underwent surgery for suspected testicular torsion did not have intraoperatively the condition confirmed. Patients treated in urological departments had significantly better perioperative outcomes compared to those treated in non-urological departments. Therefore, we advise to refer patients to urological treatment as early as possible.

The impact of perioperative risk factors on long-term survival after radical cystectomy: a prospective, high-volume cohort study.

INTRODUCTION: Radical cystectomy (RC) is the gold standard for muscle-invasive bladder cancer. Nevertheless, RC is associated with substantial perioperative morbidity and mortality. We aimed to evaluate the role of important perioperative risk factors in predicting long-term survival after RC. METHODS: An analysis of the prospective cohort of patients undergoing open RC from 2004 to 2023 at our center was performed. Patients who died within one month after RC were excluded from the study. A univariate and multivariable Cox regression analysis was performed to assess the role of sex, age, urinary diversion, preoperative values of creatinine and hemoglobin, first-day postoperative values of CRP, leucocytes, and thrombocytes, perioperative Clavien-Dindo complications, perioperative chemotherapy, admission to the intensive or intermediate care unit, as well as type of histology, pathologic T-stage, positive lymph nodes, and positive surgical margins on predicting the long-term overall survival after RC. For all analyses hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were estimated. RESULTS: A total of 1,750 patients with a median age of 70 years (IQR: 62-76) were included. Of them, 1,069 (61%) received ileal conduit and 650 (37%) neobladder. Overall, 1,016 (58%) perioperative complications occurred. At a median follow-up of 31 months (IQR: 12-71), 884 (51%) deaths were recorded. In the multivariable Cox regression analysis, increasing age (HR: 1.03, 95%CI: 1.02-1.04, p < 0.001), higher preoperative creatinine values (HR: 1.27, 95%CI: 1.12-1.44, p < 0.001), lower preoperative hemoglobin values (HR: 0.93, 95%CI: 0.89-0.97, p = 0.002), higher postoperative thrombocyte values (HR: 1.01, 95%CI: 1.01-1.02, p = 0.02), Clavien-Dindo 1-2 complications (HR: 1.26, 95%CI: 1.03-1.53, p = 0.02), Clavien-Dindo 3-4 complications (HR: 1.55, 95%CI: 1.22-1.96, p < 0.001), locally advanced bladder cancer (HR: 1.29, 95%CI: 1.06-1.55, p = 0.009), positive lymph nodes (HR: 1.74, 95%CI: 1.45-2.11, p < 0.001), and positive surgical margins (HR: 1.61, 95%CI: 1.29-2.01, p < 0.001) negatively affected long-term survival. CONCLUSION: Beside increased age and worse oncological status, impaired renal function, lower preoperative hemoglobin values, higher postoperative thrombocyte values, and perioperative complications are independent risk factors for mortality in the long term in patients undergoing open RC.

Health-related quality of life following salvage radical prostatectomy for recurrent prostate cancer after radiotherapy or focal therapy.

BACKGROUND: Salvage radical prostatectomy (sRP) is an important treatment option for patients with recurrent prostate cancer (PCa) after radiotherapy (RT) or focal therapy (FT). However, health-related quality of life (HRQOL) after sRP depending on the primary treatment is understudied. METHODS: Patients who underwent Salvage RP for recurrent PCa were analyzed. The primary outcome of this study was HRQOL assessed by the quality-of-life questionnaire (QLQ)-C30 and its prostate specific QLQ-PR25 add-on. Secondary outcomes were functional outcome parameters (erectile function, continence) and biochemical recurrence-free survival (BRFS). Statistical analyses employed the chi-square test, Mann-Whitney U test, and Kaplan-Meier method, with a p value < 0.05 denoting significance. RESULTS: 37 patients with RT as primary treatment (RT-sRP) and 22 patients with focal therapy prior sRP (FT-sRP) were analyzed. Mean global health score was not significantly different preoperatively (71.9 vs. 67.3, p = 0.89) as well as after a median of 32 months follow-up (54.9 vs. 50.6, p = 0.63) with impaired HRQOL after sRP in both groups. Baseline erectile dysfunction was more prevalent in the RT-sRP group (mean IIEF-5: 5.0) than in the FT-sRP group (mean IIEF-5: 8.5, p = 0.037). No differences were observed at follow-up for erectile function (IIEF-5-Score: 0.5 vs 2.5, p = 0.199) and continence (continence rate: 48.4% vs 52.9% (p = 0.763) between the RT-sRP and FT-sRP group. 5-year-BRFS was 60% (RT-sRP) and 68% (FT-sRP, p = 0.849). CONCLUSIONS: sRP impacts HRQOL in patients with PCa after RT and FT with no significant differences. Comparison with HRQOL and BRFS of treatment alternatives is paramount to counsel patients for appropriate treatments.

The impact of preoperative 5-alpha reductase inhibitors on functional outcomes and health-related quality of life following radical prostatectomy - A propensity score matched longitudinal study.

OBJECTIVES: While the impact of treatment with 5-alpha Reductase Inhibitors (5-ARI) on the risk of cancer-related mortality in men with prostate cancer (PC) has been extensively studied, little is known about the impact of preoperative 5-ARI use on patient-reported outcomes (PROs) following radical prostatectomy (RP). METHODS: Within our prospectively maintained institutional database of 5899 patients treated with RP for PC (2008- 2021), 99 patients with preoperative 5-ARI therapy were identified. A 1:4 propensity-score matched analysis of 442 men (n = 90 5-ARI, n = 352 no 5-ARI) was conducted. Primary endpoint was continence recovery using daily pad usage and ICIQ-SF. Health-related quality of life (HRQOL) was assessed using the validated EORTC QLQ-C30 and PR25 questionnaires. Multivariable Cox-regression-models tested the effect of preoperative 5-ARI treatment on continence-recovery (p < 0.05). RESULTS: Patients were followed up perioperatively, followed by annual assessments up to 60mo postoperatively. Preoperative mean ICIQ-SF score (2.2 vs. 0.9) was significantly higher in the 5-ARI cohort (p = 0.006). 24mo postoperatively, 68.6% (no 5-ARI) vs. 55.7% (5-ARI) had full continence recovery (p = 0.002). Multivariable Cox regression analysis, revealed preoperative 5-ARI treatment as an independent predictor for impaired continence recovery (HR 0.50, 95% CI 0.27-0.94, p = 0.03) In line, general HRQOL was significantly higher for patients without 5-ARI only up to 24mo postoperatively (70.6 vs. 61.2, p = 0.045). There was no significant impact of preoperative 5-ARI treatment on erectile function, biochemical recurrence-free survival and metastasis-free survival. CONCLUSIONS: Pre-RP 5-ARI treatment was associated with impaired continence outcomes starting 24mo postoperatively, suggesting that preoperative 5-ARI treatment can impair the long-term urinary function recovery following RP.

Reliability and practicability of PSMA-RADS 1.0 for structured reporting of PSMA-PET/CT scans in prostate cancer patients.

OBJECTIVES: As structured reporting is increasingly used in the evaluation of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) for prostate cancer, there is a need to assess the reliability of these frameworks. This study aimed to evaluate the intra- and interreader agreement among readers with varying levels of experience using PSMA-RADS 1.0 for interpreting PSMA-PET/CT scans, even when blinded to clinical data, and therefore to determine the feasibility of implementing this reporting system in clinical practice. METHODS: PSMA-PET/CT scans of 103 patients were independently evaluated by 4 readers with different levels of experience according to the reporting and data system (RADS) for PSMA-PET/CT imaging PSMA-RADS 1.0 at 2 time points within 6 weeks. For each scan, a maximum of five target lesions were freely chosen and stratified according to PSMA-RADS 1.0. Overall scan score and compartment-based scores were assessed. Intra- and interreader agreement was determined using the intraclass correlation coefficient (ICC). RESULTS: PSMA-RADS 1.0 demonstrated excellent interreader agreement for both overall scan scores (ICC ≥ 0.91) and compartment-based scores (ICC ≥ 0.93) across all four readers. The framework showed excellent intrareader agreement for overall scan scores (ICC ≥ 0.86) and compartment-based scores (ICC ≥ 0.95), even among readers with varying levels of experience. CONCLUSIONS: PSMA-RADS 1.0 is a reliable method for assessing PSMA-PET/CT with strong consistency and agreement among readers. It shows great potential for establishing a standard approach to diagnosing and planning treatment for prostate cancer patients, and can be used confidently even by readers with less experience. CLINICAL RELEVANCE STATEMENT: This study underlines that PSMA-RADS 1.0 is a valuable and highly reliable scoring system for PSMA-PET/CT scans of prostate cancer patients and can be used confidently by radiologists with different levels of experience in routine clinical practice. KEY POINTS: PSMA-RADS version 1.0 is a scoring system for PSMA-PET/CT scans. Its reproducibility needs to be analyzed in order to make it applicable to clinical practice. Excellent interreader and intrareader agreement for overall scan scores and compartment-based scores using PSMA-RADS 1.0 were seen in readers with varying levels of experience. PSMA-RADS 1.0 is a reliable tool for accurately diagnosing and planning treatment for prostate cancer patients, and can be used confidently in clinical routine.

Upstaging after Transurethral Resection of the Bladder for Non-Muscle-Invasive Cancer of the Bladder: Who Is at Highest Risk?

INTRODUCTION: Transurethral resection of the bladder (TUR-BT) is the standard initial treatment and diagnosis of bladder cancer (BC). Of note, upstaging into muscle-invasive disease (MIBC) during re-resection occurs in a significant proportion of patients. This study aimed to define risk factors at initial TUR-BT for upstaging. METHODS: TUR-BT between 2009 and 2021 were retrospectively screened (n = 3,237). We included patients with visible tumors that received their primary and re-TUR-BT at our institution. Upstaging was defined as pathological tumor stage progression into MIBC at re-TUR-BT. Clinicopathological variables were analyzed for the impact on upstaging. RESULTS: Two hundred and sixty-six patients/532 TUR-BTs were included in the final analysis. Upstaging occurred in 7.9% (21/266) patients. Patients with upstaging presented with stroma-invasive and papillary non-muscle-invasive BC at primary resection in 85.7% (18/21) and 14.3% (3/21), respectively. Detrusor muscle at primary TUR-BT was significantly less present in patients with upstaging (4.1 vs. 95.9%; p < 0.001). After multivariate analysis, solid tumor configuration (HR: 4.17; 95% CI: 1.23-14.15; p = 0.022) and missing detrusor muscle at initial TUR-BT (HR: 3.58; 95% CI: 1.05-12.24; p = 0.043) were significant risk factors for upstaging into MIBC. CONCLUSIONS: The current study defined two major risk factors for upstaging: missing detrusor muscle and solid tumor configuration. We propose that a second resection should be performed earlier if these risk factors apply.

The Prognostic Value of Perioperative Platelet and Leukocyte Values in Patients Undergoing Radical Cystectomy: A Prospective Long-Term Cohort Study.

INTRODUCTION: Studies assessing the impact of preoperative and first-day postoperative values of leukocytes, thrombocytes, and platelet/leukocyte ratio (PLR) after radical cystectomy (RC) are sparse. We aimed to assess the impact of these factors on long-term survival after RC. METHODS: An analysis of patients undergoing open RC from 2004 to 2023 at our center was performed. Leukocytosis was defined as ≥8,000 leukocytes/µL and thrombocytosis as ≥400,000 thrombocytes/µL. Similarly, the cutoff for PLR was set at 28. A multivariable Cox regression analysis was performed to assess the role of leukocytosis, thrombocytosis, and PLR on long-term survival after RC. For all analyses, hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were estimated. RESULTS: A total of 1,817 patients with a median age of 70 years (interquartile range [IQR]: 62-77) were included. Overall, 804 (44%), 175 (10%), and 1,296 (71%) patients presented with leukocytosis, thrombocytosis, and PLR ≥28 preoperatively. Accordingly, 1,414 (78%), 37 (2%), and 249 (14%) patients presented with leukocytosis, thrombocytosis, and PLR ≥28 on the first day after RC. At a median follow-up of 26 months (IQR: 8-68) after RC, 896 (49%) patients died. In the multivariate Cox regression analysis after adjusting for major perioperative risk factors, only preoperative leukocytosis (HR: 1.3, 95% CI: 1.1-1.6, p = 0.01), as well as both preoperative and first-day thrombocytosis (HR: 2.1, 95% CI: 1.5-2.9, and HR: 2.8, 95% CI: 1.6-5.1, p < 0.001, accordingly) were associated with worse overall survival. CONCLUSION: PLR should not be used as a prognostic marker for survival after RC. On the contrary, preoperative leukocytosis, as well as preoperative and first-day thrombocytosis should raise awareness among clinicians performing RC since they were independently associated with worse survival after RC.

Ligand-Receptor Interactions and Structure-Function Relationships in Off-Target Binding of the ß3-Adrenergic Agonist Mirabegron to α1A-Adrenergic Receptors.

The ß3-adrenoceptor agonist mirabegron is available for the treatment of storage symptoms of overactive bladder, including frequency, urgency, and incontinence. The off-target effects of mirabegron include binding to α1-adrenoceptors, which are central in the treatment of voiding symptoms. Here, we examined the structure-function relationships in the binding of mirabegron to a cryo-electron microscopy structure of α1A. The binding was simulated by docking mirabegron to a 3D structure of a human α1A-adrenoceptor (7YMH) using Autodock Vina. The simulations identified two binding states: slope orientation involving 10 positions and horizontal binding to the receptor surface involving 4 positions. No interactions occurred with positions constituting the α1A binding pocket, including Asp-106, Ser-188, or Phe-312, despite the positioning of the phenylethanolamine moiety in transmembrane regions close to the binding pocket by contact with Phe-288, -289, and Val-107. Contact with the unique positions of α1A included the transmembrane Met-292 during slope binding and exosite Phe-86 during horizontal binding. Exosite binding in slope orientation involved contact of the anilino part, rather than the aminothiazol end, to Ile-178, Ala-103, and Asn-179. In conclusion, contact with Met-292 and Phe-86, which are unique positions of α1A, accounts for mirabegron binding to α1A. Because of its lack of interactions with the binding pocket, mirabegron has lower affinity compared to α1A-blockers and no effects on voiding symptoms.

The impact of previous inguinal mesh hernioplasty on oncological and patient-reported outcomes following radical prostatectomy.

BACKGROUND: The impact of previous inguinal mesh hernioplasty (MH) with non-resorbable mesh prostheses on surgical performance of radical prostatectomy (RP) has been controversially discussed, with unknown impact of MH on oncologic outcomes and health-related quality of life (HRQOL) following RP. We therefore aimed to assess the influence of previous MH on metastasis-free survival (MFS), biochemical recurrence-free survival (BRFS), and HRQOL following RP. METHODS: We identified 344 patients with previous MH prior RP within our prospectively assessed institutional database of 6275 patients treated with RP for PC (2008-2019). A 1:3 propensity-score matched analysis of 1345 men (n = 319 previous MH, n = 1026 no previous MH) was conducted. Primary endpoint was MFS and secondary endpoints were BRFS and HRQOL (based on EORTC QLQ-C30). Binary logistic regression, Kaplan-Meier, and Cox regression models tested the effect of previous MH on MFS, BRFS, and HRQOL (p < 0.05). RESULTS: Median follow-up was 47 months. Patients with previous MH had significantly lower 5-year MFS (72% vs. 85%, p < 0.001) and 5-year BRFS estimates (43% vs. 57%, p < 0.001). In multivariate analysis, previous MH was confirmed as an independent predictor for impaired MFS (hazard ratio [HR]: 3.772, 95% CI 1.12-12.64, p = 0.031) and BRFS (HR: 1.862, 95% CI: 1.22-2.85, p = 0.004). These results held true if stratified for surgical approach or limited to patients with successful PLND. We found significantly shorter median time to continence recovery for patients without previous MH (p = 0.001) without significant differences in total continence recovery rates, erectile function recovery, and HRQOL. CONCLUSIONS: Our findings show an impaired oncologic outcome for patients with previous MH following RP with no significant differences regarding continence recovery, erectile function recovery, and general HRQOL.

Is PSMA PET/CT cost-effective for the primary staging in prostate cancer? First results for European countries and the USA based on the proPSMA trial.

PURPOSE: The proPSMA trial at ten Australian centers demonstrated increased sensitivity and specificity for PSMA PET/CT compared to conventional imaging regarding metastatic status in primary high-risk prostate cancer patients. A cost-effectiveness analysis showed benefits of PSMA PET/CT over conventional imaging for the Australian setting. However, comparable data for other countries are lacking. Therefore, we aimed to verify the cost-effectiveness of PSMA PET/CT in several European countries as well as the USA. METHODS: Clinical data on diagnostic accuracy were derived from the proPSMA trial. Costs for PSMA PET/CT and conventional imaging were taken from reimbursements of national health systems and individual billing information of selected centers in Belgium, Germany, Italy, the Netherlands, and the USA. For comparability, scan duration and the decision tree of the analysis were adopted from the Australian cost-effectiveness study. RESULTS: In contrast to the Australian setting, PSMA PET/CT was primarily associated with increased costs in the studied centers in Europe and the USA. Mainly, the scan duration had an impact on the cost-effectiveness. However, costs for an accurate diagnosis using PSMA PET/CT seemed reasonably low compared to the potential consequential costs of an inaccurate diagnosis. CONCLUSION: We assume that the use of PSMA PET/CT is appropriate from a health economic perspective, but this will need to be verified by a prospective evaluation of patients at initial diagnosis.

Development of PSMA-PET-guided CT-based radiomic signature to predict biochemical recurrence after salvage radiotherapy.

PURPOSE: To develop a CT-based radiomic signature to predict biochemical recurrence (BCR) in prostate cancer patients after sRT guided by positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET). MATERIAL AND METHODS: Consecutive patients, who underwent 68Ga-PSMA11-PET/CT-guided sRT from three high-volume centers in Germany, were included in this retrospective multicenter study. Patients had PET-positive local recurrences and were treated with intensity-modulated sRT. Radiomic features were extracted from volumes of interests on CT guided by focal PSMA-PET uptakes. After preprocessing, clinical, radiomics, and combined clinical-radiomic models were developed combining different feature reduction techniques and Cox proportional hazard models within a nested cross validation approach. RESULTS: Among 99 patients, median interval until BCR was the radiomic models outperformed clinical models and combined clinical-radiomic models for prediction of BCR with a C-index of 0.71 compared to 0.53 and 0.63 in the test sets, respectively. In contrast to the other models, the radiomic model achieved significantly improved patient stratification in Kaplan-Meier analysis. The radiomic and clinical-radiomic model achieved a significantly better time-dependent net reclassification improvement index (0.392 and 0.762, respectively) compared to the clinical model. Decision curve analysis demonstrated a clinical net benefit for both models. Mean intensity was the most predictive radiomic feature. CONCLUSION: This is the first study to develop a PSMA-PET-guided CT-based radiomic model to predict BCR after sRT. The radiomic models outperformed clinical models and might contribute to guide personalized treatment decisions.

Penile fractures: the price of a merry Christmas.

OBJECTIVES: To explore whether Christmas might be a risk factor for penile fractures due to the Christmas spirit related to the intimacy and euphoria of these holly jolly days. PATIENTS AND METHODS: We evaluated the incidence of penile fractures during Christmas and New Year's Eve through the GeRmAn Nationwide inpatient Data (GRAND) from the Research Data Center of the Federal Bureau of Statistics (Wiesbaden, Germany). Furthermore, we assessed the impact of COVID-19 on penile fractures and their seasonality. RESULTS: A total of 3,421 patients with a median, interquartile range (IQR) age of 42 (32-51) years had a penile fracture requiring a hospital stay from 2005 to 2021. In all, 40 (1.2%) penile fractures occurred in 51 days of Christmas (from 24/12 to 26/12 in each year). The daily incidence of penile fractures during Christmas was 0.78 with an incidence rate ratio (IRR) of 1.43 (95% confidence interval [CI] 1.05-1.95, P = 0.02). If every day was like Christmas, 43% more penile fractures would have occurred in Germany from 2005 on. Interestingly, only 28 (0.82%) penile fractures occurred during the New Year's Eve period (31/12 to 02/01 from 2005 to 2021). This resulted in an IRR of 0.98 (95% CI 0.69-1.5, P = 0.98) in the New Year's Eve period. Most patients with penile fractures were admitted to hospital at the weekend (n = 1,322; IRR 1.58, 95% CI 1.48-1.69; P < 0.001). Summer was also associated with more penile fractures (n = 929; IRR 1.11, 95% CI 1.03-1.19; P = 0.008). Both the COVID-19 pandemic (n = 385; IRR 1.06, 95% CI 0.95-1.18, P = 0.29) and its lockdown period (n = 93; IRR 1, 95% CI 0.82-1.23; P = 0.96) did not affect the incidence of penile fractures. CONCLUSION: The incidence of penile fractures displays a seasonality. Last Christmas penile fractures occurred more often. This year to save us from tears, we will NOT do something special (the new Christmas hit of the year).

Added value of randomised biopsy to multiparametric magnetic resonance imaging-targeted biopsy of the prostate in a contemporary cohort.

OBJECTIVE: To assess the added value of concurrent systematic randomised ultrasonography-guided biopsy (SBx) to multiparametric magnetic resonance imaging (mpMRI)-targeted biopsy and the additional rate of overdiagnosis of clinically insignificant prostate cancer (ciPCa) by SBx in a large contemporary, real-world cohort. PATIENTS AND METHODS: A total of 1552 patients with positive mpMRI and consecutive mpMRI-targeted biopsy and SBx were enrolled. Added value and the rate of overdiagnosis by SBx was evaluated. PRIMARY OUTCOME: added value of SBx, defined as detection rate of clinically significant PCa (csPCa; International Society of Urological Pathology [ISUP] Grade ≥2) by SBx, while mpMRI-targeted biopsy was negative or showed ciPCa (ISUP Grade 1). SECONDARY OUTCOME: rate of overdiagnosis by SBx, defined as detection of ciPCa in patients with negative mpMRI-targeted biopsy and PSA level of <10 ng/mL. RESULTS: Detection rate of csPCa by mpMRI-targeted biopsy and/or SBx was 753/1552 (49%). Added value of SBx was 145/944 (15%). Rate of overdiagnosis by SBx was 146/656 (22%). Added value of SBx did not change when comparing patients with previous prostate biopsy and biopsy naïve patients. In multivariable analysis, a Prostate Imaging-Reporting and Data System (PI-RADS) 4 index lesion (odds ratio [OR] 3.19, 95% confidence interval [CI] 1.66-6.78; P = 0.001), a PI-RADS 5 index lesion (OR 2.89, 95% CI 1.39-6.46; P = 0.006) and age (OR 1.05, 95% CI 1.03-1.08; P < 0.001) were independently associated with added value of SBx. CONCLUSIONS: In our real-world analysis, we saw a significant impact on added value and added rate of overdiagnosis by SBx. Subgroup analysis showed no significant decrease of added value in any evaluated risk group. Therefore, we do not endorse omitting concurrent SBx to mpMRI-guided biopsy of the prostate.

Assessment of single-probe dual-energy lithotripters in percutaneous nephrolithotomy: a systematic review and meta-analysis of preclinical and clinical studies.

PURPOSE: To evaluate the safety and efficacy of single-probe dual-energy (SPDE) lithotripters in patients undergoing percutaneous nephrolithotripsy (PCNL) through a systematic review and meta-analysis. METHODS: We searched PubMed, Cochrane Library, Scopus and Embase databases until July 2022 for any preclinical or clinical studies, exploring the safety and efficacy of different SPDE lithotripters in patients undergoing PCNL. We performed a meta-analysis to compare stone-free rate, bleeding, or other complications and mean operative time between SPDE lithotripters and other lithotripters (PROSPERO: CRD42021285631). RESULTS: We included 16 studies (six preclinical, seven observational and three randomized with 625 participants) in the systematic review and four in the meta-analysis. Preclinical studies suggest that SPDE lithotripters are safe and effective for the management of renal stones. Among clinical studies, four studies assessed Trilogy with no comparative arm, two compared Trilogy or ShockPulse with a dual-probe dual-energy lithotripter, two compared Trilogy with a laser, one compared ShockPulse with a pneumatic lithotripter, and one directly compared Trilogy with ShockPulse. Comparing SPDE lithotripters to other lithotripters, no significant differences were demonstrated in stone free rate (OR 1.13, 95% CI 0.53-2.38, I2 = 0%), postoperative blood transfusion (OR 1.33, 95% CI 0.34-5.19, I2 = 0%), embolization (OR 0.45, 95% CI 0.02-12.06), operative time (WMD: 2.82 min, 95% CI -7.31-12.95, I2 = 78%) and postoperative complications based on the Clavien-Dindo classification. CONCLUSIONS: SPDE lithotripters represent a promising treatment modality for patients requiring PCNL. Despite the initial encouraging findings of preclinical and isolated clinical studies, it seems that Trilogy or ShockPulse provide similar efficiency compared to older generation devices.

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.