Temporal Trends in Urinary Diversion among Patients Undergoing Radical Cystectomy Between 1986 and 2022: Experience at the University Medical Center Mainz with 2224 Cases.

BACKGROUND: Analysis of temporal trends of urinary diversion (UD) and identification of predictive factors for continent urinary diversion (CUD) in patients with bladder cancer (BC) is scarce and data on large cohorts are missing. We aimed to describe longitudinal temporal trends and predictive factors for UD among patients with BC receiving radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively analysed institutional data collected from patients undergoing RC from 1986 to 2022 to describe changes in patients' characteristics and UD. Primary end points were patients' characteristics associated with type of UD. Logistic regression analysis was used to determine predictive factors for CUD. RESULTS: In total, 2224 patients (77.16% male, 22.84% female) with a mean age of 66 years [standard deviation (SD), 10.64 years] were included. We observed an increase in mean age from 59.86 (10.8) years (1986-1990) to 69.85 (9.99) years (2016-2022) (p < 0.001). The proportion of CUD gradually declined from 43.72% (94/215; 1986-1990) to 18.38% (86/468; 2016-2022). Patients who were male [odds ratio (OR): 1.92, 95% confidence interval (CI): 1.43-2.57, p < 0.001), younger (OR: 0.88, 95% CI: 0.87-0.89, p < 0.001) and had no hydronephrosis prior to RC (OR: 2.2, 95% CI: 1.66-2.92, p < 0.001) were more likely to receive CUD. CONCLUSIONS: We report the largest European single-center cohort of UD after RC, demonstrating a significant shift from CUD to IUD, accompanied by an increasing age. Finally, our data mirrors the development and extensive experience with the Mainz Pouch-I in the 1980's and 1990's together with other colon pouches.

Comparative Retrospective Assessment of the Effectiveness and Risk Factors of Fluoroquinolones, Cephalosporines, and Selective Antibiotic Prophylaxis for Transrectal Prostate Biopsy.

INTRODUCTION: Despite increasing resistance of enterobacteria against fluoroquinolones (FLU), they are still widely used during transrectal prostate biopsy (TRPB). This study was designed to analyse infectious complications and risk factors between FLU, cephalosporines (CEPH) and selective other antibiotics (O-AB) used during TRPB. METHODS: 664 patients were included retrospectively (152 FLU, 452 CEPH and 60 O-AB). Infectious complications were defined as fever >38.0°C, the in-house definition of complicated urinary tract infection (cUTI) (if all applied: fever >38.0°C, leucocytosis >11.000/µL and positive urine dipstick) or postinterventional bacteriuria. Hospitalisation rate, duration and comorbidities were also assessed. χ2 and Fisher's exact test were used for group comparison. Multivariate regression analysis assessed the association of comorbidities with infectious complications. RESULTS: FLU and CEPH were indifferent regarding infectious complications, however in the O-AB group significantly more common compared to FLU and CEPH (11.6, 13.3, 25%, p < 0.05). Duration of hospital stay in CEPH was significantly shorter compared to FLU and O-AB (4.1 vs. 6.3 vs. 8.2 days, p < 0.05). Arterial hypertension showed increased association with fever (OR 6.002 (1.178; 30.597) p = 0.031) and cUTI (OR 6.006 (1.207; 29.891) p = 0.029). CONCLUSION: Infectious complications were low and indifferent between FLU and CEPH but significantly more frequent in O-AB. Arterial hypertension was significantly associated with postinterventional fever and cUTI.

Understanding tumor localization in multiparametric MRI of the prostate-effectiveness of 3D printed models.

Introduction: Understanding tumor localization in multiparametric MRI (mpMRI) of the prostate is challenging for urologists but of great importance in mpMRI-fused prostate biopsy or radical prostatectomy. The aim was to evaluate the effectiveness of 3D printed models of the prostate to help urologists to locate tumors. Methods and Participants: 20 urologists from University Medical Center Mainz (Germany) were asked to plot the location of a cancer suspicious lesion (PI-RADS ≥ 4) on a total of 30 mpMRI on a prostate sector diagram. The following 3 groups (as matched triplets) were divided into: mpMRI only, mpMRI with radiological report and mpMRI with 3D printed model (scaled 1:1). Statistical analysis was performed using one-way and two-way ANOVA (with bonferroni post-test). Results: Overall, localization of the suspicious lesion was superior with the radiological report (median of max. 10 [IQR]: MRI 2 [IQR 1;5], MRI + report: 8 [6.3;9], MRI + 3D model 3 [1.3;5.8]; p < 0.001). Residents with <1 year of experience had a significantly higher detection rate using a 3D printed model [5 (5;5.8)] compared to mpMRI alone [1.5 (1;3.5)] (p < 0.05). Regarding the estimation of index lesion extension, the 3D model showed a significant benefit (mean percentage difference [95% CI]: MRI alone 234% [17.1;451.5], MRI + report 114% [78.5;149.6], MRI + 3D model 17% [-7.4;41.3] (p < 0.01). Conclusion: Urologists still need the written radiological report for a sufficient understanding of tumor localization. The effectiveness of the 3D printed model regarding tumor localization is particularly evident in young residents (<1 year) and leads to a better overall assessment of the tumor extension.

Digital informed consent for urological surgery - randomized controlled study comparing multimedia-supported vs. traditional paper-based informed consent concerning satisfaction, anxiety, information gain and time efficiency.

INTRODUCTION: Due to a lack of time and staff, informed consent (IC) in clinical practice often lacks clarity, comprehensibility and scope of information. Digital media offer great potential to enhance IC. Aim of this study is to evaluate the effectiveness of multimedia-supported compared to traditional paper-based IC. METHODS: In the randomized, controlled, three-arm DICon (Digital Informed Consent for urological surgery) study 70 patients with an indication for prostate biopsy were randomized 1:1:1 to receive traditional paper-based IC vs. multimedia-supported information before IC vs. multimedia-supported information during IC. Patient satisfaction, anxiety and information gain were measured by validated questionnaires 2 weeks and directly before the procedure and time efficiency was recorded. Statistical analysis was performed using Kruskal-Wallis and Dunn's test (one-way ANOVA) and two-way ANOVA (with bonferroni post-test). RESULTS: Multimedia information prior to the consultation saved 32.9% time compared to paper-based (5.3 min. vs. 9.5 min; p < 0.05) and 60.4% time compared to shared multimedia information (5.3 min. vs. 13.9 min.; p < 0.001), with no difference in satisfaction (62.6 vs. 62.7 vs. 68.6 of max. 80; p = 0.07), anxiety (8 vs. 8.1 vs. 7 of max. 16; p = 0.35), or information gain (6.5 vs. 5.7 vs. 6.7 of max. 10; p = 0.23). Results on satisfaction (56.6 vs. 62.6 vs. 66; p = 0.06), anxiety (7.2 vs. 7.2 vs. 6.8; p = 0.84), and information gain (7 vs. 6.4 vs. 5.9; p = 0.43) remained stable over time. CONCLUSIONS: Multimedia-supported IC prior to consultation provided improved time efficiency (33% gain) compared to traditional paper-based IC, with comparable satisfaction, anxiety and information gain. Multimedia-supported information materials should therefore be used more frequently in patient education.

Integrin Expression in Localized Prostate Cancer: A TCGA and MSKCC Cohort-based Exploratory In Silico Analysis.

BACKGROUND/AIM: Diagnostic and prognostic biomarkers in localized prostate cancer (PC) are insufficient. Treatment stratification relies on prostate-specific antigen, clinical tumor staging and International Society of Urological Pathology (ISUP) grading, whereas molecular profiling remains unused. Integrins (ITG) have an important function in bidirectional signaling and are associated with progression, proliferation, perineural invasion, angiogenesis, metastasis, neuroendocrine differentiation, and a more aggressive disease phenotype in PC. However, ITG subunit expression in localized PC and their utility as prognostic biomarkers has not yet been analyzed. This study aimed to fill this gap and provide a comprehensive overview of ITG expression as well as ITG utility as biomarkers. PATIENTS AND METHODS: The Cancer Genome Atlas (TCGA) and the Memorial Sloan Kettering Cancer Center (MSKCC) prostate adenocarcinoma cohorts were analyzed regarding ITG expression in correlation to ISUP, N- and American Joint Committee on Cancer (AJCC) stage and were correlated with disease-free survival (DFS). Statistical tests used included the Mann-Whitney U-test, logrank test and uni- and multivariable cox regression analyses. RESULTS: After grouping for ISUP (1 and 2 vs. 3-5), N0 vs. N1 and AJCC stage (≤2 vs. ≥3), multiple ITGs showed significant expression differences. The most consistent results were observed for ITGα4, ITGαX, ITGα11, ITGß2 and ITGα2. In multivariable cox regression, ITGα2, ITGα10, ITGαD, ITGαB2 (TCGA), ITGα11 and ITGß4 (MSKCC) were independent predictors of DFS. CONCLUSION: The utility of ITGs as PC biomarkers was herein shown.

Change in Splenic Volume as a Surrogate Marker for Immunotherapy Response in Patients with Advanced Urothelial and Renal Cell Carcinoma-Evaluation of a Novel Approach of Fully Automated Artificial Intelligence Based Splenic Segmentation.

BACKGROUND: In the treatment of advanced urothelial (aUC) and renal cell carcinoma (aRCC), biomarkers such as PD-1 and PD-L1 are not robust prognostic markers for immunotherapy (IO) response. Previously, a significant association between IO and a change in splenic volume (SV) was described for several tumour entities. To the best of our knowledge, this study presents the first correlation of SV to IO in aUC and aRCC. METHODS: All patients with aUC (05/2017-10/2021) and aRCC (01/2012-05/2022) treated with IO at our academic centre were included. SV was measured at baseline, 3 and 9 months after initiation of IO using an in-house developed convolutional neural network-based spleen segmentation method. Uni- and multivariate Cox regression models for overall survival (OS) and progression-free survival (PFS) were used. RESULTS: In total, 35 patients with aUC and 30 patients with aRCC were included in the analysis. Lower SV at the three-month follow-up was significantly associated with improved OS in the aRCC group. CONCLUSIONS: We describe a new, innovative artificial intelligence-based approach of a radiological surrogate marker for IO response in aUC and aRCC which presents a promising new predictive imaging marker. The data presented implicate improved OS with lower follow-up SV in patients with aRCC.

Robust LC3B lipidation analysis by precisely adjusting autophagic flux.

Autophagic flux can be quantified based on the accumulation of lipidated LC3B in the presence of late-stage autophagy inhibitors. This method has been widely applied to identify novel compounds that activate autophagy. Here we scrutinize this approach and show that bafilomycin A1 (BafA) but not chloroquine is suitable for flux quantification due to the stimulating effect of chloroquine on non-canonical LC3B-lipidation. Significant autophagic flux increase by rapamycin could only be observed when combining it with BafA concentrations not affecting basal flux, a condition which created a bottleneck, rather than fully blocking autophagosome-lysosome fusion, concomitant with autophagy stimulation. When rapamycin was combined with saturating concentrations of BafA, no significant further increase of LC3B lipidation could be detected over the levels induced by the late-stage inhibitor. The large assay window obtained by this approach enables an effective discrimination of autophagy activators based on their cellular potency. To demonstrate the validity of this approach, we show that a novel inhibitor of the acetyltransferase EP300 activates autophagy in a mTORC1-dependent manner. We propose that the creation of a sensitized background rather than a full block of autophagosome progression is required to quantitatively capture changes in autophagic flux.

Smartglass augmented reality-assisted targeted prostate biopsy using cognitive point-of-care fusion technology.

INTRODUCTION: MRI-guided targeted biopsy has become standard of care for diagnosis of prostate cancer, with establishment of several biopsy techniques and platforms. Augmented reality smart glasses have emerged as novel technology to support image-guided interventions. We aimed to investigate its usage while prostate biopsy. METHODS: MRI with PIRADS-lesions ≥3 was uploaded to smart glasses (Vuzix BladeR ) and augmented reality smart glasses-assisted targeted biopsy (SMART-TB) of the prostate was performed using cognitive fusion technology at the point of care. Detection rates were compared to systematic biopsy. Feasibility for SMART-TB was assessed (10 domains from bad [1] to excellent [10]). RESULTS: SMART-TB was performed for four patients. Prostate cancer detection was more likely for SMART-TB (46%; 13/28) than for systematic biopsy (27%; 13/48). Feasibility scores were high [8-10] for practicality, multitasking, execution speed, comfort and device weight and low [1-4] for handling, battery and image quality. Median execution time: 28 min; Investment cost smart glass: 1017 USD. CONCLUSION: First description of SMART-TB demonstrated convenient feasibility. This novel technology might enhance diagnosis of prostate cancer in future.

CircEHD2, CircNETO2 and CircEGLN3 as Diagnostic and Prognostic Biomarkers for Patients with Renal Cell Carcinoma.

BACKGROUND: Circular RNA (circRNA) plays an important role in the carcinogenesis of various tumors. It is assumed that circRNAs have a high tissue and tumor specificity, thus they are discussed as cancer biomarkers. The knowledge about circRNAs in clear cell renal carcinoma (ccRCC) is limited so far, and thus we studied the expression profile of seven circRNAs (circCOL5A1, circEHD2, circEDEM2, circEGNL3, circNETO2, circSCARB1, circSOD2) in a cohort of ccRCC patients. METHODS: Fresh-frozen normal and cancerous tissues were prospectively collected from patients with ccRCC undergoing partial/radical nephrectomy. Total RNA was isolated from 121 ccRCC and 91 normal renal tissues, and the circRNA expression profile was determined using quantitative real-time PCR. RESULTS: circEHD2, circENGLN3, and circNETO2 were upregulated in ccRCC compared with non-malignant renal tissue. circENGLN3 expression was highly discriminative between normal and cancerous tissue. None of the circRNAs was correlated with clinicopathological parameters. High circEHD2 and low circNETO2 levels were an independent predictor of a shortened progression-free survival, cancer-specific survival, and overall survival in patients with ccRCC undergoing nephrectomy. CONCLUSIONS: The analysis of circRNAs may provide diagnostic and prognostic information. Thus, circRNAs could help to optimize the individual treatment and ultimately improve ccRCC patients' survival.

miR-10a-5p and miR-29b-3p as Extracellular Vesicle-Associated Prostate Cancer Detection Markers.

Extracellular vesicles (EVs) are shed by many different cell types. Their nucleic acids content offers new opportunities for biomarker research in different solid tumors. The role of EV RNA in prostate cancer (PCa) is still largely unknown. EVs were isolated from different benign and malignant prostate cell lines and blood plasma from patients with PCa (n = 18) and controls with benign prostatic hyperplasia (BPH) (n = 7). Nanoparticle tracking analysis (NTA), Western blot, electron microscopy, and flow cytometry analysis were used for the characterization of EVs. Non-coding RNA expression profiling of PC3 metastatic PCa cells and their EVs was performed by next generation sequencing (NGS). miRNAs differentially expressed in PC3 EVs were validated with qRT-PCR in EVs derived from additional cell lines and patient plasma and from matched tissue samples. 92 miRNAs were enriched and 48 miRNAs were depleted in PC3 EVs compared to PC3 cells, which could be confirmed by qRT-PCR. miR-99b-5p was significantly higher expressed in malignant compared to benign EVs. Furthermore, expression profiling showed miR-10a-5p (p = 0.018) and miR-29b-3p (p = 0.002), but not miR-99b-5p, to be overexpressed in plasma-derived EVs from patients with PCa compared with controls. In the corresponding tissue samples, no significant differences in the miRNA expression could be observed. We thus propose that EV-associated miR-10a-5p and miR-29b-3p could serve as potential new PCa detection markers.

Vicarious resilience in sexual assault and domestic violence advocates.

OBJECTIVE: There is little research related to sexual assault and domestic violence advocates' experiences, with the bulk of the literature focused on stressors and systemic barriers that negatively impact efforts to assist survivors. However, advocates participating in these studies have also emphasized the positive impact they experience consequent to their work. This study explores the positive impact. METHOD: Vicarious resilience, personal trauma experiences, peer relational quality, and perceived organizational support in advocates (n = 222) are examined. Also, overlap among the conceptual components of vicarious resilience is explored. RESULTS: The first set of multiple regressions showed that personal trauma experiences and peer relational health predicted compassion satisfaction and vicarious posttraumatic growth, with organizational support predicting only compassion satisfaction. The second set of multiple regressions showed that (a) there was significant shared variance between vicarious posttraumatic growth and compassion satisfaction; (b) after accounting for vicarious posttraumatic growth, organizational support accounted for significant variance in compassion satisfaction; and (c) after accounting for compassion satisfaction, peer relational health accounted for significant variance in vicarious posttraumatic growth. CONCLUSIONS: Results suggest that it may be more meaningful to conceptualize advocates' personal growth related to their work through the lens of a multidimensional construct such as vicarious resilience. Organizational strategies promoting vicarious resilience (e.g., shared organizational power, training components) are offered, and the value to trauma-informed care of fostering advocates' vicarious resilience is discussed. (PsycINFO Database Record

An investigation into causes and effects of high cyanide levels in the palladium-catalyzed cyanation reaction.

[reaction: see text] The palladium-catalyzed cyanation reaction is known to be sensitive to dissolved cyanide. Investigation into some causes of high levels of dissolved cyanide is presented here, along with a robust solution to this problem.

Evaluation of non-conventional polar modifiers on immobilized chiral stationary phases for improved resolution of enantiomers by supercritical fluid chromatography.

An evaluation of the use of non-conventional polar modifiers for the supercritical fluid chromatographic separation of enantiomers on immobilized chiral stationary phases is presented. The resolution of a group of nine commercially available racemates is studied on the Chiralpak IA, IB, IC, ID, IE, and IF chiral stationary phases using CO2-based eluents containing non-conventional polar modifiers such as dichloromethane, chloroform, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, acetone, ethyl acetate, toluene, 2,2,2-trifluoroethanol, and N,N-dimethylformamide. Screening experiments and method development for the commercial racemates on the immobilized columns with the non-conventional solvents demonstrated an ability to adjust the retention and improve resolution. From these results we were able to assign a general eluotropic relationship between the non-conventional solvents and methanol. A general ability to selectively adjust chromatographic retention while improving analyte solubility can lead to improved preparative chromatographic performance.

Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain.

We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.

Identification and structural elucidation of process impurities generated in the end-game synthesis of taranabant (MK-0364) via cyanuric chloride.

Taranabant (MK-0364) is a highly potent and selective cannabinoid-1 receptor (CB-1R) inverse agonist. It is being developed at Merck & Company to treat obesity. The chemical synthesis of MK-0364 drug substance involved the direct coupling of chiral amine and pyridine acid side chains mediated by cyanuric chloride. Four major process impurities were observed and characterized using high performance liquid chromatography (HPLC) coupled with ultraviolet (UV) and electrospray ionization (ESI) mass spectrometry (MS) detectors. The exact mass data was used for structural elucidation which suggests that the impurities are derivatives of cyanuric chloride formed in the coupling step. Owing to the reactive nature of these impurities, an interesting degradation phenomenon was observed during stability testing of MK-0364 drug substance when stored at 40 degrees C/75% RH and 25 degrees C/60% RH conditions. Degradation pathways were proposed to explain the changes observed in the HPLC impurity profile. Forced degradation experiments were also conducted to confirm the degradation pathways and assess the stability of the impurities. Finally, the complete stability data of the bulk drug are reported to support the hypothesis.

Practical asymmetric synthesis of a potent PDE4 inhibitor via stereoselective enolate alkylation of a chiral aryl-heteroaryl secondary tosylate.

A practical, chromatography-free catalytic asymmetric synthesis of a potent and selective PDE4 inhibitor (L-869,298, 1) is described. Catalytic asymmetric hydrogenation of thiazole ketone 5a afforded the corresponding alcohol 3b in excellent enantioselectivity (up to 99.4% ee). Activation of alcohol 3b via formation of the corresponding p-toluenesulfonate followed by an unprecedented displacement with the lithium enolate of ethyl 3-pyridylacetate N-oxide 4a generated the required chiral trisubstituted methane. The displacement reaction proceeded with inversion of configuration and without loss of optical purity. Conversion of esters 2b to 1 was accomplished via a one-pot deprotection, saponification, and decarboxylation sequence in excellent overall yield.