Inhibition of the Sterol Regulatory Element Binding Protein SREBF-1 Overcomes Docetaxel Resistance in Advanced Prostate Cancer.

Resistance to antiandrogens and chemotherapy (Cx) limits therapeutic options for patients with hormone-sensitive and hormone-resistant prostate cancer (mCRPC). In this context, up-regulation of the glucocorticoid receptor has been identified as a potential bypass mechanism in mCRPC, and a combination of docetaxel and mifepristone (Doc + RU-486), an inhibitor of the glucocorticoid receptor, re-sensitized docetaxel-resistant cell models to Cx. This study was designed to elucidate the molecular mechanisms responsible for this phenomenon. RNA sequencing was performed in docetaxel-resistant prostate cancer cell models after Doc + RU-486 treatment with consecutive functional assays. Expression of selected proteins was verified in prostatic tissue from prostate cancer patients with progressive disease. Treatment with Doc + RU-486 significantly reduced cancer cell viability, and RNA sequencing revealed sterol regulatory element of binding transcription factor 1 (SREBF-1), a transcription factor of cholesterol and lipid biosynthesis, as a significantly down-regulated target. Functional assays confirmed that SREBF-1 down-regulation is partially responsible for this observation. In concordance, SREBF-1 knockdown and pharmacologic sterol regulatory element binding protein inhibition, together with other key enzymes in the cholesterol pathway, showed similar results. Furthermore, SREBF-1 expression is significantly elevated in advanced prostate cancer tissues, showing its potential involvement in tumor progression and emerging therapy resistance. Therefore, specific inhibition of cholesterol and lipid biosynthesis might also target Cx-resistant cancer cells and represents a potential additive future therapeutic option to improve mCRPC therapy.

[Risk-adapted early detection program for prostate cancer 2.0-position paper of the German Society of Urology 2024]. / Risikoadaptierte Prostatakarzinomfrüherkennung 2.0 ­ Positionspapier der Deutschen Gesellschaft für Urologie 2024.

BACKGROUND AND OBJECTIVE: Despite the proven effectiveness of organized PSA-based screening in reducing prostate cancer-related mortality, there is currently no program in Germany covered by statutory health insurance. In accordance with the EU Council Decision (2022/0290(NLE)), the German Society of Urology (DGU) has developed a concept for risk-adapted prostate cancer early detection. MATERIALS AND METHODS: Based on a literature review of current screening studies, an algorithm for PSA-based prostate cancer early detection was developed. RESULTS: Risk-adapted prostate cancer screening involves PSA testing in the age group of 45-70 years, followed by PSA-based individual risk stratification and stepwise expansion of diagnostics through magnetic resonance imaging (MRI) to biopsy. While initially up to 2.6 million men will undergo PSA testing, a reduction in these initial examinations to fewer than 200,000 men per year will occur from year four onwards. CONCLUSIONS: The presented algorithm provides clear recommendations for risk-adapted PSA-based early detection for prostate cancer for urologists and patients. The goal is to improve diagnosis of clinically significant prostate cancer, while reducing overdiagnosis and overtreatment.

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.

Survey of Physicians and Healers Using Amygdalin to Treat Cancer Patients.

Amygdalin is purported to exhibit anti-cancer properties when hydrolyzed to hydrogen cyanide (HCN). However, knowledge about amygdalin efficacy is limited. A questionnaire evaluating the efficacy, treatment, and dosing protocols, reasons for use, HCN levels, and toxicity was distributed to physicians and healers in Germany, providing amygdalin as an anti-cancer drug. Physicians (20) and healers (18) provided amygdalin over 8 (average) years to nearly 80 annually treated patients/providers. Information about amygdalin was predominantly obtained from colleagues (55%). Amygdalin was administered both intravenously (100%) and orally (32%). Intravenous application was considered to maximally delay disease progression (90%) and relieve symptoms (55%). Dosing was based on recommendations from colleagues (71%) or personal experience (47%). If limited success became apparent after an initial 3g/infusion, infusions were increased to 27g/infusion. Treatment response was primarily monitored with established (26%) and non-established tumor markers (19%). 90% did not monitor HCN levels. Negative effects were restricted to a few dizzy spells and nausea. Only 58% were willing to participate in clinical trials or contribute data for analysis (34%). Amygdalin infusions are commonly administered by healers and physicians with few side effects. The absence of standardized treatment calls for guidelines. Since intravenous application bypasses metabolization, re-evaluation of its mode of action is required.

Challenges and perspectives in use of artificial intelligence to support treatment recommendations in clinical oncology.

Artificial intelligence (AI) promises to be the next revolutionary step in modern society. Yet, its role in all fields of industry and science need to be determined. One very promising field is represented by AI-based decision-making tools in clinical oncology leading to more comprehensive, personalized therapy approaches. In this review, the authors provide an overview on all relevant technical applications of AI in oncology, which are required to understand the future challenges and realistic perspectives for decision-making tools. In recent years, various applications of AI in medicine have been developed focusing on the analysis of radiological and pathological images. AI applications encompass large amounts of complex data supporting clinical decision-making and reducing errors by objectively quantifying all aspects of the data collected. In clinical oncology, almost all patients receive a treatment recommendation in a multidisciplinary cancer conference at the beginning and during their treatment periods. These highly complex decisions are based on a large amount of information (of the patients and of the various treatment options), which need to be analyzed and correctly classified in a short time. In this review, the authors describe the technical and medical requirements of AI to address these scientific challenges in a multidisciplinary manner. Major challenges in the use of AI in oncology and decision-making tools are data security, data representation, and explainability of AI-based outcome predictions, in particular for decision-making processes in multidisciplinary cancer conferences. Finally, limitations and potential solutions are described and compared for current and future research attempts.

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.

Value of perilesional biopsies in multiparametric magnetic resonance imaging-targeted biopsy and systematic biopsy in detection of prostate cancer: results of a prospective, non-randomized, surgeon-blinded study.

PURPOSE: The goal of this study is to address if detection rates of clinically significant prostate cancer (csPCa) can be increased by additional perilesional biopsies (PB) in magnetic resonance (MR)/ultrasound fusion prostate biopsy in biopsy-naïve men. METHODS: This prospective, non-randomized, surgeon-blinded study was conducted between February 2020 and July 2022. Patients were included with PSA levels < 20 ng/ml and ≥ one PI-RADS lesion (grades 3-5) per prostate lobe. Prostate biopsy was performed by two urologists. The first performed the MR-fusion biopsy with 3-5 targeted biopsies (TB) and 6 PB in a standardized pattern. The second performed the systematic (12-fold) biopsy (SB) without knowledge of the MR images. Primary outcome of this study is absence or presence of csPCa (≥ ISUP grade 2) comparing TB, PB and SB, using McNemar test. RESULTS: Analyses were performed for each PI-RADS lesion (n = 218). There was a statistically significant difference in csPC detection rate of TB + SB between PI-RADS 3, 4 and 5 lesions (18.0% vs. 42.5% vs. 82.6%, p < 0.001) and TB + PB (19.7% vs. 29.1% vs. 78.3%). Comparing only maximum ISUP grade per lesion, even SB plus TB plus PB did not detect more csPCa compared to SB plus TB (41.3% vs. 39.9%, p > 0.05). CONCLUSION: We present prospective study data investigating the role of perilesional biopsy in detection of prostate cancer. We detected no statistically significant difference in the detection of csPCa by the addition of PB. Therefore, we recommend continuing 12-fold bilateral SB in addition to TB.

Individualized center-based analysis of urinary and sexual functional outcome after radical prostatectomy based on the prostate cancer outcome study: a post hoc pathway to patient outcome measurement analysis for quality improvement.

PURPOSE: We evaluate differences of patient-reported outcome measurements (PROM) based urinary continence and sexual function 12 months after radical prostatectomy (RPE) based on perioperative, surgical, and patient-specific characteristics in a large European academic urology center. MATERIALS AND METHODS: All men enrolled in the Prostate Cancer Outcome Study (PCO) study who were treated with RPE between 2017 and 2021 completed EPIC-26 information surveys before and 12 months after RPE. Survey data were linked to clinical data of our institution. Logistic regression analyses were performed to examine the correlation between individual surgeons, patient characteristics, patient clinical data, and their urinary continence and sexual function. RESULTS: In total, data of 429 men were analyzed: unstratified mean (SD) EPIC-26 domain score for urinary function decreased from 93.3 (0.7) to 60.4 (1.5) one year after RPE, respectively for sexual function from 64.95 (1.6) to 23.24 (1.1). Patients with preoperative adequate urinary function (EPIC-26 score > 80) reported significantly different mean urinary function scores between 53.35 (28.88) and 66.25 (25.15), p= 0.001, stratified by surgeons experience. On binary logistic regression analyses, only nerve sparing techniques (OR: 1,83, 95% CI: 1.01;3.21; p = 0.045) and low body mass index (OR: 0.91, CI: 0.85;0.99, p= 0.032) predicted adequate postoperative urinary function. CONCLUSIONS: The results show how using provider-specific data from a larger cohort study enables to develop institution-specific analysis for functional outcomes after RPE. These models can be used for internal quality improvement as well as enhanced and provider-specific patient communication and shared decision making.

Sulforaphane Inhibits Adhesion and Migration of Cisplatin- and Gemcitabine-Resistant Bladder Cancer Cells In Vitro.

Only 20% of patients with muscle-invasive bladder carcinoma respond to cisplatin-based chemotherapy. Since the natural phytochemical sulforaphane (SFN) exhibits antitumor properties, its influence on the adhesive and migratory properties of cisplatin- and gemcitabine-sensitive and cisplatin- and gemcitabine-resistant RT4, RT112, T24, and TCCSUP bladder cancer cells was evaluated. Mechanisms behind the SFN influence were explored by assessing levels of the integrin adhesion receptors ß1 (total and activated) and ß4 and their functional relevance. To evaluate cell differentiation processes, E- and N-cadherin, vimentin and cytokeratin (CK) 8/18 expression were examined. SFN down-regulated bladder cancer cell adhesion with cell line and resistance-specific differences. Different responses to SFN were reflected in integrin expression that depended on the cell line and presence of resistance. Chemotactic movement of RT112, T24, and TCCSUP (RT4 did not migrate) was markedly blocked by SFN in both chemo-sensitive and chemo-resistant cells. Integrin-blocking studies indicated ß1 and ß4 as chemotaxis regulators. N-cadherin was diminished by SFN, particularly in sensitive and resistant T24 and RT112 cells, whereas E-cadherin was increased in RT112 cells (not detectable in RT4 and TCCSup cells). Alterations in vimentin and CK8/18 were also apparent, though not the same in all cell lines. SFN exposure resulted in translocation of E-cadherin (RT112), N-cadherin (RT112, T24), and vimentin (T24). SFN down-regulated adhesion and migration in chemo-sensitive and chemo-resistant bladder cancer cells by acting on integrin ß1 and ß4 expression and inducing the mesenchymal-epithelial translocation of cadherins and vimentin. SFN does, therefore, possess potential to improve bladder cancer therapy.

Robotic-assisted vs. open ureteral reimplantation: a multicentre comparison.

PURPOSE: Open ureteral reimplantation is considered the standard surgical approach to treat distal ureteral strictures or injuries. These procedures are increasingly performed in a minimally invasive and robotic-assisted manner. Notably, no series comparing perioperative outcomes and safety of the open vs. robotic approach are available so far. METHODS: In this retrospective multi-center study, we compared data from 51 robotic ureteral reimplantations (RUR) with 79 open ureteral reimplantations (OUR). Both cohorts were comparatively assessed using different baseline characteristics and perioperative outcomes. Moreover, a multivariate logistic regression for independent predictors was performed. RESULTS: Surgery time, length of hospital stay and dwell time of bladder catheter were shorter in the robotic cohort, whereas estimated blood loss, postoperative blood transfusion rate and postoperative complications were lower than in the open cohort. In the multivariate linear regression analysis, robotic approach was an independent predictor for a shorter operation time (coefficient - 0.254, 95% confidence interval [CI] - 0.342 to - 0.166; p < 0.001), a lower estimated blood loss (coefficient - 0.390, 95% CI - 0.549 to - 0.231, p < 0.001) and a shorter length of hospital stay (coefficient - 0.455, 95% CI - 0.552 to - 0.358, p < 0.001). Moreover, robotic surgery was an independent predictor for a shorter dwell time of bladder catheter (coefficient - 0.210, 95% CI - 0.278 to - 0.142, p < 0.001). CONCLUSION: RUR represents a safe alternative to OUR, with a shorter operative time, decreased blood loss and length of hospital stay. Prospective research are needed to further define the extent of the advantages of the robotic approach over open surgery.

Clinical Impact and Management of Incidental Renal Findings on Pre-TAVI CT Scan from the Urologist's Perspective.

INTRODUCTION: The aim of the study was to investigate prevalence and impact of incidental renal masses (IRMs) accompanying increasing computed tomography (CT) work-up for symptomatic aortic valve stenosis (sAVS) of the elderly with regard to the relevance of urological consultation for overall survival (OS). METHODS: A retrospective analysis of pre-transcatheter aortic-valve implantations (TAVIs) CT scans of patients with sAVS (N = 1,253) harboring IRM was performed for 2014-2019. According to the clinical management, groups 1 (urologic consultation) and 2 (findings ignored) were formed and analyzed in terms of OS. RESULTS: The prevalence of IRM was 9% (119/1,253). In 19% (23/119), urological advice was sought (group 1). At baseline, group 1 showed a significantly higher rate of malignancy-specific lesions compared to 2 (p < 0.01). Other clinical parameters (e.g., age, cardiological scores, comorbidities) did not differ between groups (p > 0.05). In group 1, 4 (17%) findings were histologically confirmed, of which 3 (13%) underwent surgery. There was no significant difference in median OS at a median follow-up of 24.7 months between groups 1 and 2 with 35.7 (95% CI, 5.9; 65.4) and 47.4 months (95% CI, 33.0; 61.7), respectively (p = 0.4). In Cox regression analysis, chronic kidney disease but not urologic work-up or chronic obstructive pulmonary disease or heart failure emerged as an independent unfavorable predictor of OS (HR 2.44, 95% CI 1.37; 4.36, p = 0.003). CONCLUSION: For the first time, a TAVI population with IRM was analyzed from the urologist's perspective. Urologic co-evaluation and work-up does not confer a significant benefit in terms of OS in this particular population.

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.

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.

Mistletoe Extracts from Different Host Trees Disparately Inhibit Bladder Cancer Cell Growth and Proliferation.

Extracts of European mistletoe (Viscum album) are popular as a complementary treatment for patients with many different cancer types. However, whether these extracts actually block bladder cancer progression remains unknown. The influence of different mistletoe extracts on bladder cancer cell growth and proliferation was investigated by exposing RT112, UMUC3, and TCCSup cells to mistletoe from hawthorn (Crataegi), lime trees (Tiliae), willow trees (Salicis), or poplar trees (Populi). The tumor cell growth and proliferation, apoptosis induction, and cell cycle progression were then evaluated. Alterations in integrin α and ß subtype expression as well as CD44 standard (CD44s) and CD44 variant (CD44v) expressions were evaluated. Cell cycle-regulating proteins (CDK1 and 2, Cyclin A and B) were also investigated. Blocking and knock-down studies served to correlate protein alterations with cell growth. All extracts significantly down-regulated the growth and proliferation of all bladder cancer cell lines, most strongly in RT112 and UMUC3 cells. Alterations in CD44 expression were not homogeneous but rather depended on the extract and the cell line. Integrin α3 was, likewise, differently modified. Integrin α5 was diminished in RT112 and UMUC3 cells (significantly) and TCCSup (trend) by Populi and Salicis. Populi and Salicis arrested UMUC3 in G0/G1 to a similar extent, whereas apoptosis was induced most efficiently by Salicis. Examination of cell cycle-regulating proteins revealed down-regulation of CDK1 and 2 and Cyclin A by Salicis but down-regulation of CDK2 and Cyclin A by Populi. Blocking and knock-down studies pointed to the influence of integrin α5, CD44, and the Cyclin-CDK axis in regulating bladder cancer growth. Mistletoe extracts do block bladder cancer growth in vitro, with the molecular action differing according to the cell line and the host tree of the mistletoe. Integrating mistletoe into a guideline-based treatment regimen might optimize bladder cancer therapy.