Comparison of ciprofloxacin versus fosfomycin versus fosfomycin plus trimethoprim/sulfamethoxazole for preventing infections after transrectal prostate biopsy.

BACKGROUND: To evaluate antibiotic prophylaxis in transrectal prostate biopsies due to the recommendation of the European Medicines Agency (EMA): We describe our single center experience switching from ciprofloxacin to fosfomycin trometamol (FMT) alone and to an augmented prophylaxis combining fosfomycin and trimethoprim/sulfamethoxazole (TMP/SMX). METHODS: Between 01/2019 and 12/2020 we compared three different regimes. The primary endpoint was the clinical diagnosis of an infection within 4 weeks after biopsy. We enrolled 822 men, 398 (48%) of whom received ciprofloxacin (group-C), 136 (16.5%) received FMT (group-F) and 288 (35%) received the combination of TMP/SMX and FMT (group-BF). RESULTS: Baseline characteristics were similar between groups. In total 37/398 (5%) postinterventional infections were detected, of which 13/398 (3%) vs 18/136 (13.2%) vs 6/288 (2.1%) were detected in group-C, group-F and group-BF respectively. The relative risk of infectious complication was 1.3 (CI 0.7-2.6) for group-C vs. group-BF and 2.8 (CI 1.4-5.7) for group-F vs. group-BF respectively. CONCLUSION: The replacement of ciprofloxacin by fosfomycin alone resulted in a significant increase of postinterventional infections, while the combination of FMT and TMP/SMX had a comparable infection rate to FQ without apparent adverse events. Therefore, this combined regimen of FMT and TMP/SMX is recommended.

Prostate cancer screening in Switzerland: a literature review and consensus statement from the Swiss Society of Urology.

Over a decade ago, the United States Preventive Services Taskforce (USPSTF) recommended against prostate-specific antigen (PSA)-based screening for prostate cancer in all men, which considerably influenced prostate cancer screening policies worldwide after that. Consequently, the world has seen increasing numbers of advanced stages and prostate cancer deaths, which later led the USPSTF to withdraw its initial statement. Meanwhile, the European Union has elaborated a directive to address the problem of implementing prostate cancer screening in "Europe's Beating Cancer Plan". In Switzerland, concerned urologists formed an open Swiss Prostate Cancer Screening Group to improve the early detection of prostate cancer. On the 20th of September 2023, during the annual general assembly of the Swiss Society of Urology (SGU/SSU) in Lausanne, members positively voted for a stepwise approach to evaluate the feasibility of implementing organised prostate cancer screening programs in Switzerland. The following article will summarise the events and scientific advances in the last decade during which evidence and promising additional modalities to complement PSA-based prostate cancer screening have emerged. It also aims to provide an overview of contemporary strategies and their potential harms and benefits.

Retrospective Evaluation of a Single Surgeon's Learning Curve of Robot-Assisted Radical Cystectomy with Intracorporeal Urinary Diversion via Ileal Conduit.

Robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) is increasingly being performed instead of open surgery. A criticism of this technique is the long learning curve, but limited data are available on this topic. At our center, the transition from open radical cystectomy (ORC) to iRARC began in May 2017. A retrospective analysis was conducted on the initial 53 cases of robot-assisted cystectomy with intracorporeal urinary diversion via ileal conduit, which were performed by one single surgeon. The patients were divided into four consecutive groups according to the surgeon's increasing experience, and perioperative parameters were analyzed as a surrogate for the learning curve. Over the course of the learning curve, a decline in median operation time from 415 to 361 min (p = 0.02), blood loss from 400 to 200 mL (p = 0.01), and minor complications from 71% to 15% (p = 0.02) was observed. No significant difference in overall and major complications, length of hospital stay, and total lymph node yield was shown. During the initial period of the learning curve, only the less complex cases were operated on using robotic surgery, while the more challenging ones were handled through open surgery. After experience with 28 cases, no more cystectomies were performed through open surgery. This led to an increase in operation time and length of hospital stay, as well as a higher incidence of both minor and overall complications among cases 28-40. After 40 cases, a significant decrease in these parameters was observed again. Our analysis demonstrated that operation time, blood loss, and minor complications decrease with increasing surgical experience in iRARC, while suggesting that technically challenging cases should be operated on after experience with 40 robotic cystectomies.

Patient and General Population Preferences Regarding the Benefits and Harms of Treatment for Metastatic Prostate Cancer: A Discrete Choice Experiment.

Background: Patient preferences for treatment outcomes are important to guide decision-making in clinical practice, but little is known about the preferences of patients with metastatic hormone-sensitive prostate cancer (mHSPC). Objective: To evaluate patient preferences regarding the attributed benefits and harms of systemic treatments for mHSPC and preference heterogeneity between individuals and specific subgroups. Design setting and participants: We conducted an online discrete choice experiment (DCE) preference survey among 77 patients with metastatic prostate cancer (mPC) and 311 men from the general population in Switzerland between November 2021 and August 2022. Outcome measurements and statistical analysis: We evaluated preferences and preference heterogeneity related to survival benefits and treatment-related adverse effects using mixed multinomial logit models and estimated the maximum survival time participants were willing to trade to avert specific adverse effects. We further assessed characteristics associated with different preference patterns via subgroup and latent class analyses. Results and limitations: Patients with mPC showed an overall stronger preference for survival benefits in comparison to men from the general population (p = 0.004), with substantial preference heterogeneity between individuals within the two samples (both p < 0.001). There was no evidence of differences in preferences for men aged 45-65 yr versus ≥65 yr, patients with mPC in different disease stages or with different adverse effect experiences, or general population participants with and without experiences with cancer. Latent class analyses suggested the presence of two groups strongly preferring either survival or the absence of adverse effects, with no specific characteristic clearly associated with belonging to either group. Potential biases due to participant selection, cognitive burden, and hypothetical choice scenarios may limit the study results. Conclusions: Given the relevant heterogeneity in participant preferences regarding the benefits and harms of treatment for mHSPC, patient preferences should be explicitly discussed during decision-making in clinical practice and reflected in clinical practice guidelines and regulatory assessment regarding treatment for mHSPC. Patient summary: We examined the preferences (values and perceptions) of patients and men from the general population regarding the benefits and harms of treatment for metastatic prostate cancer. There were large differences between men in how they balanced the expected survival benefits and potential adverse effects. While some men strongly valued survival, others more strongly valued the absence of adverse effects. Therefore, it is important to discuss patient preferences in clinical practice.

Apalutamide and autophagy inhibition in a xenograft mouse model of human prostate cancer.

BACKGROUND: Apalutamide (APA) is a next-generation androgen receptor antagonist for the treatment of advanced prostate cancer. We have previously shown that upregulation of autophagy is one of the mechanisms by which prostate cancer (PC) cells survive APA anti-tumor treatment in vitro. Therefore, we investigated the characteristics of the autophagic response to APA treatment, alone and in combination with autophagy inhibition, in an in vivo model. METHODS: Tumor cells were injected into previously castrated nude mice. Four groups of mice bearing LNCaP xenografts were treated with daily intraperitoneal (i.p.) injections of vehicle (control), APA (10 mg/kg), APA (10 mg/kg) + Chl (Chloroquine, 10 mg/kg) or Chl (10 mg/kg). The animals of each treatment group (3/treatment) were kept for the duration of 2 and 3 weeks. At the end of the experiments, the animals were sacrificed and all samples assessed for tumor weight and size, histological analysis, immunoblotting (WES) and immunofluorescence. RESULTS: The tumor weight was significantly reduced in mice treated with APA + Chl (203.2 ± 5.0, SEM, P = 0.0066) compared to vehicle control (380.4 ± 37.0). Importantly, the combined treatment showed a higher impact on tumor weight than APA (320.4 ± 45.5) or Chl (337.9 ± 35) alone. The mice treated with the combination of APA + Chl exhibited a reduced expression of ATG5 (autophagy-related five protein), Beclin 1 and LC3 punctuations and an increase in P62 as visualized by immunofluorescence and WES. In addition, Ki-67 nuclear staining was detected in all samples however reduced in APA + Chl (58%) compared to vehicle control (100%). The reduction in Ki-67 protein was associated with an increase in caspase 3 and endothelial CD31 protein expression. CONCLUSION: These data demonstrate that a treatment with APA + Chl leads to reduced autophagy levels and to tumor suppression compared to the APA monotherapy. Hence, the increased antitumor effect of APA in combination with autophagy inhibitors might provide a new therapeutic approach potentially translatable to patients.

Extracellular Vesicles from 3D Engineered Microtissues Harbor Disease-Related Cargo Absent in EVs from 2D Cultures.

Engineered microtissues that recapitulate key properties of the tumor microenvironment can induce clinically relevant cancer phenotypes in vitro. However, their effect on molecular cargo of secreted extracellular vesicles (EVs) has not yet been investigated. Here, the impact of hydrogel-based 3D engineered microtissues on EVs secreted by benign and malignant prostate cells is assessed. Compared to 2D cultures, yield of EVs per cell is significantly increased for cancer cells cultured in 3D. Whole transcriptome sequencing and proteomics of 2D-EV and 3D-EV samples reveal stark contrasts in molecular cargo. For one cell type in particular, LNCaP, enrichment is observed exclusively in 3D-EVs of GDF15, FASN, and TOP1, known drivers of prostate cancer progression. Using imaging flow cytometry in a novel approach to validate a putative EV biomarker, colocalization in single EVs of GDF15 with CD9, a universal EV marker, is demonstrated. Finally, in functional assays it is observed that only 3D-EVs, unlike 2D-EVs, confer increased invasiveness and chemoresistance to cells in 2D. Collectively, this study highlights the value of engineered 3D microtissue cultures for the study of bona fide EV cargoes and their potential to identify biomarkers that are not detectable in EVs secreted by cells cultured in standard 2D conditions.

Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study.

Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. Reportedly, DSF in combination with Cu2+ ions exerts multiple tumoricidal, chemo- and radio-therapy-sensitizing effects in several tumor entities. The present study aimed to quantify these DSF effects in glioblastoma stem cells in vitro, regarding dependence on ALDH1A3 expression. To this end, two patient-derived GSC cultures with differing ALDH1A3 expression were pretreated (in the presence of CuSO4, 100 nM) with DSF (0 or 100 nM) and the DNA-alkylating agent temozolomide (0 or 30 µM) and then cells were irradiated with a single dose of 0-8 Gy. As read-outs, cell cycle distribution and clonogenic survival were determined by flow cytometry and limited dilution assay, respectively. As a result, DSF modulated cell cycle distribution in both GSC cultures and dramatically decreased clonogenic survival independently of ALDH1A3 expression. This effect was additive to the impairment of clonogenic survival by radiation, but not associated with radiosensitization. Of note, cotreatment with temozolomide blunted the DSF inhibition of clonogenic survival. In conclusion, DSF targets GSCs independent of ALDH1A3 expression, suggesting a therapeutic efficacy also in glioblastomas with low mesenchymal GSC populations. As temozolomide somehow antagonized the DSF effects, strategies for future combination of DSF with the adjuvant standard therapy (fractionated radiotherapy and concomitant temozolomide chemotherapy followed by temozolomide maintenance therapy) are not supported by the present study.

Impact of short-term Dutasteride treatment on prostate-specific membrane antigen expression in a mouse xenograft model.

BACKGROUND: Dutasteride has been shown to increase expression of the prostate-specific membrane antigen (PSMA) in prostate cancer cells in previous in vitro studies. This 5-alpha-reductase inhibitor is commonly used for the treatment of symptomatic benign prostatic enlargement. The modulation of PSMA expression might affect PSMA-based prostate cancer imaging and therapy. AIM: The purpose of this work was to further analyze concentration-dependent effects of Dutasteride on PSMA expression in a mouse xenograft model. METHODS AND RESULTS: Four groups of mice bearing LNCaP xenografts were treated for 14 days with daily intraperitoneal injections of either vehicle control or different concentrations of Dutasteride (0.1, 1, 10 mg/kg). Total expression of PSMA, androgen receptor (AR), and caspase-3 protein was analyzed using immunoblotting (WES). In addition, PSMA, cleaved caspase-3 and Ki-67 expression was assessed and quantified by immunohistochemistry. Tumor size was measured by caliper on day 7 and 14, tumor weight was assessed following tissue harvesting. The mean PSMA protein expression in mice increased significantly after treatment with 1 mg/kg (10-fold) or 10 mg/kg (sixfold) of Dutasteride compared to vehicle control. The mean fluorescence intensity significantly increased by daily injections of 0.1 mg/kg Dutasteride (1.6-fold) as well as 1 and 10 mg/kg Dutasteride (twofold). While the reduction in tumor volume following treatment with high concentrations of 10 mg/kg Dutasteride was nonsignificant, no changes in AR, caspase-3, cleaved caspase-3, and Ki-67 expression were observed. CONCLUSION: Short-term Dutasteride treatments with concentrations of 1 and 10 mg/kg significantly increase the total PSMA protein expression in a mouse LNCaP xenograft model. PSMA fluorescence intensity increases significantly even using lower daily concentrations of 0.1 mg/kg Dutasteride. Further investigations are needed to elucidate the impact of Dutasteride treatment on PSMA expression in patients.

Influence of regular aspirin intake on PSA values, prostate cancer incidence and overall survival in a prospective screening trial (ERSPC Aarau).

OBJECTIVES: To analyze the influence of aspirin (ASA) intake on PSA values and prostate cancer (PCa) development in a prospective screening study cohort. METHODS: 4314 men from the Swiss section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were included. A transrectal prostate biopsy was performed in men with a PSA level ≥ 3 ng/ml. Mortality data were obtained through registry linkages. PCa incidence and grade, total PSA, free-to-total PSA and overall survival were compared between ASA users and non-users. RESULTS: Median follow-up time was 9.6 years. In 789 men (18.3%) using aspirin [ASA +], the overall PCa incidence was significantly lower (6.8% vs. 9.6%, p = 0.015), but the multivariate Cox regression analysis showed no significant decrease in risk of PCa diagnosis (HR 0.84, p = 0.297). Total PSA values were significantly lower in ASA users for both baseline (1.6 vs. 1.8 ng/ml, p = 0.007) and follow-up visits (1.75 vs. 2.1 ng/ml, p < 0.001). Multivariate Cox regression analysis predicted significantly higher overall mortality risk among ASA users (HR 1.46, p = 0.009). CONCLUSIONS: In our study population, PCa incidence was significantly reduced among patients on aspirin. While we did not observe a statistically significant PCa risk reduction during the follow-up period, we found lower PSA values among ASA users compared to non-users, with a more distinct difference after 4 years of ASA intake, suggesting a cumulative effect and a potential protective association between regular ASA intake and PCa development. As for clinical practice, lowering PSA cutoff values by 0.4 ng/ml could be considered in long-term ASA users to avoid a potential bias towards delayed PCa detection.