5-Azacytidine and 5-aza-2'-deoxycytidine behave as different antineoplastic agents in B16 melanoma.

The antiproliferative effects of 5-azacytidine (acaCyd) and 5-aza-2'-deoxycytidine (azadCyd) were studied in murine B16 melanoma and a series of B16 melanoma derived mutant strains with selective resistances to the respective drugs. The in vitro cytotoxicities of azaCyd and azadCyd on B16 wild type, expressed in terms of IC50 values, were found to be 5 microM and 0.2 microM, respectively. The in vitro cytotoxicity of both drugs was dependent on the duration of exposure. Uridine and cytidine were able to reverse the in vitro cytotoxicity of azaCyd, but not of azadCyd. Conversely, 2'-deoxycytidine was able to reverse the cytotoxic effect of azadCyd but not of azaCyd. Thymidine and 2'-deoxyuridine had no detectable effects on the in vitro cytotoxicity of either azaCyd or azadCyd. B16 melanoma mutant strains that were selected for resistance to azaCyd showed no cross-resistance to azadCyd, cytosine arabinoside or the fluorinated pyrimidine analogues FUrd, FCyd, FdUrd and FdCyd. Mutant strains that were selected for resistance to azadCyd showed no cross-resistance to azaCyd or fluorinated pyrimidine analogs, but only to cytosine arabinoside. The combined data suggest that azaCyd and azadCyd follow different routes of intracellular metabolic activation and exert their cytotoxic activity via different intracellular targets

Prostate cancer screening in Europe and Asia

Prostate cancer (PCa) is the second most common cancer among men worldwide and even ranks first in Europe. Although Asia is known as the region with the lowest PCa incidence, it has been rising rapidly over the last 20 years mostly due to the introduction of prostate-specific antigen (PSA) testing. Randomized PCa screening studies in Europe show a mortality reduction in favor of PSA-based screening but coincide with high proportions of unnecessary biopsies, overdiagnosis and subsequent overtreatment. Conclusive data on the value of PSA-based screening and hence the balance between harms and benefits in Asia is still lacking. Because of known racial variations, Asian countries should not directly apply the European screening models. Like in the western world also in Asia, new predictive markers, tools and risk stratification strategies hold great potential to improve the early detection of PCa and to reduce the worldwide existing negative aspects of PSA-based PCa screening

Comparison of clinically significant prostate cancer detection by MRI cognitive biopsy and in-bore MRI-targeted biopsy for naïve biopsy patients

Background: Multiparametric magnetic resonance imaging (mpMRI) targeted prostate biopsy increases the diagnostic accuracy of clinically significant prostate cancer (PCa). Currently there is no consensus on which type of MRI-targeted biopsy performs better in a given setting. In this study, we aimed to compare the detection rate of (clinically significant) PCa by MRI cognitive targeted biopsy (COG) and in-bore MRI-targeted biopsy (IB) techniques for naïve prostate biopsy patients in China. Methods: Our study included 85 men from Beijing United Family Hospital and Clinics and 88 men from Beijing Hospital, National Center of Gerontology. All men had no history of prostate biopsy, undergoing mpMRI scan due to elevated PSA and/or abnormal DRE. The men in Beijing United Family Hospital group received COG plus systematic biopsy. The men in Beijing Hospital group only received IB. Results: The median age in COG and IB group was 63.0 years and 70.0 years (P<0.01). The median PSA was 7.4 and 6.8 ng/mL in COG and IB group respectively (P=0.124). The detection rate of PCa was 36.5% by COG and 52.3% by IB (P=0.037). The detection rate of clinically significant PCa (Gleason score ≥7) was 23.5% and 29.5% by COG and IB (P=0.371) respectively. In COG group, combination biopsy (COG + systematic biopsy) achieved improved PCa (42.4%) and clinically s

Improving Guideline Adherence in Urology

CONTEXT: Clinical practice guidelines (CPGs) distil an evidence base into recommendations. CPG adherence is associated with better patient outcomes. However, preparation and dissemination of CPGs are a costly task involving multiple skilled personnel. Furthermore, dissemination alone does not ensure CPG adherence. Reasons for nonadherence are often complex, but understanding practice variations and reasons for nonadherence is key to improving CPG adherence and harmonising clinically appropriate and cost-effective care. OBJECTIVE: To overview approaches to improving guideline adherence, to provide urology-specific examples of knowledge-practice gaps, and to highlight potential solutions informed by implementation science. EVIDENCE ACQUISITION: Three common approaches to implementation science (the Knowledge-To-Action framework, the Consolidated Framework for Implementation Research, and the Behaviour Change Wheel), are summarised. EVIDENCE SYNTHESIS: Three implementation problems in urology are illustrated: underuse of single instillation of intravesical chemotherapy in non-muscle-invasive bladder cancer, overuse of androgen deprivation therapy in localised prostate cancer, and guideline-discordant imaging in prostate cancer. Research using implementation science approaches to address these implementation problems is discussed. CONCLUSIONS: Urologists, patients, health care providers, funders, and other key stakeholders must commit to reliably capturing and reporting data on patient outcomes, practice variations, guideline adherence, and the impact of adherence on outcomes. Leverage of implementation science frameworks is a sound next step towards improving guideline adherence and the associated benefits of evidence-based care. PATIENT SUMMARY: Clinical practice guideline documents are created by expert panels. These documents provide overviews of the evidence for the tests and treatments used in patient care. They also provide recommendations and it is expected that in most circumstances clinicians will follow these recommendations. Sometimes, health care professionals cannot or do not follow these recommendations and it is not always clear why. In this review article we look at some examples of research approaches to addressing this problem of nonadherence and we provide some examples specific to urology

A Multivariable Approach Using Magnetic Resonance Imaging to Avoid a Protocol-based Prostate Biopsy in Men on Active Surveillance for Prostate Cancer-Data from the International Multicenter Prospective PRIAS Study

Publisher Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.BACKGROUND: There is ongoing discussion whether a multivariable approach including magnetic resonance imaging (MRI) can safely prevent unnecessary protocol-advised repeat biopsy during active surveillance (AS). OBJECTIVE: To determine predictors for grade group (GG) reclassification in patients undergoing an MRI-informed prostate biopsy (MRI-Bx) during AS and to evaluate whether a confirmatory biopsy can be omitted in patients diagnosed with upfront MRI. DESIGN, SETTING, AND PARTICIPANTS: The Prostate cancer Research International: Active Surveillance (PRIAS) study is a multicenter prospective study of patients on AS (www.prias-project.org). We selected all patients undergoing MRI-Bx (targeted ± systematic biopsy) during AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A time-dependent Cox regression analysis was used to determine the predictors of GG progression/reclassification in patients undergoing MRI-Bx. A sensitivity analysis and a multivariable logistic regression analysis were also performed. RESULTS AND LIMITATIONS: A total of 1185 patients underwent 1488 MRI-Bx sessions. The time-dependent Cox regression analysis showed that age (per 10 yr, hazard ratio [HR] 0.84 [95% confidence interval {CI} 0.71-0.99]), MRI outcome (Prostate Imaging Reporting and Data System [PIRADS] 3 vs negative HR 2.46 [95% CI 1.56-3.88], PIRADS 4 vs negative HR 3.39 [95% CI 2.28-5.05], and PIRADS 5 vs negative HR 4.95 [95% CI 3.25-7.56]), prostate-specific antigen (PSA) density (per 0.1 ng/ml cm3, HR 1.20 [95% CI 1.12-1.30]), and percentage positive cores on the last systematic biopsy (per 10%, HR 1.16 [95% CI 1.10-1.23]) were significant predictors of GG reclassification. Of the patients with negative MRI and a PSA density of <0.15 ng/ml cm3 (n = 315), 3% were reclassified to GG ≥2 and 0.6% to GG ≥3. At the confirmatory biopsy, reclassification to GG ≥2 and ≥3 was observed in 23% and 7% of the patients diagnosed without upfront MRI and in 19% and 6% of the patients diagnosed with upfront MRI, respectively. The multivariable analysis showed no significant difference in upgrading at the confirmatory biopsy between patients diagnosed with or without upfront MRI. CONCLUSIONS: Age, MRI outcome, PSA density, and percentage positive cores are significant predictors of reclassification at an MRI-informed biopsy. Patients with negative MRI and a PSA density of <0.15 ng/ml cm3 can safely omit a protocol-based prostate biopsy, whereas in other patients, a multivariable approach is advised. Being diagnosed with upfront MRI appears not to significantly affect reclassification risk; hence, a confirmatory MRI-Bx cannot totally be omitted yet. PATIENT SUMMARY: A protocol-based prostate biopsy while on active surveillance can be omitted in patients with negative magnetic resonance imaging (MRI) and prostate-specific antigen density <0.15 ng/ml cm3. A confirmatory biopsy cannot simply be omitted in all patients diagnosed with upfront MRI.Peer reviewe

A four-kallikrein panel for the prediction of repeat prostate biopsy: data from the European Randomized Study of Prostate Cancer Screening in Rotterdam, Netherlands

Background: Most men with elevated levels of prostate-specific antigen (PSA) do not have prostate cancer, leading to a large number of unnecessary biopsies. A statistical model based on a panel of four kallikreins has been shown to predict the outcome of a first prostate biopsy. In this study, we apply the model to an independent data set of men with previous negative biopsy but persistently elevated PSA. Methods: The study cohort consisted of 925 men with a previous negative prostate biopsy and elevated PSA (≥3 ng ml-1), with 110 prostate cancers detected (12%). A previously published statistical model was applied, with recalibration to reflect the lower positive biopsy rates on rebiopsy. Results: The full-kallikrein panel had higher discriminative accuracy than PSA and DRE alone, with area under the curve (AUC) improving from 0.58 (95% confidence interval (CI): 0.52, 0.64) to 0.68 (95% CI: 0.62, 0.74), P<0.001, and high-grade cancer (Gleason 7) at biopsy with AUC improving from 0.76 (95% CI: 0.64, 0.89) to 0.87 (95% CI: 0.81, 0.94), P<0.003). Application of the panel to 1000 men with persistently elevated PSA after initial negative biopsy, at a 15% risk threshold would reduce the number of biopsies by 712; would miss (or delay) the diagnosis of 53 cancers, of which only 3 would be Gleason 7 and the rest Gleason 6 or less. Conclusions: Our data constitute an external validation of a previously published model. The four-kallikrein panel predicts the result of repeat prostate biopsy in men with elevated PSA while dramatically decreasing unnecessary biopsies

Distribution of Prostate Imaging Reporting and Data System score and diagnostic accuracy of magnetic resonance imaging–targeted biopsy: comparison of an Asian and European cohort

Background: This study aimed to compare the distribution of Prostate Imaging Reporting and Data System (PI-RADS) score and the diagnostic accuracy of magnetic resonance imaging (MRI)–targeted biopsy and systematic biopsy between a Chinese and a Dutch cohort. Materials and methods: Our study includes 316 men from Shanghai Changhai Hospital, China, and 266 men from the Erasmus University Medical Center, Rotterdam, the Netherlands. All men had a suspicion for prostate cancer (PCa) and were offered an multiparametric MRI (mpMRI) scan. Results: The distribution of the PI-RADS score was different between the two cohorts (P = 0.008). In the Chinese cohort of PI-RADS ≥3, the detection rate for high-grade PCa (Gleason ≥7) was 37.3% by systematic biopsy and 35.5% by MRI-targeted biopsy. The sensitivity of systematic biopsy was 0.80 for PCa and 0.75 for high-grade PCa. MRI-targeted biopsy achieved slightly higher sensitivity for PCa (0.82) and high-grade PCa (0.76). In the Dutch cohort of PI-RADS ≥3, the high-grade PCa detection rate was 44.4% and 54.5% for systematic biopsy and MRI-targeted biopsy. The sensitivity of systematic biopsy was 0.93 for PCa and 0.81 for high-grade PCa. By MRI-targeted biopsy, the sensitivity was 0.85 for PCa and 0.97 for high-grade PCa. Conclusions: The distribution of the PI-RADS score was different with more PI-RADS 4/5 in the Chinese cohort. Applying a PI-RADS ≥3 cutoff resulted in a favorable overall sensitivity. MRI-targeted biopsy showed a higher sensitivity in the detection of high-grade PCa than systematic biopsy. The sensitivity of MRI-targeted biopsy and systematic biopsy for both PCa and high-grade PCa in the Dutch cohort was superior to those in the Chinese cohort

IMAGINE-IMpact Assessment of Guidelines Implementation and Education : The Next Frontier for Harmonising Urological Practice Across Europe by Improving Adherence to Guidelines

Funding support: The IMAGINE ADT audit is supported by a seeding grant from the EAU Research Foundation.Peer reviewedPostprin