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The European Randomised Study of Screening for Prostate Cancer (ERSPC) showed that Prostate-Specific Antigen (PSA) based screening results in a significant prostate cancer mortality reduction. Although there are concerns on overdiagnosis and overtreatment, it has been shown that the benefits can outweigh the harms if screening is stopped in older ages to prevent overdiagnosis. A limited screening program (for example screening at ages 55–59 years), including active surveillance for men with low-risk tumors, can even be cost-saving, compared with testing in an opportunistic setting in the wrong ages, as currently in Europe. Further improvements are expected in the use of active surveillance and in discrimination between indolent and significant disease due to new biomarkers and magnetic resonance imaging. However, these future developments are no reason to postpone feasibility studies of high-quality PSA screening and reduce opportunistic testing at old ages.

Extracellular vesicles (including the subclass exosomes) secreted by cells contain specific proteins and RNA that could be of interest in determining new markers. Isolation/characterization of PCa-derived exosomes from bodily fluids enables us to discover new markers for this disease. Unfortunately, isolation with current techniques (ultracentrifugation) is labor intensive and other techniques are still under development. The goal of our study was to develop a highly sensitive time-resolved fluorescence immunoassay (TR-FIA) for capture/detection of PCa-derived exosomes. In our assay, biotinylated capture antibodies against human CD9 or CD63 were incubated on streptavidin-coated wells. After application of exosomes, Europium-labeled detection antibodies (CD9 or CD63) were added. Cell medium from 37 cell lines was taken to validate this TR-FIA. Urine was collected (after digital rectal exam) from patients with PCa (n = 67), men without PCa (n = 76). As a control, urine was collected from men after radical prostatectomy (n = 13), women (n = 16) and patients with prostate cancer without digital rectal exam (n = 16). Signal intensities were corrected for urinary PSA and creatinine. This TR-FIA can measure purified exosomes with high sensitivity and minimal background signals. Exosomes can be measured in medium from 37 cell lines and in urine. DRE resulted in a pronounced increase in CD63 signals. After DRE and correction for urinary PSA, CD9 and CD63 were significantly higher in men with PCa. This TR-FIA enabled us to measure exosomes with high sensitivity directly from urine and cell medium. This TR-FIA forms the basis for testing different antibodies directed against exosome membrane markers to generate disease-specific detection assays.

The European Randomised Study of Screening for Prostate Cancer (ERSPC) showed that Prostate-Specific Antigen (PSA) based screening results in a significant prostate cancer mortality reduction. Although there are concerns on overdiagnosis and overtreatment, it has been shown that the benefits can outweigh the harms if screening is stopped in older ages to prevent overdiagnosis. A limited screening program (for example screening at ages 55-59 years), including active surveillance for men with low-risk tumors, can even be cost-saving, compared with testing in an opportunistic setting in the wrong ages, as currently in Europe. Further improvements are expected in the use of active surveillance and in discrimination between indolent and significant disease due to new biomarkers and magnetic resonance imaging. However, these future developments are no reason to postpone feasibility studies of high-quality PSA screening and reduce opportunistic testing at old ages.

We aim to identify and characterize "escapes,'' men who developed metastasis and/or died from prostate cancer (PCa) despite screening, in the framework of the novel international ESCAPE-project. With this knowledge, the ultimate goal is to improve screening strategy. In this article, we focus on the study cohort of the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam. In all, 21,210 men were randomized to the screening arm of whom 19,950 were actually screened. The screening interval was 4 years. Men with prostate-specific antigen >= 3.0 ng/ml were recommended to undergo lateralized sextant prostate biopsy. The follow-up was complete until January 1, 2009. Of 19,950 screened men, 2,317 were diagnosed with PCa. Of these cancers 1,946 were detected in a screening round and 371 during an interval. The median follow-up was 11.1 years for the whole cohort and 7.3 years for men diagnosed with PCa. In total, we identified 168 escapes among 2,317 cancers (7.3%) within our screening cohort of 19,950 men (0.8%). More than half of these escapes were found in the initial screening round (94 of 168). Possible mechanisms behind escaping are nonattending, inadequate screening tests, the relative long screening interval, the age cut-off at 75 years, and undertreatment. International cooperation is crucial to compare the escapes of our cohort with other study groups participating in the ESCAPE-project which have different, more aggressive screening strategies. Subsequently, we can achieve improvements of the current screening algorithm, which hopefully will further decrease PCa-specific mortality without increasing overdiagnosis and overtreatment.

Our objective was to determine whether multivariate algorithms based on serum total PSA, the free proportion of PSA, age, digital rectal examination and prostate volume can reduce the rate of false-positive PSA results in prostate cancer screening more effectively than the proportion of free PSA alone at 95% sensitivity. A total of 1,775 consecutive 55- to 67-year-old men with a serum PSA of 4-10 microg/l in the European Randomized Study of Screening for Prostate Cancer were included. To predict the presence of cancer, multivariate algorithms were constructed using logistic regression (LR) and a multilayer perceptron neural network with Bayesian regularization (BR-MLP). A prospective setting was simulated by dividing the data set chronologically into one set for training and validation (67%, n = 1,183) and one test set (33%, n = 592). The diagnostic models were calibrated using the training set to obtain 95% sensitivity. When applied to the test set, the LR model, the BR-MLP model and the proportion of free PSA reached 92%, 87% and 94% sensitivity and reduced 29%, 36% and 22% of the false-positive PSA results, respectively. At a fixed sensitivity of 95% in the test set, the LR model eliminated more false-positive PSA results (22%) than the proportion of free PSA alone (17%) (p < 0.001), whereas the BR-MLP model did not (19%) (p = 0.178). The area under the ROC curve was larger for the LR model (0.764, p = 0.030) and the BR-MLP model (0.760, p = 0.049) than for the proportion of free PSA (0.718). A multivariate algorithm can be used to reduce unnecessary prostate biopsies in screening more effectively than the proportion of free PSA alone, but the algorithms will require updating when clinical practice develops with time.

Extracellular vesicles (including the subclass exosomes) secreted by cells contain specific proteins and RNA that could be of interest in determining new markers. Isolation/characterization of PCa-derived exosomes from bodily fluids enables us to discover new markers for this disease. Unfortunately, isolation with current techniques (ultracentrifugation) is labor intensive and other techniques are still under development. The goal of our study was to develop a highly sensitive time-resolved fluorescence immunoassay (TR-FIA) for capture/detection of PCa-derived exosomes. In our assay, biotinylated capture antibodies against human CD9 or CD63 were incubated on streptavidin-coated wells. After application of exosomes, Europium-labeled detection antibodies (CD9 or CD63) were added. Cell medium from 37 cell lines was taken to validate this TR-FIA. Urine was collected (after digital rectal exam) from patients with PCa (n = 67), men without PCa (n = 76). As a control, urine was collected from men after radical prostatectomy (n = 13), women (n = 16) and patients with prostate cancer without digital rectal exam (n = 16). Signal intensities were corrected for urinary PSA and creatinine. This TR-FIA can measure purified exosomes with high sensitivity and minimal background signals. Exosomes can be measured in medium from 37 cell lines and in urine. DRE resulted in a pronounced increase in CD63 signals. After DRE and correction for urinary PSA, CD9 and CD63 were significantly higher in men with PCa. This TR-FIA enabled us to measure exosomes with high sensitivity directly from urine and cell medium. This TR-FIA forms the basis for testing different antibodies directed against exosome membrane markers to generate disease-specific detection assays.

Prostate cancer (PC) mortality is the most valid end-point in screening trials, but could be influenced by the choice of initial treatment if treatment has an effect on mortality. In this study, PC treatment was compared between the screening and control arms in a screening trial. Data were collected from the European Randomized Study of Screening for Prostate Cancer (ERSPC). The characteristics and initial treatment of PC cases detected in the screening and the control arm were compared. Polytomous logistic regression analysis was used to assess the influence of study arm on treatment, adjusting for potential confounders and with statistical imputation of missing values. A total of 8,389 PC cases were detected, 5,422 in the screening arm and 3,145 in the control arm. Polytomous regression showed that trial arm was associated with treatment choice after correction for missing values, especially in men with high-risk PC. A control subject with high-risk PC was more likely than a screen subject to receive radiotherapy (OR: 1.43, 95% CI: 1.01-2.05, p = 0.047), expectant management (OR: 2.92, 95% CI: 1.33-6.42, p = 0.007) or hormonal treatment (OR: 1.77, 95% CI: 1.07-2.94, p = 0.026) instead of radical prostatectomy. However, trial arm had only a minor role in treatment choice compared to other variables. In conclusion, a small effect of trial arm on treatment choice was seen, particularly in men with high-risk PC. Therefore, differences in treatment between arms are unlikely to play a major role in the interpretation of the results of the ERSPC.