Marco Randazzo

Metastatic prostate cancer incidence and prostate-specific antigen testing: New insights from the European Randomized Study of Screening for Prostate Cancer

BACKGROUND The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PCa) mortality and a 1.6-fold increase in PCa incidence with prostate-specific antigen (PSA)-based screening (at 13 yr of follow-up). We evaluated PCa incidence by risk category at diagnosis across the study arms to assess the potential impact on PCa mortality. DESIGN, SETTING, AND PARTICIPANTS Information on arm, centre, T and M stage, Gleason score, serum PSA at diagnosis, age at randomisation, follow-up time, and vital status were extracted from the ERSPC database. Four risk categories at diagnosis were defined: 1, low; 2, intermediate; 3, high; 4, metastatic disease. PSA (≤100 or >100 ng/ml) was used as the indicator of metastasis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis. RESULTS AND LIMITATIONS In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03-2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16-1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89-1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52-0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller. CONCLUSIONS The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr. PATIENT SUMMARY The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer.

Absolute Effect of Prostate Cancer Screening: Balance of Benefits and Harms by Center within the European Randomized Study of Prostate Cancer Screening

Purpose: The balance of benefits and harms in prostate cancer screening has not been sufficiently characterized. We related indicators of mortality reduction and overdetection by center within the European Randomized Study of Prostate Cancer Screening (ERSPC). Experimental Design: We analyzed the absolute mortality reduction expressed as number needed to invite (NNI = 1/absolute risk reduction; indicating how many men had to be randomized to screening arm to avert a prostate cancer death) for screening and the absolute excess of prostate cancer detection as number needed for overdetection (NNO = 1/absolute excess incidence; indicating the number of men invited per additional prostate cancer case), and compared their relationship across the seven ERSPC centers. Results: Both absolute mortality reduction (NNI) and absolute overdetection (NNO) varied widely between the centers: NNI, 200–7,000 and NNO, 16–69. Extent of overdiagnosis and mortality reduction was closely associated [correlation coefficient, r = 0.76; weighted linear regression coefficient, β = 33; 95% confidence interval (CI), 5–62; R2 = 0.72]. For an averted prostate cancer death at 13 years of follow-up, 12 to 36 excess cases had to be detected in various centers. Conclusions: The differences between the ERSPC centers likely reflect variations in prostate cancer incidence and mortality, as well as in screening protocol and performance. The strong interrelation between the benefits and harms suggests that efforts to maximize the mortality effect are bound to increase overdiagnosis and might be improved by focusing on high-risk populations. The optimal balance between screening intensity and risk of overdiagnosis remains unclear. Clin Cancer Res; 22(1); 243–9. ©2015 AACR.

Pathological stage distribution in patients treated with radical prostatectomy reflecting the need for protocol‐based active surveillance: results from a contemporary European patient cohort

Study Type – Therapy (case series)

How are we going to train a generation of radiologists (and urologists) to read prostate MRI

Purpose of review Multiparametric MRI has gained tremendous importance in the daily practice for patients at risk or diagnosed with prostate cancer. Interpretation of multiparametric-MRI is a complex task, supposedly restricted to experienced radiologists. The purpose of this review is to analyze fundamentals of multiparametric-MRI interpretation and to describe how multiparametric-MRI training could be organized. Recent findings Recently, professional guidelines have been published to provide technical and interpretation frameworks and harmonize multiparametric-MRI practice, but the question of physicians training in prostate multiparametric-MRI reading is still pending. What kind of education, practice, and training makes a radiologist able to reliably interpret a prostate multiparametric-MRI? How can findings be reported to be easily understood? How much experience is needed? How can we train urologists and other physicians to review the examinations they request? Is double-reading necessary? Summary An institutional-based competency certification process for prostate multiparametric-MRI interpretation may encourage nonspecialized radiologists to qualify for prostate imaging in a standardized and reproducible way, exactly as urologists need it.

Novel biomarkers of acute kidney injury: Evaluation and evidence in urologic surgery

Patients undergoing urologic surgery are at risk of acute kidney injury (AKI) and consequently long-term deterioration in renal function. AKI is further associated with significantly higher odds of perioperative complications, prolonged hospital stay, higher mortality and costs. Therefore, better awareness and detection of AKI, as well as identification of AKI determinants in the urological surgery setting is warranted to pre-empt and mitigate further deterioration of renal function in patients at special risk. New consensus criteria provide precise definitions of diagnosis and description of the severity of AKI. However, they rely on serum creatinine (SCr), which is known to be an inaccurate marker of early changes in renal function. Therefore, several new urinary and serum biomarkers promise to address the gap associated with the use of SCr. Novel biomarkers may complement SCr measurement or most likely improve the diagnostic accuracy of AKI when used in combinations. However, novel biomarkers have to prove their clinical applicability, accuracy, and cost effectiveness prior to implementation into clinical practice. Most preferably, novel biomarkers should help to positively improve a patients long-term renal functional outcomes. The purpose of this review is to discuss currently available biomarkers and to review their clinical evidence within urologic surgery settings.

A positive family history as a risk factor for prostate cancer in a population-based study with organised prostate-specific antigen screening: results of the Swiss European Randomised Study of Screening for Prostate Cancer (ERSPC, Aarau).

To assess the value of a positive family history (FH) as a risk factor for prostate cancer incidence and grade among men undergoing organised prostate‐specific antigen (PSA) screening in a population‐based study.

Is further screening of men with baseline PSA < 1 ng ml−1 worthwhile? The discussion continues—Results of the Swiss ERSPC (Aarau)

Recent studies indicate frequent early PSA retesting unrelated of mens baseline PSA, which increases the harms of early detection especially among men with low PSA. The current study investigates the PCa incidence among men with baseline PSA <1.0 ng ml−1 in order to adjust retest intervals for more targeted early detection. Between 1998 and 2012, 2,416 men with baseline PSA <1.0 ng ml−1 were prospectively observed. Primary endpoint was PCa diagnosis. Negative predictive value (NPV) and number needed to screen (NNS) to detect one PCa were calculated. During a median follow‐up time of 12.1 years, 54 (2.2%) PCa were diagnosed with n = 26 (48.1%) among men with baseline PSA of 0.75 ≤ 1.0 ng ml−1 (upper baseline PSA quartile). The 10‐year probability of being diagnosed with PCa increased significantly from 0.19% (baseline PSA < 0.40 ng ml−1) to 2.0% (baseline PSA 0.40 ≤ 0.56 ng ml−1), 2.5% (baseline PSA 0.56 ≤ 0.75 ng ml−1) over 4.4% (baseline PSA 0.75 ≤ 1.0 ng ml−1) (all p values <0.0001), respectively. The frequency of Gleason ≥7 PCa increased from 1 (0.17%) to 8 (1.4%), 5 (0.8) over 11 (1.8%) in these groups. The 8‐year NPV for Gleason ≥ 7 PCa were 99.8 (baseline PSA < 0.40 ng ml−1), 99.8 (baseline PSA 0.40 ≤ 0.56 ng ml−1), 100 (baseline PSA 0.56 ≤ 0.75 ng ml−1) and 99.5 (baseline PSA 0.75 ≤ 1.0 ng ml−1), respectively. During 12 years, the numbers were 99.8, 98.6, 99.2, and 98.2, respectively. Therefore, due to the very low rate of Gleason ≥ 7 PCa, further screening might be omitted in men with baseline PSA < 0.4 ng ml−1. Between 0.4 and 1.0 ng ml−1, an 8‐year interval can be discussed.

Quantified analysis of histological components and architectural patterns of gleason grades in apparent diffusion coefficient restricted areas upon diffusion weighted MRI for peripheral or transition zone cancer locations: Low ADC and Malignant Glands Density

To quantify and compare the histological components and architectural patterns of Gleason grades in cancerous areas with restriction on apparent diffusion coefficient (ADC) maps.

Negative LC3b immunoreactivity in cancer cells is an independent prognostic predictor of prostate cancer specific death

Background Autophagy is a catabolic cellular process used for degradation of cytoplasmic organelles and preservation of cell viability. In this study we aimed to analyse the level of autophagy markers in benign and malignant prostate tissue and to evaluate the prognostic properties for patients with prostate cancer (PCa). Results LC3b expression was significantly upregulated in PCa, especially in metastatic and castration-resistant PCa samples compared to benign prostate tissue (p<0.001). Evaluation of expression in malignant radical prostatectomy specimens revealed an inverse association with preoperative serum PSA levels (p=0.02) and Gleason Score (p=0.07). LC3b immunoreactivity was identified as a novel predictor of PCa specific death after radical prostatectomy, independent of Gleason score, tumour stage, and surgical margin status in a multivariable cox regression analysis (hazard ratio 0.09, 95% confidence interval 0.01-0.69, p=0.021). A significant association of ATG-5 and Beclin 1 with LC3b expression could be noticed (p<0.001), but no link with other clincopathologic parameters was observed. Materials and Methods A Tissue microarray containing 468 formalin-fixed, paraffin-embedded prostate tissue cores was stained immunohistochemically for major autophagy proteins LC3b, ATG5 and Beclin 1. Immunoreactivity was semiquantitatively scored and correlated with pathologic and clinical parameters, including tumour stage, Gleason score, preoperative PSA level, biochemical recurrence rate and survival. The median clinical follow-up was 132 months. Conclusion LC3b was significantly overexpressed in malignant compared to benign prostate tissue. However, positive LC3b immunoreactivity in PCa, as a marker of increased autophagy, was independently associated with a reduced disease-specific mortality.

Design-corrected variation by centre in mortality reduction in the ERSPC randomised prostate cancer screening trial.

Objectives To calculate design-corrected estimates of the effect of screening on prostate cancer mortality by centre in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Setting The ERSPC has shown a 21% reduction in prostate cancer mortality in men invited to screening with follow-up truncated at 13 years. Centres either used pre-consent randomisation (effectiveness design) or post-consent randomisation (efficacy design). Methods In six centres (three effectiveness design, three efficacy design) with follow-up until the end of 2010, or maximum 13 years, the effect of screening was estimated as both effectiveness (mortality reduction in the target population) and efficacy (reduction in those actually screened). Results The overall crude prostate cancer mortality risk ratio in the intervention arm vs control arm for the six centres was 0.79 ranging from a 14% increase to a 38% reduction. The risk ratio was 0.85 in centres with effectiveness design and 0.73 in those with efficacy design. After correcting for design, overall efficacy was 27%, 24% in pre-consent and 29% in post-consent centres, ranging between a 12% increase and a 52% reduction. Conclusion The estimated overall effect of screening in attenders (efficacy) was a 27% reduction in prostate cancer mortality at 13 years’ follow-up. The variation in efficacy between centres was greater than the range in risk ratio without correction for design. The centre-specific variation in the mortality reduction could not be accounted for by the randomisation method.