Alvaro Paez

Prostate-cancer mortality at 11 years of follow-up

BACKGROUND Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up. METHODS The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered PSA-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer. RESULTS After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.001), and 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.10 deaths per 1000 person-years or 1.07 deaths per 1000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45 to 0.85; P=0.003). To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected. There was no significant between-group difference in all-cause mortality. CONCLUSIONS Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. (Current Controlled Trials number, ISRCTN49127736.).

Quality-of-Life Effects of Prostate-Specific Antigen Screening

BACKGROUND After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain. METHODS On the basis of ERSPC follow-up data, we used Microsimulation Screening Analysis (MISCAN) to predict the number of prostate cancers, treatments, deaths, and quality-adjusted life-years (QALYs) gained after the introduction of PSA screening. Various screening strategies, efficacies, and quality-of-life assumptions were modeled. RESULTS Per 1000 men of all ages who were followed for their entire life span, we predicted that annual screening of men between the ages of 55 and 69 years would result in nine fewer deaths from prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per prostate-cancer death avoided). The number of QALYs that were gained was 56 (range, -21 to 97), a reduction of 23% from unadjusted life-years gained. To prevent one prostate-cancer death, 98 men would need to be screened and 5 cancers would need to be detected. Screening of all men between the ages of 55 and 74 would result in more life-years gained (82) but the same number of QALYs (56). CONCLUSIONS The benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects. Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made. (Funded by the Netherlands Organization for Health Research and Development and others.).

Contamination by opportunistic screening in the European Randomized Study of Prostate Cancer Screening

All screening participants in the first round of the screening trial were asked about their previous PSA tests (ever) using a selfadministered questionnaire mailed to the subjects with the invitation. A total of 20 699 men (97% of the participants) responded. The proportion of missing/don’t know answers was 3%. The overall prevalence of previous PSA tests was 10%. The proportion of participants in the screening arm reporting previous PSA test increased from 7% in 1996 to 14% in 1999.

Polyphenols in red wine inhibit the proliferation and induce apoptosis of LNCaP cells

Objective To assess the effect of five polyphenol constituents of red wine (quercetin, morin, rutin, gallic acid and tannic acid) on the proliferation of LNCaP cells, and to quantify the extent of apoptosis with each polyphenol.

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.

Reliability of the Routine Cytological Diagnosis in Bladder Cancer

Objectives: To establish the reliability of three cytopathologists for cytological diagnosis of primary bladder tumors. Methods: Preoperative voided urine specimens of 71 patients with bladder cancer and 55 noncancer controls were retrospectively and blindly reviewed by 3 independent cytologists, and their results compared. The estimation of the interobserver agreement was calculated using the weighted κ coefficient. A multivariate analysis was carried out to identify the factors associated with the disagreement between the three observers. The sensitivity and specificity for each of the participants was calculated in order to clearly identify the origin of the disagreement, in terms of the performance of the diagnostic test in the hands of each observer. A comparison of the overall diagnostic performance was made by plotting sensitivity versus 1-specificity. Results: The weighted κ coefficient among the 3 observers was 0.46. The multivariate analysis did not identify any variable that could have caused such disagreement. Vast differences in sensitivity and specificity were detected between observer 1 (sens. 0.90, spec. 0.45) and observers 2 (sens. 0.67, spec. 0.72) and 3 (sens. 0.71, spec. 0.80), but the overall diagnostic performance (sensitivity vs. 1-specificity) was superimposable in the 3 cases (p = NS). Conclusions: Simple, reproducible and agreed-on-diagnostic criteria should be established to yield reliable results in a group of cytologists. The consideration of individual diagnostic performances can give a false idea of homogeneity between observers. In this field, concordance analysis makes quality control reliable and should be a routine procedure of any pathology department.

PSA-Use in a Spanish Industrial Area

OBJECTIVES To document the extent of prostate-specific antigen (PSA)-testing in the general population at Getafe (Spain) outside our prostate cancer (PC) screening program, and to check its performance in terms of PC detection. METHODS A total of 5371 PSA-test records (1997-1999) were reviewed and testing rates estimated per 1000 person-years. The extent of patient referral (men referred to our facilities) was calculated adjusting for PSA levels. To approach the performance of testing in the general population, our PC screening program acted as a standard for comparison. The probability of missing one PC in the general population was estimated in terms of number of men necessary to screen (NNS). Calculations were made adjusting for PSA levels. RESULTS PSA-testing rate in the general population was 21.6/1000 person-years. In the age-group 55-69 years, this rate was 86.8/1000 (152.6 in men >70 years). Referral rates were 67.9 and 39.5% for men with PSA 4-10 and >10 ng/ml, respectively. Overall PC detection rate was 1.76%. Detection rates for PSA 4-10 and >10 ng/ml were 4.66 and 12.94%, respectively. When compared with the performance of the screening program, for every 17 men with a PSA in the range 4-10 ng/ml one cancer was missed (95% confidence interval (CI), 9-580). Similarly, one cancer was lost for every four men with a PSA >10 ng/ml (95% CI, 2-8). CONCLUSIONS The extent of opportunistic testing in our setting is very high, particularly in the older age groups. Opportunistic screening renders PC detection rates lower than expected for every PSA level and cannot be encouraged.

Prostate specific antigen variation in patients without clinically evident prostate cancer.

PURPOSE We address long-term within individual variation of serum prostate specific antigen (PSA) in men without clinical or biopsy evidence of prostate cancer. MATERIALS AND METHODS We studied 943 men from a prostate cancer screening program with 2 PSA (PSA1 and PSA2) measurements available. A third PSA (PSA3) was obtained from 571 men. Only participants with no clinical evidence of cancer were included in the study. Within individual PSA variability was calculated based on indexes of percent coefficient of variation, ratio difference and PSA velocity. The relationship among these indexes, interval between measurements and number of PSA samples was assessed. RESULTS Mean interval was 670.4 days between PSA1 and PSA2, and 801.8 days between PSA2 and PSA3 (p<0.001). Mean coefficient of variation was 18% after 2 and 15.7% after 3 PSA measurements. Mean ratio differences were -0.047 ng./ml. for 2 and 0.033 ng./ml. for 3 samples. Mean PSA velocity was -0.128 ng./ml. per year for 2 and -0.055 ng./ml. per year for 3 samples, with 95% confidence intervals of 0.634 and 0.315, respectively. Variability was higher if only 2 PSA measurements were done (p<0.001). No clear relationship was found between individual variability and interval between measurements. CONCLUSIONS PSA velocity is within normal limits in almost all men (more than 95%) without clinically relevant prostate cancer. PSA individual variability is not fully dependent on the time between measurements when intervals are long, and can be substantially decreased with a third PSA sample.

ROLE OF AUTONOMIC INNERVATION IN RAT PROSTATIC STRUCTURE MAINTENANCE: A MORPHOMETRIC ANALYSIS

PURPOSE To analyze the effects of major pelvic ganglion (MPG) excision on the structure of rat prostate. MATERIALS AND METHODS We studied 80 Sprague-Dawley rats (300-350 gm. weight). Forty-two were anesthetized and the right MPG excised. After 28-30 days, the same-side prostatic ventral lobe (VL) was obtained for macroscopic, light (LM), and transmission electron microscopy (TEM) evaluation. A computerized morphometric analysis was performed on epithelial and muscle cells. Results were compared with 38 right VL of non-operated, same-aged rats. RESULTS A 36.6% reduction (0.14 gm.) of VL fresh weight was found in the denervated group (p <0.001). Mean tissue proportions observed in the LM study were 27.9% (epithelial), 48.3% (stromal), and 51.8% (glandular) in the non-operated group, versus 14.8% (p <0.001), 55.7%, and 44.4% (not significant) respectively, after MPG excision. No difference was found regarding the vascular pattern. In the denervated rats, TEM analysis found a significant reduction in total and supranuclear cell height (change in cell polarity), as well as in cytoplasm, Golgi and endoplasmic reticulum areas. Secretory granule count, total area (p <0.001), and density of apical microvilli were also reduced. On the other hand, only an increase in the area of cytoplasm ribosomal aggregates was detected in the smooth muscle cell analysis. CONCLUSIONS Our study demonstrated a rat prostatic VL atrophy in the denervated side, due to a shrinkage in the epithelial component of the gland. Ultrastructural findings also suggest an overall decrease of epithelial cell secretory activity. Finally, the increase of ribosomal aggregates found in stromal smooth muscle could reflect an activation of these cells after denervation.

Change of tumour characteristics and treatment over time in both arms of the European Randomized study of Screening for Prostate Cancer

OBJECTIVE To evaluate a change in tumour characteristics and applied treatments over time in the control arm of all centres of the European Randomized study of Screening for Prostate Cancer (ERSPC) and to compare this with similar data of the screening arm. METHODS Between 1993 and 2003, 182,160 men, aged 50-74 years, were randomised to the screening arm (N=82,816) and the control arm (N=99,184). Men in the screening arm were offered Prostate Specific Antigen (PSA) testing every 4 years whilst men in the control arm received usual care. Tumour characteristics and treatment were evaluated in all men diagnosed with prostate cancer up to December 2006 or the third screening round. Data on the control arm were divided into 3 periods: 1994-1998, 1999-2002 and 2003-2006. RESULTS Tumour characteristics were more favourable over time in both the control and the screening arm, with especially increasing proportions of T1C tumours with 29% in 1994-1998 versus 50% in 2003-2006 and 48% at the initial screening round versus 75% at the third screening round, respectively. Tumour characteristics observed in the last period of the control arm were comparable to tumour characteristics in the initial screening round. In the control arm, treatment changed over time with surgery as the most common treatment in the entire observed period, but almost doubling of expectant management and the combination of hormone therapy and radiotherapy over time. In the initial screening round, surgery was the most common treatment (42%), changing over time to expectant management as the most frequently applied treatment in the third screening round (33%). CONCLUSION Tumour characteristics in the control arm became more favourable over time and show similarity with prostate cancer cases detected at the initial screening round. The most prominent change in treatment over time was an increase of application of expectant management in both arms of the ERSPC. These observations reflect an increasing rate of opportunistic testing over time in men randomised to the control arm.