Improving Screening Strategies for Prostate Cancer

Th is thesis describes research on screening for prostate cancer. To improve understanding of the thesis, some background information will be provided in this introduction. First, a short description of the prostate and of prostate cancer will be given in Chapter 1, followed by more detailed background information on screening for prostate cancer in Chapter 2. Th e fi nal part of this introduction, Chapter 3, will outline the scope of this thesis

Non-prostatic pathology on prostate needle-biopsy – colorectal carcinoid: a case report

Introduction: Prostate needle-biopsies are among the most common specimens in routine histopathological practice; in 15% colorectal tissue is also present. Rectal pathology is described to be found in 17% of this coincidentally obtained material. Case presentation: We present a case in which colorectal carcinoid was found in the rectal mucosa obtained via transrectal prostate biopsies in a screening program for prostate cancer in a 71-year old Caucasian male. To the best of our knowledge, this was the first time that such a coincidental finding was discovered. Besides a colonoscopy with polypectomy, this coincidental detection remained without any further clinical consequences for this patient until today. Conclusion: As there is a considerable chance that abnormalities are found in the rectal tissue of prostate biopsies, it is advisable for all pathologists to include this tissue in the histology evaluation and look for potential irregularities in this simultaneously collected material

Is Prostate-Specific Antigen Velocity Selective for Clinically Significant Prostate Cancer in Screening? European Randomized Study of Screening for Prostate Cancer (Rotterdam)

Background: The value of prostate-specific antigen velocity (PSAV) in screening for prostate cancer (PCa) and especially for clinically significant PCa is unclear. Objective: To assess the value of PSAV in screening for PCa. Specifically, the role of PSAV in lowering the number of unnecessary biopsies and reducing the detection rate of indolent PCa was evaluated. Design, Setting, and Participants: All men included in the study cohort were participants in the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam section. Intervention: During the first and second screening round, a PSA test was performed on 2217 men, and all underwent a biopsy during the second screening round 4 yr later. Measurements: PSAV was calculated and biopsy outcome was classified as benign, possibly indolent PCa, or clinically significant PCa. Results and Limitations: A total of 441 cases of PCa were detected, 333 were classified as clinically significant and 108 as possibly indolent. The use of PSAV cut-offs reduced the number of biopsies but led to important numbers of missed (indolent and significant) PCa. PSAV was predictive for PCa (OR: 1.28, p < 0.001) and specifically for significant PCa (OR: 1.46, p < 0.001) in univariate analyses. However, multivariate analyses using age, PSA, prostate volume, digital rectal examination and transrectal ultrasonography outcome, and previous biopsy (yes/no) showed that PSAV was not an independent predictor of PCa (OR: 1.01, p = 0.91) or significant PCa (OR: 0.87, p = 0.30). Conclusions: The use of PSAV as a biopsy indicator would miss a large number of clinically significant PCa cases with increasing PSAV cut-offs. In this study, PSAV was not an independent predictor of a positive biopsy in general or significant PCa on biopsy. Therefore, PSAV does not improve the ERSPC screening algorithm. (c) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved

The Prostate Cancer Prevention Trial and European Randomized Study of Screening for Prostate Cancer risk calculators indicating a positive prostate biopsy: a comparison

OBJECTIVE To assess the potential problem that different tools for predicting a positive outcome of prostate biopsy can produce divergent outcomes in the same man, by comparing the risk calculators based on the Prostate Cancer Prevention Trial (PCPT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC). MATERIALS AND METHODS In the prostate-specific antigen (PSA) range of 0.2-30.0 ng/mL, the prediction curves of 'virtual' standard study participants were evaluated using both prediction tools. The effects of prostate volume, digital rectal examination, transrectal ultrasonography (TRUS), previous negative biopsy, family history, race, and age were also assessed. RESULTS Important differences in underlying study design and populations between the PCPT and ERSPC cause an essential discrepancy between the risk calculators. In the PCPT there were few biopsies in the higher PSA ranges, and in the ERSPC in the lower PSA ranges. Both risk indicators have incorporated some variables that are not used in the other, because they were insignificant in multivariate analysis. TRUS and especially prostate volume (not available in the PCPT) have a considerably larger effect on predictions in comparable PSA ranges than race, age, family history of prostate cancer, and previous negative biopsy (indicators that were excluded in ERSPC). CONCLUSIONS Before using risk calculators users must consider the properties of the underlying populations and what are the included or unavailable risk factors, and compare these to the patient. When these prerequisites are disregarded, dissimilarities will result in grossly inaccurate predictions for individual patients

Digital Rectal Examination and the Diagnosis of Prostate Cancer-a Study Based on 8 Years and Three Screenings within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam

Background: Evidence indicates that an abnormal digital rectal examination (DRE) is a risk factor for high-grade prostate cancer (PC). Objective: To deter-mine whether men with an initially suspicious DRE, a prostate-specific antigen (PSA) level >= 3.0 ng/ml, and a benign prostate biopsy are at higher risk for significant PC at rescreening than men with an initially normal DRE, and whether an adaptation of the rescreening interval is war-ranted for this group. Design, Setting, and Participants: Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam, 2218 men underwent biopsy of the prostate (from 1993 to 2000) with a benign result at initial screening. The serum PSA was determined every 4 yr. A PSA level of >= 3.0 ng/ml prompted a DRE and a lateralised sextant biopsy. Measurements: Number and characteristics of PCs found at repeat screenings and as interval cancers (ICs) were compared between men with or without a suspicious DRE result at initial screening. Multivariate logistic regression analyses were performed to evaluate if an initially suspicious DRE was a significant predictor for detecting cancer at consecutive screenings. Results and Limitations: After 4 yr, the total number of PCs detected in men with and without an initially suspicious DRE was, respectively, 27 (6%) versus 103 (6%) (p = 0.99). After 8 yr these numbers increased, respectively, to,45 (10%) versus 167 (10%) (p = 0.88). The proportion of clinically significant PCs was 2% and 3%, respectively, for the group with initially normal and abnormal DRE after 8 yr. Having a suspicious DRE result at initial screening was not a significant predictor for detecting PC after 4 yr [odds ratio (OR) = 1.15, p = 0.59) or 8 yr (OR = 1.41, p = 0.43)]. A limitation of this study is the relatively short follow-up of 8 yr. Conclusions: During a follow-up of 8 yr after initial cancer-negative biopsy, an initially suspicious DRE did not influence the chance for detection of cancer or significant cancer at later screens. An adaptation of the rescreening interval on the basis of the initial DRE-outcome is not warranted in future population-based screening for prostate cancer. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved

Induction of hepatic ABC transporter expression is part of the PPAR alpha-mediated fasting response in the mouse

Background & Aims: Fatty acids are natural ligands of the peroxisome proliferator-activated receptor alpha (PPARalpha). Synthetic ligands of this nuclear receptor, i.e., fibrates, induce the hepatic expression of the multidrug resistance 2 gene (Mdr2), encoding the canalicular phospholipid translocator, and affect hepatobiliary lipid transport. We tested whether fasting-associated fatty acid release from adipose tissues alters hepatic transporter expression and bile formation in a PPARalpha-dependent manner. Methods: A 24-hour fasting/48-hour refeeding schedule was used in wild-type and Pparalpha((-/-)) mice. Expression of genes involved in the control of bile formation was determined and related to secretion rates of biliary components. Results: Expression of Pparalpha, farne-soid X receptor, and liver X receptor alpha genes encoding nuclear receptors that control hepatic bile salt and sterol metabolism was induced on fasting in wild-type mice only. The expression of Mdr2 was 5-fold increased in fasted wild-type mice and increased only marginally in Pparalpha((-/-)) mice, and it normalized on refeeding. Mdr2 protein levels and maximal biliary phospholipid secretion rates were clearly increased in fasted wild-type mice. Hepatic expression of the liver X receptor target genes ATP binding cassette transporter a1 (Abca1), Abcg5, and Abcg8, implicated in hepatobiliary cholesterol transport, was induced in fasted wild-type mice only. However, the maximal biliary cholesterol secretion rate was reduced by approximately 50%. Conclusions: Induction of Mdr2 expression and function is part of the PPARalpha-mediated fasting response in mice. Fasting also induces expression of the putative hepatobiliary cholesterol transport genes Abca1, Abcg5, and Abcg8, but, nonetheless, maximal biliary cholesterol excretion is decreased after fasting

The value of an additional hypoechoic lesion-directed biopsy core for detecting prostate cancer

OBJECTIVE To determine the value of a hypoechoic lesion (HL)-directed biopsy in addition to a systematic sextant biopsy for detecting prostate cancer. SUBJECTS AND METHODS Within the European Randomized study of Screening for Prostate Cancer, 37 627 assays for prostate-specific antigen (PSA) were done in men aged 55-75 years (screening round 1-3, interval 4 years). A PSA level of >= 3.0 ng/mL prompted a systematic transrectal ultrasonography (TRUS)-guided lateralized sextant biopsy (4986 biopsy sessions were evaluated). If there was a HL, an additional lesion-directed biopsy was taken. RESULTS At the initial screening, 1840 men were biopsied and 532 cancers were detected (28.9%). Of the men biopsied, 436 had a HL and an additional biopsy (23.7%). In these men, 230 cancers were detected (52.8%). In 3.5% (eight of 230) only the HL-directed core showed malignancy. At the repeat and third screening, respectively, 19.3% and 18.9% of the men biopsied had prostate cancer, 16.8% and 9.3% had an HL and the additional core detected two (2.2%) and one (5.9%) cancers. At the first screen most cancers found by the additional core were clinically relevant. In later screens these cancers seemed to be minimal. CONCLUSIONS The performance of TRUS as a screening tool is poor. The value of the additional core was limited as only 3.5% of the visible cancers were detected solely by the additional biopsy (round 1). However, a substantial part of these cancers were clinically relevant and would have been missed without the additional biopsy. This finding was less clear in screening round 2 and 3, even in men who were not previously biopsied