Bangma, C.H.

Predictive Value of Four Kallikrein Markers for Pathologically Insignificant Compared With Aggressive Prostate Cancer in Radical Prostatectomy Specimens: Results From the European Randomized Study of Screening for Prostate Cancer Section Rotterdam (Article)

2013-05-15T00:00:00Z

Background: Treatment decisions can be difficult in men with low-risk prostate cancer (PCa). Objective: To evaluate the ability of a panel of four kallikrein markers in blood-total prostate-specific antigen (PSA), free PSA, intact PSA, and kallikrein-related peptidase 2-to distinguish between pathologically insignificant and aggressive disease on pathologic examination of radical prostatectomy (RP) specimens as well as to calculate the number of avoidable surgeries. Design, setting, and participants: The cohort comprised 392 screened men participating in rounds 1 and 2 of the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer. Patients were diagnosed with PCa because of an elevated PSA ≥3.0 ng/ml and were treated with RP between 1994 and 2004. Outcome measurements and statistical analysis: We calculated the accuracy (area under the curve [AUC]) of statistical models to predict pathologically aggressive PCa (pT3-T4, extracapsular extension, tumor volume >0.5 cm3, or any Gleason grade ≥4) based on clinical predictors (age, stage, PSA, biopsy findings) with and without levels of four kallikrein markers in blood. Results and limitations: A total of 261 patients (67%) had significant disease on pathologic evaluation of the RP specimen. While the clinical model had good accuracy in predicting aggressive disease, reflected in a corrected AUC of 0.81, the four kallikrein markers enhanced the base model, with an AUC of 0.84 (p < 0.0005). The model retained its ability in patients with low-risk and very-low-risk disease and in comparison with the Steyerberg nomogram, a published prediction model. Clinical application of the model incorporating the kallikrein markers would reduce rates of surgery by 135 of 1000 patients overall and 110 of 334 patients with pathologically insignificant disease. A limitation of the present study is that clinicians may be hesitant to make recommendations against active treatment on the basis of a statistical model. Conclusions: Our study provided proof of principle that predictions based on levels of four kallikrein markers in blood distinguish between pathologically insignificant and aggressive disease after RP with good accuracy. In the future, clinical use of the model could potentially reduce rates of immediate unnecessary active treatment.

Prospective Multicenter Evaluation of the Beckman Coulter Prostate Health Index Using WHO Calibration (Article)

2013-03-22T00:00:00Z

Purpose: Reported prostate specific antigen values may differ substantially among assays using Hybritech® or WHO standardization. The Beckman Coulter® Prostate Health Index and [-2]proPSA are newly approved serum markers associated with prostate cancer risk and aggressiveness. We studied the influence of assay standardization on these markers. Materials and Methods: Prostate specific antigen, percent free prostate specific antigen and [-2]proPSA were measured using Hybritech calibration in 892 men from a prospective, multicenter study undergoing prostate biopsy. We calculated the Prostate Health Index using the equation, ([-2]proPSA/free prostate specific antigen) × sqrt(P)SA. Index performance characteristics for prostate cancer detection were then determined using recalculated WHO calibration prostate specific antigen values. Results: The median Prostate Health Index was significantly higher in men with prostate cancer than in those with negative biopsies using WHO values (47.4 vs 39.8, p <0.001). The index offered improved discrimination of prostate cancer detection on biopsy (AUC 0.704) compared to percent free or total prostate specific antigen using the WHO calibration. Conclusions: The Prostate Health Index can be calculated using Hybritech or WHO standardized assays. It significantly improved prediction of the biopsy outcome over that of percent free or prostate specific antigen alone.

Timing of Curative Treatment for Prostate Cancer: A Systematic Review (Article)

2013-02-28T00:00:00Z

Context: Delaying definitive therapy unfavourably affects outcomes in many malignancies. Diagnostic, psychological, and logistical reasons but also active surveillance (AS) strategies can lead to treatment delay, an increase in the interval between the diagnosis and treatment of prostate cancer (PCa). Objective: To review and summarise the current literature on the impact of treatment delay on PCa oncologic outcomes. Evidence acquisition: A comprehensive search of PubMed and Embase databases until 30 September 2012 was performed. Studies comparing pathologic, biochemical recurrence (BCR), and mortality outcomes between patients receiving direct and delayed curative treatment were included. Studies presenting single-arm results following AS were excluded. Evidence synthesis: Seventeen studies were included: 13 on radical prostatectomy, 3 on radiation therapy, and 1 combined both. A total of 34 517 PCa patients receiving radical local therapy between 1981 and 2009 were described. Some studies included low-risk PCa only; others included a wider spectrum of disease. Four studies found a significant effect of treatment delay on outcomes in multivariate analysis. Two included low-risk patients only, but it was unknown whether AS was applied or repeat biopsy triggered active therapy during AS. The two other studies found a negative effect on BCR rates of 2.5-9 mo delay in higher risk patients (respectively defined as any with T ≥2b, prostate-specific antigen >10, Gleason score >6, >34-50% positive cores; or D'Amico intermediate risk-group). All studies were retrospective and nonrandomised. Reasons for delay were not always clear, and time-to-event analyses may be subject to bias. Conclusions: Treatment delay of several months or even years does not appear to affect outcomes of men with low-risk PCa. Limited data suggest treatment delay may have an impact on men with non-low-risk PCa. Most AS protocols suggest a confirmatory biopsy to avoid delaying treatment in those who harbour higher risk disease that was initially misclassified.

Men's preferences for prostate cancer screening: a discrete choice experiment (Article)

2013-01-29T00:00:00Z

Background:Screening for prostate cancer (PC) may save lives, but overdiagnosis and overtreatment are serious drawbacks. We aimed to determine men's preferences for PC screening, and to elicit the trade-offs they make. Methods:A discrete choice experiment (DCE) was conducted among a population-based random sample of 1000 elderly men (55-75-years-old). Trade-offs were quantified with a panel latent class model between five PC screening aspects: risk reduction of PC-related death, screening interval, risk of unnecessary biopsies, risk of unnecessary treatments, and out-of-pocket costs. Results:The response rate was 46% (459/1000). Men were willing to trade-off 2.0% (CI: 1.6%-2.4%) or 1.8% (CI: 1.3%-2.3%) risk reduction of PC-related death to decrease their risk of unnecessary treatment or biopsy with 10%, respectively. They were willing to pay \[euro]188 per year (CI: \[euro]141-\[euro]258) to reduce their relative risk of PC-related death with 10%. Preference heterogeneity was substantial, with men with higher educational levels having a lower probability to opt for PC screening than men with lower educational levels. Conclusion:Men were willing to trade-off some risk reduction of PC-related death to be relieved of the burden of biopsies or unnecessary treatments. Increasing knowledge on overdiagnosis and overtreatment, especially for men with lower educational levels, is warranted to prevent unrealistic expectations from PC screening.British Journal of Cancer advance online publication, 29 January 2013; doi:10.1038/bjc.2013.5 www.bjcancer.com.

Quality-of-life effects of prostate-specific antigen screening (Article)

2012-08-16T00:00:00Z

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.) Copyright

Identifying the best candidate for radical prostatectomy among patients with high-risk prostate cancer (Article)

2012-03-01T00:00:00Z

Background: The current role of radical prostatectomy (RP) in patients with high-risk disease remains controversial. Objective: To identify which high-risk prostate cancer (PCa) patients might have favorable pathologic outcomes when surgically treated. Design, setting, and participants: We evaluated 1366 patients with high-risk PCa (ie, at least one of the following risk factors: prostate-specific antigen [PSA] >20 ng/ml, cT3, biopsy Gleason 8-10) treated with RP and pelvic lymph node dissection (PLND) at eight European centers between 1987 and 2009. A favorable pathologic outcome was defined as specimen-confined (SC) disease - namely, pT2-pT3a, node negative PCa with negative surgical margins. Intervention: All patients underwent radical retropubic prostatectomy and PLND. Measurements: Univariable and multivariable logistic regression models tested the association between predictors and SC disease. A logistic regression coefficient-based nomogram was developed and internally validated using 200 bootstrap resamples. The Kaplan-Meier method was used to depict biochemical recurrence (BCR) and cancer-specific survival (CSS) rates. Results and limitations: Overall, 505 of 1366 patients (37%) had SC disease at RP. All preoperative variables (ie, age and PSA at surgery, clinical stage, and biopsy Gleason sum) were independent predictors of SC PCa at RP (all p ≤ 0.04). Patients with SC disease had significantly higher 10-yr BCR-free survival and CSS rates than patients without SC disease at RP (66% vs 47% and 98 vs 88%, respectively; all p < 0.001). A nomogram including PSA, age, clinical stage, and biopsy Gleason sum demonstrated 72% accuracy in predicting SC PCa. This study is limited by its retrospective design and by the lack of an external validation of the nomogram. Conclusions: Roughly 40% of patients with high-risk PCa have SC disease at final pathology. These patients showed excellent long-term outcomes when surgically treated, thus representing the ideal candidates for RP as the primary treatment for PCa. Prediction of such patients is possible using a nomogram based on routinely available clinical parameters.

Prediction of prostate cancer risk: The role of prostate volume and digital rectal examination in the ERSPC risk calculators (Article)

2012-03-01T00:00:00Z

Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators (RCs) are validated tools for prostate cancer (PCa) risk assessment and include prostate volume (PV) data from transrectal ultrasound (TRUS). Objective: Develop and validate an RC based on digital rectal examination (DRE) that circumvents the need for TRUS but still includes information on PV. Design, setting, and participants: For development of the DRE-based RC, we studied the original ERSPC Rotterdam RC population including 3624 men (885 PCa cases) and 2896 men (547 PCa cases) detected at first and repeat screening 4 yr later, respectively. A validation cohort consisted of 322 men, screened in 2010-2011 as participants in ERSPC Rotterdam. Measurements: Data on TRUS-assessed PV in the development cohorts were re-coded into three categories (25, 40, and 60 cm3) to assess the loss of information by categorization of volume information. New RCs including PSA, DRE, and PV categories (DRE-based RC) were developed for men with and without a previous negative biopsy to predict overall and clinically significant PCa (high-grade [HG] PCa) defined as T stage >T2b and/or Gleason score ≥7. Predictive accuracy was quantified by the area under the receiver operating curve. We compared performance with the Prostate Cancer Prevention Trial (PCPT) RC in the validation study. Results and limitations: Areas under the curve (AUC) of prostate-specific antigen (PSA) alone, PSA and DRE, the DRE-based RC, and the original ERSPC RC to predict PCa at initial biopsy were 0.69, 0.73, 0.77, and 0.79, respectively. The corresponding AUCs for predicting HG PCa were higher (0.74, 0.82, 0.85, and 0.86). Similar results were seen in men previously biopsied and in the validation cohort. The DRE-based RC outperformed the PCPT RC (AUC 0.69 vs 0.59; p = 0.0001) and a model based on PSA and DRE only (AUC 0.69 vs 0.63; p = 0.0075) in the relatively small validation cohort. Further validation is required. Conclusions: An RC should contain volume estimates based either on TRUS or DRE. Replacing TRUS measurements by DRE estimates may enhance implementation in the daily practice of urologists and general practitioners.

Sexual function with localized prostate cancer: Active surveillance vs radical therapy (Article)

2012-01-20T00:00:00Z

Objective: To compare sexual function of men with localized prostate cancer (PCa) on active surveillance (AS) with similar patients who received radical therapy. Patients And Methods: Two groups of men with screening-detected localized PCa were compared. The first were men on AS within the prospective protocol-based Prostate Cancer Research International: Active Surveillance study. The second were men participating in the European Randomized Study of Screening for Prostate Cancer study who had received radical prostatectomy (RP) or radiation therapy (RT). Questionnaires were completed at two different timepoints after diagnosis or treatment (6 and 12-18 months). These contained 10 items on sexual function, the mental and physical component summary from the Short-Form 12-item health survey, the Center for Epidemiologic Studies Depression scale depression measure and the State Trait Anxiety Inventory general anxiety measure. Sexual function was compared between groups, and determinants were analysed in multivariable analysis, adjusting for baseline differences. Results: A total of 65-68% of men on AS, 35-36% of those who underwent RP, 36-37% of those who underwent RT and 36% of men in the RP and RT groups combined (combined Tx) were sexually active. A total of 20-30% of men in the AS group, 86-91% of men in the RP group, 56-60% of men in the RT group and 71-76% of men in the combined Tx group were sexually inactive as a result of erectile dysfunction. A total of 44-51% of men in the AS group, 96% of men in the RP group, 73-76% of men in the RT group and 84-85% of men in the combined Tx group who were sexually active had problems getting or keeping an erection. In multivariable analysis these differences were significant, except for AS vs RT. Conclusions: Men with localized PCa on AS were more often sexually active than similar men who received radical therapy, especially RP. If not sexually active, this was less often attributable to erectile dysfunction for those on AS. If sexually active, this was less often associated with problems getting or keeping an erection for those on AS. The study was non-randomized; the latest advances in RP and RT might impact results. © 2012 THE AUTHORS. BJU INTERNATIONAL

Towards an optimal interval for prostate cancer screening (Article)

2012-01-01T00:00:00Z

Background: The rate of decrease in advanced cancers is an estimate for determining prostate cancer (PCa) screening program effectiveness. Objective: Assess the effectiveness of PCa screening programs using a 2- or 4-yr screening interval. Design, setting, and participants: Men aged 55-64 yr were participants at two centers of the European Randomized Study of Screening for Prostate Cancer: Gothenburg, Sweden (2-yr screening interval, n = 4202), and Rotterdam, the Netherlands (4-yr screening interval, n = 13 301). We followed participants until the date of PCa, the date of death, or the last follow-up at December 31, 2008, or up to a maximum of 12 yr after initial screening. Potentially life-threatening (advanced) cancer was defined as cancer with at least one of following characteristics: clinical stage ≥T3a, M1, or N1; serum prostate-specific antigen (PSA) >20.0 ng/ml; or Gleason score ≥8 at biopsy. Intervention: We compared the proportional total (advanced) cancer incidence (screen-detected and interval cases), defined as the ratio of the observed number of (advanced) cancers to the expected numbers of (advanced) cancers based on the control arm of the study. Measurements: The proportional cancer incidence from the second screening round until the end of observation was compared using a 2- or 4-yr screening interval. Results and limitations: From screening round 2 until the end of observation, the proportional cancer incidence was 3.64 in Gothenburg and 3.08 in Rotterdam (relative risk [RR]: 1.18; 95% confidence interval [CI], 1.04-1.33; p = 0.009). The proportional advanced cancer incidence was 0.40 in Gothenburg and 0.69 in Rotterdam (RR: 0.57; 95% CI, 0.33-0.99; p = 0.048); the RR for detection of low-risk PCa was 1.46 (95% CI, 1.25-1.71; p < 0.001). This study was limited by the assumption that PSA testing in the control arm was similar in both centers. Conclusions: A 2-yr screening interval significantly reduced the incidence of advanced PCa; however, the 2-yr interval increased the overall risk of being diagnosed with (low-risk) PCa compared with a 4-yr interval in men aged 55-64 yr. Individualized screening algorithms must be improved to provide the strategy for this issue.

Markers predicting response to bacillus Calmette-Guérin immunotherapy in high-risk bladder cancer patients: A systematic review (Article)

2012-01-01T00:00:00Z

Context: Currently, bacillus Calmette-Guérin (BCG) intravesical instillations are standard treatment for patients with high-grade non-muscle-invasive bladder cancer; however, no markers are available to predict BCG response. Objective: To review the contemporary literature on markers predicting BCG response, to discuss the key issues concerning the identification of predictive markers, and to provide recommendations for further research studies. Evidence acquisition: We performed a systematic review of the literature using PubMed and Embase databases in the period 1996-2010. The free-text search was extended by adding the following keywords: recurrence, progression, survival, molecular marker, prognosis, TP53, Ki-67, RB, fibronectin, immunotherapy, cytokine, interleukin, natural killer, macrophage, PMN, polymorphism, SNP, single nucleotide polymorphism, and gene signature. Evidence synthesis: If thresholds for the detection of urinary interleukin (IL)-8, IL-18, and tumour necrosis factor apoptosis-inducing ligand levels are standardised, measurement of these cytokines holds promise in the assessment of BCG therapy outcome. Studies on immunohistochemical markers (ie, TP53, Ki-67, and retinoblastoma) display contradictory results, probably because of the small patient groups that were used and seem unsuitable to predict BCG response. Exploring combinations of protein levels might prove to be more helpful to establish the effect of BCG therapy. Single nucleotide polymorphisms, either in cytokines or in genes involved in DNA repair, need to be investigated in different ethnicities before their clinical relevance can be determined. Measurement of urinary IL-2 levels seems to be the most potent marker of all the clinical parameters reviewed. Conclusions: IL-2 levels are currently the most promising predictive markers of BCG response. For future studies focusing on new biomarkers, it is essential to make more use of new biomedical techniques such as microRNA profiling and genomewide sequencing.

Selecting men diagnosed with prostate cancer for active surveillance using a risk calculator: A prospective impact study (Article)

2011-11-24T00:00:00Z

Study Type - Prognosis (cohort series) Level of Evidence2a What's known on the subject? and What does the study add? The present study is one of the first to investigate urologists' and patients' compliance with recommendations based on a risk calculator that calculates the probability of indolent prostate cancer. A threshold was set for a recommendation of active surveillance vs active treatment. Active surveillance recommendations based on a prostate cancer risk calculator were followed by most patients, but 30% with active treatment recommendations chose active surveillance instead. This indicates that the threshold may be too high for urologists and patients. OBJECTIVES: To assess urologists' and patients' compliance with treatment recommendations based on a prostate cancer risk calculator (RC) and the reasons for non-compliance. To assess the difference between patients who were compliant and non-compliant with recommendations based on this RC. PATIENTS AND METHODS: Eight urologists from five Dutch hospitals included 240 patients with prostate cancer (PCa), aged 55-75 years, from December 2008 to February 2011. The urologists used the European Randomized Study of Screening for Prostate Cancer RC which predicts the probability of potentially indolent PCa (P[indolent]), using serum prostate-specific antigen (PSA), prostate volume and pathological findings on biopsy. Inclusion criteria were PSA <20ng/mL, clinical stage T1 or T2a-c disease, <50% positive sextant biopsy cores, ≤20mm cancer tissue, ≥40mm benign tissue and Gleason ≤3 + 3. If the P(indolent) was >70%, active surveillance (AS) was recommended, and active treatment (AT) otherwise. After the treatment decision, patients completed a questionnaire about their treatment choice, related (dis)advantages, and validated measurements of other factors, e.g. anxiety. RESULTS: Most patients (45/55, 82%) were compliant with an AS recommendation. Another 54 chose AS despite an AT recommendation (54/185, 29%). The most common reason for non-compliance with AT recommendations by urologists was the patient's preference for AS (n= 30). These patients most often reported the delay of physical side effects of AT as the main advantage (n= 19). Those who complied with AT recommendations had higher mean PSA levels (8 vs 7ng/mL, P= 0.02), higher mean amount of cancer tissue (7 vs 3mm, P < 0.001), lower mean P(indolent) (36% vs 55%, P < 0.001), and higher mean generic anxiety scores (42 vs 38, P= 0.03) than those who did not comply. CONCLUSIONS: AS recommendations were followed by most patients, while 29% with AT recommendations chose AS instead. Although further research is needed to validate the RC threshold, the current version is already useful in treatment decision-making in men with localized PCa. © 2011 THE AUTHORS. BJU INTERNATIONAL

Re: Disease-specific survival of men with prostate cancer detected during the screening interval: Results of the european randomized study of screening for prostate cancerrotterdam after 11 years of follow-up (Article)

2011-11-01T00:00:00Z

Defining and predicting indolent and low risk prostate cancer (Article)

2011-10-25T00:00:00Z

The early detection of asymptomatic prostate cancer has led to the increased incidence of tumours that are unlikely to become symptomatic during life, so called indolent cancers. The prediction of low risk and indolent prostate cancer is needed to avoid overtreatment by unnecessary invasive therapies, and select men for active surveillance. Some of the currently available nomograms predicting these low risk tumours have been validated in independent populations. However, assessment to the compliance with their treatment advises based on the calculation of probability are scarce. The ultimate value of nomograms for the urologic practice can only be assessed by analysing their practical implementation.

Active surveillance and radical prostatectomy (Article)

2011-09-01T00:00:00Z

Disease-specific survival of men with prostate cancer detected during the screening interval: Results of the European Randomized Study of Screening for Prostate Cancer-Rotterdam after 11 years of follow-up (Article)

2011-08-01T00:00:00Z

Background: In a screening program, interval cancers are cancers diagnosed between two screening visits. Objective: To assess the disease-specific survival (DSS) of men with prostate cancer (PCa) detected during the screening interval. Design, setting, and participants: Within the European Randomized Study of Screening for Prostate Cancer section Rotterdam, 42 376 men identified from population registries (55-74 yr of age) were randomized to a screening or control arm. The median follow-up was 11 yr. Intervention: Men with prostate-specific antigen ≥3.0 ng/ml were recommended to undergo lateralized sextant biopsy. The screening interval was 4 yr. Measurements: The disease-specific mortality of men with interval cancers was compared with that of men with PCa in the control arm; the secondary end point was overall mortality. An independent committee determined the causes of death. Results and limitations: In the screening arm, 139 men were diagnosed with interval cancer of whom 8 died of the disease. In the control arm, the corresponding numbers were 1149 and 128, respectively. When comparing men with interval cancer to men with PCa in the control arm, no statistically significant difference in disease-specific mortality (hazard ratio [HR]:1.12; 95% confidence interval [CI], 0.53-2.36; p = 0.77) and overall mortality (HR: 0.98; 95% CI, 0.68-1.38; p = 0.90) was found, adjusted for age, prognostic factors, and treatment modality. The follow-up is too limited to address the difference in DSS stratified for screening interval. Conclusions: In the setting of population-based PCa screening at 4-yr intervals, the DSS of men with interval cancer seems to be similar to that of men with PCa in the control arm. Given that interval cancers contribute significantly to PCa mortality, further benefit in DSS in the screening arm may be achieved by decreasing the occurrence of interval cancer. However, the balance between mortality reduction and overdiagnosis should be preserved. Trial registration: ISRCTN49127736.

Disease-specific survival of men with prostate cancer detected during the screening interval: Results of the European Randomized Study of Screening for Prostate Cancer-Rotterdam after 11 years of follow-up (Article)

2011-08-01T00:00:00Z

Optimization of nonmuscle invasive bladder cancer recurrence detection using a urine based FGFR3 mutation assay (Article)

2011-08-01T00:00:00Z

Purpose: FGFR3 mutations occur in 70% of nonmuscle invasive bladder tumors. Although urine based FGFR3 mutation analysis can detect recurrence, its sensitivity may be limited if samples have few or no tumor cells. We determined whether test sensitivity depends on tumor size and the time point of urine collection, and how to increase sensitivity. Materials and Methods: A total of 440 urine samples from 18 patients with a suspicious bladder lesion at cystoscopy were collected during 6 days before surgery. Eight patients (300 samples) had an FGFR3 mutant tumor, including 4 each with a tumor greater than 3 and less than 1.5 cm. Polymerase chain reaction based FGFR3 analysis was done on all tumors and urine samples. Results: FGFR3 mutations were detected in 257 of the 300 urine samples (86%) from patients with an FGFR3 mutant tumor. Assay sensitivity was 100% for tumors greater than 3 cm and 75% for tumors less than 1.5 cm. It increased to 100% in patients with a less than 1.5 cm tumor when samples were pooled during 24 hours. Sensitivity was not influenced by the time of urine collection. All urine samples from patients with an FGFR3 wild-type tumor were negative for FGFR3 mutation. Conclusions: The sensitivity of tumor detection increased with tumor size. FGFR3 assay sensitivity depends on the number of shed tumor cells and improves by increasing urine volume. These findings suggest that there is an upper limit to the sensitivity of the FGFR3 assay when 1 urine sample is analyzed. This may also apply to other DNA or RNA based assays.

Gastrin-releasing peptide receptor-based targeting using bombesin analogues is superior to metabolism-based targeting using choline for in vivo imaging of human prostate cancer xenografts (Article)

2011-07-01T00:00:00Z

Purpose: Prostate cancer (PC) is a major health problem. Overexpression of the gastrin-releasing peptide receptor (GRPR) in PC, but not in the hyperplastic prostate, provides a promising target for staging and monitoring of PC. Based on the assumption that cancer cells have increased metabolic activity, metabolism-based tracers are also being used for PC imaging. We compared GRPR-based targeting using the68Ga-labelled bombesin analogue AMBA with metabolism-based targeting using18F-methylcholine (18F-FCH) in nude mice bearing human prostate VCaP xenografts. Methods: PET and biodistribution studies were performed with both68Ga-AMBA and18F-FCH in all VCaP tumour-bearing mice, with PC-3 tumour-bearing mice as reference. Scanning started immediately after injection. Dynamic PET scans were reconstructed and analysed quantitatively. Biodistribution of tracers and tissue uptake was expressed as percent of injected dose per gram tissue (%ID/g). Results: All tumours were clearly visualized using68Ga-AMBA.18F-FCH showed significantly less contrast due to poor tumour-to-background ratios. Quantitative PET analyses showed fast tumour uptake and high retention for both tracers. VCaP tumour uptake values determined from PET at steady-state were 6.7±1.4%ID/g (20-30 min after injection, N=8) for68Ga-AMBA and 1.6±0.5%ID/g (10-20 min after injection, N=8) for18F-FCH, which were significantly different (p<0.001). The results in PC-3 tumour-bearing mice were comparable. Biodistribution data were in accordance with the PET results showing VCaP tumour uptake values of 9.5±4.8%ID/g (N=8) for68Ga-AMBA and 2.1±0.4%ID/g (N=8) for18F-FCH. Apart from the GRPR-expressing organs, uptake in all organs was lower for68Ga-AMBA than for18F-FCH. Conclusion: Tumour uptake of68Ga-AMBA was higher while overall background activity was lower than observed for18F-FCH in the same PC-bearing mice. These results suggest that peptide receptor-based targeting using the bombesin analogue AMBA is superior to metabolism-based targeting using choline for scintigraphy of PC.

A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range (Article)

2011-05-01T00:00:00Z

Purpose: Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen × prostate specific antigen1/2) to enhance specificity to detect overall and high grade prostate cancer. Materials and Methods: We enrolled 892 men with no history of prostate cancer, normal rectal examination, prostate specific antigen 2 to 10 ng/ml and 6-core or greater prostate biopsy in a prospective multi-institutional trial. We examined the relationship of serum prostate specific antigen, free-to-total prostate specific antigen and the prostate health index with biopsy results. Primary end points were specificity and AUC using the prostate health index to detect overall and Gleason 7 or greater prostate cancer on biopsy compared with those of free-to-total prostate specific antigen. Results: In the 2 to 10 ng/ml prostate specific antigen range at 80% to 95% sensitivity the specificity and AUC (0.703) of the prostate health index exceeded those of prostate specific antigen and free-to-total prostate specific antigen. An increasing prostate health index was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to 4 + 3 = 7 disease on biopsy. The AUC of the index exceeded that of free-to-total prostate specific antigen (0.724 vs 0.670) to discriminate prostate cancer with Gleason 4 or greater + 3 from lower grade disease or negative biopsy. Prostate health index results were not associated with age and prostate volume. Conclusions: The prostate health index may be useful in prostate cancer screening to decrease unnecessary biopsy in men 50 years old or older with prostate specific antigen 2 to 10 ng/ml and negative digital rectal examination with minimal loss in sensitivity.

Exosomes as biomarker treasure chests for prostate cancer (Article)

2011-05-01T00:00:00Z

Context: Although progress has been made with regard to types of markers (protein, DNA, RNA, and metabolites) and implementation of improved technologies (mass spectrometry, arrays, and deep sequencing), the discovery of novel biomarkers for prostate cancer (PCa) in complex fluids, such as serum and urine, remains a challenge. Meanwhile, recent studies have reported that many cancer-derived proteins and RNAs are secreted through small vesicles known as exosomes. Objective: This narrative review describes recent progress in exosome research, focusing on the potential role of exosomes as novel biomarkers for PCa. The purpose of this review is to acquaint clinicians and researchers in the field of urology with the potential role of exosomes as biomarker treasure chests and with their clinical value. Evidence acquisition: Medline and Embase entries between 1966 and September 2010 were searched using the keywords exosomes, microvesicles, prostasomes, biomarkers, prostate cancer, and urology. Leading publications and articles constructively contributing to exosome research were selected for this review. Evidence synthesis: Exosomes are small vesicles (50-100 nm) secreted by almost all tissues; they represent their tissue origin. Purification of prostate- and PCa-derived exosomes will allow us to profile exosomes, providing a promising source of protein and RNA biomarkers for PCa. This profiling will contribute to the discovery of novel markers for the early diagnosis and reliable prognosis of PCa. Conclusions: Although the initial results are promising, further investigations are required to assess the clinical value of these exosomes in PCa.

Identifying and characterizing "escapes"-men who develop metastases or die from prostate cancer despite screening (ERSPC, section Rotterdam) (Article)

2011-04-06T00:00:00Z

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. Copyright

Prediction of prostate cancer in unscreened men: External validation of a risk calculator (Article)

2011-04-01T00:00:00Z

Background: Prediction models need external validation to assess their value beyond the setting where the model was derived from. Objective: To assess the external validity of the European Randomized study of Screening for Prostate Cancer (ERSPC) risk calculator (www.prostatecancer-riskcalculator.com) for the probability of having a positive prostate biopsy (P(posb)). Design, setting and participants: The ERSPC risk calculator was based on data of the initial screening round of the ERSPC section Rotterdam and validated in 1825 and 531 men biopsied at the initial screening round in the Finnish and Swedish sections of the ERSPC respectively. P(posb) was calculated using serum prostate specific antigen (PSA), outcome of digital rectal examination (DRE), transrectal ultrasound and ultrasound assessed prostate volume. Measurements: The external validity was assessed for the presence of cancer at biopsy by calibration (agreement between observed and predicted outcomes), discrimination (separation of those with and without cancer), and decision curves (for clinical usefulness). Results and limitations: Prostate cancer was detected in 469 men (26%) of the Finnish cohort and in 124 men (23%) of the Swedish cohort. Systematic miscalibration was present in both cohorts (mean predicted probability 34% versus 26% observed, and 29% versus 23% observed, both p < 0.001). The areas under the curves were 0.76 and 0.78, and substantially lower for the model with PSA only (0.64 and 0.68 respectively). The model proved clinically useful for any decision threshold compared with a model with PSA only, PSA and DRE, or biopsying all men. A limitation is that the model is based on sextant biopsies results. Conclusions: The ERSPC risk calculator discriminated well between those with and without prostate cancer among initially screened men, but overestimated the risk of a positive biopsy. Further research is necessary to assess the performance and applicability of the ERSPC risk calculator when a clinical setting is considered rather than a screening setting.

Long-term follow-up of T1 high-grade bladder cancer after intravesical bacille Calmette-Guérin treatment (Article)

2011-02-01T00:00:00Z

Study Type - Therapy (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? High-grade non muscle invasive bladder cancer is a very aggressive disease, potentially lethal if not managed adequately, because of the ability of these tumours to invade surrounding tissues and become metastatic. Treatment with intravesical BCG has been shown to delay progression to muscle invasive or/and metastatic disease, preserve the bladder, and decrease the risk of death from bladder cancer. However, most studies have analyzed patients with short follow-up, and long-term data about the real efficacy of BCG to prevent tumour recurrence, progression and impact mortality are lacking. This study has analyzed a large series of patients with high-grade non muscle invasive bladder cancer treated with intravesical BCG in two University Institutions (Toronto and Rotterdam), with a central pathology review by a very experienced uro-pathologist. It provides further insight into the long-term risks of progression of patients harbouring high-grade T1 bladder cancer treated with BCG, demonstrating that about 30% of patients are at risk of progression and that late progressions even more than 3 years after the initial resection and BCG treatment are rare but not exceptional. OBJECTIVE To report the long-term results of bacille Calmette-Guérin (BCG) intravesical therapy in relation to disease progression and recurrence in primary T1 high-grade (HG) bladder cancer (BC) confirmed by central pathological review. PATIENTS AND METHODS In all, 136 patients from two university centres (Rotterdam, n= 49; Toronto, n= 87) were diagnosed with primary T1HG BC. One experienced uro-pathologist reviewed all slides, ensuring all cases were indeed HG and that muscle was present in all specimens. Patients were treated with BCG induction (six instillations) after transurethral resection (TUR) of the tumour and followed with cystoscopy and urinary cytology. Predictors for recurrence, progression and survival were assessed with multivariable Cox regression models. RESULTS Mean (range) follow-up was 6.5 (0.3-21.6) years. There were no significant differences for recurrence (P= 0.52), progression (P= 0.35) and disease-specific survival (DSS) (P= 0.69) between the two centres. Among the cohort, 47 patients (35%) recurred and 42 (30.9%) progressed with a median time to progression of 2.1 years; 16 (38%) of these progressions occurred â ¥3 years after the initial BCG course; 22 (16%) patients who progressed died from BC. Overall, 96 (71%) patients had no evidence of disease at the last follow-up. Carcinoma in situ was the only independent predictor for recurrence in multivariate analysis (P= 0.011). No independent predictors were found for progression. CONCLUSIONS Conservative treatment with BCG is a valid option in primary T1HG BC. Nevertheless, the aggressive nature of T1HG BC is evident in the fact that 30% progressed, with a high proportion of these progression events occurring â ¥3 years after BCG. Caution should be exercised when relying on the long-term effects of BCG, and close follow-up of these patients should not be neglected. © 2010 THE AUTHORS. JOURNAL COMPILATION

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: Preliminary analysis of the results of the IMPACT study (Article)

2011-01-01T00:00:00Z

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA >3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Disease-specific mortality may underestimate the total effect of prostate cancer screening (Article)

2010-12-01T00:00:00Z

Objectives To study the difference between the disease-specific and excess mortality rate in the European Randomized Study of Screening for Prostate Cancer section Rotterdam. Methods A total of 42,376 men were randomized to systematic screening or usual care. The excess number of deaths was defined as the difference between the observed number of deaths in the prostate cancer (PC) patients and the expected number of deaths up to 31 December 2006. The expected number was derived from mortality of all study participants before a possible diagnosis with PC. The disease-specific mortality rate was based on the number of men who died from PC. The excess mortality rate based on the arm-specific excess number of deaths and the disease-specific mortality rate were compared between the two study arms. Results The overall mortality rate was not significantly different between the intervention and the control arms of the study: RR 1.02 (95% CI 0.98-1.07). The disease-specific mortality rate was 0.42 men per 1000 person-years in the intervention and 0.48 men per 1000 person-years in the control arm: RR 0.86 (95% CI 0.64-1.17). The excess mortality rate was 0.40 per 1000 personyears in the intervention arm and 0.61 men per 1000 person-years in the control arm, and the RR for excess mortality was 0.66 (95% CI 0.39-1.13). Conclusions In contrast to the disease-specific mortality rates an increased difference in the excess mortality rates was observed between the two arms. This observation may be due to a systematic underestimation of the disease-specific deaths, and/or an additional disease-related mortality that is measured by an excess mortality analysis but not by a disease-specific mortality.

On the use of prostate-specific antigen for screening of prostate cancer in European Randomised Study for Screening of Prostate Cancer (Article)

2010-11-01T00:00:00Z

Prostate-specific antigen (PSA) has been the main drive for early detection of prostate cancer (PCa), including in population-based screening as in the European Randomised Study for Screening of Prostate Cancer (ERSPC). The specificity of PSA to indicate men with biopsy detectable prostate cancer can be improved by adding information obtained by new biomarkers, such as PSA isoforms. This improvement is needed to increase the efficacy of the screening procedure for the population-based as well as the individual screening. Various PSA isoforms, kallikreins and molecular markers have been validated in various cohorts from ERSPC of men with and without PCa in order to design the optimal diagnostic procedure for screening asymptomatic men. So far, most promising results have been obtained from the analysis of free PSA, proPSA, nicked PSA and hK2. The use of free PSA in addition to total PSA reduces the number of negative sextant biopsies at a PSA cut-off level of 3 ng/ml at initial screening with 30%, at the cost of losing 10% of detectable cancers that are predominantly well differentiated on histology. Further addition of PSA isoforms and hK2 only improve ROC curves in selected samples by a maximum of 5%. Molecular markers like PCA3 and TMPRSS2 in urine do not appear to be useful but they have been assessed insufficiently so far. The level of PSA at initial screening is highly predictive for the chance of being diagnosed with PCa later on in life. The changes in PSA over time after initial screening (like PSA-velocity and PSA-doubling time) are statistically different between men with detectable cancers versus those without (PSA-doubling time 5.1 versus 6.1 years), but this does not contribute significantly to population-based screening overall. Changes in specificity need to be related to a cost efficacy evaluation in the final analysis of ERSPC.

Feasibility study of screening for bladder cancer with urinary molecular markers (the BLU-P project) (Article)

2010-11-01T00:00:00Z

Introduction: The prognosis of bladder cancer (BC) depends mainly on its histology, grade, and stage. Patients with superficial BC (70% of the urothelial carcinomas) have a relatively good prognosis, but patients diagnosed with invasive, high grade BC, and those who progress to invasive BC, have a poor prognosis and will not survive their disease in many cases due to their metastases, despite the currently available treatment options. Early detection can only be beneficial regarding mortality if the high risk cancers are recognized and treated at a localized stage. Materials and methods: Previous pilot studies on early detection consisted of home-based repeated hematuria testing and, in case of hematuria, a urologic evaluation with cytology and cystoscopy was carried out. This design resulted in too many cystoscopies. The recently initiated [Bladder Cancer Urine Marker Project (BLU-P) study www.blu-project.org] assesses the feasibility of a population-based screening for BC and at the same time evaluates a screening algorithm using next to hematuria testing, sensitive specific urine markers for BC (NMP22, FGFR3, MA analyses and MLPa) in an attempt to circumvent the high number of cystoscopies. Results: So far 1,611 men are included and 23.5% tested positive for hematuria (11.6% had one or more true positive test results). The additional molecular-based screening tests before referring to cystoscopy resulted in a decrease of the number of cystoscopies from 378 to 66 (82.5%). In those men referred for cystoscopy, so far only 1 BC case was detected. Conclusions: Further research is needed to evaluate whether this extremely low detection rate is caused by, e.g., a healthy screenee bias or that the additional selection step using the molecular urine tests is too strict and diagnoses are missed.

The implementation of screening for prostate cancer (Article)

2010-09-01T00:00:00Z

The objective of this study was to determine whether screening for prostate cancer (PC) reduces PC mortality and, if so, whether the required criteria to be introduced as a population-based screening program are satisfied. A literature review was conducted through electronic scientific databases. The screening tests, that is, PSA and digital rectal examination, have limited sensitivity and specificity for detecting PC; screening produces a beneficial stage shift and reduces PC mortality. Nevertheless, PC screening causes a large increase in the cumulative incidence, and the understanding of the economic cost and quality-of-life parameters are limited. PC screening cannot be justified yet in the context of a public health policy.

Does Local treatment of the prostate in advanced and/or lymph node metastatic disease improve efficacy of androgen-deprivation therapy? A systematic review (Article)

2010-08-01T00:00:00Z

Context: Androgen-deprivation therapy (ADT) plays a pivotal role in the management of locally advanced and metastatic prostate cancer (PCa). When and for how long to apply ADT have remained controversial issues. Objective: To review randomised studies of ADT (orchiectomy or luteinising hormone-releasing hormone analogues) in PCa - both immediate and deferred/adjuvant studies - to elucidate a possible interaction between local treatment and ADT. Evidence acquisition: Published randomised studies on ADT in various stages of PCa were included in this review. Evidence synthesis: Studies of immediate versus deferred ADT without local treatment consistently showed only limited benefit for overall survival (OS; hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.83-0.97) and cancer-specific survival (CSS; HR: 0.79; 95% CI, 0.71-0.89). In contrast, ADT as an adjuvant to radiation therapy in patients with high-risk localised disease or locally advanced disease was associated with substantial OS and CSS benefits. A similar benefit was seen in patients with proven systemic disease (node-positive patients after radical prostatectomy). Overall, the data suggest a clinically important survival benefit (HR for OS: 0.69; 95% CI, 0.61-0.79) when a local treatment has been applied to the primary tumour. Possible mechanisms of this therapeutic effect are discussed. Conclusions: We conclude that an interaction between local treatment and ADT is suggested by this systematic review. In patients with advanced and aggressive disease who are at a high risk to die from PCa and who are treated for their primary tumour with curative intent, immediate and sustained ADT improves OS and CSS significantly. The local therapy in T3 and/or lymph node-positive disease is an essential part of the optimal treatment. However, this intensive treatment is unnecessary in a substantial number of patients with T3 and/or N1 disease with a slow natural history or high competing death risk.

A standardised study to compare prostate cancer targeting efficacy of five radiolabelled bombesin analogues (Article)

2010-07-01T00:00:00Z

Purpose: Prostate-specific antigen (PSA)-based screening for prostate cancer (PC) has dramatically increased early diagnosis. Current imaging techniques are not optimal to stage early PC adequately. A promising alternative to PC imaging is peptide-based scintigraphy using radiolabelled bombesin (BN) analogues that bind to gastrin-releasing peptide receptors (GRPR) being overexpressed in PC. When labelled to appropriate radionuclides BN targeting of GRPRs may also provide applications for peptide radionuclide receptor therapy (PRRT). Assessment studies under identical experimental conditions allowing a reliable comparison of the potential of such analogues are lacking. This study was performed to evaluate and directly compare five promising radiolabelled BN analogues for their targeting efficacy for PC under standardised conditions. Methods: The BN agonists [111In]DOTA-PESIN, [111In]AMBA, [111In]MP2346 and [111In]MP2653 and one antagonist [99mTc]Demobesin-1 were evaluated in GRPR-overexpressing human PC-3 tumour-bearing mice to determine peptide stability in vivo, biodistribution and GRPR targeting potential by animal SPECT/CT imaging and ex vivo autoradiography. Results: HPLC analysis of blood showed intact Demobesin-1 at 5 and 15 min after injection (64.1 ± 1.6% and 41.0 ± 01%, respectively) being much less for the other compounds. AMBA, the second most stable analogue, showed 36.1 ± 2.7% and 9.8 ± 1.1% intact peptide after 5 and 15 min. PC-3 tumour uptake at 1 h was comparable for Demobesin-1, AMBA, PESIN and MP2346 (3.0 ± 0.4, 2.7 ± 0.5, 2.3 ± 0.5 and 2.1 ± 0.9%ID/g, respectively), but very low for MP2653 (0.9 ± 0.2%ID/g). In addition, MP2346 showed undesirably high uptake in the kidneys (7.9 ± 1.9%ID/g) being significantly less for the other analogues. AMBA, MP2346 and PESIN revealed favourable increases in tumour to blood ratios over time while changes in tumour to kidney and pancreas ratios for Demobesin-1 from 1 to 24 h after injection were significantly better than for the other analogues. All analogues visualised PC-3 tumours by SPECT/CT and autoradiography. Conclusion: In the present study the BN antagonist Demobesin-1 was the best performing analogue showing superior in vivo stability, highest tumour uptake and retention while pancreatic and renal clearance were rapid. PESIN and AMBA were the best GRP agonists with sufficient in vivo stabilities as well as high tumour uptake and retention. Based on these results all three analogues deserve further evaluation for clinical use in PC patients.

Pathological stage review is indicated in primary pT1 bladder cancer (Article)

2010-07-01T00:00:00Z

OBJECTIVE To evaluate the effect of a pathology review on the clinical outcome of patients with primary pT1 bladder cancer (BC), as the clinical course of such patients is variable. PATIENTS AND METHODS The slides of 164 primary (first diagnosis) pT1 bladder tumours from two university hospitals were reviewed by one pathologist for stage and grade (World Health Organization 1973 and 2004). Patients were initially managed conservatively with bacille Calmette-Guérin (BCG). Uni- and multivariate analyses compared the predictive value of age, gender, hospital, carcinoma in situ (CIS), tumour-size, reviewed grade and reviewed stage. RESULTS With a mean follow-up of 6.4 years, there was disease progression in 48 (29%) patients and 26 (16%) died from BC. Associated CIS was found in 55 (34%) patients. After reviewing the slides, 24 (15%) tumours were downstaged to pTa, 134 (82%) remained pT1 and six (4%) were upstaged to ≥pT2. The grade review resulted in 74 G2, 90 G3, 37 low-grade and 127 high-grade lesions for the two systems used. In multivariate analyses, reviewed stage (both P < 0.001) and CIS (P = 0.017 and 0.023) had independent significance for progression and disease-specific survival, respectively. CONCLUSION A stage review is indicated in pT1 BC, as almost 20% of pT1 tumours were up- or downstaged, and the reviewed stage predicted the patient's prognosis. Hence, pathology review identified patients with different prognoses who might benefit from other treatment strategies than BCG. We confirmed that CIS is an unfavourable sign in pT1 bladder cancer.

The value of EZH2, p27kip1, BMI-1 and MIB-1 on biopsy specimens with low-risk prostate cancer in selecting men with significant prostate cancer at prostatectomy (Article)

2010-07-01T00:00:00Z

OBJECTIVE To assess the additional prognostic value of the molecular markers EZH2, MIB-1, p27kip1 and BMI-1 on needle biopsies from men with low-risk prostate cancer, as this disease in needle biopsies shows a heterogeneous clinical outcome, and while it is known that the expression of these tissue markers is predictive of the clinical outcome after radical prostatectomy (RP) their value in prostate biopsies is largely unknown. PATIENTS AND METHODS The study included men participating in a screening study, diagnosed with low-risk prostate cancer and subsequently treated with RP. Immunohistochemical staining for EZH2, MIB-1, p27kip1 and BMI-1 on the needle biopsies were (semi)quantitatively scored and expression levels were related to significant disease at RP. Clinical low-risk prostate cancer was defined as a prostate-specific antigen (PSA) level of ≤10 ng/mL, clinical T-stage ≤2, biopsy Gleason score ≤6, a PSA density of <0.20 ng/mL/g and two or fewer positive cores. Significant PC at RP was defined as presence of any of extracapsular extension, Gleason pattern 4/5, or tumour volume ≥0.5 mL. RESULTS In all, 86 biopsy specimens were included; there was high EZH2 expression (>1.0%) in 42% and a low p27kip expression (<90%) in 63%. Significant disease was present in 44 (51%) RP specimens. A high EZH2 (odds ratio 3.19, P = 0.043) and a low p27kip1 (4.69, P = 0.036) were independent predictors for significant prostate cancer at RP. CONCLUSIONS The determination of EZH2 and p27kip1 on diagnostic needle biopsies supports the selection of men with indolent prostate cancer at RP. Especially p27kip1 could improve the pretreatment risk assessment of patients with low-risk prostate cancer.

T cell activation upon exposure to patient-derived tumor tissue: A functional assay to select patients for adoptive T cell therapy (Article)

2010-07-01T00:00:00Z

Gene-engineered T cell therapy represents a promising strategy to treat cancers. To enable pre-selection of patients sensitive to this type of treatment we have setup and validated a T cell activation assay to test antigen expression on patient-derived tumor tissues. Chimeric antibody-based receptor (CAR) directed against CAIX, currently used in a clinical trial to treat RCC patients, was used as a model receptor. Primary human T cells expressing CAIX CAR were able to respond to CAIX-positive but not CAIX-negative tumor tissue and showed an increased production of IFNγ, TNFα, IL-10 and IL-4, but not IL-2 or IL-5. Tumor tissue driven responses of primary T cells were paralleled by NFAT activation measured in CAR-transduced Jurkat T cells, which was shown to be triggered in a CAR and antigen-specific manner. Next, the reporter gene assay was applied to two independent PSMA CARs, which both mediated NFAT activation in response to tumor tissue. Taken together, a sensitive and donor-independent assay was established to measure T cell activation upon exposure to patient-derived tumor tissue, which may facilitate pre-selection of patients for clinical adoptive T cell therapy.

Multicenter Clinical Validation of PITX2 Methylation as a Prostate Specific Antigen Recurrence Predictor in Patients With Post-Radical Prostatectomy Prostate Cancer (Article)

2010-07-01T00:00:00Z

Purpose: Radical prostatectomy is potentially curative in patients with clinically localized prostate cancer. However, biochemical recurrence affects 15% to 30% of men who undergo radical prostatectomy. We previously reported the prognostic potential of PITX2 gene promoter methylation using conventional assays. In the current study we validated PITX2 methylation status as a biochemical recurrence predictor after radical prostatectomy using a novel microarray based platform in a multi-institutional setting. Materials and Methods: PITX2 methylation status was assessed in formalin fixed, paraffin embedded prostatectomy tumor tissue samples from 476 patients from a total of 4 institutions on customized EpiChip™ PITX2 microarrays. Associations between PITX2 methylation and biochemical recurrence were assessed using the log rank test and Cox regression controlling for prostate cancer features. Results: On multivariate analysis men with high methylation status were at significantly higher risk for biochemical recurrence than those with low methylation status (HR 3.0, 95% CI 2.0-4.5, p <10-5). The biochemical recurrence-free survival rate 5 years after surgery was 85% and 61% in the low and high methylation groups, respectively. In men with pathological Gleason 7 tumors the relative risk of biochemical recurrence was twice as high for high than for low PITX2 methylation (HR 2.0, 95% CI 1.2-3.3, p = 0.005). Conclusions: PITX2 methylation status assessed by EpiChip PITX2 identifies patients with prostate cancer who are most likely to have biochemical recurrence. This test independently adds to the prognostic information provided by standard clinicopathological analysis, improving prostatectomy case stratification into those at high and low risk for biochemical recurrence. This new clinical tool would be of particular benefit to assess intermediate risk cases (Gleason 7) in which risk stratification remains a challenge.

Should prostate-specific antigen screening be offered to asymptomatic men? (Article)

2010-07-01T00:00:00Z

The benefits of population-based prostate cancer screening are the detection of clinically important prostate cancers at an early, still curable, stage and the subsequent reduction of prostate cancer-specific mortality. However, a prostate-specific antigen (PSA)-based prostate cancer screening program is currently insufficient to warrant its introduction as a public health policy. The main reasons are insufficient knowledge regarding the optimal screening strategy and overdiagnosis and overtreatment of indolent prostate cancers that are unlikely to lead to complaints or death. In some countries, guidelines have been developed on screening for prostate cancer, but the diversity of recommendations illustrates the limited knowledge on the optimal strategy. Therefore, men should be well informed about the benefits and potential harms of PSA screening in order to enable them to make an informed decision. Although a mortality reduction can be achieved by early detection of prostate cancer, patients and physicians must be aware of the current side effects of screening. Algorithms that advise screening at a young age (<55 years), with screening intervals of less than 4 years and low PSA thresholds (<3 ng/ml) for prostate biopsy seem premature and are not supported by evidence.

Prostate-Specific Antigen (PSA) Isoform p2PSA in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection (Article)

2010-06-01T00:00:00Z

Background: Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA = tPSA/fPSA) lack diagnostic specificity. Objective: To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia-associated PSA (BPHA). Design, setting, and participants: Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University. Measurements: BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi = (p2PSA/fPSA) × √(tPSA). Results and limitations: The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity. Conclusions: This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7).

Prognostic factors for and outcome of locally advanced prostate cancer after radical prostatectomy (Article)

2010-06-01T00:00:00Z

Study Type - Therapy (case series) Level of Evidence 2b Objective To present the outcomes of cT3N0M0 prostate cancer after radical prostatectomy (RP) and determine the prognostic factors in biochemical progression-free survival (BPFS), clinical progression-free survival (CPFS), cancer-specific survival (CSS) and overall survival (OS) after long-term follow-up of 10 years. Patients and Methods In all, 164 patients who were assessed as clinical T3 prostate cancer by digital rectal examination (DRE), underwent RP and bilateral pelvic lymphadenectomy at Erasmus MC between 1977 and 2004 without neoadjuvant treatment. Preoperative staging computed tomography showed no signs of metastasis. Kaplan-Meier curves were constructed to show BPFS, CPFS, CSS and OS. Cox proportional hazard analysis was used to determine prognostic indicators of disease progression. Results The mean (range) follow-up was 100 (1-291) months. At 5, 10 and 15 years, BPFS was 50.4%, 43.0% and 38.3%, respectively, CPFS was 79.7%, 68.7% and 63.5%, CSS was 93.4%, 80.3% and 66.3%, and OS was 87.1%, 67.2% and 37.4%. Multivariate Cox proportional hazard analysis showed that surgical tumour grade, margin and node status were significant factors in CPFS and CSS. Surgical tumour grade, node status and preoperative PSA level were significant factors in BPFS Conclusion RP for clinically locally advanced prostate cancer may produce acceptable long-term BPFS, which is comparable with published results of radiotherapy with adjuvant endocrine therapy. Pathological tumour grade and node status were significant predicting factors in BPFS and CPFS, as well as tumour-specific survival after 100 months follow-up.

Differential expression of protease activity in serum samples of prostate carcinoma patients with metastases (Article)

2010-06-01T00:00:00Z

We present here the results from MS peptide profiling experiments of prostate carcinoma patients and controls with a specific focus on protease activity-related protein fragments. After purification with surface-active magnetic beads, MALDI-TOF profiling experiments were performed on tryptic digests of serum samples of prostate cancer patients with metastases (n = 27) and controls (n = 30). This resulted in the reproducible detection of eight differentially expressed peptides, which were then identified by nanoLC-MALDI-TOF/TOF and confirmed by MALDI-FTMS exact mass measurements. All differentially expressed peptides are derived from two homologous parts of human serum albumin; two of the eight peptides were tryptic and six were nontryptic. The presence of the nontryptic fragments indicates that a proteolysis process occurs which is not mediated by trypsin. Since the nontryptic fragments were found at significantly higher levels in control samples compared with metastases samples, it is proposed that a specific proteolytic inhibition process is in effect in the serum of prostate cancer patients. Experiments using synthetic peptides showed that this proteolytic activity occurs ex vivo and is sequence specific. Importantly, the observed prostate carcinomarelated inhibition of the proteolysis was reproduced ex vivo using synthetic peptides.

Fibroblast growth factor receptor 3 mutation analysis on voided urine for surveillance of patients with low-grade non-muscle - Invasive bladder cancer (Article)

2010-06-01T00:00:00Z

Purpose: Mutations in the fibroblast growth factor receptor 3 (FGFR3) have been found in 70% of the low-grade non-muscle-invasive bladder cancer (NMI-BC) tumors. We aim to determine the potential of FGFR3 mutation analysis on voided urine to detect recurrences during surveillance of patients with low-grade NMI-BC. Experimental Design: FGFR3 mutation status of the study inclusion tumor was determined from 200 low-grade NMI-BC patients. Patients with an FGFR3-mutant inclusion tumor were selected for analysis and monitored by cystoscopy, and voided urine samples were collected. FGFR3 mutation analysis was done on 463 prospectively collected urines. Sensitivity and predictive value of the assay were determined for detection of concomitant recurrences. Longitudinal and Cox time-to-event analyses were done to determine the predictive value for detection of future recurrences. Results: Median follow-up was 3.5 years. The sensitivity of the assay for detection of concomitant recurrences was 26 of 45 (58%). Of the 105 positive urine samples, 85 (81%) were associated with a concomitant or a future recurrence. An FGFR3-positive urine was associated with a 3.8-fold (P < 0.0001) higher risk of having a recurrence in the Cox analysis. In contrast, only 41 of 358 (11%) FGFR3-negative urine samples were associated with a recurrence. Positive predictive value increased from 25% to 90% in patients having consecutive FGFR3-positive urine tests. Conclusions: FGFR3 mutation analysis on voided urine is a simple and noninvasive diagnostic method for detection of recurrences during surveillance of patients presenting with a low-grade FGFR3-mutant NMI-BC tumor.

The effect of study arm on prostate cancer treatment in the large screening trial ERSPC (Article)

2010-05-15T00:00:00Z

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.

Do Anxiety and Distress Increase During Active Surveillance for Low Risk Prostate Cancer? (Article)

2010-05-01T00:00:00Z

Purpose: Anxiety and distress may be present in patients with low risk prostate cancer who are on active surveillance. This may be a reason to discontinue active surveillance. Materials and Methods: A total of 150 Dutch patients with prostate cancer on active surveillance in a prospective active surveillance study received questionnaires at study inclusion and 9 months after diagnosis. We assessed changes in scores on decisional conflict with the decisional conflict scale, depression with the Center for Epidemiologic Studies Depression Scale, generic anxiety with the State Trait Anxiety Inventory, prostate cancer specific anxiety with the Memorial Anxiety Scale for Prostate Cancer and the self-estimated risk of progression. We explored scores 9 months after diagnosis vs those at study inclusion for physical health (SF-12® physical component summary), personality (Eysenck Personality Questionnaire), shared decision making, prostate cancer knowledge, demographics, medical parameters and prostate specific antigen doubling time during followup. Results: Questionnaires at study inclusion and 9 months after diagnosis were completed by 129 of 150 (86%) and 108 of 120 participants (90%) a median of 2.4 and 9.2 months after diagnosis, respectively. Anxiety and distress at study inclusion were previously found to be generally favorable. Significant but clinically irrelevant decreases were seen in mean scores of the State Trait Anxiety Inventory (p = 0.016), Memorial Anxiety Scale for Prostate Cancer fear of progression subscale (p = 0.005) and the self-estimated risk of progression (p = 0.049). Anxiety and distress 9 months after diagnosis were mainly predicted by scores at study inclusion. Higher Eysenck Personality Questionnaire neuroticism score and an important role of the physician in the treatment decision had additionally unfavorable effects. Good physical health, palpable disease and older age had favorable effects. No association was seen for prostate specific antigen doubling time. Nine men discontinued active surveillance, including 2 due to nonmedical reasons. Conclusions: Anxiety and distress generally remain favorably low during the first 9 months of surveillance.

Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up (Article)

2010-05-01T00:00:00Z

CyberKnife stereotactic radiotherapy as monotherapy for low- to intermediate-stage prostate cancer: Early experience, feasibility, and tolerance (Article)

2010-05-01T00:00:00Z

Purpose: The CyberKnife (CK), a linear accelerator mounted on a robotic device, enables excellent dose conformation to the target and minimizes dose to surrounding normal tissue. It is a very suitable device for performing hypofractionated stereotactic body radiotherapy as monotherapy for low- to intermediate-risk prostate cancer patients. We report our early experience using this technique. Materials and Methods: Between June 2008 and June 2009, 10 patients underwent CK monotherapy as treatment for their prostate cancer (stage ≤T2b, Gleason score (GS) ≤7, initial PSA ≤15μg/L). The prescribed dose was 38 Gy in four daily fractions of 9.5 Gy. The International Prostate Symptom Score and Radiation Therapy Oncology Group symptom scale were prospectively administered before and at 0.5, 1, 2, 3, 6, and 12 months. Results: Median age of the patients was 71 years (range, 66-76). Three patients had stage T2a and 7a T1c disease, one patient had GS of 7, and all others had GS of 6. Median follow-up was 5.1 months. Median initial PSA was 8.3 ng/mL (range, 1.3-13.6 ng/mL). Median planning target volume delineated on computed tomography after matching with the magnetic resonance imaging scan was 107 cc (range, 42-158 cc). The median V100 of the prostate was 95.8% (range, 94.8-97.2). The D95 of the prostate was 38.3 Gy (range, 38.1-38.8 Gy). The constraints for the bladder, rectum, and urethra were well met. The International Prostate Symptom Scores after 3 months were stable compared with the pretreatment scores. Urinary and bowel Radiation Therapy Oncology Group symptoms were mild and within the expected levels. Conclusions: This regimen of stereotactic CK monotherapy for low- to intermediate-risk prostate cancer with excellent dose coverage of the prostate was well tolerated. Data collection is ongoing for further assessment of toxicity and PSA response.

Short-term outcomes of the prospective multicentre 'Prostate Cancer Research International: Active Surveillance' study (Article)

2010-04-01T00:00:00Z

Study Type - Therapy (prospective cohort) Level of Evidence 2b Objective To evaluate the short-term outcomes of the prospective international Prostate Cancer Research International: Active Surveillance ('PRIAS') study (Dutch Trial Register NTR1718), as active surveillance (AS) for early prostate cancer might provide a partial solution to the current overtreatment dilemma in this disease. Patients and methods The first 500 (of >950) participants with asymptomatic T1c/T2 prostate cancer, with a prostate-specific antigen (PSA) level of ≤10.0 ng/mL, a PSA density of <0.2 ng/mL/mL, a Gleason score of ≤3 + 3 = 6, and one or two positive biopsy cores, were analysed. The follow-up protocol consisted of frequent PSA measurements, digital rectal examinations, and standard repeat biopsies (the first after 1 year). The primary outcome is survival free of active therapy; the secondary endpoints are reasons for stopping AS, findings in 1-year repeat biopsies, and outcomes after radical prostatectomy (RP). Results Patients were included between December 2006 and July 2008. The median (25-75th percentile) follow-up after diagnosis was 1.02 (0.6-1.5) years. The 2-year survival rate free from active therapy was 73%. Of the 82 men who changed to active therapy during the follow-up, 68 (83%) did so based on the protocol. Of the 261 repeat biopsies available for analysis, 90 (34%) showed no cancer, while 57 (22%) showed a Gleason score of >6 or more than two positive biopsy cores. There was a relatively unfavourable PSA doubling time of 0-10 years in 53% (102/194) and 62% (33/53) of men with favourable and unfavourable re-biopsy results, respectively. After RP, four of 24 (17%) men had T3 disease and 12 (50%) had a Gleason score of >6. Conclusion AS seems feasible, but mortality outcomes are unknown. A strict follow-up protocol including standard 1-year repeat biopsies resulted in a quarter of men stopping AS after 2 years.

Orgasmic dysfunction after open radical prostatectomy: Clinical correlates and prognostic factors (Article)

2010-03-01T00:00:00Z

Introduction: Erectile function after radical retropubic prostatectomy (RRP) is extensively discussed in literature. However, less is known about orgasm after RRP. Aim: To analyze sexual function, in particularly orgasmic function, in men before and after RRP. Methods: Between 1977 and 2007 a RRP was performed in 1,021 men. All men were interviewed by their follow-up physician using a standardized interview about sexual function before and after RRP at regular intervals during a 2-year follow-up. The questions were related to sexual interest, sexual activity, spontaneous erections, and orgasmic function. Main Outcome Measures: Sexual function, in particularly orgasmic function, before and after RRP. Factors potentially influencing orgasmic function, such as patients age, type of operation, pathological stage and continence status were analyzed for their predictive value. Results: Information about preoperative and postoperative sexual activity and spontaneous erection was available in 596 and 698 men, respectively. Additional questions were asked on sexual interest (N = 425) and orgasmic function (N = 458).Pre-operatively, sexual interest, sexual activity, spontaneous erections and orgasmic function were normal in 99%, 82.1%, 90.0% and 90% of men, respectively. After operation these values decreased to 97.2%, 67.3%, 29.4% and 66.8%, respectively. Orgasmic function was preserved in 141 of 192 men (73.4%) after a bilateral nerve sparing procedure, in 90 out of 127 men (70.9%) after a unilateral nerve-sparing procedure and in 75 of 139 men (54.0%) after non-nerve sparing technique. Postoperatively, orgasm was present in 123 (77.4%) men below the age of 60 years and in 183 (61.2%) men of 60 years and older (P < 0.0001). Orgasmic function was significantly affected by age ≥60 years, non-nerve sparing procedure and severe incontinence (more than two pads/day). Conclusions: After RRP, orgasmic function is still present in the majority of men. A non-nerve sparing operation, age, and severe urinary incontinence are risk factors for orgasmic dysfunction after RRP.

Eleven-Year Outcome of Patients with Prostate Cancers Diagnosed During Screening After Initial Negative Sextant Biopsies (Article)

2010-02-01T00:00:00Z

Background: The appropriate way of biopsying a prostate remains controversial. Is sextant biopsy still adequate with repeat screening? Objective: Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), lateralized sextant biopsies were applied. In this analysis we use distant end points to study the fate of prostate cancers (PCa) potentially missed by initial biopsies. Design, setting, and participants: This retrospective study included 19 970 men ages 55-74 identified from the Rotterdam population registry and screened repeatedly for PCa between 1993 and 2005. PCa detected later in men with initially negative biopsies were considered as missed. Rescreening every 4 yr and a complete follow-up of 11 yr allowed an inventory of progressive and deadly disease in these men. Intervention: Sextant biopsies initially, later lateralized, in screen-positive men. Measurements: The fate of PCa potentially missed by initial sextant biopsies in terms of progression-free and PCa-specific survival were the main outcome measures. Kaplan-Meier analysis was used to evaluate differences between subgroups. Results and limitations: In 3056 men with negative biopsies at the first screen, 287 PCa were subsequently detected. Of these 287 cases, 26 developed progressive disease and 7 died of PCa. Poor outcomes were encountered mainly in 20 interval cases. The seven PCa deaths in men with initially negative biopsies amounted to only 0.03% compared to the 0.35% PCa death rate in the whole population of 19 970 men. Limitations include the retrospective character of this analysis. Conclusions: The number of potentially missed cancers with a poor outcome in terms of progression-free survival and deaths from PCa is very low. Despite some limitations, our data show that lateralized sextant biopsy is not obsolete if repeated screening is applied.

Informed decision making on PSA testing for the detection of prostate cancer: An evaluation of a leaflet with risk indicator (Article)

2010-02-01T00:00:00Z

Background: Population-based screening for prostate cancer (PCa) remains controversial. To help men making informed decisions about prostate specific antigen (PSA) screening a risk indicator (www.uroweb.org) was developed. This risk indicator is embedded in a leaflet that informs men about the pros and cons of PCa screening and enables calculation of the individual risk of having a biopsy detectable PCa. Aim: To assess the effect of providing a leaflet including individualized risk estimation on informed decision making of men, i.e. knowledge about PCa and PSA screening, attitude towards undergoing a PSA test and intention to have a PSA test. Methods: An intervention study among 2000 men, aged 55-65 years, randomly selected from the population registry of the city of Dordrecht, the Netherlands, in 2008. Men were sent a questionnaire on knowledge of PCa, attitude and intention to have a PSA test. Men without a history of (screening for) PCa were sent the leaflet and Questionnaire 2 within 2 weeks after returning Questionnaire 1. Validated health and anxiety measures were used. Results: One thousand and twenty seven of 2000 men completed Questionnaire 1 (51%), of whom 298 were excluded due to a history of (screening for) PCa. Of the 729 remaining men, 601 completed Questionnaire 2 as well. At the second assessment significantly more men met the requirements of informed decision making (15% versus 33%, p < 0.001), more men had relevant knowledge (284/601, 50% versus 420/601, 77%, p < 0.001) and the intention to have a PSA test had increased (p < 0.001). Conclusions: Providing information on PCa screening combined with individualized risk estimation enhanced informed decision making and may be used for shared decision making on PSA screening of physicians and patients.

Cystoscopy Revisited as the Gold Standard for Detecting Bladder Cancer Recurrence: Diagnostic Review Bias in the Randomized, Prospective CEFUB Trial (Article)

2010-01-01T00:00:00Z

Purpose: We evaluated the influence of knowledge of urine test outcome on the accuracy of cystoscopy (diagnostic review bias) during surveillance in patients with low grade, nonmuscle invasive urothelial carcinoma. Materials and Methods: We performed a prospective, single-blind, randomized, multicenter clinical trial of surveillance by microsatellite analysis urine test in 448 patients with nonmuscle invasive (pTa, pT1, G1, G2) urothelial carcinoma. Positive or negative urine test results were only communicated to the urologist in the intervention arm of 226 patients, in which cystoscopy was done if the test was positive, and at 3, 12 and 24 months. Urine test results were not communicated in the control arm of 222 patients who underwent standard 3-month cystoscopy. The primary outcome measure was the number of histologically proven bladder cancer recurrences. Results: At a median 34-month followup 218 recurrences were detected in the intervention arm compared to 163 in the control arm (p <0.001). Of 131 cystoscopies done with knowledge of a positive urine test 42 recurrences were detected. Only 6 recurrences were found in the 120 cystoscopies done without information on the positive test result (chi-square p <0.001). There was no difference in recurrence detection when urine test results were negative in the intervention and control arms (18 of 260 patients or 7% and 18 of 326 or 6%, respectively, p = 0.45). Conclusions: Diagnostic review bias should be considered in the evaluation of point of care urine tests for bladder cancer monitoring. Awareness of a positive urine test result significantly improves the urothelial carcinoma detection rate using cystoscopy.

False-negative prostate needle biopsies: Frequency, histopathologic features, and follow-up (Article)

2010-01-01T00:00:00Z

Little is known about the frequency, histopathologic characteristics, and clinical consequences of false-negative prostate biopsies, that is, biopsies classified as benign but containing adenocarcinoma or atypical suspicious glands [atypical small acinar proliferations (ASAP)]. Objective of this study was to evaluate false-negative prostate biopsy in a prostate cancer screening setting. Prostate biopsy sets of 196 participants of a screening trial, which had been reported as "benign" at initial diagnosis, followed by a diagnosis of adenocarcinoma in a subsequent screening round were reviewed by 2 urologic pathologists. Adenocarcinoma was identified in 19 biopsy cores corresponding to 16 (8.2%) patients and ASAP in 24 cores, corresponding to 19 patients (9.7%). All missed prostate cancers were Gleason score 6 (3+3). After correction for patient selection, the overall false-negative biopsy rate was estimated to be 2.4%; 1.1% for prostate cancer; and 1.3% for ASAP. Clinicopathologic features at the time of initial biopsy and of subsequent prostate cancer diagnosis did not differ between patients with a false-negative or true benign biopsy. Relatively low number of atypical glands (<10 glands), intense intermingling with preexistent glands or lack of architectural disorganization were the most prominent risk factors for a false-negative diagnosis. Another potential pitfall was the presence of prostate cancer variants, as 1 adenocarcinoma was of foamy gland type and 3 of pseudohyperplastic type. Routine examination of at least 1 level of prostate biopsy sets at high magnification and awareness of histologic prostate cancer variants might reduce the risk of missing or misinterpreting a relevant lesion at prostate biopsy evaluation.

A Risk-Based Strategy Improves Prostate-Specific Antigen-Driven Detection of Prostate Cancer (Article)

2010-01-01T00:00:00Z

Background: Screening for prostate cancer (PC) is controversial due to uncertainties about its efficiency. Objective: We aimed to develop strategies to reduce the number of unnecessary biopsies while still detecting most clinically important PC cases. Design, setting, and participants: In 1850 men initially screened and biopsied (prostate-specific antigen [PSA] value ≥3.0 ng/ml) in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, we calculated both the probability of having a positive lateralized sextant biopsy [P(biop+)] and the probability of having an indolent cancer [P(ind)] if PC was detected at biopsy (n = 541). Analyses of repeat screening included 225 cancers in 1201 men. Interventions: The P(biop+) was based on applying a logistic regression model that included ultrasound volume, digital rectal exam, and transrectal ultrasound in addition to the PSA value. The P(ind) was based on a recently validated nomogram. Measurements and limitations: At initial screening the fraction of positive biopsies was 29% (541 of 1850). Applying an additional P(biop+) cut-off of 12.5% implied that 613 of the 1850 men (33%) would not have been biopsied. This would result in an increase in the positive predictive value (PPV) to 38% (468 of 1237). At repeat screening a similar P(biop+) cut-off would result in an increase in the PPV from 19% (225 of 1201) to 25% (188 of 760). Thirteen percent of PC cases would not have been diagnosed, of which 70% (initial screening) and 81% (repeat screening) could be considered as potentially indolent. None of the deadly PC cases would have been missed. A PSA cut-off of ≥4.0 ng/ml resulted in similar numbers of biopsied cases saved but considerably higher numbers of missed diagnoses. Conclusions: An individualized screening algorithm using other available prebiopsy information in addition to PSA level can result in a considerable reduction of unnecessary biopsies. Very few important PC cases, for which diagnosis at a subsequent screening visit might be too late for treatment with curative intent, would be missed.

Prostate cancer mortality in screen and clinically detected prostate cancer: Estimating the screening benefit (Article)

2010-01-01T00:00:00Z

Background: To estimate the benefits of prostate-specific antigen (PSA) screening on prostate cancer (Pca) metastasis and Pca-specific mortality, we compared two populations with a well-defined difference in intensity of screening. Methods: Between 1997 and 1999, a total of 11,970 men, aged 55-74 years, were included in the intervention arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) section Rotterdam. Control population consisted of 133,287 men, aged 55-74 years, between 1998 and 1999 in Northern Ireland (NI). Men were followed for Pca incidence, Pca metastasis and cause of death until 31st December 2006. Results: Median age in both groups was 63 years at study entry (p = 0.184). In Rotterdam 94.2% of men and in NI 6% of men underwent PSA testing. In Rotterdam, 1153 men (9.6%) were diagnosed with Pca with median baseline PSA of 5.1 ng/ml. In NI, 3962 men (3.0%, p < 0.001) were diagnosed with Pca with median baseline PSA of 18.0 ng/ml (p < 0.001). The relative risk of Pca metastasis during observation in the intervention population compared to control population was 0.47 (95% confidence interval (CI), 0.35-0.63; p < 0.001). The relative risk of Pca-specific mortality was also lower in the intervention population compared to the control population after a median follow-up of 8.5 years: 0.63 (95% CI, 0.45-0.88; p = 0.008); absolute mortality reduction was 1.8 deaths per 1000 men. Conclusions: A relative reduction in Pca metastasis of 53% and Pca mortality of 37% was observed in the intervention population after 8.5 years of observation. The impact of overdiagnosis, quality of life benefits and cost-effectiveness need to be assessed before population-based PSA screening can be recommended.

The requirements of a specialist Prostate Cancer Unit: A discussion paper from the European School of Oncology (Article)

2010-01-01T00:00:00Z

The widely recognised benefits of a multidisciplinary approach to treating cancer may be particularly important in prostate cancer, where there are so many treatment options to choose from. It offers patients the best chance of receiving high-quality medical procedures administered by a team of specialists in prostate disease, which is able to tailor treatment and observational strategies to their needs, and ensure access to specialist counselling, supportive care and rehabilitation. This article proposes Prostate Cancer Units as the most suitable structures for organising specialist multidisciplinary care for patients at all stages, from newly diagnosed to advanced disease, including preventing and managing the main complications, whether physical, emotional or psychological, arising from the disease and its treatment. Following the German example with prostate cancer, the British example with urological malignancies and the European breast cancer units, this article proposes general recommendations and mandatory requirements for Prostate Cancer Units, with a view to laying the basis for a network of certified units across Europe. Such a network could help improve standards of care throughout the region, providing patients, practitioners and health authorities with a means of identifying high-quality units and providing a system of quality control and audit. The article is intended as a contribution to the debate within the European uro-oncologic community on the best way to organise prostate cancer care.

Prostate Cancer Mortality Reduction by Prostate-Specific Antigen-Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC) (Article)

2009-10-01T00:00:00Z

Background: Prostate-specific antigen (PSA) based screening for prostate cancer (PCa) has been shown to reduce prostate specific mortality by 20% in an intention to screen (ITS) analysis in a randomised trial (European Randomised Study of Screening for Prostate Cancer [ERSPC]). This effect may be diluted by nonattendance in men randomised to the screening arm and contamination in men randomised to the control arm. Objective: To assess the magnitude of the PCa-specific mortality reduction after adjustment for nonattendance and contamination. Design, setting, and participants: We analysed the occurrence of PCa deaths during an average follow-up of 9 yr in 162 243 men 55-69 yr of age randomised in seven participating centres of the ERSPC. Centres were also grouped according to the type of randomisation (ie, before or after informed written consent). Intervention: Nonattendance was defined as nonattending the initial screening round in ERSPC. The estimate of contamination was based on PSA use in controls in ERSPC Rotterdam. Measurements: Relative risks (RRs) with 95% confidence intervals (CIs) were compared between an ITS analysis and analyses adjusting for nonattendance and contamination using a statistical method developed for this purpose. Results and limitations: In the ITS analysis, the RR of PCa death in men allocated to the intervention arm relative to the control arm was 0.80 (95% CI, 0.68-0.96). Adjustment for nonattendance resulted in a RR of 0.73 (95% CI, 0.58-0.93), and additional adjustment for contamination using two different estimates led to estimated reductions of 0.69 (95% CI, 0.51-0.92) to 0.71 (95% CI, 0.55-0.93), respectively. Contamination data were obtained through extrapolation of single-centre data. No heterogeneity was found between the groups of centres. Conclusions: PSA screening reduces the risk of dying of PCa by up to 31% in men actually screened. This benefit should be weighed against a degree of overdiagnosis and overtreatment inherent in PCa screening.

Anxiety and distress during active surveillance for early prostate cancer (Article)

2009-09-01T00:00:00Z

BACKGROUND: Patients on active surveillance (AS) for early prostate cancer (PC) may experience feelings of anxiety and distress while living with "untreated" cancer. In this study, these feelings were quantified, and their associations with various psychologic, medical, demographic, and decision-related factors were assessed. METHODS: Men with recently diagnosed PC who participated in a prospective protocol-based AS program (the Prostate Cancer Research International: Active Surveillance study [PRAIS]) received a questionnaire (N = 150). Scores concerning decisional conflict (the Decisional Conflict Scale), depression (the Center for Epidemiologic Studies Depression Scale), generic anxiety (the abridged State-Trait Anxiety Inventory), and PC-specific anxiety (the Memorial Anxiety Scale for Prostate Cancer) were compared with reference values and the literature. Associations with scores on physical health (the Medical Outcomes Study 12-item short-form Physical Component Summary), personality (the Eysenck Personality Questionnaire), shared decision-making, knowledge of PC, and demographic and medical parameters were determined with univariate and multivariate linear regression analyses. RESULTS: The questionnaire response rate was 86% (129 of 150 men). Of all respondents, 81%, 92%, 83%, and 93% scored better than reference values for clinically significant uncertainty regarding the treatment decision, depression, generic anxiety, and PC-specific anxiety, respectively. Scores were comparable to or more favorable than those of men (reported in literature) who underwent other treatments for localized PC. In multivariate analysis, the following associations emerged: a perceived important role of the physician in shared decision-making was associated with higher decisional conflict, better physical health was associated with lower depression, neurotic personality was associated with higher depression and with generic and PC-specific anxiety, and higher prostate-specific antigen level was associated with higher PC-specific anxiety. CONCLUSIONS: Men on protocol-based AS mainly reported favorable levels of anxiety and distress. A neurotic personality score was associated with unfavorable effects. These findings may help to optimize patient selection for AS or to select men for supportive measures.

Body mass index as a prognostic marker for biochemical recurrence in dutch men treated with radical prostatectomy (Article)

2009-08-01T00:00:00Z

OBJECTIVE To investigate whether body mass index (BMI) is a prognostic factor for biochemical recurrence (BCR) in Dutch men after radical prostatectomy (RP), as although epidemiological studies of obesity in relation to prostate cancer have provided conflicting results, recent studies from the USA suggest that a higher BMI is a risk factor for progression of prostate cancer. PATIENTS AND METHODS Of the 1417 patients with prostate cancer who had RP at two University hospitals, 1302 were included in the present study. BMI (kg/m2) classes were defined as normal (<25), overweight (25-30) and obese (≥30). The median follow-up was 59 months and clinical data were obtained retrospectively from charts. BCR was defined as two consecutive prostate-specific antigen (PSA) levels of >0.1 ng/mL. RESULTS In all, 600 patients were classified as having normal weight (43.9%), 665 as overweight (48.6%) and 103 as obese (7.5%). Overall, 297 patients developed BCR after RP; the 10-year risk (95% confidence interval) of BCR was 31.9 (26.6-37.2)%, 30.5 (25.8-35.2)% and 23.9 (14.9-32.9)% for patients in the three categories, respectively (P = 0.836). Multivariable proportional hazard regression analyses of BMI and established prognostic factors for BCR did not change these results. CONCLUSION BMI appeared to have no prognostic value for BCR in Dutch patients with clinically localized prostate cancer and treated with RP.

Predictive models in diagnosing indolent cancer (Article)

2009-07-01T00:00:00Z

The early detection of prostate cancer has led to the increased incidence of tumors that are unlikely to become symptomatic during life: so-called indolent cancers. The ability to predict indolent prostate cancer is needed to avoid over treatment by unnecessary invasive therapies and to select men for active surveillance. For this report, the currently available nomograms that predict these low-risk tumors were reviewed. Many of these nomograms were based on clinical patient series, thus, their general application is restricted. Those nomograms based on screening series of the general population need further validation before generalized application is feasible.

Gleason score 7 screen-detected prostate cancers initially managed expectantly: Outcomes in 50 men (Article)

2009-06-01T00:00:00Z

Objective To assess whether men newly diagnosed with Gleason 7 prostate cancer are eligible for active surveillance (AS) instead of radical treatment. AS is an appropriate initial strategy in selected men who are presently diagnosed with prostate cancer, as many tumours will not progress during a patient's lifetime. Patients and Methods Cancer-specific-, overall and treatment-free survival were analysed retrospectively in men with Gleason score 7 cancer who were initially managed expectantly. All were screen-detected in four centres of the European Randomized Study of Screening for Prostate Cancer. Results In 50 men active therapy was initially withheld if they had Gleason 7 disease; 29 of 50 (58%) would otherwise have been suitable for AS, as they had a prostate-specific antigen (PSA) level of ≤10.0 ng/mL, a PSA density of <0.2 ng/mL/mL, stage T1c/T2, and two or fewer positive biopsy-cores; 44 of 50 (88%) had a Gleason score 3 + 4 = 7. The mean (range) age of the men was 69.5 (59.6-76.2) years and the median (interquartile range) follow-up was 2.6 (0.8-5.0) years; the mean American Society of Anesthesiologists score was 1.8. The 6-year cancer-specific survival (nine patients at risk) was 100%, which sharply contrasted with the 68% overall survival. Men alive at the time of analysis had a favourable PSA level and PSA-doubling time. The 6-year treatment-free survival was only 59%, with most patients switching to active therapy, justified on the basis of their PSA level. However, men with otherwise favourable tumour characteristics and a Gleason score of 3 + 4 = 7 remained treatment-free significantly longer than their counterparts with unfavourable other tumour features and a Gleason score of 4 + 3 = 7. Conclusion In selected patients with screen-detected Gleason 3 + 4 = 7 prostate cancer, AS might be an option, especially in those with comorbidity and/or a short life-expectancy.

Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues (Article)

2009-06-01T00:00:00Z

Prostate Cancer (PC) is a type of cancer that is often diagnosed at very early stages due to improved detection among man in the Western world. Current imaging techniques are not optimal to determine extent of minimal early stage PC even though this is of great clinical importance. Human PC and high-grade PIN have shown high Gastrin-Releasing Peptide Receptor (GRPR) expression, while normal prostate tissue and BPH revealed to be predominantly GRPR-negative. Radiolabelled Gastrin-Releasing Peptide (GRP) or bombesin (BN) analogues targeting the GRPR can be used as non-invasive tools to diagnose, monitor and potentially treat PC. These BN analogues have already proven to be able to image PC in both tumour-bearing mice and clinical patients showing no important side effects. It's desirable that new peptides require fast-track standardised comparative testing in relevant PC models to select the best performing BN analogues for further evaluation in patients. Although knowledge about GRPR expression and development of new BN analogues can be extended, it is time to study performance of BN analogues for peptide receptor based imaging in patients validating results of PC imaging using histopathology as a golden standard.

Higher free testosterone level is associated with faster visual processing and more flanker interference in older men (Article)

2009-05-01T00:00:00Z

The aim of this study was to investigate the relation between free testosterone (FT) level and basic cognitive functions in older men. Three cognitive computer tasks were aimed to measure visual-processing speed, ability to suppress inappropriate responses, and visuospatial cognition, respectively. The tasks employed were a visual backward masking task, the Eriksen flanker task, and a mental rotation task. Participants were 72 older men (mean age = 67.2 years, range 57-79). The influence of FT, age, alcohol consumption, and education on task performances was examined by means of multiple linear regression analysis. FT level was positively associated with accuracy on the short intervals (33 and 50 ms) of the backward masking task and negatively with response latency on congruent flanker-task trials. These results indicate faster visual-processing speed in older men with higher FT levels. FT level was positively associated with interference elicited by irrelevant incongruent flankers, which implies that older men with higher levels of free testosterone exert less inhibitory control. Consistent with previous research, higher FT levels were associated with faster 'same-different' responses for unrotated mental rotation stimuli, but not with the slopes of the response time rotation functions. Older age was associated with lower backward masking accuracy at 33 ms and with lower overall mental rotation accuracy. Higher education level was associated with faster processing speed for congruent flankers and with higher overall mental rotation accuracy. Alcohol consumption did not affect the task performances. Our results suggest that higher FT levels in older men may promote sustained visual-processing speed and visuospatial ability, probably at the expense of some inhibitory functioning.

The development of multiple bladder tumour recurrences in relation to the FGFR3 mutation status of the primary tumour (Article)

2009-05-01T00:00:00Z

Non-muscle invasive bladder cancers (NMI-BCs) represent 75% of bladder cancers upon presentation. After removal of the primary tumour by transurethral resection, multiple recurrences continue to develop in 70% of patients. Consequently, prolonged and costly surveillance by cystoscopy is required. Mutations in the FGFR3 oncogene are common in NMI-BCs and are associated with a lower chance of progression to muscle-invasive disease. Here we analysed the consistency of FGFR3 mutations in primary and recurrent tumours. This knowledge is of crucial importance if FGFR3 mutation analysis on urinary cells is to be used as an alternative for cystoscopical surveillance. To this end, we monitored the disease process and FGFR3 mutation status of primary and recurrent tumours in 118 patients with NMI-BC. During median follow-up of 8.8 years, these patients underwent 2133 cystoscopies and 80 patients developed 414 recurrences. FGFR3 mutations were equally prevalent in primary and recurrent tumours (63%). Patients can have different types of FGFR3 mutations in different tumours. Recurrence risk was not significantly different for patients with a mutant or wild-type primary tumour. Recurrence rates varied widely between patients but were constant for a patient and were unrelated to FGFR3 status.Inthe mutant patient group, in contrast to the wild-type group, recurrences continued to develop after 10 years. In 81% of the recurrences of patients with a mutant primary tumour, a mutation was found. Moreover, recurrences in this patient group were of lower stage and grade than those of patients with a wild-type primary tumour (p 0.001). These results suggest that surveillance by FGFR3 mutation analysis on voided urine in combination with a reduced cystoscopy frequency of patients presenting with an FGFR3 mutant tumour is worth investigating.

Screening and prostate-cancer mortality in a randomized european study (Article)

2009-03-26T00:00:00Z

Background The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen(PSA) testing on death rates from prostate cancer. Methods We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. Results In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80(95% confidence interval [CI], 0.65 to 0.98; adjusted P = 0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round(excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73(95% CI, 0.56 to 0.90). Conclusions PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis.(Current Controlled Trials number, ISRCTN49127736.) Copyright

Microsatellite Analysis of Voided-Urine Samples for Surveillance of Low-Grade Non-Muscle-Invasive Urothelial Carcinoma: Feasibility and Clinical Utility in a Prospective Multicenter Study (Cost-Effectiveness of Follow-Up of Urinary Bladder Cancer Trial [CEFUB]) (Article)

2009-03-01T00:00:00Z

Background: Microsatellite analysis (MA) of voided-urine samples has been promoted as an alternative for cystoscopy surveillance (UCS) of patients with low-grade non-muscle-invasive papillary urothelial carcinoma (UC). Objective: To assess the feasibility and clinical utility of MA on voided-urine samples in a routine setting to detect or predict bladder cancer recurrences. Design, setting, and participants: We evaluated 228 patients monitored by MA of voided-urine samples and synchronous UCS who participated in a longitudinal prospective study in 10 hospitals. Follow-up started after diagnosis of a primary or recurrent pTa, pT1, grade 1 or grade 2 papillary UC. Measurements: Clinico-pathological parameters and fibroblast growth factor receptor 3 (FGFR3) gene mutation status of the inclusion tumour were determined. MA outcome was analysed in 1012 urine samples during a mean follow-up of 41 mo. Poor DNA quality prevented MA in 19% (197/1012) of the samples, leaving 815 visits for a cross-sectional analysis of sensitivity and specificity. We determined the predictive value (PPV) in a longitudinal analysis for 458 series with persistent MA results. Factors influencing diagnostic quality of MA were investigated. Kaplan-Meier analysis was performed to relate MA results to recurrence. Results and limitations: Cross-sectional sensitivity and specificity of MA for detection of a recurrence were 58% (49/84) and 73% (531/731), respectively. One pT1 grade 3 UC was missed. In a longitudinal analysis, the 2-yr risk to develop a recurrence reached 83% if MA outcome was persistently positive and 22% when MA was persistently negative. PPV of MA was higher with wild-type FGFR3 gene status and smoking habits. All four upper urinary tract tumours detected were preceded by a positive MA test. Conclusions: Consecutive positive MA results are a strong predictor for future recurrences, but sensitivity needs to be improved, for example, by patient selection and testing of additional genetic markers in urine samples.

Can dutasteride delay or prevent the progression of prostate cancer in patients with biochemical failure after radical therapy? Rationale and design of the Avodart after Radical Therapy for Prostate Cancer Study (Article)

2009-03-01T00:00:00Z

OBJECTIVE: To describe the Avodart after Radical Therapy for prostate cancer Study (ARTS), investigating the use of dutasteride (a dual 5α-reductase inhibitor that suppresses intraprostatic dihydrotestosterone, reduces tumour volume and improves other markers of tumour regression in prostate cancer) to prevent or delay disease progression in patients with biochemical recurrence after therapy with curative intent. PATIENTS AND METHODS: An increasing serum prostate-specific antigen (PSA) level after radical prostatectomy (RP) or radiotherapy (RT) is indicative of recurrent prostate cancer and typically pre-dates clinically detectable metastatic disease by several years. ARTS is an ongoing European multicentre trial in which patients are stratified by previous therapy (RP with or without salvage RT vs primary RT) and randomized to double-blind treatment with dutasteride 0.5 mg or placebo once daily for 2 years. Eligible patients will have a PSA doubling time (DT) of 3-24 months. Biochemical recurrence is defined as three increases in PSA level from the nadir, with each increase ≥4 weeks apart and each PSA level ≥0.2 ng/mL, and a final PSA level of ≥0.4 ng/mL (after RP) or ≥2 ng/mL (after primary RT). Study endpoints include time to PSA doubling, time to disease progression, treatment response (PSA decrease or an increase of ≤15% from baseline), changes in PSA and PSADT, and changes in anxiety (Memorial Anxiety Scale for Prostate Cancer). CONCLUSIONS: ARTS will be the first study to evaluate the effects of dutasteride on PSADT, disease progression and treatment response in patients with biochemical failure after RP or RT, and should help to elucidate the potential role of dual 5α-reductase inhibition in prostate cancer.

Screening for Prostate Cancer in 2008 II: The Importance of Molecular Subforms of Prostate-Specific Antigen and Tissue Kallikreins (Article)

2009-03-01T00:00:00Z

Context: Over the past decades, prostate-specific antigen (PSA), its isoforms, and other members of the tissue kallikrein family have been of continuous interest with regard to early detection and screening for prostate cancer (PCa). Objective: This review strives to give an overview of the possible clinical utilities of these markers, focused on early diagnostics and PCa screening. Evidence acquisition: Using the Medline database, a literature search was performed on the role of molecular subforms of PSA and other members of the tissue kallikrein family in PCa detection. Evidence synthesis: With respect to PSA isoforms, only the combination of the various truncated forms (pPSA) shows additional value over total PSA (tPSA) and free PSA (fPSA) in PCa detection within the range of 2-10 ng/ml tPSA. At a high sensitivity for PCa, the specificity of the ratio of pPSA to fPSA (%pPSA) is, in general, better than that of the ratio of fPSA to tPSA (%fPSA), with a gain of 5-11%. The (-2)pPSA, (-4)pPSA, (-5)pPSA, (-7)pPSA, and benign PSA (BPSA) isoforms generally show no additional value over either pPSA or the existing parameters of tPSA and fPSA. Of the other members of the tissue kallikrein family, most studies on human kallikrein 2 (hK2) show an additional value of the ratio of hK2 to fPSA (%hK2) over %fPSA alone in PCa prediction. Other tissue kallikreins cannot be recommended for diagnosing PCa, due to the lack of additional value over tPSA or fPSA or to insufficient research. Regarding a prognostic role, the value of PSA subforms as well as of other members of the tissue kallikrein family is limited with regard to existing parameters. Conclusions: pPSA and hK2 are able to improve PCa diagnosis in the range of 4-10 ng/ml tPSA over the existing variables tPSA and fPSA.

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

2009-02-01T00:00:00Z

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.

Human xenograft models as useful tools to assess the potential of novel therapeutics in prostate cancer (Article)

2009-01-13T00:00:00Z

With docetaxel as effective chemotherapy for hormone refractory prostate cancer (HRPC), the number of new treatment combinations for HRPC is expanding demanding a fast-track screening system. This review elaborates on the use of xenograft models to select the most promising combination therapies for entering into phase II clinical trials.

Platinum Priority - Reply from Authors re: Peter C. Albertsen. The Treatment Paradigm Shifts Again on Prostate Cancer. (Article)

2009-01-01T00:00:00Z

20-25% lower concentrations of total and free prostate-specific antigen (PSA) after calibration of PSA assays to the WHO reference materials - Analysis of 1098 patients in four centers (Article)

2009-01-01T00:00:00Z

Aim: To examine the potential clinical implications of the recalibration of total prostate-specific antigen (PSA) and free PSA (fPSA) assays to the World Health Organization (WHO) standard materials. Material and methods: Data from 1098 patients with or without clinically detected prostate cancer (PCa) from four independent cohort studies were compared using commercial assays calibrated to the traditional Hybritech® PSA (PSA-Hyb) and fPSA (fPSA-Hyb) standards and to the WHO 96/670 (PSA-WHO) and 96/668 (fPSA-WHO) standards. The Access® Immunoassay System (Beckman Coulter, Inc.) was used in all studies. Results: All studies showed 20% to 25% lower PSA and fPSA test results with the WHO-standardized assays. No significant change in %fPSA (fPSA/ PSA × 100) was observed. Continuing to use the traditional clinical PSA cutoffs obtained with the Hybritech standard after changing to the PSA-WHO standard could result in up to one-third of prostate cancer cases being missed. Conclusions: Manufacturers should fully inform laboratories about a calibration change and its clinical impact. Laboratory reports for PSA measurements should indicate the assay's manufacturer and which calibration standard was used to avoid misleading information concerning PCa risk.

20-25% lower concentrations of total and free prostate-specific antigen (PSA) after calibration of PSA assays to the WHO reference materials - Analysis of 1098 patients in four centers (Article)

2009-01-01T00:00:00Z

Bladder cancer biomarkers and their role in surveillance and screening (Article)

2009-01-01T00:00:00Z

Early detection of bladder cancer and its recurrences is essential for improved prognosis and long-term survival. The detection and follow-up of these patients is currently based on cystoscopy, which is expensive and invasive, and, in most cases, cytology, which is non-invasive but not very sensitive. During recent years, many urine-based tests have been developed and tested in different patient populations. In this review we discuss new developments for biomarkers in bladder cancer that have potential use in surveillance and screening. In almost all publications authors compare sensitivity of the test with a concomitantly executed cystoscopy, for example, determine cross-sectional sensitivity. However, it has also been shown that false positive test results may be followed by a positive cystoscopy in the near future, showing that cystoscopy itself does not provide 100% sensitivity. This suggests that for a proper evaluation of urine-based tests, longitudinal studies should be carried out and the results communicated to the urologist.

Clinical impact of new prostate-specific antigen WHO standardization on biopsy rates and cancer detection (Article)

2008-12-01T00:00:00Z

BACKGROUND: Clinicians may be unaware that replacement of the historical total prostate-specific antigen (tPSA) standard with the WHO 96/670 international standard leads to difficulties in interpreting tPSA results. Our aim was to investigate the relationship between the Hybritech and WHO calibrations of the Beckman Coulter tPSA assay, and to assess the impact on prostate cancer (PCa) detection. METHODS: tPSA concentrations were measured in 106 serum samples with both Hybritech and WHO calibrations. The established relationships were used for an in silico experiment with a cohort of 5865 men. Differences in prostate biopsy rates, PCa detection, and characteristics of missed cancers were calculated at biopsy thresholds of 3.0 and 4.0 μg/L. RESULTS: A linear relationship was observed between the 2 calibrations, with a 20.3% decrease in tPSA values with the WHO standard compared with the Hybritech calibration. Applying the WHO calibration to the cohort of 5865 men yielded a 20% or 19% decrease in prostate biopsies and a 19% or 20% decrease in detected cancers compared with the Hybritech calibration, at a cutoff for biopsy of 3.0 or 4.0 μg/L, respectively. The decrease in detected cancers declined to 9% or 11% if an abnormal result in a digital rectal examination or a transrectal ultrasound evaluation was used as trigger for prostate biopsy (cutoff of 3.0 or 4.0 μg/L, respectively). CONCLUSIONS: Application of the WHO standard for tPSA assays with commonly used tPSA thresholds leads to a significant decrease in PCa detection. Careful assessment of the relationship between the WHO standard and the thresholds used for prostate biopsy is hence necessary.

Histopathological characteristics of lymph node metastases predict cancer-specific survival in node-positive prostate cancer (Article)

2008-12-01T00:00:00Z

OBJECTIVE: To correlate the histopathological characteristics of lymph node metastases in prostate cancer with cancer-specific survival (CSS). PATIENTS AND METHODS: The histopathological slides from 142 patients who had had a pelvic lymph node dissection for node-positive prostate cancer were reviewed. For each patient we recorded the number of lymph nodes removed, the number of positive nodes, the diameter of the largest metastasis and extranodal extension (ENE). The lymph node metastases were graded according to the Gleason system. These variables were correlated with CSS. RESULTS: The mean age of the patients was 62.4 years and the mean preoperative prostate-specific antigen level was 40.2 ng/mL. The median follow-up was 77.5 months, and the median overall and CSS were 91 and 112 months, respectively. On univariable analysis the following variables correlated with poor CSS: a nodal Gleason score of >7 (hazard ratio 2.4, P < 0.001), a diameter of the largest metastasis of >3 mm (2.2, P = 0.025), more than two lymph node metastases (2.0, P = 0.003), and ENE in more than one lymph node (1.9, P = 0.014). Multivariable analysis showed only the nodal Gleason score and the diameter of the largest metastasis to be independent predictors of CSS (1.8, P = 0.021, and 2.2, P = 0.046, respectively). CONCLUSION: The histopathological characteristics of lymph node metastases in prostate cancer have predictive value for the clinical outcome. The nodal Gleason score and the diameter of the largest metastasis are independent predictors of survival.

Words of wisdom. Re: Prostate cancer stem cells: a new target for therapy. Maitland NJ, Collins AT. (Article)

2008-10-01T00:00:00Z

Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer (Article)

2008-09-15T00:00:00Z

In this study, we describe the properties of novel ETV1 fusion genes, encoding N-truncated ETV1 (dETV1), and of full-length ETV1, overexpressed in clinical prostate cancer. We detected overexpression of novel ETV1 fusion genes or of full-length ETV1 in 10% of prostate cancers. Novel ETV1 fusion partners included FOXP1, an EST (EST14), and an endogenous retroviral repeat sequence (HERVK17). Like TMPRSS2, EST14 and HERVK17 were prostate-specific and androgen-regulated expressed. This unique expression pattern of most ETV1 fusion partners seems an important determinant in prostate cancer development. In transient reporter assays, full-length ETV1 was a strong transactivator, whereas dETV1 was not. However, several of the biological properties of dETV1 and full-length ETV1 were identical. On stable overexpression, both induced migration and invasion of immortalized nontumorigenic PNT2C2 prostate epithelial cells. In contrast to dETV1, full-length ETV1 also induced anchorage- independent growth of these cells. PN T2C2 cells stably transfected with dETV1 or full-length ETV1 expression constructs showed small differences in induced expression of target genes. Many genes involved in tumor invasion/metastasis, including uPA/uPAR and MMPs, were up-regulated in both cell types. Integrin β3 (ITGB3) was clearly up-regulated by full-length ETV1 but much less by dETV1. Based on the present data and on previous findings, a novel concept of the role of dETV1 and of full-length ETV1 overexpression in prostate cancer is proposed.

Prostate-Specific Antigen Kinetics in Clinical Decision-Making During Active Surveillance for Early Prostate Cancer-A Review (Article)

2008-09-01T00:00:00Z

Context: The kinetics of prostate specific antigen (PSA) are generally assumed to be indicative of tumour progression and are therefore used in clinical decision-making in men on active surveillance for early prostate cancer. Objective: This review aims to provide support for exploiting PSA kinetics in an active surveillance setting. Evidence acquisition: We searched the Medline database and reviewed the evidence on both the relation between PSA kinetics before radical treatment for prostate cancer and outcome, as well as the role of PSA kinetics during active surveillance. Furthermore, the benefits and setbacks of different derivatives of PSA kinetics, minimum required time interval and number of measurements, practical recommendations, and pitfalls of their use in clinical practice are discussed. Evidence synthesis: The evidence concerning the prognostic value of the PSA velocity (PSA-V) and PSA doubling time (PSA-DT) is sparse, especially in active surveillance. PSA kinetics should therefore be combined with other diagnostic measures as the trigger for deferred radical treatment or repeat prostate biopsies. There seems to be consensus among several reports on the unfavourable outcome relating to a PSA-DT <3-4 yr and on the favourable prognostic value of a PSA-DT >10 yr or a decreasing PSA level. Online tools provide help with calculations and insight on disease development. The best method of calculation, number of measurements, and time interval between measurements is unknown for now. Conclusions: Despite the current deficits in our understanding of the natural behaviour of early prostate cancer and its relation to serum PSA levels, and despite several secondary factors playing a role in PSA kinetics, PSA kinetics are a practical parameter we can offer men on active surveillance to assess the status of their disease.

Is It Necessary to Detect All Prostate Cancers in Men with Serum PSA Levels <3.0 ng/ml? A Comparison of Biopsy Results of PCPT and Outcome-Related Information from ERSPC (Article)

2008-05-01T00:00:00Z

Context: The European Randomized Study of Screening for Prostate Cancer (ERSPC) section Rotterdam was initiated in 1993. Men who initially presented with prostate-specific antigen (PSA) values <3.0 ng/ml were not biopsied (with few exceptions). In the Prostate Cancer Prevention Trial (PCPT) eligible men who initially presented with PSA values <3.0 ng/ml were all biopsied during or at the end of a 7-yr study period. Objective: To compare biopsy rates in PCPT and cancer detection rates, interval cancers, and prostate cancer deaths in ERSPC. Report the number of additional biopsies needed to detect these cases using PCPT policy. Evidence acquisition: 21,210 men, aged 55-74 yr, were randomised to screening; 19,970 were actually screened between November 1993 and December 1999. A total of 15,852 initially presented with PSA values of <3.0 ng/ml; after excluding 79 detected at first screens, 15,773 remained as the study population. A second and third screening round followed after 4- and 8-yr intervals. All cancers found in three rounds of screening or as interval cancers during the 12-yr interval were identified and characterised. Evidence synthesis: Screening for prostate cancer and routine clinical management, comparison of detection rates and outcome data. During the 12-yr observation period, which may be too short, 700 cancers were found, 620 through screening and 80 as interval cancers. None of the screen-detected cases but 6 of the 80 men with interval cancers died of prostate cancer. Applying the positive predictive value of 21.7% of the PCPT trial 3472 cancers would have been detected in ERSPC Rotterdam had all men with PSA values <3.0 ng/ml been biopsied. Assuming 80 interval cancers and 6 deaths from prostate cancer might have been prevented if all 15,773 eligible men had undergone biopsy. Conclusions: The present data suggest a very much unfavourable "number needed to be biopsied" to find one missed cancer or to detect the deadly interval cancers.

A novel murine model of allogeneic vaccination against prostate cancer (Article)

2008-04-01T00:00:00Z

Prostate cancer continues to be a major cause of death in men. Surgical and medical treatments of the disease have improved, but metastasic disease remains a significant clinical problem. Novel therapies such as whole cell vaccination offer the potential of treating disease by stimulating the immune system. To study the efficacy of a whole cell vaccine in prostate cancer two strains of mice were used: C57BL/6 (H-2Kb) and C3H/HeJ (H-2Kk) in combination with four different cell lines. Thus, a model was constructed of allogeneic and syngeneic vaccine, as well as a challenge tumour for each strain. Two novel cell lines were developed during this study. Firstly, the non tumourigeneic PMC-1 was derived from a normal mouse prostate and immortalized with HPV16. Secondly, the tumourigeneic PMC-1 C6ras1p1 was transformed with human ras gene which formed tumours in both SCID and C3H/HeJ mice. Protection, and the nature of the immune response to syngeneic and allogeneic vaccine, in males and females was examined in both strains. Vaccination with both syngeneic and allogeneic irradiated whole cell vaccines induced protection from syngeneic challenge in females. However, no protection was observed when allogeneic vaccine was given to male mice. This correlated with the immune response. Two types of cellular immune responses were generated in females. A NK-mediated response was observed in C57BL/6 mice, whilst C3H/HeJ mice developed a CTL response. Little or no cellular immune response was observed in males. The cytokine profile in C3H/HeJ females was a mixture of Th1 and Th2 whilst a mainly Th1 profile was observed in C57BL/6 mice. Male mice showed a diminished cytokine secretion compared to females which was further depressed after challenge. The difference in immunity was largely as expected, since tolerance to prostate antigens should not normally develop in female mice. However, this makes this model particularly relevant clinically since it directly mimics the human situation and thus may accelerate the development of whole cell vaccines for clinical use.

The Long-Term Relationship between a Real Change in Prostate Volume and a Significant Change in Lower Urinary Tract Symptom Severity in Population-Based Men: The Krimpen Study (Article)

2008-04-01T00:00:00Z

Objective: We used the database of a longitudinal community-based study to investigate whether real changes in prostate volume (PV) (ie, changes greater than the combination of intra- and interobserver variation of volume measurement) corresponded with significant changes in symptom severity. Methods: In a community-based study of men aged 50-78 yr, the International Prostate Symptom Score (IPSS) and PV were measured at baseline and at 4.2-yr follow-up. Of 1417 men, 864 completed both rounds. A significant change in IPSS was defined as a change of ≥ 4 points. A real change in PV was defined as a percent change of ≥ 26%, or an absolute change of ≥ 10 cc. Results: After 4.2 yr, about 20% of the men had experienced a significant increase in IPSS and 16-23% had a real increase in PV. The age-adjusted odds ratio for a significant increase in symptom severity, which contrasts men who have a real increase in PV and men who do not show such an increase, is 1.38 (95%CI, 1.05-1.85]. The age-adjusted odds ratio for a significant decrease in symptom severity, which contrasts men with a real increase in PV and those without such an increase, is 1.50 (95%CI, 1.11-2.85). Conclusions: Benign prostatic hyperplasia can be characterised as a progressive disease in a certain proportion of men older than 50 yr. Men with growing prostates are at a greater risk of symptomatic deterioration. Men who have prostates that do not grow significantly are more likely to improve symptomatically.

Early Detection of Prostate Cancer in 2007. Part 1: PSA and PSA Kinetics (Article)

2008-03-01T00:00:00Z

Objective: This is the first of two review papers attempting to clarify the best way to detect prostate cancer (PCa) in 2007. Screening for PCa has not yet been shown to lower PCa mortality. Still, opportunistic screening is wide spread in Europe and in most other parts of the world. Methods: Current literature and data from screening studies are reviewed and discussed. Prostate-specific antigen (PSA) has been and remains one of the corner stones of early detection of PCa. Traditionally used cut-off values cannot be applied in an uncritical fashion after it was shown that a significant amount of overdiagnosis and that large proportions of cancers and poorly differentiated cancers are present in the low PSA ranges. The paper addresses the continued relevance of PSA cut-off values. The diagnostic value of PSA velocity is reviewed in conjunction with PSA cut-off values and as a possible replacement of total PSA. A need for more selective screening in the low PSA ranges is pointed out. Results and conclusions: The data show that men presenting initially with PSA values below 1 do not have to be rescreened for a period of 8 yr. In the PSA range 1-2.9 ng/ml, new parameters are needed that improve specificity and are selective for screening for aggressive lesions. PSA velocity so far has not been shown to be useful in the early detection of PCa but may be useful in detecting aggressive PCa selectively. For the time being, it seems sensible to continue using PSA cut-off values such as 3.0 or 4.0 ng/ml provided overtreatment is decreased by using available nomograms.

Can non-malignant biopsy features identify men at increased risk of biopsy-detectable prostate cancer at re-screening after 4 years? (Article)

2008-02-01T00:00:00Z

OBJECTIVES: To identify pathological features in non-malignant sextant prostate needle biopsies and assess their predictive value for detecting prostate cancer on biopsy 4 years later. PATIENTS AND METHODS: We selected and reviewed the biopsy specimens of 121 men that were diagnosed as non-malignant during the first screening round of the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam section. Of these 61 (50.4%) were positive for cancer during the second round (the result of a matched random sample). The biopsies were indicated by prostate-specific antigen levels of ≥ 3.0 ng/mL. Specimens were scored for high-grade prostatic intraepithelial neoplasia (HGPIN), active and chronic inflammation, biopsy core length and glandular core length. The predictive value of the pathological features for detecting prostate cancer after 4 years was assessed. RESULTS: In the first-round biopsies the incidence of HGPIN was 7.1%; there was active inflammation in 22.4% and chronic inflammation in 51.0%. The mean core length was 9.3 mm and mean glandular core length 7.4 mm; the mean total biopsy length (sum of core lengths) was 56.3 mm and mean total glandular length (sum of glandular core lengths) was 44.6 mm. None of the pathological features in the initial round was significantly related to the detection of cancer in the second round. CONCLUSIONS: In this study of non-malignant prostate biopsy specimens from a screened population, no pathological features could be identified that were predictive for detecting prostate cancer on biopsy 4 years later.

Outcomes of Men with Screen-Detected Prostate Cancer Eligible for Active Surveillance Who Were Managed Expectantly (Article)

2008-01-01T00:00:00Z

Background: The incidence of small, localised, well-differentiated prostate cancer (PCa) is increasing, mainly as a result of screening. Many of these cancers will not progress, and radical therapy may lead to substantial overtreatment. Active surveillance (AS) has emerged as an alternative. Objective: To retrospectively validate the currently used criteria for eligibility for AS. Design, setting, and participants: For this cohort study, data from 616 men who were diagnosed with PCa between 1994 and 2007 at a mean age of 66.3 yr in four centres of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were combined. All patients fit the criteria for AS (prostate-specific antigen [PSA] ≤10.0 ng/ml, PSA-density <0.2 ng/ml per ml, stage T1C/T2, Gleason score ≤3 + 3 = 6, and ≤2 positive biopsy cores), and initially they were managed expectantly. Median follow-up was 3.91 yr. Measurements: Disease specific-, overall-, and treatment-free survival were studied. Present PSA characteristics were assessed and also compared between men who were switching to deferred active therapy during follow-up and men remaining untreated. Results and limitations: The calculated (Kaplan-Meier) 10-yr PCa-specific survival (21 patients at risk) was 100%, which sharply contrasted with 77% overall survival. Men still alive showed favourable PSA characteristics. Although the calculated 10-yr treatment-free survival was only 43%, objective signs of progression often did not indicate the shift to radical treatment. The cohort consisted of men on AS and those on watchful waiting (WW); information on comorbidity or psychological distress was not available. Conclusions: AS seems justified in selected men with screen-detected PCa. Prospective protocol-based AS programs are necessary to optimise selection criteria and to find the appropriate trigger points for switching to active therapy. Possible negative psychological reactions with AS against improved quality of life by withholding side-effects from radical treatment should be considered.

Establishing normal reference ranges for prostate volume change with age in the population-based Krimpen-study: Prediction of future prostate volume in individual men (Article)

2007-12-01T00:00:00Z

BACKGROUND. We aim to establish the normal pattern of prostate volume change with age to provide a baseline from which accelerated prostate growth might be identified in patients with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH). METHODS. In a community-based study, prostate volume was determined at baseline and after 2.1 and 4.2 years in men without prostate cancer. A bivariate multilevel growth curve model was used to estimate the pattern of change of prostate volume with age. RESULTS. The average percentage increase of total prostate volume and transition zone volume per year of follow-up was 2.2% and 3.5%, respectively. The final model showed that prostate volume was related to age only. The future prostate volume of an individual can be predicted based on his age and known history of prostate volume. The model was also used to calculate time needed for the prostate volume to increase with a certain percentage, for men with different baseline prostate volume values at different ages. CONCLUSIONS. This method establishes normal prostate volume values by age using prostate volume history in men without prostate cancer. The model provides baseline data from which disease progression might be detected.

Prospective Validation of Active Surveillance in Prostate Cancer: The PRIAS Study (Article)

2007-12-01T00:00:00Z

hK2 and Free PSA, a Prognostic Combination in Predicting Minimal Prostate Cancer in Screen-Detected Men within the PSA Range 4-10 ng/ml (Article)

2007-11-01T00:00:00Z

Objectives: The purpose of screening for prostate cancer is to decrease the disease-specific mortality. However not every screen-detected prostate cancer is a threat to the patient's life. The risk of overdetection and subsequent overtreatment in prostate cancer has been recognised. The purpose of this investigation was to evaluate the role of tumour markers total PSA, free PSA, and hK2, and their combinations in predicting minimal prostate cancer. Methods: Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam, The Netherlands, prebiopsy serum samples were analysed for 100 selected men who underwent a radical prostatectomy for their screen-detected prostate cancer. All had a PSA value between 4 and 10 ng/ml prior to diagnosis. Minimal prostate cancer is defined as organ confined, Gleason score ≤6 (no Gleason grade 4 or 5), and tumour volume <0.5 ml. Results: Sera and tumour volumes from 91 men were available for analysis. Minimal prostate cancer was diagnosed in 16.5% of the selected cases. Mean tumour volume was 1.2 ml (range: 0.04-13.5); hK2, the algorithms hK2/fPSA, and hK2/%fPSA have significant correlations with tumour volume. Both algorithms also yielded the best test results in predicting minimal disease with an area under the receiver operator characteristics curve of 82%. Conclusions: hK2 and percent free PSA have added prognostic value for the detection of minimal prostate cancer in screen-detected cases within PSA range 4-10 ng/ml. These biomarkers can possibly be used to select less invasive treatment options like active surveillance and to prevent overtreatment.

Gene therapy in The Netherlands: Highlights from the low countries (Article)

2007-10-01T00:00:00Z

Gene therapy is an active research area in The Netherlands and Dutch scientists involved in fundamental and clinical gene therapy research significantly contribute to the progresses made in this field. This ranges from the establishment of the 293, 911 and PER.C6 cell lines, which are used worldwide for the production of replication-defective adenoviral vectors, to the development of targeted viral vectors and T lymphocytes as well as of non-viral vectors. Several milestones have been achieved in Dutch clinical gene therapy trials, including the first treatment worldwide of patients with adenosine deaminase deficiency with genetically corrected hematopoietic stem cells in collaboration with French and British scientists. Until now, about 230 patients with various diseases have been treated with viral and non-viral gene therapy in this country. Ongoing and upcoming Dutch clinical trials focus on the translation of new developments in gene therapy research, including the restoration of genetic defects other than SCID, and the use of oncolytic adenoviruses and targeted T cells for the treatment of cancer. The growing commercial interest in Dutch clinical gene therapy is reflected by the involvement of two Dutch companies in ongoing trials as well as the participation of Dutch clinical centres in large phase III international multicenter immuno-gene therapy trials on prostate cancer sponsored by an American company. Translational gene therapy research in The Netherlands is boosted at a governmental level by the Dutch Ministry of Health via a dedicated funding programme. This paper presents an overview on milestones in Dutch basic gene therapy research as well as on past, present and future clinical gene therapy trials in The Netherlands. Copyright

An inventory of shedding data from clinical gene therapy trials (Article)

2007-10-01T00:00:00Z

Viruses are the most commonly used vectors for clinical gene therapy. The risk of dissemination of a viral vector into the environment via excreta from the treated patient, a phenomenon called shedding, is a major safety concern for the environment. Despite the significant number of clinical gene therapy trials that have been conducted worldwide, there is currently no overview of actual shedding data available. In this article, an inventory of shedding data obtained from a total of 100 publications on clinical gene therapy trials using retroviral, adenoviral, adeno-associated viral and pox viral vectors is presented. In addition, the experimental set-up for shedding analysis including the assays used and biological materials tested is summarized. The collected data based on the analysis of 1619 patients in total demonstrate that shedding of these vectors occurs in practice, mainly determined by the type of vector and the route of vector administration. Due to the use of non-quantitative assays, the lack of information on assay sensitivity in most publications, and the fact that assay sensitivity is expressed in various ways, general conclusions cannot be made as to the level of vector shedding. The evaluation of the potential impact and consequences of the observations is complicated by the high degree of variety in the experimental design of shedding analysis between trials. This inventory can be supportive to clinical gene therapy investigators for the establishment of an evidence-based risk assessment to be included in a clinical protocol application, as well as to national regulatory authorities for the ongoing development of regulatory guidelines regarding gene therapy. Copyright

How common is PSA screening in elderly men with limited life expectancies? Commentary (Article)

2007-10-01T00:00:00Z

A small chimeric promoter for high prostate-specific transgene expression from adenoviral vectors (Article)

2007-06-01T00:00:00Z

BACKGROUND. Specificity of transgene expression is important for safety during gene therapeutical applications. For prostate cancer, transcriptional targeting has been applied but was hampered by loss of specificity and low activity. We constructed a small chimeric promoter for high and prostate-specific transgene expression from adenoviral vectors. METHODS. A chimeric promoter, composed of the prostate-specific antigen (PSA) enhancer and the rat probasin promoter, was cloned into an adenoviral vector and its activity was compared to vectors containing conventional prostate-specific promoters and the constitutive Cytomegalovirus (CMV) promoter in in vitro and in vivo prostate cancer models. RESULTS. The chimeric PSA-probasin promoter was the most active prostate-specific promoter reaching up to 20% of CMV promoter activity while maintaining prostate-specificity. CONCLUSIONS. The chimeric PSA-probasin promoter is a small promoter that can be utilized in viral vectors for high prostate-specific transgene expression.

Prostate Cancer in the Swedish Section of ERSPC-Evidence for Less Metastases at Diagnosis but not for Mortality Reduction (Article)

2007-03-01T00:00:00Z

A Swedish randomized screening study, which is a part of European Randomized Study of Screening for Prostate Cancer (ERSPC), reported the risks involved in diagnosing prostate cancer among men. The study included the effectiveness of intention-to-screen analysis program in terms of reducing metastatic disease at the time of diagnosis. The study found a total of 48% and 70% of different control group prostate cancers. The ERSPC study also found that the metastatic disease and the avoidance of metastatic disease are important end points of the study, and the proportion of men with metastatic disease are predicted to die of prostate cancer depending on the the diagnosis of the disease. The death rates in different cancer control arms change with mortality follow-up during the years after the 8-10 yr period. The results of ERSPC study show that over 10-yr period, the incidence of metastatic disease in men can be reduced by almost 50%.

Overdiagnosis and overtreatment of early detected prostate cancer (Article)

2007-03-01T00:00:00Z

Early detection of prostate cancer is associated with the diagnosis of a considerable proportion of cancers that are indolent, and that will hardly ever become symptomatic during lifetime. Such overdiagnosis should be avoided in all forms of screening because of potential adverse psychological and somatic side effects. The main threat of overdiagnosis is overtreatment of indolent disease. Men with prostate cancer that is likely to be indolent may be offered active surveillance. Evaluation of active surveillance studies and validation of new biological parameters for risk assessment are expected.

Comparison of two assays for human kallikrein 2 (Article)

2003-01-01T00:00:00Z

BACKGROUND: We compared two recently developed research assays for the measurement of human kallikrein 2 (hK2) in serum: one fully automated assay (Beckman Coulter Access immunoanalyzer) and one manual assay based on the DELFIA technology. METHODS: We used two subsets of clinical specimens consisting of 48 samples from prostate cancer patients and 210 samples from participants in an ongoing screening study (ERSPC). Both subsets were measured in the Rotterdam laboratory, and the prostate cancer samples were used for analytical comparison with the originating sites for the assays: Beckman Coulter Research Department (San Diego, CA) and Turku University (Turku, Finland). RESULTS: Both the Beckman Coulter and the Turku assays performed very similarly between the Rotterdam laboratory and the originating sites: the R(2) value for both comparisons was 0.99, and the slope difference between sites was <20%. Deming regression analysis of the DELFIA (y) and Access (x) assays yielded the following: for the prostate cancer group, y = 1.17x - 0.01 (R(2) = 0.88; n = 48); and for the ERSPC group, y = 0.62x - 0.01 (R(2) = 0.77). Breakdown of the latter group into subgroups (nondiseased, benign prostatic hyperplasia, and prostate cancer samples) gave only minor differences. The Access calibrators were underrecovered by 13% in the DELFIA assay, whereas the DELFIA calibrators were overrecovered by 45% in the Access assay. CONCLUSION: The DELFIA and Access assays for hK2, which have similar analytical features, show differences that cannot be explained by calibration.

Urologie voorbij het verdwijnpunt (Inaugural Lecture)

2002-06-27T00:00:00Z

Prostate specific antigen and ultrasonography in detection and follow-up of prostate carcinoma (Doctoral Thesis)

1995-12-20T00:00:00Z