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1.
Delila Gasi Tandefelt Joost L. Boormans Hetty A. van der Korput Guido W. Jenster Jan Trapman 《European urology》2013
Background
The molecular basis of the clinical heterogeneity of prostate cancer (PCa) is not well understood.Objective
The purpose of our study was to identify and characterize genes in a clinically relevant gene expression signature in a subgroup of primary PCa positive for transmembrane protease, serine 2 (TMPRSS2)–v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG).Design, setting, and participants
We studied gene expression profiles by unsupervised hierarchical clustering in 48 primary PCas from patients with a long clinical follow-up. Results were correlated with clinical outcome and validated in an independent patient cohort. Selected genes from a defined classifier were tested in vitro for biologic properties.Intervention
Initial treatment of primary tumors was radical prostatectomy.Outcome measurements and statistical analysis
Associations between clinical and histopathologic variables were evaluated by the Pearson χ2 test, Mann-Whitney U test, or Kruskal-Wallis test, where appropriate. The log-rank test or Breslow method was used for statistical analysis of Kaplan-Meier survival curves.Results and limitations
Most tumors that overexpressed ERG clustered separately from other primary PCas. No differences in any clinical end points between ERG-positive and ERG-negative cancers were detected. Importantly, within the ERG-positive samples, two subgroups were identified, which differed significantly in prostate-specific antigen recurrence-free survival, and cancer-specific and overall survival. From our findings, we defined a gene expression classifier of 36 genes. In a second, completely independent tumor set, the classifier also distinguished ERG-positive subgroups with different clinical outcome. In both patient cohorts, the classifier was not predictive in ERG-negative tumors. Biologic processes regulated by genes in the classifier included cell adhesion and bone remodeling. Tumor growth factor-β signaling was indicated as the main differing signaling pathway between the two ERG subgroups. In vitro biologic assays of two selected genes from the classifier (inhibin, beta A [INHBA] and cadherin 11, type 2, OB-cadherin (osteoblast) [CDH11]) supported a functional role in PCa progression. Possible multifocality and limited number of PCa samples can be limitations of the study.Conclusions
The classifier identified can contribute to prediction of tumor progression in ERG-positive primary prostate tumors and might be instrumental in therapy decisions. 相似文献2.
Nguyen PN Violette P Chan S Tanguay S Kassouf W Aprikian A Chen JZ 《European urology》2011,59(3):407-414
Background
The TMPRSS2:ERG fusion is both prevalent and unique to prostate cancer (PCa) and has great potential for noninvasive diagnosis of PCa in bodily fluids.Objectives
To evaluate the specificity and sensitivity of the TMPRSS2:ERG fusion in urine from diverse clinical contexts and to explore potential clinical applications.Design, setting, and participants
A total of 101 subjects were enrolled in 2008 from urologic oncology clinics to form three study groups: 44 PCa free, 46 confirmed PCa, and 11 negative prostate biopsies. The PCa-free group included females, healthy young men, and post–radical prostatectomy (RP) patients. The confirmed PCa group was composed of patients under active surveillance, scheduled for treatment, or with metastatic disease.Measurements
Urine was collected after attentive digital rectal exam (DRE) and coded to blind group allocation for laboratory test. RNA from urine sediments was analyzed using a panel of four TMPRSS2:ERG fusion markers with quantitative polymerase chain reaction (qPCR).Results and limitations
Our fusion markers demonstrated very high technical specificity and sensitivity for detecting a single fusion-positive cancer cell (VCaP) in the presence of at least 3000 cells in urine sediments. In clinical analysis, there were no fusion-positive samples in the PCa-free group (0 of 44 samples), while there were 16 of 46 (34.8%) fusion-positive samples in the confirmed PCa group. The fusion incidence varied significantly among the three PCa subgroups. The clinical sensitivity increased to 45.4% in cancer patients prior to treatments. The fusion markers were detected in 2 of 11 (18.2%) biopsy-negative patients, suggesting potentially false negative biopsies. This study is not prospective and is limited in sample sizes.Conclusions
Our novel panel of TMPRSS2:ERG fusion markers provided a very specific and sensitive tool for urine-based detection of PCa. Theses markers can potentially be used to diagnose patients with PCa who have negative biopsies. 相似文献3.
Danila DC Anand A Sung CC Heller G Leversha MA Cao L Lilja H Molina A Sawyers CL Fleisher M Scher HI 《European urology》2011,60(5):897-904
4.
Gisele H.J.M. Leyten Daphne Hessels Sander A. Jannink Frank P. Smit Hans de Jong Erik B. Cornel Theo M. de Reijke Henk Vergunst Paul Kil Ben C. Knipscheer Inge M. van Oort Peter F.A. Mulders Christina A. Hulsbergen-van de Kaa Jack A. Schalken 《European urology》2014
Background
Prostate cancer antigen 3 (PCA3) and v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) gene fusions are promising prostate cancer (PCa) specific biomarkers that can be measured in urine.Objective
To evaluate the diagnostic and prognostic value of Progensa PCA3 and TMPRSS2-ERG gene fusions (as individual biomarkers and as a panel) for PCa in a prospective multicentre setting.Design, setting, and participants
At six centres, post–digital rectal examination first-catch urine specimens prior to prostate biopsies were prospectively collected from 497 men. We assessed the predictive value of Progensa PCA3 and TMPRSS2-ERG (quantitative nucleic acid amplification assay to detect TMPRSS2-ERG messenger RNA [mRNA]) for PCa, Gleason score, clinical tumour stage, and PCa significance (individually and as a marker panel). This was compared with serum prostate-specific antigen and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator. In a subgroup (n = 61) we evaluated biomarker association with prostatectomy outcome.Outcome measurements and statistical analysis
Univariate and multivariate logistic regression analysis and receiver operating curves were used.Results and limitations
Urine samples of 443 men contained sufficient mRNA for marker analysis. PCa was diagnosed in 196 of 443 men. Both PCA3 and TMPRSS2-ERG had significant additional predictive value to the ERSPC risk calculator parameters in multivariate analysis (p < 0.001 and resp. p = 0.002). The area under the curve (AUC) increased from 0.799 (ERSPC risk calculator), to 0.833 (ERSPC risk calculator plus PCA3), to 0.842 (ERSPC risk calculator plus PCA3 plus TMPRSS2-ERG) to predict PCa. Sensitivity of PCA3 increased from 68% to 76% when combined with TMPRSS2-ERG. TMPRSS2-ERG added significant predictive value to the ERSPC risk calculator to predict biopsy Gleason score (p < 0.001) and clinical tumour stage (p = 0.023), whereas PCA3 did not.Conclusions
TMPRSS2-ERG had independent additional predictive value to PCA3 and the ERSPC risk calculator parameters for predicting PCa. TMPRSS2-ERG had prognostic value, whereas PCA3 did not. Implementing the novel urinary biomarker panel PCA3 and TMPRSS2-ERG into clinical practice would lead to a considerable reduction of the number of prostate biopsies. 相似文献5.
Context
Oestrogens were proven effective in the hormonal treatment of advanced prostate cancer (PCa) >60 yr ago and are still used as second-line hormonal therapy. Paradoxically, oestrogens might also be involved in the development and progression of PCa.Objective
To examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression.Evidence acquisition
Recent data obtained from animal, experimental, and clinical studies were reviewed.Evidence synthesis
The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERα], oestrogen receptor beta [ERβ]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERα is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. Preliminary clinical studies with the ERα antagonist toremifene have identified the ERα as a promising target for PCa prevention. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumour suppressor. The ERβ is generally retained in hormone-naïve PCa but is partially lost in castration-resistant disease. The progressive emergence of the ERα and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth. The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling. TMPRSS2-ERG expression has been found to be increased by ERα agonist (oestrogens) and decreased by ERβ agonists.Conclusions
Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERα antagonists and ERβ agonists to prevent PCa and delay disease progression. Tumours equipped with the pertinent receptors are potential candidates for this new therapeutic approach. 相似文献6.
Stefan Steurer Pascale Sophia Mayer Meike Adam Antje Krohn Christina Koop Daniel Ospina-Klinck Ali Attarchi Tehrani Ronald Simon Pierre Tennstedt Markus Graefen Corinna Wittmer Benedikt Brors Christoph Plass Jan Korbel Joachim Weischenfeldt Guido Sauter Hartwig Huland Maria Christina Tsourlakis Sarah Minner Thorsten Schlomm 《European urology》2014
Based on next-generation sequencing of early-onset prostate cancer (PCa), we earlier demonstrated that PCa in young patients is prone to rearrangements involving androgen-regulated genes—such as transmembrane protease, serine 2 (TMPRSS2)–v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion—and provided data suggesting that this situation might be caused by increased androgen signaling in younger men. In the same study, an accumulation of chromosomal deletions was found in cancers of elderly patients. To determine how age-dependent molecular features relate to cancer phenotype, an existing data set of 11 152 PCas was expanded by additional fluorescence in situ hybridization analyses of phosphatase and tensin homolog (PTEN), 6q15 and 5q21. The results demonstrate that the decrease in TMPRSS2–ERG fusions with increasing patient age is limited to low-grade cancers (Gleason ≤3 + 4) and that the significant increase in the deletion frequency with age was strictly limited to ERG-negative cancers for 6q15 and 5q21 but to ERG-positive cancers for PTEN. These data suggest that the accumulation of non–androgen-linked genomic alterations with advanced patient age may require an appropriate microenvironment, such as a positive or negative ERG status. The strong link of ERG activation to young patient age and low-grade cancers may help to explain a slight predominance of low-grade cancers in young patients. 相似文献
7.
8.
Himisha Beltran Roman Yelensky Garrett M. Frampton Kyung Park Sean R. Downing Theresa Y. MacDonald Mirna Jarosz Doron Lipson Scott T. Tagawa David M. Nanus Philip J. Stephens Juan Miguel Mosquera Maureen T. Cronin Mark A. Rubin 《European urology》2013
Background
Most personalized cancer care strategies involving DNA sequencing are highly reliant on acquiring sufficient fresh or frozen tissue. It has been challenging to comprehensively evaluate the genome of advanced prostate cancer (PCa) because of limited access to metastatic tissue.Objective
To demonstrate the feasibility of a novel next-generation sequencing (NGS)–based platform that can be used with archival formalin-fixed paraffin-embedded (FFPE) biopsy tissue to evaluate the spectrum of DNA alterations seen in advanced PCa.Design, setting, and participants
FFPE samples (including archival prostatectomies and prostate needle biopsies) were obtained from 45 patients representing the spectrum of disease: localized PCa, metastatic hormone-naive PCa, and metastatic castration-resistant PCa (CRPC). We also assessed paired primaries and metastases to understand disease heterogeneity and disease progression.Intervention
At least 50 ng of tumor DNA was extracted from FFPE samples and used for hybridization capture and NGS using the Illumina HiSeq 2000 platform.Outcome measurements and statistical analysis
A total of 3320 exons of 182 cancer-associated genes and 37 introns of 14 commonly rearranged genes were evaluated for genomic alterations.Results and limitations
We obtained an average sequencing depth of >900X. Overall, 44% of CRPCs harbored genomic alterations involving the androgen receptor gene (AR), including AR copy number gain (24% of CRPCs) or AR point mutation (20% of CRPCs). Other recurrent mutations included transmembrane protease, serine 2 gene (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (avian) gene (ERG) fusion (44%); phosphatase and tensin homolog gene (PTEN) loss (44%); tumor protein p53 gene (TP53) mutation (40%); retinoblastoma gene (RB) loss (28%); v-myc myelocytomatosis viral oncogene homolog (avian) gene (MYC) gain (12%); and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α gene (PIK3CA) mutation (4%). There was a high incidence of genomic alterations involving key genes important for DNA repair, including breast cancer 2, early onset gene (BRCA2) loss (12%) and ataxia telangiectasia mutated gene (ATM) mutations (8%); these alterations are potentially targetable with poly(adenosine diphosphate-ribose)polymerase inhibitors. A novel and actionable rearrangement involving the v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) was also detected.Conclusions
This first-in-principle study demonstrates the feasibility of performing in-depth DNA analyses using FFPE tissue and brings new insight toward understanding the genomic landscape within advanced PCa. 相似文献9.
Massimo Lazzeri Alexander Haese Alexandre de la Taille Joan Palou Redorta Thomas McNicholas Giovanni Lughezzani Vincenzo Scattoni Vittorio Bini Massimo Freschi Amy Sussman Bijan Ghaleh Philippe Le Corvoisier Josep Alberola Bou Salvador Esquena Fernández Markus Graefen Giorgio Guazzoni 《European urology》2013
Background
Strategies to reduce prostate-specific antigen (PSA)–driven prostate cancer (PCa) overdiagnosis and overtreatment seem to be necessary.Objective
To test the accuracy of serum isoform [−2]proPSA (p2PSA) and its derivatives, percentage of p2PSA to free PSA (fPSA; %p2PSA) and the Prostate Health Index (PHI)—called index tests—in discriminating between patients with and without PCa.Design, setting, and participants
This was an observational, prospective cohort study of patients from five European urologic centers with a total PSA (tPSA) range of 2–10 ng/ml who were subjected to initial prostate biopsy for suspected PCa.Outcome measurements and statistical analysis
The primary end point was to evaluate the specificity, sensitivity, and diagnostic accuracy of index tests in determining the presence of PCa at prostate biopsy in comparison to tPSA, fPSA, and percentage of fPSA to tPSA (%fPSA) (standard tests) and the number of prostate biopsies that could be spared using these tests. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis.Results and limitations
Of >646 patients, PCa was diagnosed in 264 (40.1%). Median tPSA (5.7 vs 5.8 ng/ml; p = 0.942) and p2PSA (15.0 vs 14.7 pg/ml) did not differ between groups; conversely, median fPSA (0.7 vs 1 ng/ml; p < 0.001), %fPSA (0.14 vs 0.17; p < 0.001), %p2PSA (2.1 vs 1.6; p < 0.001), and PHI (48.2 vs 38; p < 0.001) did differ significantly between men with and without PCa. In multivariable logistic regression models, p2PSA, %p2PSA, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (all p < 0.001). At a PHI cut-off of 27.6, a total of 100 (15.5%) biopsies could have been avoided. The main limitation is that cases were selected on the basis of their initial tPSA values.Conclusions
In patients with a tPSA range of 2–10 ng/ml, %p2PSA and PHI are the strongest predictors of PCa at initial biopsy and are significantly more accurate than tPSA and %fPSA.Trial registration
The study is registered at http://www.controlled-trials.com, ref. ISRCTN04707454. 相似文献10.
Background
The diagnostic performance of a genetic score based on single nucleotide polymorphisms (SNPs) is unknown in the prostate-specific antigen (PSA) range of 1–3 ng/ml. A substantial proportion of men in this PSA span have prostate cancer (PCa), but biomarkers to determine who should undergo a prostate biopsy are lacking.Objective
To evaluate whether a genetic risk score identifies men in the PSA range of 1–3 ng/ml who are at higher risk for PCa.Design, setting, and participants
Men aged 50–69 yr with PSA 1–3 ng/ml and without a previous prostate biopsy were selected from the STHLM2 cohort. Of 2696 men, 49 SNPs were genotyped, and a polygenic risk score was calculated. Of these men, 860 were invited according to risk score, and 172 underwent biopsy.Outcome measurements and statistical analysis
The risk of PCa was assessed using univariate and multivariate logistic regression analysis.Results and limitations
PCa was diagnosed in 47 of 172 participants (27%), with Gleason sum 6 in 36 of 47 men (77%) and Gleason sum ≥7 in 10 of 47 men (21%); one man had intraductal cancer. The genetic score was a significant predictor of a positive biopsy (p = 0.028), even after adjusting for PSA, ratio of free to total PSA, prostate volume, age, and family history. There was an increase in the odds ratio of 1.60 (95% confidence interval, 1.05–2.45) with increasing genetic risk score. The absolute risk difference of positive biopsy was 19 percentage points, comparing the high and low genetic risk group (37% vs 18%).Conclusions
A risk score based on SNPs predicts biopsy outcome in previously unbiopsied men with PSA 1–3 ng/ml. Introducing a genetic-based risk stratification tool can increase the proportion of men being classified in line with their true risk of PCa. 相似文献11.
Background
It remains unclear whether adding long-term prostate-specific antigen velocity (PSAV) to baseline PSA values improves classification of prostate cancer (PCa) risk and mortality in the general population.Objective
To determine whether long-term PSAV improves classification of PCa risk and mortality in the general population.Design, setting, and participants
We studied 503 men aged 30–80 yr, with and without PCa, who had repeated PSA measurements over 20 yr and up to 28 yr before PCa diagnosis. These were selected from among 7455 men in the Copenhagen City Heart Study, a prospective, general population study with follow-up from 1981 through 2010. Results were subsequently applied to all 1 351 441 men aged 40–80 yr living in Denmark from 1997 through 2006.Outcome measurements and statistical analysis
PCa risk and mortality were assessed using Cox regression. Improvement in risk classification was assessed using the net reclassification index (NRI).Results
Age-adjusted hazard ratios for PCa risk and mortality were 2.7–5.3 and 2.3–3.4, respectively, for long-term PSAV when added to models already including baseline PSA values. For PCa risk and mortality, adding long-term PSAV to models already including baseline PSA values and age yielded continuous NRIs of 98–99% and 56–106%, respectively. Used on a nationwide scale (eg, for men aged 60–64 yr), long-term PSAV >0.35 versus ≤0.35 ng/ml per year appropriately reclassified 128 of 10 000 men with PCa and 8095 of 10 000 men with no PCa. Correspondingly, inappropriately reclassified were 49 of 10 000 men with PCa and 1658 of 10 000 men with no PCa.Conclusions
Long-term PSAV in addition to baseline PSA value improves classification of PCa risk and mortality. Applying long-term PSAV nationwide, the ratio of appropriately to inappropriately classified men would typically be 5:1. 相似文献12.
Monique J. Roobol Fritz H. SchröderPim van Leeuwen Tineke WoltersRoderick C.N. van den Bergh Geert J.L.H. van LeendersDaphne Hessels 《European urology》2010
Background
The performance characteristics of serum prostate-specific antigen (PSA) as a diagnostic test for prostate cancer (PCa) are poor. The performance of the PCa antigen 3 (PCA3) gene as a primary diagnostic is unknown.Objective
Assess the value of PCA3 as a first-line diagnostic test.Design, setting and participants
Participants included men aged 63–75 who were invited for rescreening in the period from September 2007 to February 2009 within the European Randomised Study of Screening for Prostate Cancer, Rotterdam section.Interventions
Lateral sextant biopsies were performed if the serum PSA value was ≥3.0 ng/ml and/or the PCA3 score was ≥10.Measurements
Measurements included distribution and correlation of PSA value and PCA3 score and their relation to the number of cases and the characteristics of PCa detected. Additional value of PCA3 was included in men with previous negative biopsy and/or PSA <3.0 ng/ml.Results and limitations
In 721 men, all biopsied, 122 PCa cases (16.9%) were detected. Correlation between PSA and PCA3 is poor (Spearman rank correlation: ρ = 0.14; p < 0.0001). A PSA ≥3.0 ng/ml misses 64.7% of the total PCa that can be detected with the sextant biopsy technique and 57.9% of serious PCa (T2a or higher and/or Gleason grade ≥4, n = 19), and 68.2% of biopsies could have been avoided; the respective data for PCA3 ≥35 are 32%, 26.3%, and 51.7%. Performance of PCA3 in men with low PSA (area under the curve [AUC]: 0.63) and/or previous negative biopsy (AUC: 0.68) is unclear but has limited reliability due to small numbers.Conclusions
PCA3 as a first-line screening test shows improvement of the performance characteristics and identification of serious disease compared with PSA in this prescreened population. 相似文献13.
Tobias Nordström Markus Aly Mark S. Clements Caroline E. Weibull Jan Adolfsson Henrik Grönberg 《European urology》2013
Background
Prostate-specific antigen (PSA) testing has increased in several countries. There is incomplete knowledge of PSA testing patterns.Objective
Determine the prevalence of PSA testing and explore patterns of PSA retesting in Stockholm County, Sweden.Design, setting, and participants
A population-based study was performed. Through registry linkages, we collected population information, data on PSA tests, pathology reports, and clinical information. The study population comprised males living in Stockholm County in 2011 (n = 1 034 129), of which 229 872 had a PSA test during the period 2003–2011.Outcome measurements and statistical analysis
We determined limited-duration-point prevalence of PSA testing and performed survival analysis on PSA retesting for men aged 40–89 yr.Results and limitations
The number of PSA tests increased from 54 239 in 2003 to 124 613 in 2011. During the 9-yr study period, 46%, 68%, and 77% of men without a prior prostate cancer (PCa) diagnosis and aged 50–59 yr, 60–69 yr, and 70–79 yr, respectively, had a PSA test. During 2010 and 2011, 25%, 40%, and 46% of men aged 50–59 yr, 60–69 yr, and 70–79 yr, respectively, had a PSA test. The prevalence of PSA testing increased from 2003 to 2011. The probability of retesting was PSA and age dependent, with a 26-mo cumulative incidence of 0.337 (95% confidence interval, 0.333–0.341) if the first PSA value was <1 ng/ml. The main limitations were (1) that PSA data prior to 2003 were not available and (2) that the study cohort was restricted to men who were alive in 2011.Conclusions
Although screening for PCa is not recommended in Sweden, PSA testing in Stockholm County was high across ages ranging from 40 to 89 yr and increased during the period 2003–2011. The probability of PSA retesting was high, regardless of the original PSA level. These results contrast with current clinical recommendations and raise calls for a change, either through structured PCa testing or more detailed guidelines on PSA testing. 相似文献14.
Giovanni Lughezzani Massimo Lazzeri Alexander Haese Thomas McNicholas Alexandre de la Taille Nicolò Maria Buffi Nicola Fossati Giuliana Lista Alessandro Larcher Alberto Abrate Alessandro Mistretta Vittorio Bini Joan Palou Redorta Markus Graefen Giorgio Guazzoni 《European urology》2014
Background
External validation of a prediction tool is mandatory to assess the tool's accuracy and generalizability within different patient cohorts.Objective
To externally validate a previously developed Prostate Health Index (PHI)–based nomogram for predicting the presence of prostate cancer (PCa) at biopsy.Design, setting, and participants
The study population consisted of 883 patients who were scheduled for a prostate biopsy at one of five European tertiary care centers. Total prostate-specific antigen (tPSA), free prostate-specific antigen (fPSA), and [−2]pro–prostate-specific antigen (p2PSA) levels were determined. The fPSA-to-tPSA ratio (%fPSA), p2PSA, and PHI ([p2PSA / fPSA] × √tPSA) were calculated.Intervention
Extended initial and repeat prostate biopsy.Outcome measurements and statistical analysis
Logistic regression models were fitted to test the predictors of PCa and to determine their predictive accuracy. A calibration plot was used to evaluate the extent of overestimation or underestimation between nomogram predictions and observed PCa rate. Decision curve analysis (DCA) provided an estimate of the net benefit obtained by using the PHI-based nomogram.Results and limitations
Of 833 patients, 365 (41.3%) were diagnosed with PCa at extended prostate biopsy. In accuracy analyses, PHI was the most informative predictor of PCa (0.68), outperforming tPSA (0.51) and %fPSA (0.64). The predictive accuracy of the previously developed nomogram was 75.2% (95% confidence interval, 71.4–78.1). Calibration of the nomogram was good in patients at a low to intermediate predicted probability of PCa, while calibration was suboptimal, with a tendency to overestimate the presence of PCa, in high-risk patients. Finally, DCA demonstrated that the use of the PHI-based nomogram resulted in the highest net benefit. The main limitation of the study is the fact that only Caucasian patients were included.Conclusions
At external validation, the previously developed PHI-based nomogram confirmed its ability to determine the presence of PCa at biopsy. These findings provide further evidence supporting the potential role of the nomogram in the biopsy decision pathway for European men with suspected PCa.Patient summary
In the current study, we externally validated a Prostate Health Index–based nomogram to predict the presence of prostate cancer (PCa) at biopsy. This tool may help clinicians determine the need for a prostate biopsy in European patients with suspected PCa. 相似文献15.
Jennifer R. Rider Fredrik Sandin Ove Andrén Peter Wiklund Jonas Hugosson Pär Stattin 《European urology》2013
Background
Limited data exist on long-term outcomes among men with prostate cancer (PCa) from population-based cohorts incorporating information on clinical risk category.Objective
To assess 15-yr mortality for men with PCa treated with noncurative intent according to clinical stage, Gleason score (GS), serum levels of prostate specific antigen (PSA), comorbidity, and age.Design, setting, and participants
Register-based cohort study of 76 437 cases in the National Prostate Cancer Register (NPCR) of Sweden diagnosed from 1991 through 2009 and treated with noncurative intent. Each case was placed in one of five risk categories: (1) low risk: T1–T2 tumor, PSA level <10 ng/ml, and GS ≤6; (2) intermediate risk: T1–T2 tumor and PSA level 10–<20 ng/ml or GS 7; (3) high risk: T3 tumor or PSA level 20–<50 ng/ml or GS ≥8; (4) regional metastases: N1 or T4 tumor or PSA level 50–100 ng/ml; and (5) distant metastases: M1 tumor or PSA ≥100 ng/ml.Outcome measurements and statistical analysis
Ten- and 15-yr cumulative risk of death after diagnosis from PCa, cardiovascular disease, and other causes.Results and limitations
Among men with a Charlson Comorbidity Index (CCI) score of 0, no differences were found in observed versus expected all-cause mortality in the low-risk group. Observed mortality was only slightly greater in the intermediate-risk group, but men with high-risk localized PCa or more advanced disease had substantially higher mortality than expected. CCI was strongly associated with cumulative 10-yr mortality from causes other than PCa, especially for men <65 yr. Limitations include potential misclassification in risk category due to GS assignment.Conclusions
PCa mortality rates vary 10-fold according to risk category. The risk of death from causes other than PCa is most strongly related to comorbidity status in younger men. 相似文献16.
Axel Heidenreich Per-Anders Abrahamsson Walter Artibani James Catto Francesco Montorsi Hein Van Poppel Manfred Wirth Nicolas Mottet 《European urology》2013
Background
The recommendations and the updated EAU guidelines consider early detection of PCa with the purpose of reducing PCa-related mortality and the development of advanced or metastatic disease.Objective
This paper presents the recommendations of the European Association of Urology (EAU) for early detection of prostate cancer (PCa) in men without evidence of PCa-related symptoms.Evidence acquisition
The working panel conducted a systematic literature review and meta-analysis of prospective and retrospective clinical studies on baseline prostate-specific antigen (PSA) and early detection of PCa and on PCa screening published between 1990 and 2013 using Cochrane Reviews, Embase, and Medline search strategies.Evidence synthesis
The level of evidence and grade of recommendation were analysed according to the principles of evidence-based medicine. The current strategy of the EAU recommends that (1) early detection of PCa reduces PCa-related mortality; (2) early detection of PCa reduces the risk of being diagnosed and developing advanced and metastatic PCa; (3) a baseline serum PSA level should be obtained at 40–45 yr of age; (4) intervals for early detection of PCa should be adapted to the baseline PSA serum concentration; (5) early detection should be offered to men with a life expectancy ≥10 yr; and (6) in the future, multivariable clinical risk-prediction tools need to be integrated into the decision-making process.Conclusions
A baseline serum PSA should be offered to all men 40–45 yr of age to initiate a risk-adapted follow-up approach with the purpose of reducing PCa mortality and the incidence of advanced and metastatic PCa. In the future, the development and application of multivariable risk-prediction tools will be necessary to prevent over diagnosis and over treatment. 相似文献17.
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. 相似文献18.
Roberto L. Muller Leah Gerber Daniel M. Moreira Gerald Andriole Ramiro Castro-Santamaria Stephen J. Freedland 《European urology》2012
Background
Findings of studies on the association between androgens and prostate cancer (PCa) are mixed. Androgens may affect prostate-specific antigen (PSA) levels, thereby influencing biopsy recommendations. Also, androgens may stimulate prostate growth at very low levels with no additional effects at higher levels (saturation model).Objective
To test whether androgens were associated with PCa risk in the placebo arm of a prospective study in which biopsies were performed regardless of PSA level.Design, setting, and participants
Of 8122 men in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, 4073 men (50.1%) received placebo. Key entry criteria were PSA 2.5–10 ng/ml and one prior negative biopsy.Intervention
Per-protocol biopsies at 2 and 4 yr; for-cause biopsies at physician discretion.Outcome measurements and statistical analysis
Multivariable logistic regression was used to test the association between baseline log-transformed testosterone and dihydrotestosterone (DHT) levels and the risk of detecting either PCa or low-grade PCa (Gleason score <6) compared with high-grade PCa (Gleason score >7). In secondary analysis, we stratified the analysis by low baseline androgen levels (testosterone <10 nmol/l; DHT <0.76 nmol/l) compared with normal baseline androgen levels.Results and limitations
Of 4073 men, 3255 (79.9%) had at least one biopsy after randomization and were analyzed. Androgen levels tested continuously or by quintiles were generally unrelated to PCa detection or grade. PCa detection was similar among men with low compared with normal baseline testosterone levels (25.5% and 25.1%; p = 0.831). In secondary analysis, higher testosterone levels at baseline were associated with higher PCa detection (odds ratio: 1.23; 95% confidence interval, 1.06–1.43; p = 0.006) only if men had low baseline testosterone (<10 nmol/l). For men with normal baseline testosterone (≥10 nmol/l), higher testosterone levels at baseline were unrelated to PCa risk (p = 0.33). No association was found for DHT and PCa (all p > 0.85).Conclusions
Baseline serum testosterone and DHT levels were unrelated to PCa detection or grade. Our findings of the lowest testosterone levels being associated with the lowest PCa risk with no further changes with higher testosterone support a saturation model but must be confirmed in future studies using an a priori defined hypothesis.ClinicalTrials.gov identifier
NCT00056407. 相似文献19.
Monique J. Roobol Xiaoye Zhu Fritz H. Schröder Geert J.L.H. van Leenders Ron H. van Schaik Chris H. Bangma Ewout W. Steyerberg 《European urology》2013
Background
Inconclusive test results often occur after prostate-specific antigen (PSA)–based screening for prostate cancer (PCa), leading to uncertainty on whether, how, and when to repeat testing.Objective
To develop and validate a prediction tool for the risk of PCa 4 yr after an initially negative screen.Design, setting, and participants
We analyzed data from 15 791 screen-negative men aged 55–70 yr at the initial screening round of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer.Outcome measurements and statistical analysis
Follow-up and repeat screening at 4 yr showed either no PCa, low-risk PCa, or potentially high-risk PCa (defined as clinical stage >T2b and/or biopsy Gleason score ≥7 and/or PSA ≥10.0 ng/ml). A multinomial logistic regression analysis included initial screening data on age, PSA, digital rectal examination (DRE), family history, prostate volume, and having had a previous negative biopsy. The 4-yr risk predictions were validated with additional follow-up data up to 8 yr after initial screening.Results and limitations
Positive family history and, especially, PSA level predicted PCa, whereas a previous negative biopsy or a large prostate volume reduced the likelihood of future PCa. The risk of having PCa 4 yr after an initially negative screen was 3.6% (interquartile range: 1.0–4.7%). Additional 8-yr follow-up data confirmed these predictions. Although data were based on sextant biopsies and a strict protocol-based biopsy indication, we suggest that men with a low predicted 4-yr risk (eg, ≤1.0%) could be rescreened at longer intervals or not at all, depending on competing risks, while men with an elevated 4-yr risk (eg, ≥5%) might benefit from immediate retesting. These findings need to be validated externally.Conclusions
This 4-yr future risk calculator, based on age, PSA, DRE, family history, prostate volume, and previous biopsy status, may be a promising tool for reducing uncertainty, unnecessary testing, and overdiagnosis of PCa. 相似文献20.
Sebastien Crouzet Xavier Rebillard Daniel Chevallier Pascal Rischmann Gilles Pasticier Gregory Garcia Olivier Rouviere Jean-Yves Chapelon Albert Gelet 《European urology》2010