81 results on '"Hessels D"'
Search Results
2. DD3PCA3-based molecular urine analysis for the diagnosis of prostate cancer
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Mulders, P, Hessels, D, Van Balken, B, Karthaus, H, and Schalken, J
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- 2003
3. A 2-gene mRNA urine test for detection of high-grade prostate cancer prior to initial prostate biopsy
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Schalken, J.A., primary, Trooskens, G., additional, Steyaert, S., additional, Hessels, D., additional, Brawer, M.K., additional, Vlaeminck-Guillem, V., additional, Groskopf, J., additional, Van Criekinge, W., additional, and Haese, A., additional
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- 2019
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4. 10 Prospectieve multicenter-evaluatie van PCA3 + TMPRSS2-ERG als diagnostisch en prognostisch markerpanel voor prostaatkanker
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Leyten, G. H. J. M., Hessels, D., Cornel, E. B., de Reyke, T. M., Vergunst, H., Kil, P., Knipscheer, B. C., van Oort, I. M., Mulders, P. F. A., and Schalken, J. A.
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- 2011
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5. New targets for therapy in prostate cancer: differential display code 3 (DD3(PCA3)), a highly prostate cancer-specific gene
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Schalken, J.A., Hessels, D., and Verhaegh, G.W.C.T.
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Molecular diagnosis, prognosis and monitoring [UMCN 1.2] - Abstract
Item does not contain fulltext Identification of new markers for diagnosis and new targets for therapy would represent a considerable advance in the treatment of prostate cancer. Differential display code 3 (DD3(PCA3)) is a novel gene with characteristics that indicate its potentially valuable role in early identification of malignancy and in the construction of interventions directed specifically toward malignantly transformed cells. DD3(PCA3) has a messenger RNA product that is highly overexpressed in tumors. Compared with other genetic markers that are associated with prostate tissue, DD3(PCA3) is the most specific marker for malignant disease. Indeed, it is not expressed in any other normal human tissue, including breast, bladder, testis, gastrointestinal organ, and musculoskeletal tissue. This specific relation of DD3(PCA3) to prostate tissue has been confirmed by reverse transcription-polymerase chain reaction analysis. Clonal investigation of the DD3(PCA3) transcription unit indicates that the gene has 4 distinct exons, which can give rise to a number of differently sized transcripts. Open reading frame analysis has also confirmed that the DD3(PCA3) exons are populated by an unusual number of stop codons. The dramatic prostate-specific expression and pronounced upregulation of DD3(PCA3) in prostate cancer suggest a unique transcriptional regulation. A quantitative assay for DD3(PCA3) would be a potentially valuable tool for the detection of malignant cells in blood, urine, or other clinical specimens, and it could have important implications for the earlier diagnosis and molecular staging of prostate cancer. Although further studies are needed, gene therapies based on identification to delineate the range of transcription factors that interact with the DD3(PCA3) promoter represent a promising area for preclinical investigation.
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- 2003
6. 383 Multicenter validation study of a urine-based molecular biomarker algorithm to predict high-grade prostate cancer
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Hendriks, R.J., primary, Dijkstra, S., additional, Trooskens, G., additional, Van Criekinge, W., additional, Cornel, E.B., additional, Jannink, S.A., additional, De Jong, H., additional, Hessels, D., additional, Smit, F.P., additional, Melchers, W.J.G., additional, Leyten, G.H.J.M., additional, De Reijke, T.M., additional, Vergunst, H., additional, Kil, P., additional, Knipscheer, B.C., additional, Hulsbergen-Van De Kaa, C.A., additional, Mulders, P.F.A., additional, Van Oort, I.M., additional, Van Neste, L., additional, and Schalken, J.A., additional
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- 2016
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7. The role of PCA3 in the diagnosis of prostate cancer
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Hessels, D., Schalken, J.A., Witjes, J.A., Mulders, P.F.A., and Radboud University Nijmegen
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Genetics and epigenetic pathways of disease [NCMLS 6] ,Translational research [ONCOL 3] ,urologic and male genital diseases - Abstract
Contains fulltext : 81968.pdf (Publisher’s version ) (Open Access) Serum PSA has shown to be the most valuable tool in the detection, staging and monitoring of prostate cancer (PCa). However, the substantial overlap in serum PSA values between men with non-malignant prostatic diseases and PCa is the limitation of PSA as a prostate tumor marker. In patients with serum PSA values between 3-10 ng/ml, the negative biopsy rate is 60-75%. In this thesis, the focus is on improving the specificity in PCa diagnosis by using PCa-specific genes in adjunct to serum PSA testing. Prostate cancer gene 3 (PCA3) was identified as the prime candidate biomarker for the detection of PCa. The strong association between PCA3 over-expression and malignant transformation of prostate epithelium has prompted its potential use as a biomarker for the diagnosis of PCa. Since PCA3 is a non-coding RNA, an RNA-based molecular assay for PCA3 was developed. The studies in this thesis demonstrated and validated the potential of an RUO quantitative PCA3-based urine test to detect PCa cells in urinary sediments after digital rectal examination (DRE) and showed that PCA3 could aid in the prediction of biopsy outcome. PCa is a heterogeneous disease and the combination of tests for PCA3 and TMPRSS2-ERG gene-fusions were shown to improve the sensitivity without compromising specificity. In 2006, the RUO-PCA3 test has been translated to an IVD validated technology platform (Gen-Probe Inc.) and the CE-marked version of this test is the first, fully translated RNA-based molecular diagnostic urine test for PCa that is now available to urologists. This test can contribute to the decision making in the diagnosis of PCa. The value of the PCA3 test to predict the biological behaviour of prostate tumors is not fully matured, although some studies show promising results. Non-invasive biomarker-based assays for the diagnosis of PCa have now become reality. RU Radboud Universiteit Nijmegen, 02 juli 2010 Promotores : Schalken, J.A., Witjes, J.A., Mulders, P.F.A. 167 p.
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- 2010
8. Preliminary evaluation of the effect of dutasteride on PCA3 in post-DRE urine sediments: a randomized, open-label, parallel-group pilot study
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Gils, M.P.M.Q., Hessels, D., Peelen, W.P., Vergunst, H., Mulders, P.F.A., and Schalken, J.A.
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Genetics and epigenetic pathways of disease [NCMLS 6] ,Translational research [ONCOL 3] ,Aetiology, screening and detection [ONCOL 5] ,urologic and male genital diseases - Abstract
Contains fulltext : 81903schalken.pdf (Publisher’s version ) (Closed access) BACKGROUND: Dutasteride is commonly used in patients that are also at risk for prostate cancer (PCa). Therefore, the influence of dutasteride on PCa markers has to be studied. To date, only the effect of dutasteride on serum prostate-specific antigen (PSA) has been studied. This was the first study to investigate the effect of dutasteride on the new PCa marker PCA3, longitudinally and in a dose dependent manner. METHODS: From April 25, 2005 to October 31, 2006, 16 subjects with benign prostatic hyperplasia (BPH) and 9 subjects with clinically localized PCa were enrolled at the urological outpatient clinics of one university hospital and one community hospital. Eight subjects with BPH and five with PCa received 0.5 mg dutasteride once daily for 3 months, eight with BPH and four with PCa received 3.5 mg. No subjects were withdrawn because of adverse effects. RESULTS: In all four groups both 0.5 and 3.5 mg dutasteride had a variable effect on the PCA3 score. In contrast, its other effects were consistent as it rapidly reduced serum DHT by >or=90%, over time increased serum T by 20-30%, over time halved serum PSA and decreased prostate volume by 10-16%. CONCLUSIONS: In this exploratory/pilot study the effect of dutasteride on the PCA3 score was variable. This should be taken into account while using PCA3 in diagnostics. As this study was exploratory, the influence of androgen-deprivation therapy on the PCA3 score should be analyzed further.
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- 2009
9. 351 QUATTRO, a four gene prognostic biomarker panel for prostate cancer
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Leyten, G.H.J.M., primary, Hessels, D., additional, Jannink, S.A., additional, Smit, F.P., additional, De Jong, H., additional, Melchers, W.J.G., additional, Cornel, E.B., additional, De Reijke, T.M., additional, Vergunst, H., additional, Kil, P., additional, Knipscheer, B.C., additional, Hulsbergen-Van De Kaa, C.A., additional, Mulders, P.F.A., additional, Van Oort, I.M., additional, and Schalken, J.A., additional
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- 2014
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10. Multifocal urothelial cell cancer and p53 mutation analysis
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Poel, H.G. van der, Hessels, D., Bussemakers, M.J.G., Schalken, J.A., and Witjes, J.A.
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Clinical evaliation of new prognostic markers for urological cancers ,Klinische evaluatie van nieuwe prognostische markers voor urologische tumoren - Abstract
Item does not contain fulltext 2 p.
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- 1998
11. Predictive value of P53 mutations in bladder washings for progression od high risk superficial bladder cancer
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Vet, J.A.M., Witjes, J.A., Marras, S.A.E., Hessels, D., Poel, H.G. van der, Debruyne, F.M.J., and Schalken, J.A.
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Clinical evaliation of new prognostic markers for urological cancers ,Klinische evaluatie van nieuwe prognostische markers voor urologische tumoren - Abstract
Item does not contain fulltext 6 p.
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- 1996
12. 913 Prospective multicenter evaluation of PCA3+TMPRSS2-ERG as a diagnostic and prognostic marker panel for prostate cancer
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Leyten, G.H.J.M., primary, Hessels, D., additional, Cornel, E.B., additional, De, Reijke T.M., additional, Vergunst, H., additional, Kil, P., additional, Knipscheer, B.C., additional, Van Oort, I.M., additional, Mulders, P.F.A., additional, and Schalken, J.A., additional
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- 2012
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13. DD3, a very sensitive and specific merker to detect prostate tumors. Reply to: Gandino O, Santulli M, Cardillo MR, Stigliano A, Toscano V. Correspondence re: J.B. de Kok et al
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Verhaegh, G.W.C.T., Kok, J.B. de, Hessels, D., Smit, F.P., and Schalken, J.A.
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Molecular diagnosis, prognosis and monitoring [UMCN 1.2] - Abstract
Item does not contain fulltext
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- 2003
14. 974 PREDICTING PROSTATE BIOPSY OUTCOME IN A SCREENING SETTING PSA, PCA3, A KALLIKREIN PANEL, THE RISKCALCULATOR OR A COMBINATION? ERSPC ROTTERDAM
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Roobol, M.J., primary, Hessels, D., additional, Vickers, A.J., additional, Schalken, J.A., additional, Van Leeuwen, P., additional, Wolters, T., additional, Van Den Berqh, R.C.N., additional, Schröder, F.H., additional, and Lilia, H., additional
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- 2010
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15. 786 IDENTIFICATION OF ETS GENE FUSIONS USING AFFYMETRIX EXON 1.0 ARRAYS
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Smit, F.P., primary, Salagierski, M., additional, Hessels, D., additional, Jannink, S.A., additional, and Schalken, J.A., additional
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- 2009
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16. 896 THE EFFECT OF DUTASTERIDE ON THE PCA3 SCORE: A RANDOMIZED, OPEN-LABEL, PARALLEL-GROUP PILOT STUDY
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Van, Gils M.P.M.Q., primary, Mulders, P.F.A., additional, Vergunst, H., additional, Hessels, D., additional, Peelen, W.P., additional, Rittenhouse, H.G., additional, and Schalken, J.A., additional
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- 2009
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17. DETECTION OF TMPRSS2-ERG FUSION TRANSCRIPTS AND PCA3 IN URINARY SEDIMENTS MAY IMPROVE DIAGNOSIS OF PROSTATE CANCER
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Hessels, D., primary, Smit, F.P., additional, Verhaegh, G.W., additional, Witjes, J.A., additional, Schalken, J.A., additional, and Cornel, E.B., additional
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- 2008
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18. 114 THE TIME RESOLVED FLUORESCENCE-BASED PCA3 TEST ON URINARY SEDIMENTS AFTER EXTENDED DIGITAL RECTAL EXAMINATION; A DUTCH MULTICENTER VALIDATION OF THE DIAGNOSTIC PERFORMANCE
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Van Gils, M., primary, Hessels, D., additional, Van Hooij, O., additional, Jannink, S., additional, Peelen, P., additional, Hanssen, S., additional, Witjes, J.A., additional, Cornel, E., additional, Karthaus, H., additional, Smits, G., additional, Dijkman, G., additional, Mulders, P., additional, and Schalken, J., additional
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- 2007
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19. Mulholland drive
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Hessels, D. Scott, primary
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- 2005
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20. p53‐Independent Apoptosis Induced by Menadione in the Human Colon Carcinoma Cell Line Caco‐2
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KARCZEWSKI, J. M., primary, VET, J. A. M., additional, HESSELS, D., additional, and NOORDHOEK, J., additional
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- 2000
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21. The relationship between hatching egg weight and subsequent performance of broiler chickens.
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Morris, R. H., Hessels, D. F., and Bishop, R. J.
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- 1968
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22. THE PROGNOSTIC VALUE OF PCA3 GENE-BASED ANALYSIS OF URINE SEDIMENTS AFTER EXTENDED DIGITAL RECTAL EXAMINATION
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Hessels, D., Van Gils, M., Witjes, F., Jansen, C., Peelen, P., Van Hooij, O., Jannink, S., Hanssen, S., Mulders, P., and Schalken, J.
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- 2006
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23. DETAILED ANALYSIS OF HISTOPATHOLOGICAL PARAMETERS AND PCA3 TEST RESULTS
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Van Gils, M., Hessels, D., Hulsbergen-van de Kaa, C., Witjes, F., Knipscheer, B., Jansen, C., Peelen, P., Van Hooij, O., Jannink, S., Hanssen, S., Mulders, P., and Schalken, J.
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- 2006
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24. Correspondence re: J. B. de Kok et al., DD3, a very sensitive and specific marker to detect prostate tumors. Cancer Res., 62: 2695-2698, 2002 (multiple letters)
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Gandini, O., Santulli, M., Cardillo, M. R., Antonio STIGLIANO, Toscano, V., Verhaegh, G. W., Kok, J. B., Hessels, D., Smit, F., and Schalken, J. A.
25. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors
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Kok, J. B., Gerald Verhaegh, Roelofs, R. W., Hessels, D., Kiemeney, L. A., Aalders, T. W., Swinkels, D. W., and Schalken, J. A.
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Epidemiologie ,Epidemiology ,Urological oncology ,Urologische oncologie ,Ontwikkeling en kwaliteitsborging in de laboratoriumgeneeskunde ,Innovation and Quality assurance in laboratory medicine - Abstract
Item does not contain fulltext We identified DD3(PCA3) as one of the most prostate cancer-specific genes at present (M. J. Bussemakers et al. Cancer Res., 59: 5975-5979, 1999). Consequently, DD3(PCA3) is an interesting candidate for use as a diagnostic and/or prognostic marker. In this study we developed a method for the accurate quantification of DD3(PCA3) mRNA, using real-time quantitative reverse transcription-PCR. DD3(PCA3) was expressed at low levels in normal prostate but not in 21 selected other normal tissues, blood, or 39 tumor samples other than prostate. The diagnostic and prognostic value of DD3(PCA3) in normal, hyperplastic, and malignant prostate tissues was determined and compared with another promising tumor marker for prostate cancer, telomerase reverse transcriptase (hTERT gene), the expression of which is related to telomerase activity. Sensitivity and specificity estimates for both genes were calculated as the area under the receiver-operating characteristics curve (AUC-ROC). DD3(PCA3) (AUC-ROC, 0.98) demonstrated better diagnostic efficacy than hTERT (AUC-ROC, 0.88). Moreover, the median increase in mRNA expression in tumor tissues compared with nonmalignant prostate tissues was much higher for DD3(PCA3) (34-fold) than for hTERT (6-fold). In tumor tissues, the median expression of DD3(PCA3) was much higher than hTERT (5849 versus 10 normalized mRNA copies). A significant relationship was observed only between tumor stage and hTERT gene expression. We conclude that expression of the DD3(PCA3) gene is a very sensitive and specific marker for the detection of prostate tumor cells in a high background of normal (prostate) cells. Consequently, DD3 measurements may be used for clinical application in prostate needle biopsies or bodily fluids such as blood, ejaculate, urine, or prostate massage fluid.
26. Heterogeneous expression of E-cadherin and p53 in prostate cancer: Clinical implications
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Ruijter, E., Kaa, C., Aalders, T., Ruiter, D., Miller, G., Debruyne, F., Schalken, J., Schröder, F. H., Beeker, C. G. M., Blijenberg, B. G., Boeken Kruger, A. E., Eman, I., Hoedemaeker, R. F., Kirkels, W. J., Kranse, R., Kwast, Th H., Noordzij, M. A., Poel, H. J. A., Romijn, J. C., Steenbrugge, G. J., Trapman, J., Verkaik, N. S., Bussemakers, M. J. G., Hessels, D., Oosterhof, G. O. N., Ruijter, T. E. G., Schalken, J. A., Thomas, C. M. G., Witjes, J. A., Ylikoski, A., Lövgren, T., Lövgren, J., Pettersson, K., Piironen, T., Mansikka-Savolainen, S., Ahlgren, G., Beeker, C., Bjartell, A., Björk, T., Lilja, H., Lundwall, A., Abrahamsson, P. A., Bratt, O., Colleen, S., Elfring, P., Frederiksen, H., Mårtensson, S., Hamdy, F. C., Leung, H. Y., David Neal, and Robson, C. N.
27. 279 DETECTION OF TMPRSS2-ERG FUSION TRANSCRIPTS AND PCA3 IN URINARY SEDIMENTS MAY IMPROVE DIAGNOSIS OF PROSTATE CANCER
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Hessels, D., Smit, F.P., Verhaegh, G.W., Witjes, J.A., Schalken, J.A., and Cornel, E.B.
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- 2008
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28. 104 - A 2-gene mRNA urine test for detection of high-grade prostate cancer prior to initial prostate biopsy.
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Schalken, J.A., Trooskens, G., Steyaert, S., Hessels, D., Brawer, M.K., Vlaeminck-Guillem, V., Groskopf, J., Van Criekinge, W., and Haese, A.
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PROSTATE cancer , *PROSTATE biopsy , *URINALYSIS , *MESSENGER RNA - Published
- 2019
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29. Clinically significant Prostate Cancer diagnosed using a urinary molecular biomarker-based risk score: two case reports.
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Minnee P, Hessels D, Schalken JA, and Van Criekinge W
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- Aged, Early Detection of Cancer methods, Humans, Male, Risk Assessment methods, Biomarkers, Tumor urine, Homeodomain Proteins urine, Prostatic Neoplasms diagnosis, Prostatic Neoplasms urine, Transcription Factors urine
- Abstract
Background: Identifying men for a repeat prostate biopsy is a conundrum to urologists. Risk calculators (RCs) such as the European Randomized Study of Screening for Prostate Cancer (ERSPC) RCs have been developed to predict the outcome of prostate biopsies and have been shown to improve diagnostic accuracy compared to PSA alone. However, it was recently shown that the outcome for high-grade prostate cancer (PCa) upon biopsy tended to be underestimated in men with previous negative biopsies using ERSPC RC model 4. For these men, an individualized approach combining the clinical information with the outcome of biomarker-related urine tests may help to make a more informed decision., Case Presentation: Two men, aged 66 and 69 respectively when presented in the clinic, show the typical dilemma of urologist and patient for electing repeat prostate biopsy. Both men had normal DRE findings, did not have a family history of PCa, presented with serum PSA values between 3 and 10 ng/ml and the first biopsies were negative for disease. The ERSPC RC4 did not indicate a biopsy in these men. The urinary molecular biomarker-based test for HOXC6 and DLX1, combining biomarker-expression profiling with clinical risk factors, resulted in SelectMDx Risk scores for these men that were higher than the cut-off of the test. Based on this outcome, mpMRI was performed with an outcome of PI-RADS ≥4 in both men. Histopathological evaluation of TRUS-guided biopsies confirmed high-grade PCa., Conclusions: The urinary molecular biomarker-based risk score played a pivotal role in the diagnosis of clinically significant PCa whereas ERSPC RC4 outcome would not have indicated further diagnostic follow-up in these two cases. The timely diagnosis was shown to be crucial for the curative treatment by radical retropubic prostatectomy and the potential life-years gained for these two vital males.
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- 2019
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30. Multicenter Optimization and Validation of a 2-Gene mRNA Urine Test for Detection of Clinically Significant Prostate Cancer before Initial Prostate Biopsy.
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Haese A, Trooskens G, Steyaert S, Hessels D, Brawer M, Vlaeminck-Guillem V, Ruffion A, Tilki D, Schalken J, Groskopf J, and Van Criekinge W
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- Aged, Biomarkers, Tumor urine, Biopsy, Humans, Male, Middle Aged, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Retrospective Studies, Homeodomain Proteins genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms urine, RNA, Messenger urine, Transcription Factors genetics
- Abstract
Purpose: A 2-gene, urine based molecular test that combines mRNA biomarkers with clinical factors can risk stratify patients for clinically significant prostate cancer. To ensure the generalizability of assay results we optimized and validated the clinical model for men with serum prostate specific antigen less than 10 ng/ml who were undergoing initial prostate biopsy., Materials and Methods: Urine samples were collected from 1,955 men from The Netherlands, France and Germany prior to an initial prostate biopsy and study subjects were divided into training and validation cohorts. Urinary HOXC6 and DLX1 mRNA levels were quantified and RNA results were then combined with other risk factors in a clinical model optimized to detect ISUP (International Society of Urological Pathology) Grade Group 2 or greater prostate cancer in men with prostate specific antigen less than 10 ng/ml. Results in the validation cohort were compared with the PCPTRC (Prostate Cancer Prevention Trial Risk Calculator), version 2.0., Results: The optimal clinical model included urinary HOXC6 and DLX1 mRNA levels, patient age, digital rectal examination and prostate specific antigen density (serum prostate specific antigen/prostate volume). In the 715 validation cohort subjects with prostate specific antigen less than 10 ng/ml the AUC was 0.82 with 89% sensitivity, 53% specificity and 95% negative predictive value. The PCPTRC AUC was 0.70. The full validation cohort of 916 men including all prostate specific antigen levels yielded an AUC of 0.85 with 93% sensitivity, 47% specificity and 95% negative predictive value. The PCPTRC AUC was 0.76., Conclusions: The 2-gene based urine assay, which is optimized for biopsy naïve patients with serum prostate specific antigen less than 10 ng/ml, demonstrated high sensitivity and negative predictive value to detect clinically significant prostate cancer. These data support using the test to help guide initial prostate biopsy decisions.
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- 2019
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31. Urinary Molecular Biomarker Test Impacts Prostate Biopsy Decision Making in Clinical Practice.
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Shore N, Hafron J, Langford T, Stein M, DeHart J, Brawer M, Hessels D, Schalken J, Van Criekinge W, Groskopf J, and Wojno K
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Introduction: There is an unmet need for noninvasive methods to better identify patients at increased risk for clinically significant prostate cancer. SelectMDx® is a molecular urine test validated for the detection of Gleason score 7 and higher cancers (ISUP [International Society of Urological Pathology] Grade Group 2-5). In this multicenter trial we evaluated the test's impact on prostate biopsy decision making in clinical practice., Methods: The study involved 5 U.S. community urology practices which sequentially enrolled 418 patients who received a SelectMDx test between May 2016 and April 2017 while undergoing evaluation for initial prostate biopsy. All tests were ordered by the urologist for patient management. We determined biopsy and prostate cancer detection rates in patients with SelectMDx positive versus SelectMDx negative results., Results: Of the 418 subjects evaluated with SelectMDx 253 (61%) had negative results and 165 (39%) had positive results. Subsequent biopsy rates for SelectMDx positive and negative cases were 60% (99) and 12% (32), respectively (p <0.001). Time from SelectMDx result to biopsy was shorter for those with positive vs negative results (median 2 vs 5 months, p=0.001). Of patients who underwent biopsy within 3 months of testing 71 (43%) with positive results underwent biopsy and 27 had cancers identified, including 10 greater than Grade Group 2. Of 9 patients with SelectMDx negative results (3.6%) who underwent biopsy 4 were diagnosed with cancer, all Grade Group 2 or less., Conclusions: SelectMDx had a significant impact on initial prostate biopsy decision making. Biopsy rates in SelectMDx positive cases were fivefold higher than in SelectMDx negative cases. These results describe the clinical utility of SelectMDx in real-world community urology practice.
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- 2019
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32. Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.
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Govers TM, Hessels D, Vlaeminck-Guillem V, Schmitz-Dräger BJ, Stief CG, Martinez-Ballesteros C, Ferro M, Borque-Fernando A, Rubio-Briones J, Sedelaar JPM, van Criekinge W, and Schalken JA
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- Biomarkers, Tumor, Biopsy methods, Clinical Decision-Making, Cost-Benefit Analysis, Decision Trees, Europe epidemiology, France, Germany, Humans, Italy, Male, Models, Statistical, Prostatic Neoplasms mortality, Prostatic Neoplasms therapy, Public Health Surveillance, Quality of Life, Quality-Adjusted Life Years, Sensitivity and Specificity, Spain, Biopsy economics, Prostatic Neoplasms diagnosis, Prostatic Neoplasms epidemiology
- Abstract
Background: Low specificity of prostate-specific antigen results in a considerable number of unnecessary prostate biopsies in current practice. SelectMDx® predicts significant prostate cancer upon biopsy and is used to reduce the number of unnecessary initial prostate biopsies. Furthermore, potential overtreatment of insignificant prostate cancer can be reduced. Besides the diagnostic accuracy of the test, also the context in a specific country determines the potential health benefit and cost-effectiveness. Therefore, the health benefit and cost-effectiveness of SelectMDx were assessed in France, Germany, Italy, and Spain., Subject and Methods: A decision model was used to compare the current standard of care in which men undergo initial prostate biopsy in case of an elevated prostate-specific antigen, to a strategy in which SelectMDx was used to select men for biopsy. Model inputs most relevant to each of the four countries were obtained. With use of the model long-term quality-adjusted life years (QALYs) and healthcare costs were calculated for both strategies., Results: In all four countries, the SelectMDx resulted in QALY gain and cost savings compared with the current standard of care. In France, SelectMDx resulted in 0.022 QALYs gained and cost savings of €1217 per patient. For Germany, the model showed a QALY gain of 0.016 and a cost saving of €442. In Italy, the QALY gain and cost savings were 0.031 and €762. In Spain 0.020 QALYs were gained and €250 costs were saved., Conclusions: The results of the model showed that with SelectMDx, QALYs could be gained while saving healthcare costs in the initial diagnosis of prostate cancer. The significant presence of overtreatment in the current standard of care in all four countries was the main factor that resulted in the beneficial outcomes with SelectMDx.
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- 2019
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33. Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker-Based Risk Score.
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Van Neste L, Hendriks RJ, Dijkstra S, Trooskens G, Cornel EB, Jannink SA, de Jong H, Hessels D, Smit FP, Melchers WJ, Leyten GH, de Reijke TM, Vergunst H, Kil P, Knipscheer BC, Hulsbergen-van de Kaa CA, Mulders PF, van Oort IM, Van Criekinge W, and Schalken JA
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- Aged, Biomarkers, Tumor genetics, Clinical Decision-Making methods, Humans, Male, Middle Aged, Neoplasm Grading, Patient Selection, Prostate pathology, Prostate-Specific Antigen analysis, Reproducibility of Results, Research Design, Risk Assessment methods, Risk Factors, Homeodomain Proteins genetics, Medical Overuse prevention & control, Prostatic Neoplasms pathology, Prostatic Neoplasms therapy, Prostatic Neoplasms urine, RNA, Messenger analysis, RNA, Messenger urine, Transcription Factors genetics
- Abstract
Background: To reduce overdiagnosis and overtreatment, a test is urgently needed to detect clinically significant prostate cancer (PCa)., Objective: To develop a multimodal model, incorporating previously identified messenger RNA (mRNA) biomarkers and traditional risk factors that could be used to identify patients with high-grade PCa (Gleason score ≥7) on prostate biopsy., Design, Setting, and Participants: In two prospective multicenter studies, urine was collected for mRNA profiling after digital rectal examination (DRE) and prior to prostate biopsy. The multimodal risk score was developed on a first cohort (n=519) and subsequently validated clinically in an independent cohort (n=386)., Outcome Measurements and Statistical Analysis: The mRNA levels were measured using reverse transcription quantitative polymerase chain reaction. Logistic regression was used to model patient risk and combine risk factors. Models were compared using the area under the curve (AUC) of the receiver operating characteristic, and clinical utility was evaluated with a decision curve analysis (DCA)., Results and Limitations: HOXC6 and DLX1 mRNA levels were shown to be good predictors for the detection of high-grade PCa. The multimodal approach reached an overall AUC of 0.90 (95% confidence interval [CI], 0.85-0.95) in the validation cohort (AUC 0.86 in the training cohort), with the mRNA signature, prostate-specific antigen (PSA) density, and previous cancer-negative prostate biopsies as the strongest, most significant components, in addition to nonsignificant model contributions of PSA, age, and family history. For another model, which included DRE as an additional risk factor, an AUC of 0.86 (95% CI, 0.80-0.92) was obtained (AUC 0.90 in the training cohort). Both models were successfully validated, with no significant change in AUC in the validation cohort, and DCA indicated a strong net benefit and the best reduction in unnecessary biopsies compared with other clinical decision-making tools, such as the Prostate Cancer Prevention Trial risk calculator and the PCA3 assay., Conclusions: The risk score based on the mRNA liquid biopsy assay combined with traditional clinical risk factors identified men at risk of harboring high-grade PCa and resulted in a better patient risk stratification compared with current methods in clinical practice. Therefore, the risk score could reduce the number of unnecessary prostate biopsies., Patient Summary: This study evaluated a novel urine-based assay that could be used as a noninvasive diagnostic aid for high-grade prostate cancer (PCa). When results of this assay are combined with traditional clinical risk factors, risk stratification for high-grade PCa and biopsy decision making are improved., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
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34. Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer.
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Leyten GH, Hessels D, Smit FP, Jannink SA, de Jong H, Melchers WJ, Cornel EB, de Reijke TM, Vergunst H, Kil P, Knipscheer BC, Hulsbergen-van de Kaa CA, Mulders PF, van Oort IM, and Schalken JA
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Carrier Proteins genetics, Carrier Proteins urine, Cell Cycle Proteins, Early Detection of Cancer, Homeodomain Proteins genetics, Homeodomain Proteins urine, Humans, Male, Middle Aged, Neoplasm Grading, Prostatic Neoplasms genetics, Prostatic Neoplasms urine, Quinolines, ROC Curve, Transcription Factors genetics, Transcription Factors urine, Transcriptome, Biomarkers, Tumor urine, Prostatic Neoplasms diagnosis
- Abstract
Purpose: Serum PSA (sPSA) testing has led to the identification of patients with indolent prostate cancer, and inevitably overtreatment has become a concern. Progensa PCA3 urine testing was shown to improve the diagnosis of prostate cancer, but its diagnostic value for aggressive prostate cancer is limited. Therefore, urinary biomarkers that can be used for prediction of Gleason score ≥7 prostate cancer in biopsies are urgently needed., Experimental Design: Using gene expression profiling data, 39 prostate cancer biomarkers were identified. After quantitative PCR analysis on tissue specimens and urinary sediments, eight promising biomarkers for the urinary detection of prostate cancer were selected (ONECUT2, HOXC4, HOXC6, DLX1, TDRD1, NKAIN1, MS4A8B, PPFIA2). The hypothesis that biomarker combinations improve the diagnostic value for aggressive prostate cancer was tested on 358 urinary sediments of an intention-to-treat cohort., Results: A urinary three-gene panel (HOXC6, TDRD1, and DLX1) had higher accuracy [area under the curve (AUC), 0.77; 95% confidence interval (CI), 0.71-0.83] to predict Gleason score ≥7 prostate cancer in biopsies compared with Progensa PCA3 (AUC, 0.68; 95% CI, 0.62-0.75) or sPSA (AUC, 0.72; 95% CI, 0.65-0.78). Combining the three-gene panel with sPSA further improved the predictive accuracy (AUC, 0.81; 95% CI, 0.75-0.86). The accuracy of the three-gene predictive model was maintained in subgroups with low sPSA concentrations., Conclusions: The urinary three-gene panel (HOXC6, TDRD1, and DLX1) represents a promising tool to identify patients with aggressive prostate cancer, also in those with low sPSA values. The combination of the urinary three-gene panel with sPSA bears great potential for the early diagnosis of patients with clinically significant prostate cancer., (©2015 American Association for Cancer Research.)
- Published
- 2015
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35. Prostate cancer antigen 3: diagnostic outcomes in men presenting with urinary prostate cancer antigen 3 scores ≥100.
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Schröder FH, Venderbos LD, van den Bergh RC, Hessels D, van Leenders GJ, van Leeuwen PJ, Wolters T, Barentsz JO, and Roobol MJ
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- Aged, Biopsy, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Organ Size, Predictive Value of Tests, Prostatic Neoplasms pathology, Prostatic Neoplasms urine, Antigens, Neoplasm urine, Biomarkers, Tumor urine, Prostate pathology, Prostatic Neoplasms diagnosis
- Abstract
Objective: To describe the results of 3 rounds of diagnostic testing and linkage to the Dutch Cancer Registry for men with an initial prostate cancer antigen 3 (PCA3) score ≥100., Methods: Within an earlier reported comparative study of PCA3 vs prostate-specific antigen in a prescreened population, 90 men with a PCA3 score ≥100 were identified and underwent biopsy, 28 prostate cancers (PCs) were found, 62 men remained at risk of a diagnosis of PC. All men were offered repeat testing; 6 PCs were found in 20 men at rebiopsy. Men with at least 1 negative biopsy (n = 56) were invited to undergo magnetic resonance imaging (MRI) studies and MRI-guided biopsies if indicated. Linkage to the Dutch Cancer Registry after 2.8 years of follow-up was performed for men with negative biopsies., Results: Of the 56 men at risk, 28 agreed to participate in further testing. They were offered MRI studies; only 7 men agreed, and in 2, suspicious lesions were found and biopsies carried out. Only 1 PC was diagnosed and classified as T1c, Gleason 3 + 3 = 6. The overall findings of 3 rounds of testing and of linkage to the cancer registry show that eventually 35 PCs were detected in 90 men with PCA3 scores ≥100 (positive predictive value 38.9%)., Conclusion: Finding no PC despite extended diagnostic efforts in many men with initial PCA3 scores ≥100 is unexpected and might be clinically relevant., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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36. Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer.
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Leyten GH, Hessels D, Jannink SA, Smit FP, de Jong H, Cornel EB, de Reijke TM, Vergunst H, Kil P, Knipscheer BC, van Oort IM, Mulders PF, Hulsbergen-van de Kaa CA, and Schalken JA
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers urine, Gene Fusion, Humans, Male, Middle Aged, Predictive Value of Tests, Prognosis, Prospective Studies, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics, Serine Endopeptidases genetics, Trans-Activators genetics, Transcriptional Regulator ERG, Antigens, Neoplasm urine, Prostatic Neoplasms urine, Serine Endopeptidases urine, Trans-Activators urine
- Abstract
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., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
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- 2014
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37. Recurrent gene fusions in prostate cancer: their clinical implications and uses.
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Hessels D and Schalken JA
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- Gene Fusion genetics, Genetic Markers, Humans, Male, Oncogene Proteins, Fusion genetics, Carcinoma genetics, Gene Expression Regulation, Neoplastic genetics, Oncogene Fusion genetics, Prostatic Neoplasms genetics
- Abstract
Gene fusions, resulting from chromosomal rearrangements, have been attributed to leukaemias and soft tissue sarcomas. The recent discovery of a recurrent gene fusion TMPRSS2-ERG in approximately half of the prostate cancers tested indicates that gene fusions also play a role in the onset of common epithelial cancers. Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. It is a heterogeneous disease, both in terms of pathology and clinical presentation. Since the discovery of the TMPRSS2-ERG fusion, other gene fusions have been reported, most of which result in the androgen-regulated over-expression of the oncogene ERG or other ETS transcription factors. The high prevalence of these gene fusions represents a distinct class of tumours, which may give more insight in the heterogeneity of the disease. These gene fusions are of interest as biomarkers for diagnosis of prostate cancer, and some of them could be useful in predicting the presence of aggressive disease. This review focuses on the biological significance and clinical implementation of gene fusions, and particularly the most commonly reported TMPRSS2-ERG fusion, in prostate cancer.
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- 2013
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38. Urinary biomarkers for prostate cancer: a review.
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Hessels D and Schalken JA
- Subjects
- Adenomatous Polyposis Coli Protein genetics, Adenomatous Polyposis Coli Protein urine, Antigens, Neoplasm genetics, Antigens, Neoplasm urine, Antigens, Surface genetics, Antigens, Surface urine, Exosomes, Gene Expression, Glutamate Carboxypeptidase II genetics, Glutamate Carboxypeptidase II urine, Glutathione S-Transferase pi genetics, Glutathione S-Transferase pi urine, Humans, Male, MicroRNAs urine, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion urine, Prostatic Neoplasms diagnosis, Racemases and Epimerases genetics, Racemases and Epimerases urine, Receptors, Retinoic Acid genetics, Receptors, Retinoic Acid metabolism, Sensitivity and Specificity, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins urine, Biomarkers, Tumor genetics, Biomarkers, Tumor urine, Prostatic Neoplasms genetics, Prostatic Neoplasms urine
- Abstract
Although the routine use of serum prostate-specific antigen (PSA) testing has undoubtedly increased prostate cancer (PCa) detection, one of its main drawbacks is its lack of specificity. As a consequence, many men undergo unnecessary biopsies or treatments for indolent tumours. PCa-specific markers are needed for the early detection of the disease and the prediction of aggressiveness of a prostate tumour. Since PCa is a heterogeneous disease, a panel of tumour markers is fundamental for a more precise diagnosis. Several biomarkers are promising due to their specificity for the disease in tissue. However, tissue is unsuitable as a possible screening tool. Since urine can be easily obtained in a non-invasive manner, it is a promising substrate for biomarker testing. This article reviews the biomarkers for the non-invasive testing of PCa in urine.
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- 2013
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39. Rational basis for the combination of PCA3 and TMPRSS2:ERG gene fusion for prostate cancer diagnosis.
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Robert G, Jannink S, Smit F, Aalders T, Hessels D, Cremers R, Mulders PF, and Schalken JA
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- Gene Expression Regulation, Neoplastic genetics, Humans, Male, Prostate-Specific Antigen genetics, Prostatic Hyperplasia diagnosis, Prostatic Hyperplasia genetics, Up-Regulation genetics, Antigens, Neoplasm genetics, Biomarkers, Tumor genetics, Gene Fusion genetics, Oncogene Proteins, Fusion genetics, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics
- Abstract
Background: The prostate cancer gene 3 (PCA3) and TMPRSS2:ERG gene fusion are promising prostate cancer (PCa) specific biomarkers. Our aim was to simultaneously quantify the expression levels of PCA3 and TMPRSS2:ERG in a panel of benign prostatic hyperplasia (BPH), normal prostate adjacent to PCa (NP) and PCa tissue samples, to provide a rational basis for the understanding of the false-positive and false-negative results of the urine assays., Methods: The tissue samples were carefully histopathologically characterized to obtain homogeneous groups. The mRNA was isolated, transcribed into cDNA and the relative expressions of PCA3 and TMPRSS2:ERG were measured using a quantitative real-time polymerase chain reaction. The expression levels of PCA3 and TMPRSS2:ERG were compared between the different groups., Results: We included 48 BPH, 32 NP, and 48 PCa. The PCA3 expression levels progressively increased from BPH to NP (3 times) and finally to PCa (30 times). There were one false-positive sample and seven false-negative samples. The TMPRSS2:ERG gene fusion was found in 8.3% of the BPH, 15.6% of the NP, and 50% of the PCa samples. The use of TMPRSS2:ERG in the PCA3 negative cases allowed diagnosis of four of the seven false-negative samples and added one false-positive, but we had to define a cut-off value to avoid eight false-positive results., Conclusions: Considering tissue expression of the markers, most of the false-negative results of the PCA3 test were corrected by TMPRSS2:ERG (57%) and the combination of both had a higher sensitivity for PCa diagnosis. Some of the control samples did express TMPRSS2:ERG and a cut-off value had to be defined to avoid false-positive results., (Copyright © 2012 Wiley Periodicals, Inc.)
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- 2013
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40. Biomarkers for the diagnosis of prostatic inflammation in benign prostatic hyperplasia.
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Robert G, Smit F, Hessels D, Jannink S, Karthaus HF, Aalders T, Jansen K, de la Taille A, Mulders PF, and Schalken JA
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- Biomarkers urine, CTLA-4 Antigen genetics, CTLA-4 Antigen metabolism, Histocytochemistry, Humans, Inducible T-Cell Co-Stimulator Protein genetics, Inducible T-Cell Co-Stimulator Protein metabolism, Male, Prospective Studies, Prostatic Hyperplasia genetics, Prostatic Hyperplasia pathology, Prostatic Hyperplasia urine, Prostatitis genetics, Prostatitis pathology, Prostatitis urine, RNA, Messenger chemistry, RNA, Messenger genetics, Receptors, CCR7 genetics, Receptors, CCR7 metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Statistics, Nonparametric, Prostatic Hyperplasia diagnosis, Prostatitis diagnosis
- Abstract
Background: Chronic prostatic inflammation could be a central mechanism in benign prostatic hyperplasia (BPH) progression. Currently, the histological examination of prostate biopsies remains the only way to diagnose prostatic inflammation. Our objective was to find new noninvasive biomarkers for the diagnosis of prostatic inflammation., Methods: Ninety BPH samples were investigated in two steps. First, a hypothesis was generated using a profiling procedure with a panel of 96 genes on an initial set of 30 samples. Then, the candidate biomarkers were validated on a large number of samples (n = 90). Gene expression was compared with the histological prostatic inflammation score based on the density and the confluence of lymphoid nodules. Finally, protein transcripts of the candidate biomarkers were investigated in urine samples and compared with clinical data., Results: Of the 96 genes, nine were significantly correlated with the inflammation score on the initial set of patients. Four of them were validated on the complete set of patients: CCR7, CD40LG, CTLA4, and ICOS. ICOS and CTLA4 protein levels were readily measured in urine samples using a conventional ELISA procedure. High-ICOS expression in urine was associated with a higher post-void residual and a lower maximum urinary flow rate., Conclusions: Four genes were significantly upregulated at the mRNA level in the prostate tissue of patients with severe inflammation score. Two proteins were measured in urine samples, and were associated with maximum uroflowmetry and post-void residual. A prospective clinical study is needed to confirm their clinical relevance., (Copyright © 2011 Wiley-Liss, Inc.)
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- 2011
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41. Performance of prostate cancer antigen 3 (PCA3) and prostate-specific antigen in Prescreened men: reproducibility and detection characteristics for prostate cancer patients with high PCA3 scores (≥ 100).
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Roobol MJ, Schröder FH, van Leenders GL, Hessels D, van den Bergh RC, Wolters T, and van Leeuwen PJ
- Subjects
- Aged, Biopsy, Freezing, Humans, Male, Middle Aged, Netherlands, Predictive Value of Tests, Prognosis, Prostatic Neoplasms immunology, Prostatic Neoplasms pathology, Reproducibility of Results, Sensitivity and Specificity, Specimen Handling, Antigens, Neoplasm urine, Mass Screening methods, Prostate-Specific Antigen blood, Prostatic Neoplasms diagnosis
- Abstract
Background: Prostate cancer antigen 3 (PCA3) is considered to be prostate cancer (PCa) specific and highly overexpressed in cancer. Therefore a high PCA3 score should result in a high positive predictive value (PPV) and specificity for a positive biopsy., Objective: Our aim was to reevaluate, retest PCA3, and rebiopsy men with an initial PCA3 ≥ 100 and no PCa detected and compare the results with a random cohort of men with an initial PCA3<100., Design, Setting, and Participants: We invited men 63-75 yr of age with a PCA3 ≥100 for retesting and a control group with an initial PCA3 < 100 to participate in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam., Interventions: Blood and urine sampling were used to determine prostate-specific antigen (PSA) and PCA3. Prostate biopsies were performed if the PSA was ≥2.5 ng/ml and/or the PCA3 score was ≥ 35., Measurements: We correlated the initial and reevaluated PCA3 scores. Our assessment of the PPV after rebiopsy was based on the newly determined PCA3 score., Results and Limitations: After a mean study period of 19 mo, more cases of PCa were detected in rebiopsied men with initial PCA3 scores ≥ 100 than in the controls with PCA3 scores < 100 (30.0% vs 18.8%). Combining initial and rebiopsy data resulted in a PPV of 52.2% in men with PCA3 ≥ 100. Over time, changes in PSA and PCA3 levels were quite different., Conclusions: In spite of our rescreened population, PPV and specificity were comparable with all reported studies of men with PCA3 scores ≥ 100. These findings do not explain why these PCA3 scores were excessively high in spite of the absence of biopsy-detectable PCa., (Copyright © 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
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- 2010
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42. Performance of the prostate cancer antigen 3 (PCA3) gene and prostate-specific antigen in prescreened men: exploring the value of PCA3 for a first-line diagnostic test.
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Roobol MJ, Schröder FH, van Leeuwen P, Wolters T, van den Bergh RC, van Leenders GJ, and Hessels D
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- Aged, Humans, Male, Middle Aged, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Antigens, Neoplasm genetics, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics
- Abstract
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 > or =3.0 ng/ml and/or the PCA3 score was > or =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 > or =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 > or =4, n=19), and 68.2% of biopsies could have been avoided; the respective data for PCA3 > or =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., (Copyright 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
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- 2010
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43. Differential expression of PCA3 and its overlapping PRUNE2 transcript in prostate cancer.
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Salagierski M, Verhaegh GW, Jannink SA, Smit FP, Hessels D, and Schalken JA
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- Aged, Antigens, Neoplasm genetics, Biomarkers, Tumor genetics, Carrier Proteins genetics, Humans, Male, Middle Aged, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Phosphoric Monoester Hydrolases, Prostatic Neoplasms diagnosis, Protein Isoforms biosynthesis, Protein Isoforms genetics, Transcription, Genetic physiology, Tumor Cells, Cultured, Antigens, Neoplasm biosynthesis, Biomarkers, Tumor biosynthesis, Carrier Proteins biosynthesis, Gene Expression Regulation, Neoplastic, Genes, Overlapping, Prostatic Neoplasms genetics
- Abstract
Background: PCA3 is one of the most prostate cancer (PrCa)-specific markers described so far. Recently, a new genomic structure of PCA3 as well as new flanking and overlapping gene transcripts has been identified. Furthermore, a co-regulation of PCA3 and its overlapping gene PRUNE2(BMCC1) has been suggested. Our aim was to assess the diagnostic performance of a new PCA3 isoform (PCA3-TS4) and to study the interactions between PCA3 and BMCC1 in PrCa., Methods: We used SYBR Green quantitative (q)PCR with specific primers to compare PCA3 and BMCC1 expression of normal versus tumor tissue of human prostate. PCA3-TS4 plasmid was created to calculate the absolute amounts of PCA3 transcripts. The androgen regulation of PCA3 and BMCC1 expression was studied in LNCaP and 22Rv1 cells stimulated with 5alpha-dihydrotestosterone., Results: We have not found any relevant diagnostic advantage of the PCA3-TS4 isoform over the "classical" PCA3 isoform in our group of PrCa patients. Additionally, PCA3-TS4 appears to be only a minor PCA3 transcript. We were also unable to confirm the hypothesis that BMCC1 isoforms are androgen-induced in vitro., Conclusions: Despite the presence of the recently identified marginal PCA3 transcripts in human PrCa, the previously described major PCA3 isoform still constitutes the best target for diagnostic purposes. PCA3 and BMCC1 are overlapping genes in reverse orientation that do not appear to be co-regulated., ((c) 2009 Wiley-Liss, Inc.)
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- 2010
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44. Predictive value of PCA3 in urinary sediments in determining clinico-pathological characteristics of prostate cancer.
- Author
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Hessels D, van Gils MP, van Hooij O, Jannink SA, Witjes JA, Verhaegh GW, and Schalken JA
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Humans, Male, Middle Aged, Neoplasm Staging, Predictive Value of Tests, Prognosis, Prostatic Neoplasms surgery, Urinalysis, Antigens, Neoplasm urine, Biomarkers, Tumor urine, Prostatic Neoplasms pathology, Prostatic Neoplasms urine
- Abstract
Purpose: PCA3 urine tests have shown to improve the specificity in prostate cancer (PCa) diagnosis, and have thus the potential to reduce the number of unnecessary prostate biopsies and to predict repeat biopsy outcomes. In this study, PCA3 was correlated with clinical stage, biopsy Gleason score (GS), radical prostatectomy GS, tumor volume, and pathological stage to assess its potential as predictor of PCa aggressiveness., Methods: In this study, 351 men admitted for prostate biopsies based on serum PSA levels >3 ng/ml, an abnormal DRE, and/or a family history of PCa were included. Post-DRE urinary sediments from 336 men were tested using a transcription-mediated amplification-based PCA3 test, and assay results were correlated with clinical stage and biopsy GS. In a sub-cohort of 70 men who underwent radical prostatectomy, the PCA3 values were correlated to their radical prostatectomy GS, tumor volume, and pathological stage., Results: In this patient cohort we could not find a correlation between clinical stage, biopsy GS, radical prostatectomy GS, tumor volume, and pathological stage., Conclusions: The predictive value of PCA3 for PCa aggressiveness features as reported in earlier studies cannot be confirmed in our study. Experimental differences (urine sediments vs. whole urine) and cohort may explain this. The exact place of PCA3 as prognostic test for PCa remains the subject of investigation., ((c) 2009 Wiley-Liss, Inc.)
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- 2010
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45. Preliminary evaluation of the effect of dutasteride on PCA3 in post-DRE urine sediments: a randomized, open-label, parallel-group pilot study.
- Author
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van Gils MP, Hessels D, Peelen WP, Vergunst H, Mulders PF, and Schalken JA
- Subjects
- 5-alpha Reductase Inhibitors, Antigens, Neoplasm biosynthesis, Antigens, Neoplasm genetics, Azasteroids adverse effects, Biomarkers, Tumor genetics, Dihydrotestosterone blood, Dose-Response Relationship, Drug, Dutasteride, Enzyme Inhibitors adverse effects, Humans, Longitudinal Studies, Male, Middle Aged, Pilot Projects, Prostate-Specific Antigen blood, Prostatic Hyperplasia pathology, Prostatic Hyperplasia urine, Prostatic Neoplasms pathology, Prostatic Neoplasms urine, RNA, Messenger biosynthesis, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Testosterone blood, Antigens, Neoplasm urine, Azasteroids therapeutic use, Biomarkers, Tumor urine, Enzyme Inhibitors therapeutic use, Prostatic Hyperplasia drug therapy, Prostatic Neoplasms drug therapy
- Abstract
Background: Dutasteride is commonly used in patients that are also at risk for prostate cancer (PCa). Therefore, the influence of dutasteride on PCa markers has to be studied. To date, only the effect of dutasteride on serum prostate-specific antigen (PSA) has been studied. This was the first study to investigate the effect of dutasteride on the new PCa marker PCA3, longitudinally and in a dose dependent manner., Methods: From April 25, 2005 to October 31, 2006, 16 subjects with benign prostatic hyperplasia (BPH) and 9 subjects with clinically localized PCa were enrolled at the urological outpatient clinics of one university hospital and one community hospital. Eight subjects with BPH and five with PCa received 0.5 mg dutasteride once daily for 3 months, eight with BPH and four with PCa received 3.5 mg. No subjects were withdrawn because of adverse effects., Results: In all four groups both 0.5 and 3.5 mg dutasteride had a variable effect on the PCA3 score. In contrast, its other effects were consistent as it rapidly reduced serum DHT by >or=90%, over time increased serum T by 20-30%, over time halved serum PSA and decreased prostate volume by 10-16%., Conclusions: In this exploratory/pilot study the effect of dutasteride on the PCA3 score was variable. This should be taken into account while using PCA3 in diagnostics. As this study was exploratory, the influence of androgen-deprivation therapy on the PCA3 score should be analyzed further.
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- 2009
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46. The use of PCA3 in the diagnosis of prostate cancer.
- Author
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Hessels D and Schalken JA
- Subjects
- Biomarkers urine, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Epithelium metabolism, Epithelium pathology, Humans, Male, Prostatic Neoplasms pathology, Prostatic Neoplasms urine, Tissue Distribution, Antigens, Neoplasm biosynthesis, Antigens, Neoplasm genetics, Antigens, Neoplasm urine, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics
- Abstract
Although the routine use of serum PSA testing has undoubtedly increased prostate cancer detection, one of its main drawbacks has been its lack of specificity, which results in a high negative biopsy rate. Consequently, a large population of men with chronically elevated serum PSA and one or more negative biopsies has emerged. More accurate tests are needed that can help identify which patients are at high risk of developing prostate cancer, and for whom repeat prostate biopsies are mandatory. To improve the specificity of prostate cancer diagnosis, prostate-cancer-specific markers, such as prostate cancer gene 3 (PCA3), are needed. The strong association between PCA3 mRNA overexpression and malignant transformation of prostate epithelium indicates its potential as a diagnostic biomarker. Quantification of PCA3 mRNA levels in urine was found to help predict the outcome of prostate biopsies. The intensive and time-consuming reverse-transcriptase polymerase chain reaction PCA3 urine test has been translated successfully into the fast and easy transcription-mediated amplification (TMA)-based PCA3 test. This test is the first RNA-based molecular diagnostic assay in body fluids for prostate cancer that is available to urologists. This Review describes the translation of the molecular marker PCA3 from the research laboratory to clinical practice.
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- 2009
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47. Detailed analysis of histopathological parameters in radical prostatectomy specimens and PCA3 urine test results.
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van Gils MP, Hessels D, Hulsbergen-van de Kaa CA, Witjes JA, Jansen CF, Mulders PF, Rittenhouse HG, and Schalken JA
- Subjects
- Cadherins metabolism, DNA-Binding Proteins metabolism, Enhancer of Zeste Homolog 2 Protein, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Staging, Polycomb Repressive Complex 2, Predictive Value of Tests, Prognosis, Prostatic Neoplasms surgery, Transcription Factors metabolism, alpha Catenin metabolism, Antigens, Neoplasm urine, Biomarkers, Tumor urine, Prostatectomy, Prostatic Neoplasms pathology, Prostatic Neoplasms urine
- Abstract
Background: Due to the drawbacks of serum prostate-specific antigen, there is an ongoing search for new diagnostic and prognostic prostate cancer (PCa) markers. PCA3 has proven to be of value in the diagnosis of PCa. However, so far few attempts have been made to investigate the prognostic value of PCA3. Our objective was to further investigate the prognostic value of PCA3., Methods: In this study we correlated the PCA3 score in urinary sediments after digital rectal examination in 62 men with the classical prognostic parameters assessed in radical prostatectomy specimens (i.e. Gleason score, pathological tumor stage and total tumor volume) and moreover, with the expression of three immunohistochemical markers for PCa biological aggressiveness (i.e. E-cadherin, alpha-catenin and EZH2). The results from this study serve as a reflection on and a valuable adjunct to recently published results., Results: We did not find a significant correlation of the PCA3 score with the classical prognostic parameters assessed in radical prostatectomy specimens or the expression of the immunohistochemical markers for PCa biological aggressiveness. However, we did observe a trend for a higher PCA3 score in significant PCa versus insignificant PCa, aberrant E-cadherin staining versus normal E-cadherin staining and increased EZH2 staining versus normal EZH2 staining., Conclusions: In this study we could not prove the prognostic value of PCA3. Further research with large numbers of men and adequate follow-up is needed to provide a definitive answer to the question if PCA3 is not only a diagnostic but also a prognostic PCa marker., (Copyright (c) 2008 Wiley-Liss, Inc.)
- Published
- 2008
- Full Text
- View/download PDF
48. Detection of TMPRSS2-ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer.
- Author
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Hessels D, Smit FP, Verhaegh GW, Witjes JA, Cornel EB, and Schalken JA
- Subjects
- Biomarkers, Tumor, Humans, Male, Prognosis, Prostatic Neoplasms mortality, Prostatic Neoplasms urine, Reverse Transcriptase Polymerase Chain Reaction, Antigens, Neoplasm urine, Oncogene Proteins, Fusion genetics, Prostatic Neoplasms diagnosis, RNA, Messenger urine
- Abstract
Purpose: Early detection of prostate cancer can increase the curative success rate for prostate cancer. We studied the diagnostic usefulness of TMPRSS2-ERG fusion transcripts as well as the combination of prostate cancer antigen 3 (PCA3) RNA and TMPRSS2-ERG fusion transcripts in urinary sediments after digital rectal examination (DRE)., Experimental Design: A total of 78 men with prostate cancer-positive biopsies and 30 men with prostate cancer-negative biopsies were included in this study. After DRE, the first voided urine was collected, and urinary sediments were obtained. We used semiquantitative reverse transcription-PCR (RT-PCR) analysis followed by Southern blot hybridization with a radiolabeled probe for the detection TMPRSS2-ERG fusion transcripts in these urinary sediments. A quantitative RT-PCR assay for PCA3 was used to determine the PCA3 score in the same sediments., Results: TMPRSS2-ERG fusion transcripts can be detected in the urine after DRE with a sensitivity of 37%. In this cohort of patients, the PCA3-based assay had a sensitivity of 62%. When both markers were combined, the sensitivity increased to 73%. Especially in the cohort of men with persistently elevated serum prostate-specific antigen levels and history of negative biopsies, the high positive predictive value of 94% of TMPRSS2-ERG fusion transcripts could give a better indication which patients require repeat biopsies., Conclusion: In this report, we used for the first time the combination of the prostate cancer-specific biomarkers TMPRSS2-ERG and PCA3, which significantly improves the sensitivity for prostate cancer diagnosis.
- Published
- 2007
- Full Text
- View/download PDF
49. Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features.
- Author
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van Leenders GJ, Dukers D, Hessels D, van den Kieboom SW, Hulsbergen CA, Witjes JA, Otte AP, Meijer CJ, and Raaphorst FM
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma pathology, Aged, Enhancer of Zeste Homolog 2 Protein, Gene Expression Profiling, Humans, Immunoenzyme Techniques, Ligases, Male, Middle Aged, Neoplasm Recurrence, Local, Polycomb Repressive Complex 1, Polycomb Repressive Complex 2, Polycomb-Group Proteins, Proportional Hazards Models, Prostate-Specific Antigen blood, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Statistics, Nonparametric, Ubiquitin-Protein Ligases, Adenocarcinoma genetics, DNA-Binding Proteins genetics, Gene Expression Regulation, Neoplastic, Nuclear Proteins genetics, Prostatic Neoplasms genetics, Proto-Oncogene Proteins genetics, Repressor Proteins genetics, Transcription Factors genetics
- Abstract
Objectives: Polycomb group (PcG) proteins are involved in maintenance of cell identity and proliferation. The protein EZH2 is overexpressed in disseminated prostate cancer, implicating a role of PcG complexes in tumor progression. In this study, we evaluated the expression of eight members of both PcG complexes in clinicopathologically defined prostate cancer., Methods: Components of both PcG protein complexes PRC2 (EZH2, EED, YY1) and PRC1 (BMI1, RING1, HPH1, HPC1, HPC2) were immunohistochemically identified in tissue microarrays of 114 prostate cancer patients. Protein expression was semi-quantitatively scored and correlated with pathologic parameters and recurrence of prostate-specific antigen (PSA)., Results: Whereas BMI1, RING1, HPC1 and HPH1 were all abundantly present in normal and malignant prostate epithelium, expression of EZH2 occurred in only <10% of cells. Expression of EZH2, BMI1 and RING1 were all significantly enhanced in tumours with Gleason score (GS) > or = 8, extraprostatic extension, positive surgical margins, and PSA recurrence. When only the subgroup of GS < or = 6 was considered, representing the tumour grade in the majority of needle biopsies, EZH2 and BMI1 were also predictive for PSA recurrence. In a multivariable analysis, BMI1 was the only PcG protein with an independent prognostic value., Conclusions: PcG proteins EZH2, BMI1, and RING1 are associated with adverse pathologic features and clinical PSA recurrence of prostate cancer. Whereas BMI1 and RING1 are abundantly present in prostate cancer, EZH2 is expressed at relatively low levels, making it a less obvious target for therapy.
- Published
- 2007
- Full Text
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50. Molecular PCA3 diagnostics on prostatic fluid.
- Author
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van Gils MP, Cornel EB, Hessels D, Peelen WP, Witjes JA, Mulders PF, Rittenhouse HG, and Schalken JA
- Subjects
- Antigens, Neoplasm genetics, Antigens, Neoplasm urine, Biopsy, Humans, Male, Middle Aged, Predictive Value of Tests, Prostate-Specific Antigen genetics, Prostate-Specific Antigen urine, Prostatic Neoplasms urine, RNA, Messenger chemistry, RNA, Messenger genetics, ROC Curve, Reverse Transcriptase Polymerase Chain Reaction, Antigens, Neoplasm analysis, Body Fluids chemistry, Prostatic Neoplasms diagnosis
- Abstract
Background: The PCA3 test on urine can improve specificity in prostate cancer (PCa) diagnosis and could prevent unnecessary prostate biopsies. In this study, we evaluated the PCA3 test on prostatic fluid and compared this with the PCA3 test on urine in a clinical research setting., Methods: Prostatic fluid and urine samples from 67 men were collected following digital rectal examination (DRE). The sediments were analyzed using the quantitative APTIMA PCA3 test. The results were compared with prostate biopsy results., Results: Using a PCA3 score of 66 as a cut-off value, the test on prostatic fluid had 65% sensitivity for the detection of PCa, 82% specificity and a negative predictive value of 82%. At a cut-off value of 43, the test on urine had 61% sensitivity, 80% specificity and a negative predictive value of 80%., Conclusions: The PCA3 test can be performed on both urine and prostatic fluid in the diagnosis of PCa with comparable results., (Copyright 2007 Wiley-Liss, Inc.)
- Published
- 2007
- Full Text
- View/download PDF
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