Ruben G H M Cremers

Radboud University Medical Centre (Radboudumc), Nymegen, Gelderland, Netherlands

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Publications (10)74.71 Total impact

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    ABSTRACT: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. To report the first year's screening results for all men at enrolment in the study. We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy. PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.
    European Urology 01/2014; · 10.48 Impact Factor
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    ABSTRACT: Objective Some studies have suggested an inverse association between acne vulgaris and the acne-related bacterium Propionibacterium acnes and prostate cancer (PCa). Self-reported acne might be an easily obtainable marker to identify men at relatively low risk of PCa and might be incorporated into PCa risk calculators. This study aimed to evaluate the association between self-reported acne and PCa in a large case-referent study. Methods and materials The case group comprised 942 patients with PCa recruited from a population-based cancer registry in 2003 to 2006, 647 of whom met the criteria for aggressive PCa. The referents (n = 2,062) were a random sample of the male general population. All subjects completed a questionnaire on risk factors for cancer, including questions about acne. Odds ratios (ORs) and 95% confidence interval (CI) were calculated using multivariable logistic regression for PCa and aggressive PCa as separate end points, while adjusting for age and family history of PCa. Results A history of acne was reported by 320 cases (33.9%) and 739 referents (35.8%). Self-reported acne was significantly associated neither with PCa (adjusted OR = 0.95, 95% CI: 0.80–1.12) nor with aggressive PCa (adjusted OR = 0.97, 95% CI: 0.80–1.18). Conclusion Self-reported acne is not suitable as a marker to identify men at low risk of aggressive PCa.
    Urologic Oncology: Seminars and Original Investigations. 01/2014;
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    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. Prostate © 2012 Wiley Periodicals, Inc.
    The Prostate 06/2012; · 3.84 Impact Factor
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    ABSTRACT: A family history of prostate cancer (PCa) is an established risk factor for PCa. In case of a positive family history, the balance between positive and adverse effects of prostate-specific antigen (PSA) testing might be different from the general population, for which the European Randomized Study of Screening for Prostate Cancer (ERSPC) showed a beneficial effect on mortality. This, however, went at the cost of considerable overtreatment. This study assessed Dutch physicians' knowledge of heredity and PCa and their 'post-ERSPC' attitude towards PCa testing, including consideration of family history. In January 2010, all Dutch urologists and clinical geneticists (CGs) and 300 general practitioners (GPs) were invited by email to complete an anonymous online survey, which contained questions about hereditary PCa and their attitudes towards PCa case-finding and screening. 109 urologists (31%), 69 GPs (23%) and 46 CGs (31%) completed the survey. CGs had the most accurate knowledge of hereditary PCa. All but 1 CG mentioned at least one inherited trait with PCa, compared to only 25% of urologists and 9% of GPs. CGs hardly ever counseled men about PCa testing. Most urologists and GPs discuss possible risks and benefits before testing for PCa with PSA. Remarkably, 35-40% of them do not take family history into consideration. Knowledge of urologists and GPs about heredity and PCa is suboptimal. Hence, PCa counseling might not be optimal for men with a positive family history. Multidisciplinary guidelines on this topic should be developed to optimize personalized counseling.
    Familial Cancer 12/2011; 11(2):195-200. · 1.94 Impact Factor
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    ABSTRACT: To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
    Nature Genetics 09/2011; 43(11):1098-103. · 35.21 Impact Factor
  • R.G.H.M. Cremers, L.A.L.M. Kiemeney, E.B. Cornel
    Tijdschrift voor Urologie. 05/2011; 1(3).
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    ABSTRACT: Goals of this study are to report the outcomes and tolerance of salvage radiotherapy (SRT) after prostatectomy, to identify risk factors for failure after SRT and to evaluate how these results compare with published results of immediate post-operative adjuvant radiotherapy (ART). Men receiving SRT for elevated PSA levels after radical prostatectomy (RP) were included. Biochemical progression-free survival (bPFS), overall survival (OS) and disease-specific survival (DSS) were estimated. Risk factors for biochemical failure and death were evaluated. Late toxicity and quality of life were evaluated. Secondary bPFS (defined as bPFS from prostatectomy until progression after radiotherapy) was calculated for high-risk patients (pT3 and/or positive surgical margins) in order to compare SRT outcomes with ART. 197 Men were included. Five-year bPFS after SRT was 59% (95% CI 49-69%). Five-year OS and DSS were 90% (85-96%) and 97% (93-100%), respectively. Capsular perforation (pT≥T3), negative surgical margins and serum PSA>1 ng/ml at the start of RT were significant predictors of lower bPFS. Patients without any negative factors had a 5-year bPFS of 89%. No severe late toxicity was reported. Five-year secondary bPFS for SRT in high-risk patients was 78% and comparable with published results for ART. Salvage radiotherapy for patients with organ-confined prostate cancer was effective and well tolerated. SRT outcomes were comparable with published ART results for high-risk patients. Initially monitoring serum PSA and considering early SRT for these patients are not harmful and might be a valuable alternative for immediate ART.
    Radiotherapy and Oncology 12/2010; 97(3):467-73. · 4.52 Impact Factor
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    ABSTRACT: Androgens are assumed to play a central role in the pathophysiology of both prostate cancer (PC) and androgenic alopecia (AA). A correlation between the two phenotypes may be relevant for identification of men at high risk of PC. We evaluated the association between AA at different ages and PC in a large case-control study. The case group comprised 938 PC patients recruited from a population-based cancer registry. The controls (n = 2160) were a random sample of the male general population. All subjects completed a questionnaire on risk factors for cancer, including questions on hair pattern at different ages using an adapted version of the Hamilton-Norwood scale, race and family history of PC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression. Baldness at early age appeared to be associated with a lower risk of PC (baldness at age 20: OR = 0.86; 95% CI 0.69-1.07 and baldness at age 40: OR = 0.81; 95% CI 0.70-0.96). Baldness at completion of the questionnaire was not associated with PC: OR = 1.10; 95% CI 0.89-1.34. An isolated 'frontal baldness' or 'vertex baldness' pattern was not significantly associated with PC at any age. Presence of a combined 'frontal and vertex' baldness pattern at age 40 was associated with a decreased risk of PC (OR = 0.62; 95% CI 0.45-0.86). There were no significant associations between AA and aggressive PC. We did not find consistent positive associations between AA at different ages and PC. Surprisingly, if anything, baldness at early age is inversely related to PC in this study. Androgenic alopecia is not useful as an indicator of men at high risk of PC.
    European journal of cancer (Oxford, England: 1990) 12/2010; 46(18):3294-9. · 4.12 Impact Factor
  • Maarten C Bosland, Ruben G H M Cremers, Lambertus A Kiemeney
    European Urology 10/2010; 58(4):631-2. · 10.48 Impact Factor
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    ABSTRACT: Prostate cancer occurrence and stage distribution changed dramatically during the end of the 20th century. This study aimed to quantify and explain trends in incidence, stage distribution, survival and mortality in the Netherlands between 1989 and 2006. Population-based data from the nationwide Netherlands Cancer Registry and Causes of Death Registry were used. Annual incidence and mortality rates were calculated and age-adjusted to the European Standard Population. Trends in rates were evaluated by age, clinical stage and differentiation grade. 120,965 men were newly diagnosed with prostate cancer between 1989 and 2006. Age-adjusted incidence rates increased from 63 to 104 per 100,000 person-years in this period. Two periods of increasing incidence rates could be distinguished with increases predominantly in cT2-tumours between 1989 and 1995 and predominantly in cT1c-tumours since 2001. cT4/N+/M+-tumour incidence rates decreased from 23 in 1993 to 18 in 2006. The trend towards earlier detection was accompanied by a lower mean age at diagnosis (from 74 in 1989 to 70 in 2006), increased frequency of treatment with curative intent and improved 5-year relative survival. Mortality rates decreased from 34 in 1996 to 26 in 2007. The increase of prostate cancer incidence in the early 1990s was probably caused by increased prostate cancer awareness combined with diagnostic improvements (transrectal ultrasound, (thin) needle biopsies), but not PSA testing. The subsequent peak since 2001 is probably attributable to PSA testing. The decline in prostate cancer mortality from 1996 onwards may be the consequence of increased detection of cT2-tumours between 1989 and 1995. Unfortunately, data on the use of PSA tests and other prostate cancer diagnostics to support these conclusions are lacking.
    European journal of cancer (Oxford, England: 1990) 07/2010; 46(11):2077-87. · 4.12 Impact Factor

Publication Stats

88 Citations
74.71 Total Impact Points

Institutions

  • 2010–2014
    • Radboud University Medical Centre (Radboudumc)
      • • Department for Health Evidence
      • • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
    • University of Illinois at Chicago
      • Department of Pathology (Chicago)
      Chicago, IL, United States