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The Hague, Netherlands

van Rhijn B.W.G.,Erasmus University Rotterdam | van Rhijn B.W.G.,A+ Network | van Leenders G.J.L.H.,Erasmus University Rotterdam | Ooms B.C.M.,Haaglanden MC | And 6 more authors.
European Urology | Year: 2010

Background: A new grading system for bladder cancer (BCa) was adopted in 2004 to reduce observer variability and provide better prognostic information. Objective: We compared the World Health Organization (WHO) 1973 and 2004 systems for observer variability and prognosis. Design, setting, and participants: Slides of 173 primary non-muscle-invasive BCa were reviewed two times by four pathologists. Measurements: Intra- and interobserver variability were assessed using κ statistics. We determined the mean grade (eg, G1/low malignant potential is 1 grade point, G2/low grade is 2 grade points) of the pathologists per grading cycle. Kaplan-Meier analyses were applied for prediction of recurrence and progression. Results and limitations: For WHO 2004 and 1973 grading, the agreement between the pathologists was 39-74% (κ: 0.14-0.58) and 39-64% (κ: 0.15-0.41), respectively. The intraobserver agreement varied from 71% to 88% (κ: 0.55-0.81). The mean grade of a pathologist was constant (difference below 0.1 grade point) irrespective of the grading system. Conversely, mean-grade differences among the pathologists were high, up to 0.7 grade point. The mean grades for the WHO 2004 system were 0.3-0.5 grade point higher than those of WHO 1973. Mean grade distinguished low and high graders among the pathologists and was strongly linked with risk of progression in each grade category. Conclusions: The variation in mean grade among individual pathologists exceeded the grade shift caused by WHO 2004 grading. Knowledge of the pathologist's mean grade allows a better assessment of the prognostic value of grading. Mean grade has the potential to become a tool for quality assurance in pathology. © 2009 European Association of Urology.

Van Rhijn B.W.G.,Erasmus University Rotterdam | Van Rhijn B.W.G.,University of Toronto | Zuiverloon T.C.M.,Erasmus University Rotterdam | Vis A.N.,Erasmus University Rotterdam | And 10 more authors.
European Urology | Year: 2010

Background: The European Organization for Research and Treatment of Cancer (EORTC) risk scores are not validated in an independent patient population. Molecular grade (mG) based on fibroblast growth factor receptor 3 (FGFR3) gene mutation status and MIB-1 expression was proposed as an alternative to pathologic grade in bladder cancer (BCa) [1]. Objective: To validate the EORTC risk score and to determine its relation to mG in a series with long-term follow-up as well as to determine reproducibility of pathologic grade and mG. Design, setting, and participants: In this multicenter study, we included 230 patients with primary non-muscle-invasive BCa (NMIBC). Measurements: Four uropathologists reviewed the slides. FGFR3 mutation status was examined by two assays. MIB-1 was assessed by immunohistochemistry. The EORTC risk scores for recurrence and progression were determined. Multivariable analyses were used to find prognostic factors. Results and limitations: Median follow-up was 8.62 yr (interquartile range: 6.6-11.8). FGFR3 mutations were significantly related to favorable disease parameters, whereas altered MIB-1 was frequently seen with pT1, high grade, and high EORTC risk scores. EORTC risk scores were significant in multivariable analyses for recurrence and progression. In multivariable analyses for progression and disease-specific survival, the mG had independent significance. The addition of mG to the multivariable model for progression increased the predictive accuracy from 74.9% to 81.7% (p < 0.001; Mantel-Haenszel test). The mG (89%) was more reproducible than the pathologic grade (41-74%). Conclusions: We validated the EORTC risk scores for primary NMIBC in a clinical and biomarker setting. Next to EORTC risk score, mG proved highly reproducible and predictive. Our long-term results justify an independent prospective analysis of mG and EORTC risk scores. © 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Van Den Bent M.J.,Erasmus MC | Gao Y.,Erasmus MC | Kerkhof M.,Haaglanden MC | Kros J.M.,Erasmus University Rotterdam | And 7 more authors.
Neuro-Oncology | Year: 2015

The efficacy of novel targeted therapies is often tested at the time of tumor recurrence. However, for glioblastoma (GBM) patients, surgical resections at recurrence are performed only in a minority of patients; therefore, molecular data are predominantly derived from the initial tumor. Molecular data of the initial tumor for patient selection into personalized medicine trials can therefore be used only when the specific genetic change is retained in the recurrent tumor. Methods In this study we determined whether EGFR amplification and expression of the most common mutation in GBMs (EGFRvIII) is retained at tumor recurrence. Because retention of genetic changes may be dependent on the initial treatment, we only used a cohort of GBM samples that were uniformly treated according to the current standard of care (ie, chemo-irradiation with temozolomide). Results Our data show that, in spite of some quantitative differences, the EGFR amplification status remains stable in the majority (84%) of tumors evaluated. EGFRvIII expression remained similar in 79% of GBMs. However, within the tumors expressing EGFRvIII at initial diagnosis, approximately one-half lose their EGFRvIII expression at tumor recurrence. Conclusions The relative stability of EGFR amplification indicates that molecular data obtained in the primary tumor can be used to predict the EGFR status of the recurrent tumor, but care should be taken in extrapolating EGFRvIII expression from the primary tumor, particularly when expressed at first diagnosis. © 2015 The Author(s).

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