Molecular Grade (FGFR3/MIB-1) and EORTC Risk Scores Are Predictive in Primary Non–Muscle-Invasive Bladder Cancer

Rhijn, Bas W.G. van; Zuiverloon, Tahlita C.M.; Vis, André N.; Radvanyi, François; Leenders, Geert J.L.H. van; Ooms, Bert C.M.; Kirkels, Wim J.; Lockwood, Gina; Boevé, Egbert R.; Jöbsis, A. C.; Zwarthoff, Ellen C.; Kwast, Theodorus H. van der

doi:10.1016/j.eururo.2010.05.043

Cited by 172 publications

(101 citation statements)

References 19 publications

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“…In most previous approaches, different standards and cut-off points of Ki67 and VEGF were proposed to predict the cancer prognosis, which, however, failed to reach an agreement (Santos et al, 2003). Our study kept the threshold as Ki67 LI 25%, which was proposed by van Rhijn BW (van Rhijn et al, 2003;van Rhijn et al, 2010). For VEGF expression, Suguru Shirotake et al proposed that NMIBC with greater VEGF expression and stronger microvessel density (MVD) had an earlier recurrence and a significantly higher recurrence rate (Shirotake et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…It is an established independent predictor of recurrence and progression for many malignancies (Li et al, 2004;Viale et al, 2008). In previous studies, increased Ki67 expression was proven to be related to tumor grade, stage, recurrence, progression and the survival of bladder cancer (Margulis et al, 2006;Yurakh et al, 2006;Gonul et al, 2008;Margulis et al, 2009;van Rhijn et al, 2010). It is an independent risk factor for prognosis (Burger et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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A Novel Molecular Grading Model: Combination of Ki67 and VEGF in Predicting Tumor Recurrence and Progression in Non-invasive Urothelial Bladder Cancer

Chen

Deng²,

Xu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Purpose: To assess efficacy of Ki67 combined with VEGF as a molecular grading model to predict outcomes with non-muscle invasive bladder cancer (NMIBC). Materials: 72 NMIBC patients who underwent transurethral resection (TUR) followed by routine intravesical instillations were retrospectively analyzed in this study. Univariate and multivariate analyses were performed to confirm the prognostic values of the Ki67 labeling index (LI) and VEGF scoring for tumor recurrence and progression. Results: The novel molecular grading model for NMIBC contained three molecular grades including mG1 (Ki67 LI≤25%, VEGF scoring≤8), mG2 (Ki67 LI>25%, VEGF scoring ≤ 8; or Ki67 LI ≤ 25%, VEGF scoring > 8), and mG3 (Ki67 LI > 25%, VEGF scoring > 8), which can indicate favorable, intermediate and poor prognosis, respectively. Conclusions: The described novel molecular grading model utilizing Ki67 LI and VEGF scoring is helpful to effectively and accurately predict outcomes and optimize personal therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Novel Molecular Grading Model: Combination of Ki67 and VEGF in Predicting Tumor Recurrence and Progression in Non-invasive Urothelial Bladder Cancer

Chen

Deng²,

Xu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…The cutoff levels were 25% (Ki-67), 10% (P53) and 50% (P27). 12,15 We used immunohistochemical staining of whole slides for the Rotterdam cases and tissue microarray technology was used in Toronto.…”

Section: Immuno-histochemistrymentioning

confidence: 99%

“…10 Surprisingly, FGFR3 mutations were related to favorable bladder cancer with 84% of pTaG1 tumors having a mutation as compared with 7% of ZpT2G3 lesions. 11 In non-muscle invasive bladder cancer, FGFR3 mutations were associated with a low risk for progression [12][13][14][15] and genetically stable disease. 16,17 On the other hand, increased expression of the proliferation marker Ki-67, nuclear overexpression of P53 and decreased expression of the cell-cycle inhibitor P27 have been linked to higher grade and progressive non-muscle invasive bladder cancer.…”

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confidence: 99%

Molecular and clinical support for a four-tiered grading system for bladder cancer based on the WHO 1973 and 2004 classifications

et al. 2015

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Currently, the use of two classification systems for bladder cancer grade is advocated in clinical guidelines because the WHO2004 classification has not been sufficiently validated with biological markers and follow-up. The slides of 325 primary non-muscle invasive bladder cancers from three hospitals were reviewed by one uropathologist in two separate sessions for the WHO1973 (G1, G2 and G3) and 2004 (papillary urothelial neoplasm of low malignant potential (LMP), low-grade (LG) and high-grade (HG)) classifications. FGFR3 status was examined with PCR-SNaPshot analysis. Expression of Ki-67, P53 and P27 was analyzed by immunohistochemistry. Clinical recurrence and progression were determined. We performed validation and crossvalidation of the two systems for grade with molecular markers and clinical outcome. Multivariable analyses were done to predict prognosis and pT1 bladder cancer. Grade review resulted in 88 G1, 149 G2 and 88 G3 lesions (WHO1973) and 79 LMP, 101 LG and 145 HG lesions (WHO2004). Molecular validation of both grading systems showed that FGFR3 mutations were associated with lower grades whereas altered expression (Ki-67, P53 and P27) was found in higher grades. Clinical validation showed that the two classification systems were both significant predictors for progression but not for recurrence. Cross-validation of both WHO systems showed a significant stepwise increase in biological (molecular markers) and clinical (progression) potential along the line: G1-LG-G2-HG-G3. The LMP and G1 categories had a similar clinical and molecular profile. On the basis of molecular biology and multivariable clinical data, our results support a four-tiered grading system using the 1973 and 2004 WHO classifications with one low-grade (LMP/LG/G1) category that includes LMP, two intermediate grade (LG/G2 and HG/G2) categories and one high-grade (HG/G3) category.

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“…Although, high recurrence rates are observed, progression rates in patients with primary pTaG1/2 bladder cancer remain limited, ranging from 1% to6%. 3,4 Yet, due to the high mortality rates associated with muscle-invasive bladder cancer, a life-long followup by cystoscopy is required. Cystoscopy is an expensive and invasive procedure, causing pain and discomfort to the patient.…”

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confidence: 99%

Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer

et al. 2015

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The potential risk of recurrence and progression in patients with non-muscle-invasive bladder cancer necessitates followup by cystoscopy. The risk of progression to muscle-invasive bladder cancer is estimated based on the European Organisation of Research and Treatment of Cancer score, a combination of several clinicopathological variables. However, pathological assessment is not objective and reproducibility is insufficient. The use of molecular markers could contribute to the estimation of tumor aggressiveness. We recently demonstrated that methylation of GATA2, TBX2, TBX3, and ZIC4 genes could predict progression in Ta tumors. In this study, we aimed to validate the markers in a large patient set using DNA from formalin-fixed and paraffin-embedded tissue. PALGA: the Dutch Pathology Registry was used for patient selection. We included 192 patients with pTaG1/2 bladder cancer of whom 77 experienced progression. Methylation analysis was performed and log-rank analysis was used to calculate the predictive value of each methylation marker for developing progression over time. This analysis showed better progression-free survival in patients with low methylation rates compared with the patients with high methylation rates for all markers (Po0.001) during a followup of ten-years. The combined predictive effect of the methylation markers was analyzed with the Coxregression method. In this analysis, TBX2, TBX3, and ZIC4 were independent predictors of progression. On the basis of methylation status of TBX2 and TBX3, patients were divided into three new molecular grade groups. Survival analysis showed that only 8% of patients in the low molecular grade group progressed within 5 years. This was 29 and 63% for the intermediate-and high-molecular grade groups. In conclusion, this new moleculargrade based on the combination of TBX2 and TBX3 methylation is an excellent marker for predicting progression to muscle-invasive bladder cancer in patients with primary pTaG1/2 bladder cancer.

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Molecular Grade (FGFR3/MIB-1) and EORTC Risk Scores Are Predictive in Primary Non–Muscle-Invasive Bladder Cancer

Cited by 172 publications

References 19 publications

A Novel Molecular Grading Model: Combination of Ki67 and VEGF in Predicting Tumor Recurrence and Progression in Non-invasive Urothelial Bladder Cancer

A Novel Molecular Grading Model: Combination of Ki67 and VEGF in Predicting Tumor Recurrence and Progression in Non-invasive Urothelial Bladder Cancer

Molecular and clinical support for a four-tiered grading system for bladder cancer based on the WHO 1973 and 2004 classifications

Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer

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