Treatment of Anaplastic Histology Wilms' Tumor: Results From the Fifth National Wilms' Tumor Study

Dome, Jeffrey S.; Cotton, Cecilia A.; Perlman, Elizabeth J.; Breslow, Norman E.; Kalapurakal, John A.; Ritchey, Michael L.; Grundy, Paul E.; Malogolowkin, Marcio H.; Beckwith, J. Bruce; Shamberger, Robert C.; Haase, Gerald M.; Coppes, Max J.; Coccia, Peter F.; Kletzel, Morris; Weetman, Robert M.; Donaldson, Milton H.; Macklis, Roger M.; Green, Daniel M.

doi:10.1200/jco.2005.04.7852

Cited by 308 publications

(252 citation statements)

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“…Histological diagnosis requires an invasive biopsy, with risk of morbidity and sampling error in large heterogeneous lesions such as seen in the abdomen 3, 4. A conclusive diagnosis based on conventional imaging alone can be difficult, with similar morphological appearances of some childhood tumors 5…”

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Diffusion‐weighted MRI and intravoxel incoherent motion model for diagnosis of pediatric solid abdominal tumors

Meeus

Zarinabad

Manias

et al. 2017

Magnetic Resonance Imaging

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BackgroundPediatric retroperitoneal tumors in the renal bed are often large and heterogeneous, and their diagnosis based on conventional imaging alone is not possible. More advanced imaging methods, such as diffusion‐weighted (DW) MRI and the use of intravoxel incoherent motion (IVIM), have the potential to provide additional biomarkers that could facilitate their noninvasive diagnosis.PurposeTo assess the use of an IVIM model for diagnosis of childhood malignant abdominal tumors and discrimination of benign from malignant lesions.Study TypeRetrospective.PopulationForty‐two pediatric patients with abdominal lesions (n = 32 malignant, n = 10 benign), verified by histopathology.Field Strength/Sequence1.5T MRI system and a DW‐MRI sequence with six b‐values (0, 50, 100, 150, 600, 1000 s/mm2).AssessmentParameter maps of apparent diffusion coefficient (ADC), and IVIM maps of slow diffusion coefficient (D), fast diffusion coefficient (D*), and perfusion fraction (f) were computed using a segmented fitting model. Histograms were constructed for whole‐tumor regions of each parameter.Statistical TestsComparison of histogram parameters of and their diagnostic performance was determined using Kruskal–Wallis, Mann–Whitney U, and receiver‐operating characteristic (ROC) analysis.ResultsIVIM parameters D* and f were significantly higher in neuroblastoma compared to Wilms' tumors (P < 0.05). The ROC analysis showed that the best diagnostic performance was achieved with D* 90th percentile (area under the curve [AUC] = 0.935; P = 0.002; cutoff value = 32,376 × 10−6 mm2/s) and f mean values (AUC = 1.00; P < 0.001; cutoff value = 14.7) in discriminating between neuroblastoma (n = 11) and Wilms' tumors (n = 8). Discrimination between tumor types was not possible with IVIM D or ADC parameters. Malignant tumors revealed significantly lower ADC, D, and higher D* values than in benign lesions (all P < 0.05).Data ConclusionIVIM perfusion parameters could distinguish between malignant childhood tumor types, providing potential imaging biomarkers for their diagnosis. Level of Evidence: 4 Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2018;47:1475–1486.

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confidence: 99%

Diffusion‐weighted MRI and intravoxel incoherent motion model for diagnosis of pediatric solid abdominal tumors

Meeus

Zarinabad

Manias

et al. 2017

Magnetic Resonance Imaging

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“…1,2 Modern multimodal management can cure 95% of patients with WT with the most favorable risk profile [3][4][5][6][7] but at the cost of significant short-and long-term morbidity. 8 -11 In addition, there remains a persistent cohort of children who ultimately fail therapy and die.…”

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β-Catenin and K-RAS Synergize to Form Primitive Renal Epithelial Tumors with Features of Epithelial Wilms' Tumors

Clark

Polosukhina

Love

et al. 2011

The American Journal of Pathology

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Wilms' tumor (WT) is the most common childhood renal cancer. Although mutations in known tumorassociated genes (WT1, WTX , and CATNB) occur only in a third of tumors, many tumors show evidence of activated ␤-catenin-dependent Wnt signaling, but the molecular mechanism by which this occurs is unknown. A key obstacle to understanding the pathogenesis of WT is the paucity of mouse models that recapitulate its features in humans. Herein, we describe a transgenic mouse model of primitive renal epithelial neoplasms that have high penetrance and mimic the epithelial component of human WT. Introduction of a stabilizing ␤-catenin mutation restricted to the kidney is sufficient to induce primitive renal epithelial tumors; however, when compounded with activation of K-RAS, the mice develop large, bilateral, Wilms' tumor (WT) is an embryonal tumor of the kidney that is the most common childhood renal cancer and the fourth most common childhood malignancy overall. 1,2Modern multimodal management can cure 95% of patients with WT with the most favorable risk profile 3-7 but at the cost of significant short-and long-term morbidity. -11In addition, there remains a persistent cohort of children who ultimately fail therapy and die.3 Consequently, the main research priorities for WT are to lower the toxicity while maintaining efficacy of existing therapy for lowerrisk patients and to develop novel therapeutics for higherrisk patients. Achieving these goals depends on understanding the mechanisms underlying WT oncogenesis and progression.WTs are triphasic, embryonic tumors that classically have varying amounts of blastemal elements, primitive mesenchymal stroma, and primitive epithelia. They are generally thought to arise from nephrogenic rests (ie, embryonic tissue) derived from the metanephric mesenchyme during renal development. The genetic aberrations underlying this process are known to be heterogeneous 12 and can include inactivating mutations of Wilms' tumor 1 gene (WT1), 13,14 Wilms' tumor gene found on chromosome X (WTX), [15][16][17] and stabilizing/activating mutations of ␤-catenin (CTNNB1). 18,19 The precise mechaSupported in part by NIH grants K08 CA113452 (P.E.C.), DK065123 (R.Z.), DK075594 (R.Z.), DK65123 (R.Z.), and P30 DK079341 (P.E.C. and R.Z.); an American Heart Association Established Investigator Award (R.Z.); and a Merit Award from the Department of Veterans Affairs (R.Z.).Accepted for publication August 10, 2011. CME Disclosure: None of the authors disclosed any relevant financial relationships.Address reprint requests to Peter E. Clark, M.D., Associate Professor Urologic Surgery, Vanderbilt University Medical Center, A-1302 Medical Center North, Nashville, TN 37232-2765. E-mail: peter.clark@ vanderbilt.edu.

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“…Loss of heterozygosity for 1q and 16q have also been suggested as adverse prognostic factors (11). Moreover, poor outcome and diffuse anaplasia have been associated with atypical mitoses and aneuploidy/tetraploidy at flow cytometry (4,12,13). The criteria for anaplasia include bizarre, often multipolar, mitoses and enlarged hyperchromatic nuclei.…”

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Defective Chromosome Segregation and Telomere Dysfunction in Aggressive Wilms' Tumors

Stewénius¹,

Jin²,

Øra

et al. 2007

Clinical Cancer Research

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Purpose: In many childhood neoplasms, prognostic subgroups have been defined based on specific chromosome changes. In Wilms' tumor (WT), such subclassification has been hampered by the diverse and relatively unspecific pattern of chromosomal imbalances present in these tumors. Unspecific patterns of cytogenetic imbalances in tumors are often caused by mitotic segregation errors due to short dysfunctional telomeres. As an alternative to cytogenetic classification, we therefore have evaluated whether the rate of telomere-dependent chromosomal instability could influence the clinical course in WT patients. Experimental Design: Telomere function and mitotic segregation errors were assessed in 12 cultured tumors and in tumor tissue sections from 41WT patients. Results: Abnormal telomere shortening was found in cultured cells and in tissue sections from highly aggressive tumors. In vitro, dysfunctional telomeres were associated to specific cell division abnormalities, including anaphase bridges and multipolar mitoses. Assessment of mitotic figures in tissue sections revealed that anaphase bridges and multipolar mitoses were predominantly, but not exclusively, present in high-risk tumors and were predictors of poor event-free and overall survival. Conclusions: Telomere-dependent mitotic instability is present in a subgroup of WT, predominately consisting of high-risk tumors.

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Treatment of Anaplastic Histology Wilms' Tumor: Results From the Fifth National Wilms' Tumor Study

Abstract: The prognosis for patients with stage I AH is worse than that for patients with stage I FH. Novel treatment strategies are needed to improve outcomes for patients with AH, especially those with stage III to V disease.

Cited by 308 publications

References 20 publications

Diffusion‐weighted MRI and intravoxel incoherent motion model for diagnosis of pediatric solid abdominal tumors

Diffusion‐weighted MRI and intravoxel incoherent motion model for diagnosis of pediatric solid abdominal tumors

β-Catenin and K-RAS Synergize to Form Primitive Renal Epithelial Tumors with Features of Epithelial Wilms' Tumors

Defective Chromosome Segregation and Telomere Dysfunction in Aggressive Wilms' Tumors

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