Article

The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report

University of Cologne, Köln, North Rhine-Westphalia, Germany
Journal of Clinical Oncology (Impact Factor: 18.43). 01/2009; 27(2):289-97. DOI: 10.1200/JCO.2008.16.6785
Source: PubMed

ABSTRACT Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification.
The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Children's Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors.
Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to < or = 85%, > or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively.
By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.

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    • "2012). Features like age of the patient at diagnosis, stage of the disease, and nonrandom chromosomal aberrations are well-established parameters for stratification of risk and treatment as well as for predicting the disease outcome in patients (Cohn et al., 2009; Monclair et al., 2009). Neuroblastoma patients with nonrandom chromosomal alterations MNA (MYCN amplification )/1p (shorter arm of the chromosome 1) deletion/17q (longer arm of the chromosome 17) gain (seen in 20% of patients) or 11q deletion (11q-) /17q gain (seen in 30% of patients) are often associated with high-risk tumors and an unfavorable outcome. "
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    ABSTRACT: Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cancer Cell 11/2014; 26(5):722-737. DOI:10.1016/j.ccell.2014.09.014 · 23.89 Impact Factor
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    • "Different studies have shown that the genomic changes are frequently associated with certain clinical sub-types of neuroblastoma and suggest that pan-genomic data based on microarray techniques will improve neuroblastoma risk estimation (Ambros et al., 2009; Bilke et al., 2005; Coco et al., 2012; George et al., 2007; Schleiermacher et al., 2011; Spitz et al., 2006). Based on the statistical evaluation of 8.800 neuroblastoma tumors it became clear that genomic information helps to refine current risk classification systems (Cohn et al., 2009). Recent publications demonstrate that besides SCAs, spanning a few Mb in size up to a whole chromosomal arm, some other aberrations frequently can be found in different tumor entities. "
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    ABSTRACT: Neuroblastoma is the most common extra-cranial solid tumor in childhood. Presence of disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and at relapse is a common event in stage M neuroblastomas. Although the clinical heterogeneity of disseminated neuroblastomas is frequently associated with genomic diversity, so far, only little information exists about the genomic status of DTCs. This lack of knowledge is mainly due to the varying amount of BM infiltrating tumor cells, which is usually below 30% even at diagnosis thereby hampering systematic analyses. Thus, a valuable chance to analyze metastatic and relapse clones is, so far, completely unexploited. In this study, we show that the enrichment of tumor cells in fresh or DMSO frozen BM samples with a minimum of 0.05% or 0.1% infiltration rate, respectively, by applying magnetic bead-based technique increased the DTC content to a sufficient level to allow SNP array analyses in 49 out of 69 samples. In addition, we successfully used non-enriched BM samples with ≥30% DTCs including non-stained and immunostained cytospin and BM smear slides for SNP array analyses in 44 cases. We analyzed the genomic profile of DTCs by an ultra-high density SNP array technique with highest performance detecting all segmental chromosomal aberrations, amplified regions, acquired loss of heterozygosity events and minor aberrations affecting single genes or parts thereof.
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    • "Data were collected from the database using a standardized form. Additional information concerning the international neuroblastoma risk group (INRG) staging [5] and classification [6] was extracted directly from individual patient charts. To accomplish this, histologic category, grade of tumor differentiation, MYCN, 11q aberration, and ploidy information were obtained. "
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