Virginie F Viprey1, Walter M Gregory, Maria V Corrias, Andrei Tchirkov, Katrien Swerts, Ales Vicha, Sandro Dallorso, Penelope Brock, Roberto Luksch, Dominique Valteau-Couanet, Vassilios Papadakis, Genevieve Laureys, Andrew D Pearson, Ruth Ladenstein, Susan A Burchill. 1. Virginie F. Viprey and Susan A. Burchill, Leeds Institute of Cancer and Pathology; Walter M. Gregory, Clinical Trials Research Unit, University of Leeds, Leeds; Penelope Brock, Great Ormond Street Hospital, London; Andrew D. Pearson, Institute of Cancer Research/Royal Marsden National Health Service Foundation Trust, Sutton, United Kingdom; Maria V. Corrias and Sandro Dallorso, Gaslini Institute, Genoa; Roberto Luksch, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milano, Italy; Andrei Tchirkov, Centre Hospitalier Universitaire Clermont-Ferrand and Clermont Université, Université d'Auvergne, Clermont-Ferrand; Dominique Valteau-Couanet, Institut Gustave Roussy, Villejuif, France; Katrien Swerts and Genevieve Laureys, University Hospital Ghent, Ghent, Belgium; Ales Vicha, Charles University and University Hospital Motol, Prague, Czech Republic; Vassilios Papadakis, Agia Sofia Children's Hospital, Athens, Greece; and Ruth Ladenstein, Children's Cancer Research Institute/St Anna Children's Hospital, Vienna, Austria.
Abstract
PURPOSE: To evaluate the hypothesis that detection of neuroblastoma mRNAs by reverse transcriptase quantitative polymerase chain reaction (RTqPCR) in peripheral blood (PB) and bone marrow aspirates (BM) from children with stage 4 neuroblastoma are clinically useful biomarkers of risk. METHODS: RTqPCR for paired-like homeobox 2b (PHOX2B), tyrosine hydroxylase (TH), and doublecortin (DCX) mRNA in PB and BM of children enrolled onto the High-Risk Neuroblastoma Trial-1 of the European Society of Pediatric Oncology Neuroblastoma Group (HR-NBL1/SIOPEN) was performed at diagnosis and after induction therapy. RESULTS: High levels of TH, PHOX2B, or DCX mRNA in PB or BM at diagnosis strongly predicted for worse event-free survival (EFS) and overall survival (OS) in a cohort of 290 children. After induction therapy, high levels of these mRNAs predicted worse EFS and OS in BM but not in PB. Combinations of mRNAs in BM did not add to the predictive power of any single mRNA. However, in the original (n = 182) and validation (n = 137) PB cohorts, high TH (log10TH > 0.8) or high PHOX2B (log10PHOX2B > 0.28) identify 19% of children as ultrahigh risk, with 5-year EFS and OS rates of 0%; OS rate was 25% (95% CI, 16% to 36%) and EFS rate was 38% (95% CI, 28% to 49%) in the remaining children. The magnitude of reduction in mRNA level between diagnosis and postinduction therapy in BM or PB was not of additional predictive value. CONCLUSION: High levels of TH and PHOX2B mRNA in PB at diagnosis objectively identify children with ultrahigh-risk disease who may benefit from novel treatment approaches. The level of TH, PHOX2B, and DCX mRNA in BM and/or PB at diagnosis might contribute to an algorithm to improve stratification of children for treatment.
PURPOSE: To evaluate the hypothesis that detection of neuroblastoma mRNAs by reverse transcriptase quantitative polymerase chain reaction (RTqPCR) in peripheral blood (PB) and bone marrow aspirates (BM) from children with stage 4 neuroblastoma are clinically useful biomarkers of risk. METHODS: RTqPCR for paired-like homeobox 2b (PHOX2B), tyrosine hydroxylase (TH), and doublecortin (DCX) mRNA in PB and BM of children enrolled onto the High-Risk Neuroblastoma Trial-1 of the European Society of Pediatric Oncology Neuroblastoma Group (HR-NBL1/SIOPEN) was performed at diagnosis and after induction therapy. RESULTS: High levels of TH, PHOX2B, or DCX mRNA in PB or BM at diagnosis strongly predicted for worse event-free survival (EFS) and overall survival (OS) in a cohort of 290 children. After induction therapy, high levels of these mRNAs predicted worse EFS and OS in BM but not in PB. Combinations of mRNAs in BM did not add to the predictive power of any single mRNA. However, in the original (n = 182) and validation (n = 137) PB cohorts, high TH (log10TH > 0.8) or high PHOX2B (log10PHOX2B > 0.28) identify 19% of children as ultrahigh risk, with 5-year EFS and OS rates of 0%; OS rate was 25% (95% CI, 16% to 36%) and EFS rate was 38% (95% CI, 28% to 49%) in the remaining children. The magnitude of reduction in mRNA level between diagnosis and postinduction therapy in BM or PB was not of additional predictive value. CONCLUSION: High levels of TH and PHOX2B mRNA in PB at diagnosis objectively identify children with ultrahigh-risk disease who may benefit from novel treatment approaches. The level of TH, PHOX2B, and DCX mRNA in BM and/or PB at diagnosis might contribute to an algorithm to improve stratification of children for treatment.
Authors: Yania Yáñez; David Hervás; Elena Grau; Silvestre Oltra; Gema Pérez; Sarai Palanca; Mar Bermúdez; Catalina Márquez; Adela Cañete; Victoria Castel Journal: J Cancer Res Clin Oncol Date: 2015-10-24 Impact factor: 4.553
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Authors: Julie R Park; Rochelle Bagatell; Susan L Cohn; Andrew D Pearson; Judith G Villablanca; Frank Berthold; Susan Burchill; Ariane Boubaker; Kieran McHugh; Jed G Nuchtern; Wendy B London; Nita L Seibel; O Wolf Lindwasser; John M Maris; Penelope Brock; Gudrun Schleiermacher; Ruth Ladenstein; Katherine K Matthay; Dominique Valteau-Couanet Journal: J Clin Oncol Date: 2017-05-04 Impact factor: 44.544
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