Event-free survival of infants and toddlers enrolled in the HR-NBL-1/SIOPEN trial is associated with the level of neuroblastoma mRNAs at diagnosis

Maria V Corrias, Stefano Parodi, Andrei Tchirkov, Tim Lammens, Ales Vicha, Claudia Pasqualini, Catarina Träger, Yania Yáñez, Sandro Dallorso, Luigi Varesio, Roberto Luksch, Genevieve Laureys, Dominique Valteau-Couanet, Adela Canete, Ulrike Pöetschger, Ruth Ladenstein, Susan A Burchill

Research output: Contribution to journalArticle

Abstract

BACKGROUND: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS).

METHODS: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgene™ blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures.

RESULTS: Bone marrow tyrosine hydroxylase (TH) or paired-like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23%) infants/toddlers with 5-year EFS of 20% (95%CI: 4%-44%). Prognostic significance was maintained after adjusting for over-fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two-fold increased risk of an event (p = 0.032), and identified 23 (34%) infants/toddlers with 5-year EFS of 29% (95%CI: 12%-48%). Time-dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow-up.

CONCLUSIONS: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high-risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted.

Original languageEnglish
Pages (from-to)e27052
JournalPediatric Blood and Cancer
Volume65
Issue number7
DOIs
Publication statusPublished - Jul 2018

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Homeobox Genes
Neuroblastoma
Disease-Free Survival
Tyrosine 3-Monooxygenase
Messenger RNA
Bone Marrow
Social Identification
ROC Curve
Reverse Transcription
Biomarkers
RNA
Polymerase Chain Reaction

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Event-free survival of infants and toddlers enrolled in the HR-NBL-1/SIOPEN trial is associated with the level of neuroblastoma mRNAs at diagnosis. / Corrias, Maria V; Parodi, Stefano; Tchirkov, Andrei; Lammens, Tim; Vicha, Ales; Pasqualini, Claudia; Träger, Catarina; Yáñez, Yania; Dallorso, Sandro; Varesio, Luigi; Luksch, Roberto; Laureys, Genevieve; Valteau-Couanet, Dominique; Canete, Adela; Pöetschger, Ulrike; Ladenstein, Ruth; Burchill, Susan A.

In: Pediatric Blood and Cancer, Vol. 65, No. 7, 07.2018, p. e27052.

Research output: Contribution to journalArticle

Corrias, MV, Parodi, S, Tchirkov, A, Lammens, T, Vicha, A, Pasqualini, C, Träger, C, Yáñez, Y, Dallorso, S, Varesio, L, Luksch, R, Laureys, G, Valteau-Couanet, D, Canete, A, Pöetschger, U, Ladenstein, R & Burchill, SA 2018, 'Event-free survival of infants and toddlers enrolled in the HR-NBL-1/SIOPEN trial is associated with the level of neuroblastoma mRNAs at diagnosis', Pediatric Blood and Cancer, vol. 65, no. 7, pp. e27052. https://doi.org/10.1002/pbc.27052
Corrias, Maria V ; Parodi, Stefano ; Tchirkov, Andrei ; Lammens, Tim ; Vicha, Ales ; Pasqualini, Claudia ; Träger, Catarina ; Yáñez, Yania ; Dallorso, Sandro ; Varesio, Luigi ; Luksch, Roberto ; Laureys, Genevieve ; Valteau-Couanet, Dominique ; Canete, Adela ; Pöetschger, Ulrike ; Ladenstein, Ruth ; Burchill, Susan A. / Event-free survival of infants and toddlers enrolled in the HR-NBL-1/SIOPEN trial is associated with the level of neuroblastoma mRNAs at diagnosis. In: Pediatric Blood and Cancer. 2018 ; Vol. 65, No. 7. pp. e27052.
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abstract = "BACKGROUND: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS).METHODS: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgene™ blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures.RESULTS: Bone marrow tyrosine hydroxylase (TH) or paired-like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23{\%}) infants/toddlers with 5-year EFS of 20{\%} (95{\%}CI: 4{\%}-44{\%}). Prognostic significance was maintained after adjusting for over-fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two-fold increased risk of an event (p = 0.032), and identified 23 (34{\%}) infants/toddlers with 5-year EFS of 29{\%} (95{\%}CI: 12{\%}-48{\%}). Time-dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow-up.CONCLUSIONS: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high-risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted.",
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T1 - Event-free survival of infants and toddlers enrolled in the HR-NBL-1/SIOPEN trial is associated with the level of neuroblastoma mRNAs at diagnosis

AU - Corrias, Maria V

AU - Parodi, Stefano

AU - Tchirkov, Andrei

AU - Lammens, Tim

AU - Vicha, Ales

AU - Pasqualini, Claudia

AU - Träger, Catarina

AU - Yáñez, Yania

AU - Dallorso, Sandro

AU - Varesio, Luigi

AU - Luksch, Roberto

AU - Laureys, Genevieve

AU - Valteau-Couanet, Dominique

AU - Canete, Adela

AU - Pöetschger, Ulrike

AU - Ladenstein, Ruth

AU - Burchill, Susan A

N1 - © 2018 Wiley Periodicals, Inc.

PY - 2018/7

Y1 - 2018/7

N2 - BACKGROUND: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS).METHODS: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgene™ blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures.RESULTS: Bone marrow tyrosine hydroxylase (TH) or paired-like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23%) infants/toddlers with 5-year EFS of 20% (95%CI: 4%-44%). Prognostic significance was maintained after adjusting for over-fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two-fold increased risk of an event (p = 0.032), and identified 23 (34%) infants/toddlers with 5-year EFS of 29% (95%CI: 12%-48%). Time-dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow-up.CONCLUSIONS: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high-risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted.

AB - BACKGROUND: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS).METHODS: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgene™ blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures.RESULTS: Bone marrow tyrosine hydroxylase (TH) or paired-like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23%) infants/toddlers with 5-year EFS of 20% (95%CI: 4%-44%). Prognostic significance was maintained after adjusting for over-fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two-fold increased risk of an event (p = 0.032), and identified 23 (34%) infants/toddlers with 5-year EFS of 29% (95%CI: 12%-48%). Time-dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow-up.CONCLUSIONS: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high-risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted.

U2 - 10.1002/pbc.27052

DO - 10.1002/pbc.27052

M3 - Article

C2 - 29603574

VL - 65

SP - e27052

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 7

ER -