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
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
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DOI：
10.1002/pbc.27052
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发表时间：
2018-07-01
影响因子：
3.2
通讯作者：
Burchill, Susan A.
中科院分区：
文献类型：
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作者：
Corrias, Maria V.;Parodi, Stefano;Burchill, Susan A.
本研究的目的是评估M期婴儿(确诊时12个月，MYCN扩增)和幼儿(12~18个月，任何MYCN状态)骨髓和外周血中神经母细胞瘤mRNAs水平是否可预测无事件生存(EFS)。结果骨髓酪氨酸羟基酶(TH)或成对类同源盒2b(PHOX2B)的水平与EFS的恶化有关；调整了年龄和MYCN状态的危险比分别为1.5和1.8。TH和PHOX2B在最高三胎中的表达预示着更糟糕的结局(p=0.015)，并发现20名(23%)婴儿/幼儿的5年EFS为20%(95%可信区间：4%-44%)。在调整了过度适应偏差(p=0.038)、年龄和近月营养不良状态后，预后意义仍然存在。在外周血中，最高三分位数的PHOX2B水平预测事件风险增加两倍(p=0.032)，并确定23名(34%)婴儿/幼儿五年EFS为29%(95%可信区间：12%-48%)。骨髓中TH和PHOX2B的联合检测及外周血中PHOX2B检测的时间依赖性分析证实了联合检测TH、PHOX2B和外周血PHOX2B的预后价值。结论确诊时骨髓TH和PHOX2B及外周血PHOX2B的高水平有助于早期发现一组高危婴幼儿神经母细胞瘤，可作为替代治疗的候选对象。与其他生物标记物的整合以及在其他国际试验中的验证是有必要的。
BackgroundThe 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).MethodsBone 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.ResultsBone 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.ConclusionsHigh 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.