Unit of Experimental Therapy in Oncology, Istituto Giannina Gaslini, Genoa, Italy.
CHU Clermont-Ferrand, Service de Cytogénétique Médicale and Université Clermont Auvergne, Clermont-Ferrand, France.
Pediatr Blood Cancer. 2018 Jul;65(7):e27052. doi: 10.1002/pbc.27052. Epub 2018 Mar 30.
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).
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.
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.
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.
本研究旨在评估骨髓和外周血中神经母细胞瘤 mRNA 水平是否可预测诊断为 M 期婴儿（≤12 个月龄，MYCN 扩增）和幼儿（12-18 个月，任何 MYCN 状态）的事件无进展生存（EFS）。
欧洲高危神经母细胞瘤试验中入组的 97 例婴儿/幼儿于诊断时采集骨髓抽吸物和外周血样，置于 PAXgene 血 RNA 管中。采用逆转录定量聚合酶链反应（qPCR）按标准程序进行分析。
骨髓酪氨酸羟化酶（TH）或配对样同源框 2b（PHOX2B）水平处于最高三分位的患者 EFS 较差；经年龄和 MYCN 状态调整的风险比分别为 1.5 和 1.8。TH 和 PHOX2B 同时处于最高三分位预示更差的结局（p=0.015），并确定了 20 例（23%）患儿 5 年 EFS 为 20%（95%CI：4%-44%）。经过度拟合偏倚校正后（p=0.038），预后意义仍保持不变，且校正了年龄和 MYCN 状态。在外周血中，最高三分位的 PHOX2B 水平预示事件风险增加两倍（p=0.032），并确定了 23 例（34%）患儿 5 年 EFS 为 29%（95%CI：12%-48%）。时间依赖性受试者工作特征分析证实了骨髓中 TH 和 PHOX2B 联合及外周血中 PHOX2B 在随访第一年的预后价值。
高骨髓 TH 和 PHOX2B 及外周血 PHOX2B 水平可在诊断时早期识别出一组高危神经母细胞瘤婴儿和幼儿，他们可能是替代治疗的候选者。需要与其他生物标志物整合，并在其他国际试验中验证。
