多模态骨髓分析对高危神经母细胞瘤微小残留病和免疫治疗靶点的敏感检测——一项多中心研究

IF 12.8 1区 医学 Q1 ONCOLOGY
Nina U Gelineau, Eva Bozsaky, Lieke M J van Zogchel, Fikret Rifatbegovic, Daria Lazic, Andrea Ziegler, Ahmad Javadi, Lily Zappeij-Kannegieter, Ulrike Pötschger, Marta Fiocco, Peter F Ambros, Inge M Ambros, Bernd Bodenmiller, Ellen C van der Schoot, Ruth Ladenstein, Marie Bernkopf, Godelieve A M Tytgat, Sabine Taschner-Mandl
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引用次数: 0

摘要

背景:肿瘤细胞骨髓播散在包括神经母细胞瘤在内的各种癌症中很常见,与预后不良相关,因此需要骨髓微小残留病(MRD)的敏感检测方法,并为治疗分层提供生物标志物检测。目前的标准诊断,包括骨髓抽吸和环钻活检的细胞形态学和组织学评估,缺乏敏感性,导致许多患者未检测到MRD,并且不允许分子生物标志物评估。方法:本研究评估了来自两个中心的108名高危神经母细胞瘤患者的509份骨髓标本的先进多模态高灵敏度MRD检测技术。我们采用自动免疫荧光加间期荧光原位杂交(AIPF)和逆转录酶定量聚合酶链反应(RT-qPCR)面板来定量弥散性肿瘤细胞(dtc)、二联神经节脂苷2 (GD2)和CD56/神经细胞粘附分子(NCAM)水平,以及肾上腺素能(ADRN)和间充质(MES)表型mRNA标志物。结果:与标准护理方法相比,这种多模态分析显著提高了MRD检测;RT-qPCR-ADRN、AIPF和CM/组织学检测结果为395份,223份结果一致(64份阳性,159份阴性)。114个样品没有产生结果,因为没有制备细胞自旋(n = 96)或结果不确定(所有技术n = 18)。AIPF和RT-qPCR在检测MRD、表征ADRN-和mes表型以及GD2免疫治疗靶点方面具有互补性。RT-qPCR-ADRN单独检测到的肿瘤细胞负荷低。诊断时高DTC浸润显示双侧骨髓疾病,而MRD通常只涉及一侧骨髓疾病。RT-qPCR-MES,尽管敏感性较低,但发现了37例额外的病例,并显示化疗后MES标志物的清除延迟,复发前增加。结论:我们的研究结果表明,在国际多中心环境下,将高灵敏度技术与标准护理评估相结合是可行的。先进的多模态MRD检测,监测表型开关和评估免疫治疗靶点对于改善神经母细胞瘤和其他癌症患者的预后至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma - a multi-center study.

Background: Bone marrow dissemination of tumor cells, common in various cancers, including neuroblastoma, is associated with poor outcome, necessitating sensitive detection methods for bone marrow minimal residual disease (MRD) and offer detection of biomarkers for therapy stratification. Current standard-of-care diagnostics, involving cytomorphological and histological assessment of bone marrow aspirates and trephine biopsies, lack sensitivity, leading to undetected MRD in many patients, and do not allow molecular biomarker assessment.

Methods: This study evaluates advanced multi-modal high-sensitivity MRD detection techniques in 509 bone marrow specimens from 108 high-risk neuroblastoma patients across two centers. We employed automatic immunofluorescence plus interphase fluorescence in situ hybridization (AIPF) and reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) panels to quantify disseminated tumor cells (DTCs), disialoganglioside 2 (GD2) and CD56/Neural cell adhesion molecule (NCAM) levels, and adrenergic (ADRN) and mesenchymal (MES)-phenotype mRNA markers.

Results: This multi-modal analysis significantly improved MRD detection compared to standard-of-care methods; 395 samples yielded results for RT-qPCR-ADRN, AIPF and CM/histology and 223 showed concordant results (64 positive, 159 negative). 114 samples did not produce results as either no cytospins were prepared (n = 96) or results were inconclusive (all techniques n = 18). AIPF and RT-qPCR complemented each other in detecting MRD and characterizing ADRN- and MES-phenotypes and GD2 immunotherapy target. RT-qPCR-ADRN alone frequently detected low tumor cell burden. High DTC infiltration at diagnosis showed bilateral bone marrow disease, whereas MRD settings often involved only one side. RT-qPCR-MES, despite lower sensitivity, identified 37 additional cases and showed delayed clearance of MES markers post-chemotherapy, with increases prior to relapse.

Conclusions: Our findings demonstrate the feasibility of integrating high-sensitivity techniques with standard-of-care assessments in an international multicenter setting. Advanced multi-modal MRD detection, monitoring phenotype switches and assessing immunotherapy targets are crucial for improving patient outcomes in neuroblastoma and other cancers.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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