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Background <p>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.</p> Methods <p>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.</p> Results <p>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 (<i>n</i> = 96) or results were inconclusive (all techniques <i>n</i> = 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.</p> Conclusions <p>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.</p>

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Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月2日

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  • 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

摘要

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.