BACKGROUND Predictive preclinical models play an important role in the assessment of new treatment strategies and as avatar models for personalised medicine; however, reliable and timely model generation is challenging. We investigated the feasibility of establishing patient-derived xenograft (PDX) models of high-risk neuroblastoma from a range of tumour-bearing patient materials and assessed approaches to improve engraftment efficiency. METHODS PDX model development was attempted in NSG mice by using tumour materials from 12 patients, including primary and metastatic solid tumour samples, bone marrow, pleural fluid and residual cells from cytogenetic analysis. Subcutaneous, intramuscular and orthotopic engraftment were directly compared for three patients. RESULTS PDX models were established for 44% (4/9) of patients at diagnosis and 100% (5/5) at relapse. In one case, attempted engraftment from pleural fluid resulted in an EBV-associated atypical lymphoid proliferation. Xenogeneic graft versus host disease was observed with attempted engraftment from lymph node and bone marrow tumour samples but could be prevented by T-cell depletion. Orthotopic engraftment was more efficient than subcutaneous or intramuscular engraftment. CONCLUSIONS High-risk neuroblastoma PDX models can be reliably established from diverse sample types. Orthotopic implantation allows more rapid model development, increasing the likelihood of developing an avatar model within a clinically useful timeframe.

中文翻译：

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加快开发高风险神经母细胞瘤患者源性异种移植模型，以进行临床前测试和个性化治疗。

背景技术预测的临床前模型在评估新的治疗策略和作为个性化医学的化身模型中起着重要的作用。但是，可靠，及时的模型生成具有挑战性。我们调查了从一系列带有肿瘤的患者材料中建立高危神经母细胞瘤患者源性异种移植（PDX）模型的可行性，并评估了提高移植效率的方法。方法使用12例患者的肿瘤材料，包括原发性和转移性实体瘤样品，骨髓，胸水和细胞遗传学分析的残留细胞，尝试在NSG小鼠中开发PDX模型。直接比较了三名患者的皮下，肌肉内和原位植入。结果为诊断时44％（4/9）的患者和复发时100％（5/5）的患者建立了PDX模型。在一种情况下，尝试从胸膜液植入会导致EBV相关的非典型淋巴样增生。尝试从淋巴结和骨髓肿瘤样品中植入，观察到异种移植物抗宿主疾病，但可以通过T细胞清除来预防。原位植入比皮下或肌肉内植入更有效。结论高可靠的神经母细胞瘤PDX模型可以从各种样本类型中可靠地建立。原位植入允许更快的模型开发，增加在临床有用的时间范围内开发化身模型的可能性。尝试从胸膜液中植入导致EBV相关的非典型淋巴样增生。尝试从淋巴结和骨髓肿瘤样品中植入，观察到异种移植物抗宿主疾病，但可以通过T细胞耗竭来预防。原位植入比皮下或肌肉内植入更有效。结论高可靠的神经母细胞瘤PDX模型可以从各种样本类型中可靠地建立。原位植入允许更快的模型开发，增加在临床有用的时间范围内开发化身模型的可能性。尝试从胸膜液中植入导致EBV相关的非典型淋巴样增生。尝试从淋巴结和骨髓肿瘤样品中植入，观察到异种移植物抗宿主疾病，但可以通过T细胞清除来预防。原位植入比皮下或肌肉内植入更有效。结论高可靠的神经母细胞瘤PDX模型可以从各种样本类型中可靠地建立。原位植入允许更快的模型开发，增加在临床有用的时间范围内开发化身模型的可能性。原位植入比皮下或肌肉内植入更有效。结论高可靠的神经母细胞瘤PDX模型可以从各种样本类型中可靠地建立。原位植入允许更快的模型开发，增加在临床有用的时间范围内开发化身模型的可能性。原位植入比皮下或肌肉内植入更有效。结论高可靠的神经母细胞瘤PDX模型可以从各种样本类型中可靠地建立。原位植入允许更快的模型开发，增加在临床有用的时间范围内开发化身模型的可能性。