Savvopoulos Symeon, Misener Ruth, Panoskaltsis Nicki, Pistikopoulos Efstratios N, Mantalaris Athanasios
IEEE Trans Biomed Eng. 2016 Nov;63(11):2396-2404. doi: 10.1109/TBME.2016.2533658. Epub 2016 Feb 23.
Chronic lymphocytic leukemia (CLL) is the most common peripheral blood and bone marrow cancer in the developed world. This manuscript proposes mathematical model equations representing the disease dynamics of B-cell CLL. We interconnect delay differential cell cycle models in each of the tumor-involved disease centers using physiologically relevant cell migration. We further introduce five hypothetical case studies representing CLL heterogeneity commonly seen in clinical practice and demonstrate how the proposed CLL model framework may capture disease pathophysiology across patient types. We conclude by exploring the capacity of the proposed temporally- and spatially distributed model to capture the heterogeneity of CLL disease progression. By using global sensitivity analysis, the critical parameters influencing disease trajectory over space and time are: 1) the initial number of CLL cells in peripheral blood, the number of involved lymph nodes, the presence and degree of splenomegaly; 2) the migratory fraction of nonproliferating as well as proliferating CLL cells from bone marrow into blood and of proliferating CLL cells from blood into lymph nodes; and 3) the parameters inducing nonproliferative cells to proliferate. The proposed model offers a practical platform that may be explored in future personalized patient protocols once validated.
慢性淋巴细胞白血病（CLL）是发达国家最常见的外周血和骨髓癌症。本手稿提出了代表B细胞CLL疾病动态的数学模型方程。我们利用生理相关的细胞迁移，将每个肿瘤累及疾病中心的延迟微分细胞周期模型相互连接起来。我们进一步引入了五个代表临床实践中常见的CLL异质性的假设案例研究，并展示了所提出的CLL模型框架如何能够涵盖不同患者类型的疾病病理生理学。我们通过探索所提出的时空分布模型捕捉CLL疾病进展异质性的能力来得出结论。通过全局敏感性分析，影响疾病在空间和时间上轨迹的关键参数为：1）外周血中CLL细胞的初始数量、受累淋巴结的数量、脾肿大的存在情况和程度；2）非增殖性以及增殖性CLL细胞从骨髓迁移到血液中的比例，以及增殖性CLL细胞从血液迁移到淋巴结中的比例；3）诱导非增殖细胞增殖的参数。一旦经过验证，所提出的模型提供了一个实用平台，可在未来的个性化患者治疗方案中进行探索。
