由于辐射诱导淋巴细胞减少症（RIL）与多种疾病的生存率相关，尤其是在将放射治疗（RT）与免疫疗法相结合时，近年来受到了关注。本研究的目的是使用动态血液循环模型结合患者观察到的淋巴细胞减少情况，推导循环淋巴细胞的体内放射敏感性，并研究RT传递参数的影响。我们组装了一个肝细胞癌患者组，他们接受了质子RT-单独治疗15次（fx），使用常规剂量率（束开时间，BOT，120s），并且他们在RT和随访期间有可用的每周绝对淋巴细胞计数（ALC）。我们结合显式的肝血液流动建模，使用一种时间依赖的全身血液流动计算框架HEDOS，计算了循环淋巴细胞的剂量容积直方图，针对不同的BOT（1s-300s）和分数（5fx，15fx）。然后，我们使用线性细胞存活模型和指数模型来确定患者特定的淋巴细胞辐射敏感性α和恢复σ。通过这种方式，得出的患者特定α的中位数为0.65 Gy-1（范围为0.30-1.38）。将BOT降低到1s会导致平均治疗结束时的ALC增加27.5％，与5fx方案结合后增加到60.3％。将剂量速率降低到常规水平的5fx可平均增加17.0％。提高剂量速率和减少次数的好处是患者特定的-淋巴细胞高度敏感的患者从降低BOT中获益最大，而淋巴细胞恢复慢的患者从缩短分数方案中获益最大。 我们观察到，在相同的分数方案中提高剂量速率比减少分数的ALC减少更显着。高剂量速率可使淋巴细胞更加节约，特别是对于存在放射敏感淋巴细胞风险的患者。版权所有©2023 Elsevier Inc. 保留所有权利。

Radiation induced lymphopenia (RIL) has recently gained attention due to its correlation with survival in a range of indications, particularly when combining radiotherapy (RT) with immunotherapy. The purpose of this study is to use a dynamic blood circulation model combined with observed lymphocyte depletion in patients to derive the in vivo radiosensitivity of circulating lymphocytes and study the effect of RT delivery parameters.We assembled a cohort of 17 hepatocellular carcinoma patients treated with proton RT-alone in 15 fractions (fx) using conventional dose rates (beam-on time, BOT, 120s) for who weekly absolute lymphocyte counts (ALC) during RT and follow-up were available. We utilized HEDOS, a time-dependent, whole-body, blood flow computational framework, in combination with explicit liver blood flow modeling, to calculate the dose volume histograms for circulating lymphocytes for changing BOTs (1s - 300s) and fractionations (5fx, 15fx). From this, we utilized the linear cell survival model and an exponential model to determine patient-specific lymphocyte radiation sensitivity, α, and recovery, σ, respectively.The in vivo derived patient-specific α had a median of 0.65 Gy-1 (range 0.30 - 1.38). Decreasing BOT to 1s led to an increased average end-of-treatment ALC of 27.5%, increasing to 60.3% when combined with the 5fx regimen. Decreasing to 5fx at the conventional dose rate led to an increase of 17.0% on average. The benefit of both increasing dose rate and reducing the number of fractions was patient-specific - patients with highly sensitive lymphocytes benefited most from decreasing BOT, while patients with slow lymphocyte recovery benefited most from the shorter fractionation regimen.We observed that increasing dose rate at the same fractionation reduced ALC depletion more significantly than reducing the number of fractions. High dose rates led to an increased sparing of lymphocytes when shortening the fractionation regimen, particularly for patients with radiosensitive lymphocytes at elevated risk.Copyright © 2023 Elsevier Inc. All rights reserved.