Imaging lymphatic function in patients with breast cancer related lymphedema

描述(申请人提供)：这项工作将首次将新的非侵入性结构和功能磁共振成像(MRI)方法应用于轻、中度乳腺癌相关淋巴水肿(BCRL)患者，以测试淋巴损害与可能预示疾病进展和个性化治疗反应的成像生物标记物之间的关系的基本假设。BCRL是一种慢性衰弱疾病，由腿部、手臂和肩部淋巴流动障碍引起。乳房切除和放射治疗后继发的淋巴水肿是一个日益严重的健康问题，据报道，平均有20%的女性在乳腺癌治疗后三年内发生，多达94%的女性在乳腺癌治疗后五年内发生。虽然淋巴水肿无法治愈，但已有研究表明，对早期或亚临床疾病阶段的患者进行行为调整和积极的治疗管理可以预防或减少长期损害。然而，可用于确定淋巴水肿风险最高的患者的信息非常有限。几种专门的成像方法已经证明，淋巴流速降低和相关的淋巴收缩功能受损可能预示着淋巴水肿的风险，然而这些方法需要放射性示踪剂和/或外源性造影剂，通常只在专门的中心可用，在常规的患者治疗中不进行。我们最近证明，动脉自旋标记(ASL)是一种流行的、无创的测量血流的MRI方法，可以用于测量淋巴液体流向腋窝淋巴结的流量，此外，使用该技术报告的淋巴速度与使用外源性造影剂的类似测量结果一致。此外，我们已经证明，化学交换饱和转移(CEST)MRI可以用来表征临床前BCRL期患者在肢体体积改变之前的间质蛋白积聚。重要的是，自旋标记和CEST都使用大多数医院提供的标准MRI设备，因此可以很容易地传播到临床或研究中心，寻求扩大他们的能力，以表征淋巴损害。在这里，我们建议评估健康人(目标1)和BCRL患者在临床前、轻度和中度损害阶段(目标2)的淋巴流速和间质蛋白积聚的范围，最后评估淋巴系统如何妥协手动淋巴引流治疗的变化，以及淋巴流速和间质蛋白积聚在多大程度上可以预测淋巴水肿的进展(目标3)。这项工作将首次将一种非侵入性、多模式MRI方案应用于人类淋巴系统，以更好地表征不断增长的乳腺癌幸存者人口中的淋巴功能障碍和淋巴水肿风险。

DESCRIPTION (provided by applicant): This work will apply novel, noninvasive structural and functional magnetic resonance imaging (MRI) methods to patients with mild and moderate breast cancer-related lymphedema (BCRL) for the first time to test fundamental hypotheses about relationships between lymphatic compromise and imaging biomarkers that may portend disease progression and individualized therapy response. BCRL is a chronic, debilitating disease caused by lymphatic flow obstruction in the legs, arms, and shoulder regions. Lymphedema secondary to mastectomy and radiation therapy is a growing health concern and has been reported to occur, on average, in 20% of women within three years after breast cancer treatment and in as many as 94% of women five years after breast cancer treatment. While there is no cure for lymphedema, it has been shown that behavioral adjustments and aggressive therapeutic management of patients in early or subclinical disease stages can prevent or reduce long-term impairment. However, very limited information is available for identifying patients at highest risk for lymphedema. Several specialized imaging methods have demonstrated that reduced lymphatic flow velocity and related lymphatic contractility impairment may portend lymphedema risk, however these approaches require radioactive tracers and/or exogenous contrast agents, are generally only available in specialized centers, and are not performed in routine patient management. We have very recently demonstrated that arterial spin labeling (ASL), a popular and noninvasive MRI method for measuring blood flow, can be adapted to measure flow of lymphatic fluid to axillary lymph nodes, and furthermore that lymphatic velocities reported using this technique are consistent with similar measures using exogenous contrast agents. Additionally, we have shown that chemical exchange saturation transfer (CEST) MRI can be used to characterize interstitial protein accumulation in patients in preclinical BCRL stages prior to limb volume changes. Importantly, both spin labeling and CEST utilize standard MRI equipment available at most hospitals and therefore can easily be disseminated to clinical or research centers seeking to expand their abilities to characterize lymphatic compromise. Here, we propose to assess the ranges of lymphatic flow velocities and interstitial protein accumulation in healthy individuals (Aim 1) and BCRL patients in preclinical, mild, and moderate stages of impairment (Aim 2), and finally to assess how lymphatic system compromise changes in response to manual lymphatic drainage therapy and to what extent lymphatic flow velocity and interstitial protein accumulation may predict lymphedema progression (Aim 3). This work will for the first time apply a noninvasive, multi-modal MRI protocol, which has demonstrated clinical potential in neuroscience, liver, and breast applications, to the human lymphatic system to better characterize lymphatic dysfunction and lymphedema risk in the growing breast cancer survivor population.