Imaging lymphatic function in patients with breast cancer related lymphedema

描述（由申请人提供）：这项工作将首次对轻度和中度乳腺癌相关淋巴水肿（BCRL）患者应用新颖的、无创的结构和功能磁共振成像（MRI）方法，以测试关于淋巴损害与可能预示疾病进展和个体化治疗反应的成像生物标志物之间关系的基本假设。BCRL是一种慢性衰弱性疾病，由腿部、手臂和肩部的淋巴流阻塞引起。乳房切除术和放射治疗继发淋巴水肿是一个日益严重的健康问题，据报道，平均20%的妇女在乳腺癌治疗后三年内出现淋巴水肿，在乳腺癌治疗后五年内多达94%的妇女出现淋巴水肿。虽然淋巴水肿无法治愈，但研究表明，在早期或亚临床疾病阶段对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，关于确定淋巴水肿高危患者的信息非常有限。一些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性损伤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提供，而不是在常规的患者管理中进行。我们最近已经证明，动脉自旋标记（ASL），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流向腋下淋巴结，此外，使用这种技术报告的淋巴速度与使用外源性造影剂的类似测量一致。此外，我们已经证明，化学交换饱和转移（CEST） MRI可用于表征临床前BCRL阶段患者在肢体体积变化之前的间质蛋白积累。重要的是，自旋标记和CEST都使用大多数医院可用的标准MRI设备，因此可以很容易地传播到临床或研究中心，以扩大其表征淋巴损害的能力。在这里，我们建议评估健康个体（目的1）和临床前、轻度和中度损害阶段的BCRL患者（目的2）的淋巴流速和间质蛋白积累范围，最后评估淋巴系统对人工淋巴引流治疗的反应如何改变，以及淋巴流速和间质蛋白积累在多大程度上可以预测淋巴水肿进展（目的3）。这项工作将首次将非侵入性、多模态MRI方案应用于人类淋巴系统，以更好地表征日益增长的乳腺癌幸存者群体中的淋巴功能障碍和淋巴水肿风险，该方案已在神经科学、肝脏和乳房应用中证明了临床潜力。

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.