Imaging Biomarkers of Lymphatic Dysfunction

摘要 这项工作的目标是应用新的，非侵入性的磁共振成像（MRI）方法， 淋巴循环功能障碍，以测试有关水肿的危险因素和治疗的基本假设。 乳腺癌治疗相关性水肿（BCRL）继发于手术腋窝淋巴结（LN） 夹层和刺激，是一种慢性和终身疾病，影响高达21.4%的患者接受 常见的乳腺癌治疗方法。减少病情发作和改善管理是主要的 每年有50，000 - 80，000名新患者的临床需求未得到满足，新的努力集中在改善 通过更明智的LN解剖和活检决策提高生活质量，优化术后复杂性 缓解充血疗法（CDT），并探索新的药理学和外科手术。然而，在这方面， 我们对这些疗法的优化实施和细节的认识存在根本性差距 它们所引起的生理变化。主要的潜在限制是缺乏成像技术 现有的方法可用于直接评估淋巴功能，目前还没有达成共识 关于治疗效果评价的有效结果测量。相反，LN的去除通常 基于前哨淋巴结活检和外科医生的额外主观性。治疗评价通常基于 粗略的测量，如肢体体积的变化或患者报告的症状，这提供了很少的 关于潜在机制变化的信息，可用于进一步完善这些疗法。的一部分 我们正在进行的BCRL进展和治疗的INFORM临床试验，我们已经证明了新的， 非侵入性MRI方法，以确定亚临床疾病阶段的BCRL风险，以及可视化 淋巴功能的内部变化作为新兴疗法的结果。在这里，我们建议扩展这些 提高BCRL治疗诊断学能力的研究。(Aim（1）预防。我们将应用新的解剖学和 功能性淋巴结成像方法用于确定活检证实的转移性淋巴结的特异性淋巴结特征;结果 可用于更好地告知LN剥离并降低良性LN切除的发生率。(Aim（二） 进步。我们将通过检验以下假设来提高对BCRL风险进展的理解， 浅表组织轮廓和皮下脂肪积聚在经历以下情况的患者中更普遍： BCRL进展，因此可用于在明显的BCRL进展之前对患者进行积极治疗的分类。 症状和不可逆的损伤。(Aim 3）治疗。我们将进行重复测量交叉试验， 使用分级负压测试蛋白质富集硬化组织的动员的假设 联合CDT的治疗上级单独的标准CDT。总体目标是制定客观的指标 淋巴功能障碍，可用于癌症和BCRL疗法的新兴治疗试验， 减少与这种流行和慢性疾病相关的症状的发生率和严重程度。

ABSTRACT The goal of this work is to apply novel, noninvasive magnetic resonance imaging (MRI) methods for visualizing lymphatic circulation dysfunction to test fundamental hypotheses about lymphedema risk factors and therapies. Breast cancer treatment-related lymphedema (BCRL) arises secondary to surgical axillary lymph node (LN) dissection and irritation, and is a chronic and lifelong condition affecting a high 21.4% of patients receiving common breast cancer therapies. Reducing condition onset and improving management represent major unmet clinical needs for these 50,000 - 80,000 new patients per year, and emerging efforts focus on improving quality of life through more informed LN dissection and biopsy decisions, optimizing post-surgical complex decongestive therapy (CDT), and exploring novel pharmacological and surgical procedures. However, fundamental gaps in our knowledge persist regarding optimized implementation of these therapies and details of the physiological changes they elicit. The major underlying limitation is that there is a shortage of imaging methods available that can be used to evaluate lymphatic function directly, and there is currently no consensus regarding effective outcome measures for therapeutic efficacy evaluation. Rather, LN removal is frequently based on sentinel LN biopsy and additional subjectivity of the surgeon. Therapy evaluation is frequently based on coarse measurements such as changes in limb volume or patient-reported symptoms, which provide little information on underlying mechanistic changes that could be used to further refine these therapies. As part of our ongoing INFORM clinical trial of BCRL progression and therapy, we have demonstrated potential for new, noninvasive MRI approaches to identify BCRL risk in sub-clinical disease stages, as well as to visualize internal changes in lymphatic functioning as a result of emerging therapies. Here, we propose to extend these studies to improve abilities for BCRL theranostics. (Aim 1) Prevention. We will apply new anatomical and functional LN imaging approaches to identify LN profiles specific to biopsy-confirmed metastatic LNs; findings could be used to better inform LN dissection and reduce the incidence of benign LN removal. (Aim 2) Progression. We will improve our understanding of BCRL risk progression by testing the hypothesis that superficial tissue profiles and subcutaneous adipose accumulation are more prevalent in patients experiencing BCRL progression, and thereby could be used to triage patients for aggressive therapies prior to overt symptoms and irreversible damage. (Aim 3) Therapy. We will perform a repeated-measures cross-over trial to test the hypothesis that mobilization of protein enriched hardened tissue using graded negative pressure therapy in conjunction CDT is superior to standard CDT alone. The overall goal is to develop objective markers of lymphatic dysfunction that can be used in emerging therapeutic trials of cancer and BCRL therapies to reduce both the incidence and severity of symptoms associated with this prevalent and chronic condition.