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)方法进行可视化 淋巴循环功能障碍，以检验有关淋巴水肿危险因素和治疗的基本假设。 乳腺癌治疗相关淋巴水肿(BCRL)继发于外科腋窝淋巴结(LN) 夹层和刺激，是一种慢性和终生疾病，影响高达21.4%的患者接受治疗 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50,000-80,000名新患者的未得到满足的临床需求，新出现的努力侧重于改善 通过更知情的LN解剖和活检决策提高生活质量，优化手术后综合体 减充血疗法(CDT)，以及探索新的药理和外科手术方法。然而， 在这些疗法和细节的优化实施方面，我们知识中的根本差距仍然存在 它们所引起的生理变化。主要的潜在限制是成像不足。 现有的可用于直接评估淋巴功能的方法，目前尚无共识 关于疗效评估的有效结果衡量标准。相反，LN的去除是经常的 根据前哨LN活检和外科医生的附加主观性。治疗评估通常是基于 根据粗略的测量，如肢体体积的变化或患者报告的症状，这些测量几乎不能提供 关于可用于进一步改进这些疗法的潜在机制变化的信息。作为以下内容的一部分 我们正在进行的BCRL进展和治疗的INFORE临床试验，我们已经展示了新的， 非侵入性MRI方法识别亚临床疾病阶段的BCRL风险，以及可视化 淋巴功能的内部变化是新出现的治疗方法的结果。在这里，我们建议延长这些 提高BCRL治疗能力的研究。(目标1)预防。我们将应用新的解剖学和 功能性LN成像方法识别经活检证实的转移性LN的LN特征：发现 可用于更好地告知LN剥离，减少良性LN切除的发生率。(目标2) 进步。我们将通过检验以下假设来提高我们对BCRL风险进展的理解 浅层组织轮廓和皮下脂肪堆积在以下患者中更常见 BCRL进展，因此可以用于在公开之前对患者进行积极治疗 症状和不可逆转的损害。(目标3)治疗。我们将进行重复措施交叉试验，以 利用分级负压验证蛋白质动员强化硬化组织的假说 联合CDT治疗优于单纯标准CDT治疗。总体目标是开发客观的标记 淋巴功能障碍，可用于新兴的癌症治疗试验和BCRL疗法 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.