Early Detection and Intervention of Surgery-Induced Lymphatic Insufficiency

描述(申请人提供)：淋巴循环不足，临床表现为淋巴水肿，是乳腺癌患者术后最常见的并发症，严重影响他们的生活质量。乳腺癌相关性淋巴水肿是由于肿瘤分期和预后的淋巴清扫以及术后放射治疗引起的淋巴阻塞引起的。受损的淋巴管不能正确运输间质液体、免疫细胞和组织更新 分子，所有这些都聚集在受影响的区域，最终导致毁容和疼痛的组织肿胀。据报道，乳腺癌相关淋巴水肿的发生率从6%到50%不等，这取决于手术类型、后续治疗、肥胖和切除淋巴结的数量。重要的是，随着乳腺癌存活率一年比一年高，预计会有更多的患者患上淋巴水肿。目前在处理乳腺癌相关淋巴水肿方面面临的挑战包括缺乏标准化的诊断标准，临床症状的发生不可预测，以及缺乏有效的治疗方法来解决除物理压迫以外的潜在分子病因。这项研究的目的是确定一个发生淋巴水肿的分子迹象，可以在临床症状出现之前准确地预测和诊断淋巴功能不全。我们建议将受影响组织中局部游离透明质酸的含量表征为生物标志，这将 不仅有助于建立标准化的诊断标准，而且还可以预测疾病是否发生以及何时发生。此外，为了进一步扩展我们最近的研究，证明维甲酸(RAS)在淋巴再生和淋巴水肿方面的治疗效果，我们的目标是优化和改进RA的治疗方案，以帮助治疗淋巴水肿。通过创新性地将透明质酸辅助的早期检测和基于RA的分子治疗相结合，我们的目标是开发一个针对乳腺癌相关淋巴水肿的早期干预系统原型，并为未来游离透明质酸作为潜在的临床应用奠定实验基础。 生物标记物和RAS作为治疗药物治疗人类淋巴水肿患者。

DESCRIPTION (provided by applicant): Lymphatic circulation insufficiency, clinically manifested as lymphedema, is the most common post- operative complication among breast cancer patients and significantly compromises their quality of life. Breast cancer-associated lymphedema is caused by lymphatic obstruction due to lymph node dissection performed for tumor staging and prognosis, and post-operative irradiation therapy for cancer treatment. Damaged lymphatics fail to properly transport interstitial fluids, immune cells and tissue turnover molecules, all of which accumulate in the affected area, eventually causing a disfiguring and painful tissue swelling. Reported incidence of breast cancer-associated lymphedema ranges from 6% to 50%, depending on surgery types, follow-up treatments, obesity and number of resected lymph nodes. Importantly, as the breast cancer survival rate increases each year, more patients are expected to develop and suffer from lymphedema. Current challenges in managing breast cancer-related lymphedema include the lack of standardized diagnostic criteria, unpredictable onset of clinical symptoms, and the lack of effective treatments addressing the underlying molecular etiology other than physical compression. The goal of this study is to identify a molecular sign of developing lymphedema that can precisely predict and diagnose lymphatic insufficiency before the clinical symptoms appear. We propose to characterize the local free hyaluronan content in the affected tissues as a bio-signature that will not only help to set up standardized diagnostic criteria, but also to predict whether and when the disease occurs. In addition, to further extend our recent study demonstrating the therapeutic efficacy of retinoic acids (RAs) in lymphatic regeneration and lymphedema, we aim to optimize and improve the therapeutic protocol of RA to help treat lymphedema. By innovatively combining the hyaluronan-assisted early detection and RA-based molecular therapies, we aim to develop a prototype early intervention system against breast cancer-related lymphedema, and to establish an experimental foundation for potential future clinical use of free hyaluronan as a biomarker and RAs as therapeutic agents to treat human lymphedema patients.