Molecular Lymphosonography for Sentinel Lymph Node Characterization

用于前哨淋巴结特征的分子淋巴超声检查

• 批准号: 8682412
• 负责人: Andrej Lyshchik
• 金额: $ 20.23万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-04 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682412
• 关键词: Affinity; American Joint Committee on Cancer; Anaphylaxis; Anatomy; Animal Model; Animals; Benign; Binding; Biopsy; Breast; Contrast Media; Cutaneous; Deposition; Detection; Development; Diagnosis; Diagnostic Imaging; Disease; Drainage procedure; Dyes; Excision; Family suidae; Funding; Goals; Healthcare; Histology; Human; Image; In Vitro; Injection of therapeutic agent; Integrins; Intravenous; Investigation; Ionizing radiation; Isotopes; Ligand Binding; Ligands; Lymph Node Involvement; Lymphatic; Malignant - descriptor; Malignant Neoplasms; Maps; Methods; Microbubbles; Modeling; Molecular; Molecular Target; Neoplasm Metastasis; Norway; Operative Surgical Procedures; Outcome; P-Selectin; Pathology; Patients; Procedures; Prognostic Factor; Radioisotopes; Radionuclide Imaging; Reference Standards; Regional Lymph Node Involvement; Research; Resected; Sentinel Lymph Node; Sentinel Lymph Node Mapping; Signal Transduction; Site; Specificity; Staging; Staging System; Staining method; Stains; Surface; Surgeon; Surgical Management; Technetium 99m; Techniques; Tissues; Tumor Angiogenesis; Tumor Burden; Ultrasonography; United States National Institutes of Health; Vascular Endothelial Growth Factor Receptor-2; angiogenesis; diagnostic accuracy; imaging modality; improved; innovation; intravenous administration; intravenous injection; lymph nodes; melanoma; minimally invasive; molecular marker; overexpression; public health relevance; tool; tumor; validation studies

DESCRIPTION (provided by applicant): Accurate detection and characterization of sentinel lymph nodes (SLNs) that receive drainage from a primary cancer (e.g., breast or melanoma) have a direct impact on patient management. Two methods are currently used to identify SLNs; peritumoral injection of radioisotopes followed by scintigraphy and injection of dye with detection of dye-stained SLNs at surgery. However, each of these methods has potential limitations that can adversely impact the detection of SLNs and the accuracy of disease staging. Furthermore, isotope imaging requires ionizing radiation, blue dye can cause anaphylactic reactions and neither of these techniques provides an accurate noninvasive depiction of lymphatic anatomy. Our group has demonstrated that contrast-enhanced ultrasound imaging (CEUS) after subdermal administration of a tissue-specific ultrasound contrast agent (UCA), can be used to noninvasively map lymphatic drainage and localize SLNs (so called "lymphosonography"). Our NIH funded investigations using a swine model with naturally occurring melanomas have confirmed that CEUS is superior to radioisotope imaging detecting almost 20 % more SLNs. However, the ability of lymphosonography to characterize SLNs as malignant or benign was slightly worse than that of standard grayscale ultrasound (80 % vs. 86 %, respectively). The specificity of CEUS improves with the use of a targeted UCA, in which targeting ligands are attached to the surface of the agent to improve affinity. Hence, the current proposal will expand on the concept of lymphosonography by including a triple-targeted molecular UCA to improve SLN characterization. We hypothesize that subdermal lymphosonogray followed by intravenous (IV) injection of a triple-targeted UCA (targeted to avb3 integrin, P-selectin and VEGFR2) will permit superior detection of SLNs as well as accurate characterization as benign or metastatic. Following an in vitro validation study, 20 melanoma-bearing swine with around 125 SLNs will be studied. An RES-specific UCA will be injected around each melanoma to permit detection of the SLNs. Then the triple-targeted UCA (i.e., molecular lymphosonography) will be injected IV and the presence or absence of metastatic deposits will be determined. Finally, blue dye will be injected around the melanoma and a surgeon will resect the dye-stained SLNs, which will be submitted to pathology to determine if they contain metastases. The accuracy of tumor detection in the SLNs identified by molecular lymphosonography will be compared to that of standard CEUS (i.e., using a non-targeted UCA) with pathology as the reference standard. The potential benefits of this innovative study will be the development of a minimally-invasive imaging method (molecular lymphosonography) to identify SLNs and accurately diagnose metastatic SLN involvement, thereby significantly reducing the need to perform excisional lymph node biopsies, reducing procedure-related complications and improving patient outcome.

描述（由申请人提供）：从原发性癌症（例如乳腺癌或黑色素瘤）接收排水的前哨淋巴结（SLN）的准确检测和表征对患者管理有直接影响。目前使用两种方法来识别SLN。放射性同位素的周围注射，然后进行闪烁显像和注射染料并检测 手术中的染料染色SLN。但是，这些方法中的每一种都有潜在的局限性，可能会对SLN的检测和疾病分期的准确性产生不利影响。此外，同位素成像需要电离辐射，蓝色染料会引起过敏反应，而这些技术都不提供准确的淋巴解剖学无创描绘。我们的小组表明，在施用组织特异性超声对比剂（UCA）后，对比增强的超声成像（CEU）可用于非侵袭性地映射淋巴引流并定位SLN（所谓的“淋巴结术”）。我们的NIH使用具有天然黑色素瘤的猪模型进行了资助的研究，已经证实，CEUS优于放射性同位素成像，检测到近20％的SLN。但是，淋巴发表表征SLN为恶性或良性的能力比标准灰度超声（分别为80％和86％）稍差。 CEU的特异性通过使用靶向UCA的使用来提高，其中靶向配体连接到代理表面以提高亲和力。因此，当前的建议将通过包括三个靶向的分子UCA来改善SLN表征，从而扩展淋巴发出术的概念。我们假设下淋巴结淋巴结膜，然后静脉内（IV）注射三靶标UCA（靶向AVB3整合蛋白，P-链蛋白酶和VEGFR2），将允许对SLN的良好检测以及良性或转移性的精确表征。经过一项体外验证研究，将研究20只具有125个SLN的黑色素瘤。每种黑色素瘤周围都会注入一个特异性的UCA，以允许检测SLN。然后将注入三靶标UCA（即分子淋巴发出），并确定转移沉积物的存在或不存在。最后，将在黑色素瘤周围注入蓝色染料，外科医生将切除染料染色的SLN，该SLN将提交给病理学，以确定它们是否含有转移。通过分子淋巴发表鉴定的SLN中肿瘤检测的准确性将与标准CEU（即使用具有病理学的非靶向UCA）作为参考标准进行比较。这项创新研究的潜在好处将是开发微创成像方法（分子淋巴结造影），以鉴定SLN并准确诊断转移性SLN的参与，从而大大减少了进行兴奋的淋巴结活检，从而减少了与之相关的并发症并改善患者的结果。