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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

基本信息

批准号：
8831623
负责人：
Andrej Lyshchik
金额：
$ 16.86万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-04 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8831623
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 Health 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 contrast enhanced diagnostic accuracy imaging modality improved innovation intravenous administration intravenous injection lymph nodes melanoma minimally invasive molecular marker overexpression tool tumor validation studies

项目摘要

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）：接受原发性癌症引流的前哨淋巴结（SLN）的准确检测和表征（例如，乳腺癌或黑色素瘤）对患者管理有直接影响。目前有两种方法用于鉴别前哨淋巴结：瘤周注射放射性同位素，然后进行放射性造影和注射染料检测染色的前哨淋巴结然而，这些方法都有潜在的局限性，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，蓝色染料可引起过敏反应，这些技术都不能提供准确的淋巴解剖结构的非侵入性描述。我们的研究小组已经证明，在皮下注射组织特异性超声造影剂（UCA）后，对比增强超声成像（CEUS）可用于非侵入性地绘制淋巴引流和定位SLN（所谓的“淋巴超声检查”）。我们的NIH资助的研究使用了具有自然发生的黑色素瘤的猪模型，已经证实CEUS上级放射性同位素成像，检测到几乎20%以上的SLN。然而，淋巴超声检查鉴别前哨淋巴结恶性或良性的能力略差于标准灰阶超声（分别为80%和86%）。CEUS的特异性随着靶向UCA的使用而提高，其中靶向配体连接到试剂的表面以提高亲和力。因此，目前的建议将扩大淋巴超声检查的概念，包括一个三靶向分子UCA，以改善SLN的表征。我们假设，皮下淋巴细胞超声波造影后静脉注射三靶向UCA（靶向avb 3整合素，P-选择素和VEGFR 2）将允许上级检测SLN以及准确的定性为良性或转移性。在体外验证研究之后，将研究20头带有约125个SLN的黑色素瘤猪。将在每个黑素瘤周围注射RES特异性UCA，以检测SLN。然后是三重靶向UCA（即，分子淋巴超声检查），并确定是否存在转移性沉积物。最后，将在黑色素瘤周围注射蓝色染料，外科医生将切除染料染色的前哨淋巴结，并将其提交病理学检查，以确定它们是否含有转移。通过分子淋巴超声检查鉴定的SLN中肿瘤检测的准确性将与标准CEUS的准确性进行比较（即，使用非靶向UCA），病理学作为参考标准。这项创新研究的潜在益处是开发一种微创成像方法（分子淋巴超声），以识别SLN并准确诊断转移性SLN受累，从而显著减少进行切除淋巴结活检的需要，减少手术相关并发症并改善患者结局。