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High Sensitivity Molecular Ultrasound Imaging in Pancreatic Cancer

胰腺癌的高灵敏度分子超声成像

基本信息

批准号：
9302759
负责人：
Jeremy Dahl
金额：
$ 20.08万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302759
关键词：
Animal Model Biological Markers Cancer Detection Cancer Etiology Cessation of life Characteristics Clinical Detection Development Diagnosis Diagnostic tests Disease Early Diagnosis Excision Goals Histology Human Image Imaging Techniques Immunofluorescence Immunologic Incidence Malignant Neoplasms Malignant neoplasm of pancreas Methods Microbubbles Molecular Molecular Target Noise Operative Surgical Procedures Outcomes Research Pancreas Pancreatic Ductal Adenocarcinoma Patients Phase Reference Standards Research Sensitivity and Specificity Series Signal Transduction Source Specificity Stage at Diagnosis Symptoms System Techniques Testing Time Tissues Transgenic Mice Translating Tumor stage Ultrasonography advanced disease base chronic pancreatitis clinical development clinical translation clinically significant design diagnostic accuracy differential expression experience experimental study high risk imaging approach imaging capabilities imaging system improved in vivo imaging system molecular imaging molecular marker mouse model pre-clinical technique development tumor

项目摘要

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a very lethal form of cancer. While patient survival is highly dependent upon tumor stage, most patients already have advanced disease at the time of diagnosis due to the lack of clinical symptoms experienced by the patient until the tumor has progressed to a significant size. Also, there is a lack of both sensitive and specific imaging tests to detect early stage PDAC. Methods to detect PDAC at early stages are critically needed to improve the survival of patients with PDAC. While overall survival at diagnosis is only about 4-6 months, 30-40% of patients diagnosed at stage I disease can survive 5 years. The best currently available diagnostic test which is routinely performed in patients at high risk for PDAC is endoscopic ultrasound (EUS). However, EUS has low sensitivity and specificity and poor interobserver reliability for detecting small foci of PDAC. Combining EUS with molecular imaging capabilities (molecular CEUS) has the potential to increase our ability to detect early stage PDAC with high diagnostic accuracy. We have identified and validated a new biomarker, Thy1, which is differentially expressed in human PDAC but only minimally present in normal pancreas or chronic pancreatitis. Currently, we are developing a clinical grade Thy1-targeted contrast microbubble (MB) that allows detection of PDAC with high specificity in preclinical animal models. However, a barrier to the clinical translation of Thy1-targeted MB is the expected low concentration of targeted MB in small foci of early stage PDAC. This low concentration reduces our ability to visualize MB with conventional molecular CEUS imaging techniques because the signal to noise ratio (SNR) in tumors may not be high enough to differentiate small PDAC foci from background signal. This reduces our overall sensitivity to detect early stage PDAC. In this application, we propose to develop and test a high-sensitivity molecular CEUS imaging system using a combination of short-lag spatial coherence (SLSC) beamforming with Thy1-targeted MB. The SLSC beamforming technique utilizes the coherence characteristics of US signals to differentiate desired MB from those originating from background noise sources. This new beamforming technique will be implemented on a clinical US imaging system and tested and compared to conventional CEUS methods both in tissue mimicking phantoms as well as in a transgenic mouse model of PDAC development using Thy1-targeted MB. Because PDAC may arise in a setting of chronic pancreatitis, we will also test the SNR of molecular CEUS in PDAC on a chronic pancreatitis background. Molecular CEUS imaging signal will be correlated with histology and ex vivo quantitative immunofluorescence of Thy1 expression as reference standards. Successful completion of our research will result in a new Thy1-targeted molecular CEUS approach for early PDAC detection with improved SNR and specificity that can be further developed for clinical translation in the next phase of this research.

抽象的胰腺导管腺癌（PDAC）是一种非常致命的癌症。虽然患者的生存率很高根据肿瘤分期，大多数患者在诊断时已经处于晚期疾病，因为在肿瘤发展到相当大的尺寸之前，患者没有出现任何临床症状。还，缺乏敏感且特异的影像学测试来检测早期 PDAC。 PDAC的检测方法迫切需要在早期阶段进行治疗以提高 PDAC 患者的生存率。虽然总体生存率诊断仅需约4-6个月，30-40%在I期疾病诊断的患者可存活5年。这目前对 PDAC 高风险患者常规进行的最佳诊断测试是超声内镜（EUS）。然而，EUS 的敏感性和特异性较低，观察者间的可靠性较差用于检测 PDAC 的小病灶。将 EUS 与分子成像功能（分子 CEUS）相结合可以具有提高我们检测早期 PDAC 的能力并具有高诊断准确性的潜力。我们已经鉴定并验证了一种新的生物标志物 Thy1，它在人类 PDAC 中差异表达，但仅少量存在于正常胰腺或慢性胰腺炎中。目前，我们正在开发临床级 Thy1 靶向对比微泡 (MB) 可在临床前动物中以高特异性检测 PDAC 模型。然而，Thy1 靶向 MB 临床转化的一个障碍是预期的低浓度早期 PDAC 小病灶中的靶向 MB。这种低浓度降低了我们观察 MB 的能力传统的分子 CEUS 成像技术，因为肿瘤的信噪比 (SNR) 可能无法足够高以区分小 PDAC 焦点与背景信号。这降低了我们的整体敏感度检测早期 PDAC。在此应用中，我们建议使用短滞后空间相干 (SLSC) 波束成形与 Thy1 目标 MB 的组合。 SLSC 波束成形技术利用 US 信号的相干特性来区分所需的 MB 来自背景噪声源的那些。这种新的波束成形技术将在临床超声成像系统，并在组织模拟方面与传统 CEUS 方法进行了测试和比较体模以及使用 Thy1 靶向 MB 进行 PDAC 发育的转基因小鼠模型。因为 PDAC 可能出现在慢性胰腺炎的情况下，我们还将在 PDAC 上测试分子 CEUS 的 SNR 慢性胰腺炎背景。分子CEUS成像信号将与组织学和离体相关 Thy1表达的定量免疫荧光作为参考标准。顺利完成我们的研究将产生一种新的 Thy1 靶向分子 CEUS 方法，用于早期 PDAC 检测，并具有改进的在本研究的下一阶段，可以进一步开发用于临床转化的信噪比和特异性。