High Sensitivity Molecular Ultrasound Imaging in Pancreatic Cancer

摘要 胰腺导管腺癌(PDAC)是一种非常致命的癌症。虽然患者的存活率很高 根据肿瘤分期的不同，大多数患者在诊断时已是晚期疾病，原因是 在肿瘤发展到显著大小之前，患者缺乏临床症状。另外， 目前尚缺乏检测早期PDAC的灵敏和特异的影像检查。检测PDAC的方法 早期治疗是提高PDAC患者存活率的关键。虽然总体存活率在 确诊时间只有4-6个月左右，确诊为I期疾病的患者有30-40%可以存活5年。这个 目前对PDAC高危患者常规进行的最好的诊断测试是 内窥镜超声(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与分子成像能力(分子CEU)相结合具有 有可能提高我们检测早期PDAC的能力，并具有很高的诊断准确性。 我们已经发现并验证了一个新的生物标记物，Thy1，它在人类PDAC中有差异表达，但 仅在正常胰腺或慢性胰腺炎中微量存在。目前，我们正在开发一种临床等级 Thy1靶向造影剂微泡(MB)可在临床前动物中检测高特异性的PDAC 模特们。然而，Thy1靶向MB的临床翻译的一个障碍是预期的低浓度 靶向于早期PDAC的小病灶。这种低浓度降低了我们将MB可视化的能力 传统的分子CEUS成像技术，因为肿瘤的信噪比(SNR)可能不是 高到足以区分小的PDAC焦点和背景信号。这降低了我们对以下问题的总体敏感性 检测早期PDAC。 在这项应用中，我们建议开发和测试一个高灵敏度的分子CEUS成像系统，使用 短时滞空间相干(SLSC)波束形成与Thy1靶向MB的组合。补充法律援助计划委员会 波束形成技术利用US信号的相干特性来区分所需的MB和 来自背景噪声源的噪声。这项新的波束形成技术将在 临床超声成像系统，并与传统的CEUS方法在组织模拟方面进行了测试和比较 在使用Thy1靶向MB的PDAC发育的转基因小鼠模型中也是如此。因为 PDAC可能发生在慢性胰腺炎的情况下，我们还将测试PDAC中分子CEU的SNR 慢性胰腺炎背景。分子CEUS成像信号将与组织学和体外实验相关联 以免疫荧光定量检测Thy1的表达作为参考标准。成功完成我们的 研究将导致一种新的针对Thy1的分子CEUS方法，用于早期PDAC检测，具有改进的 SNR和特异性，可以在下一阶段的研究中进一步开发用于临床翻译。

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.