Subharmonic Contrast Ultrasound for Improved Characterization of Adnexal Masses

 描述（由申请人提供）：卵巢癌是女性十大最常见的癌症类型之一，据估计，美国每71名女性中就有1名在其一生中会患上卵巢癌。令人遗憾的是，几乎75%的妇女被诊断患有晚期疾病，这大大增加了死亡率。因此，早期和准确的表征附件肿块是临床上的当务之急，以提高患者的生存和成像技术可以发挥关键作用，在实现这一目标。目前，附件肿块的成像与标准的阴道超声（EV US），对比增强磁共振成像（MRI）或计算机断层扫描（CT），但功能性生物标志物可能是重要的预后参数，以改善这种群众的特点。我们小组一直在开发一种新的对比特异性超声成像模式：亚谐波成像（SHI），因为相对于其他超声造影模式，它对组织回波的抑制效果很好。我们已经证明，SHI可以检测到缓慢，小体积的血流与肿瘤血管生成在人类使用临床批准剂量的美国造影剂。最近，我们创建了SHI动力学的参数图像（即，逐像素时间强度曲线; TIC），并发现癌症相对于良性病变具有显著更高的灌注（p = 0.0014）。因此，该项目的基本目的是基于来自US造影剂微泡的次谐波信号导出定性和定量SHI生物标志物，其可用于改善附件肿块的良性或恶性表征。SHI算法将在最先进的US扫描仪（EPIQ; Philips Healthcare，博瑟尔，WA）上实施，该扫描仪配有宽带宽、弯曲阵列EV探头，用于附件肿块的体内SHI（特定目标1）。将对6只犬的卵巢进行成像，以证明SHI描绘大血管和微血管的能力（后者作为肿瘤血管生成的模型）。接下来，将使用SHI TIC估计卵巢中的灌注，并将结果与中子活化测定进行比较。作为一项概念验证的初步研究，我们将招募大约45名附件肿块的女性，根据恶性肿瘤风险指数（RMI）进行手术。将使用EV SHI对受试者进行研究，以确定和优化TIC参数作为SHI生物标志物，从而评价附件微血管分布，以尝试诊断良性或恶性疾病。TIC参数也将转换为SHI参数图像，并与标准EV US以及MRI和RMI病变表征进行比较，病理学作为参考标准（特定目标2）。最后，将EV SHI成像血管生成的能力与CD 31染色的手术标本进行比较，CD 31是血管生成的免疫组织化学预测因子（特异性目的3）。这将是将该方法转化为临床试验以筛查附件肿块高危患者的长期目标的第一步。

 DESCRIPTION (provided by applicant): Ovarian cancer is one of the ten most common types of cancer in women and an estimated 1 in 71 women in the United States will develop ovarian cancer in their lifetime. Regrettably, almost 75 % of women are diagnosed with advanced disease, which greatly increases mortality. Hence, earlier and accurate characterization of adnexal masses is a clinical imperative in order to improve patient's survival and imaging techniques can play a critical role in fulfilling this goal. Currently adnexal masses are imaged with standard endovaginal ultrasound (EV US), with contrast enhanced magnetic resonance imaging (MRI) or computed tomography (CT), but functional biomarkers may be important prognostic parameters to improve on the characterization of such masses. Our group has been developing a new contrast-specific US imaging modality: subharmonic imaging (SHI), because of the excellent suppression of tissue echoes relative to other US contrast modes. We have shown that SHI can detect the slow, small volume blood flow associated with tumor angiogenesis in humans using clinically approved dosages of US contrast agents. Recently, we created parametric images of SHI kinetics (i.e., pixel by pixel time intensity curves; TICs) and found cancers to have significantly higher perfusion relative to benign lesions (p = 0.0014). Hence, the fundamental aim of this project is to derive qualitative and quantitative SHI biomarkers, based on subharmonic signals from US contrast microbubbles, which can be used to improve the characterization of adnexal masses as benign or malignant. The SHI algorithm will be implemented on a state-of-the-art US scanner (EPIQ; Philips Healthcare, Bothell, WA) with a broad bandwidth, curved array EV transducer for in vivo SHI of adnexal masses (Specific Aim 1). The ovaries of 6 canines will be imaged to demonstrate the ability of SHI to depict macro- and micro-vascularity (the latter as a model for tumor angiogenesis). Next, perfusion in the ovaries will be estimated using SHI TICs and results compared to a neutron activation assay. As a proof-of-concept, pilot study, we will enroll approximately 45 women with adnexal masses scheduled for surgery based on the risk of malignancy index (RMI). Subjects will be studied with EV SHI to identify and optimize TIC parameters as SHI biomarkers to evaluate adnexal microvascularity in an attempt to diagnose benign or malignant disease. The TIC parameters will also be converted into SHI parametric images and compared to the standard EV US as well as MRI and RMI lesion characterization with pathology as the reference standard (Specific Aim 2). Finally, the ability of EV SHI to image angiogenesis will be compared to surgical specimens stained for CD31, an immunohistochemical predictor of angiogenesis (Specific Aim 3). This will be a first step towards the long-term goal of translating this method into a clinical trial for screening of high-risk patients with adnexal masses.