Micro-tumor detection by quantifying tumor-induced vascular abnormalities (PQ-13)

描述（由申请人提供）：目前的成像模式允许检测由约107个细胞组成或在1立方毫米范围内的肿瘤。成像灵敏度的任何提高都为肿瘤检测和治疗结果提供了有价值的进步;然而，检测灵敏度的大幅提高将为我们在临床实践中如何使用成像提供根本性的改变。超声（US）可能会在未来的肿瘤成像中发挥重要和扩大的作用，因为它是安全的，低成本的，易于携带。然而，由于基本的分辨率限制，临床US只能检测几毫米或更大的肿瘤肿块。为了提高这种检测灵敏度，需要在用于成像肿瘤的US方法中进行范式转变。这个项目提出了这样的转变。众所周知，肿瘤在整个血管生成过程中显著地扭曲微血管。数据显示，微血管结构的实质性变化发生在仅10秒至100秒的肿瘤细胞到达后，这些变化延伸到血管， 肿瘤的直径相对较大（直径数百微米），并且微血管变化远远超出肿瘤边缘，甚至在疾病发作后不久。这些独特的微血管“癌症特征”为我们提供了一种克服传统分辨率限制的方法，否则会损害微肿瘤检测。因此，我们对提高微癌成像灵敏度的创新反应是检测这些微血管变化，而不是实体瘤本身。先前的研究小组已经使用光学显微镜说明了这一概念的潜力，但光学显微镜本身就不适合这种应用，因此我们将利用一种新的超声方法。虽然以前，超声没有提供效用，在评估微血管结构的变化，我们的小组最近实施了一种新的美国成像技术，称为“声学血管造影”，它提供了最高的信噪比和高分辨率的微血管结构成像。因此，这种新的成像技术能够实现微血管分割和迂曲度定量。我们的第一个假设是，我们可以优化这种成像方法，为临床实施提供足够的空间分辨率和穿透深度。我们的第二个假设是，当肿瘤比目前的检测极限小至少两到三个数量级时，我们可以使用声学血管造影来检测肿瘤引起的微血管变化。我们的第三个假设是，我们可以开发当前的分割和分析算法，这些算法将表征微血管形态，并提供一种特异性和敏感的分类方法，用于检测有微肿瘤风险的组织。令人鼓舞的初步数据已经说明了我们使用声学血管造影术仅基于微血管形态分析来区分小肿瘤和健康组织的能力，这些进一步的研究将使这项有前途的新技术得到全面发展。我们的方法将涉及体外研究以及临床前体内研究，使用临床相关的乳腺癌基因工程模型。

DESCRIPTION (provided by applicant): Current imaging modalities allow detection of tumors composed of approximately 107 cells or in the range of 1 cubic millimeter. Any increase in imaging sensitivity provides valuable advances in tumor detection and also treatment outcomes; however, a major increase in detection sensitivity would provide a radical change in how we might employ imaging in clinical practice. Ultrasound (US) will likely play a significant and expanding role in oncological imaging in the future because it is safe, low-cost, and readily portable. However, due to fundamental resolution limitations, clinical US can only detect tumor masses on the order of a few millimeters, or larger. In order to improve this detection sensitivity a paradigm shift in the US approach for imaging tumors is needed. This project proposes such a shift. It is well known that tumors dramatically distort microvasculature throughout the angiogenic process. Data show that substantial changes in microvasculature structure occur after the arrival of only 10s to 100s of tumor cells, that these changes extend to vessels that are relatively large (hundreds of microns in diameter), and that microvascular changes extend well beyond tumor margins, even soon after the onset of disease. These unique microvascular "cancer signatures" provide us with a means to overcome traditional resolution limitations which otherwise impair micro-tumor detection. Thus, our innovative response to improving imaging sensitivity to micro-cancers is to detect these microvascular changes, rather than the solid tumor itself. Prior groups have illustrated the potential for this concept using optical microscopy however optical microscopy is inherently non-clinically translatable for this application, and hence we will utilize a novel ultrasound approach. Although previously, ultrasound has not provided utility in assessing changes in microvascular structure, our group has recently implemented a new US imaging technique called "Acoustic Angiography" which provides supreme signal-to-noise and high resolution for imaging microvessel structure. This new imaging technique thus enables microvessel segmentation and tortuosity quantification. Our first hypothesis is that we can optimize this imaging approach for adequate spatial resolution and depth of penetration for clinical implementation. Our second hypothesis is that we can use acoustic angiography to detect tumor-induced microvascular changes when tumors are at least two to three orders of magnitude smaller than current detection limits. Our third hypothesis is that we can develop current segmentation and analysis algorithms which will characterize microvessel morphology and provide a specific and sensitive classification approach for detecting tissue that is at risk for hosting micro-tumors. Encouraging preliminary data have already illustrated our ability use acoustic angiography to discriminate small tumors and healthy tissue based on an analysis of microvessel morphology alone, and these further studies will enable a comprehensive development of this promising new technology. Our approach will involve in-vitro studies as well as preclinical in-vivo studies using clinically-relevant geneticaly engineered models of breast cancer.