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大约107个细胞组成或在1立方毫米范围内的肿瘤。任何成像灵敏度的提高都为肿瘤检测和治疗结果提供了有价值的进步；然而，检测灵敏度的重大提高将为我们在临床实践中如何应用成像提供根本性的改变。超声（US）可能在未来的肿瘤成像中发挥重要的和扩大的作用，因为它是安全的，低成本的，方便携带。然而，由于基本分辨率的限制，临床超声只能检测到几毫米或更大的肿瘤肿块。为了提高这种检测灵敏度，美国肿瘤成像方法的范式转变是必要的。这个项目提出了这样一种转变。众所周知，肿瘤在整个血管生成过程中显著扭曲微血管系统。数据显示，仅在肿瘤细胞到达10 - 100秒后，微血管结构就发生了实质性的变化，这些变化延伸到血管

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.