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

描述（由申请人提供）：众所周知，肿瘤在整个血管生成过程中会显著扭曲微血管。数据显示，微血管结构的实质性变化发生在仅100个肿瘤细胞到达后，这些变化延伸到相对较大的血管（直径为数百微米），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”是一种生物标志物，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，但是光学显微镜本身就不适合这种应用，因此我们使用了一种新的超声方法。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。令人鼓舞的初步临床前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。母公司资助涉及这项有前途的新技术的全面发展，包括成像技术的优化，以及临床前体内研究，使用临床相关的乳腺癌基因工程啮齿动物模型，以建立评估肿瘤相关血管生成生物标志物的灵敏度和特异性，作为早期检测肿瘤大小的函数。在此补充/修订申请中，我们建议将母基金资助的技术纳入试点临床试验。我们的目标是证明这种新的成像技术，声学血管造影，将是有效的人类患者。我们的方法涉及60例疑似乳腺癌患者的临床研究。将结果的灵敏度和特异性与传统超声成像（护理标准）以及金标准病理学进行比较，因为每例患者将接受病变活检或切除。虽然这项小型临床试点研究将无法完全评估声学血管造影在早期癌症检测中的作用，但这项研究的结果将提供必要的金标准比较数据，以评估这种新的生物标志物成像技术的潜在功效，并帮助我们优化技术，并设计更大规模的临床试验。

DESCRIPTION (provided by applicant): 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 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" are a biomarker which provides 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 are using 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. Encouraging preliminary pre-clinical data in have already illustrated our ability use acoustic angiography to discriminate small tumors and healthy tissue based on an analysis of microvessel morphology alone. The parent grant involves a comprehensive development of this promising new technology, including both optimizations of the imaging technique, as well as preclinical in-vivo studies using clinically-relevant genetically engineered rodent models of breast cancer to establish sensitivity and specificity in assessing the biomarker of tumor associated angiogenesis as a function of tumor size for early detection. In this supplement/revision application, we propose to carry the technology from the parent grant into a pilot clinical trial. Our goal is to demonstrate that this new imaging technology, Acoustic Angiography, will be effective in human patients. Our approach involves a 60 patient clinical study on patients with suspected breast cancer. Results will be compared for sensitivity and specificity against traditional ultrasound imaging (standard of care), as well as gold standard pathology provided as each patient will receive a biopsy or excision of the lesion. Although this small clinical pilot study will not be able to fully evaluatethe role of Acoustic Angiography in early cancer detection, the results of this study will provide necessary comparison data against gold standards to evaluate the potential efficacy of this new biomarker imaging technique, and help us optimize the technology and design a larger scale clinical trial as we move towards translation.