Contrast-Enhanced Ultrasound for Diagnosis and Therapy of Cholangiocarcinoma

项目摘要： 肝内胆管细胞癌是一种侵袭性上皮性肿瘤，预后差， 由胆道内壁引起的疾病。ICC的管理选择有限， 一般预后都不好目前，不适合切除的患者的治疗选择 标准化，包括全身治疗和局部治疗，如消融、经动脉 化疗栓塞（TACE）和经动脉放射性栓塞（TARE）。使用TARE，放射性微球 通过放置在供应肿瘤的肝动脉分支中的导管输送，从而提供局部的 并持续释放辐射然而，根据改良的缓解评价标准， 在mRECIST中，肿瘤的平均存活率范围为25-60%，中位存活率保持在约13-15.5个月。 超声造影（CEUS）利用静脉注射气体微泡。我们集团 已经证明了2D和3D动态CEUS预测肝细胞癌（HCC）缓解的能力 并监测反应。我们还展示了使用次谐波频率的能力 这些药物的成分，以非侵入性地测量肿瘤间质液压力（IFP）的过程中， 化疗。另外，这些超声造影剂的独特性质是它们产生超声造影剂的能力。 使用更高强度的超声脉冲的稳定或惯性空化。重要的是，微泡空化已经被 显示通过诱导血管内皮细胞凋亡使血管生成血管对放疗敏感。 本研究的目的是：1）确定定量容积CEUS预测ICC的能力 治疗前对TARE的反应，2）表征使用局部UCA的安全性和初步疗效 惯性空化以改善ICC对放射性栓塞的反应，以及3）确定CEUS是否估计肿瘤 灌注、IFP和残余血管可以预测治疗后7-14天ICC对放射性栓塞的反应。 作为本临床试验的一部分，患者将接受4次容积CEUS检查，结合其标准 放射性栓塞治疗。第一次检查的定量数据将在TARE之前获得，并用于 确定CEUS是否可以预测治疗反应的可能性（目的1）。CEUS考试2-4将获得2 TARE后2小时至2周，并将包括快速补充序列，以诱导惯性微泡 气穴现象然后将安全性和肿瘤反应与历史对照进行比较，以确定 微泡空化治疗（目的2）。最后，在CEUS期间获得的肿瘤灌注和血管数据 将对检查2-4进行量化，以确定这些参数是否可用于预测长期治疗 响应（目标3）。如果成功，本提案中验证的技术有望改善ICC 通过确定哪些患者将从TARE中获益最多，改善对TARE的肿瘤反应， 及早发现无反应的疾病，从而减少用替代疗法重新治疗的时间。

Project Summary: Intrahepatic cholangiocarcinoma (ICC) is an aggressive epithelial tumor with poor prognosis and high morbidity arising from the lining of the biliary tract. Management options for ICC are limited and the disease generally carries a poor prognosis. Treatment options for patients not eligible for resection are currently not standardized and include systemic therapies and loco-regional therapies such as ablation, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE). Using TARE, radioactive microspheres are delivered via a catheter placed in the hepatic artery branch supplying the tumor, thereby providing a localized and sustained release of radiation. However, response rates on modified response evaluation criteria in solid tumors (mRECIST) range from 25-60% and median survival remains at approximately 13-15.5 months. Contrast-enhanced ultrasound (CEUS) utilizes the intravenous injection of gas microbubbles. Our group has demonstrated the ability of 2D and 3D dynamic CEUS to predict hepatocellular carcinoma (HCC) response to TACE a priori and also monitor response. We have also shown the ability to use the subharmonic frequency components from these agents to non-invasively measure tumor interstitial fluid pressures (IFP) over the course of chemotherapy. Additionally, a unique property of these ultrasound contrast agents is their ability to generate stable or inertial cavitation using higher intensity ultrasound pulses. Importantly, microbubble cavitation has been shown to sensitize angiogenic vessels to radiotherapy by inducing vascular endothelial-cell apoptosis. The aims of this project are 1) to determine the ability of quantitative volumetric CEUS to predict ICC response to TARE prior to therapy, 2) to characterize the safety and preliminary efficacy of using localized UCA inertial cavitation to improve ICC response to radioembolization, and 3) to determine if CEUS estimated tumor perfusion, IFP, and residual vascularity can predict ICC response to radioembolization 7-14 days post treatment. As part of this clinical trial, patients will undergo 4 volumetric CEUS exams combined with their standard of care radioembolization. Quantitative data from the first exam will be obtained prior to TARE and used to determine if CEUS can predict the likelihood of treatment response (aim 1). CEUS exams 2-4 will be obtained 2 hours to 2 weeks post TARE and will include flash-replenishment sequences to induce inertial microbubble cavitation. Safety and tumor response will then be compared to historical controls to determine the effect of microbubble cavitation on therapy (aim 2). Finally, tumor perfusion and vascularity data obtained during CEUS exams 2-4 will be quantified to determine if these parameters can be used to predict longer term treatment response (aim 3). If successful, the techniques validated in this proposal are expected to improve ICC management by identifying which patients would benefit most from TARE, improving tumoral response to TARE, identifying non-responding disease early and thereby reducing the time to retreatment with alternative therapies.