Dynamic-CT-based biomarker for predicting clinical outcome in CRC

描述（由申请人提供）：结直肠癌（CRC）是美国癌症死亡的第二大原因，并导致显著的发病率和死亡率。患者的五年生存率取决于诊断时的肿瘤分期，肿瘤分期在治疗决策中起着重要作用。因此，准确的治疗前诊断评估和结直肠癌分期是很重要的。此外，血管生成在结直肠癌的生长和转移过程中起着重要作用，并被报道为一种有用的预后标志物，类似于许多其他癌症。因此，在体内定量的肿瘤血管生成率在改善CRC的管理有希望。灌注计算机断层扫描（PCT）采集高时间分辨率图像，从而能够通过模拟示踪剂动力学来评估体内组织的血流动力学变化。PCT已被报道用于表征肿瘤血管生成，并且是比传统肿瘤分期更敏感的预测CRC患者总生存期（OS）的成像生物标志物。然而，在临床实践中，PCT协议是高时间分辨率和所需的总辐射剂量之间的权衡。因此，非常需要使用从四个时间相位（包括造影前相位、动脉相位、门脉相位和延迟相位）导出的动态CT成像，因为它更容易获得，并且对患者产生的辐射暴露比PCT低得多。然而，四相动态CT中的低时间分辨率在示踪剂动力学建模中存在几个障碍，主要是因为缺乏时间增强信息，这限制了获得可靠生理信息的能力。因此，我们将开发一种新的示踪剂动力学的连续时间建模，而没有任何离散化的增强曲线。这种方法将能够估计输入和响应增强的起始时间点之间的时滞以及四相动态CT中的其他动力学参数。我们假设所提出的示踪剂动力学模型可以成为一种有效的成像生物标志物，用于CRC复发的风险分层和OS的预测。为了探索这些假设，所提出的项目的具体目标是：（1）开发一种新颖的单输入连续时间示踪剂动力学模型，而无需任何离散化来拟合 在结肠的四期动态CT中的时间增强曲线，和（2）从四期动态CT开发基于动力学模型的成像生物标志物，并评估它们在预测CRC患者的临床结果中的性能。基于四相动态CT的新型成像生物标志物的成功开发为开发量身定制的最佳治疗而无需对患者进行过度辐射暴露提供了很高的希望。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer death in the United States and is responsible for significant morbidity and mortality. A patient's five-year survival rate depend on the tumor stage at the time of diagnosis, and stage of the tumor plays a substantial role in decision-making regarding treatment. Thus, precise pre-treatment diagnostic evaluation and staging of colorectal cancer are important. In addition, angiogenesis plays an important role in the process of growth and metastasis in CRC and is reported as a useful prognostic marker, similar to many other carcinomas. Thus, in vivo quantification of the tumor angiogenesis rate holds promise in improving the management of CRC. Perfusion computed tomography (PCT) acquires high temporal resolution images, thus enabling evaluation of hemodynamic changes of tissue in vivo by modeling tracer kinetics. PCT has been reported to characterize tumor angiogenesis, and to be a more sensitive imaging biomarker for predicting of overall survival (OS) of CRC patients than conventional tumor staging. In clinical practice, however, the PCT protocol is a trade-off between high-temporal resolution and the total radiation dose required. Thus, the use of dynamic CT imaging derived from four temporal phases, which include pre-contrast, arterial, portal, and delayed phases, is highly desirable, because it is more readily available and yields substantially lower radiation exposure to the patients than that of PCT. However, low temporal resolution in four-phase dynamic CT presents several barriers in modeling tracer kinetics, primarily because of the lack of temporal enhancement information, which limits the ability to obtain reliable physiological information. We will thus develop a novel continuous-time modeling of tracer kinetics without any discretization of the enhancement curves. Such an approach will enable estimation of the time lag between onset time points of input and response enhancements as well as other kinetic parameters in four-phase dynamic CT. We hypothesize that the proposed tracer kinetic model can be an effective imaging biomarker for the risk stratification of recurrence of CRC and for prediction of OS. To explore these hypotheses, the specific aims of the proposed project are (1) Develop a novel single-input continuous-time tracer kinetic model without any discretization to fit temporal enhancement curves in four-phase dynamic CT of the colon, and (2) develop kinetic-model-based imaging biomarkers from four-phase dynamic CT and evaluate their performance in predicting clinical outcome in CRC patients. Successful development of a novel imaging biomarker based on four-phase dynamic CT holds high promise for the development of tailor-made optimal therapy without excessive radiation exposure to the patient.