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，是造成显著发病率和死亡率的原因。患者的五年生存率取决于诊断时的肿瘤分期，而肿瘤分期在治疗决策中起着重要作用。因此，精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，体内肿瘤血管生成率的量化有望改善结直肠癌的治疗。灌注计算机断层扫描（PCT）获得高时间分辨率的图像，从而能够通过建模示踪动力学来评估体内组织的血流动力学变化。据报道，PCT表征肿瘤血管生成，是一种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方案是在高时间分辨率和所需的总辐射剂量之间的权衡。因此，动态CT成像的四个时间期，包括对比前期、动脉期、门静脉期和延迟期，是非常可取的，因为它比PCT更容易获得，对患者的辐射暴露也更低。然而，四期动态CT的低时间分辨率给示踪动力学建模带来了一些障碍，主要是因为缺乏时间增强信息。这限制了获取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连续时间模型，而不需要任何增强曲线的离散化。这种方法可以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的其他动力学参数。我们假设所提出的示踪动力学模型可以作为CRC复发风险分层和预测OS的有效成像生物标志物。为了探索这些假设，提出的项目的具体目标是：(1)开发一种新的单输入连续时间示踪剂动力学模型，不需要任何离散化来拟合

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.