Association between pre-diagnosis hepatic fat infiltration and risk of liver metastasis and mortality in a large cohort of stage I-III colorectal cancer survivors

项目总结/摘要 I-III期结直肠癌患者切除术后肝转移的发生 提示在CRC诊断之前存在临床上检测不到的肝微转移。非 酒精性脂肪肝（NAFLD）正在迅速成为全球最常见的肝病， 估计在美国人口中的患病率为20-30%。迄今为止，各种证据支持我们的 肝脏脂肪在增强CRC肝转移中的潜在作用的假设;下一步是 证明肝脂肪定量评估作为I-III期预后生物标志物的实用性 临床环境中的CRC患者。在美国，几乎所有的CRC患者都接受了计算机断层扫描（CT） 诊断时扫描，NAFLD是一种高度流行和可治疗的疾病，因此，如果我们的假设是 证实，我们希望建立一个安全和具有成本效益的预后生物标志物，这是目前缺乏的。 最近扩展的C-SCANS（CRC-肌肉减少症和近期生存）队列来自于 Kaiser Permanente北方加州癌症登记处，确定了I-III期CRC患者 在2006年至2018年之间确诊，年龄18 - 80岁，接受手术切除。入选标准 包括患者在诊断后4个月内和治疗前有基线CT图像。 在目标1中， 将在CRC诊断时进行的CT扫描中测量肝脂肪（定量评估）， 在治疗之前。首先，将手动进行测量，然后使用新型机器 基于学习的工具，用于肝脏分割以及肝脏和脾脏衰减的测量。在目标2和 3，我们将检查（a）肝脏脂肪浸润增加是否与肝脏疾病的风险增加有关。 转移、复发和CRC死亡率，以及（B）相关性是否被合并症改变 与代谢综合征相关的危险因素。在目标4中，我们将检查肝脂肪是否影响 通过直接和/或间接作用（例如，通过代谢综合征介导）。 具体来说，我们假设肝脂肪的直接作用在解释肝硬化中更重要。 肝脂肪与肝转移的关系大于间接作用。身体成分数据， 包括 每个患者的骨骼肌和总脂肪、皮下脂肪和内脏脂肪以及肝脂肪， 在相同的CT扫描上测量，结合行为风险因素评估，临床数据， 和代谢血浆标记物，提供了一个前所未有的机会， 研究这些影响。因此，这种具有成本效益和创新性的应用将满足以下迫切需求 更准确的预后生物标志物和相对安全的干预措施，以改善I至III期的预后 CRC患者。考虑到NAFLD患病率的惊人上升，该应用具有以下潜力： 降低大量I-III期CRC患者的发病率和死亡率。

PROJECT SUMMARY/ABSTRACT Development of liver metastases among stage I-III colorectal cancer (CRC) patients following resection suggests the presence of clinically undetectable liver micro-metastases prior to CRC diagnosis. Non- alcoholic fatty liver disease (NAFLD) is quickly emerging as the most common liver disease worldwide with an estimated prevalence of 20-30% in the U.S. population. To date, various lines of evidence support our hypothesis of the potential role of liver fat in enhancing CRC liver metastasis; the next step is to demonstrate the utility of quantitative assessment of hepatic fat as a prognostic biomarker for stage I-III CRC patients in clinical settings. Almost all CRC patients in the U.S. get a computerized tomography (CT) scan at diagnosis, and NAFLD is a highly prevalent and treatable disease, thus, if our hypothesis is confirmed, we hope to establish a safe and cost-efficient prognostic biomarker, which is currently lacking. The recently expanded C-SCANS (CRC-Sarcopenia and Near-term Survival) cohort was derived from the Kaiser Permanente Northern California cancer registry, with ascertainment of patients with stage I-III CRC diagnosed between 2006 and 2018, aged 18−80 years, who underwent surgical resection. Inclusion criteria include that patients had baseline CT images within 4 months of diagnosis, and prior to treatment. In Aim 1, hepatic fat (quantitative assessment) will be measured in CT scans performed at time of CRC diagnosis, and prior to treatment. First, measurements will be performed manually, and then using a novel machine learning-based tool for liver segmentation, and measurement of liver and spleen attenuation. In Aims 2 and 3, we will examine (a) whether increased hepatic fat infiltration is associated with higher risk of liver metastases, recurrence, and CRC mortality, and (b) whether associations are modified by comorbidities and risk factors related to the metabolic syndrome. In Aim 4, we will examine whether hepatic fat affects liver metastases through a direct and/or indirect effect (e.g., mediated through the metabolic syndrome). Specifically, we hypothesize that the direct effect of hepatic fat is more important in explaining the relationship between hepatic fat and liver metastases than the indirect effect. Data on body composition, including skeletal muscle and total, subcutaneous and visceral fat, and hepatic fat for each patient are measured on the same CT scans, which combined with assessment of behavioral risk factors, clinical data, and metabolic plasma markers around the same time , provide an unprecedented opportunity to rigorously study these effects. Thus, this cost-efficient and innovative application will address the urgent need for more accurate prognostic biomarkers and relatively safe interventions to improve prognosis in stage I to III CRC patients. Considering the alarming rise in prevalence of NAFLD, this application has the potential to reduce morbidity and mortality in a substantial number of stage I-III CRC patients.