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

项目摘要/摘要 I-III期结直肠癌患者术后肝转移的发生 提示在结直肠癌诊断前存在临床无法检测到的肝脏微转移。非- 酒精性脂肪性肝病(NAFLD)正迅速成为全球最常见的肝病， 据估计，美国人口中的患病率为20%-30%。到目前为止，各种证据支持我们的 假设肝脏脂肪在促进结直肠癌肝转移中的潜在作用；下一步是 证明定量评估肝脏脂肪作为I-III期预后生物标记物的有效性 临床环境中的结直肠癌患者。美国几乎所有的结直肠癌患者都接受了计算机断层扫描(CT)。 在诊断时扫描，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 如果得到证实，我们希望建立一种安全、经济的预后生物标志物，这是目前所缺乏的。 最近扩大的C扫描(CRC-Sarcopenia和近期生存)队列来自于 Kaiser Permanente North California癌症登记，确定I-III期CRC患者 2006年至2018年确诊，年龄18岁，−80岁，接受手术切除。纳入标准 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， 肝脏脂肪(定量评估)将在诊断为结直肠癌时进行的CT扫描中进行测量， 在治疗之前。首先，将手动进行测量，然后使用新型机器 基于学习的肝脏分割工具，并测量肝和脾的衰减。在AIMS 2和 我们将研究(A)肝脏脂肪渗透增加是否与肝脏风险增加有关。 转移、复发和结直肠癌死亡率，以及(B)合并症是否改变了相关性 以及与代谢综合征相关的危险因素。在目标4中，我们将检查肝脏脂肪是否会影响 通过直接和/或间接影响(例如，通过代谢综合征调节)的肝转移。 具体地说，我们假设肝脏脂肪的直接作用在解释 肝脂肪与肝转移的关系比间接作用大。关于身体成分的数据， 包括 每个患者的骨骼肌和总脂肪、皮下脂肪、内脏脂肪和肝脏脂肪是 在相同的CT扫描上测量，结合行为风险因素的评估，临床数据， 与代谢性血浆标志物几乎同时，提供了前所未有的机会，严格 研究这些影响。因此，这种具有成本效益和创新性的应用程序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改善I-III期的预后 结直肠癌患者。考虑到NAFLD患病率的惊人上升，这一应用程序有可能 降低相当数量的I-III期结直肠癌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.