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

大量 I-III 期结直肠癌幸存者中诊断前肝脂肪浸润与肝转移风险和死亡率之间的关联

• 批准号: 10295142
• 负责人: EDWARD GIOVANNUCCI
• 金额: $ 71.31万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295142
• 关键词: Address; Adhesions; Affect; Behavior assessment; Behavioral; Biological Markers; Body Composition; California; Cancer Survivor; Cells; Central obesity; Clinical; Clinical Data; Colorectal Cancer; Data; Data Set; Development; Diabetes Mellitus; Diagnosis; Disease; Distant Metastasis; Dose; Dyslipidemias; Etiology; Excision; Fatty acid glycerol esters; Foundations; Future; Goals; Guidelines; Hepatic; Image; Individual; Infiltration; Inflammatory; Intervention; Link; Liver; Liver Cirrhosis; Liver diseases; Machine Learning; Manuals; Measurement; Measures; Mediating; Metabolic; Metabolic syndrome; Metastatic Neoplasm to the Liver; Methods; MicroRNAs; Micrometastasis; Morbidity - disease rate; Neoplasm Circulating Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Plasma; Population; Prevalence; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Prognosis; Prognostic Factor; Prognostic Marker; Recurrence; Relapse; Risk; Risk Factors; Role; Scanning; Seeds; Signal Pathway; Site; Skeletal Muscle; Soil; Spleen; Standardization; Subgroup; Test Result; Testing; Thinness; Time; Visceral fat; X-Ray Computed Tomography; aged; attenuation; base; behavioral pharmacology; cancer diagnosis; cohort; colon cancer patients; colorectal cancer metastasis; colorectal cancer progression; comorbidity; cost; cost efficient; design; future implementation; high risk; improved; inclusion criteria; innovation; liver development; mortality; neoplasm registry; non-alcoholic fatty liver disease; non-diabetic; novel; physical inactivity; radiologist; response; risk stratification; sarcopenia; sociodemographics; subcutaneous; tool; tumor-immune system interactions

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.

项目概要/摘要 I-III 期结直肠癌 (CRC) 患者切除后发生肝转移 表明在非结直肠癌诊断之前存在临床无法检测到的肝脏微转移。 酒精性脂肪肝病（NAFLD）正迅速成为全球最常见的肝脏疾病， 据估计，美国人口中的患病率为 20-30%。 迄今为止，各种证据都支持我们的观点。 假设肝脏脂肪在增强结直肠癌肝转移中具有潜在作用；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效用 临床环境中的 CRC 患者几乎所有 CRC 患者都会接受计算机断层扫描 (CT)。 诊断时进行扫描，NAFLD 是一种高度流行且可治疗的疾病，因此，如果我们的假设是 确认后，我们希望建立一种安全且具有成本效益的预后生物标志物，而这是目前所缺乏的。 最近扩展的 C-SCANS（CRC-肌肉减少症和近期生存）队列源自 Kaiser Permanente 北加州癌症登记处，确定 I-III 期 CRC 患者 2006年至2018年间诊断，年龄18-80岁，接受手术切除的患者。 包括患者在诊断后 4 个月内和治疗前获得基线 CT 图像。 在目标 1 中， 肝脂肪（定量评估）将通过 CRC 诊断时进行的 CT 扫描进行测量， 首先，在治疗之前，将手动进行测量，然后使用新型机器进行测量。 用于肝脏分割以及肝脏和脾脏衰减测量的学习工具。 3、我们将检查（a）肝脏脂肪浸润增加是否与肝病风险较高相关 转移、复发和 CRC 死亡率，以及 (b) 相关性是否会因合并症而改变 以及与代谢综合征相关的危险因素 在目标 4 中，我们将检查肝脂肪是否会影响。 通过直接和/或间接作用（例如，通过代谢综合征介导）发生肝转移。 具体来说，我们认为肝脂肪的直接影响对于解释这一现象更为重要。 肝脂肪与肝转移之间的关系不是对身体成分的间接影响。 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 扫描上进行测量，并结合行为风险因素、临床数据的评估， 和代谢血浆标记物大约在同一时间，提供了一个前所未有的机会来严格 因此，这种具有成本效益的创新应用将满足对这些影响的迫切需求。 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 考虑到 CRC 患者 NAFLD 患病率的惊人上升，该应用有潜力。 降低大量 I-III 期 CRC 患者的发病率和死亡率。