Non-invasive Assessment of Skeletal Muscle Loss in Cancer Patients

描述(申请人提供)：这项研究的长期目标是开发一种非侵入性的方法，用于早期评估癌症患者的从头3MH产生，以此作为评估哪些患者未来发展为骨骼肌萎缩的高风险的方法。该方法是基于已知3-甲基组氨酸(3MH)从头产生的速率常数在这一亚组癌症患者中的增加，这是由于他们独特的肿瘤-宿主相互作用的结果。因此，我们假设，摄入单剂量3-甲基组氨酸(D-3MH)后同位素衰减曲线末端的速率常数提供了这种增加风险的准确测量，并且该速率常数可以从在此期间获得的定时现场尿样中非侵入性地测量。此外，我们假设，在给药期间摄入3MH的膳食不会对结果产生负面影响，从而使整个过程具有临床意义。在第一阶段，我们将通过测试以下假设来确定我们的总体方法的可行性：(I)现场尿样中的同位素浓缩与相应的血浆样本相同，以及(Ii)直到并包括剂量时间的肉类摄入量不影响同位素衰变曲线末端的斜率。测试这两个假设的有效性是第一阶段研究的中心焦点，对于开发一种既科学合理又非侵入性和临床相关的方法至关重要。我们将在10名健康的老年男性志愿者身上测试我们方法的可行性。如果第一阶段测试成功，我们建议在第二阶段的资助下，进行一项统计上强大的前瞻性调查，以证明在新诊断的肺癌和胃肠道癌症患者中进行的这项测试可以预测肌肉萎缩的未来发展。我们预计，第一阶段和第二阶段合并研究的结果将导致制造和销售一种合适的“测试试剂盒”，用于早期识别有风险的癌症患者肌肉蛋白分解增加的情况，以便进行医疗干预并防止未来的肌肉萎缩。 项目简介：在不同类型的癌症患者中，骨骼肌丢失是一种重要但不可预测的现象。临床上显着的骨骼肌丢失是不能逆转的，而且预后不佳。它的早期评估很重要，因为它将允许选择癌症患者采取预防策略。该项目的目的是开发一种非侵入性的方法，用于癌症患者骨骼肌降解增加的早期评估。我们的方法是基于(非放射性)稳定同位素示踪方法的发展，通过监测在晚餐时摄入少量标记的3-甲基组氨酸后第二天早上现场尿样中标记/未标记的3-甲基组氨酸的比率，允许准确地定量测量肌肉丧失过程中早期的骨骼肌降解。

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop a non-invasive approach for early assessment of de novo 3MH production in cancer patients as a way of assessing which patients are at high risk for future development of skeletal muscle atrophy. The approach is based on the known increase in the rate constant for de novo production of 3-methylhistidine (3MH) in this sub-set of cancer patients as a consequence of their unique tumor-host interactions. As such, we hypothesize that the rate constant for the terminal portion of the isotope decay curve following ingestion of a single oral dose of deuterated-3-methylhistidine (D-3MH) provides an accurate measure of this increased risk and that this rate constant can be measured non-invasively from timed spot urine samples obtained during this period. Furthermore, we hypothesize that consumption of 3MH- containing meals up to the time of dosing will not adversely affect the results making the entire procedure clinically relevant. During Phase I, we will establish the feasibility of our over all approach by testing the following hypotheses: (i) isotope enrichment in spot urine samples is identical with the corresponding plasma samples, and (ii) meat intake up to and including the time of dosing does not influence the slope of the terminal portion of the isotope decay curve. Testing the validity of these two hypotheses is the central focus of the Phase-I research and is crucial to the development of an approach that is both scientifically sound as well as non-invasive and clinically relevant. We will test the feasibility of our approach in ten healthy older adult male volunteers. If Phase-I testing is successful, we propose, with Phase-II funding, to conduct a statistically powerful prospective investigation to demonstrate that this test conducted in newly diagnosed lung and gastrointestinal cancer patients predicts future development of muscle wasting. We expect the outcome of the combined Phase-I and Phase-II research to lead to the manufacture and marketing of a suitable "Test Kit" for early identification of increased muscle proteolysis in at-risk cancer patients so that medical intervention can take place and prevent future muscle atrophy. Project Narrative: Skeletal muscle loss is an important, but unpredictable, occurrence in patients with different types of cancer. Clinically significant skeletal muscle loss cannot be reversed and has poor prognostic implications. Its early assessment is important because it would permit selection of cancer patients for preventive strategies. The purpose of this project is to develop a non-invasive method for early assessment of increased skeletal muscle degradation in patients with cancer. Our approach is based on development of a (non-radioactive) stable isotope tracer approach to permit accurate quantitative measurement of skeletal muscle degradation early in the course of muscle loss by monitoring spot urine samples for the ratio of labeled/unlabeled 3-methylhistidine the morning after consuming a small amount of labeled 3-methylhistidine along with dinner.