Investigating Correlates and Therapeutics of Fatigue in Cancer Patients

疲劳是一种多维症状，影响38%的社区个人和42%的初级保健患者。这是慢性病和癌症中最常见和最令人虚弱的症状之一。它对直接和间接的卫生经济结果都有重大影响，估计每年损失3.3亿美元的生产时间，主要是由于工作绩效下降。在癌症中，疲劳对日常活动、身体健康/功能以及与重要他人的关系的负面影响最大。疲劳被描述为一种持续的主观疲劳感，干扰了正常的功能。它可以与正常的日常疲劳区分开来，因为它更频繁、更无情、更不可预测，而且无法通过休息来解决。疲劳可能受到生理因素(如炎症或中枢神经系统功能障碍)、心理社会因素(如抑郁或焦虑)和生活方式因素(如饮食、锻炼、饮酒、吸烟或社会角色)的综合影响。疲劳还与导致症状负担的其他症状(如疼痛、抑郁)共存，从而对患者与健康相关的生活质量产生负面影响。疲劳的病因尚不清楚，但据信有中枢和外周两种成分。中枢性疲劳被认为是由于5-羟色胺能通路在运动过程中限制肌肉纤维募集而导致中枢神经系统驱动力下降，从而减少肌肉糖酵解、耗氧量和心血管功能。外周疲劳是指特定肌肉即使在神经驱动力增强的情况下也无法执行任务。这被认为是由动作电位失效、跨桥形成障碍或兴奋收缩偶联失效引起的，神经刺激增加。尽管越来越多的文献表明这两种机制可能存在相互作用，但中枢性和外周性疲劳之间的相互作用尚不清楚。 研究小组继续招募参与者参加他们的研究，调查分子-遗传相关性，以及癌症相关疲劳的可能治疗方法。该小组最近取得了与癌症治疗相关的谷氨酸能受体激活的重大发现，该受体引发炎症，这可能解释了与癌症治疗相关的疲劳体验。进一步的验证正在通过临床研究、动物项目和体外实验进行。PI正在与国家癌症研究所多学科前列腺癌诊所的合作者密切合作，继续招募研究参与者。研究小组还与NIH的几个核心实验室合作，以进一步开展他们的调查。

Fatigue is a multidimensional symptom that impacts 38% of community-based individuals and 42% of primary care patients. It is one of the most common and most debilitating symptoms in chronic illness and in cancer. It has significant repercussions on both direct and indirect health economic outcomes, costing an estimated annual lost productive time of US$330 million mostly due to reduced work performance. In cancer, fatigue had the greatest negative impact on daily activity, physical well-being/function, and relationships with significant others. Fatigue is described as a persistent, subjective sense of tiredness that interferes with usual functioning. It can be distinguished from normal everyday tiredness, because it is more frequent, unrelenting, unpredictable, and unresolved by rest. Fatigue may be influenced by a combination of physiological factors (e.g., inflammation or central nervous system dysfunction), psychosocial factors (e.g., depression or anxiety), and lifestyle factors (e.g., diet, exercise, alcohol use, tobacco use, or social role). Fatigue also co-occurs with other symptoms (e.g., pain, depression) contributing to symptom burden, which negatively affects health-related quality of life of patients. The etiology of fatigue is unknown, but it is believed to have central and peripheral components. Central fatigue is hypothesized to result from a decrease in central nervous system drive brought about by serotonergic pathways limiting muscle fiber recruitment during exertion reducing muscle glycolysis, oxygen consumption, and cardiovascular function. Peripheral fatigue is the inability of a particular muscle to perform a task even with an increased neural drive. This is thought to be caused by an action potential failure, cross-bridge formation impairment, or excitation contraction coupling failure amidst increased neural stimulation. The interplay between central and peripheral types of fatigue remains unclear although an increasing body of literature has indicated a potential interaction of both mechanisms. The research team continues to enroll participants for their studies that investigate the molecular-genetic correlates, as well as possible therapeutics of cancer-related fatigue. The group recently made significant discoveries related to the activation of glutamatergic receptors associated with cancer therapy that trigger inflammation that may explain the fatigue experience related to cancer therapy. Further validation is being conducted through clinical studies, animal projects and in vitro experiments. The PI is working closely with collaborators from the Multidisciplinary Prostate Cancer Clinics of the National Cancer Institute to continue to recruit study participants. The study team is also collaborating with several NIH core laboratories to further their investigations.