Understanding Psychosocial and Immunologic Responses in Indolent Lymphoproliferative Disorders

 描述(申请人提供)：2015年，美国将诊断出约71,850例非霍奇金淋巴瘤[NHL]。大约35%的非霍奇金淋巴瘤患者会出现惰性疾病，进展非常缓慢，但被认为是无法治愈的。由于在确诊后立即开始治疗对生存没有好处，因此在出现与疾病相关的症状之前，“观察和等待”[WW]方法(即经常对患者进行监测)是护理的标准。WW的好处包括降低医疗成本和避免与治疗相关的副作用；然而，许多患者报告在WW阶段增加了痛苦和癌症相关的担忧。与一种不治之症的未知轨迹相关的不确定性可能会令人痛苦，并成为一种强大的压力源，导致心理和生理后果。值得注意的是，一些人可能更容易受到不确定情况的影响。不同特征的个体差异，如“不能容忍不确定性”[IU]和神经质，与更大的压力和生理唤醒有关。随着时间的推移，与应激相关的免疫改变可能会对疾病的进展产生临床后果，因为免疫缺陷是NHL的强烈风险因素。自然杀伤细胞对心理压力特别敏感，是控制非霍奇金淋巴瘤的关键。在人类中，NK细胞数量减少，NK细胞活性降低，NK细胞激活受体表达减少与NHL疾病进展和生存期缩短有关，而宿主免疫力较强与病程更缓慢相关。T细胞也是启动NHL免疫反应的关键效应者，通过使用现代流式细胞术，它们的生物标志物表型现在可以提供免疫功能的敏感指标。考虑到与WW方法相关的焦虑和痛苦，以及免疫因素在疾病进展中的作用，惰性NHL提供了一种独特的疾病模型，可以在其中检查未经治疗的癌症患者群体的生物行为路径。因此，在癌症应激的生物行为模型的指导下，我们建议对225名接受WW治疗的新诊断的惰性NHL患者进行前瞻性的纵向研究，以调查较差的心理社会功能(以较高的应激和焦虑为特征)是否与NK功能活动(脱颗粒反应)抑制和激活的NK细胞受体表达减少有关，这反过来又对随着时间的推移疾病的进展具有预后意义。具体目的是：目的1.检查心理社会功能(例如，感觉到的压力、焦虑)与NK细胞和T细胞激活标志物的表达以及随时间推移的功能活动的关系；目的2.评估这些免疫标志物是否与较短的治疗时间间隔有关；以及目的3.确定可能预测随着时间的推移结果较差的特征。研究结果将具有直接的翻译相关性，包括早期识别高危患者或疾病进展的可能性，以及开发非药物方法来减少这一未被研究的患者群体的发病率。

 DESCRIPTION (provided by applicant): In 2015, about 71,850 cases of non-Hodgkin lymphoma [NHL] will be diagnosed in the US. Approximately 35% of patients with NHL will present with indolent disease, which progresses very slowly, but is considered incurable. Because there is no survival benefit to initiating treatment immediately after diagnosis, a "watch-and- wait" [WW] approach (in which patients are monitored frequently) is the standard of care until disease-related symptoms emerge. The benefits of WW include reduced healthcare costs and avoidance of treatment-related side effects; however, many patients report elevated levels of distress and cancer-related worry during the WW phase. The uncertainty associated with the unknown trajectory of an incurable disease can be distressing and act as a powerful stressor, resulting in both psychological and physiological consequences. Notably, some individuals may be more affected by uncertain situations. Individual differences in various characteristics, such as "intolerance of uncertainty" [IU] and neuroticism, have been associated with greater stress and physiologic arousal. Over time, stress-related immune alterations may have clinical consequences for disease progression, since immune deficits are a strong risk factor for NHL. Natural killer [NK] cells, which are particularly sensitive to psychological stress, are critical i controlling NHL. In humans, lower numbers of NK cells, reduced viability of NK cells, and diminished expression of NK cell activating receptors have been associated with NHL disease progression and shorter survival, whereas stronger host immunity is associated with a more indolent disease course. T cells are also key effectors in mounting immune responses to NHL, and through the use of modern flow cytometry, their biomarker phenotypes can now provide sensitive indicators of immune function. Given the anxiety and distress associated with a WW approach, and the role of immune factors in disease progression, indolent NHL offers a unique disease model within which to examine biobehavioral pathways in an untreated cancer patient population. Thus, guided by a biobehavioral model of cancer stress, we propose to conduct a prospective, longitudinal study of 225 newly diagnosed patients with indolent NHL undergoing WW, to investigate whether poorer psychosocial functioning (as characterized by higher stress and anxiety) is associated with suppressed NK functional activity (degranulation response) and reduced expression of activating NK cell receptors, which in turn, have prognostic implications for disease progression over time. The specific aims are: Aim 1. To examine associations of psychosocial functioning (e.g., perceived stress, anxiety) with expression of NK cell and T cell activation markers and functional activity over time; Aim 2. To assess whether these immunologic markers are associated with a shorter interval of time to treatment; and Aim 3. To identify characteristics that may predict poorer outcomes over time. Study findings will have direct translational relevance, including a potential for early identification of patients at-risk or disease progression and the development of non-pharmacologic approaches for reducing morbidity in this understudied patient population.