Understanding Psychosocial and Immunologic Responses in Indolent Lymphoproliferative Disorders

 描述（由申请人提供）：2015年，美国将诊断出约71，850例非霍奇金淋巴瘤[NHL]。大约35%的NHL患者会出现惰性疾病，进展非常缓慢，但被认为是不可治愈的。由于在诊断后立即开始治疗没有生存益处，因此“观察和等待”[WW]方法（其中频繁监测患者）是护理标准，直到出现疾病相关症状。WW的好处包括降低医疗费用和避免治疗相关的副作用;然而，许多患者报告在WW阶段的痛苦和癌症相关的担忧水平升高。与不治之症的未知轨迹相关的不确定性可能是令人痛苦的，并作为一个强大的压力源，导致心理和生理后果。值得注意的是，有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“不确定性的耐受性”[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，应激相关的免疫改变可能会对疾病进展产生临床后果，因为免疫缺陷是NHL的一个强有力的风险因素。自然杀伤[NK]细胞对心理压力特别敏感，在控制NHL中至关重要。在人类中，NK细胞数量减少、NK细胞活力降低和NK细胞活化受体表达减少与NHL疾病进展和生存期缩短相关，而较强的宿主免疫力与更缓慢的病程相关。T细胞也是对NHL产生免疫应答的关键效应子，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，在其中检查未经治疗的癌症患者群体的生物行为途径。因此，在癌症应激生物行为模型的指导下，我们建议对225例接受WW的新诊断惰性NHL患者进行前瞻性纵向研究，以调查较差的心理社会功能是否（以较高的压力和焦虑为特征）与NK功能活性抑制有关（脱颗粒反应）和活化NK细胞受体的表达减少，这反过来对疾病随时间的进展具有预后意义。具体目标是：目标1。检查心理社会功能的关联（例如，感知的压力，焦虑）与NK细胞和T细胞活化标志物的表达和功能活动随时间的推移;目的2.评估这些免疫学标志物是否与较短的治疗时间间隔相关;目的3。识别可能预测随时间推移不良结局的特征。研究结果将具有直接的翻译相关性，包括早期识别风险患者或疾病进展的可能性，以及开发非药物方法来降低该研究不足的患者人群的发病率。

 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.