癌末患者之症狀群集與惡病質：著重於脂締素之角色

Symptom Cluster and Cachexia in Advanced Cancer Patients: Focusing on Adiponectin

蔡兆勳(Jaw-Shiun Tsai)

指導教授 ： 莊立民 ； 陳慶餘

國立臺灣大學/醫學院/臨床醫學研究所/博士(2011年)

https://doi.org/10.6342/NTU.2011.00840

摘要

癌症是目前醫學一項重要的挑戰，因為每年全世界有幾百萬人死於癌症。因此，安寧緩和醫療對癌症末期病人的照護非常重要。症狀控制是安寧緩和醫療非常重要的一部份。癌末病人的症狀包括多重性、同時發生、高嚴重度等特徵。症狀群集是目前癌末病人症狀評估、處置及研究的新領域。過去幾年，在這方面已有快速的進展。然而，產生症狀群集的機轉、身體症狀及心理困擾與症狀群集的關係、症狀群集跟病人預後的關係，目前參考資料匱乏，有待進一步研究。為改善症狀控制的效果，我們收集了427位癌症末期病人的資料進行研究，透過因素分析（factor analysis）確認五個症狀群集，分別命名為能量耗損(loss of energy, LE)，進食不佳(poor intake, PI)，自主神經失調(autonomic dysfunction, AD)，呼吸消化障礙(aerodigestive impairment, AI)，疼痛(pain complex, PC)。根據因素分析所得到的五個症狀群集的因素分數（factor score），我們進一步利用群集分析（cluster analysis）將病人分成六組，每組病人具有特別的症狀群集型態。更重要的是，病人的存活時間（survival）、身體功能（functional performance）、骨骼轉移（bone metastasis）、體液堆積（fluid accumulation）跟這六組病人的症狀群集有顯著相關。了解症狀群集的相關因素，將為癌末病人的症狀控制提供更好的臨床照護策略。
惡病質（cachexia）是癌症病人經常發生的能量代謝異常狀態，是影響癌症病人預後的重要因素之一，惡病質相關症狀的發生具有重要的臨床意義。脂締素（adiponectin）在身體能量代謝方面扮演重要的角色，通常血漿中脂締素的濃度跟身體質量指數（body mass index）呈現負相關。為了探討脂締素在癌症病人能量代謝異常的角色，我們進一步研究91位癌症病人血清脂締素濃度跟身體質量指數的關係，特別重視病人的身體功能及存活期。我們發現只有在身體功能較好的病人(ECOG=1)，血清中脂締素濃度跟身體質量指數呈現負相關，但是在身體功能較差的病人（ECOG≧2）並沒有這樣的關係。我們也發現血清中脂締素濃度合併身體功能及腫瘤遠處轉移，在身體功能較差的病人（ECOG≧2）是存活期的獨立預測因子。
肌肉和脂肪組織的同時消瘦是癌症惡病質重要的特徵。發炎反應在癌症惡病質過程扮演重要角色。在癌症惡病質動物的骨骼肌、脂肪組織及腫瘤組織，經常看到巨噬細胞的浸潤增加。脂締素除了在脂肪細胞表現，最近的研究也證實巨噬細胞（macrophage）會表現脂締素。為了解單核球（monocyte）所製造的脂締素在癌症惡病質的角色，我們建立了單核球的體外模式，探討單核球製造的脂締素對單核球功能的影響。我們第一個發現rosiglitazone (RSG)可以促進單核球peroxisome proliferator-activated receptor-gamma （PPARγ）的表現和功能，同時促進脂締素在單核球及巨噬細胞的表現。RSG促進單核球表現的脂締素，可以透過活化AMP-activated protein kinase (AMPK)的訊息傳遞路徑減少整合素（integrin α5）的表現，進而抑制纖維結合素(fibronectin)所誘導的單核球黏著(adhesion)。
為了進一步探討血漿脂締素濃度、單核細胞（mononuclear cell）脂締素表現程度及癌症病人存活期的關係，我們收集了28位胃癌病人和57位自願者當對照組。我們發現胃癌病人單核細胞表現脂締素的程度較對照組低，同時也發現胃癌病人單核細胞表現脂締素的程度是病人存活時間的獨立預測因子。
惡病質相關的症狀是末期癌症病人很重要的症狀群集內容。血清脂締素在癌症惡病質扮演重要角色，同時也是癌症病人存活期的獨立預測因子。單核球本身製造的脂締素不僅具有抑制單核球黏著的作用，同時也跟胃癌病人的存活期有關。透過這一系列研究，我們發現血清脂締素及單核細胞表現的脂締素都是癌症的生物指標，跟癌症病人的惡病質和存活期有關。

關鍵字

脂締素 ； 單核球黏著 ； 癌症惡病質 ； 症狀群集 ； 存活期

並列摘要

Cancer is a great challenge in medicine, because there are several million people died of cancer worldwide every year. Thus, hospice and palliative care is very important in advanced cancer patients. Symptom management is an essential component of hospice and palliative care. The symptoms of advanced cancer patients are multiple, concurrent and severe in intensity. Research on symptom clusters is now a frontier in the studies of the management of patients with advanced cancers. A rapid progress has been made in the studies on symptom clustering in past few years. However, investigation of the underlying mechanisms for the aggregation of symptoms, associations of physical signs and psychological distress with symptom clustering, and the relation of symptom clustering to prognosis in cancer patients are still lacking. For better quality of palliative are, we recruited 427 advanced cancer patients and identified five symptom clusters by exploratory factor analysis, namely, loss of energy (LE), poor intake (PI), autonomic dysfunction (AD), aerodigestive impairment (AI), and pain complex (PC). Based on the factor scores of five symptom clusters, we further used non-hierarchical cluster analysis to divide the patients into six groups. Each group was characterized by a particular pattern which composed of different symptom clusters. Survival, functional performance, bone metastasis, and fluid accumulation were significantly associated with symptom clustering in six groups of patients. The underlying mechanisms of symptom clustering provide a good clinical decision making for better symptom control in advanced cancer patients.
Cachexia is important clinical manifestation of cancer patients, which is a disorder of energy homeostasis. Adiponectin is an important regulator of energy homeostasis. Since plasma adiponectin levels are negatively correlated with body mass index, we investigated the relation of serum adiponectin levels with survival and body mass index in 91 cancer patients, with more focus on functional status and the survival of patients. We found that the inverse relation between serum adiponectin levels and BMI was only observed in cancer patients with better functional performance (ECOG=1), but not in the ECOG≧2 group. We also found serum adiponectin level, in addition to functional performance and tumor metastasis, is an independent predictor for survival in cancer patients with poor functional status（ECOG≧2）.
Muscle and adipose tissue wasting is a prominent stigma of cancer cachexia. Inflammation is an important underlying mechanism in development of cancer cachexia. In histopathological examination, macrophage infiltration in skeletal muscle, adipose tissue and tumor microenvironment are frequently observed. Not only adipocytes but also macrophages express adiponectin. To understand the role of locally monocyte-produced adiponectin in development of cancer cachexia, we employed an in vitro monocyte culture system to study the effect of de novo synthesized adiponectin on monocyte functions. Our studies provided the first evidence to show that rosiglitazone (RSG) can upregulate the expression and function of peroxisome proliferator-activated receptor-gamma（PPARγ）and adiponectin in human monocytes/macrophages. The locally upregulated expression of adiponectin by the PPARγ agonist RSG inhibits the fibronectin-induced monocyte adhesion via an AMP-activated protein kinase (AMPK)-dependent pathway to downregulate integrin.
To further investigate the association among plasma adiponectin levels, adiponectin mRNA expression levels in mononuclear cells and survival in cancer patients, we recruited a group of 28 gastric cancer patients and 57 volunteers. We found that compared with volunteers in the control group, adiponectin mRNA expression levels were significantly lower in mononuclear cells of gastric cancer patients. We also found that adiponectin mRNA expression level in mononuclear cells is an independently predictive factor for their survival.
Cachexia-related symptoms are important components of symptom clustering in advanced cancer patients. Serum adiponectin levels play an important role in cancer cachexia and are an independent factor for patients’ survival. Furthermore, monocyte-produced adiponectin can inhibit monocyte adhesion and associate with survival in gastric cancer patients. Through series of our studies, we have delineated a novel biomarker, both circulating and monocyte-derived adiponectin, in clinical correlation with cancer cachexia and outcome.

並列關鍵字

adiponectin ； monocyte adhesion ； cancer cachexia ； symptom cluster ； survival

參考文獻

82. Hsieh MY, Tsai JS, Chen CY, Chiu TY. Therapeutic update on symptom clusters in advanced cancer patients. Formosan Journal of Medicine. 2011;15:62-69.（in Chinese）

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