2013-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658236摘要：肋膜積液是臨床上常見的疾病，許多不同的原因都有可能造成肋膜積液。肋膜腔穿刺與積水分析仍然是診斷肋膜液成因的主要方式。由於結核分枝桿菌很難從肋膜液培養出來同時惡性胸水細胞學假陰性結果高達 40％，因此在台灣困難確診的滲出性肋膜積液最常見的原因是惡性腫瘤及結核病。儘管腺苷脫氨酶（ADA）對於診斷結核性肋膜積液的特異性高達（95％），但對於惡性血液病和細菌感染卻缺乏特異性。其他診斷方式如 T細胞 IFN -γ釋放檢測和核酸擴增試驗均因靈敏度差而不適合臨床上使用。最近利用代謝體分析找出結核分枝桿菌體外培養產生的四種獨特揮發性化合物（苯乙酸甲酯，甲基P - anisate，甲基菸酸和 O - phenylanisole），此外，在抹片陽性的結核病患者的吐出氣體中可以檢測到甲基菸酸，因此可做為診斷肺結核之依據。我們未來借助代謝體分析這個強大的工具，將可發現結核性肋膜炎新的診斷生物標記。 肺癌在全世界是一個造成疾病死亡率相當高的疾病，近年來由於標靶治療的進步使得肺癌患者的存活延長。雖然如此，標靶藥物的使用仍然會有抗藥性的出現。如何預測標靶藥物的療效，與避免抗藥性將有助於改善肺癌患者的存活。然而，不同的 EGFR 突變測試有不同的靈敏度，同時肺癌組織也不容易取得因此限制了臨床上的使用。由於肺癌是惡性肋膜積液最常見的原因，而且肺癌患者時常需要抽取肋膜積液以緩解症狀。因此，肋膜積液是一個生物標記檢測理想的 biofluid，可作為預測標靶治療（如 EGFR 或 EML4 - ALK 抑製劑）在肺癌患者的治療效果與耐藥性的產生。代謝體學（metabolomics）為系統生物學(systems biology)中質體學（＂omics＂）的一部份，其主要為整體而大規模的量測不同生理狀態下的體內代謝物(metabolites)分布。由於基因表現於生物體最終是以代謝物的方式呈現，因此一些環境或疾病的變化最終都會造成代謝物濃度與分布的改變。比較不同疾病或狀態下代謝物分布的改變，可以了解基因表現及各種蛋白酶作用所帶來的變化，因而代謝體的研究方法可視為整合性的評估多項生物體途徑與反應最終結果。許多研究利用 NMR 或 MS，來探討其在疾病的早期診斷、預後判斷、與監測治療反應上的應用與角色。在本研究中，我們希望應用代謝體學來探討不同成因的肋膜液中代謝物與代謝體的變化，希望能藉此發現與肋膜液成因相關的生物標記，與預測肺癌標靶治療的效果。希望進一步闡釋關連的生物機轉與作用路徑。<br> Abstract: Pleural effusion is a common presentation in clinical practice and can be resulted from a large variety of malignant or benign processes. Because of difficulty in isolation of Mycobacterium tuberculosis in pleural fluid and the presence of false negative cytological results of malignant pleural effusions in up to 40% of cases, the most common causes for undiagnosed exudative pleural effusions are malignancy and tuberculosis in Taiwan. Despite the fact that the specificity of adenosine deaminase(ADA) for discriminating TB from malignant effusions is high (95%), it is disappointingly low for effusions caused by hematological malignancies and bacterial infection due to its nonspecific nature. Other specific diagnostic tests, such as T-cell-based IFN-γ release assays and nucleic acid amplification tests, are limited by very poor sensitivity. Recentily, four specific compounds (methyl phenylacetate, methyl p-anisate, methyl nicotinate and o-phenylanisole) from Mtb cultures grown in vitro were identified as distinctive volatile markers using metabolomic analysis. Furthermore, methyl nicotinate has been detected in the breath of smear-positive TB patients at statistically significant levels compared with healthy controls. With the aid of this powerful tool, metabolomics will shed light on new biomarker discovery for diagnosis of tuberculous pleurisy. Lung cancer is the leading cause of cancer deaths worldwide, efforts to improve the survival of these patients is currently focused on new target-based therapies directed against key signaling pathways involved in lung cancer growth and malignant progression. Among these, patient EGFR mutational status is the best predictor of benefit from EGFR TKI therapy. However, variable sensitivity of EGFR mutation tests and lung cancer tissue unavailability lead to limited clinical use. Lung cancer is the most common cause of malignant pleural effusion, and we perform thoracentesis frequently on an out patient basis for diagnosis testing and symptomatic relief. Therefore, pleural effusion is an ideal biofluid for markers detection, which may predict treatment response and acquired resistance of target-based therapies (such as EGFR or EML4-ALK inhibitors) in lung cancer patients. Metabolomics, an omic science in systemic biology, is the global quantitative assessment of endogenous metabolites within a biological system. Advances in metabolic profiling technologies and methods of pattern recognition enable the monitoring of hundreds of metabolites from tissue or body fluids associated with disease physiology. Metabolomics, when used as a translational research tool, can provide a link between the laboratory and clinic. The current proposal is aimed to establish the metabolomic profiling of pleural effusions in tuberculous pleurisy patients, lung cancer patients and controls (hear failure/liver cirrhosis patient), in order to setup a useful noninvasive tool for tuberculous pleurisy diagnosis, malignant pleural effusion diagnosis and predicting treatment response and acquired resistance of target-based therapies in lung cancer patients.代謝體學肋膜液結核性肋膜炎肺癌標靶治療metabolomicspleural effusiontuberculous pleurisylung cancertarget-based therapy.