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研究生:吳宜珍
研究生(外文):I-Chen Wu
論文名稱:環境因子(嚼食檳榔及幽門螺旋桿菌感染)和生物指標與食道鱗狀上皮細胞癌的相關性
論文名稱(外文):Relationship of Environmental Factors (Betel Quid chewing and Helicobacter pylori infection) and Biological Markers with Esophageal Squamous Cell Carcinoma
指導教授:吳登強
指導教授(外文):Deng-Chyang Wu
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:97
語文別:中文
論文頁數:62
中文關鍵詞:嚼食檳榔幽門螺旋桿菌感染生物指標食道鱗狀上皮細胞癌
外文關鍵詞:Betel Quid chewingHelicobacter pylori infectionBiological MarkersEsophageal Squamous Cell Carcinoma
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食道鱗狀上皮細胞癌是台灣男性癌症死因的第六位,且其五年存活率非常低(<10%),因此找出罹患食道鱗狀上皮細胞癌的高危險群和有助於早期診斷的分子指標非常重要。吸菸、飲酒是口腔癌和食道癌已知的主要危險因子,嚼食檳榔是台灣口腔癌的重要危險因子,也可能與食道癌的發生有關。此外,我們近來的研究發現幽門螺旋桿菌感染與食道鱗狀上皮細胞癌存在著負相關,幽門螺旋桿菌感染在台灣地區成人的盛行率高達50%,且與許多上消化道疾病有關。因此我們設計研究的目標為:(1)對於在台灣地區新發現與食道鱗狀上皮細胞癌相關的環境因子,包括嚼食檳榔和幽門螺旋桿菌感染作進一步的探討,並找出對後者合理的解釋機制,(2)用microarray篩選於食道鱗狀上皮細胞癌發生時出現明顯表現的基因,並應用在臨床檢體,檢驗目標基因與食道癌的診斷、分期及預後的相關性,以期找出適合的分子指標,以及(3)進行臨床隨機試驗,比較新發明的非侵襲性幽門螺旋桿菌診斷法的準確度,各線幽門螺旋桿菌廓清療法的效果及cytochrome P450 2C19基因多型性對療效的影響。
此博士論文的主要結果為:(1)由個案-對照研究證實吸菸、飲酒及嚼食檳榔是食道鱗狀上皮細胞癌的三大危險因子,且三者間有加成作用,同時有吸菸、飲酒及嚼食檳榔習慣者與無使用此三種物質的人相比,有195.6倍的機會得到食道癌;此外,幽門螺旋桿菌感染與食道鱗狀上皮細胞癌存在負相關,由細胞實驗證實其可能機轉之一是幽門螺旋桿菌感染可引起食道鱗狀上皮細胞癌的細胞凋亡。(2)骨泌素(osteopontin)和食道鱗狀上皮細胞癌的發生及分期有關,但不能用來預測病患的預後。(3)新發明的糞便幽門螺旋桿菌抗原檢測法和傳統呼氣測試有同樣的準確度,而前者更方便且經濟;另外,以esomeprazole或rabeprazole為主的第一線三合療法有同樣的療效,除菌率約90%,且不受cytochrome P450 2C19 (CYP 2C19)基因多型性影響。然而在第二、三線療法帶有CYP 2C19不良代謝型者比帶有快速代謝型者殺菌成功率高。
由本論文所得的結果,我們建議對長期吸菸、飲酒及嚼食檳榔者進行定期內視鏡篩檢食道癌,於可疑病灶進行切片,除了病理診斷外可加測骨泌素的表現。此外,在臨床上需進行幽門螺旋桿菌檢查和廓清時,糞便抗原檢測法是一種方便、快速且有不錯的準確度;而給予第一線療法時不需使用特定的質子幫浦抑制劑或檢驗CYP 2C19的基因多型性,但在二、三線療法時,檢驗CYP 2C19的基因多型性可能有助於預測殺菌成功率。
Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer death among men in Taiwan and the five-year survival rate is very low (< 10%). Therefore, it is important to identify the high-risk patients and to develop a biological marker for early diagnosis. Smoking and alcohol drinking are known major risks for cancers of the oral cavity and esophagus. Betel quid chewing is an important risk factor of oral cancer in Taiwan; it is also possibly associated with ESCC. Besides, our previous study has linked Helicobacter pylori (Hp) seropositivity to an inverse association with ESCC. The prevalence of Hp is about 50% among Taiwanese adults and it is associated many upper gastroenterological disorders. Therefore, my research purposes include 1. to examine the effect of environmental factors, including consumption of cigarette, alcohol and betel quid, and Hp infection, on ESCC risk. We also try to develop and test the hypothesis to explain the latter association; 2. to apply the maker identified by microarry technique on clinical samples to examine whether it is associated with the carcinogenesis, progression and survival of ESCC; and 3. to compare the accuracy of newly developed non-invasive tests and the efficacy of different eradication therapies for Hp infection. The effect of CYP 2C19 polymorphism on eradication rates of different regimen was also examined.
We have obtained the following results: 1. smoking, alcohol drinking and betel quid chewing are three major risks for ESCC and there is a joint effect. Subjects who regularly consumed those three substances at the same time have a 195.6-times risk than those who did not. Besides, there is an inverse association between Hp seropositivity and ESCC risk, which could come from the apoptotic effect of Hp on ESCC cells. 2. osteopontin expression is associated with carcinogensis and progression, but not survival of ESCC. 3. the accuracy of the newly-developed stool Hp antigen test is comparable to C13 urea-breath test, but the former method is simpler and cheaper. Moreover, the efficacy of esomeprazole- and rabaprazole-based first-line triple therapies is comparable and is not affected by CYP 2C19 polymorphism. However, subjects with CYP 2C19 poor metabolizer seem to have better eradication rates than those with extensive metabolizer when receiving rescue therapies.
According to our results, we suggest regular surveillance among habitual smokers, drinkers and betel quid chewers. Biopsy with pathological diagnosis and detection of osteopontin expression could be done on the suspected lesions. For those who need testing and treatment for Hp infection, stool antigen test is a simple, rapid and accurate method. Physicians don’t need to choose certain proton pump inhibitor or test the CYP2C19 genotype in first-line therapy. However, CYP2C19 genotyping could be useful in second or third line therapies.
中文摘要 ------------------------------------------ 3-4
英文摘要 ------------------------------------------ 5-6
研究架構 ------------------------------------------ 7
背景 ---------------------------------------------- 8-13
Part I、環境因子生物指標與食道鱗狀上皮細胞癌的相關性
一、菸、酒、檳榔與食道鱗狀上皮細胞癌的相關性
研究方法 ------------------------------- 14-15 結果 ----------------------------------- 15-20
二、幽門螺旋桿菌感染與食道鱗狀上皮細胞癌的相關性
研究方法 ------------------------------- 21-26
結果 ----------------------------------- 27-33
*結論 ----------------------------------------- 33

Part II、生物指標在食道鱗狀上皮細胞癌的應用
研究方法 ------------------------------- 34-36
結果 ----------------------------------- 37-41
*結論 ----------------------------------------- 38
Part III、幽門螺旋桿菌之診斷及廓清療法
一、 糞便抗原檢驗法的適用性
研究方法 ------------------------------- 42-44
結果 ----------------------------------- 45-46
二、 不同質子幫浦抑制劑在第一線療法的差異及CYP 2C19基因多型性對各線療法的影響
研究方法 ------------------------------- 47-48
結果 ----------------------------------- 49-53
*結論 ------------------------------------------ 54

參考文獻 ---------------------------------------- 55-60
發表或完稿---------------------------------------- 61-62
附件 (第一作者論文pdf檔) ------------------------- 63~
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