臺灣博碩士論文加值系統

腸胃道基質肉瘤是在腸胃道最惡性的基質腫瘤。可觸摸腹部腫瘤及急性腹痛是腸胃道基質肉瘤最常見的臨床表現。大部份腸胃道基質肉瘤被偵測到是在胃部。這種腫瘤的大小以及腫瘤分裂的活動性是非常重要影響預後的兩個因子，並且據此將腫瘤加以風險分類。在早期治療腸胃道基質肉瘤時，化學治療和放射治療的反應都不佳，手術則是目前唯一可以治癒腸胃道基質肉瘤的方法。近期，標靶治療藥物-Imatinib在這種腸胃道基質肉瘤治療上得到好的反應。而大部份的腸胃道基質肉瘤都常會有產生基因突變，一般都在 c-kit基因和PDGFR-α基因突變，而這種突變也正是標靶治療藥物-Imatinib Mesylate攻擊的所在。無論如何在這些研究中，尚有許多因子還未出現臨床顯著性。因此我們分析這些臨床病理因子特徵，來評估它們在已切除的腸胃道基質肉瘤的復發及轉移所扮演角色。
從2001年八月至2006年的三月，收集31個具侵犯性的腸胃道基質肉瘤術後病理臘塊包埋組織，並且將這些組織做免疫化學染色(CD-117, SMA, CD-34, S-100, Desmin, Bcl-2, PDGFR-α)。這些腸胃道基質肉瘤病人包括在我們樣本中主要是依據腫瘤大小、分裂的活動性以及CD-117陽性反應。而侵犯性腸胃道基質肉瘤的定義則是將中度風險及高風險的病人包含在內。這次主要是去評估經過外科手術後的腸胃道基質肉瘤病患有那些會影響復發的因子。
結果顯示在中等風險及高風險腸胃道基質肉瘤病患的比較中：年紀、腫瘤復發、是可以達到統計學上差異性，中等風險病患比高風險病患要有更長復發期。而高風險病患明顯有不好的預後。另外在性別、切除的完整性和Bcl-2對於腫瘤術後復發及轉移性有顯著影響，而其他因子並無影響復發的顯著性。PDGFR-α的表現在這些高KIT(CD-117)表現度病理切片中有29%強，但是對於這些病患疾病惡化並無影響性。目前接受Imatinib治療的病患中，並沒有因疾病惡化而死亡的病例。
綜合論之；男性的病患、腫瘤切除完整性和Bcl-2都是可以預期腫瘤復發的因子。腸胃道基質肉瘤風險的分類不僅對疾病的惡化預測有幫助，同時也能有效於疾病的復發預測。

Gastrointestinal stromal tumors (GISTs) are the most malignant mesenchymal tumor in the gastrointestinal (GI) tract. Palpable abdominal mass and acute abdomen pain are the major common symptoms in the GISTs. Most of GISTs were detected in the stomach. The tumor size and mitosis counts are the most important factors to predict the prognosis and to define the risk categories. The GISTs are poor responder to chemotherapy and radiotherapy and the only cure method is surgical resection for the primary GISTs in time. Recently, a target therapy using imatinib had a promising reponse rate. However, in some GISTs mutation in constitutively activated C-kit gene mutation (CD 117) and platelet-derived growth factor receptor alpha (PDGFR-α), which are the major therapeutic target for imatinib mesylate (Gliveec), are frequently identified. However, the clinical significance of these factors in GIST is not well characterized in this study. We therefore analyzed the clinicopatholical factors to evaluate the role of these factors in the the recurrence and metastasis of the primary resected GIST.
Between August 2001 and March 2006, 31 advanced GIST patient’s paraffin embedded specimens were collected Immunohistochemical staining of CD-117, SMA, CD-34, S-100, Desmin, Bcl-2, PDGFR-α were performed in these specimens. Patients were classified on the basis of tumor size, the mitotic rate and CD117 positively. Advanced GISTs were defined as intermediate (I) and high risk (II) group. To evaluate what prognostic factors influences tumor recurrence and metastasis after resection of advanced gastrointestinal stromal tumors.
Results revealed that age (p=0.048) and tumor recurrence (p=0.036) had significant differences between (I) and (II) group. The intermediated risk group had longer disease free time than high risk group (27 months Vs 17.5 months). It is evidence that high risk group GISTs were belong to poor disease free survival (p=0.047). Between the tumor recurrence group and non-recurrence group, there were significant differences in sex (p=0.013), incomplete resection (p=0.035), and Bcl-2 (p=0.046). Otherwise, most factors ( including age, clinical signs and symptoms, tumor location, immunochemical stains and PDGFR-α) had no significant differences in the recurrence group. PDGFR-α expression (29%) also was noted in the CD 117 overexpression specimens and no significant influence in disease progression. No mortality case was found in the advanced GISTs treated with imatinib.
In conclusion, the results from this study that male, resection margin and Bcl-2 are predictive factors for GISTs tumor recurrence. Meanwhile, the GIST risk classification not only has the help to forecast the GIST progression also to be able effectively to forecast the GIST recurrence.

目次
誌謝....................................................I
目次....................................................II
中文摘要................................................V
英文摘要................................................VII
圖目錄..................................................IX
表目錄..................................................X
第一章 緒論.............................................1
第一節 背景資料........................................1
第二節 文獻討論........................................2
1.2.1 流行病學和臨床診斷...........................2
1.2.2 病理診斷.....................................3
1.2.3 風險分類.....................................4
1.2.4 GISTs致癌分子機制............................5
1.2.5 GISTs的處置與預後............................7
1.2.5.1 GISTs的手術處理..........................7
1.2.5.2 GISTs的標靶藥物處理......................8
第二章 研究動機.........................................10
第三章 實驗材料與方法...................................11
第一節 實驗樣本來源....................................11
第二節 實驗方法與步驟..................................12
2.1 組織免疫化學染色...............................12
2.2 蠟塊檢體抽取DNA................................13
2.2.1 PCR反應(聚合酶連鎖反應)....................13
2.2.2 Agrose clectrophoresis.....................13
2.2.3 DNA序列分析儀-核酸自動分析儀..............14
第三節 實驗統計方式....................................14
第四章 實驗結果與分析...................................15
第一節 高風險性(II)及中等風險程度(I)比較...............15
第二節 復發、轉移性GISTs(III)與未復發的GISTs(IV)的比較.17
第五章 討論.............................................19
第一節 臨床表徵與復發..................................19
第二節 免疫組織染色與復發..............................21
第三節 病理組織細胞型態與復發..........................22
第四節 c-kit基因與復發.................................22
第五節 GISTs復發後標靶藥物治療與追蹤...................23
第六章 結論.............................................25
參考文獻................................................48
附錄
圖-1 KIT接受體蛋白之結構.............................56
圖-2 Imainib結構式...................................57
圖-3 Bcl-2 protein在細胞凋亡(Apopfosis)所扮演抑制角色.........58
圖-4處理GISTs的流程圖................................59
表-1 GISTs病患的風險性分類...........................60
表-2 各種化學治療配方對GISTs的反應率.................61
表-3 c-kit和PDGFR-α的Primer序列......................62

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