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  • 學位論文

mTOR抑制劑用於降低腎臟移植患者的癌症發生率與死亡率之研究

The study of mammalian target of rapamycin (mTOR) inhibitors lower the incidence of malignancy and mortality rate in post-renal transplantation patient

指導教授 : 陳保中
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摘要


研究背景 先前的研究指出mammalian target of rapamycin inhibitors (mTOR抑制劑)用在腎臟移植的患者身上,有抑制腫瘤的功效;然而mTOR抑制劑對全癌症發生率影響的程度,以至於對特定癌症發生率影響的程度,到死亡率的影響,目前仍是存在爭議,也因為mTOR抑制劑當中的sirolimus是2000年起開始上市使用,因此跟以往使用的免疫抑制劑間的交互作用仍未有定論。因此本篇研究藉由全民健保資料庫去分析,在腎臟移植患者身上,使用mTOR抑制劑與否以及使用的劑量多寡,對於全癌症、特定癌症及死亡率發生的影響程度。 研究方法 我們使用2000年到2008年間的全民健保資料庫中的重大傷病檔,選用其中末期腎臟病透析患者(ICD-9: 585)以及腎臟移植術後(ICD-9: V420)兩個族群進行世代研究。首先在配對年紀、性別、收入和地域性後,比較兩組癌症的發生率,接著選用一種常見的mTOR抑制劑藥物sirolimus當代表,並將腎臟移植術後的世代分成有使用過sirolimus和從未使用過sirolimus兩組,分析全癌症發生率、特定癌症發生率以及死亡率的影響,另外加入干擾因子進行敏感試驗分析,和分析不同sirolimus累積劑量對死亡率的影響。所有的統計分析是使用SAS 9.4進行。 研究結果 在腎臟移植的世代中發現,比起規則透析的世代有著較高癌症發生率,這個結果和之前的一些研究相似,但是本研究的結果在統計分析下是沒有顯著意義(HR 1.16 [95% CI 0.96–1.41],推論可能是因為2000年以後開始廣泛使用mTOR抑制劑的因素。再將腎臟移植的世代進一步分成有無使用sirolimus的兩個族群,發現使用sirolimus能降低全癌症、泌尿上皮細胞癌以及肝細胞癌的發生率,且皆有統計上顯著意義;只有大腸直腸癌的發生率呈現沒有統計顯著的上升。最後在死亡率部分,sirolimus可能會降低死亡率,而且在累積劑量的分層分析中顯示,隨著累積劑量愈大,愈能降低死亡率,但這些降低死亡率的結果均未達統計上顯著意義。 結論 mTOR抑制劑使用在腎臟移植後,能降低特定癌症的發生率,並可能改善腎臟移植患者的存活率,跟累積劑量可能也有相關性,但受限於本次世代研究的規模,有些結果並未能達統計學上的意義,因此仍需日後相關的研究協助探討。

並列摘要


Background Previous clinical studies suggested that mammalian target of rapamycin inhibitors (mTORi) had antineoplastic effects in renal transplantation cohort. However, overall cancer incidence and mortality rate in mTORi-exposed subjects post renal transplantation are equivocal. Objective We aimed to assess the association between the use of mTOR inhibitor and the risk of developing specific cancer types and mortality rate in renal transplantation cohort. RESEARCH DESIGN AND METHODS We conducted two nationwide, population based, cohort studies using the Taiwan National Health Insurance Research Database. In the first cohort, enrollees were defined as patients who received dialysis between 2000 and 2008. We separated this cohort into receiving renal transplantation group and dialysis group, which were matched by sex, age, income and area. Among the 9,394 eligible enrollees, we used Cox regression to assess the risk of cancer between two groups. The second cohort, subjects were defined as patients who received renal transplantation between 2000 and 2008. We separated the cohort into sirolimus-exposed subjects and sirolimus-unexposed subjects. We compared the overall cancer incidence, specific cancer types incidence and mortality rate between sirolimus-exposed subjects and sirolimus-unexposed subjects. RESULTS An increased risk of cancer was observed in patient post renal transplantation compared with those who in dialysis, although it was not significant (HR 1.16 [95% CI 0.96–1.41]. A decreased risk of cancer was observed in sirolimus-exposed subjects rather than sirolimus-unexposed subjects in renal transplantation subjects (crude HR 0.21 [95% CI 0.13–0.34]; adjusted HR 0.25 [95% CI 0.15–0.41]). Sirolimus-exposed subjects may decrease the incidence of urothelial cancer and hepatoma. Colorectal cancer showed an insignificant increased incidence in sirolimus-exposed subjects compared to sirolimus-unexposed subjects. We found lower mortality incidence in sirolimus-exposed subjects compared to sirolimus-unexposed subjects, although this difference was not significant. As sirolimus dosage increased, mortality incidence trended down. CONCLUSIONS The use of mTOR inhibitor may be associated with a decreased risk of cancer and mortality rate in patients post renal transplantation. Further studies are warranted to confirm our findings.

參考文獻


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