- 學位論文
淋巴惡性疾病之流行病學及分子致病機轉探討
Epidemiological and Molecular Investigation of Malignant Lymphoid Diseases
摘要
淋巴系統惡性腫瘤是由淋巴系統的細胞癌化所產生，其中包含了惡性淋巴癌及多發性骨髓瘤。這2種疾病占了所有血液惡性疾病的大宗，惡性淋巴癌的發生率排名第一，而多發性骨髓瘤排名第三，這兩個疾病危險因子的流行病學研究，新治療方式的研發以及探索新的分子致病機轉一直是熱門的研究課題。 我們研究主要有2個方向，第一個方向是探討惡性淋巴癌相關的流行病學，利用全國大型資料庫分析藥物化學預防與惡性淋巴癌發生之關聯性，接著探討淋巴癌化學治療造成之免疫力低下對病人的影響，接者分析老人瀰漫性大B細胞淋巴癌在實際臨床之治療策略及預後因子。第二個研究方向為探討多發性骨髓瘤新分子致病機轉以及其臨床意義。 第一部分研究主題為探討惡性淋巴癌風險之流行病學研究。我們探討使用降血脂藥物statin與後續發生非何杰金氏淋巴癌風險之關聯性。利用全民健保資料庫的重大傷病檔取得2005年至2008年非何杰金氏淋巴癌病人共1715人，接著與2005年百萬人抽樣檔依年齡及性別作配對為對照組(共16942人)，往前回溯至1996年1月1日來分析2組使用statin之情形。最後使用定義每日劑量(defined daily dose)及累積定義每日劑量(cumulative defined daily dose)來分析statin的使用量。經多變數分析發現使用statin可能與後續淋巴癌風險的下降有關，可以達到48%。此外，若是使用statin量及時間增加，降低後續淋巴癌風險的現象也越顯著。 第二部分研究主題為探討淋巴癌病人化學治療發生疱疹之風險研究。我們利用全民健保資料庫的重大傷病檔分析2002年至2008年非何杰金氏淋巴癌病人使用化學治療後疱疹的發生率及危險因子，我們共分析了3865位病人，包含2188位病人使用傳統化學治療及1677位病人使用傳統化學治療合併rituximab標靶治療。整體而言，472位病人(12.21%)得到疱疹，傳統化學治療這組有258位(11.79%)，傳統化學治療合併rituximab標靶治療這組有214位(12.76%)。此外，大多數的疱疹發生在診斷後的2年內。多變數分析傳統化學治療者組，我們發現女性，多次的化學治療以及造血幹細胞移植是產生疱疹的危險因子。 而女性，糖尿病，多次的化學治療，造血幹細胞移植及較高劑量的標靶藥物rituximab暴露是傳統化學治療合併標靶治療這組病人產生疱疹的危險因子。接著我們探討rituximab加入傳統化學治療的影響，利用propensity score來配對，2組各有1582位病人來進行分析，我們發現使用rituximab會增加短期、即診斷後2年內的疱疹風險，但與長期(追蹤7年)的疱疹風險無太大關聯。 第三部分為老人族群瀰漫性大B細胞淋巴癌研究。基於老年癌症病人為一特殊的族群，我們分析老年瀰漫性大B細胞淋巴癌病人之實際治療策略，治療副作用及預後因子。 本研究收集2008至2014年在本院治療之病人共133位，中位數年齡為74歲。治療策略的分析發現有23位病人只接受類固醇或是支持性治療，尤其是年紀大或是體能條件不佳者，治療策略就趨於保守。此外，有104位病人接受R-COP或是R-CHOP之全身性化療，較年輕或是體能條件較佳者會接受包含anthracycline處方之較高強度的化療(R-CHOP)。 在治療副作用方面，使用包含anthracycline處方之化療(R-CHOP)病人有較高之白血球低下風險。 在預後分析方面，所有病人之中位無惡化存活期及整體存活期分別為15及21個月。若是只分析接受R-COP或是R-CHOP之全身性化療族群，中位無惡化存活期及整體存活期分別為32及37個月。若是以多變數分析全體病人之預後因子，年紀大於80歲，骨髓侵犯及高風險的aaIPI分數都與較差之無惡化存活期及整體存活期相關。在死因分析方面，大多數都是死於淋巴癌惡化。最後分析診斷後四個月內早期死亡的病人，危險因子包含了年紀大於80歲，骨髓侵犯及高風險的aaIPI分數。而病人在診斷時就有腫瘤溶解症候群也會有早期死亡的趨勢。 第四部分研究主題為探討大片段非編碼RNA於多發性骨髓瘤表現及臨床意義。經由生物資訊研究及搜尋相關RNA資料庫，我們認為一個大片段非編碼RNA，MALAT1 (metastasis associated lung adenocarcinoma transcript 1) ，可能在多發性骨髓瘤的機轉扮演角色。利用定量聚合脢連鎖反應分析多發性骨髓瘤病人治療前後及正常人骨髓檢體之MALAT1表現，發現新診斷多發性骨髓瘤病人之MALAT1為過度表現(over-expression)，大約比正常人高到3倍 (mean ∆CT: -5.54 ± 0.16 vs. -3.95 ± 0.21, 3.01-fold change; P < 0.001)。同時此RNA的表現與疾病狀態有關連，即病人治療後疾病得到控制時，此RNA表現量就會顯著下降 (mean ∆CT: -5.54 ± 0.16 vs. -3.84 ± 0.09, 3.25-fold change; P < 0.001)，但是當疾病惡化或是復發時此RNA表現量就會顯著上升。 接著進一步研究此RNA的臨床相關性，我們發現初診斷時的表現量與預後，包含無惡化存活期及整體存活期，均無明顯相關，但是進一步分析治療後MALAT1表現量下降的程度，我們發現MALAT1表現量下降程度較高的病人有較長的無惡化存活期 (24 months vs. 11 months; P = 0.001)，更重要的是下降程度較低的病人有較高的早期惡化或是復發之風險，利用多變數分析也證實這個假設 (HR:4.38, 95%信賴區間1.48-12.99, P = 0.008)。
並列摘要
Malignant lymphoid disease is a group of malignant diseases developing from the cells of lymphatic system, including malignant lymphoma and multiple myeloma. This group of diseases accounts for a large portion of hematological malignancies. With the respect to current incidences, non-Hodgkin lymphoma (NHL) and multiple myeloma are the most and third most common among hematological malignancies. Our study included epidemiological studies on NHL and molecular investigations on multiple myeloma. In the first part, we evaluated the association between previous exposure of statin, a lipid-lowering agent and the development of NHL. This nationwide population-based case–control study was conducted by using the National Health Insurance Research Database (NHIRD) of Taiwan. The NHL group (N= 1715) consisted of the patients with a first-time diagnosis of NHL between 2005 and 2008. The cases of the control group (N= 17150) were pair-matched to the NHL group by sex, year of birth and date of NHL diagnosis (index date). The data of statin administration in both groups was retrospectively collected from index date to January 1, 1996. The cumulative defined daily dose (cDDD) was estimated to evaluate the statin exposure. The analysis revealed that previous statin administration was associated with a reduced risk of subsequent NHL with an adjusted OR of 0.52 (95% CI, 0.43-0.62). In addition, the chemo-preventive effect of the statin was exerted in a dose-response manner. The adjusted ORs were 0.69 (95% CI, 0.51-0.94), 0.56 (95% CI, 0.42-0.76), 0.55 (95% CI, 0.42-0.71), and 0.37 (95% CI, 0.26-0.54) for statin administration of fewer than 28, 28 to 90, 91 to 365, and more than 365 cumulative defined daily doses (cDDDs), respectively, relative to the group without the statin administration. In the second part, we investigated the incidence of and risk factors for herpes zoster in patients with NHL receiving anti-lymphoma chemotherapy. The overall incidence density of herpes zoster was 12.21% (472/3865); 11.79% (258/2188) of the patients received conventional chemotherapy and 12.76% (214/1677) of the patients received rituximab-containing chemotherapy. For the patients who received conventional chemotherapy, the risk factors included female gender, multiple courses of chemotherapy and autologous hematopoietic stem cell transplantation. For the patients who received rituximab-containing chemotherapy, the risk factors included female gender, diabetes mellitus, multiple courses of chemotherapy, autologous hematopoietic stem cell transplantation and higher accumulated rituximab dose. The majority of the herpes zoster episodes occurred within the first two years after the diagnosis of NHL. After adjusting for the propensity score matching, rituximab-containing chemotherapy was not associated with a higher overall incidence density of herpes zoster (P= 0.155). However, the addition of rituximab to conventional chemotherapy increased the short-term risk of herpes zoster with adjusted hazard ratios of 1.38 (95% confidence intervals (CI) = 1.05-1.81, P= 0.021) and 1.37 (95% CI= 1.08-1.73, P= 0.010) during the 1-year and 2-year follow-up periods, respectively. In the third part, we investigated treatment strategy, prognostic factors, and risk factors of early death in elderly patients with diffuse large B-cell lymphoma (DLBCL). The patients with younger age and better performance status were more likely to receive intensive frontline treatment. The median progression-free survival (PFS) and overall survival were 15 and 21 months, respectively. Anthracycline-containing chemotherapy achieved a higher remission rate and had a trend of better overall survival at expanse of higher risk of severe neutropenia. Multivariate analysis revealed that very old age, a high-risk age-adjusted international prognostic index (aaIPI) score, and bone marrow involvement were associated with poorer PFS and overall survival. Progression of lymphoma was the major cause of death in the study population. With respect to early mortality, approximately 25% of patients died within 120 days of their diagnosis. The risk factors for early mortality included very old age, a high-risk aaIPI score, and bone marrow involvement. The appearance of symptoms or signs of tumor lysis syndrome at diagnosis had a trend of early death. In the fourth part, we investigated the role and clinical relevance of the long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in multiple myeloma. The expression of MALAT1 was exam by Real-time quantitative reverse transcription polymerase chain reaction. The results revealed that MALAT1 was overexpressed in the newly diagnosed patients compared with post-treatment patients (mean ∆CT: -5.54 ± 0.16 vs. -3.84 ± 0.09, 3.25-fold change; P < 0.001) and healthy individuals (mean ∆CT: -5.54 ± 0.16 vs. -3.95 ± 0.21, 3.01-fold change; P < 0.001). The expression of MALAT1 strongly correlated with disease status, and the magnitude of change in MALAT1 post-treatment had prognostic relevance. The patients with early progression had a significantly smaller change in MALAT1 after treatment (mean ∆CT change: 1.26 ± 1.06 vs. 2.09 ± 0.79, P = 0.011). A cut-off value of the change in MALAT1 (∆CT change: 1.5) was obtained, and the patients with a greater decrease in MALAT1 (difference in ∆CT >1.5) had significantly longer progression-free survival compared with the patients with a smaller MALAT1 change (24 months vs. 11 months; P = 0.001). For the post-treatment patients, the risk of early progression could be predicted using this cut-off value.