2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645665摘要：骨髓化生不良症候群(myelodysplastic syndrome, MDS) 是一種骨髓細胞功能異常(clonal disorder)且可能出現癌症變化的疾病。它在臨床上的表現主要是血球下降，合併貧血、血小板低下及免疫力不足。而且疾病分期也成多樣性。同時針對其致病的機轉仍然不甚清楚。目前已知血管新生在solid tumor之腫瘤形成、擴散及轉移中扮演舉足輕重的角色。近來的研究報告也指出：在血液的惡性腫瘤疾病裡，血管新生對於其致病機轉也有其重要地位。一般認為是血癌細胞及其附近之間質細胞(stromal cell) 分泌許多促使血管新生的物質(angiogenic substances)，其會分布在microenvironment中，而這些物質會活化血管內皮細胞(endothelial cells)以產生血管新生，進而加速腫瘤之生長。最近的研究顯示，血管新生與血液腫瘤包括MDS亦有密切關係。MDS病人骨髓的微小血管密度（microvascular density簡稱MVD) 被發現較正常人高；另外，血管內皮生長因子（簡稱VEGF）及其受體（VEGRF）、鹼性纖維母細胞生長因子（簡稱bFGF）、angiogenin、angiopoietin, endostatin等與血管新生有關因子的表現，在骨髓化生不良症候群亦會改變；我們先前的研究發現急性骨髓性白血病其血管新生現象與其腫瘤間之關聯，且 Ang-2 的表現更是與病患預後有顯著相關(Hou, 2008 and Shih, 2008)。同時，我們也利用動態磁振造影(Dynamic contrast-enhanced magnetic resonance image, DCE-MRI)成功的評估急性血癌骨髓血管新生的量化，作為預後評估的獨立因子，發表於血液學頂尖期刊(Shih, Blood, 2009)；並可利用它作為個人化醫療以及標靶治療的生物指標。此外, 部份國外的研究也顯示血管新生變化可能在骨髓分化不良症候群的疾病進展上扮演重要角色。根據Moehler (2003)及Wimazal (2006)的研究顯示：骨髓分化不良症候群在疾病進展時(亦即急性骨髓性白血病變化時)，MVD的數值會增加，暗示著血管新生可能扮演重要的角色；然而Campioni (2004) 及 Lundberg (2006)的報告卻無法發現這樣的變化。由於骨髓化生不良症候群的疾病臨床表現及分類多樣性，且這些的研究多屬回朔性且病患人數較少，也沒有明確的預後比較，因此為了了解骨髓化生不良症候群(MDS)其血管新生現象與其腫瘤間之關聯、臨床症狀及表徵與存活分析，故藉者磁振造影(DCE-MRI)定期檢測血管新生的變化，以研究骨髓化生不良症候群，希望能找到MDS與血管新生 (angiogenesis) 間之關係，釐清DCE-MRI的檢查結果是否可用來預測病人的預後及疾病進展，及其與組織學MVD及血管新生相關因子表現的關聯性。本研究預計從台大醫院血液科新診斷為骨髓化生不良症候群之病患, 三年內共計150~200位, (第四年為純追蹤)，在診斷時及後續追踪的過程中，將做系列的檢查，包括利用動態磁振的影像結果(DCE-MRI)而做功能分析 (tissue perfusion analysis)，骨髓切片及抺片觀察細胞形態(correlation between the MVD and DCE-MRI parameters)，並以免疫組織染色檢測MVD及VEGF、VEGFR、bFGF及angiopoietin；另外，骨髓細胞將以cDNA microarray測定血管新生相關基因的表現，並以酵素免疫分析法定量血管新生相關因子的濃度。這些檢查結果彼此間的相關性、及其與臨床表現、疾病進展及預後的關聯將一併分析。臨床上分析的指標含括性別、年齡、白血球數目、芽細胞量、血色素、血小板數目、LDH數值、染色體變化、有無家族史及是否曾接受化學或放射治療等，以及治療上之效果。研究之展望及預期效果：研究的目的在於觀察骨髓化生不良症候群之病患有關血管新生表現的差異，同時觀察數值高低與臨床上的表徵有無差異，將可了解DCE-MRI檢查在骨髓化生不良症候病人的臨床意義，其結果是否可做為預後的指標及預期疾病的轉化，及其與血管新生因子表現的相關性。進而分析數值高低與存活率(overall survival)、疾病進展(disease progression)的關聯。<br> Abstract: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hemopoietic disorders, characterized by peripheral blood cytopenia of one or more lineages with mostly normocellular or hypercellular bone marrow (BM). Its pathogenesis is largely unknown, and may be due to multi-step process with aberration of cellular function and ineffective hematopoiesis leading to – apoptosis and pancytopenia; or different pathway to uncontrolled cell proliferation and be leukemic change. For the majority of patients, there are few therapeutic options other than supportive care.Recently, more evidences showed that angiogenesis is not only required for growth, progression, and metastasis of solid tumors through the pioneering work of Folkman but also plays a crucial role in hematologic malignancies. Greater understanding of angiogenesis in MDS will enable our understanding in the development of this disease and the mechanism for its progression. Microvessel density (MVD) of the bone marrow and expression of several angiogenic mediators including vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR), basic fibroblast growth factor (bFGF) etc. were found higher in MDS patients than in normal controls. Angiogenesis inhibitors targeting the neovascular development have shown promising results in the treatment of refractory MDS. It will then be very helpful to have a noninvasive technique that can monitor angiogenesis and predict the prognosis and treatment response in MDS patients. In this study, we will evaluate whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), a noninvasive and safe technique, can fulfill the requirements.The DCE-MRI techniques not only allow a direct quantification blood vessel density but also provide information on the functional status of the blood vessels e.g. permeability. We therefore evaluate the clinical implication of angiogenesis by DCE-MRI in patients with MDS.Method and Patients: We will investigate the angiogenesis in a cohort of patients with newly diagnosed MDS by DCE-MRI at our institute during three years period and totally 150 to 200 subjects (average around 60 subjects per year) will be included. The 4th year will keep following up the previous included patients. Serial DCE-MRI examination will be performed and the sequential changes from the time of diagnosis to disease progression and acute transformation will be analyzed. Bone marrow MVD and expression of angiopoietin 1 and 2, VEGF, VEGFR-1, VEGFR-2 and bFGF will be evaluated by immunohistochemical staining of the bone marrow biopsy specimens and real-time quantitative PCR (RQ-PCR) of bone marrow leukemia cells. Angiogenesis mediators in bone marrow and peripheral blood plasma will be analyzed by enzyme immunoassay and those in cells by cDNA microarray. The results obtained from the above examinations will be correlated with each other and with the clinical features and outcome of the patients.Perspective results and significance: From the study, we will evaluate and understand the difference of angiogenesis evaluated from DCE-MRI and other angiogenic factors among MDS patients. The results will also be correlated with clinical features, MVD and expression of angiogenesis mediators and outcome of these patients. We may find out the clinical implications of DCE-MRI, earlier detection for those with high risk of leukemic transformation and design customized therapy in MDS patients.