2018-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/676968摘要：腦轉移是成人最常見的顱內腫瘤。一般估計大約 10 到 30%的癌症病患會在 病程中發生腦轉移,其中肺癌(約佔 40 到 50%)為最主要的原發部位。過去腦轉移病患之預後不佳，但是隨著影像學檢查與放射治療技術的進步，加上化學及標靶治療的進展，腦轉移病患之存活率已較以往改善，而腦轉移發生率則較過去增加，使其治療成為臨床上重要的議題。轉移性腦腫瘤的治療方式，包括開顱手術、化學或標靶治療、放射線治療與支持性照護等，其中腦部放射線治療包含全腦放射治療、影像導引低分次放射治療與立體定位放射手術等治療方式，是針對腦轉移有效且標準的治療方式，並可減少腦轉移相關神經學症狀及延長存活期。儘管如此，腦部放射治療亦有可能造成神經功能退化等相關副作用，而影響病患生活品質。現今臨床上仍缺乏有效的生物標記來預測腦轉移的預後，從而擬定個人化的治療策略，選擇較適合的放射治療技術，以提高治療係數，降低治療引起的副作用風險，以改善疾病控制率與生活品質。此外目前對於腦轉移的發生機轉仍未明，對於單一腦轉移、寡轉移、多發性轉移與軟腦膜轉移等轉移模式之間是否存在機轉差異亦缺乏了解。現今研究發現原發腫瘤與周邊血液胞外體的組合蛋白表現特徵可能與發生腦轉移的機率以及機制有關聯性 ，但目前仍缺乏足夠的研究證據支持其臨床應用。本計畫主持人近期的研究顯示表皮生長因子的突變狀態與非小細胞肺癌侷限性腦轉移病患接受立體定位放射手術預後具有相關性。具表皮生長因子突變之基因型具有較佳的腦轉移控制率，或可減少全腦放射治療的必要性與副作用。在初步研究數據分析亦證實本研究團隊能夠在周邊血液樣本中，分離循環胞外體必且檢測出特定組合蛋白之表現量。因此本研究計畫以二年時間收集100位符合試驗條件病患之血液檢體，並追蹤臨床治療成效。本研究使用粒徑篩析層析法分離高純度的血漿或血清胞外體，以定量各型組合蛋白，同時將檢測原發及轉移病灶的組合蛋白表現，以深入探討胞外體組合蛋白表現譜其在腦轉移之角色、相關機轉與對預後的影響。本研究預期能夠為非小細胞肺癌腦轉移病患探索前瞻性的分子生物標記以改善對治療預後評估的準確率，開發個人化的治療策略。<br> Abstract: Brain metastases are the most common brain tumors in adults. It is estimated that around 10-30% of cancer patients would develop brain metastases during the course of their illness. The majority of brain metastases originate from primary cancers of the lung (40~50%). Historically, patients with brain metastases had very limited survival. With the advances in diagnostic modalities, radiotherapy/radiosurgery technologies, and effective systemic therapies, its outcome is improving and incidence is increasing in patients with otherwise well controlled systemic disease. The treatment options for brain metastases include craniotomy, chemotherapy or target therapy, radiotherapy, and supportive care. In radiation therapy, whole brain radiotherapy, hypofractionated image-guided conformal radiotherapy, and stereotactic radiosurgery are effective in controlling intracranial disease, and decreasing the risk of tumor related neurological symptoms. Radiotherapy may also prolong survival in selected patients with brain metastases. Despite of its important role in brain metastases treatment, cranial irradiation may cause side effects in neurocognitive function decline and affect the quality of life of patients. At present, there is lack of reliable circulating biomarkers to predict the outcomes of brain metastases after cranial irradiation. In the era of precision medicine, predictive biomarkers allow radiation oncologists to individualized strategy in maximizing the therapeutic ratio and minimize treatment related toxicities. These efforts may improve disease control as well as quality of life. Furthermore, the underlying mechanisms of brain metastases remained unclear. It is unknown whether there are differences in molecular pathogenesis between difference brain metastases models including single brain metastasis, limited brain metastases, multiple brain metastases, and leptomeningeal metastases. The recent researches showed that the patterns of integrins expressions circulating exosomes, and primary tumors may be associated with the risks and pathogenesis of brain metastases. However, the clinical application of exosome integrins as a biomarker in brain metastases required further investigation. The recent research from principal investigator revealed that EGFR mutation status is associated with outcomes for NSCLC patients with limited brain metastases receiving stereotactic radiosurgery. Patients with EGFR mutant tumor had better intracranial control. The finding suggested whole brain radiotherapy could be deferred for better neurocognitive outcome. In the preliminary results, the principal investigator sucessfully isolated circulating exosomes and showed expression of exosomal integrins. Therefore, the investigator proposes this 2-year research project. The present study plan to enroll 100 patients for evaluation and validation of the association between the outcomes of brain metastases and the patterns of exosomal integrins expressions. The serum or plasma exosomes will be isolated using the method of size exclusion chromatography. The quantification and characterization of exosome integrins will be performed by ELISA, western blot, and proximity ligation assay, and will be correlated with the expressions in primary or metastatic tumors by immunohistochemistry analysis. The principal investigator anticipates identifying the promising molecular biomarkers to predict the outcomes of upfront, and deferred cranial irradiation for brain metastases, advancing our understanding in mechanisms of brain metastases, and assisting development of individualized strategy for NSCLC patients with brain metastases.腦轉移非小細胞肺癌放射治療立體定位放射手術預後胞外泌體組合蛋白循環生物標記Brain metastasisNon-small cell lung cancerradiotherapystereotactic radiosurgeryprognosisexosomeintegrinscirculating biomarker