發(fā)布時間：2018-04-25 16:05

  本文選題：局部晚期 + 非小細胞肺癌　； 參考：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文

【摘要】：第一部分:局部晚期非小細胞肺癌同步放化療的治療結(jié)果目的:評價局部晚期非小細胞肺癌(non-small-cell lung cancer,NSCLC)患者同步放化療的療效和不良反應(yīng)。方法:回顧性分析2001年1月至2010年12月間初治接受同步放化療的251例局部晚期NSCLC患者的臨床資料,其中IIIa期76例,IIIb期175例。放療中位劑量為 60 Gy,其中調(diào)強放療(intensity modulated radiation therapy,IMRT)174 例,三維適形放療(three dimensional-conformal radiotherapy,3D-CRT)51 例,常規(guī)放療 26例。全組患者接受EP方案(依托泊苷加順鉑)化療112例,接受PC方案(紫杉醇加卡鉑)化療99例,接受拓撲替康單藥化療18例,接受其他方案化療22例。分析同步放化療的療效及不良反應(yīng)。結(jié)果:全組有244例患者可評價近期療效,其中完全緩解(complete response,CR)6 例(2.5%),部分緩解(partial response,PR)183 例(75.0%),疾病穩(wěn)定(stable disease,SD)42 例(17.2%),疾病進展(progressive disease,PD)13 例(5.3%)。全組患者中位隨訪時間62個月,中位生存時間為21個月,其1、3、5年生存率分別為69.2%、31.2%和23.2%。全組患者中位無進展生存時間為10個月,其1、3、5年無進展生存率分別為40.9%、22.1%和17.7%。Ⅲa期和Ⅲb期NSCLC患者的5年生存率分別為29.2%和20.7%,差異無統(tǒng)計學(xué)意義(p=0.133)。全組有244例患者可評價治療失敗模式,其中61例(25.0%)出現(xiàn)局部區(qū)域進展,55例(22.5%)出現(xiàn)遠處轉(zhuǎn)移,77例(31.6%)出現(xiàn)局部區(qū)域進展+遠處轉(zhuǎn)移�！�3級放射性肺炎、放射性食管炎及白細胞減少的發(fā)生率分別為4.4%、11.2%和26.7%。結(jié)論:局部晚期NSCLC同步放化療的療效較好,不良反應(yīng)患者可耐受。同步放化療是不可手術(shù)的局部晚期NSCLC的標(biāo)準(zhǔn)治療。第二部分:局部晚期非小細胞肺癌同步放化療后的鞏固化療結(jié)果分析目的:對于局部晚期非小細胞肺癌(non-small-cell lung cancer,NSCLC)患者,同步放化療后鞏固化療的作用尚存在爭議。基于此,本研究旨在分析鞏固化療的療效和毒性。方法:回顧性分析2001年1月至2010年12月在我院接受根治性同步放化療的局部晚期NSCLC患者的病例資料。結(jié)果:203例患者中,113例(55.7%)接受了鞏固化療。中位鞏固化療周期數(shù)為3個,89.4%的患者完成了≥2周期的鞏固化療。鞏固化療組的總生存(overall survival,OS)顯著優(yōu)于非鞏固化療組(中位OS,27個月vs.16個月;5年OS,30.4%vs.22.5%;p=0.012)。鞏固化療組和非鞏固化療組的中位無進展生存(progression free survival,PFS)分別為12個月和9個月(p=0.291)。亞組分析顯示男性(HR:0.63;95%Cl,0.44-0.90)、年齡60 歲(HR:0.63;95%CI,0.42-0.95)、非鱗狀細胞癌(HR:0.44;95%CI,0.25-0.76)、療前卡氏評分≥80(HR:0.67;95%CI,0.48-0.93)、Ⅲb 期(HR:0.64;95%CI,0.43-0.95)、同步放化療后療效為穩(wěn)定(stable disease,SD)(HR:0.31;95%CI,0.14-0.65)和放療劑量≥60 Gy(HR:0.69;95%CI,0.48-1.00)的患者能夠從鞏固化療中顯著獲益。毒性方面,鞏固化療組≥3級的血液學(xué)毒性發(fā)生率更高,但是兩組差異沒有達到統(tǒng)計學(xué)意義(45.1%vs.34.4%;p=0.123)。結(jié)論:同步放化療的基礎(chǔ)上加以鞏固化療可能能夠進一步延長局部晚期NSCLC患者的生存而并沒有增加治療相關(guān)毒性,特別是對于男性、年齡60歲、非鱗癌、療前卡氏評分≥80、Ⅲb期、SD和放療劑量≥60 Gy的患者。但該研究結(jié)果仍然需要大規(guī)模前瞻性研究的證實。第三部分:MicroRNA-29c靶向VEGFA抑制肺腺癌進展的機制研究目的:肺腺癌具有侵襲性強和預(yù)后異質(zhì)性大的特點,目前其發(fā)生發(fā)展的機制尚未被闡明。越來越多的證據(jù)顯示microRNAs(miRNAs)的異常調(diào)控與多種腫瘤的發(fā)生發(fā)展密切相關(guān)。本研究目的為尋找肺腺癌的預(yù)后相關(guān)miRNA并研究其影響腫瘤進展的機制。方法:對87例病理證實為IIIa-N2期肺腺癌的福爾馬林固定石蠟包埋(formalin-fixed paraffin-embedded,FFPE)標(biāo)本進行miRNA芯片檢測以尋找預(yù)后相關(guān)miRNA。采用脂質(zhì)體轉(zhuǎn)染法瞬時轉(zhuǎn)染miR-29c過表達和干擾質(zhì)粒,MTS實驗檢測細胞增殖能力變化,Transwell實驗檢測細胞遷移/侵襲能力變化。生物信息學(xué)和雙熒光素酶報告基因?qū)嶒烆A(yù)測和驗證miR-29c與靶基因的關(guān)系,將miR-29c過表達和抑制后通過qRT-PCR、ELISA和Western blot檢測靶基因mRNA、分泌蛋白和細胞內(nèi)的蛋白變化。利用人臍靜脈內(nèi)皮細胞(human umbilical vein endothelial cell,HUVEC)成管實驗檢測miRNA對血管生成的影響。通過免疫組化(Immunohistochemistry,IHC)檢測患者FFPE標(biāo)本中miR-29c與微血管密度(microvessel density,MVD)和靶基因表達的相關(guān)性。結(jié)果:miRNA芯片及生存分析結(jié)果顯示miR-29c表達下調(diào)與患者的不良預(yù)后顯著相關(guān)。在體外實驗中miR-29c抑制細胞增殖、遷移和侵襲。生物信息學(xué)和雙熒光素酶報告基因?qū)嶒灠l(fā)現(xiàn)miR-29c能夠直接結(jié)合血管內(nèi)皮生長因子A(vascular endothelial growth factor A,VEGFA)的 3'-UTR 區(qū)域,qRT-PCR、ELISA 和 Western blot實驗結(jié)果發(fā)現(xiàn)miR-29c能夠在轉(zhuǎn)錄和翻譯水平下調(diào)VEGFA的表達。體外實驗中miR-29c能夠抑制HUVEC成管。高表達VEGFA能夠基本完全逆轉(zhuǎn)miR-29c導(dǎo)致的細胞增殖、遷移/侵襲和血管生成能力下降。在患者FFPE標(biāo)本中miR-29c與MVD和VEGFA的表達具有顯著相關(guān)性。結(jié)論:miR-29c通過靶向VEGFA在肺腺癌的進展中發(fā)揮抑癌作用,miR-29c有望作為肺腺癌預(yù)后的分子標(biāo)志物和有價值的藥物作用靶點。
[Abstract]:Part 1: therapeutic results of synchronous radiotherapy for locally advanced non-small cell lung cancer: To evaluate the efficacy and adverse reactions of concurrent chemoradiotherapy in patients with locally advanced non small cell lung cancer (non-small-cell lung cancer, NSCLC). Methods: a retrospective analysis of 251 locally advanced NSCL treated with synchronous radiotherapy from January 2001 to December 2010 The clinical data of C patients were 76 cases of IIIa phase and 175 cases in IIIb phase. The median dose of radiotherapy was 60 Gy, of which 174 cases were intensity modulated radiation therapy (intensity modulated radiation therapy, IMRT), 51 cases of three-dimensional conformal radiotherapy (three dimensional-conformal radiotherapy, 51 cases) and 26 cases with conventional radiotherapy. 112 cases were treated with PC regimen (paclitaxel plus carboplatin) chemotherapy in 99 cases, topotecan chemotherapy 18 cases, and other regimen chemotherapy 22 cases. Analysis of the curative effect and adverse reaction of concurrent chemoradiotherapy. Results: 244 patients in the whole group can evaluate the short-term effect, including complete remission (complete response, CR) 6 cases (2.5%), partial relief (partial response PR) 183 cases (75%), disease stability (stable disease, SD) 42 cases (17.2%), disease progression (progressive disease, PD) 13 cases (5.3%). The whole group was followed up for 62 months with a median survival time of 21 months, and its 1,3,5 year survival rate was 69.2%, 31.2% and 23.2%. group patients had no progression free survival for 10 months, and their 1,3,5 years did not advance. The 5 year survival rates of 40.9%, 22.1%, 17.7%. III A and III B NSCLC patients were 29.2% and 20.7%, respectively, with no statistical significance (p=0.133). 244 patients in the whole group evaluated the treatment failure mode, of which 61 cases (25%) had local regional progress, 55 (22.5%) had distant metastasis and 77 (31.6%) had local regional progress. Spreading + distant metastasis. The incidence of radiation pneumonitis of more than 3 levels, radiation esophagitis and leukocyte reduction were 4.4%, 11.2% and 26.7%., respectively: local advanced NSCLC radiotherapy and chemotherapy were better, patients with adverse reactions were tolerable. Synchronous radiochemotherapy was the standard treatment of Unoperable locally advanced NSCLC. Second part: locally advanced non small fine Analysis of the outcome of consolidation chemotherapy after synchronous radiotherapy and chemotherapy for cell lung cancer: for patients with locally advanced non-small cell lung cancer (non-small-cell lung cancer, NSCLC), the role of chemotherapy after concurrent chemoradiotherapy is still controversial. Based on this, the purpose of this study was to analyze the efficacy and toxicity of consolidation chemotherapy. Methods: a retrospective analysis from January 2001 to 2010 1 Results: 113 cases (55.7%) received consolidation chemotherapy in 203 patients in February. 113 of the 203 patients received consolidation chemotherapy. The median consolidation chemotherapy cycle number was 3, and 89.4% of the patients completed the consolidation chemotherapy for more than 2 cycles. The total survival (overall survival, OS) in the consolidation chemotherapy group was significantly better than non curing. The treatment group (median OS, 27 months vs.16 months; 5 years OS, 30.4%vs.22.5%; p=0.012). The median progression free survival (progression free survival, PFS) in the consolidation and non consolidation chemotherapy group was 12 months and 9 months respectively (p=0.291). The subgroup analysis showed that the male (HR:0.63; 95%Cl, 60), the age 60 years old, non squamous cells Cancer (HR:0.44; 95%CI, 0.25-0.76), before treatment, KRL score was more than 80 (HR:0.67; 95%CI, 0.48-0.93), stage III B (HR:0.64; 95%CI, 0.43-0.95). The curative effect was stable after concurrent chemoradiotherapy (stable disease) and radiotherapy doses of more than 60. The incidence of hematological toxicity in the cure group was more than 3, but the two groups were not statistically significant (45.1%vs.34.4%; p=0.123). Conclusion: the consolidation chemotherapy based on concurrent chemo chemotherapy could further prolong the survival of locally advanced NSCLC patients and did not increase the treatment related toxicity, especially for men, age 6. 0 years old, non squamous cell carcinoma, pre therapy score of more than 80, stage III B, SD and radiation dose more than 60 Gy. But the results still need a large prospective study. The third part: the mechanism of MicroRNA-29c targeting VEGFA to inhibit the progression of lung adenocarcinoma: lung adenocarcinoma is characterized by strong invasion and prognosis heterogeneity, and it is currently occurring The mechanism of development has not been clarified. More and more evidence shows that abnormal regulation of microRNAs (miRNAs) is closely related to the occurrence and development of various tumors. The purpose of this study is to search for the prognosis related miRNA of lung adenocarcinoma and to study the mechanism of its impact on the progression of the tumor. Methods: 87 cases of formalin fixed stone confirmed as IIIa-N2 lung adenocarcinoma were confirmed by pathology. Formalin-fixed paraffin-embedded (FFPE) specimens were tested for miRNA chip detection to find the prognosis related miRNA. using liposome transfection for transient transfection of miR-29c overexpression and interference plasmids, MTS test to detect cell proliferation ability, Transwell test to detect cell migration / invasiveness. Bioinformatics and double luciferase The relationship between miR-29c and target gene was predicted and verified by the reporter gene experiment. The target gene mRNA, secretory protein and protein changes were detected by qRT-PCR, ELISA and Western blot after the overexpression and inhibition of miR-29c. The angiogenesis of human umbilical vein endothelial cells (human umbilical vein endothelial cell) was tested for angiogenesis. The correlation between miR-29c and microvascular density (microvessel density, MVD) and target gene expression in FFPE specimens of patients with FFPE was detected by Immunohistochemistry (IHC). Results: miRNA chip and survival analysis showed that the downregulation of miR-29c expression was significantly related to the poor prognosis of the patients. The miR-29c inhibition in vitro was fine. Cell proliferation, migration and invasion. Bioinformatics and double luciferase reporter gene experiments found that miR-29c can directly bind the 3'-UTR region of vascular endothelial growth factor A (vascular endothelial growth factor A, VEGFA), and the qRT-PCR, ELISA, and Western experiments found that it can down the transcription and translation levels MiR-29c can inhibit HUVEC tube in vitro. High expression of VEGFA can completely reverse miR-29c induced cell proliferation, migration / invasion and decrease of angiogenesis. The expression of miR-29c and MVD and VEGFA in FFPE specimens of patients has significant correlation. Conclusion: miR-29c through target to VEGFA in the progression of adenocarcinoma of the lung to play a tumor suppressor. MiR-29c is expected to serve as a molecular marker for lung adenocarcinoma prognosis and a valuable target for drug use.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R734.2

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