發(fā)布時間：2018-07-13 11:57

【摘要】：第一部分沙利度胺聯(lián)合照射對人食管癌荷瘤鼠皮下移植瘤血管生成影響的研究目的:觀察沙利度胺或(和)照射對人食管癌裸鼠移植瘤血管內(nèi)皮細(xì)胞生長因子(VEGF)表達(dá)以及血管生成的影響。方法:將32只人食管鱗癌移植瘤荷瘤裸鼠隨機(jī)分為4組:對照組、沙利度胺組、照射組、照射+沙利度胺組,每組8只。照射組和照射+沙利度胺組荷瘤鼠腫瘤予6Me V電子線照射,照射劑量為20Gy/10f/12d,每周5次。沙利度胺組和照射+沙利度胺組每天胃灌注沙利度胺溶液一次(200mg/kg/d),連續(xù)12天。隔天對荷瘤鼠稱重并測量腫瘤體積。照射后13天處死荷瘤鼠并計算腫瘤抑制率,用免疫組織化學(xué)法檢測移植瘤瘤組織VEGF和微血管密度(MVD)的表達(dá)水平。結(jié)果:實(shí)驗過程中,對照組和沙利度胺組瘤體體積逐步增長,對照組增長速度較快,照射組和照射+沙利度胺組瘤體體積先增長后縮小,照射+沙利度胺組縮小最顯著。各組荷瘤鼠瘤體重量比較,差異有統(tǒng)計學(xué)意義(P0.05);照射+沙利度胺組抑瘤率最高,高達(dá)66.96%。沙利度胺的放射增敏比(SER)為1.56。析因分析顯示,沙利度胺與照射對降低荷瘤鼠瘤體重量具有明顯的協(xié)同作用(F照射×沙利度胺=4.266,P=0.048)。與照射組相比較,照射+沙利度胺組中裸鼠移植瘤組織中VEGF蛋白表達(dá)有所降低(P0.05);照射組MVD值高于照射+沙利度胺組(P0.05)。結(jié)論:沙利度胺聯(lián)合照射可提高射線對人食管癌裸鼠移植瘤的殺傷作用;沙利度胺可降低放療后瘤體內(nèi)VEGF的表達(dá)、降低瘤體內(nèi)微血管密度。第二部分食管癌放療或放化療中腫瘤病理反應(yīng)和血清血管內(nèi)皮生長因子變化對預(yù)后的影響目的:分析非手術(shù)食管癌患者放療或放化療過程中腫瘤組織病理反應(yīng)和血清血管內(nèi)皮生長因子(VEGF)的變化及其對預(yù)后的影響。方法:對89例經(jīng)病理證實(shí)的食管癌患者進(jìn)行放療,其中同步放化療65例,單純放療24例;放療方案:三維適形或調(diào)強(qiáng)放療;化療方案:脂質(zhì)體紫杉醇+順鉑,同步化療2周期,鞏固化療2周期。放療第4周行胃鏡檢查,并取病理活檢,病理反應(yīng)根據(jù)放療后腫瘤組織病理學(xué)特點(diǎn)分為輕度、中度、重度反應(yīng)。在放療前、放療第4周、放療結(jié)束后1周測定患者血清VEGF水平。另采集30例健康體檢者血清作為對照組。結(jié)果:全組患者完全緩解(CR)率和部分緩解(PR)率分別為56.2%和40.4%,總有效率96.6%。全組1、2、3年生存(OS)率分別為70.8%、49.4%、33.3%,1、2、3年無進(jìn)展生存(PFS)率分別為61.8%、35.3%、28.2%,1、2、3年局部控制(LC)率分別為76.9%、59.7%、50.0%。輕度病理反應(yīng)組1、2、3年OS率均低于重度反應(yīng)組(P均0.05);輕度病理反應(yīng)組1、2、3年P(guān)FS率均低于中、重度反應(yīng)組(P均0.05);輕度病理反應(yīng)組1、2、3年LC率均低于中、重度反應(yīng)組(P均0.05)。血清VEGF水平增高組1、2、3年OS率均低于降低組(P均0.05);增高組3年P(guān)FS率低于降低組(P0.05)。病理反應(yīng)與放療前血清VEGF水平、VEGF變化均無相關(guān)關(guān)系(P均0.05)。重度反應(yīng)組放療中、放療后血清VEGF水平較放療前下降,差異有統(tǒng)計學(xué)意義(P0.05)。多因素分析顯示,TNM分期、VEGF變化是影響食管癌患者OS的獨(dú)立因素(P均0.05)。結(jié)論:放療或放化療過程中腫瘤組織病理反應(yīng)和血清VEGF變化可預(yù)測非手術(shù)食管癌的療效,監(jiān)測治療中腫瘤組織病理反應(yīng)和VEGF變化對指導(dǎo)臨床個體化治療有重要意義。第三部分食管癌放療或放化療中血清血管內(nèi)皮生長因子變化規(guī)律及檢測時機(jī)的研究目的:觀察食管癌患者放療或放化療過程中血清血管內(nèi)皮生長因子(VEGF)的變化,探尋放療或放化療中血清VEGF變化規(guī)律以及其最佳檢測時機(jī)。方法:76例食管癌患者行根治性放療,其中53例行同期化療,單純放療23例;放療方案:三維適形或調(diào)強(qiáng)放療;化療方案:脂質(zhì)體紫杉醇+順鉑,同步化療2周期,鞏固化療2周期。放療前、放療中每周、放療后1周內(nèi)連續(xù)采集患者血清并測定VEGF水平。另采集30例健康體檢者血清作為對照組。結(jié)果:食管癌患者不同時間點(diǎn)檢測的血清VEGF水平均高于健康對照組(79.6±39.2)ng/L,差異均有統(tǒng)計學(xué)意義(t=2.165~3.896,P均0.05)。隨著放療進(jìn)行,患者血清VEGF水平總體呈逐漸降低趨勢(F=6.806,P=0.001)。放療中血清VEGF水平跟放療前比較,21例患者血清VEGF增高,增高時間大多在放療第2、3周或放療后1周內(nèi)。結(jié)論:放療第2、3周和放療后1周內(nèi)可能是篩選血清VEGF增高食管癌患者的較好時間窗,此時檢測對指導(dǎo)臨床個體化治療有重要意義。第四部分沙利度胺聯(lián)合放化療治療食管癌隨機(jī)對照研究目的:評價沙利度胺聯(lián)合放化療治療食管癌的安全性及療效。方法:對食管鱗癌患者進(jìn)行根治性放化療。放療方案:三維適形或調(diào)強(qiáng)放療;化療方案:脂質(zhì)體紫杉醇+順鉑,同步化療2周期,鞏固化療2周期。放療前、放療第2~4周、放療結(jié)束后1周內(nèi)測定患者血清VEGF水平。將血清VEGF水平增高的患者隨機(jī)分為兩組:試驗組31例、對照組30例。試驗組給予沙利度胺+放化療,對照組行常規(guī)放化療。結(jié)果:沙利度胺不良反應(yīng)主要表現(xiàn)為不同程度嗜睡。全組患者完全緩解(CR)率和部分緩解(PR)率分別為68.9%和24.6%,總有效率為93.5%。51例患者完成治療且隨訪資料齊全,其中試驗組26例,對照組25例。全組1、2、3年生存(OS)率分別為70.6%、34.1%、22.5%;1、2、3年無進(jìn)展生存(PFS)率分別為56.9%、29.5%、22.0%;1、2、3年局部控制(LC)率分別為81.0%、59.1%、52.6%。局部晚期患者(Ⅱ、Ⅲ期)分層分析顯示,試驗組患者3年OS率、3年P(guān)FS率、3年LC率均高于對照組,差異均有統(tǒng)計學(xué)意義(P均0.05);兩組局部晚期患者PFS曲線比較,差異有統(tǒng)計學(xué)意義(P0.05)。放療后與放療中血清VEGF水平比較,試驗組和對照組降低、穩(wěn)定、增高的病例數(shù)分別為14、14、2例和6、18、6例,差異有統(tǒng)計學(xué)意義(P0.05)。試驗組放療后血清VEGF降低患者1年OS率、1年P(guān)FS率和1、2、3年LC率均高于血清VEGF增高患者(P均0.05)。多因素分析顯示:TNM分期是影響患者生存期的因素,TNM分期和放療后是否有腫瘤殘存是影響患者無進(jìn)展生存期的因素。結(jié)論:沙利度胺可改善放療中血清VEGF水平增高的局部晚期食管癌患者預(yù)后,其治療毒副作用可耐受。
[Abstract]:The effect of thalidomide combined irradiation on the angiogenesis of subcutaneous transplanted tumor in human esophageal cancer mice: the effect of thalidomide or (and) irradiation on the expression of vascular endothelial growth factor (VEGF) and angiogenesis in human esophageal cancer xenografts in nude mice. Square method: 32 human esophageal squamous cell carcinoma xenografts were randomly assigned to nude mice It was divided into 4 groups: the control group, thalidomide group, irradiation group, and thalidomide group, 8 in each group. The tumor of the irradiated group and the thalidomide group was irradiated with 6Me V electron line, the dose was 20Gy/10f/12d and 5 times a week. The thalidomide group and the thalidomide group were injected with thalidomide once a day (200mg/kg/d), for 12 days. The tumor mice were weighed and measured the tumor volume every other day. The tumor mice were killed 13 days after irradiation and the tumor inhibition rate was calculated. The expression level of VEGF and microvascular density (MVD) was detected by immunohistochemistry. Results: during the experiment, the volume of the tumor body in the control group and thalidomide group increased gradually, and the control group grew faster. The volume of the tumor in the group and the thalidomide group first increased and then reduced, and the most significant reduction in the irradiation + thalidomide group. The difference was statistically significant (P0.05). The rate of tumor suppressor in the thalidomide group was the highest, and the radiosensitivity ratio of 66.96%. thalidomide (SER) was 1.56. factorial analysis. Compared with the irradiated group, the expression of VEGF protein in the transplanted tumor tissues of the irradiated group was decreased (P0.05), and the MVD value of the irradiated group was higher than that of the irradiated group (P0.05). Conclusion: the combination of thalidomide and salidamide (P0.05) in the irradiated group was higher than that in the irradiated group (P0.05). Conclusion: the combined irradiation of thalidomide can improve the injection of MVD in the irradiated group. Conclusion: the combined irradiation of thalidomide can improve the radiation of the tumor in the irradiated group (P0.05). The killing effect of line on human esophageal carcinoma in nude mice; thalidomide can reduce the expression of VEGF in the tumor body after radiotherapy and decrease the microvascular density in the tumor. The effect of the pathological changes of tumor and serum vascular endothelial growth factor on the prognosis in second part of the radiotherapy or radiotherapy and chemotherapy of esophageal cancer and the effect of the changes of serum vascular endothelial growth factor on the prognosis: analysis of radiotherapy or radiotherapy for non operative esophageal cancer patients Changes in the pathological changes of tumor tissue and serum vascular endothelial growth factor (VEGF) during chemotherapy and its effect on the prognosis. Methods: 89 patients with pathologically confirmed esophageal cancer were treated with radiotherapy, including 65 cases of synchronous radiotherapy and chemotherapy, 24 cases of radiotherapy alone; radiotherapy scheme: three-dimensional conformal or intensity modulated radiation therapy; chemotherapy regimen: liposome paclitaxel + cisplatin, 2 cycles of chemotherapy and 2 cycles of chemotherapy were consolidated. Gastroscopy was performed for fourth weeks and pathological biopsy was taken for fourth weeks. The pathological changes were divided into mild, moderate and severe reaction according to the pathological features of the tumor after radiotherapy. Before radiotherapy, fourth weeks after radiotherapy and 1 weeks after radiotherapy, 30 cases of health examination were taken as control. Results: the rate of complete remission (CR) and partial remission (PR) were 56.2% and 40.4%, respectively, and the total effective rate of 96.6%. was 70.8%, 49.4%, 33.3%, and 33.3%, and 1,2,3 was 61.8%, 35.3%, 28.2%, respectively, and the rate of LC was 76.9%, 59.7%, and 50.0%. mild pathological reaction group 1,2,3. The annual OS rate was lower than that in the severe reaction group (P 0.05), and the PFS rate in the mild pathological reaction group was lower than that in the medium and the severe reaction group (P was 0.05), and the LC rate of the mild pathological reaction group was lower than that of the moderate and severe reaction group (P 0.05). The OS rate of 1,2,3 year's 1,2,3 year in the serum VEGF group was lower than that in the lower group (P was 0.05), and the 3 year rate of the increased group was lower than that of the lower group. There was no correlation between the serum VEGF level and VEGF changes before radiotherapy (P 0.05). The serum VEGF level in the severe reaction group was lower than that before radiotherapy (P0.05). The multivariate analysis showed that TNM staging was an independent factor affecting OS in patients with tube cancer (P 0.05). Conclusion: Radiotherapy or chemoradiation The pathological response of tumor tissue and changes of serum VEGF in the course of treatment can predict the efficacy of non operative esophagus cancer. Monitoring the histopathological response and changes of VEGF in the treatment of cancer is of great significance for guiding clinical individualized treatment. The study on the changes of the serum vascular endothelial growth factor in third parts of the radiotherapy or radiotherapy and chemotherapy of esophageal cancer and the timing of detection Objective: To observe the changes of serum vascular endothelial growth factor (VEGF) during radiotherapy or radiotherapy and chemotherapy in patients with esophageal cancer, and to explore the change of serum VEGF in radiotherapy or radiotherapy and chemotherapy. Methods: 76 cases of esophageal cancer patients were treated with radical radiotherapy, of which 53 cases were treated with the same stage chemotherapy, 23 cases were treated with radiotherapy alone; Intensity modulated radiation therapy; chemotherapy regimen: liposome paclitaxel + cisplatin, synchronous chemotherapy for 2 cycles and 2 cycles of chemotherapy. Before radiotherapy, the patient serum was collected and VEGF level was measured continuously within 1 weeks after radiotherapy. 30 cases of healthy persons were collected as control group. Results: the serum levels of VEGF in patients with tube cancer at different time points were all high In the healthy control group (79.6 + 39.2) ng/L, the difference was statistically significant (t=2.165~3.896, P 0.05). With the radiotherapy, the serum VEGF level of the patients was gradually decreasing (F=6.806, P=0.001). The serum VEGF level in the radiotherapy was compared with that before the radiotherapy. The serum VEGF increased in 21 patients, and the increase time was mostly at week 2,3 or 1 weeks after radiotherapy. Conclusion: 2,3 weeks and 1 weeks after radiotherapy may be a better time window for screening serum VEGF for patients with esophageal cancer. The detection is of great significance for guiding clinical individualized treatment. A randomized controlled study of thalidomide combined with radiotherapy and chemoradiotherapy for esophageal cancer: evaluation of thalidomide combined with chemoradiotherapy for esophageal cancer Methods: radical radiotherapy and chemotherapy for patients with esophageal squamous cell carcinoma. Radiotherapy scheme: three dimensional conformal or intensity modulated radiation therapy; chemotherapy regimen: liposome paclitaxel + cisplatin, 2 cycles of chemotherapy, 2 cycles of chemotherapy. Before radiotherapy, week 2~4, and 1 weeks after radiotherapy, the serum level of patients is increased. The level of serum VEGF is increased. The patients were randomly divided into two groups: 31 cases in the experimental group and 30 cases in the control group. The experimental group was given thalidomide plus chemotherapy, and the control group was treated with conventional radiotherapy and chemotherapy. Results: the adverse reaction of thalidomide was mainly characterized by different degree of lethargy. The total remission rate and partial remission rate (PR) rate of the whole group were 68.9% and 24.6% respectively, and the total effective rate was 93.5%.51 patients. There were 26 cases in the experimental group and 25 cases in the control group. The 1,2,3 year survival (OS) rate was 70.6%, 34.1%, 22.5%, respectively, and the rate of PFS was 56.9%, 29.5%, and 22%, respectively, and 1,2,3 was 81%, 59.1%, and 1,2,3, respectively, in 1,2,3 years (II, stage III), and the experimental group 3 The annual OS rate, the 3 year PFS rate and the 3 year LC rate were all higher than the control group, the difference was statistically significant (P 0.05). The PFS curve of the two groups of locally advanced patients was statistically significant (P0.05). Compared with the serum VEGF level in the radiotherapy, the experimental group and the control group were lower, stable, and increased, respectively, 14,14,2 cases and 6,18,6 cases respectively, the difference has unification. The study significance (P0.05). The 1 year OS rate of serum VEGF decreased in the experimental group, the 1 year PFS rate and the 1,2,3 year LC rate were higher than the serum VEGF increase (P 0.05). The multivariate analysis showed that the TNM staging is the factor affecting the patient's survival time. The TNM staging and the residual tumor after radiotherapy are the factors affecting the patient's progression free survival. Conclusion: Sand Leidomide can improve the prognosis of locally advanced esophageal cancer patients with higher serum VEGF level in radiotherapy, and its side effects can be tolerated.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R735.1

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