本文選題：同步推量 + 調(diào)強(qiáng)放療�。� 參考：《新疆醫(yī)科大學(xué)》2015年博士論文

【摘要】：目的:建立術(shù)前同步推量調(diào)強(qiáng)放療(SIB-IMRT)技術(shù)制作肢體軟組織肉瘤(STS)安全外科邊界的方法。評價該方法的近期臨床療效和不良反應(yīng)。了解SIB-IMRT對肢體STS外科邊界組織形態(tài)、腫瘤細(xì)胞增殖與凋亡、微血管密度及其調(diào)控的影響,評價SIB-IMRT技術(shù)制作肢體STS外科邊界的有效性。方法:1)收集我科于2012年1月至2015年1月間收治的局部晚期肢體STS患者32例。應(yīng)用SIB-IMRT技術(shù)制作肢體STS外科邊界。放療計劃:GTVs(外科邊界靶區(qū))3.5Gy/次,PTV(計劃靶區(qū))3.0Gy/次,5-7野,1次/天,共13次,5次/周,3周完成;放療結(jié)束后3-6周行手術(shù)切除。術(shù)前同步化療兩周期,術(shù)后輔助化療4-6周期。①通過自身配對資料秩和檢驗比較放療前后肢體周徑變化;②根據(jù)RECIST標(biāo)準(zhǔn)評價療效;③評價術(shù)后切緣情況;④運(yùn)用序貫試驗設(shè)計評價術(shù)后6個月內(nèi)無復(fù)發(fā)生存情況及外科邊界區(qū)腫瘤壞死率;⑤依據(jù)CTCAE4.0和RTOG/EORTC標(biāo)準(zhǔn)評價放療后不良反應(yīng)。2)調(diào)取上述患者SIB-IMRT前后外科邊界組織蠟塊,自身配對。①制作HE染色切片、Masson染色切片、PTAH染色切片,觀察SIB-IMRT后外科邊界區(qū)組織形態(tài)變化;②采用免疫組織化學(xué)法(IHC)定量檢測SIB-IMRT前后外科邊界區(qū)腫瘤細(xì)胞Ki-67、Bcl-2和Caspase-3蛋白的表達(dá);③采用TUNEL法測定SIB-IMRT前后外科邊界區(qū)腫瘤細(xì)胞凋亡情況;④采用RNA原位分子雜交法(RISH)定量檢測SIB-IMRT前后外科邊界區(qū)腫瘤細(xì)胞Bcl-2 mRNA和Caspase-3 mRNA的表達(dá);⑤采用熒光原位雜交技術(shù)(FISH)定量檢測SIB-IMRT前后外科邊界區(qū)腫瘤細(xì)胞Bcl-2基因擴(kuò)增情況。3)①采用IHC法檢測SIB-IMRT前后外科邊界組織CD34、CD105的表達(dá),比較SIB-IMRT前后外科邊界腫瘤微血管密度(MVD)的差異;②采用IHC法定量檢測外科邊界區(qū)腫瘤細(xì)胞VEGF和HIF-1α蛋白的表達(dá),比較其SIB-IMRT前后的差異;③分析HIF-1α、VEGF蛋白和MVD的相關(guān)性;比較臨床分期對SIB-IMRT前后HIF-1α、VEGF和MVD的影響。結(jié)果:1)SIB-IMRT技術(shù)制作局部晚期肢體STS外科邊界的放療計劃可行。SIB-IMRT前后肢體周徑差異有統(tǒng)計學(xué)意義(Z=-4.470,P0.05);SIB-IMRT后部分緩解(PR)14例,病灶穩(wěn)定(SD)18例;隨訪12-36個月,4例肺轉(zhuǎn)移,4例死亡,6例復(fù)發(fā),復(fù)發(fā)率18.7%;術(shù)后無復(fù)發(fā)生存時間5-32個月,無復(fù)發(fā)中位生存時間15個月;SIB-IMRT技術(shù)制作外科邊界有效率60%;外科邊界區(qū)腫瘤壞死率腫瘤壞死率;急性放射性皮膚損傷1級26例,2級4例,3級2例。皮膚晚期毒性1級29例,2級3例;皮下組織晚期毒性1級31例,2級1例。骨晚期毒性:0級27例,1級5例;關(guān)節(jié)晚期毒性:0級30例,1級2例。2)①HE染色切片、Masson染色、PTAH染色顯示SIB-IMRT后外科邊界區(qū)腫瘤細(xì)胞明顯減少,壞死增多,纖維組織增生,假包膜增厚,橫紋肌變性;②SIB-IMRT前后外科邊界區(qū)腫瘤細(xì)胞Ki-67蛋白、Bcl-2蛋白、Caspase-3蛋白的表達(dá)差異有統(tǒng)計學(xué)意義(t值=6.160,P0.05;t值=4.828,P0.05;t值=-5.335,P0.05);③SIB-IMRT前后外科邊界區(qū)腫瘤細(xì)胞凋亡指數(shù)(AI)差異有統(tǒng)計學(xué)意義(t值=-3.590,P0.05);④SIB-IMRT前后外科邊界區(qū)腫瘤細(xì)胞Bcl-2 mRNA和Caspase-3 mRNA的表達(dá)差異有統(tǒng)計學(xué)意義(t值=3.452,P0.05;t值=-3.611,P0.05);⑤SIB-IMRT前后外科邊界區(qū)腫瘤細(xì)胞Bcl-2基因擴(kuò)增差異有統(tǒng)計學(xué)意義(t值=3.893,P0.05)。3)①SIB-IMRT前后外科邊界區(qū)以CD34標(biāo)記腫瘤MVD差異有統(tǒng)計學(xué)意義(t值=3.589,P0.05);以CD105標(biāo)記腫瘤MVD差異有統(tǒng)計學(xué)意義(t值=2.539,P0.05);②SIB-IMRT前后外科邊界區(qū)腫瘤細(xì)胞VEGF蛋白、HIF-1α蛋白的表達(dá)差異有統(tǒng)計學(xué)意義(t值=5.301,P0.05;t值=3.198,P0.05)。結(jié)論:1)SIB-IMRT技術(shù)制作局部晚期肢體STS外科邊界對提高R0切除率具有重要意義,可改善無復(fù)發(fā)生存時間,近期療效確切,縮短術(shù)前放療療程,患者耐受性較好。該技術(shù)制作局部晚期肢體STS外科邊界是安全、有效的。2)SIB-IMRT可使肢體STS外科邊界區(qū)腫瘤實質(zhì)細(xì)胞減少、纖維間質(zhì)增生、假包膜增厚,便于手術(shù)切除。SIB-IMRT可使肢體STS外科邊界區(qū)腫瘤細(xì)胞Ki-67蛋白、Bcl-2蛋白、Bcl-2 mRNA表達(dá)降低,Caspase-3蛋白、Caspase-3 mRNA表達(dá)升高,從而誘導(dǎo)STS細(xì)胞凋亡,抑制STS細(xì)胞增殖。3)SIB-IMRT可使肢體STS外科邊界區(qū)腫瘤細(xì)胞HIF-1α和VEGF蛋白表達(dá)降低,抑制腫瘤微血管生成,可能會減少術(shù)前放療待手術(shù)期轉(zhuǎn)移風(fēng)險。MVD與HIF-1α和VEGF蛋白表達(dá)相關(guān),VEGF、HIF-1α蛋白和MVD可能是SIB-IMRT技術(shù)制作局部晚期肢體STS外科邊界的療效評價指標(biāo)和預(yù)后因素。
[Abstract]:Objective: to establish a method for the preparation of the safety surgical boundary of soft tissue sarcoma (STS) in limb soft tissue sarcoma (SIB-IMRT) before operation. To evaluate the short-term clinical efficacy and adverse reactions of this method. To understand the effect of SIB-IMRT on the boundary of limb STS surgery, tumor cell proliferation and apoptosis, microvascular density and its regulation and control, and evaluate SIB-IM The effectiveness of RT technique in making the limb STS surgical boundary. Methods: 1) 32 cases of locally advanced limb STS patients in our department from January 2012 to January 2015 were collected. SIB-IMRT technique was used to make limb STS surgical boundary. The radiotherapy plan: GTVs (surgical border target area) 3.5Gy/, PTV (planned target area) 3.0Gy/ times, 5-7 fields, 1 times / day, 13 times, 5 times / week, 3. Week completion; 3-6 weeks after radiotherapy, surgical resection was performed. Preoperative synchronous chemotherapy was two cycles and postoperative adjuvant chemotherapy 4-6 cycles. (1) comparison of limb circumference changes before and after radiotherapy by self matched data rank and test; (2) evaluate the curative effect according to RECIST standard; (3) evaluate the postoperative margin of cutting edge; (4) use sequential test design to evaluate no recurrence within 6 months after operation. The survival situation and the tumor necrosis rate in the surgical boundary area; 5. According to the CTCAE4.0 and RTOG/EORTC criteria to evaluate the postoperative adverse reaction.2), the paraffin block of the surgical border tissue was taken before and after the SIB-IMRT. (1) the HE staining section, Masson staining section, PTAH staining section, and the morphological changes in the surgical boundary area after SIB-IMRT were observed. Immunohistochemical method (IHC) was used to detect the expression of Ki-67, Bcl-2 and Caspase-3 protein in the surgical boundary area before and after SIB-IMRT; (3) the apoptosis of the tumor cells in the surgical boundary area before and after SIB-IMRT was measured by TUNEL method. (4) the Bcl-2 mRN of the tumor cells in the surgical boundary area before and after the SIB-IMRT was detected by the RNA in situ hybridization (RISH) method. The expression of A and Caspase-3 mRNA; (5) using fluorescence in situ hybridization (FISH) for quantitative detection of Bcl-2 gene amplification in the tumor cells of surgical border region before and after SIB-IMRT (.3). (1) the expression of CD34, CD105, before and after SIB-IMRT was detected by IHC method, and the difference of microvascular density was compared between the peripheral and before and after the SIB-IMRT. To detect the expression of VEGF and HIF-1 alpha protein in the tumor cells in the surgical boundary area, compare the difference between the tumor cells before and after the SIB-IMRT; analyze the correlation between the HIF-1 alpha, the VEGF protein and the MVD; compare the effects of the clinical staging on HIF-1 a, VEGF and MVD before and after SIB-IMRT. Results: 1) SIB-IMRT technique is feasible for the radiotherapy plan of the locally advanced limb STS surgery boundary. The limb circumference of IB-IMRT was statistically significant (Z=-4.470, P0.05), 14 cases were remission (PR) after SIB-IMRT, and 18 cases were stable (SD), followed up for 12-36 months, 4 cases of lung metastasis, 4 cases of death, 6 cases of recurrence, and the recurrence rate of 18.7%; no recurrence survival time was 5-32 months after operation, and no recurrent median survival time was 15 months; SIB-IMRT technique made surgical boundary. Efficiency 60%, tumor necrosis rate, necrosis rate of tumor necrosis rate in surgical border area, 1 grade 26 cases of acute radionuclide skin injury, 4 cases of grade 2, 2 cases of grade 3, 29 cases of advanced toxicity of skin 1, 2 3 cases, 31 cases of advanced toxicity of subcutaneous tissue, recurrent cases of advanced toxicity of subcutaneous tissue, advanced toxicity of joint, Masson HE staining section, Masson staining, PT AH staining showed that the tumor cells in the surgical border area were significantly reduced, necrosis increased, fibrous tissue proliferated, pseudo capsule thickening, and rhabdomyic degeneration, and the expression of Ki-67 protein, Bcl-2 protein and Caspase-3 protein in the surgical boundary area before and after SIB-IMRT was statistically significant (t value =6.160, P0.05; t =4.828, P0.05; P0.05); There was significant difference between the tumor cell apoptosis index (AI) in the surgical boundary area before and after SIB-IMRT (t value =-3.590, P0.05), and the difference of the expression of the tumor cells Bcl-2 mRNA and Caspase-3 mRNA in the surgical boundary area before and after SIB-IMRT was statistically significant (t =3.452, There were statistical significance (t value =3.893, P0.05).3). (1) there were statistical significance (t value, P0.05) of CD34 labeled tumor MVD in the surgical boundary area before and after SIB-IMRT (t value =3.589, P0.05); The difference has statistical significance (t value =5.301, P0.05; t value =3.198, P0.05). Conclusion: 1) SIB-IMRT technology to make local extremities STS surgery boundary is of great significance to improve the rate of R0 excision. It can improve the non recurrence survival time, the short-term effect is accurate, the treatment course of preoperative radiotherapy is shortened, the patient is well tolerated. This technique is used to make local advanced limb STS surgery. The boundary is safe and effective.2) SIB-IMRT can reduce the tumor parenchyma cells in the extremities of the limb STS surgical border area, the fibrous interstitial hyperplasia, the thickening of the pseudo capsule, and the operation of.SIB-IMRT can make the tumor cell Ki-67 protein, Bcl-2 protein, Bcl-2 mRNA expression decrease, Caspase-3 protein, Caspase-3 mRNA, and induce the expression of the tumor cells in the border area of STS surgery. S cell apoptosis and inhibition of STS cell proliferation.3) SIB-IMRT can reduce the expression of HIF-1 alpha and VEGF protein in the tumor cells of the extremities STS surgical border area and inhibit the formation of tumor microvasculature, which may reduce the risk of.MVD and HIF-1 alpha and VEGF protein expression in pre operation radiotherapy, VEGF, HIF-1 alpha protein and may be part of the production of.MVD Evaluation of outcome and prognostic factors of advanced extremity STS surgical margins.
【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R738.7

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