同步推量调强放疗制作肢体软组织肉瘤安全外科边界的研究

发布时间：2018-07-06 07:23

本文选题：同步推量 + 调强放疗　；参考：《新疆医科大学》2015年博士论文

【摘要】：目的:建立术前同步推量调强放疗(SIB-IMRT)技术制作肢体软组织肉瘤(STS)安全外科边界的方法。评价该方法的近期临床疗效和不良反应。了解SIB-IMRT对肢体STS外科边界组织形态、肿瘤细胞增殖与凋亡、微血管密度及其调控的影响,评价SIB-IMRT技术制作肢体STS外科边界的有效性。方法:1)收集我科于2012年1月至2015年1月间收治的局部晚期肢体STS患者32例。应用SIB-IMRT技术制作肢体STS外科边界。放疗计划:GTVs(外科边界靶区)3.5Gy/次,PTV(计划靶区)3.0Gy/次,5-7野,1次/天,共13次,5次/周,3周完成;放疗结束后3-6周行手术切除。术前同步化疗两周期,术后辅助化疗4-6周期。①通过自身配对资料秩和检验比较放疗前后肢体周径变化;②根据RECIST标准评价疗效;③评价术后切缘情况;④运用序贯试验设计评价术后6个月内无复发生存情况及外科边界区肿瘤坏死率;⑤依据CTCAE4.0和RTOG/EORTC标准评价放疗后不良反应。2)调取上述患者SIB-IMRT前后外科边界组织蜡块,自身配对。①制作HE染色切片、Masson染色切片、PTAH染色切片,观察SIB-IMRT后外科边界区组织形态变化;②采用免疫组织化学法(IHC)定量检测SIB-IMRT前后外科边界区肿瘤细胞Ki-67、Bcl-2和Caspase-3蛋白的表达;③采用TUNEL法测定SIB-IMRT前后外科边界区肿瘤细胞凋亡情况;④采用RNA原位分子杂交法(RISH)定量检测SIB-IMRT前后外科边界区肿瘤细胞Bcl-2 mRNA和Caspase-3 mRNA的表达;⑤采用荧光原位杂交技术(FISH)定量检测SIB-IMRT前后外科边界区肿瘤细胞Bcl-2基因扩增情况。3)①采用IHC法检测SIB-IMRT前后外科边界组织CD34、CD105的表达,比较SIB-IMRT前后外科边界肿瘤微血管密度(MVD)的差异;②采用IHC法定量检测外科边界区肿瘤细胞VEGF和HIF-1α蛋白的表达,比较其SIB-IMRT前后的差异;③分析HIF-1α、VEGF蛋白和MVD的相关性;比较临床分期对SIB-IMRT前后HIF-1α、VEGF和MVD的影响。结果:1)SIB-IMRT技术制作局部晚期肢体STS外科边界的放疗计划可行。SIB-IMRT前后肢体周径差异有统计学意义(Z=-4.470,P0.05);SIB-IMRT后部分缓解(PR)14例,病灶稳定(SD)18例;随访12-36个月,4例肺转移,4例死亡,6例复发,复发率18.7%;术后无复发生存时间5-32个月,无复发中位生存时间15个月;SIB-IMRT技术制作外科边界有效率60%;外科边界区肿瘤坏死率肿瘤坏死率;急性放射性皮肤损伤1级26例,2级4例,3级2例。皮肤晚期毒性1级29例,2级3例;皮下组织晚期毒性1级31例,2级1例。骨晚期毒性:0级27例,1级5例;关节晚期毒性:0级30例,1级2例。2)①HE染色切片、Masson染色、PTAH染色显示SIB-IMRT后外科边界区肿瘤细胞明显减少,坏死增多,纤维组织增生,假包膜增厚,横纹肌变性;②SIB-IMRT前后外科边界区肿瘤细胞Ki-67蛋白、Bcl-2蛋白、Caspase-3蛋白的表达差异有统计学意义(t值=6.160,P0.05;t值=4.828,P0.05;t值=-5.335,P0.05);③SIB-IMRT前后外科边界区肿瘤细胞凋亡指数(AI)差异有统计学意义(t值=-3.590,P0.05);④SIB-IMRT前后外科边界区肿瘤细胞Bcl-2 mRNA和Caspase-3 mRNA的表达差异有统计学意义(t值=3.452,P0.05;t值=-3.611,P0.05);⑤SIB-IMRT前后外科边界区肿瘤细胞Bcl-2基因扩增差异有统计学意义(t值=3.893,P0.05)。3)①SIB-IMRT前后外科边界区以CD34标记肿瘤MVD差异有统计学意义(t值=3.589,P0.05);以CD105标记肿瘤MVD差异有统计学意义(t值=2.539,P0.05);②SIB-IMRT前后外科边界区肿瘤细胞VEGF蛋白、HIF-1α蛋白的表达差异有统计学意义(t值=5.301,P0.05;t值=3.198,P0.05)。结论:1)SIB-IMRT技术制作局部晚期肢体STS外科边界对提高R0切除率具有重要意义,可改善无复发生存时间,近期疗效确切,缩短术前放疗疗程,患者耐受性较好。该技术制作局部晚期肢体STS外科边界是安全、有效的。2)SIB-IMRT可使肢体STS外科边界区肿瘤实质细胞减少、纤维间质增生、假包膜增厚,便于手术切除。SIB-IMRT可使肢体STS外科边界区肿瘤细胞Ki-67蛋白、Bcl-2蛋白、Bcl-2 mRNA表达降低,Caspase-3蛋白、Caspase-3 mRNA表达升高,从而诱导STS细胞凋亡,抑制STS细胞增殖。3)SIB-IMRT可使肢体STS外科边界区肿瘤细胞HIF-1α和VEGF蛋白表达降低,抑制肿瘤微血管生成,可能会减少术前放疗待手术期转移风险。MVD与HIF-1α和VEGF蛋白表达相关,VEGF、HIF-1α蛋白和MVD可能是SIB-IMRT技术制作局部晚期肢体STS外科边界的疗效评价指标和预后因素。
[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.
【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R738.7

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