【作者】 李计成；

【导师】 李金泉； 周幽心；

【作者基本信息】 苏州大学 ， 神经外科学， 2007， 硕士

【摘要】 目的:应用碘-131标记嵌合肿瘤坏死治疗(iodine-131-labeled chimeric tumor necrosis treatment, ¹³¹I-chTNT)单克隆抗体经Ommaya囊注入脑胶质瘤残瘤腔内,探讨其治疗复发性高级别脑胶质瘤（III-IV）患者的疗效及安全性。方法:脑胶质瘤复发患者29例全部经病理证实为WHO分级Ⅲ～Ⅳ,随机分成¹³¹I-chTNT治疗组(¹³¹I-chTNT组)13例和卡莫司汀化疗组（化疗组）16例。患者均行第二次手术并大部切除肿瘤,肿瘤组织送病理检查,术后3日行MRI增强扫描。①治疗组术中切除肿瘤后于肿瘤残腔内放置Ommaya管,球囊端置于切口旁头皮下,术后7d开始口服10%碘化钾口服液封闭甲状腺,手术后14d囊内注入¹³¹I-chTNT（30.1±5.8 mCi）,于第一次注药后第15d重复经Ommaya囊注射¹³¹I-chTNT,剂量（28.5±5.5 mCi）,体积都为1.5ml。注射¹³¹I-chTNT后的次日行SPECT全身扫描。②化疗组患者术中切除肿瘤后不予置管,肿瘤组织常规送检,术后3天复查增强MRI,术后14天静脉注射卡莫司汀（BCNU）（100mg/m2×3d）,间隔6周重复一次,一共三次。所有患者均于术后3月、6月和12月时行门诊随访检查并评估疗效,内容包括:检查血常规,肝功能、肾功能、抗抗体检查,观察药物对机体造血、肝、肾功能及免疫的影响;增强MRI扫描,判断肿瘤复发情况;记录KPS评分,评价生活质量,记录治疗后生存时间。¹³¹I-chTNT治疗组还需另外测定甲状腺功能。结果:¹³¹I-chTNT组中位复发时间>24周,化疗组中位复发时间为22周,两组KPS评分（Karnofsky评分标准）术后KPS评分（p=0.84>0.05）,无明显差异, 3月时（p=0.072>0.05）,两组间无差异, 6月时（p=0.040<0.05）,12月时（p=0.047<0.05）两组间有差异。¹³¹I-chTNT组患者中位生存时间>52周,化疗组患者中位生存时间为43.3周。瘤周2cm范围吸收剂量为35.1Gy（12.1～65.2 Gy ）,MRI显示瘤周2cm内无弥散、边缘不规则以T1低信号T2高信号特点的水肿带的表现。¹³¹I-chTNT对肝、肾、造血等未见严重永久性毒性损伤,¹³¹I-chTNT组患者甲状腺功能术后T3=1.2±0.6 ng/mL,术后3月时T3=1.5±0.5 ng/mL,术后6月时T3=1.6±0.4 ng/mL,术后12月T3=1.4±0.7 ng/mL,术后T4=85.50±25.3ng /mL,术后3月时T4=90.2±15.1 ng /mL,术后6月时T4=89.6±17.2 ng /mL,术后12月时T4=86.1±20.1 ng /mL,术后时FT3=4.74±1.2 pmol/L,术后3月时FT3=5.70±0.5 pmol/L ,术后6月时FT3=6.2±0.6 pmol/L,术后12月时FT3=5.78±0.8 pmol/L均在正常值范围之内,¹³¹I-chTNT组4例患者出现轻度反应,1例患者注射药物后恶心行甲氧氯普胺10mg肌肉注射10分钟后缓解。1例患者注药后立刻出现肢体麻木和运动性失语,15分钟后麻木感消失,语言功能恢复。1例患者出现头皮感染,行抗生素加换药治疗1周后痊愈。1例患者血小板80×109/L,化疗组中8例患者出现毒性反应,1例患者白细胞2.8×109/L,2例患者白细胞分别为3.3×109/L和3.5×109/L, 1例静脉炎,对症治疗痊愈。4例患者轻度脱发。两组患者毒副作用行非参数秩和检验,在血常规和血生化上都为p>0.05。¹³¹I-chTNT组患者SPECT扫描结果显示放射性药物主要聚集在肿瘤病灶部位,甲状腺、骨髓等正常组织无异常聚集。在13例¹³¹I-chTNT患者的抗chTNT抗体检查中有两例失检,9例患者抗chTNT抗体滴度最高值出现在首次注药后3月,2例患者滴度最高值出现在首次注药后6月,随访期间未见有关抗chTNT抗体过敏反应发生。结论:瘤内注射¹³¹I-chTNT治疗人复发性高级别脑胶质瘤的疗效显著。瘤内注射治疗剂量的¹³¹I-chTNT对人体不造成明显的损害,该方法是安全的。更多还原

【Abstract】 Objective: To explore the clinical efficacity and safety of intratumoral radioimmunotherapy for recurrent high grade gliomas with iodine-131-labeled chimeric tumor necrosis treatment (¹³¹I-chTNT) via Ommaya reservoir.Methods: Twenty-nine postoperative patients with recurrent high grade gliomas World Health Organization（WHO） gradeⅢ-Ⅳapproved by pathology were randomly divided into ¹³¹I-chTNTgroup（13cases） and BCNU group（16cases）. All the patients recieved reoperation and MRI examination 3 days later.During reoperation the Ommaya reservoir was placed in the resection cavity at the time of tumor debulking. Sacculus proprius was covered by scalp near incision. Seven days later,10%KI was took orally to block thyroid from uptaking of ¹³¹I .Fourteen days later , ¹³¹I-chTNT （30.1±5.8 mCi）was injected into the residual tumor via Ommaya reservoir. The treatment（28.5±5.5 mCi） was repeated on the postoperative day 28-30. SPECT body scan was applicated in the following day of administration.BCNU group was treated with BCNU（100mg/m2×3d） systemically fourteen days after operation. Administration with BCNU needs three Course of treatment of 6 weeks. All patients were followed up by out-patient clinic periodically on 3 and 6 months.Results: All patients received subtotal surgical treatment. In ¹³¹I-chTNT group, 11 cases （84.6 %） remained stable 3 months later, 2（15.4%） progress. 6 months later, ten cases（76.9%） remained stable, 3 cases（23.1%） progress. In BCNU group, 12cases （75.0%） remained stable 3 months later, 4 cases（25.0%） progress. 6 months later, 8 cases（50.0%） remained stable, 8 cases（50.0%） progress. The difference of progression between groups was statistically analyzed the log rank test. It shows that there was significant difference in 6 months group（p=0.03<0.05）, no significant difference in 3 months group（p=0.129>0.05）. Cox regression proportional hazard model were performed to analyze both the two 6-months groups. It demonstrated proportion of aging factor （p=0.036<0.05）, 95% confidence intervals of which was 0.89～1.0; treating factor（p=0.001<0.005）, 95% confidence intervals of which was 1.2～1.7; factors of gental and histological classification （p>0.05）. Median progression of cases in ¹³¹I-chTNT group were more than 52 weeks, while cases in BCNU group was 24 weeks. KPS of the two groups were statistically analyzed by Wilconxon W test. There was no significant difference between two groups in KPS after operation（p=0.84>0.05） and 3 months（p=0.072>0.05）. However ,there was significant difference between two groups in KPS after 6 months（p=0.040<0.05） and 12 months（p=0.047<0.05）. Median survival of cases in ¹³¹I-chTNT group（>52weeks） was more long than cases in BCNU group significantly. COX regression proportional hazard model were performed to analyze both two groups. It demonstrated proportion of aging factor （p=0.010<0.05）, 95% confidence intervals of which was 1.03～1.45; treating factor（p=0.012<0.05）, 95% confidence intervals of which was 0.67～9.8; factors of histological classification（p=0.8>0.05）, 5% confidence intervals of which was 1.73～4.34. In ¹³¹I-chTNT group, there were 4 cases of adverse reaction; 1 case of nausea after injection of drug, alieviated 10 minutes after 10mg metoclopramide intramuscular injection; 1 case of numbness and Broca aphasia immediately after injection, numbness dissapeared after 15 minutes; 1 case of scalp infection, healed after 1 week antibiotics treatment; 1 case platelet was 80×109/l. In BCNU group, there were 8 cases of adverse reaction; 3 cases leukocyte was less than 3.0×109/l; 1 case of phlebitis, healed after allopathy. Result of SPECT scan suggested that ¹³¹I mostly located in tumor, no ¹³¹I aggregation was observed in thyroid and bone marrow. No observed toxicity was related to HAMA in ¹³¹I-chTNT.Conclusion: Intratumoral radiotherapy by postoperative ¹³¹I-chTNT via Ommaya reservoir performs efficiently , demonstrates a significant virtue compared with BCNU group for recurrent high grade tumors. No observed toxicity was related to HAMA in ¹³¹I-chTNT. It is safe and untoxious on liver,kidney and bone marrow clinically.更多还原