复发性高级别人脑胶质瘤～（131）I-chTNT间质治疗的临床研究
|
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, ~(131)I-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~(131)I-chTNT治疗组(~(131)I-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~(131)I-chTNT(30.1±5.8 mCi),于第一次注药后第15d重复经Ommaya囊注射~(131)I-chTNT,剂量(28.5±5.5 mCi),体积都为1.5ml。注射~(131)I-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。~(131)I-chTNT治疗组还需另外测定甲状腺功能。
结果:~(131)I-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。~(131)I-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。~(131)I-chTNT对肝、肾、造血等未见严重永久性毒性损伤,~(131)I-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,~(131)I-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。~(131)I-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~(131)I-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~(131)I-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~(131)I-chTNT对人体不造成明显的损害,该方法是安全的。
Objective: To explore the clinical efficacity and safety of intratumoral radioimmunotherapy for recurrent high grade gliomas with iodine-131-labeled chimeric tumor necrosis treatment (~(131)I-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 ~(131)I-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 ~(131)I .Fourteen days later , ~(131)I-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 ~(131)I-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 ~(131)I-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 ~(131)I-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 ~(131)I-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 ~(131)I mostly located in tumor, no ~(131)I aggregation was observed in thyroid and bone marrow. No observed toxicity was related to HAMA in ~(131)I-chTNT.
Conclusion: Intratumoral radiotherapy by postoperative ~(131)I-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 ~(131)I-chTNT. It is safe and untoxious on liver,kidney and bone marrow clinically.
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~(131)I-chTNT治疗组(~(131)I-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~(131)I-chTNT(30.1±5.8 mCi),于第一次注药后第15d重复经Ommaya囊注射~(131)I-chTNT,剂量(28.5±5.5 mCi),体积都为1.5ml。注射~(131)I-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。~(131)I-chTNT治疗组还需另外测定甲状腺功能。
结果:~(131)I-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。~(131)I-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。~(131)I-chTNT对肝、肾、造血等未见严重永久性毒性损伤,~(131)I-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,~(131)I-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。~(131)I-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~(131)I-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~(131)I-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~(131)I-chTNT对人体不造成明显的损害,该方法是安全的。
Objective: To explore the clinical efficacity and safety of intratumoral radioimmunotherapy for recurrent high grade gliomas with iodine-131-labeled chimeric tumor necrosis treatment (~(131)I-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 ~(131)I-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 ~(131)I .Fourteen days later , ~(131)I-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 ~(131)I-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 ~(131)I-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 ~(131)I-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 ~(131)I-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 ~(131)I mostly located in tumor, no ~(131)I aggregation was observed in thyroid and bone marrow. No observed toxicity was related to HAMA in ~(131)I-chTNT.
Conclusion: Intratumoral radiotherapy by postoperative ~(131)I-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 ~(131)I-chTNT. It is safe and untoxious on liver,kidney and bone marrow clinically.
引文
1. Hopkins K,Chandler C,Eatough J,et al. Direct injection of 90Y MAbs into glioma tumor resection cavities leads to limited diffusion of the radioimmunoconjugates into normal brain parenchyma: a model to estima absorbed radiation dose. Int J Radiat Oncol Biol Phys . 1998 ; 40 : 835-844.
2. 段国升,朱诚. 手术学全集.神经外科卷[M]. 人民军医出版社. 1994; 12.
3. Masks JE, Baglan RJ, Prassad SC, et al . Cerebral radionecrosis : Incidence and risk in relation to dose , time , fractionation and volume. Int J Radiat Oncol Phys. 1981; 7 :243.
4. Bleehen NM, Stenning SP. A Medical research counciltrial of two radio-therapy doses in treatment of grades 3 and 4 astrocytoma. Br J Cancer. 1991; 64 :769.
5. Klepper LIa. Method of calculating the equivalent tumor dose as a function as to irradiated tumor tissue volume [J]. MedTekh. 2001;15:1782-1791.
6. Larson DA,Flickinger JC, Loeffer JS,et al. The radiobiology of radiosurgery. Int J Radiat Oncol Bio phys. 1994; 25:557-561.
7. Sheline GE, Wara WW, Smith V. Therapeutic irradiation and train injury. Int J Radiat Oncol Bio Phys. 1980; 6 :1215.
8. Hall EJ. The biological basis of endocrinetherapy : The henschke memorial secture. Endocurie Hypertherm Oncol . 1985; 1 :141-149.
9. 吴在德,郑树,吴承远,等. 高等教育教材. 人民卫生出版社. 2000; 306.
10. Stenwart DJ. A critique of the role of the blood - brain barrier Ⅰ the chemotherapy of human brain tumors. J Neurooncol. 1994; 20 :121.
11. HALL EJ. radiobiology for the radiologist Philadelphia. JB Lippincott. 1994;2:234-245.
12. 蒋宁一. 肿瘤核医学. 人民卫生出版社. 2002;250.
13. Mahaley MS, Day ED. Immunological studies of human gliomas. J Neurosurg.1965; 23:363-370.
14. Kemshead JT, Papanastassiou V, Coakham HB, et al. Monoclonal antibodies in the treatment of central nervous system malignancies. Eur J Cancer. 1992; 28:511–513.
15. Jain RK, Baxter LT. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: Significance of elevated interstitial pressure. Cancer Res. 1988; 48:7022-7032.
16. Ilkcan Cokgor, Gamal Akabani, Chien-Tsun Kuan,et al. Phase I Trial Results of Iodine-131–Labeled Antitenascin Monoclonal Antibody 81C6 Treatment of Patients With Newly Diagnosed Malignant Gliomas. Journal of Clinical Oncology. 2000; 18(22):3862-3872.
17. Chen FM , Epstein AL , Li Z , et al. A comparative autoradiographic study demonstrating differential intra-tumor localization of monoclonal antibodies to cell surface (Lym-1) and intracellular (TNT-1) antigens. J Nucl Med. 1990; 31:1059-1066..
18. Shapiro WR, Carpenter SP, Roberts K,et al. (131)I-chTNT-1/B mAb: tumour necrosis therapy for malignant astrocytic glioma. Expert Opin Biol Ther. 2006; 6(5):539-545.
19. Ravi D, Sunil Krishnan, Tom R, et al. Phase II trial of carmustine, cisplatin, and oral etoposide chemotherapy before radiotherapy for grade 3 astrocytoma (anaplastic astrocytoma). Int J Radiat Oncol Biol Phys. 2005; 61(2):380-386.
20. Leslie A, Khawli, Peisheng Hu, et al. Multiple uses of tumor necrosis therapy(TNT) for the treatment and imaging of solid tumors:preclinical considerations and progress. Update on cancer therapeutics. 2006; 33-47.
21. 李金泉, 鲍耀东, 周岱, 等. 125IUdR对人脑胶质瘤细胞SHG44的杀伤作用. 核技术. 2001; 24(11):881-884.
22. Salcman M, Kaplan RS, Durken TB, et al. Effect of age and reoperation on survival in the combined modality treatment of malignant astrocytomas. Neurosurgery. 1982;10:454-463.
23. Sandra A. Rempel, Steve Dudas, Shugang Ge, et al.Identification and Localization of the Cytokine SDF1 and Its Receptor, CXC Chemokine Receptor 4, to Regions of Necrosis and Angiogenesis in Human Glioblastoma. Clinical Cancer Research. 2000; 6:102-111.
24. Walker KE, Galicich JH, Krol G, et al.Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. 1989; 16:1405-1496.
25. Patterson AV, Saunders MP, GrecoO, etal. Prodrugsingenetic chemoradiotherapy. J Curr Pharm Des. 2003; 9(26):2131-2154.
26. Bigner DD, Brown MT, Friedman AH, et al. Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: Phase I trial results. J Clin Oncol . 1998; 16:2202-2212.
27. 傅相平, 李安民, 张志文, 等. 131I-肿瘤细胞核人鼠嵌合单抗脑胶质瘤瘤内放免治疗研究. 中华实验外科杂志. 2005 ; 22(1):102-102.
28. Leibel SA, Sheline GE. Radiation therapy for neoplasms of the brain.J Neurosurg. 1987; 66:1-22.
1. 于新, 刘宗惠, 孙春雷, 等. 恶性胶质瘤再手术治疗的探讨. 中华神经外科杂志, 1996, 12 (6) : 339 - 341.
2. OriuchiN, Tomiyoshi K, Inoue T, et al. Independent thallium – 201 accumulation and fluorine - 18 - fluorodeoxyglucose metabolism in glioma. J NuclMed. 1996; 37 (3) : 457 - 462.
3. Klepper Lia. Method of calculating the equivalent tumor dose as a function as to irradiated tumor tissue volume [J], MedTekh, 2001; 15(2):120-132.
4. Eyupoglu IY, Hahnen E, Buslei R, et al. Suberoylanilide hydroxamic acid ( SAHA) has potent anti - glioma p roperties in vitro, ex vivo and in vivo. J Neurochem. 2005; 93 (4): 992 - 999.
5. Karlsson T, Henriksson R, Hedman H. Induction of apoptosis in resistant glioma cells by synthetic cap spase - activation. J Neurooncol. 2004; 66 (1 - 2) : 71 - 79.
6. Bleehen NM, Stenning SP. A Medical research counciltrial of two radio-therapy doses in treatment of grades 3 and 4 astrocytoma. Br J Cancer . 1991 ; 64 :769.
7. Walker MD, Sticke TA, Sheline GE. An analysis of dose - effect relationship in the radiotherapy of malignant gliomas. Int J R ADIAT Oncol BiolPhys. 1979; 5 :1725.
8. Masks JE, Baglan RJ, Prassad SC, et al. Cerebral radionecrosis: Incidence and risk in relation to dose , time , fractionation and volume. Int J Radiat Oncol Phys. 1981; 7 :243.
9. Sheline GE, Wara WW, Smith V. Therapeutic irradiation and train injury. Int J Radiat Oncol Bio Phys. 1980;6:1215.
10. Hall EJ . The biological basis of endocrinetherapy : The henschke memorial secture 1984. Endocurie Hypertherm Oncol. 1985; 1:141.
11. 吴在德, 郑树, 吴承远, 等. 高等教育教材. 外科学. 第5版. 人民卫生出版社. 2000; 306.
12. Stenwart DJ . A critique of the role of the blood - brain barrier Ⅰ the chemotherapy of human brain tumors. J Neurooncol 1994; 20:121.
13. HALL ej. radiobiology for the radiologist Philadelphia. JB Lippincott. 1994; 20(12):621-632.
14. 田增民. 现代立体定向神经外科学. 中国科技出版社. 1997; 135-136.
15. 蒋宁一. 肿瘤核医学. 人民卫生出版社. 2002;250.
16. Press OW. Physics for practitioners: the use of radiolabeled monoclonal antibodies inB-cell non-Hodgkin’s lymphoma. Semin Hematol. 2003; 7(4suppl7):2-8.
17. Rennen HJ, Makarewicz J, Oyen WJ, et al. The effect of molecular weight on nonspecific accumulation of (99m)Tc-labeled proteins in inflammatory foci. Nucl Med Biol. 2001; 28(4):401-408.
18. Goldenberg DM. Targeted therapy of cancer weith radiolabeled antibodies. J Nucl . 2002; 43(5):693-713.
19. 王骊丽, 韩 骅, 等. 人-鼠嵌合抗体表达载体的构建和抗人HER2 抗体的表达. 细胞与分子免疫学杂志(Chin J Cell Mol Immunol) . 2004; 20(3):136-137.
20. Wilder RB, DeNardo GL, DeNardo SJ, Radioimmunotherapy: recent results and future directions [J ] . J Clin Oncol . 1996; 14 ( 4) : 1383-1400.
21. Han SH, Zonenberg BA, de Klerk JMH. 186Re-etidronate in breast cancer patients with metastatic bone pain[J ] . J Nucl Med . 1999; 40(4) :639-642.
22. Quirijnen JM, Han SH, Zonnenberg BA,et al. Efficacy of Rhenium-186- etidronate in prostate cancer patients with metastatic bone pain[J ] . J Nucl Med. 1996; 37 (9) :1511-1515.
23. Epenetos AA, Hird VV, Lambert H, et al. Long term survival of patients with advanced ovarian cancer treated with intraperitoneal radioimmunotherapy[J ] . Int J Gynecl Cancer. 2000; 10 ( Suppl) : 44-46.
24. Reardon DA, Akabani G, Coleman RE, et al. Phase Ⅱ trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas [J]. J Clin Oncol. 2002; 20(5): 1389-1397.
25. Goetz C, Riva P, Poepperl G, et al. Locoregional radioimmunotherapy in selected patients with malignant glioma: experiences,side effects and survival times [J]. J Neurooncol. 2003; 62(3): 321-328.
26. Zalutsky MR. Current status of therapy of solid tumors: brain tumor therapy [J]. J Nucl . 2005; 46(Suppl 1): 151-156.
2. 段国升,朱诚. 手术学全集.神经外科卷[M]. 人民军医出版社. 1994; 12.
3. Masks JE, Baglan RJ, Prassad SC, et al . Cerebral radionecrosis : Incidence and risk in relation to dose , time , fractionation and volume. Int J Radiat Oncol Phys. 1981; 7 :243.
4. Bleehen NM, Stenning SP. A Medical research counciltrial of two radio-therapy doses in treatment of grades 3 and 4 astrocytoma. Br J Cancer. 1991; 64 :769.
5. Klepper LIa. Method of calculating the equivalent tumor dose as a function as to irradiated tumor tissue volume [J]. MedTekh. 2001;15:1782-1791.
6. Larson DA,Flickinger JC, Loeffer JS,et al. The radiobiology of radiosurgery. Int J Radiat Oncol Bio phys. 1994; 25:557-561.
7. Sheline GE, Wara WW, Smith V. Therapeutic irradiation and train injury. Int J Radiat Oncol Bio Phys. 1980; 6 :1215.
8. Hall EJ. The biological basis of endocrinetherapy : The henschke memorial secture. Endocurie Hypertherm Oncol . 1985; 1 :141-149.
9. 吴在德,郑树,吴承远,等. 高等教育教材. 人民卫生出版社. 2000; 306.
10. Stenwart DJ. A critique of the role of the blood - brain barrier Ⅰ the chemotherapy of human brain tumors. J Neurooncol. 1994; 20 :121.
11. HALL EJ. radiobiology for the radiologist Philadelphia. JB Lippincott. 1994;2:234-245.
12. 蒋宁一. 肿瘤核医学. 人民卫生出版社. 2002;250.
13. Mahaley MS, Day ED. Immunological studies of human gliomas. J Neurosurg.1965; 23:363-370.
14. Kemshead JT, Papanastassiou V, Coakham HB, et al. Monoclonal antibodies in the treatment of central nervous system malignancies. Eur J Cancer. 1992; 28:511–513.
15. Jain RK, Baxter LT. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: Significance of elevated interstitial pressure. Cancer Res. 1988; 48:7022-7032.
16. Ilkcan Cokgor, Gamal Akabani, Chien-Tsun Kuan,et al. Phase I Trial Results of Iodine-131–Labeled Antitenascin Monoclonal Antibody 81C6 Treatment of Patients With Newly Diagnosed Malignant Gliomas. Journal of Clinical Oncology. 2000; 18(22):3862-3872.
17. Chen FM , Epstein AL , Li Z , et al. A comparative autoradiographic study demonstrating differential intra-tumor localization of monoclonal antibodies to cell surface (Lym-1) and intracellular (TNT-1) antigens. J Nucl Med. 1990; 31:1059-1066..
18. Shapiro WR, Carpenter SP, Roberts K,et al. (131)I-chTNT-1/B mAb: tumour necrosis therapy for malignant astrocytic glioma. Expert Opin Biol Ther. 2006; 6(5):539-545.
19. Ravi D, Sunil Krishnan, Tom R, et al. Phase II trial of carmustine, cisplatin, and oral etoposide chemotherapy before radiotherapy for grade 3 astrocytoma (anaplastic astrocytoma). Int J Radiat Oncol Biol Phys. 2005; 61(2):380-386.
20. Leslie A, Khawli, Peisheng Hu, et al. Multiple uses of tumor necrosis therapy(TNT) for the treatment and imaging of solid tumors:preclinical considerations and progress. Update on cancer therapeutics. 2006; 33-47.
21. 李金泉, 鲍耀东, 周岱, 等. 125IUdR对人脑胶质瘤细胞SHG44的杀伤作用. 核技术. 2001; 24(11):881-884.
22. Salcman M, Kaplan RS, Durken TB, et al. Effect of age and reoperation on survival in the combined modality treatment of malignant astrocytomas. Neurosurgery. 1982;10:454-463.
23. Sandra A. Rempel, Steve Dudas, Shugang Ge, et al.Identification and Localization of the Cytokine SDF1 and Its Receptor, CXC Chemokine Receptor 4, to Regions of Necrosis and Angiogenesis in Human Glioblastoma. Clinical Cancer Research. 2000; 6:102-111.
24. Walker KE, Galicich JH, Krol G, et al.Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. 1989; 16:1405-1496.
25. Patterson AV, Saunders MP, GrecoO, etal. Prodrugsingenetic chemoradiotherapy. J Curr Pharm Des. 2003; 9(26):2131-2154.
26. Bigner DD, Brown MT, Friedman AH, et al. Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: Phase I trial results. J Clin Oncol . 1998; 16:2202-2212.
27. 傅相平, 李安民, 张志文, 等. 131I-肿瘤细胞核人鼠嵌合单抗脑胶质瘤瘤内放免治疗研究. 中华实验外科杂志. 2005 ; 22(1):102-102.
28. Leibel SA, Sheline GE. Radiation therapy for neoplasms of the brain.J Neurosurg. 1987; 66:1-22.
1. 于新, 刘宗惠, 孙春雷, 等. 恶性胶质瘤再手术治疗的探讨. 中华神经外科杂志, 1996, 12 (6) : 339 - 341.
2. OriuchiN, Tomiyoshi K, Inoue T, et al. Independent thallium – 201 accumulation and fluorine - 18 - fluorodeoxyglucose metabolism in glioma. J NuclMed. 1996; 37 (3) : 457 - 462.
3. Klepper Lia. Method of calculating the equivalent tumor dose as a function as to irradiated tumor tissue volume [J], MedTekh, 2001; 15(2):120-132.
4. Eyupoglu IY, Hahnen E, Buslei R, et al. Suberoylanilide hydroxamic acid ( SAHA) has potent anti - glioma p roperties in vitro, ex vivo and in vivo. J Neurochem. 2005; 93 (4): 992 - 999.
5. Karlsson T, Henriksson R, Hedman H. Induction of apoptosis in resistant glioma cells by synthetic cap spase - activation. J Neurooncol. 2004; 66 (1 - 2) : 71 - 79.
6. Bleehen NM, Stenning SP. A Medical research counciltrial of two radio-therapy doses in treatment of grades 3 and 4 astrocytoma. Br J Cancer . 1991 ; 64 :769.
7. Walker MD, Sticke TA, Sheline GE. An analysis of dose - effect relationship in the radiotherapy of malignant gliomas. Int J R ADIAT Oncol BiolPhys. 1979; 5 :1725.
8. Masks JE, Baglan RJ, Prassad SC, et al. Cerebral radionecrosis: Incidence and risk in relation to dose , time , fractionation and volume. Int J Radiat Oncol Phys. 1981; 7 :243.
9. Sheline GE, Wara WW, Smith V. Therapeutic irradiation and train injury. Int J Radiat Oncol Bio Phys. 1980;6:1215.
10. Hall EJ . The biological basis of endocrinetherapy : The henschke memorial secture 1984. Endocurie Hypertherm Oncol. 1985; 1:141.
11. 吴在德, 郑树, 吴承远, 等. 高等教育教材. 外科学. 第5版. 人民卫生出版社. 2000; 306.
12. Stenwart DJ . A critique of the role of the blood - brain barrier Ⅰ the chemotherapy of human brain tumors. J Neurooncol 1994; 20:121.
13. HALL ej. radiobiology for the radiologist Philadelphia. JB Lippincott. 1994; 20(12):621-632.
14. 田增民. 现代立体定向神经外科学. 中国科技出版社. 1997; 135-136.
15. 蒋宁一. 肿瘤核医学. 人民卫生出版社. 2002;250.
16. Press OW. Physics for practitioners: the use of radiolabeled monoclonal antibodies inB-cell non-Hodgkin’s lymphoma. Semin Hematol. 2003; 7(4suppl7):2-8.
17. Rennen HJ, Makarewicz J, Oyen WJ, et al. The effect of molecular weight on nonspecific accumulation of (99m)Tc-labeled proteins in inflammatory foci. Nucl Med Biol. 2001; 28(4):401-408.
18. Goldenberg DM. Targeted therapy of cancer weith radiolabeled antibodies. J Nucl . 2002; 43(5):693-713.
19. 王骊丽, 韩 骅, 等. 人-鼠嵌合抗体表达载体的构建和抗人HER2 抗体的表达. 细胞与分子免疫学杂志(Chin J Cell Mol Immunol) . 2004; 20(3):136-137.
20. Wilder RB, DeNardo GL, DeNardo SJ, Radioimmunotherapy: recent results and future directions [J ] . J Clin Oncol . 1996; 14 ( 4) : 1383-1400.
21. Han SH, Zonenberg BA, de Klerk JMH. 186Re-etidronate in breast cancer patients with metastatic bone pain[J ] . J Nucl Med . 1999; 40(4) :639-642.
22. Quirijnen JM, Han SH, Zonnenberg BA,et al. Efficacy of Rhenium-186- etidronate in prostate cancer patients with metastatic bone pain[J ] . J Nucl Med. 1996; 37 (9) :1511-1515.
23. Epenetos AA, Hird VV, Lambert H, et al. Long term survival of patients with advanced ovarian cancer treated with intraperitoneal radioimmunotherapy[J ] . Int J Gynecl Cancer. 2000; 10 ( Suppl) : 44-46.
24. Reardon DA, Akabani G, Coleman RE, et al. Phase Ⅱ trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas [J]. J Clin Oncol. 2002; 20(5): 1389-1397.
25. Goetz C, Riva P, Poepperl G, et al. Locoregional radioimmunotherapy in selected patients with malignant glioma: experiences,side effects and survival times [J]. J Neurooncol. 2003; 62(3): 321-328.
26. Zalutsky MR. Current status of therapy of solid tumors: brain tumor therapy [J]. J Nucl . 2005; 46(Suppl 1): 151-156.