131I—MIBG与化疗联合治疗神经母细胞瘤的研究现状

神经母细胞瘤是一种侵犯儿童、恶性程度高、对射线敏感的肿瘤，近年来主要用131I-间碘苄胍(131I—MIBG)与化疗进行联合治疗，获得了良好的效果。主要综述131I—MIBG与化疗、免疫治疗等联合治疗神经母细胞瘤的几个不同方法和路径，并讨论了联合治疗的机制。     

131I-MIBG治疗神经母细胞瘤的机制、原理和现状

对于神经母细胞瘤复发或顽症而其它治疗手段又无效的患者,131I-MIBG(131I-间碘苄胍)曾作为一种缓解性治疗手段。因其治疗效果颇佳,就产生了将它与其它治疗手段联用,或作为首期治疗(UP-fronttreatment)的想法。目前的研究结果表明,131I-MIBG的辐射效应与化疗的协同作用将会成为最佳的临床治疗手段,可避免采用那些更具毒性和侵袭性的治疗方法。     

DDP联合CTX节律化疗治疗晚期神经母细胞瘤疗效观察

目的探讨DDP、CTX小剂量持续化疗在儿童神经母细胞瘤治疗中的应用价值。方法将25例患儿随机分为A、B两组;A组给予常规治疗方案（CTX700mg/m2,d3和DDP80mg/m2分4天使用,3周为一个疗程）,B组给予节律化疗方案（CTX90mg/m2和DDP10mg/m2）。观察两组病例治疗的有效率及手术切除率。结果 A组13例,化疗总疗程71例次,有效率10/13（76.9%）;B组12例,化疗总疗程数90例次,有效率11/12（91.7%）。两组患儿化疗后手术切除率分别为61.5%、75.0%,两组比较差异无统计学意义（P〉0.05）;不良反应发生率分别为42.3%、3.3%,两组比较差异有统计学意义（P〈0.05）。结论两种化疗方案在本次实验中治疗的有效率无明显差异,节律化疗方案能明显减少化疗的不良反应。     

^131I—MIBG治疗神经母细胞瘤的机制,原理和现状

对于神经母细胞瘤复发或顽症而其它治疗手段又无效的患者,＾１３１Ｉ－ＭＩＧＢ（＾１３１Ｉ－间碘胍）一种缓解性治疗手段。因其治疗效果颇佳,就产生了将它与其它治疗手段联用,或作为首期治疗的想法。目前的研究结果表明、＾１３１Ｉ－ＭＩＢＧ的辐射效应与化疗的协同作用将会成为最佳的监护可避免采用那些更具毒性和侵袭性的治疗方法。     

放射性碘化MIBG在肾上腺素能肿瘤定位诊断和治疗中的应用

阐述了放射性碘化ＭＩＢＧ用于肾上腺素能肿瘤诊断和治疗的生理学机制，详细介绍了放射性碘化ＭＩＢＧ显像的适应症、方法、正常和异常图像特点和诊断效能；并对肾上腺素能肿瘤＾１３１Ｉ－ＭＩＢＧ治疗的适应症、方法、疗效和毒副反应作了介绍。     

1 31 I-MIBG 肾上腺髓质显像定量分析的临床应用

建立肾上腺髓质显像的定量诊断指标。方法本文对２５例对照者,１９例嗜铬细胞瘤患者及９例肾上腺髓质增生患者的肾上腺髓质及髓外嗜铬细胞瘤组织摄取＾１３１Ｉ－ＭＩＢＧ（间碘苄胍）进行了定量分析,以建立定量诊断指标。按常规方法方法于注射显像剂后２４ｈ、４８ｈ、７２ｈ分别行前位及后位全身显像。采用ＲＯＩ技术分别计算出肾上腺（包括髓外嗜铬细胞瘤组织）与心肌,肝脏,脾脏,肺和本底的比值。结果除肾上腺／脾比值外,上     

131I-MIBG治疗58例恶性嗜铬细胞瘤的临床疗效与副反应

目的 探讨用＾１３１Ｉ间－碘苄胍（ＭＩＢＧ）治疗５８例恶性嗜铬细胞瘤软组织转移灶的临床价值。方法 第一疗程每月静脉滴注＾１３１Ｉ－ＭＩＢＧ２５９０～３７００ＭＢｑ，共６个月，此后每隔２～３个月继续治疗１－３次，用ＭＩＲＤ法测试肿瘤吸收剂量，结果 （１）５８例患者按肿瘤大小分成３组，第１组肿瘤体积〈８ｃｍ＾３（１１例）第２组８－２０ｃｍ＾３（２１例）第３组〉２０ｃｍ＾３（２６例）第１组１１例肿瘤平均     

^131I—抗神经母细胞瘤单抗放射免疫治疗的实验研究

将纯种ＢＡＬＢ／Ｃ裸鼠１１２只随机分为１６组，接种神经母细胞瘤（ＮＢ）。给予不同剂量＾１３１Ｉ标记抗ＮＢ特异单抗３Ｆ８行放射免疫治疗。同时进行肿瘤体积测量、放射免疫显像、＾１３１Ｉ－３Ｆ８生物学分布以及肿瘤对＾１８ＦＤＧ的摄取率测定，以此作为指标观察疗效。结果显示：治疗后，＾１３１Ｉ－３Ｆ８在肿瘤组织内特异浓聚；肿瘤体积缩小，缩小的速率与治疗剂量成正相关；肿瘤对＾１３ＦＤＧ的摄取短期内有一过性增高     

MIBG及其衍生物的研究进展

MIBG(间碘苄胍)是神经递质去甲肾上腺素的功能性类似物,其转运、潴留与释放机制均与去甲肾上腺素相似。放射性核素标记的MIBG及其衍生物既可用于嗜铬细胞瘤、神经母细胞瘤等神经嵴起源肿瘤的诊断与治疗,也可用于心肌交感神经显像,评估心肌交感神经元的完整性与功能。     

美国药典论坛收载的碘[^131I／^123I]苄胍注射液

介绍了美国药典论坛收载的碘「＾１３１Ｉ／＾１２３Ｉ」苄注射液标准。     

Hepatic absorbed radiation dosimetry during I-131 Metaiodobenzylguanadine (MIBG) therapy for refractory neuroblastoma

Purpose  To compare the prediction of therapeutic hepatic radiation-absorbed dose rates from tracer imaging plus a linearity assumption to estimation based on intra-therapy imaging in ¹³¹I metaiodobenzylguanidine (MIBG) therapy of refractory neuroblastoma. Materials and methods  Conjugate-view images of the liver were obtained before therapy for seven patients at seven times after a tracer infusion of ¹³¹I MIBG and at three times after the therapy infusion. Measured liver activities were converted to dose-rate estimates. Three statistical models of the rates assuming double exponential dependences on time were examined. One of the three models allowed for a multiplicative correction to the therapeutic late-phase dose-rate amplitude. Results from that model: (1) the tracer prediction of the late-phase absorbed-dose-rate amplitude was a factor of 1.75 times the intra-therapy-estimated value, and (2) the difference between tracer prediction of the radiation-absorbed dose and intra-therapy estimation of it was statistically significant, and (3) the liver radiation-absorbed dose did not reach 30 Gy. Conclusions  A statistical modeling analysis finds that the radiation-absorbed dose after therapy appears to be lower than that which is predicted from the linear scaling with administered activity of the tracer radiation-absorbed dose. Hepatocyte toxicity is the most likely reason but it is not high enough to produce clinically observable results.     

Local delivery of <Superscript>131</Superscript>I-MIBG to treat peritoneal neuroblastoma

Internal radiotherapy involving systemic administration of iodine-131 metaiodobenzylguanidine (¹³¹I-MIBG) in neural crest tumours such as neuroblastoma has shown considerable success. Although peritoneal seeding of neuroblastoma occurs less often than metastases to organs such as the liver, no effective treatments exist in this clinical setting. Previous reports have demonstrated the effectiveness of peritoneal application of chemotherapeutic drugs or radiolabelled monoclonal antibodies in several kinds of carcinomas. Local delivery of ¹³¹I-MIBG should produce more favourable dosimetry in comparison with its systemic administration in the treatment of peritoneal neuroblastoma. In the current investigation, a peritoneal model of neuroblastoma was established in Balb/c nu/nu mice by i.p. injection of SK-N-SH neuroblastoma cells. Two weeks after cell inoculation, comparative biodistribution studies were performed following i.v. or i.p. administration of ¹³¹I-MIBG. Mice were treated with 55.5 MBq of ¹³¹I-MIBG administered either i.v. or i.p. at 2 weeks. Intraperitoneal injection of ¹³¹I-MIBG produced significantly higher tumour accumulation than did i.v. injection (P<0.01). Therapeutic ratios of i.p. injection were 4- to 14-fold higher than those of i.v. injection. Radiotherapy with i.v. administered ¹³¹I-MIBG failed to improve the survival of mice; mean survival of untreated mice and mice treated with i.v. administration of ¹³¹I-MIBG was 59.3±3.9 days and 60.6±2.8 days, respectively. On the other hand, radiotherapy delivered via i.p. administration of ¹³¹I-MIBG prolonged survival of mice to 94.7±17.5 days (P<0.02 vs untreated controls and mice treated with i.v. ¹³¹I-MIBG therapy). Radiation doses absorbed by tumours at 55.5 MBq of ¹³¹I-MIBG were estimated to be 4,140 cGy with i.p. injection and 450 cGy with i.v. injection. These results indicate the benefits of locoregional delivery of ¹³¹I-MIBG in the treatment of peritoneal neuroblastoma.     

Uptake of 131I-MIBG by medullary carcinoma of thyroid in familial cases

Medullary carcinoma of the thyroid (MCT) and pheochromocytoma are APUD tumors. MIBG (Meta Iodo Benzyl Guanidine) uptake by pheochromocytomas is now well known but very few cases of MIBG uptake in sporadic MCT have been described. We report here the two first cases of inherited MCT with MIBG uptake.     

Detection of metastatic medullary thyroid cancer with 131I-MIBG scans in Sipple's syndrome

While ¹³¹I-meta-iodobenzyl guanidine (¹³¹I-MIBG) scanning has made possible the scintigraphic visualization of pheochromocytoma and neuroblastoma, an accumulation of this agent has recently been reported in medullary thyroid cancer. We present the case of a patient with Sipple's syndrome (multiple endocrine neoplasia type IIa), in whom we were able to identify distant metastases and local invasion of medullary thyroid cancer as well as primary thyroid tumour and right adrenal pheochromocytoma, using ¹³¹I-MIBG scans. This case highlights the usefulness of ¹³¹I-MIBG in the detection of metastatic medullary thyroid cancer and suggests that this agent may also be of therapeutic use in the treatment of tumours.     

Dosimetry of iodine 131 metaiodobenzylguanidine for treatment of resistant neuroblastoma: results of a UK study

In 1987, the United Kingdom Children's Cancer Study Group (UKCCSG) set up a multi-centre study to investigate the toxicity of iodine 131 metaiodobenzyl-guanidine (mIBG) in the treatment of resistant neuroblastoma. Since December 1987, 25 children suffering from neuroblastoma have been treated with¹³¹I-mIBG at six UK centres. All centres followed standardised physics and clinical protocols to provide consistent toxicity and dosimetry data. These protocols describe the methods employed for both the tracer study using¹³¹I-mIBG and the subsequent therapy. Whole-body dosimetry calculations were performed on data from the tracer study. The activity administered for therapy was the amount predicted to deliver a predefined whole-body dose. Estimates of doses delivered to various organs during treatment are given in Table 1.On behalf of the mIBG Targetting Group of the United Kingdom Children's Cancer Study Group (UKCCSG), University of Leicester, Leicester, UK:Members of the mIBG Targetting Group: Christie Hospital, Manchester- P. Nuttall, S. Owens (Physics), H.R. Gattamaneni (Radiotherapy); Cookridge Hospital, Leeds - M. Sheppard, S. Packar (Physics), S. Cartright, R. Taylor (Radiotherapy); Newcastle General Hospital - A. Simpson, P. Bartholomew (Physics), H. Lucraft (Radiotherapy); Medical School, University of Newcastle upon Tyne - A. Pearson (Paediatric Oncology); Royal Hospital for Sick Children, Edinburgh - T. Eden (Paediatric Oncology); Royal Manchester Childrens' Hospital - P. Morris-Jones (Paediatric Oncology); Royal Marsden Hospital, Sutton - R. Ott, M. Rosenbloom (Physics), S. Meller, R. Corbett, R. Pinkerton (Paediatric Oncology); Royal South Hants Hospital, Southampton - V. Hall (Radiotherapy); Royal Victoria Infirmary, Newcastle upon Tyne - A. Craft (Paediatrics); Southampton General Hospital - G. Blake, M. Tristam (Physics), J. Kohler (Paediatric Oncology), V. Lewington (Nuclear Medicine); St Bartholomews Hospital, London - K. Britton, L. Hawkins (Nuclear Medicine), J. Kingston, J. Moyes (Paediatric Oncology), J. Malpas (Oncology), N. Plowman (Radiotherapy); Western General Hospital, Edinburgh - J. Hannan (Physics), M. Merrick (Nuclear Medicine), A. Rodger (Radiotherapy); Western Infirmary, Glasgow - T. Hilditch (Physics), A. Barrett (Radiotherapy), T. Wheldon, J. O'Donoghue (Radiobiology); Amersham International, Bucks-R. Bayly; UKCCSG Offices, Leicester-J. Barnes.     

Modification by nifedipine of 131I-meta-iodobenzylguanidine kinetics in malignant phaeochromocytoma

Following a case report that oral nifedipine can suppress the secretion of noradrenaline by phaeochromocytoma, we examined the effect of nifedipine on the tumour kinetics of tracer ¹³¹I-meta-iodobenzylguanidine (¹³¹I-mIBG) in five patients referred for mIBG radionuclide therapy for disseminated malignant phaeochromocytoma. In one subject a striking modification of mIBG kinetics was found that resulted in a doubling of the absorbed dose to tumour while the patient was taking nifedipine. At the same time, urinary excretion of noradrenaline was suppressed by a factor of three. The effect of nifedipine in this patient was confirmed when tracer studies were repeated nine months later. The changes in tumour kinetics were shown to be due to prolonged retention of mIBG rather than increased tumour blood flow or alteration of the curve of mIBG plasma concentration as a function of time.     

Radiation exposure in nurses during care of 131I-MIBG therapy for pediatric patients with high-risk neuroblastoma

Annals of Nuclear Medicine - 131I-meta-iodo-benzyl-guanidine (131I-MIBG) therapy has been used in children with high-risk neuroblastoma, who, in Japan, are cared for by trained nurses. To determine...     

Toxicity of upfront 131I-metaiodobenzylguanidine (131I-MIBG) therapy in newly diagnosed neuroblastoma patients: a retrospective analysis

Purpose

In the treatment of patients with high-risk neuroblastoma, different doses of ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) are administered at different time points during treatment. Toxicity, mainly haematological (thrombocytopenia), from ¹³¹I-MIBG therapy is known to occur in extensively chemotherapy pretreated neuroblastoma patients. Up to now, acute toxicity from ¹³¹I-MIBG as initial treatment has never been studied in a large cohort. The aim of this retrospective study was to document acute toxicity related to upfront ¹³¹I-MIBG.

Methods

All neuroblastoma patients (stages 1–4 and 4S) treated upfront with ¹³¹I-MIBG at the Emma Children’s Hospital, Academic Medical Centre (1992 – 2008) were included in this retrospective analysis. The acute toxicity (during therapy) and short-term toxicity (1st month following therapy) of the first two ¹³¹I-MIBG therapies were studied.

Results

Of 66 patients (34 boys, 32 girls; median age 2.2 years, range 0.1 – 9.4 years), 49 had stage 4 disease, 5 stage 4S, 6 stage 3, 1 stage 2 and 5 stage 1. The median first dose was 441 MBq/kg (range 157 – 804 MBq/kg). The median second dose was 328 MBq/kg (range 113 – 727 MBq/kg). The most frequently observed symptoms were nausea and vomiting (21 %, maximum grade II). The main toxicity was grade IV haematological, occurring only in stage 4 patients, after the first and second ¹³¹I-MIBG therapies: anaemia (5 % and 4 %, respectively), leucocytopenia (3 % and 4 %) and thrombocytopenia (2 % and 4 %). No stem cell rescue was needed.

Conclusion

The main acute toxicity observed was haematological followed by nausea and vomiting. One patient developed posterior reversible encephalopathy syndrome during ¹³¹I-MIBG therapy, possibly related to ¹³¹I-MIBG. We consider ¹³¹I-MIBG therapy to be a safe treatment modality.