Local and Systemic Toxicity of Intravitreal Melphalan for Vitreous Seeding in Retinoblastoma A Preclinical and Clinical Study
Local and Systemic Toxicity of Intravitreal Melphalan for Vitreous Seeding in Retinoblastoma A Preclinical and Clinical Study
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DOI：
10.1016/j.ophtha.2014.03.028
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发表时间：
2014-09-01
期刊：
影响因子：
13.7
通讯作者：
Abramson, David H.
中科院分区：
文献类型：
--
作者：
Francis, Jasmine H.;Schaiquevich, Paula;Abramson, David H.
目的：玻璃体内注射美法仑正在成为视网膜母细胞瘤中难治性玻璃体种子的有效治疗方法，但对其毒性的了解有限。本研究评估视网膜和全身毒性的玻璃体内美法仑视网膜母细胞瘤患者，临床前验证在兔model.Design：临床和临床前，前瞻性，cohort study.Participants：在临床研究中，16例患者的眼睛接受107玻璃体内注射30微克美法仑给予每周，中位数为6.5倍（范围，5-8）。在动物研究中，12新西兰/荷兰带色素兔给予3个每周注射15微克的玻璃体内美法仑或vehicle.Methods：视网膜电图（ERG）反应记录在人类和兔子。对于临床研究，在基线、每次注射前即刻和每次随访访视时记录ERG反应;这些研究中有82项被视为可评价。中位随访时间为5.2个月（范围，1-11）。在46例患者访视时，在注射当天获得全血细胞计数（CBC）。在动物研究中，沿着荧光素血管造影、CBC和美法仑血浆浓度获得ERG反应。人道杀害后，眼睛的组织病理学进行了evaluated.Main结果措施：对于临床研究，我们测量峰峰值ERG振幅在30 Hz的明视闪烁刺激与玻璃体内美法仑之前和之后的ERG研究之间的比较。对于动物研究，我们收集ERG参数之前和之后的玻璃体内美法仑注射与组织病理学findings.Results：通过线性回归分析，在视网膜母细胞瘤患者每周玻璃体内注射的过程中，对于每一个额外的注射，ERG振幅下降约5.8 μ V。ERG保持稳定，一旦治疗过程完成。在视网膜母细胞瘤患者中，没有3级或4级血液学事件。第二次注射后一周，与溶剂组相比，美法仑组的a波和b波振幅显著下降（P
Purpose: Intravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model.Design: Clinical and preclinical, prospective, cohort study.Participants: In the clinical study, 16 patient eyes received 107 intravitreal injections of 30 mu g melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 mu g of intravitreal melphalan or vehicle to the right eye.Methods: Electroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated.Main Outcome Measures: For the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings.Results: By linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 mu V. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P