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Clinical Efficacy, Safety and Pharmacokinetics of Tracing Injection of Mitoxantrone Hydrochloride for Tracing Sentinel Lymph Nodes in Thyroid Carcinoma: A Phase Ⅰ Clinical Trial
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摘要:
目的 探究示踪用盐酸米托蒽醌注射液在甲状腺癌根治术中对淋巴结染色、示踪的效果及其安全性和耐受性。 方法 本研究釆用单中心、开放、空白对照试验设计，按剂量递增原则，逐剂量组进行人体耐受性试验和药代动力学试验。前瞻性纳入2016年12月至2017年3月北京协和医院拟行甲状腺癌根治术的患者为受试者，并分为空白对照组和试验组。空白对照组进行常规手术，不注射示踪剂；试验组暴露术野后拟分别在甲状腺腺体注射0.2 mL、0.4 mL、0.6 mL、0.8 mL、1.2 mL示踪用盐酸米托蒽醌注射液，由低至高依次进行5个剂量组的爬坡试验。主要疗效指标为淋巴结示踪率和淋巴结染色率，次要疗效指标为淋巴结染色程度评分和示踪持续成功率。记录给药后受试者体征变化，进行安全性评定。给药前及给药后10 min、20 min、30 min、60 min、90 min、120 min，分别采集受试者静脉血计算药代动力学参数。 结果 共纳入27例受试者，其中空白对照组3例；试验组0.2 mL、0.4 mL、0.6 mL、0.8 mL、1.2 mL 5个剂量组分别为3例、3例、6例、6例、6例。当试验进行至第3个剂量组(0.6 mL)时，受试者注射部位对药物注射剂量承载已达饱和，终止试验，故实际共15例受试者完成试验。空白对照组均未出现淋巴结染色。试验组中，12例受试者中央区淋巴结全部染色，部分侧颈部淋巴结也出现染色，甲状旁腺不被染色、呈负显影。0.2 mL、0.4 mL、0.6 mL剂量组给药前后淋巴结染色程度评分存在显著性差异(P < 0.05)，平均淋巴结染色率分别为90.47%、91.67%、91.36%，平均淋巴结示踪率分别为79.17%、100%、98.67%。试验组淋巴结清扫持续时间为5~20 min，均未出现染色的淋巴结褪色，示踪持续成功率为100%。安全性评价中，空白对照组和试验组均未发生严重不良事件，且不良事件发生原因与该示踪剂肯定无关。药代动力学试验显示，该示踪经剂经腺体注射给药后快速被吸收，注射后10 min血液浓度达峰值(最高血药浓度为13.1 μg/L)，并迅速被消除。 结论 甲状腺癌根治术中使用0.2~0.6 mL示踪用盐酸米托蒽醌注射液，可起到较好的淋巴结示踪作用，且安全性高、耐受性好。 -
关键词:
- 示踪用盐酸米托蒽醌注射液 /
- 甲状腺癌 /
- 淋巴结
Abstract:Objective To investigate the staining and tracing effect of mitoxantrone hydrochloride injection for tracing lymph nodes in radical thyroidectomy, and its safety and tolerability. Methods In this study, a single-centered, open-labeled, blank control trial was designed. According to the principle of dose escalation, the human tolerance test and kinetic test were performed in dose groups one by one. Patients scheduled for radical thyroidectomy in Peking Union Medical College Hospital from December 2016 to March 2017 were prospectively enrolled as subjects. The subjects were divided into the blank control group and the test groups. The blank control group routinely underwent surgery without tracer injection; the test groups were injected with 0.2 mL, 0.4 mL, 0.6 mL, 0.8 mL, or 1.2 mL of mitoxantrone hydrochloride for tracing in the thyroid gland after exposing the surgical field, and an escalation test was performed in the five dose groups from low to high. The primary efficacy measures were lymph node tracing rate and lymph node staining rate; the secondary efficacy measures were staining-degree scores of lymph nodes and the success rate of tracing persistence. Changes in signs of subjects were recorded for safety assessment. Venous blood was collected from the subjects before administration and at 10 min, 20 min, 30 min, 60 min, 90 min and 120 min after administration to calculate the kinetic parameters. Results A total of 27 subjects were included, including 3 subjects in the blank control group, and 3, 3, 6, 6 and 6 subjects in the 0.2 mL, 0.4 mL, 0.6 mL, 0.8 mL and 1.2 mL dose group, respectively. When the test proceeded to the third dose group (0.6 mL), the injection site of the subjects was saturated with the injection dose, and the test was terminated. Therefore, a total of 15 subjects completed the test. No lymph node was stained in blank control group.The lymph nodes of 12 subjects showed blue staining, and the parathyroid glands were not stained and negatively visualized. There was significant difference in the staining-degree scores of lymph nodes before and after administration in the 0.2 mL, 0.4 mL and 0.6 mL dose groups (P < 0.05). The average staining rates of lymph nodes were 90.47%, 91.67% and 91.36%, respectively. And the average tracing rates of lymph nodes were 79.17%, 100% and 98.67%, respectively. In the test groups, the duration of lymph node dissection was 5-20 min; no stained lymph nodes faded, and the success rate of tracing was 100%. In the safety evaluation, no serious adverse events occurred in the blank control group and test groups, and the cause of adverse events was certainly not related to this tracer. Kinetic tests showed that the tracer was rapidly absorbed after glandular injection; the blood concentration peaked at 10 min after injection (the maximum plasma concentration was 13.1 μg/L) and it was rapidly eliminated. Conclusions The use of 0.2-0.6 mL mitoxantrone hydrochloride injection in radical thyroidectomy can play a better role in tracing lymph nodes, with high safety and good tolerance. 作者贡献：陈革、陈少博、刘玮楠、张圣洁、孙健负责撰写临床试验方案、受试者管理、给药、临床监护、采集生物样本、撰写总结报告等；陈少博负责撰写、修订论文；陈革负责研究设计；杨瑞负责药代动力学试验检测；王淑君负责示踪用盐酸米托蒽醌注射液药学研究。利益冲突：无 -
图 1 示踪用盐酸米托蒽醌注射液辅助甲状腺切除手术示意图
A. 甲状腺切除后进行中央区淋巴结清扫时(e为颈总动脉，f为气管)，可清楚区分未染色的甲状旁腺(a、b)以及染色的淋巴结(c、d)；B.术中可清晰区分未染色的甲状旁腺(a)及染色的甲状腺(b)
表 1 不同剂量试验组淋巴结染色程度评分#
试验剂量(mL) 受试者编号 染色为0分的淋巴结数(n) 染色为0.5分的淋巴结数(n) 染色为1分的淋巴结数(n) 平均评分 P值 0.2 a 0 3 4 0.786 0.000 b 0 0 3 1.000 - c 2 4 5 0.636 0.000 0.4 d 2 4 6 0.667 0.000 e 0 5 8 0.808 0.000 f 1 3 7 0.773 0.000 0.6 g 1 2 6 0.778 0.000 h 3 7 12 0.705 0.000 i 0 5 6 0.772 0.000 j 1 5 3 0.611 0.001 k 1 4 17 0.864 0.000 l 1 5 2 0.813 0.002 #给药后淋巴结染色程度评分于术后病理科进行；-: 所有淋巴结皆完全染色，无法计算P值 
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表 2 不同剂量试验组不同直径淋巴结染色率(%)
试验剂量(mL) 受试者编号 淋巴结直径(mm) P值 ≤2 > 2~5 > 5~10 > 10 0.2 a 100 100 - 100 b - 100 - - c - 80.0 100 - 平均淋巴结染色率 100 88.9 100 100 0.587 0.4 d 87.5 66.7 - 100 e - 100 100 100 f 100 88.9 - - 平均淋巴结染色率 90.0 90.9 100 100 0.707 0.6 g - 88.3 100 - h 0 85.7 100 - i - 100 100 - j - 88.9 - - k - 93.8 100 - l 87.5 - - - 平均淋巴结染色率 77.8 90.6 100 - 0.358 -: 未发现该直径的淋巴结
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