Pilot study for the treatment of cutaneous neurofibromas in neurofibromatosis type 1 patients using topical sirolimus gel
Pilot study for the treatment of cutaneous neurofibromas in neurofibromatosis type 1 patients using topical sirolimus gel
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使用外用西罗莫司凝胶治疗 1 型神经纤维瘤病患者皮肤神经纤维瘤的初步研究
DOI：
10.1016/j.jaad.2022.08.066
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发表时间：
2023
影响因子：
13.8
通讯作者：
Katayama Ichiro
中科院分区：
文献类型：
--
作者：
Wataya-Kaneda Mari;Watanabe Yoshiyuki;Nakamura Ayumi;Yamamoto Kouji;Okada Kiyoshi;Maeda Shinichiro;Nimura Keisuke;Saga Kotaro;Katayama Ichiro
1型神经纤维瘤病（NF 1）是一种涉及丛状（pNFs）和皮肤58神经纤维瘤（cNFs）的遗传性疾病，其中MAPK（丝裂原活化蛋白59激酶）和mTORC 1（雷帕霉素的机械靶点）的组成性激活促进肿瘤发生。1与60 pNFs 2的情况不同，尚未对损害生活质量的cNFs进行临床试验。mTORC 1除了参与细胞增殖外，还参与肿瘤微血管形成。因此，mT 0 RC 162抑制剂对NF 1肿瘤似乎极其有效，其中微环境对于肿瘤发生是必不可少的。3 cNF严格定位于真皮。为了确定西罗莫司凝胶的疗效和安全性，于2016年3月16日至2017年1月11日进行了一项64例随机、双盲、安慰剂对照的初步研究。该试验检查了0.2%和0.4%西罗莫司凝胶，其通过局部应用将高浓度的西罗莫司递送至真皮4。67名参与者通过补充方法中描述的68个网络响应系统被随机分配到每个研究凝胶或安慰剂组。简而言之，将指定的研究性69制剂每天两次应用于患者的病变，持续24周。18例NF 1患者（9 70例男性，9例女性），年龄27-68岁。除一人外，所有参与者均完成了试验。71主要终点是24周时使用计算机断层扫描72（CT）和CT体积软件（Fuji Film）5测量的肿瘤体积缩小。主要次要终点是24周时使用直尺（长直径）× 74（短直径）计算的3个靶肿瘤的平均肿瘤尺寸缩小73。为了评价安全性，进行了实验室检查和血液西罗莫司测量75。每位参与者提供了书面知情同意书。该方案经大坂大学医院机构审查委员会批准，符合赫尔辛基宣言。78. CT结果表明，肿瘤体积缩小呈剂量依赖性。在0.4%西罗莫司组中肿瘤79体积减小（图1）。在0.2%西罗莫司和活性药物（西罗莫司组合并0.2%和0.4%）组中发现使用标尺测量的统计学显著肿瘤大小80减小（图2）。0.4%西罗莫司治疗前后靶82 cNF的代表性照片和CT图像显示肿瘤缩小（补充图1）。83.主要不良反应为瘙痒。未观察到显著不良事件。84例西罗莫司血药浓度最高值为0.73ng/mL，为一过性，较85例西罗莫司血药浓度低1/10 ~ 1/20
Neurofibromatosis type 1 (NF1) is a genetic disorder involving plexiform (pNFs) and cutaneous 58 neurofibromas (cNFs) in which the constitutive activation of MAPK (mitogen-activated protein 59 kinase) and mTORC1 (mechanistic target of rapamycin) promote tumorigenesis. 1 Unlike the case for 60 pNFs2, no clinical trials have been conducted on cNFs that impair quality of life. mTORC1 is 61 involved in the tumor microenvironmentin addition to cell proliferation. Therefore, mTORC1 62 inhibitors appear extremely effective against NF1 tumors, where the microenvironment is essential for 63 tumorigenesis. 3 cNFs strictly localize to the dermis. To determine sirolimus gel efficacy and safety, a 64 randomized, double-blind, placebo-controlled, pilot study was performed March 16, 2016–January 11, 65 2017. The trial examined 0.2% and 0.4% sirolimus gel, which delivered high concentrations of 66 sirolimus to the dermis via topical application4. 67 Participants were randomly assigned to each investigational gel or placebo group via a 68 web-response system as described in the supplemental methods. Briefly, the assigned investigational 69 formulation was applied to a patient’s lesions twice daily for 24 weeks. Eighteen patients with NF1 (9 70 men, 9 women) aged 27–68 years were enrolled. All participants, except one, completed the trial. The 71 primary endpoint was tumor volume reduction at 24 weeks measured using computed tomography 72 (CT) with Vincent-CT-volumetric software (Fuji Film) 5. The main secondary endpoint was the 73 average tumor size reduction of three target tumors calculated using a ruler (long-diameter)× 74 (short-diameter) at 24 weeks. To evaluate safety, laboratory tests and blood sirolimus measurements 75 were performed. Each participant provided written informed consent. The protocol was approved by 76 the Institutional Review Board of Osaka University Hospital and complied with the Declaration of 77 Helsinki. 78The CT results indicated that a dose-dependent tumor volume reduction occurred. Tumor 79 volume was reduced in the 0.4% sirolimus group (Figure 1). Statistically significant tumor size 80 reductions measured using a ruler were found in the 0.2% sirolimus and active drug (0.2% and 0.4% 81 sirolimus groups combined) groups (Figure 2). Representative photographs and CT images of a target 82 cNF before and after 0.4% sirolimus treatment revealed tumor shrinkage (Supplementary Figure 1). 83 The major adverse drug reaction was pruritus. No significant adverse events were observed. The 84 highest blood sirolimus concentration, 0.73 ng/mL, was transient and was 1/10–1/20 lower than that 85