Assessing the outcomes of everolimus on renal angiomyolipoma associated with tuberous sclerosis complex in China: a two years trial.
Assessing the outcomes of everolimus on renal angiomyolipoma associated with tuberous sclerosis complex in China: a two years trial.
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评估依维莫司治疗中国结节性硬化症相关肾血管平滑肌脂肪瘤的疗效：一项为期两年的试验
DOI：
10.1186/s13023-018-0781-y
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发表时间：
2018-03-27
影响因子：
3.7
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Cai Y;Guo H;Wang W;Li H;Sun H;Shi B;Zhang Y
背景结节性硬化症(TSC)是一种罕见的常染色体显性遗传病，以多种良性肿瘤的发展为特征。肾血管平滑肌脂肪瘤(RAML)发生在高达80%的TSC患者中，是成人TSC相关死亡的主要原因。本研究的目的是评价依维莫司治疗中国人TSC-RAML(TSC-RAML)的疗效和安全性。方法在这项为期两年的非随机开放试验中，18例TSC-RAML患者的最大直径至少有一个3 cm或更大，以评价中国患者使用伊维莫司治疗的疗效和安全性。伊维洛莫斯只在前12个月服用。主要终点是在没有新的RAML≥1 cm和没有 ≥ 2级的RAML相关出血的情况下，RAML体积相对于基线减少50%或更多。次要终点包括：安全性、肺功能和皮损反应率。所有患者均行RAML系列计算机体层摄影、脑部病变磁共振成像及肺功能检查。不良事件使用CTCAE V4.0进行调查。所有分析均采用显著性水平0.0 5，并在SPSS19.0软件中生成。结果≥在靶区体积总和中较基线减少50%的患者比例从3个月的5 2.94%增加到6个月和12个月的58.82%和66.67%。在依维莫司治疗期间，淋巴管肌瘤病患者的第一秒用力呼气量(FEV_1)较治疗前增加了276 ± 78 (P<； 0.001)，用力肺活量(FVC)增加了433 ± 170(P<； 0.001)，残气量减少了408 ± 243(P= 0.009)。血管肌脂肪瘤体积和肺功能接近，但没有完全恢复到基线值。治疗12个月后皮损有效率为37.5%，停药12个月后皮损有效率降至21.4%。最常见的不良反应是口腔粘膜炎、月经不调、腹痛、高甘油三酯血症和头痛。最常见的3级不良事件是月经不调和口腔粘膜炎。此外，1例患者在接受依维莫司治疗期间死于Raml自发性出血，尽管在治疗3个月时Raml体积减少了60.68%。另1例死于上皮样Raml进展，并伴有腹膜后多发淋巴结转移，术后1个月死于严重感染。结论血管肌肉脂肪瘤在依维莫司治疗过程中有所消退，但停药后体积有增大趋势。依维莫司耐受性良好，在中国TSC-RAML患者中显示出良好的活性，但我们应警惕早期危及生命的大RAML出血和上皮样RAML的淋巴转移。试验登记：ChiCTR-OPC-14005488。2014年11月17日注册。
BackgroundTuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder characterized by the development of numerous benign tumors. Renal angiomyolipoma (RAML) occur in up to 80% of TSC patients, which is a leading cause of TSC-related death in adult patients. The aim of the study was to evaluate the efficacy and safety profiles of everolimus in Chinese patients of TSC associated with RAML(TSC-RAML).MethodsIn this 2-years, nonrandomized, open-label trial, 18 patients of TSC-RAML, with at least one RAML 3 cm or larger in its longest diameter, were enrolled to assess the efficacy and safety of everolimus therapy in Chinese patients. Everolimus was administered for the first 12 months only. The primary endpoint was a reduction of 50% or more relative in RAML volume to the baseline in the absence of new RAML ≥1 cm and no RAML-related bleeding of grade ≥ 2. The secondary endpoints included: safety, lung function and skin lesions response rate. Serial computed tomography of RAML, magnetic resonance imaging of brain lesions and pulmonary-function tests were performed. Adverse events were investigated using CTCAE v4.0. All analyses used a significance level of 0.05 and were generated in SPSS19.0 software.ResultsThe proportion of patients who achieved ≥50% reduction from baseline in the sum of volumes of target lesions increased from 52.94% at 3 months, to 58.82% and 66.67% at months 6 and 12, respectively. During the period of everolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 s (FEV1) increased by 276 ± 78 ml (P< 0.001), the forced vital capacity (FVC) increased by 433 ± 170 ml (P< 0.001), and the residual volume decreased by 408 ± 243 ml (P= 0.009), as compared with baseline values. The angiomyolipoma volume and the lung function approached, but did not completely return to, the baseline values. The skin lesions response rate was 37.5% after 12 months of therapy falling to 21.4% at 12 months after stopping everolimus. The most common adverse events were mucositis oral, irregular menstruation, abdominal pain, hypertriglyceridemia and headache. The most common grade 3 adverse events were irregular menstruation and mucositis oral. In addition, one patient died from RAML spontaneous haemorrhage during treatment with everolimus, even with reduction in RAML volume of 60.68% at 3 months. A second death was due to epithelioid RAML progression, with metastasis to multiple retroperitoneal lymph node, who died from severe infection one month after surgery.ConclusionsAngiomyolipomas regressed somewhat during everolimus therapy but tended to increase in volume after the therapy was stopped. Everolimus was well tolerated and showed promising activity in Chinese patients with TSC-RAML, however, we should alert the life-threatening hemorrhage of large RAML in the early period and the lymph node metastasis of epithelioid RAML.Trial registrationChiCTR-OPC-14005488 . Registered November 17, 2014.
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结节性硬化症复杂诊断标准更新：2012年iinternation Tuberous硬化症复杂共识会议的建议。
影响因子：
3.8
作者：
Northrup H;Krueger DA;International Tuberous Sclerosis Complex Consensus Group
通讯作者：
International Tuberous Sclerosis Complex Consensus Group
影响因子：
168.9
作者：
Bissler, John J.;Kingswood, J. Christopher;Budde, Klemens
通讯作者：
Budde, Klemens
影响因子：
6.1
作者：
Kingswood, J. Chris;Jozwiak, Sergiusz;Franz, David N.
通讯作者：
Franz, David N.
影响因子：
3.7
作者：
Bissler JJ;Kingswood JC;Radzikowska E;Zonnenberg BA;Belousova E;Frost MD;Sauter M;Brakemeier S;de Vries PJ;Berkowitz N;Voi M;Peyrard S;Budde K
通讯作者：
Budde K
DOI：
10.1016/s0190-9622(03)01475-0
发表时间：
2003-11-01
影响因子：
13.8
作者：
Heald, P;Mehlmauer, M;Reich, SD
通讯作者：
Reich, SD