Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial.
Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial.
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DOI：
10.1016/s2213-2600(13)70090-0
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发表时间：
2013-08
影响因子：
76.2
通讯作者：
McCormack, Francis X.
中科院分区：
文献类型：
--
作者：
Young, Lisa R.;Lee, Hye-Seung;Inoue, Yoshikazu;Moss, Joel;Singer, Lianne G.;Strange, Charlie;Nakata, Koh;Barker, Alan F.;Chapman, Jeffrey T.;Brantly, Mark L.;Stocks, James M.;Brown, Kevin K.;Lynch, Joseph P., III;Goldberg, Hilary J.;Downey, Gregory P.;Swigris, Jeffrey J.;Taveira-DaSilva, Angelo M.;Krischer, Jeffrey P.;Trapnell, Bruce C.;McCormack, Francis X.
VEGF-D是一种淋巴管生成生长因子，在肿瘤转移中起关键作用。大多数淋巴管平滑肌瘤病患者血清VEGF-D浓度升高，淋巴管平滑肌瘤病是一种与mTOR激活结节性硬化症基因突变、淋巴结病、转移性扩散和肺囊肿形成相关的罕见肿瘤。我们使用来自西罗莫司的多中心国际淋巴管平滑肌瘤病疗效（MILES）试验的数据来评估血清VEGF-D浓度作为淋巴管平滑肌瘤病患者严重程度和西罗莫司治疗反应的标志物的有用性。在MILES试验中，1秒用力呼气量（FEV1）为预测值70%或更低的淋巴管平滑肌瘤病患者被随机分配（1：1）接受西罗莫司或安慰剂盲态治疗12个月。在基线、6个月和12个月时测量血清VEGF-D浓度。我们使用线性回归模型来评估基线VEGF-D浓度与疾病严重程度标志物的相关性，并使用线性混合效应模型来评估VEGF-D浓度与临床、生理和患者报告结果的组间差异的相关性。在我们的分析中，我们纳入了安慰剂组的42例患者和西罗莫司组的45例患者。个体患者的基线VEGF-D浓度范围为0.34 ng/mL至16.7 ng/mL。需要辅助供氧的患者的基线VEGF-D浓度高于不需要辅助供氧的患者（1·7 ng/mL [IQR 0·99-3·36] vs 0·84 ng/mL [0·52-1·39]; p <0.0001），有支气管扩张反应的患者比无支气管扩张反应的患者（2.01 ng/mL [0.99 - 2.86] vs 1.00 ng/mL [0.61 - 2.15]; 0.0273）。西罗莫司组和安慰剂组基线时的中位血清VEGF-D浓度相似，西罗莫司组在6个月和12个月时较基线下降，但安慰剂组大致保持稳定。基线log（VEGF-D）每增加一个单位，基线至12个月FEV1变化的组间差异为134 mL（p = 0.0007）。在西罗莫司组中，23例VEGF-D应答者中有15例（65%）基线至12个月FEV1改善（即基线至12个月VEGF-D浓度下降幅度大于安慰剂组任何患者），15例VEGF-D非应答者中有4例（27%）改善（p = 0.0448）。血清VEGF-D是淋巴管平滑肌瘤病的生物学合理和有用的生物标志物，与疾病的严重程度和治疗反应相关。血清VEGF-D浓度的测量可以为西罗莫司治疗淋巴管平滑肌瘤病患者的风险-获益分析提供信息，并减少临床试验所需的患者数量。
VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99–3·36] vs 0·84 ng/mL [0·52–1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99–2·86] vs 1·00 ng/mL [0·61–2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk–benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials.