雷帕鸣治疗肺淋巴管肌瘤病（LAM）的最新报告

在上周结束的美国胸科年会上，Yong和McCormack等报告了雷帕鸣治疗LAM的初步结果。这项研究主要是观察雷帕鸣 (Sirolimus, rapamycin) 治疗血管肌脂瘤的作用，有25例病人参加，其中包括10例LAM病人。在为期一年的观察中，10例中有8例肺功能改善。平均FEV1(第一秒用力呼出气量)改善168ml (-40 ~ 470ml)，平均FVC(用力肺活量)改善435ml (-120 ~ 1100 ml)，残气量平均减少425ml。CT扫描显示肺部的囊性病变较治疗前改善21% (但统计学上没有显示差异)。一项血清指标血管内皮生长因子-D，在LAM病人中比正常人增高8倍，雷帕鸣治疗后比治疗前显著下降了70%。主要的副反应为高脂血症和口腔溃疡，25例中有4例提前中止了研究。这项初步的观察表明，雷帕鸣在改善LAM病人的肺功能和肺部囊性病变方面可能是有效的，而血管内皮生长因子-D可以作为一个血清标记来监测治疗反应。      （徐凯峰）

Improved Airflow and Reduction in Gas Trapping and Serum VEGF-D Levels in LAM Patients Treated with Sirolimus

L.R. Young, J. Elwing, J.J. Bissler, D.N. Franz, T. Altes, V. Schmithorst, A. Brody, F.X. McCormack, Cincinnati, OH, Philadelphia, PA

Lymphangioleiomyomatosis (LAM) and tuberous sclerosis (TS) are disorders associated with dysregulated mTOR/Akt signaling, benign kidney tumors called angiomyolipomas (AMLs), pulmonary and lymphatic smooth muscle cell infiltration and cystic destruction of the lung. Others have reported that the lymphangiogenesis factor, VEGF-D, is elevated in LAM patients (Seyama et al, PATS, 2:A390, 2005). 25 patients with LAM and/or TS were enrolled in a one year, open-label trial testing the effect of the inhibitor of mTOR/Akt signaling, Sirolimus, on AML size. PFTs and quantitative chest CT to estimate cyst volume were performed at regular study visits. ELISA analyses of serum VEGF-D levels were performed on a subset of patients. After 12 months of Sirolimus, AMLs partially regressed (40-60%), and lung function parameters improved in 8 of 10 LAM patients. The mean increase in FEV1 was 168cc (-40cc to +470cc), the mean increase in FVC was 435cc (-120cc to +1100cc), and RV declined by an average of 425cc. DLCO, TLC, and TGV did not change. By CT scan, the cyst volume decreased by a mean of 21% of baseline (n=10, p=.056). After 6-12 months of Sirolimus, serum VEGF-D levels declined by an average of 70% in LAM patients, from a baseline that was elevated 8-fold compared to normal controls (n=9, 3161±750 pg/mL vs. 389±44 pg/mL, p=.006). Hyperlipidemia and mouth ulcers were the most common adverse events, and four patients discontinued Sirolimus. This preliminary study suggests that mTOR inhibition with Sirolimus may improve lung function and cyst volume in LAM patients and VEGF-D levels may serve as a biomarker of therapeutic response. Further controlled studies with functionally relevant endpoints are needed.
（Date: Sunday, May 21, 2006）