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Previous Volume 358:140-151 January 10, 2008 Number 2 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Paul, E. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.

Methods We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed.

Results Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (±SD) angiomyolipoma volume at 12 months was 53.2±26.6% of the baseline value (P<0.001) and at 24 months was 85.9±28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV₁) increased by 118±330 ml (P=0.06), the forced vital capacity (FVC) increased by 390±570 ml (P<0.001), and the residual volume decreased by 439±493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV₁ was 62±411 ml above the baseline value, the FVC was 346±712 ml above the baseline value, and the residual volume was 333±570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections.

Conclusions Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808 [ClinicalTrials.gov] .)

Source Information

From the Divisions of Nephrology and Hypertension (J.J.B.), Pulmonary Medicine (L.R.Y.), Neurology (G.C., J.M.L., D.N.F.), Radiology (V.J.S., T.L., A.S.B.), and Biostatistics (J.B., S.S.), Cincinnati Children's Hospital Medical Center; and the Division of Pulmonary and Critical Care, University of Cincinnati College of Medicine (F.X.M., L.R.Y., J.M.E.) — both in Cincinnati.

Drs. McCormack, Young, and Franz contributed equally to the article.

Address reprint requests to Dr. Bissler at Cincinnati Children's Hospital Medical Center, MLC 7022, 3333 Burnet Ave., Cincinnati, OH 45229-3039, or at john.bissler{at}cchmc.org.

Full Text of this Article

Related Letters:

Sirolimus for Lymphangioleiomyomatosis Lesions
Egan J. J., Remund K. F., Corris P., Bissler J. J., Young L. R., McCormack F. X.
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N Engl J Med 2008; 358:1963-1964, May 1, 2008. Correspondence

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