Document Detail

Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis.
MedLine Citation:
PMID:  18184959     Owner:  NLM     Status:  MEDLINE    
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. ( number, NCT00457808.)
John J Bissler; Francis X McCormack; Lisa R Young; Jean M Elwing; Gail Chuck; Jennifer M Leonard; Vincent J Schmithorst; Tal Laor; Alan S Brody; Judy Bean; Shelia Salisbury; David N Franz
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Publication Detail:
Type:  Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The New England journal of medicine     Volume:  358     ISSN:  1533-4406     ISO Abbreviation:  N. Engl. J. Med.     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2008-01-10     Completed Date:  2008-01-15     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  0255562     Medline TA:  N Engl J Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  140-51     Citation Subset:  AIM; IM    
Copyright Information:
2008 Massachusetts Medical Society
Data Bank Information
Bank Name/Acc. No.:
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MeSH Terms
Angiomyolipoma / drug therapy*,  etiology,  pathology
Brain / pathology
Immunosuppressive Agents / adverse effects,  therapeutic use*
Kidney Diseases / pathology
Liver Diseases / pathology
Lung / physiopathology,  radiography
Lung Neoplasms / complications*,  pathology,  physiopathology
Lymphangioleiomyomatosis / complications*,  pathology,  physiopathology
Magnetic Resonance Imaging
Middle Aged
Protein Kinase Inhibitors / therapeutic use
Protein Kinases / metabolism
Respiratory Function Tests
Sirolimus / adverse effects,  therapeutic use*
TOR Serine-Threonine Kinases
Tuberous Sclerosis / complications*,  genetics
Grant Support
CA103486/CA/NCI NIH HHS; M01 RR08084/RR/NCRR NIH HHS; R21 CA103486/CA/NCI NIH HHS; R21 CA103486-01/CA/NCI NIH HHS; R21 CA103486-02/CA/NCI NIH HHS
Reg. No./Substance:
0/Immunosuppressive Agents; 0/Protein Kinase Inhibitors; EC 2.7.-/Protein Kinases; EC protein, human; EC Serine-Threonine Kinases; W36ZG6FT64/Sirolimus
Comment In:
N Engl J Med. 2008 Jan 10;358(2):190-2   [PMID:  18184966 ]
N Engl J Med. 2008 May 1;358(18):1963-4; author reply 1964   [PMID:  18450609 ]

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