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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003ELung function in lymphangioleiomyomatosis (LAM) stabilized and symptoms and quality-of-life improved significantly during treatment with sirolimus, according to results of the Multicenter International LAM Efficacy of Sirolimus [MILES] Trial.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EPulmonary Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELower Respiratory Infections\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003ELung function in lymphangioleiomyomatosis (LAM) stabilized and symptoms and quality-of-life (QoL) improved significantly during treatment with sirolimus, according to results of the Multicenter International LAM Efficacy of Sirolimus (MILES) Trial, reported Francis X. McCormack, MD, University of Cincinnati, Cincinnati, Ohio, USA, on behalf of the NIH Rare Lung Diseases Consortium.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EFEV\u003Csub\u003E1\u003C\/sub\u003E increased by 1 ml in the sirolimus group compared with a 12-ml decrease with placebo (p\u0026lt;0.0001) over the course of the 1-year treatment period. Forced vital capacity (FVC) also improved with sirolimus, but exercise tolerance and measures of gas exchange did not change. There was a 50% reduction in serum levels of vascular endothelial growth factor-D (VEGF-D), which stimulates pathological growth in LAM. Functional and symptomatic improvement lasted only so long as patients remained on sirolimus.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003ELAM is a rare cystic lung disease that affects women. The condition arises from mutations in the tuberous sclerosis complex (TSC) genes that regulate mammalian target of rapamycin (mTOR) [Carsillo and Henske. \u003Cem\u003EProc Natl Acad Sci\u003C\/em\u003E 2000]. Additionally, lung lesions that are associated with LAM exhibit abnormal mTOR activation, providing a rationale to investigate treatment with sirolimus, which inhibits mTOR [Goncharova et al. \u003Cem\u003EJ Biol Chem\u003C\/em\u003E 2002].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EIn a small open-label trial, tumors that were associated with TSC or LAM shrunk by 50% during treatment with sirolimus, and lung function improved by as much as 13% [Bissler et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2008].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EThe accumulation of clinical and preclinical evidence led to the multicenter trial, reported by Dr. McCormack. Investigators at 13 sites in the United States, Canada, and Japan randomized 89 patients with moderate lung impairment to sirolimus or placebo for 12 months, followed by an additional 12 months of follow-up. The primary endpoint was the change in FEV\u003Csub\u003E1\u003C\/sub\u003E from baseline to 12 months.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EBaseline characteristics did not differ significantly between treatment groups. The patients had an FEV\u003Csub\u003E1\u003C\/sub\u003E of 49% of predicted, FVC of 80%, total lung capacity of 105%, functional residual capacity of 113%, residual volume of 141%, and carbon monoxide diffusion capacity of 43%, consistent with moderately severe obstructive lung impairment, air trapping, and reduced diffusing capacity.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EPatients who were randomized to active therapy received sirolimus 2 mg. Sirolimus levels were measured at every visit after baseline, and the dose was adjusted to maintain a serum level of 5 to 15 ng\/ml.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EThe observation period of the trial was truncated after a planned interim analysis in February 2010 showed that the stopping rule for efficacy had been met.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EAmong patients in the sirolimus arm, FEV\u003Csub\u003E1\u003C\/sub\u003E had stabilized or improved in 46% of patients compared with 12% in the placebo group (p\u0026lt;0.001). Moreover, the change in FEV\u003Csub\u003E1\u003C\/sub\u003E averaged \u2212134 ml in the placebo group versus an increase of 19 ml with sirolimus, resulting in a between-group difference of 153 ml (p\u0026lt;0.001).\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003E\u201cThe clinical relevance of an FEV\u003Csub\u003E1\u003C\/sub\u003E difference of 153 ml is important to consider,\u201d said Dr. McCormack. \u201cIt represents more than a 10% increase from baseline mean FEV\u003Csub\u003E1\u003C\/sub\u003E of 1.37 liters for these patients. It exceeds the estimated minimal clinically important difference in FEV\u003Csub\u003E1\u003C\/sub\u003E for COPD of 100 to 140 ml, which can be perceived by patients and is typical for bronchodilator response. Another reason that a 153-ml difference might be important is that in any patient with advanced disease, any stabilization that may delay transplantation and associated risk is of value.\u201d\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EThe change in FVC averaged a decrease of 129 ml in the placebo group versus an increase of 97 ml in the sirolimus group. Sirolimus was associated with significant improvement in functional performance and QoL versus placebo (p=0.03). FEV\u003Csub\u003E1\u003C\/sub\u003E began to decrease soon after patients stopped treatment, although the mean value in the sirolimus group exceeded that of the placebo group through the end of the 12-month follow-up period.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003ESirolimus was associated with a higher incidence of adverse events. The most common adverse events were stomatitis, diarrhea, nausea, hypercholesterolemia, acneiform rash, and lower-extremity edema.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003E\u201cTherapy with sirolimus may be useful in selected LAM patients,\u201d concluded Dr. McCormack. \u201cLonger-term studies are needed to determine if benefit can be sustained with continued therapy.\u201d\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2011 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/11\/4\/10.2.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzn2pe\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}