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Mitomycin\u2010C (MMC) inhibits fibroblast proliferation and synthesis of extracellular matrix proteins, and thereby modulates wound healing and scarring. MMC application at the time of endoscopic dilation and laser surgery has been suggested to improve outcomes, but this has not been studied in a rigorous manner. This study examines the hypothesis that two topical applications of MMC given 3\u20136 weeks apart will result in decreased scarring\/restenosis of the airway, when compared to a single topical application.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design:<\/jats:title><jats:p>A randomized, prospective, double\u2010blind, placebo\u2010controlled clinical trial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>Twenty\u2010six patients with laryngotracheal stenosis due to idiopathic subglottic stenosis, postintubation stenosis, or Wegener's granulomatosis entered a protocol to receive three endoscopic CO<jats:sub>2<\/jats:sub> laser and dilation procedures over a 3\u2010month interval. At the first procedure, after radial CO<jats:sub>2<\/jats:sub> laser incision and airway dilation, all patients received topical application of MMC (0.5 mg\/mL) to the airway lesion. One month later, a second endoscopic incision and dilation was performed and the patients were randomized to either a second application of mitomycin\u2010C or to application of saline placebo. A third dilation procedure was performed 2 months later, without MMC application. Patients were followed for up to 5 years for relapse of airway stenosis with clinical symptoms sufficient to require a subsequent procedure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>The relapse rates at 1, 3, and 5 years were 7%, 36%, and 69% for patients treated with two applications of MMC compared to 33%, 58%, and 70% for patients treated with one application of MMC. The median interval to relapse was 3.8 years in the two\u2010application group, compared with 2.4 years in the one\u2010application group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p>This prospective randomized double\u2010blind placebo\u2010controlled trial suggests that, in the endoscopic management of laryngotracheal stenosis, two applications of MMC given 3\u20134 weeks apart after airway radial incision and dilation reduces the restenosis rate for 2 to 3 years after treatment when compared to a single application. However, restenosis and delayed symptom recurrence continues so that at 5 years the relapse rates are the same. Thus, MMC may postpone, but does not prevent, the recurrence of symptomatic stenosis in the majority of patients. 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