Eugene J. Sullivan

Efficacy and safety of sirolimus in lymphangioleiomyomatosis

BACKGROUND Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM. METHODS We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)). RESULTS During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups. CONCLUSIONS In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).

Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management

BACKGROUND Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that primarily affects women. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of LAM. METHODS Systematic reviews were performed to summarize evidence pertinent to our questions. The evidence was summarized and discussed by a multidisciplinary panel. Evidence-based recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS After considering the panels confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were formulated for or against specific interventions. These included recommendations for sirolimus treatment and vascular endothelial growth factor D testing and recommendations against doxycycline and hormonal therapy. CONCLUSIONS Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

Strategic Plan for Lung Vascular Research: An NHLBI-ORDR Workshop Report

The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype-phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs. Recommendations from this workshop will be used within the Lung Vascular Biology and Disease Extramural Research Program for planning and strategic implementation purposes.

Role of Tc-99m MIBI in the evaluation of single pulmonary nodules: a preliminary report

BACKGROUND Survival in bronchial carcinoma is closely related to the stage of the disease at the time of diagnosis and a single pulmonary nodule represents a potentially curable stage. This study was conducted to assess the feasibility of using Tc-99m labelled 2-methoxy isobutyl isonitrile (MIBI) to differentiate benign from malignant single pulmonary nodules. METHODS A prospective study was conducted in the outpatient pulmonary clinic at the Cleveland Clinic Foundation. Twenty five patients with single pulmonary nodules considered indeterminate by their physicians and undergoing a procedure for tissue diagnosis were evaluated by Tc-99m MIBI SPECT scanning prior to definitive testing. Assessment of MIBI uptake was done qualitatively (subjectively) and quantitatively and correlated with the histopathology and nodule size. RESULTS Of the 21 patients with malignant lesions, 18 had increased uptake of MIBI corresponding to the location of the nodule and were considered positive. The predominant tumour types were large cell (n = 5) and adenocarcinoma (n = 10). All four patients with benign lesions had negative MIBI scans. For malignancy the overall specificity was 100%, sensitivity was 85.7%, positive predictive value was 100%, and negative predictive value was 57%. Quantitative uptake of MIBI correlated with the diameter of the nodule with a correlation coefficient of 0.61 by Spearmans rank sum test. This relationship was statistically significant (p = 0.02). CONCLUSION This preliminary study suggests that Tc-99m MIBI has a very high specificity and positive predictive value for malignant single pulmonary nodules and might be a useful non-invasive diagnostic modality in their management.

Air travel in women with lymphangioleiomyomatosis

Background and objective: The safety of air travel in patients with pneumothorax-prone pulmonary diseases, such as lymphangioleiomyomatosis (LAM), has not been studied to any great extent. A questionnaire-based evaluation of air travel in patients with LAM was conducted to determine experiences aboard commercial aircraft. Methods: A survey was sent to women listed in the US LAM Foundation registry (n = 389) and the UK LAM Action registry (n = 59) to assess air travel, including problems occurring during flight. Women reporting a pneumothorax in flight were followed up to ascertain further details about the incident. Results: 327 (73%) women completed the survey. 308 women answered the travel section, of whom 276 (90%) had “ever” travelled by aeroplane for a total of 454 flights. 95 (35%) women had been advised by their doctor to avoid air travel. Adverse events reported included shortness of breath (14%), pneumothorax (2%, 8/10 confirmed by chest radiograph), nausea or dizziness (8%), chest pain (12%), unusual fatigue (11%), oxygen desaturation (8%), headache (9%), blue hands (2%), haemoptysis (0.4%) and anxiety (22%). 5 of 10 patients with pneumothorax had symptoms that began before the flight: 2 occurred during cruising altitude, 2 soon after landing and 1 not known. The main symptoms were severe chest pain and shortness of breath. Discussion and conclusion: Adverse effects occurred during air travel in patients with LAM, particularly dyspnoea and chest pain. Hypoxaemia and pneumothorax were reported. The decision to travel should be individualised; patients with unexplained shortness of breath or chest pain before scheduled flights should not board. Patients with borderline oxygen saturations on the ground should be evaluated for supplemental oxygen therapy during flight. Although many women had been advised not to travel by air, most travelled without the occurrence of serious adverse effects.

CorrespondenceComments on the Salmeterol Multicenter Asthma Research Trial

dose-dependent and gene-dependent manner.2,3 While the prolongation of QTc is a risk for torsades de pointes, a necessary cofactor appears to be increased transmural dispersion of repolarization.3 Transmural dispersion of repolarization is sympathetically mediated and has been demonstrated to increase with therapy with systemic -agonists, but is likely affected by inhaled agents as well.2,3 The race aspects of the findings in the SMART are particularly interesting because the risk of drug-induced torsades de pointes with -agonist therapy is dependent on genetic polymorphisms for the genes associated with the long QT syndrome.3 It has been shown that African Americans have substantially greater heterogeneity in those genes, a finding of as yet still unknown consequence.4 While we are in the process of conducting a trial comparing the effects of albuterol on QTc in asthmatic patients compared to nonasthmatic patients, it would be helpful to know specifically what the cause of death was in the SMART trial in the 11 patients who died while receiving salmeterol, but whose causes of death were not ruled to be asthma and thus were not detailed in the study. Additionally, of the 13 reported deaths in the salmeterol group that were ruled to be asthma-related, 7 listed either no cause of death or a primary cardiovascular disorder on the death certificate (Table 5 in the article by Nelson et al1). While I noted that a coroners report was available for one patient, it would be helpful to know whether further autopsy data are available or are being sought since previous series5 have reported autopsy findings that are inconsistent with a pulmonary cause of death in patients who have been reported to have died of asthma.