Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial.

BACKGROUND: 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide. METHODS: This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129. FINDINGS: Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53-3·84) and 2·88 in the cyclophosphamide group (1·19-4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019). INTERPRETATION: Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile. FUNDING: National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.

Adult Bronchoscopy Training: Current State and Suggestions for the Future: CHEST Expert Panel Report.

BACKGROUND: The determination of competency of trainees in programs performing bronchoscopy is quite variable. Some programs provide didactic lectures with hands-on supervision, other programs incorporate advanced simulation centers, whereas others have a checklist approach. Although no single method has been proven best, the variability alone suggests that outcomes are variable. Program directors and certifying bodies need guidance to create standards for training programs. Little well-developed literature on the topic exists. METHODS: To provide credible and trustworthy guidance, rigorous methodology has been applied to create this bronchoscopy consensus training statement. All panelists were vetted and approved by the CHEST Guidelines Oversight Committee. Each topic group drafted questions in a PICO (population, intervention, comparator, outcome) format. MEDLINE data through PubMed and the Cochrane Library were systematically searched. Manual searches also supplemented the searches. All gathered references were screened for consideration based on inclusion criteria, and all statements were designated as an Ungraded Consensus-Based Statement. RESULTS: We suggest that professional societies move from a volume-based certification system to skill acquisition and knowledge-based competency assessment for trainees. Bronchoscopy training programs should incorporate multiple tools, including simulation. We suggest that ongoing quality and process improvement systems be introduced and that certifying agencies move from a volume-based certification system to skill acquisition and knowledge-based competency assessment for trainees. We also suggest that assessment of skill maintenance and improvement in practice be evaluated regularly with ongoing quality and process improvement systems after initial skill acquisition. CONCLUSIONS: The current methods used for bronchoscopy competency in training programs are variable. We suggest that professional societies and certifying agencies move from a volume- based certification system to a standardized skill acquisition and knowledge-based competency assessment for pulmonary and thoracic surgery trainees.

Dyspnea in Chronic Fatigue Syndrome (CFS): comparison of two prospective cross-sectional studies.

Chronic Fatigue Syndrome (CFS) subjects have many systemic complaints including shortness of breath. Dyspnea was compared in two CFS and control cohorts to characterize pathophysiology. Cohort 1 of 257 CFS and 456 control subjects were compared using the Medical Research Council chronic Dyspnea Scale (MRC Score; range 0-5). Cohort 2 of 106 CFS and 90 controls answered a Dyspnea Severity Score (range 0-20) adapted from the MRC Score. Subsets of both cohorts completed CFS Severity Scores, fatigue, and other questionnaires. A subset had pulmonary function and total lung capacity measurements. Results show MRC Scores were equivalent between sexes in Cohort 1 CFS (1.92 [1.72-2.16]; mean [95% C.I.]) and controls (0.31 [0.23-0.39]; p<0.0001). Receiver-operator curves identified 2 as the threshold for positive MRC Scores in Cohort 1. This indicated 54% of CFS, but only 3% of controls, had significant dyspnea. In Cohort 2, Dyspnea Score threshold of 4 indicated shortness of breath in 67% of CFS and 23% of controls. Cohort 2 Dyspnea Scores were higher for CFS (7.80 [6.60-9.00]) than controls (2.40 [1.60-3.20]; p<0.0001). CFS had significantly worse fatigue and other complaints compared to controls. Pulmonary function was normal in CFS, but Borg scores and sensations of chest pain and dizziness were significantly greater during testing than controls. General linear model of Cohort 2 CFS responses linked Dyspnea with rapid heart rate, chest pain and dizziness. In conclusion, sensory hypersensitivity without airflow limitation contributed to dyspnea in CFS. Correlates of dyspnea in controls were distinct from CFS suggesting different mechanisms.

An unusual case of persistent extrinsic bronchial compression.

Bronchomalacia is defined as diffuse or segmental bronchial weakness and easy compressibility. We present a rare case of a 67-year-old man with chronic cough as a consequence of focal bronchomalacia caused by persistent extrinsic compression of the left lower lobe bronchus by the descending aorta and the left lower lobe branch of the pulmonary artery. Focal bronchomalacia discovered during adulthood is most often acquired and can be attributed to extrinsic compression by abnormal blood vessels due to hypertension and lung transplantation or to bronchial disease processes. The natural history of bronchomalacia is typically progressive.

The origin of the constant carbohydrate diet.

The Constant Carbohydrate diet, based entirely on carbohydrate exchanges, is now widely used in the dietary treatment of diabetes mellitus. Being based on sound scientific principles and simple in design, the Constant Carabohydrate diet is appropriate for all those having diabetes mellitus, young or old, no matter their ethncity. This report describes why and how it was developed in 1951. Its simplicity makes it adaptable to all ethnic diets.

Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease.

RATIONALE: The Scleroderma Lung Study enrolled 158 patients with scleroderma-related interstitial lung disease in a placebo-controlled trial of oral cyclophosphamide (CYC). Although treatment-related benefits in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of benefit beyond 1 year was unclear. OBJECTIVES: A second year of follow-up was performed to determine if these effects persisted after stopping treatment. METHODS: A detailed analysis of data obtained over the two years of the study was performed. MEASUREMENTS AND MAIN RESULTS: Using a longitudinal joint model, we analyzed FVC, total lung capacity, transitional dyspnea index, Rodnan skin scores, and the Health Assessment Questionnaire-Disability Index during the second year, after adjusting for baseline values, baseline fibrosis score, and nonignorable missing data. Evaluable subjects (72 CYC; 73 placebo) included 93 who completed all visits plus 52 who completed at least 6 months of therapy and returned at 24 month or had their 24-month data imputed. The beneficial effects of CYC on pulmonary function and health status continued to increase through 18 months, after which they dissipated, whereas skin improvements dissipated after 12 months. In contrast, the positive effect on dyspnea persisted through 24 months. Adverse events were uncommon. CONCLUSIONS: One year of CYC improved lung function, skin scores, dyspnea, and health status/disability, effects which either persisted or increased further for several months after stopping therapy. However, except for a sustained impact on dyspnea, all of these effects waned and were no longer apparent at 24 months. Treatment strategies aimed at extending the positive therapeutic effects observed with CYC should be considered. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).

Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice.

Cervical remodeling during pregnancy and parturition is a single progressive process that can be loosely divided into four overlapping phases termed softening, ripening, dilation/labor, and post partum repair. Elucidating the molecular mechanisms that facilitate all phases of cervical remodeling is critical for an understanding of parturition and for identifying processes that are misregulated in preterm labor, a significant cause of perinatal morbidity. In the present study, biomechanical measurements indicate that softening was initiated between gestation days 10 and 12 of mouse pregnancy, and in contrast to cervical ripening on day 18, the softened cervix maintains tissue strength. Although preceded by increased collagen solubility, cervical softening is not characterized by significant increases in cell proliferation, tissue hydration or changes in the distribution of inflammatory cells. Gene expression studies reveal a potentially important role of cervical epithelia during softening and ripening in maintenance of an immunomucosal barrier that protects the stromal compartment during matrix remodeling. Expression of two genes involved in repair and protection of the epithelial permeability barrier in the gut (trefoil factor 1) and skin (serine protease inhibitor Kazal type 5) were increased during softening and/or ripening. Another gene whose function remains to be elucidated, purkinje cell protein 4, declines in expression as remodeling progressed. Collectively, these results indicate that cervical softening during pregnancy is a unique phase of the tissue remodeling process characterized by increased collagen solubility, maintenance of tissue strength, and upregulation of genes involved in mucosal protection.

Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lung disease: results from the scleroderma lung study.

OBJECTIVE: To assess the impact of cyclophosphamide (CYC) on the health-related quality of life (HRQOL) of patients with scleroderma after 12 months of treatment. METHODS: One hundred fifty-eight subjects participated in the Scleroderma Lung Study, with 79 each randomized to CYC and placebo arms. The study evaluated the results of 3 measures of health status: the Short Form 36 (SF-36), the Health Assessment Questionnaire (HAQ) disability index (DI), and Mahler's dyspnea index, and the results of 1 preference-based measure, the SF-6D. The differences in the HRQOL between the 2 groups at 12 months were calculated using a linear mixed model. Responsiveness was evaluated using the effect size. The proportion of subjects in each treatment group whose scores improved at least as much as or more than the minimum clinically important difference (MCID) in HRQOL measures was assessed. RESULTS: After adjustment for baseline scores, differences in the HAQ DI, SF-36 role physical, general health, vitality, role emotional, mental health scales, and SF-36 mental component summary (MCS) score were statistically significant for CYC versus placebo (P < 0.05). Effect sizes were negligible (<0.20) for all of the scales of the SF-36, HAQ DI, and SF-6D at 12 months. In contrast, a higher proportion of patients who received CYC achieved the MCID compared with placebo in the HAQ DI score (30.9% versus 14.8%), transitional dyspnea index score (46.4% versus 12.7%), SF-36 MCS score (33.3% versus 18.5%), and SF-6D score (21.3% versus 3.8%). CONCLUSION: One year of treatment with CYC leads to an improvement in HRQOL in patients with scleroderma lung disease.

A severely affected female infant with x-linked dominant chondrodysplasia punctata: a case report and a brief review of the literature.

We recently performed an autopsy on a premature female newborn with rhizomesoacromelic limb shortening of the upper and lower extremities, craniofacial dysmorphism, and chondrodysplasia punctata. A diagnosis of Conradi-Hunermann-Happle syndrome or X-linked dominant chondrodysplasia punctata was made based on elevated cholest-8(9)-ene-3beta-ol in serum and tissues. Molecular analysis of EBP, mutations of which are responsible for this malformation syndrome, revealed a monoallelic missense mutation, c.328 G>A (R110Q). We present this case as an illustration of an unusually severe manifestation of this disorder in a female, with additional unusual features including lack of skin manifestations and apparent bilateral symmetry of the skeletal findings.

Cyclophosphamide versus placebo in scleroderma lung disease.

BACKGROUND: We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease. METHODS: At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic high-resolution computed tomography, or both. Patients received oral cyclophosphamide (< or =2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year. Pulmonary function was assessed every three months during the first year, and the primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC. RESULTS: Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P<0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant. CONCLUSIONS: One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study.

A 36-year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves' patients.

This report details the 26- and 36-yr outcomes of 116 patients under the age of 20 yr with Graves' disease who were treated with radioiodine between 1953 and 1973. Contacted by telephone and mail in 1991-1992, 107 of them supplied personal historical data, and their physicians furnished interval histories, physical examinations, and laboratory data. This was repeated in 2001-2002, with 98 of them being contacted. At the time of treatment, the patients' ages ranged between 3 yr, 7 months and 19 yr, 9 months. Six were less than 6 yr of age, 11 were between 6 and 11 yr, 45 were between 11 and 15 yr, and 45 were between 16 and 19 yr. The average length of follow-up in 1991-1992 was 26.1 yr; that in 2001-2002 was 36.2 yr. None of the patients developed cancer of the thyroid or leukemia. Early on, when the objective of treatment was euthyroidism, the dose of radioiodine was low, and retreatment was frequently needed. Later, the doses used were increased. Over time, all but two patients became hypothyroid. Pregnancies did not result in an unusual number of congenital anomalies or spontaneous abortions. Treating young people with Graves' disease with radioiodine is safe and effective over the long term.