Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis. A Randomized, Controlled, Multicenter Clinical Trial.

RATIONALE: Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant-antioxidant imbalance and oxidative stress. OBJECTIVES: Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes. METHODS: In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEV1 between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment. Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability. MEASUREMENTS AND MAIN RESULTS: Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant (ß-carotene, coenzyme Q10, γ-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups. CONCLUSIONS: Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT01859390).

Effect of treatment of cystic fibrosis pulmonary exacerbations on systemic inflammation.

RATIONALE: In cystic fibrosis (CF), pulmonary exacerbations present an opportunity to define the effect of antibiotic therapy on systemic measures of inflammation. OBJECTIVES: Investigate whether plasma inflammatory proteins demonstrate and predict a clinical response to antibiotic therapy and determine which proteins are associated with measures of clinical improvement. METHODS: In this multicenter study, a panel of 15 plasma proteins was measured at the onset and end of treatment for pulmonary exacerbation and at a clinically stable visit in patients with CF who were 10 years of age or older. MEASUREMENTS AND MAIN RESULTS: Significant reductions in 10 plasma proteins were observed in 103 patients who had paired blood collections during antibiotic treatment for pulmonary exacerbations. Plasma C-reactive protein, serum amyloid A, calprotectin, and neutrophil elastase antiprotease complexes correlated most strongly with clinical measures at exacerbation onset. Reductions in C-reactive protein, serum amyloid A, IL-1ra, and haptoglobin were most associated with improvements in lung function with antibiotic therapy. Having higher IL-6, IL-8, and α1-antitrypsin (α1AT) levels at exacerbation onset were associated with an increased risk of being a nonresponder (i.e., failing to recover to baseline FEV1). Baseline IL-8, neutrophil elastase antiprotease complexes, and α1AT along with changes in several plasma proteins with antibiotic treatment, in combination with FEV1 at exacerbation onset, were predictive of being a treatment responder. CONCLUSIONS: Circulating inflammatory proteins demonstrate and predict a response to treatment of CF pulmonary exacerbations. A systemic biomarker panel could speed up drug discovery, leading to a quicker, more efficient drug development process for the CF community.

Non-physician providers as clinical providers in cystic fibrosis: survey of U.S. programs.

BACKGROUND AND METHODS: Non-physician providers (NPPs) including nurse practitioners (NPs) and physician assistants (PAs) are important members of CF care teams, but limited data exist about the extent NPPs are involved in CF care. A subcommittee was established by the CF Foundation to gather information about current involvement of NPPs. Surveys were sent to adult, pediatric and affiliate CF program directors (PDs) and NPPs working in US CF programs. RESULTS: Responses were received from 108 PDs (49% pediatric, 34% adult, 17% affiliate). Overall, 53% of the 108 programs had NPPs and 70% had or planned to hire NPPs. Reasons for NPP use included ideal clinical role (75%), expansion of services (72%), and physician shortage (40%). The survey collected 73 responses from NPPs (96% NPs, 4% PAs) who worked in pediatric (49%), adult (29%), affiliate (3%), or multiple programs (19%). Training occurred on the job in 88% and from prior CF experience in 21%. NPPs provided coverage in outpatient clinics (82%), inpatient care (64%), and weekend and/or night call (22%). In addition to clinical roles, NPPs are involved in education (95%), research (81%), and leadership (55%). The major obstacle reported by PDs and NPPs was billing with only 12% of programs reporting NPP salaries covered by billing revenue alone. Salary support included hospital support (67%), billing (39%), center grant (35%), and other grant/contract (25%). NPPs bill for outpatient and inpatient care in 65% and 28% of programs, respectively. CONCLUSIONS: NPPs are working with physicians in many centers and have the potential to help meet the increasing clinical workforce demands. Further evaluation of financial issues is indicated to continue the support of NPP jobs in CF. Roles and expectations need to be clearly defined. Initial and ongoing training standards and opportunities should be explored.

Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial.

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia (CFRD FH-) is not associated with microvascular or macrovascular complications, leading to controversy about the need for treatment. The Cystic Fibrosis Related Diabetes Therapy (CFRDT) Trial sought to determine whether diabetes therapy improves BMI in these patients. RESEARCH DESIGN AND METHODS: A three-arm multicenter randomized trial compared 1 year of therapy with premeal insulin aspart, repaglinide, or oral placebo in subjects with cystic fibrosis who had abnormal glucose tolerance. RESULTS: One hundred adult patients were enrolled. Eighty-one completed the study, including 61 with CFRD FH- and 20 with severly impaired glucose tolerance (IGT). During the year before therapy, BMI declined in all groups. Among the group with CFRD FH-, insulin-treated patients lost 0.30 +/- 0.21 BMI units the year before therapy. After 1 year of insulin therapy, this pattern reversed, and they gained 0.39 +/- 21 BMI units (P = 0.02). No significant change in the rate of BMI decline was seen in placebo-treated patients (P = 0.45). Repaglinide-treated patients had an initial significant BMI gain (0.53 +/- 0.19 BMI units, P = 0.01), but this effect was not sustained. After 6 months of therapy they lost weight so that by 12 months there was no difference in the rate of BMI change during the study year compared with the year before (P = 0.33). Among patients with IGT, neither insulin nor repaglinide affected the rate of BMI decline. No significant differences were seen in the rate of lung function decline or the number of hospitalizations in any group. CONCLUSIONS: Insulin therapy safely reversed chronic weight loss in patients with CFRD FH-.

Phase I study of adenovirus p53 administered by bronchoalveolar lavage in patients with bronchioloalveolar cell lung carcinoma: ECOG 6597.

PURPOSE: This pilot phase I trial evaluated the safety and maximum-tolerated dose of p53 gene transfer using an adenovirus vector (Ad-p53) delivered via bronchoalveolar lavage (BAL) to patients with bronchioloalveolar lung carcinoma (BAC). PATIENTS AND METHODS: Patients were initially administered two treatments of Ad-p53 to a single involved lobe, beginning at 2 x 10(9) viral particles (vp) per dose and escalated to a maximum of 2 x 10(12) vp. If a clinical benefit was seen and the treatment was well tolerated, additional doses could be administered to additional lobes. RESULTS: Twenty-five patients were treated at doses between 2 x 10(9) and 2 x 10(12) vp. At 2 x 10(12) vp, one patient experienced grade 4 pulmonary toxicity, and one patient died 25 days after his second cycle; therefore, a cohort of 10 patients was treated at the recommended phase II dose of 5 x 10(11) vp, with no grade 4 toxicity observed. The most frequent toxicities included low-grade fever, hypoxia, and dyspnea. Of the 23 assessable patients, 16 had stable disease as their best response. Subjective improvement in breathing was noted in eight patients. Limited distribution of vector was observed, with transient detection in patient sputum for 1 to 2 days after administration. CONCLUSION: Ad-p53 can be administered safely by BAL at 5 x 10(11) vp with repeated dosing. Stabilization of disease and symptomatic improvement may warrant further studies of Ad-p53 or other adenoviruses administered by BAL in patients with BAC.

Proteomic patterns of preinvasive bronchial lesions.

PURPOSE: A proteomics approach is warranted to further elucidate the molecular steps involved in lung tumor development. We asked whether we could classify preinvasive lesions of airway epithelium according to their proteomic profile. EXPERIMENTAL DESIGN: We obtained matrix-assisted laser desorption/ionization time-of-flight mass spectrometry profiles from 10-microm sections of fresh-frozen tissue samples: 25 normal lung, 29 normal bronchial epithelium, and 20 preinvasive and 36 invasive lung tumor tissue samples from 53 patients. Proteomic profiles were calibrated, binned, and normalized before analysis. We performed class comparison, class prediction, and supervised hierarchic cluster analysis. We tested a set of discriminatory features obtained in a previously published dataset to classify this independent set of normal, preinvasive, and invasive lung tissues. RESULTS: We found a specific proteomic profile that allows an overall predictive accuracy of over 90% of normal, preinvasive, and invasive lung tissues. The proteomic profiles of these tissues were distinct from each other within a disease continuum. We trained our prediction model in a previously published dataset and tested it in a new blinded test set to reach an overall 74% accuracy in classifying tumors from normal tissues. CONCLUSIONS: We found specific patterns of protein expression of the airway epithelium that accurately classify bronchial and alveolar tissue with normal histology from preinvasive bronchial lesions and from invasive lung cancer. Although further study is needed to validate this approach and to identify biomarkers of tumor development, this is a first step toward a new proteomic characterization of the human model of lung cancer tumorigenesis.