Kevin K Brown

University of Colorado, Denver, Colorado, United States

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Publications (166)1114.36 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background:The current UIP/IPF CT classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive effect of probable CT UIP on histology, and to determine the effect of the promoter polymorphism in the MUC5B gene (rs35705950) on histologic and CT UIP diagnosis. Methods:The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within one year of chest CT. UIP diagnosis on CT was categorized as inconsistent with, indeterminate, probable, or definite UIP by 2-3 pulmonary radiologists. Tissue slides were scored by two expert pulmonary pathologists. All subjects with available DNA (N=200) were genotyped for rs35705950. Results:The proportion of CT diagnoses were as follows: inconsistent with 69/201 (34.3%), indeterminate 72/201 (35.8%), probable 34/201 (16.9%), and definite 26/201 (12.9%) UIP. Subjects with probable CT UIP were more likely to have histologic probable/definite UIP than subjects with indeterminate CT UIP (82.4% [28/34] versus 54.2% [39/72]; p-value 0.01). CT and microscopic honeycombing were not associated with each other (p-value 0.76). The minor (T) allele of the MUC5B polymorphism was associated with concordant CT and histologic UIP diagnosis (p-value: 0.03). Conclusions:Probable CT UIP is associated with a higher rate of histologic UIP than indeterminate CT UIP suggesting that they are distinct groups and should not be combined into a single CT category as currently recommended by guidelines. CT and microscopic honeycombing may be dissimilar entities. The T allele at rs35705950 predicts a UIP diagnosis by both chest CT and histology.
    Chest 10/2014; · 7.13 Impact Factor
  • Brett Ley, Kevin K Brown, Harold R Collard
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    ABSTRACT: Molecular biomarkers are highly desired in idiopathic pulmonary fibrosis (IPF) where they hold the potential to elucidate underlying disease mechanisms, accelerated drug development, and advance clinical management. Currently, there are no molecular biomarkers in widespread clinical use for IPF, and the search for potential markers remains in its infancy. Proposed core mechanisms in the pathogenesis of IPF for which candidate markers have been offered include alveolar epithelial cell dysfunction, immune dysregulation, and fibrogenesis. Useful markers reflect important pathologic pathways, are practically and accurately measured, have undergone extensive validation, and are an improvement upon the current approach for their intended use. The successful development of useful molecular biomarkers is a central challenge for the future of translational research in IPF and will require collaborative efforts among those parties invested in advancing the care of patients with IPF.
    American journal of physiology. Lung cellular and molecular physiology. 09/2014;
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    ABSTRACT: While widespread use of animal modeling has transformed pulmonary research, the overarching goal of biomedical research is to enhance our understanding of human physiology and pathology. Thus, we believe that future gains in understanding human lung disease will be enhanced when studying patient-derived samples becomes an integral part of the investigational process. For idiopathic pulmonary fibrosis (IPF), investigators need quality human specimens, collected in a standardized fashion, along with carefully annotated, long-term clinical and outcomes data to address current knowledge gaps. Access to human lung tissues through commercial entities or the Lung Tissue Resource Consortium, an NHLBI-funded consortium, has demonstrated the feasibility of this approach. However, these samples are not always well-annotated or collected uniformly, and are limited in their breadth to address future IPF research needs. Therefore, we propose leveraging ongoing and future studies in IPF to establish a biorepository which will meet current and future needs of IPF investigations. Specifically, we propose that blood, cell, and lung samples, linked to robust longitudinal clinical phenotyping generated from future industry, federally-sponsored, and investigator-initiated clinical studies be prospectively and uniformly collected and stored in a biorepository and linked registry. Here we outline standardized methodologies that would allow specimens and clinical data collected from different studies to be integrated and accessible to the IPF research community for investigations which will inform future basic and translational research in IPF. Such a biorepository needs the combined efforts of all stakeholders, to be driven by projected future scientific needs and to be available to all qualified researchers. We believe this infrastructure is crucial, is feasible, and would accelerate research in IPF.
    Annals of the American Thoracic Society. 08/2014;
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    ABSTRACT: Background:The feasibility of an interventional clinical trial in idiopathic pulmonary fibrosis (IPF) using death and hospitalization as primary endpoints is an area of uncertainty. This manuscript aims to illustrate the impact of cohort enrichment and study duration on sample size requirements for IPF clinical trials in which death alone or death plus hospitalization serve as the primary endpoint, using data from a large well-characterized clinical trial population. Methods:Event rate estimates for death and hospitalization were determined from patients enrolled into the NIH-sponsored idiopathic pulmonary fibrosis clinical research network clinical trials. Standard sample size formulae were applied to estimate the total sample size required for varying gender, age, and pulmonary function (GAP) stage-based cohorts. Results:Risk estimates for death and hospitalization in the clinical trial cohort were substantially lower than published. An IPF trial with death as its primary endpoint, enrolling GAP stage 1 and 2 subjects over one year with a minimum follow-up of 1 year, would require an estimated 7986 subjects to achieve 90% power for a hazard ratio of 0.70. Alternatively, an IPF trial with death plus hospitalization as its primary endpoint, enrolling GAP stage 2 and 3 subjects over two years with a minimum follow-up of 1 year, would require an estimated 794 subjects for the same power and hazard ratio. Conclusion:Study design decisions, in particular cohort enrichment strategies, have a substantial impact on sample size requirements for IPF clinical trials using time to event primary endpoints such as death and death plus hospitalization.
    Chest 08/2014; · 7.13 Impact Factor
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    ABSTRACT: Assessment of health-related quality of life (HRQL) is particularly important in patients with progressive and incurable diseases such as idiopathic pulmonary fibrosis (IPF). The St George¿s Respiratory Questionnaire (SGRQ) has frequently been used to measure HRQL in patients with IPF, but it was developed for patients with obstructive lung diseases. The aim of this review was to examine published data on the psychometric performance of the SGRQ in patients with IPF. A comprehensive search was conducted to identify studies reporting data on the internal consistency, construct validity, test-retest reliability, and interpretability of the SGRQ in patients with IPF, published up to August 2013. In total, data from 30 papers were reviewed. Internal consistency was moderate for the SGRQ symptoms score and excellent for the SGRQ activity, impact and total scores. Validity of the SGRQ symptoms, activity, impact and total scores was supported by moderate to strong correlations with other patient-reported outcome measures and with a measure of exercise capacity. Most correlations were moderately strong between SGRQ activity or total scores and forced or static vital capacity, the most commonly used marker of IPF severity. There was evidence that changes in SGRQ domain and total scores could detect within-subject improvement in health status, and differentiate groups of patients whose health status had improved, declined or remained unchanged. Although the SGRQ was not developed specifically for use with patients with IPF, on balance, its psychometric properties are adequate and suggest that it may be a useful measure of HRQL in this patient population. However, several questions remain unaddressed, and further research is needed to confirm the SGRQ¿s utility in IPF.
    Health and Quality of Life Outcomes 08/2014; 12(1):124. · 2.27 Impact Factor
  • Aryeh Fischer, Kevin K Brown
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    ABSTRACT: The intersection of interstitial lung disease (ILD) and connective tissue disease (CTD) is complex and commonly includes the scenario whereby ILD is identified in patients with pre-existing CTD, is the presenting manifestation of an occult CTD, or arises within the context of a suggestive form of CTD. Determining that an ILD is CTD-associated is important because this knowledge often impacts management and prognosis. Identifying occult CTD in patients with presumed idiopathic ILD can be challenging and requires a comprehensive, often multidisciplinary, evaluation. There is much uncertainty and controversy surrounding the suggestive forms of CTD-associated ILD (CTD-ILD) and prospective studies are needed to provide a better understanding of the natural history of these cohorts, how to best manage them, and to determine whether they behave similar to classifiable forms of CTD-ILD. © 2014 American College of Rheumatology.
    Arthritis care & research. 07/2014;
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    ABSTRACT: The usual interstitial pneumonia pattern of lung injury (UIP) may occur in the setting of connective tissue disease (CTD), but it is most commonly found in the absence of a known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF). To observe and compare longitudinal changes in pulmonary function and survival between patients with biopsy-proven UIP found in the clinical context of either CTD or IPF. We used longitudinal data analytic models to compare groups (IPF N=321 and CTD-UIP N=56) on percent predicted forced vital capacity (FVC%) or diffusing capacity (DLCO%), and we used both unadjusted and multivariable techniques to compare survival between these groups. There were no significant differences between groups in longitudinal changes in FVC% or DLCO% up to diagnosis, or from diagnosis to ten years beyond (over which time, the mean decrease in FVC% per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP, p=0.49 for difference; and the mean decrease in DLCO% per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP, p=0.60 for difference). Despite the lack of differences in pulmonary function, subjects with IPF had worse survival in unadjusted (log rank p=0.003) and certain multivariable analyses. Despite no significant differences in changes in pulmonary function over time, patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients with IPF-an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF.
    Chest 04/2014; · 7.13 Impact Factor
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    ABSTRACT: Background and Objective Cystatin C (CysC), a novel marker of renal function, predicts left heart failure and cardiovascular mortality. The hypothesis that serum CysC levels correlate with right ventricular (RV) morphology, function and pressure in pulmonary arterial hypertension (PAH) was tested.Methods As part of a prospective study, 14 PAH subjects and 10 matched controls underwent same-day echocardiography, cardiac magnetic resonance imaging (CMR), and phlebotomy for CysC, brain natriuretic peptide (BNP), and N-terminal BNP (NT-ProBNP). RV ejection fraction (RVEF), end-diastolic volume, end-systolic volume and mass were calculated using CMR. RV systolic pressure (RVSP), strain and diastolic function (including tricuspid valve (TV) E velocity, A velocity, e′ velocity, E/A ratio and E/e′ ratio) were assessed using echocardiography.ResultsRVSP was significantly elevated in PAH subjects versus controls (57 ± 17 vs. 28 ± 8 mm Hg, P < 0.0001). CysC was abnormally elevated in the PAH cohort when compared with controls (1.00 ± 0.23 vs 0.78 ± 0.05 mg/L, P = 0.001). CysC positively correlated with RVSP (rho 0.61, P = 0.002), RV end-diastolic volume (rho 0.50, P = 0.01), RV end-systolic volume (rho 0.58, P = 0.003), mass index (rho 0.66, P = 0.0004), strain (rho 0.51, P = 0.01) and strain rate (rho 0.51, P = 0.01) and negatively correlated with RVEF (rho −0.58, P = 0.003) and TV e′ (rho −0.75, P < 0.0001). The same correlations with BNP and NT-ProBNP were comparable with CysC.Conclusions In a small cohort, CysC accurately correlates with RV pressure, function and morphology. CysC may represent a novel PAH biomarker.
    Respirology 04/2014; · 2.78 Impact Factor
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    ABSTRACT: Present guidelines for the diagnosis of idiopathic pulmonary fibrosis require histological confirmation of surgical lung biopsy samples when high-resolution CT images are not definitive for usual interstitial pneumonia. We aimed to assess the predictive value of high-resolution CT in a cohort of patients with suspected idiopathic pulmonary fibrosis from a previous randomised trial. ARTEMIS-IPF was a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial of ambrisentan for adults aged 40-80 years with well-defined idiopathic pulmonary fibrosis and 5% or less honeycombing on high-resolution CT. In December, 2010, an interim analysis showed lack of efficacy and the trial was stopped. In the present follow-on analysis, we assessed patients who were screened for ARTEMIS-IPF who underwent high-resolution CT as part of screening and surgical lung biopsy as part of standard clinical care. A radiologist and a pathologist from a central panel independently assessed anonymised CT scans and biopsy samples. We calculated the positive and negative predictive value of high-resolution CT (classified as usual interstitial pneumonia, possible usual interstitial pneumonia, and inconsistent with usual interstitial pneumonia) for confirmation of histological patterns of usual interstitial pneumonia. This study is registered with ClinicalTrials.gov, number NCT00768300. 315 (29%) of 1087 consecutively screened patients in ARTEMIS-IPF had both high-resolution CT and surgical lung biopsy samples. 108 of 111 patients who met high-resolution CT criteria for usual interstitial pneumonia had histologically confirmed usual interstitial pneumonia (positive predictive value 97·3%, 95% CI 92·3-99·4), as did 79 of 84 patients who met high-resolution CT criteria for possible usual interstitial pneumonia (94·0%, 86·7-98·0). 22 of 120 patients had an inconsistent high-resolution CT pattern for usual interstitial pneumonia that was histologically confirmed as not or possible usual interstitial pneumonia (negative predictive value 18·3%, 95% CI 11·9-26·4). In the appropriate clinical setting, for patients with possible usual interstitial pneumonia pattern on high resolution CT, surgical lung biopsy sampling might not be necessary to reach a diagnosis of idiopathic pulmonary fibrosis if high-resolution CT scans are assessed by experts at regional sites familiar with patterns of usual interstitial pneumonia and management of idiopathic interstitial pneumonia. Gilead Sciences.
    The lancet. Respiratory medicine. 04/2014; 2(4):277-84.
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    ABSTRACT: Rheumatoid arthritis (RA) is a systemic inflammatory disorder affecting approximately 1.3 million adults in the United States. Approximately 10% of these individuals with RA have clinically evident interstitial lung disease (RA-ILD), and an additional one-third demonstrate subclinical ILD on chest CT scan. The risk of death for individuals with RA-ILD is three times higher than for patients with RA without ILD, with a median survival after ILD diagnosis of only 2.6 years. Despite the high prevalence and mortality of RA-ILD, little is known about its molecular features and its natural history. At present, we lack a standard validated approach to the definition, diagnosis, risk stratification, and management of RA-ILD. In this perspective, we discuss the importance of clinical and translational research and how ongoing research efforts can address important gaps in our knowledge over the next few years. Furthermore, recommendations are made to design multicenter collaborative studies that will expedite the development of clinical trials designed to decrease the significant morbidity and mortality associated with RA-ILD.
    Chest 03/2014; 145(3):454-63. · 7.13 Impact Factor
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    ABSTRACT: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.
    Thorax 12/2013; · 8.38 Impact Factor
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    ABSTRACT: PURPOSE Recent international guidelines support 3 classes of UIP diagnosis on CT: Definite UIP, possible UIP, and inconsistent with UIP; the probable UIP class is not included in this diagnostic scheme. The purpose of this study was to evaluate the importance of the probable UIP imaging classification, using histological correlation. METHOD AND MATERIALS HRCT scans from 1,764 subjects in a large multicenter database of subjects with known or suspected interstitial lung disease were scored by two thoracic radiologists. CT findings and UIP diagnosis with level of confidence (not UIP, possible, probable, definite) were recorded. Definite UIP was defined as peripheral predominant, basal predominant reticular abnormality with honeycombing. Probable UIP was defined as peripheral predominant, basal predominant reticular abnormality without honeycombing. Possible UIP was defined as reticular abnormality with features not sufficiently characteristic to reach definite or probable levels. 258 subjects had histological scoring. Histological findings and UIP diagnosis with level of confidence were recorded by two pulmonary pathologists. Two-tailed Fisher exact test was used to compare proportions of histological scores for each UIP category. RESULTS In those with probable UIP on CT, UIP was histologically scored as definite, possible/probable, and not considered in 48.8% (20/41), 41.5% (17/41), and 9.8% (4/41) of subjects, respectively, compared with 30.7% (23/75), 37.3% (28/75), and 32.0% (24/75) for those with possible UIP on CT (p= .0154). Corresponding histologic diagnoses for those with definite UIP on CT were 46.4% (13/28), 39.3% (11/28), and 14.3% (4/28) of subjects, respectively, very similar to the distribution of diagnoses in probable UIP (p=.883). The proportions of histological scores for probable UIP and not UIP on CT were significantly different (p<.001). CONCLUSION In those with probable UIP on CT, the distribution of histological diagnoses is significantly different from those with possible UIP, but very similar to those with definite UIP. CLINICAL RELEVANCE/APPLICATION Patients with a probable UIP diagnosis on CT should not be categorized as possible UIP.
    Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
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    ABSTRACT: The clinical outcome of idiopathic pulmonary fibrosis (IPF) is poor, with a 50% survival rate at 3 years. Furthermore, current treatments provide little amelioration of symptoms. Despite significant advances in understanding the clinical features and pathobiology of IPF, further advances have been hampered by a lack of suitable animal models of the disease. Interestingly, spontaneously occurring disorders with a similarity to IPF have been recognized in the dog, cat, horse, and donkey. These disorders share clinical and pathologic features with human IPF and are emerging diseases of veterinary importance. To improve awareness about these disorders in domestic animals and stimulate interactions between disciplines, and to facilitate the elucidation of mechanisms of fibrosing lung disorders using a comparative natural-occurrence disease model approach. A 1-day meeting joined physicians, veterinarians, pathologists, researchers, and advocacy experts to discuss information available in this area. A review of the literature was conducted, and an executive committee discussed the findings and prepared a summary statement during subsequent meetings. Results: Clinical, diagnostic, and treatment opportunities were identified, and common areas of interest where collaborative efforts could accelerate discovery regarding etiological factors, methods for early detection, determinants of disease progression, and novel therapies were defined. Comparing fibrosing lung disorders in humans and domestic animals will allow for a better understanding of the similarities and differences among species and may offer novel insights into the underlying mechanisms of spontaneously occurring fibrotic lung diseases.
    Annals of the American Thoracic Society. 12/2013; 10(6):S224-9.
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    ABSTRACT: The clinical course of IPF is characterized by progressive decline in lung function and eventual mortality. We sought to determine if future declines in pulmonary function and/or mortality can be predicted from prior trends in pulmonary function tests (PFT). 4431 PFTs and mortality were analyzed from 734 IPF subjects collected from 1981 to 2008. Kaplan-Meier method was used for mortality analyses. Mixed models were used to describe longitudinal pulmonary function dynamics since PFTs were observed at varying time points from baseline. During the first year of follow up 135 subjects (73%) had stable FVC while 50 subjects (37%) showed a decline in FVC. During months 12-24 (1-2 years after diagnosis) a stable FVC occurred with the same frequency among both subjects whose FVC had declined during year one and whose FVC had remained stable 84.0% and 80.7% respectively, p=0.59. Among subjects alive at the end of year 1, those with a stable FVC were more likely to be alive at the end of year 2 than those whose FVC declined: HR 0.91 [95%CI 0.87-0.94] and 0.71 [0.62-0.78] respectively. PFT decline predicts early mortality, but not future declines in physiology, regardless of time since diagnosis.
    Chest 11/2013; · 7.13 Impact Factor
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    ABSTRACT: The median survival of patients with idiopathic pulmonary fibrosis continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the National Heart, Lung and Blood Institute held a workshop aimed at coordinating research efforts and accelerating the development of idiopathic pulmonary fibrosis therapies. Basic, translational and clinical researchers gathered with representatives from the National Heart Lung and Blood Institute, patient advocacy groups, pharmaceutical companies and the Food and Drug Administration to review the current state of idiopathic pulmonary fibrosis research and identify priority areas, opportunities for collaborations and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: 1) biology of alveolar epithelial injury and aberrant repair, 2) role of extracellular matrix, 3) preclinical modeling, 4) the role of inflammation and immunity, 5) genetic, epigenetic and environmental determinants, 6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional and patient communities and the National Heart Lung and Blood Institute.
    American Journal of Respiratory and Critical Care Medicine 10/2013; · 11.04 Impact Factor
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    ABSTRACT: Background: In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical "gold standard" of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs. Purpose: The objective of this statement is to update the 2002 ATS/ERS classification of IIPs. Methods: An international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011. Results: Substantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis-interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia is recognized to be heterogeneous. Acute exacerbation of IIPs is now well defined. A substantial percentage of patients with IIP are difficult to classify, often due to mixed patterns of lung injury. A classification based on observed disease behavior is proposed for patients who are difficult to classify or for entities with heterogeneity in clinical course. A group of rare entities, including pleuroparenchymal fibroelastosis and rare histologic patterns, is introduced. The rapidly evolving field of molecular markers is reviewed with the intent of promoting additional investigations that may help in determining diagnosis, and potentially prognosis and treatment. Conclusions: This update is a supplement to the previous 2002 IIP classification document. It outlines advances in the past decade and potential areas for future investigation.
    American Journal of Respiratory and Critical Care Medicine 09/2013; 188(6):733-48. · 11.04 Impact Factor
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    ABSTRACT: VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99-3·36] vs 0·84 ng/mL [0·52-1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99-2·86] vs 1·00 ng/mL [0·61-2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk-benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials.
    The lancet. Respiratory medicine. 08/2013; 1(6):445-452.
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    ABSTRACT: The cornerstone of hypersensitivity pneumonitis (HP) management is having patients avoid the inciting antigen (IA). Often, despite an exhaustive search, an IA cannot be found. to examine whether identifying the IA impacts survival in patients with chronic HP. We used the Kaplan-Meier method to display, and the log-rank test to compare, survival curves of patients with well-characterized chronic HP stratified on identification of an IA exposure. A Cox proportional hazards (PH) model was used to identify independent predictors in time-to-death analysis. Of 142 patients, 67 (47%) had an identified IA, and 75 (53%) had an unidentified IA. Compared with survivors, patients who died (n=80, 56%) were older, more likely to have smoked, had lower TLC percent predicted (%) and FVC%, had higher severity of dyspnea, were more likely to have pulmonary fibrosis, and were less likely to have an identifiable IA. In a Cox PH model, the inability to identify an IA (hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.01-3.07), older age (HR 1.04; 95% CI 1.01-1.07), the presences of pulmonary fibrosis (HR 2.43; 95% CI, 1.36-4.35), a lower FVC% (HR 1.36; 95% CI, 1.10-1.68) and a history of smoking (HR 2.01; 95%C1, 1.15-3.50) were independent predictors of shorter survival. After adjusting for mean age, presence of fibrosis, mean FVC%, mean DLco% and history of smoking, survival was longer for patients with an identified IA exposure than those with an unidentified IA exposure (median 8.75 vs. 4.88 years, p=0.047). Among patients with chronic HP, when adjusting for a number of potentially influential predictors including the presence of fibrosis, the inability to identify an IA was independently associated with shortened survival.
    Chest 07/2013; · 7.13 Impact Factor
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    ABSTRACT: Background VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. Methods In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. Findings We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99—3·36] vs 0·84 ng/mL [0·52—1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99—2·86] vs 1·00 ng/mL [0·61—2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). Interpretation Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk—benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials. Funding National Institutes of Health, US Department of Defense.
    Lancet Respiratory Medicine. 06/2013;
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    ABSTRACT: BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disease with a median survival of only 3-5 years that is diagnosed using a combination of clinical, radiographic and pathologic criteria. Histologically, IPF is characterised by usual interstitial pneumonia (UIP), a fibrosing interstitial pneumonia with a pattern of heterogeneous, subpleural regions of fibrotic and remodelled lung. We hypothesised that gene expression profiles of lung tissue may identify molecular subtypes of disease that could classify subtypes of IPF/UIP that have clinical implications. METHODS AND FINDINGS: We collected transcriptional profiles on lung tissue from 119 patients with IPF/UIP and 50 non-diseased controls. Differential expression of individual transcripts was identified using an analysis of covariance (ANCOVA) model incorporating the clinical diagnosis of each patient as well as age, gender and smoking status. Validation was performed in an independent cohort of 111 IPF/UIP and 39 non-diseased controls. Our analysis identified two subtypes of IPF/UIP based on a strong molecular signature associated with expression of genes previously associated with fibrosis (matrix metalloproteinases, osteopontin, keratins), cilium genes and genes with unknown function. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing and higher expression of both the airway mucin gene MUC5B and the metalloproteinase MMP7, a gene recently implicated in attenuating ciliated cell differentiation during wound repair. CONCLUSIONS: Expression of cilium genes appears to identify two unique molecular phenotypes of IPF/UIP. The different molecular profiles may be relevant to therapeutic responsiveness in patients with IPF/UIP.
    Thorax 06/2013; · 8.38 Impact Factor

Publication Stats

6k Citations
1,114.36 Total Impact Points

Institutions

  • 2002–2014
    • University of Colorado
      • • Department of Medicine
      • • Division of Pulmonary Sciences and Critical Care Medicine
      • • Department of Radiology
      Denver, Colorado, United States
  • 2013
    • Imperial College London
      Londinium, England, United Kingdom
  • 2006–2013
    • National Jewish Health
      • • Division of Radiology
      • • Department of Pediatrics
      Denver, Colorado, United States
    • Duke University
      Durham, North Carolina, United States
  • 2004–2012
    • University of Washington Seattle
      • Division of Pulmonary and Critical Care Medicine
      Seattle, WA, United States
    • National Institutes of Health
      • Group of Lung and Upper Aerodigestive Cancer Research
      Bethesda, MD, United States
  • 2002–2012
    • Duke University Medical Center
      • • Division of Pulmonary, Allergy, and Critical Care Medicine
      • • Department of Medicine
      Durham, North Carolina, United States
  • 2009
    • National Heart, Lung, and Blood Institute
      Maryland, United States
    • National Research Center (CO, USA)
      Boulder, Colorado, United States
  • 2008–2009
    • University of Cincinnati
      • Division of Pulmonary, Critical Care & Sleep Medicine
      Cincinnati, OH, United States
  • 2007–2008
    • National Institute of Environmental Health Sciences
      • Laboratory of Respiratory Biology (LRB)
      Durham, North Carolina, United States
  • 2005–2008
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, CA, United States
    • University of Michigan
      Ann Arbor, Michigan, United States
    • University of Alberta
      • Department of Radiology and Diagnostic Imaging
      Edmonton, Alberta, Canada
  • 2003
    • University of Vermont
      • Department of Medicine
      Burlington, VT, United States
  • 2000
    • Texas Tech University Health Sciences Center
      • Department of Medicine
      Lubbock, TX, United States