The purpose of this study was to train and validate machine learning models for predicting rapid decline of forced expiratory volume in 1 s (FEV
) in individuals with a smoking history at-risk-for ...chronic obstructive pulmonary disease (COPD), Global Initiative for Chronic Obstructive Lung Disease (GOLD 0), or with mild-to-moderate (GOLD 1-2) COPD. We trained multiple models to predict rapid FEV
decline using demographic, clinical and radiologic biomarker data. Training and internal validation data were obtained from the COPDGene study and prediction models were validated against the SPIROMICS cohort.
We used GOLD 0-2 participants (
= 3,821) from COPDGene (60.0 ± 8.8 years, 49.9% male) for variable selection and model training. Accelerated lung function decline was defined as a mean drop in FEV
% predicted of > 1.5%/year at 5-year follow-up. We built logistic regression models predicting accelerated decline based on 22 chest CT imaging biomarker, pulmonary function, symptom, and demographic features. Models were validated using
= 885 SPIROMICS subjects (63.6 ± 8.6 years, 47.8% male).
The most important variables for predicting FEV
decline in GOLD 0 participants were bronchodilator responsiveness (BDR), post bronchodilator FEV
% predicted (FEV
.pp.post), and CT-derived expiratory lung volume; among GOLD 1 and 2 subjects, they were BDR, age, and PRM
. In the validation cohort, GOLD 0 and GOLD 1-2 full variable models had significant predictive performance with AUCs of 0.620 ± 0.081 (
= 0.041) and 0.640 ± 0.059 (
< 0.001). Subjects with higher model-derived risk scores had significantly greater odds of FEV
decline than those with lower scores.
Predicting FEV
decline in at-risk patients remains challenging but a combination of clinical, physiologic and imaging variables provided the best performance across two COPD cohorts.
Abstract
Approximately 30-40% of human gliomas exhibit mutations in the tumor suppressor gene PTEN resulting in deregulation of the phosphoinositide 3-kinase/Akt survival signaling pathway. In a ...significant number of GBMs tumor initiation is additionally driven by an oncogenic signal stemming from the gene locus amplification of the Platelet derived growth factor receptor (PDGFR), also leading to Akt and mammalian target of rapamycin (mTOR) activation. Phosphorylated, active Akt controls a plethora of cellular responses by regulating a large number of substrates, such as GSK-3, BAD, Forkhead transcription factors (FOXO), and MDM2. Elevated Akt activity increases tumor cell growth, survival and impairs apoptosis. Thus blocking Akt phosphorylation to treat cancer in particular gliomas has therapeutic potential. Here we demonstrate the pre-clinical use of a bioluminescent molecular reporter to evaluate Akt kinase inhibition in real time in a genetically engineered PDGF-driven PTEN-deficient mouse model of GBM. Glial cell specific delivery of the bioluminescent reporter was achieved by RCAS-TVA technology. In brief, we utilized genetically engineered PTEN loxP/loxP,
Ink4a-Arf -/-, nestin-TVA transgenic animals and delivered the Akt reporter along with Cre recombinase and PDGF by intracranial implantation of chicken cells expressing avian virus containing the specific cargo. PTEN deletion in nestin positive cells resulted in increased Akt kinase phosphorylation as demonstrated by western blotting. Tumor growth was monitored by MRI and Bioluminescence imaging (BLI) technology. The design of the previously described Akt reporter allows for detectable bioluminescence only in the absence of Akt kinase activity due to the reconstitution of the wt luciferase enzyme. To evaluate the therapeutic potential of PI3-kinase- and Akt inhibitors in this pre-clinical GBM model, tumors were treated with either perifosine or API-2. Increased bioluminescence activity was observed in gliomas in a time- and dose-dependent manner with both inhibitors. These findings demonstrate that the Akt reporter provided a quantitative surrogate for Akt activity in PTEN-deficient gliomas. In conclusion we have provided a novel approach of pairing molecular imaging with a murine GBM model to investigate targeted agents. This may aid the future identification of most efficacious drug combinations impinging on PI3-kinase/Akt signaling in gliomas.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5304. doi:10.1158/1538-7445.AM2011-5304
Whether CC16 plays a direct role in lung health or it represents an early indicator of alterations in airway epithelial cell functions, understanding the trajectories of serum CC16 from childhood ...into adult life and the early factors that control such trajectories is a critical initial step to evaluate the possible use of this protein in risk stratification and/or early prevention of lung disease. Apart from rs3741240, no other factor was associated with CC16 levels at birth. ...we limited the final multivariable random effects models to postnatal CC16 levels between ages 6 and 32 years. ...this tracking explained a minority of the variability in serum CC16. ...other factors related to environmental exposures, developmental processes, and/or lung diseases are likely to also play a role in controlling serum CC16 levels. ...in the largest prospective study on serum CC16 to date, we have observed significant intrasubject tracking from birth up to age 32 years and identified a set of genetic, host, and parental factors that are associated with CC16 trajectories.
Studies have shown that COPD and smoking are associated with increased suicide risk. To date, there are no prospective studies examining suicide risk among individuals with smoking exposure along a ...spectrum of pulmonary diseases ranging from normal spirometry to severe COPD.
Which clinical variables predict death by suicide or overdose of indeterminate intent in a large cohort of individuals with smoking exposure within the Genetic Epidemiology of COPD (COPDGene) study?
We studied data from 9,930 participants involved in COPDGene, a multisite, prospective cohort study of individuals with smoking exposure. Primary cause of adjudicated deaths was identified by using death certificates, family reports, and medical records. Time to death by suicide/overdose was examined as the primary outcome in Cox regression models including age, sex, race, BMI, pack-years, current smoking status, airflow limitation (FEV1 % predicted), dyspnea (modified Medical Research Council scale score ≥ 2), 6-min walk distance, supplemental oxygen use, and severe exacerbations in the prior year with time-varying covariates and other causes of death as a competing risk.
The cohort was 47% female and 33% Black (67% White); they had a mean ± SD age of 59.6 ± 9.0 years and a mean FEV1 % predicted of 76.1 ± 25.5. Sixty-three individuals died by suicide/overdose. Factors associated with risk of suicide/overdose were current smoking (hazard ratio HR, 6.44; 95% CI, 2.64-15.67), use of sedative/hypnotics (HR, 2.33; 95% CI, 1.24-4.38), and dyspnea (HR, 2.23; 95% CI, 1.34-3.70). Lower risk was associated with older age (per-decade HR, 0.45; 95% CI, 0.31-0.67), higher BMI (HR, 0.95; 95% CI, 0.91-0.99), and African-American race (HR, 0.41; 95% CI, 0.23-0.74). Severity of airflow limitation (FEV % predicted) was not associated with suicide risk.
In this well-characterized cohort of individuals with smoking exposure with and without COPD, risk factors for suicide/overdose were identified that emphasize the subjective experience of illness over objective assessments of lung function.
The purpose of this study was to anatomically correlate ventilation defects with regions of air trapping by whole lung, lung lobe, and airway segment in the context of airway mucus plugging in ...asthma.
A total of 34 asthmatics 13M:21F, 13 mild/moderate, median age (range) of 49.5 (36.8-53.3) years and 21 severe, 56.1 (47.1-62.6) years and 4 healthy subjects 1M:3F, 38.5 (26.6-52.2) years underwent HP
He MRI and CT imaging. HP
He MRI was assessed for ventilation defects using a semi-automated k-means clustering algorithm. Inspiratory and expiratory CTs were analyzed using parametric response mapping (PRM) to quantify markers of emphysema and functional small airways disease (fSAD). Segmental and lobar lung masks were obtained from CT and registered to HP
He MRI in order to localize ventilation defect percent (VDP), at the lobar and segmental level, to regions of fSAD and mucus plugging. Spearman's correlation was utilized to compare biomarkers on a global and lobar level, and a multivariate analysis was conducted to predict segmental fSAD given segmental VDP (sVDP) and mucus score as variables in order to further understand the functional relationships between regional measures of obstruction.
On a global level, fSAD was correlated with whole lung VDP (
= 0.65,
< 0.001), mucus score (
= 0.55,
< 0.01), and moderately correlated (-0.60
r
-0.56,
< 0.001) to percent predicted (%p) FEV1, FEF25-75 and FEV1/FVC, and more weakly correlated to FVC%p (-0.38
-0.35,
< 0.001) as expected from previous work. On a regional level, lobar VDP, mucus scores, and fSAD were also moderately correlated (r from 0.45-0.66,
< 0.01). For segmental colocalization, the model of best fit was a piecewise quadratic model, which suggests that sVDP may be increasing due to local airway obstruction that does not manifest as fSAD until more extensive disease is present. sVDP was more sensitive to the presence of a mucus plugs overall, but the prediction of fSAD using multivariate regression showed an interaction in the presence of a mucus plugs when sVDP was between 4% and 10% (
< 0.001).
This multi-modality study in asthma confirmed that areas of ventilation defects are spatially correlated with air trapping at the level of the airway segment and suggests VDP and fSAD are sensitive to specific sources of airway obstruction in asthma, including mucus plugs.
Abstract only
TPS5094
Background: MET overexpression predicts prostate cancer invasion and bone metastasis; inhibition of MET/VEGF pathways has synergistic activity in CRPC (Knudsen et al. Adv Cancer ...Res 2004; Aftab et al. Clin Transl Oncol 2011). Cabo is a small molecule that inhibits multiple receptor tyrosine kinases, including MET and VEGFR2. A phase II randomized discontinuation trial of Cabo showed clinical activity in CRPC, including reduction of soft tissue lesions, prolongation of progression-free survival (PFS), resolution of bone scans, and reductions in bone turnover markers, pain and narcotic use (Smith et al, JCO 2013). To further define the activity of Cabo in pts with CRPC and bone metastases, we launched a phase II trial to characterize the effects of Cabo on bone metabolism and tumor activity in prostate cancer bone lesions. We hypothesize that the clinical activity of Cabo correlates with measurable pharmacodynamic effects on bone micro-environment. Methods: After informed consent, chemotherapy-naive pts with progressive CRPC and bone metastases accessible to CT-guided biopsy, adequate performance status/organ function, are treated with Cabo 60 mg once daily. Primary endpoint: proportion of pts progression-free (PF) at 12 weeks. Secondary endpoints: safety, PFS, response proportion/duration, PSA response, PSA time-to-progression. A Simon's two-stage mini-max design permits early termination after the first 27 evaluable pts in case of unfavorable results. Alternatively, up to 46 evaluable pts will be accrued. Cabo would not be of interest if the 12-week PF proportion is <0.45; it would be of definite clinical interest if the 12-week PF proportion is >0.65 (5% type I error, 85% power). Perfusion/diffusion-weighted MRI (parametric response maps) and bone lesion biopsies are required at baseline and 6 weeks after starting Cabo. Doxycycline is administered prior to bone biopsy for bone labeling. Bone cores are sent for dynamic histomorphometry and immunohistochemistry (phospho-MET/MET, phospho-VEGFR2/VEGFR2, phospho-Akt/Akt). Serum is collected at several time-points to measure markers of bone metabolism. 13 of 27 first-stage pts have been enrolled and started Cabo. Clinical trial information: NCT01428219.
Cardiovascular disease (CVD) is the most important comorbidity in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations not only contribute to COPD progression but may also ...elevate the risk of CVD. This study aimed to determine whether COPD exacerbations increase the risk of subsequent CVD events using up to 15 years of prospective longitudinal follow-up data from the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study.
The COPDGene study is a large, multicenter, longitudinal investigation of COPD, including subjects at enrollment aged 45 to 80 years with a minimum of 10 pack-years of smoking history. Cox proportional hazards models and Kaplan-Meier survival curves were used to assess the risk of a composite end point of CVD based on the COPD exacerbation rate. Frequent exacerbators exhibited a higher cumulative incidence of composite CVD end points than infrequent exacerbators, irrespective of the presence of CVD at baseline. After adjusting for covariates, frequent exacerbators still maintained higher hazard ratios (HRs) than the infrequent exacerbator group (without CVD: HR, 1.81 95% CI, 1.47-2.22; with CVD: HR, 1.92 95% CI, 1.51-2.44). This observation remained consistently significant in moderate to severe COPD subjects and the preserved ratio impaired spirometry population. In the mild COPD population, frequent exacerbators showed a trend toward more CVD events.
COPD exacerbations are associated with an increased risk of subsequent cardiovascular events in subjects with and without preexisting CVD. Patients with COPD experiencing frequent exacerbations may necessitate careful monitoring and additional management for subsequent potential CVD.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT00608764.
Studies have shown that COPD and smoking are associated with increased suicide risk. To date, there are no prospective studies examining suicide risk among individuals with smoking exposure along a ...spectrum of pulmonary diseases ranging from normal spirometry to severe COPD.
Which clinical variables predict death by suicide or overdose of indeterminate intent in a large cohort of individuals with smoking exposure within the Genetic Epidemiology of COPD (COPDGene) study?
We studied data from 9,930 participants involved in COPDGene, a multisite, prospective cohort study of individuals with smoking exposure. Primary cause of adjudicated deaths was identified by using death certificates, family reports, and medical records. Time to death by suicide/overdose was examined as the primary outcome in Cox regression models including age, sex, race, BMI, pack-years, current smoking status, airflow limitation (FEV
% predicted), dyspnea (modified Medical Research Council scale score ≥ 2), 6-min walk distance, supplemental oxygen use, and severe exacerbations in the prior year with time-varying covariates and other causes of death as a competing risk.
The cohort was 47% female and 33% Black (67% White); they had a mean ± SD age of 59.6 ± 9.0 years and a mean FEV
% predicted of 76.1 ± 25.5. Sixty-three individuals died by suicide/overdose. Factors associated with risk of suicide/overdose were current smoking (hazard ratio HR, 6.44; 95% CI, 2.64-15.67), use of sedative/hypnotics (HR, 2.33; 95% CI, 1.24-4.38), and dyspnea (HR, 2.23; 95% CI, 1.34-3.70). Lower risk was associated with older age (per-decade HR, 0.45; 95% CI, 0.31-0.67), higher BMI (HR, 0.95; 95% CI, 0.91-0.99), and African-American race (HR, 0.41; 95% CI, 0.23-0.74). Severity of airflow limitation (FEV % predicted) was not associated with suicide risk.
In this well-characterized cohort of individuals with smoking exposure with and without COPD, risk factors for suicide/overdose were identified that emphasize the subjective experience of illness over objective assessments of lung function.
Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk ...population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry.
We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD.
Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated.
The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment.
Pulmonary endothelial damage has been shown to precede the development of emphysema in animals, and vascular changes in humans have been observed in COPD and emphysema.
Is intraparenchymal vascular ...pruning associated with longitudinal progression of emphysema on CT imaging or decline in lung function over 5 years?
The Genetic Epidemiology of COPD Study enrolled ever smokers with and without COPD from 2008 through 2011. The percentage of emphysema-like lung, or “percent emphysema,” was assessed at baseline and after 5 years on noncontrast CT imaging as the percentage of lung voxels < –950 Hounsfield units. An automated CT imaging-based tool assessed and classified intrapulmonary arteries and veins. Spirometry measures are postbronchodilator. Pulmonary arterial pruning was defined as a lower ratio of small artery volume (< 5 mm2 cross-sectional area) to total lung artery volume. Mixed linear models included demographics, anthropomorphics, smoking, and COPD, with emphysema models also adjusting for CT imaging scanner and lung function models adjusting for clinical center and baseline percent emphysema.
At baseline, the 4,227 participants were 60 ± 9 years of age, 50% were women, 28% were Black, 47% were current smokers, and 41% had COPD. Median percent emphysema was 2.1 (interquartile range, 0.6-6.3) and progressed 0.24 percentage points/y (95% CI, 0.22-0.26 percentage points/y) over 5.6 years. Mean FEV1 to FVC ratio was 68.5 ± 14.2% and declined 0.26%/y (95% CI, –0.30 to –0.23%/y). Greater pulmonary arterial pruning was associated with more rapid progression of percent emphysema (0.11 percentage points/y per 1-SD increase in arterial pruning; 95% CI, 0.09-0.16 percentage points/y), including after adjusting for baseline percent emphysema and FEV1. Arterial pruning also was associated with a faster decline in FEV1 to FVC ratio (–0.04%/y per 1-SD increase in arterial pruning; 95% CI, –0.008 to –0.001%/y).
Pulmonary arterial pruning was associated with faster progression of percent emphysema and more rapid decline in FEV1 to FVC ratio over 5 years in ever smokers, suggesting that pulmonary vascular differences may be relevant in disease progression.
ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov
Display omitted
PDF
