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BACKGROUND: Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. PURPOSE: To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 ((3)He) MRI. MATERIALS AND METHODS: In this secondary analysis of a Health Insurance Portability and Accountability Act–compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized (3)He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. RESULTS: Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th–75th percentile, 7.3%–38.3%) versus 1.4% (25th–75th percentile, 0.1%–5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th–75th percentile, 7.1%–18.9%) versus 3.1% (25th–75th percentile, 1.1%–4.4%) in those without plugs (P < .001). CONCLUSION: Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

Hyperpolarized xenon 129 MRI and spectroscopy are sensitive to abnormal interstitial barrier uptake and red blood cell transfer in participants with nonspecific interstitial pneumonia.

BACKGROUND Hyperpolarized 129 Xe magnetic resonance imaging (MRI) provides a non-invasive assessment of regional pulmonary gas exchange function. This technique has demonstrated that chronic obstructive pulmonary disease (COPD) patients exhibit ventilation defects, reduced interstitial barrier tissue uptake, and poor transfer to capillary red blood cells (RBCs). However, the behavior of these measurements following therapeutic intervention is unknown. PURPOSE To characterize changes in 129 Xe gas transfer function following administration of an inhaled long-acting beta-agonist/long-acting muscarinic receptor antagonist (LABA/LAMA) bronchodilator. STUDY TYPE Prospective. POPULATION Seventeen COPD subjects (GOLD II/III classification per Global Initiative for Chronic Obstructive Lung Disease criteria) were imaged before and after 2 weeks of LABA/LAMA therapy. FIELD STRENGTH/SEQUENCES Dedicated ventilation imaging used a multi-slice 2D gradient echo sequence. Three-dimensional images of ventilation, barrier uptake, and RBC transfer used an interleaved, radial, 1-point Dixon sequence. Imaging was acquired at 3 T. ASSESSMENT 129 Xe measurements were quantified before and after LABA/LAMA treatment by ventilation defect + low percent (vendef + low ) and by barrier uptake and RBC transfer relative to a healthy reference population (bar%ref and RBC%ref ). Pulmonary function tests, including diffusing capacity of the lung for carbon monoxide (DLCO ), were also performed before and after treatment. STATISTICAL TESTS Paired t-test, Pearson correlation coefficient (r). RESULTS Baseline vendef + low was 57.8 ± 8.4%, bar%ref was 73.2 ± 19.6%, and RBC%ref was 36.5 ± 13.6%. Following treatment, vendef + low decreased to 52.5 ± 10.6% (P

The magnitude and regional heterogeneity of airway obstructions in severe asthmatics is likely linked to insufficient drug delivery, as evidenced by the inability to mitigate exacerbations with inhaled aerosol medications. To understand the correlation between morphometric features, airflow distribution, and inhaled dosimetry, we perform dynamic computational simulations in two healthy and four asthmatic subjects. Models incorporate computed tomography-based and patient-specific central airway geometries and hyperpolarized 3He MRI-measured segmental ventilation defect percentages (SVDPs), implemented as resistance boundary conditions. Particles [diameters ( dp) = 1, 3, and 5 μm] are simulated throughout inhalation, and we record their initial conditions, both spatially and temporally, with their fate in the lung. Predictions highlight that total central airway deposition is the same between the healthy subjects (26.6%, dp = 3 μm) but variable among the asthmatic subjects (ranging from 5.9% to 59.3%, dp = 3 μm). We found that by preferentially releasing the particles during times of fast or slow inhalation rates we enhance either central airway deposition percentages or peripheral particle delivery, respectively. These predictions highlight the potential to identify with simulations patients who may not receive adequate therapeutic dosages with inhaled aerosol medication and therefore identify patients who may benefit from alternative treatment strategies. Furthermore, by improving regional dose levels, we may be able to preferentially deliver drugs to the airways in need, reducing associated adverse side effects. NEW & NOTEWORTHY Although it is evident that exacerbation mitigation is unsuccessful in some asthmatics, it remains unclear whether or not these patients receive adequate dosages of inhaled therapeutics. By coupling MRI and computed tomography data with patient-specific computational models, our predictions highlight the large intersubject variability, specifically in severe asthma.

Background Recent studies demonstrate that antifibrotic drugs previously reserved for idiopathic pulmonary fibrosis (IPF) may slow progression in other interstitial lung diseases (ILDs), creating an urgent need for tools that can sensitively assess disease activity, progression, and therapy response across ILDs. Hyperpolarized xenon 129 (

BACKGROUND. Hyperpolarized (129)Xe MRI provides a non-invasive assessment of regional pulmonary gas exchange function. This technique has demonstrated that chronic obstructive pulmonary disease (COPD) patients exhibit ventilation defects, reduced interstitial barrier tissue uptake, and poor transfer to capillary red blood cells (RBCs). However, the behavior of these measurements following therapeutic intervention is unknown. PURPOSE. To characterize changes in (129)Xe gas transfer function following administration of an inhaled long-acting beta-agonist/long-acting muscarinic receptor antagonist (LABA/LAMA) bronchodilator. STUDY TYPE. Prospective. POPULATION. 17 COPD subjects (GOLD ll/lll classification per Global Initiative for Chronic Obstructive Lung Disease criteria) were imaged before and after 2 weeks of LABA/LAMA therapy. FIELD STRENGTH/SEQUENCES. Dedicated ventilation imaging used a multi-slice 2D gradient echo sequence. 3D images of ventilation, barrier uptake and RBC transfer used an interleaved, radial, 1-point Dixon sequence. Imaging was acquired at 3T. ASSESSMENT. (129)Xe measurements were quantified before and after LABA/LAMA treatment by ventilation defect+low percent (ven(def+low)) and by barrier uptake and RBC transfer relative to a healthy reference population (bar(%ref) and RBC(%ref)). Pulmonary function tests, including diffusing capacity of the lung for carbon monoxide (DL(co)), were also performed before and after treatment. STATISTICAL TESTS: Paired t-test, Pearson correlation coefficient (r). RESULTS. Baseline ven(def+low) was 57.8±8.4%, bar(%ref) was 73.2%±19.6%, and RBC(%ref) was 36.5%±13.6%. Following treatment, ven(def+low) decreased to 52.5±10.6% (p

Hyperpolarized (129)Xe MRI has emerged as a novel means to evaluate pulmonary function via 3D mapping of ventilation, interstitial barrier uptake, and RBC transfer. However, the physiological interpretation of these measurements has yet to be firmly established. Here, we propose a model that uses the three components of (129)Xe gas-exchange MRI to estimate accessible alveolar volume (V(A)), membrane conductance, and capillary blood volume contributions to DL(CO). (129)Xe ventilated volume (VV) was related to V(A) by a scaling factor k(V) = 1.47 with 95% confidence interval [1.42, 1.52], relative (129)Xe barrier uptake (normalized by the healthy reference value) was used to estimate the membrane-specific conductance coefficient k(B) = 10.6 [8.6, 13.6] mL/min/mmHg/L, whereas normalized RBC transfer was used to calculate the capillary blood volume-specific conductance coefficient k(R) = 13.6 [11.4, 16.7] mL/min/mmHg/L. In this way, the barrier and RBC transfer per unit volume determined the transfer coefficient K(CO), which was then multiplied by image-estimated V(A) to obtain DL(CO). The model was built on a cohort of 41 healthy subjects and 101 patients with pulmonary disorders. The resulting (129)Xe-derived DL(CO) correlated strongly (R(2) = 0.75, P < 0.001) with the measured values, a finding that was preserved within each individual disease cohort. The ability to use (129)Xe MRI measures of ventilation, barrier uptake, and RBC transfer to estimate each of the underlying constituents of DL(CO) clarifies the interpretation of these images while enabling their use to monitor these aspects of gas exchange independently and regionally. NEW & NOTEWORTHY The diffusing capacity for carbon monoxide (DL(CO)) is perhaps one of the most comprehensive physiological measures used in pulmonary medicine. Here, we spatially resolve and estimate its key components—accessible alveolar volume, membrane, and capillary blood volume conductances—using hyperpolarized (129)Xe MRI of ventilation, interstitial barrier uptake, and red blood cell transfer. This image-derived DL(CO) correlates strongly with measured values in 142 subjects with a broad range of pulmonary disorders.

PURPOSE: The MR properties (chemical shifts and R(2)* decay rates) of dissolved-phase hyperpolarized (HP) (129)Xe are confounded by the large magnetic field inhomogeneity present in the lung. This work improves measurements of these properties using a model-based image reconstruction to characterize the R(2)* decay rates of dissolved-phase HP (129)Xe in healthy subjects and patients with idiopathic pulmonary fibrosis (IPF). METHODS: Whole lung MRS and 3D radial MRI with four gradient echoes were performed after inhalation of HP (129)Xe in healthy subjects and patients with IPF. A model-based image reconstruction formulated as a regularized optimization problem was solved iteratively to measure regional signal intensity in the gas, barrier, and red blood cell (RBC) compartments, while simultaneously measuring their chemical shifts and R(2)* decay rates. RESULTS: The estimation of spectral properties reduced artifacts in images of HP (129)Xe in the gas, barrier, and RBC compartments and improved image SNR by over 20%. R(2)* decay rates of the RBC and barrier compartments were lower in patients with IPF compared to healthy subjects (P < 0.001 and P=0.005, respectively) and correlated to DL(CO) (R=0.71 and 0.64, respectively). Chemical shift of the RBC component measured with whole lung spectroscopy was significantly different between IPF and normal subjects (P = 0.022). CONCLUSION: Estimates for R(2)* in both barrier and RBC dissolved-phase HP (129)Xe compartments using a regional signal model improved image quality for dissolved phase images and provided additional biomarkers of lung injury in IPF.

Rationale and Objectives To determine lobar ventilation patterns in asthmatic lungs with hyperpolarized 3He magnetic resonance imaging (HP 3He MRI). Materials and Methods Eighty-two subjects (14 normal, 48 mild-to-moderate asthma, and 20 severe asthma) underwent HP 3He MRI, computed tomography (CT), and pulmonary function testing. After registering proton to 3He images, we segmented the lungs from proton MRI and further segmented the five lung lobes (right upper lobe [RUL], right middle lobe [RML], and right lower lobe [RLL]; left upper lobe and left lower lobe [LLL]) by referring to the lobar segmentation from CT. We classified the gas volume into four signal intensity levels as follows: ventilation defect percent (VDP), low ventilation percent, medium ventilation percent, and high ventilation percent. The local signal intensity variations in the ventilated volume were estimated using heterogeneity score (Hs). We compared each ventilation level and Hs measured in the whole lung and lobar regions across the three subject groups. Results In mild-to-moderate asthma, the RML and RUL showed significantly greater VDP than the two lower lobes (RLL and LLL) (P ≤ .047). In severe asthma, the pattern was more variable with the VDP in the RUL significantly greater than in the RLL (P = .026). In both asthma groups, the lower lobes (RLL and LLL) showed significantly higher high ventilation percent and Hs compared to the three upper lobes (all P ≤ .015). Conclusions In asthma, the RML and RUL showed greater ventilation abnormalities, and the RLL and LLL were more highly ventilated with greater local heterogeneity. These findings may facilitate guided bronchoscopic sampling and localized airway treatment in future studies.

Background There is an unmet need for an objective biomarker to predict asthma exacerbations. Objective Our aim was to assess the ventilation defect percent (VDP) on hyperpolarized helium-3 magnetic resonance imaging as a predictor of exacerbation frequency following imaging. Methods Subjects underwent hyperpolarized helium-3 and conventional clinical measurements, including pulmonary function tests, during a period of disease stability, and exacerbations were recorded prospectively over the following 2 years. We used a Poisson regression tree model to estimate an optimal VDP threshold for classifying subjects into high- versus low-exacerbation groups and then used statistical regression to compare this VDP threshold against conventional clinical measures as predictors of exacerbations. Results A total of 67 individuals with asthma (27 males and 40 females, 28 with mild-to-moderate asthma and 39 with severe asthma) had a median VDP of 3.75% (1.2% [first quartile]-7.9% [third quartile]). An optimal VDP threshold of 4.28% was selected on the basis of the maximum likelihood estimation of the regression tree model. Subjects with a VDP greater than 4.28% (n = 32) had a median of 1.5 exacerbations versus 0.0 for subjects with a VDP less than 4.28% (n = 35). In a stepwise multivariate regression model, a VDP greater than 4.28% was associated with an exacerbation incidence rate ratio of 2.5 (95% CI = 1.3-4.7) versus a VDP less than or equal to 4.28%. However, once individual medical history was included in the model, VDP was no longer significant. Nonetheless, VDP may provide an objective and complementary quantitative marker of individual exacerbation risk that is useful for monitoring individual change in disease status, selecting patients for therapy, and assessing treatment response. Conclusion VDP measured with magnetic resonance imaging shows promise as a biomarker of prospective asthma exacerbations.

Rationale and Objectives This study aimed to compare the performance of a semiautomated ventilation defect segmentation approach, adaptive K -means, with manual segmentation of hyperpolarized helium-3 magnetic resonance imaging in subjects with exercise-induced bronchoconstriction (EIB). Materials and Methods Six subjects with EIB underwent hyperpolarized helium-3 magnetic resonance imaging and spirometry tests at baseline, post exercise, and recovery over two separate visits. Ventilation defects were analyzed by two methods. First, two independent readers manually segmented ventilation defects. Second, defects were quantified by an adaptive K -means method that corrected for coil sensitivity, applied a vesselness filter to estimate pulmonary vasculature, and segmented defects adaptively based on the overall low-intensity signals in the lungs. These two methods were then compared in four aspects: (1) ventilation defect percent (VDP) measurements, (2) correlation between spirometric measures and measured VDP, (3) regional VDP variations pre- and post exercise challenge, and (4) Dice coefficient for spatial agreement. Results The adaptive K -means method was ~5 times faster, and the measured VDP bias was under 2%. The correlation between predicted forced expiratory volume in 1 second over forced vital capacity and VDP measured by adaptive K -means ( ρ = −0.64, P 0.0001) and by the manual method ( ρ = −0.63, P 0.0001) yielded almost identical 95% confidence intervals. Neither method of measuring VDP indicated apical/basal or anterior dependence in this small study cohort. Conclusions Compared to the manual method, the adaptive K -means method provided faster, reproducible, comparable measures of VDP in EIB and may be applied to a variety of lung diseases.

Combined, medical imaging data and respiratory computer simulations may facilitate novel insight into pulmonary disease phenotypes, including the structure/function relationships within the airways. This integration may ultimately enable improved classification and treatment of asthma. Severe asthma (15% of asthmatics) is particularly challenging to treat, as these patients do not respond well to inhaled therapeutics. Methods: This study combines medical image data with patient-specific computational models to predict gas distributions and airway mechanics in healthy and asthmatic subjects. We achieve this by integrating segmental volume defect percent (SVDP), measured from hyperpolarized 3 He MRI and computed tomography images, to create models of patient-specific gas flow within the conducting airways. Predicted and measured SVDP distributions are achieved when the prescribed resistances are increased systematically. Results: Because of differences in airway morphology and regional function, airway resistances and flow structures varied between the asthmatic subjects. Specifically, while mean SVDP was similar between the severe asthmatics (4.30 ± 5.22 versus 3.54 ± 5.98%), one subject exhibited abnormal flow structures, high near wall flow gradients, and enhanced conducting airway resistances (17.3E-3 versus 1.1E-3 cmH 2 O-s/mL) in comparison to the other severe asthmatic subject. Conclusion: By coupling medical imaging data with computer simulations, we provide detailed insight into pathological flow characteristics and airway mechanics in asthmatics, beyond what could be inferred independently.

In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into (1) a brief introduction, (2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, (3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, (4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study: (5) metabolic pathways in cancer and cardiac disease and (6) lung function in both pre-clinical and clinical research studies, concluding with (7) some future directions and challenges, and (8) an overall summary.

This chapter explores the application of magnetic resonance imaging (MRI) to the study of asthma with an emphasis on the role of hyperpolarized (HP) gases. Asthma affects millions of people worldwide and trends indicate increasing incidence particularly among children. In the first three sections of the chapter we focus on a general overview of asthma as a disease, characterize the obstructive physiology involved in asthma, and describe its clinical presentation. These sections include the rationale for imaging in asthma specifically as a useful tool to advance our understanding of the basic phenotypes of this disease and of its regional heterogeneity in the lungs. Subsequent sections are dedicated more specifically to the role of HP gas MRI for breath-held and dynamic imaging of airway obstruction in asthma and the physiologic meaning of the observed “ventilation defects.” Different approaches to the analysis and quantification of the observed ventilation defects in asthma are also briefly addressed. Specific clinical research applications of HP 3He MRI in the study of the spatial and temporal ventilation patterns in asthma phenotypes are described, including exercise-induced asthma, childhood asthma, and severe asthma. Images of ventilation are being used to explore mechanisms of airway closure and disease progression, and to target and evaluate regional disease and response to therapy. The use of diffusion-weighted MRI of HP gases to investigate lung microstructure in asthma is given a brief treatment, since the technique has shown promise in preliminary investigations of childhood asthma but is still in its early stages. The final sections are dedicated to emerging techniques as they apply to the study of asthma, especially the ongoing transition to HP 129Xe MRI with its added potential to study gas exchange. Finally, there is a brief discussion of what has been learned about asthma thus far, what remains to be studied, and the possible future role of HP gas MRI in this important area.

Introduction. The objective of this study was to investigate clinical effectiveness and incremental lifetime costs associated with first-line bevacizumab in older patients with metastatic colorectal cancer (mCRC). Methods. Patients diagnosed with mCRC in 2004–2007 were identified from the Surveillance, Epidemiology, and End Results-Medicare database and stratified by first-line treatment (no chemotherapy [CTx], CTx alone, CTx plus bevacizumab). The impact of first-line bevacizumab on survival was investigated using a propensity score adjusted multivariate Cox proportional hazards model. Mean lifetime costs for each cohort were calculated using Medicare claims for all services rendered between diagnosis and end of follow-up, adjusting for death and censoring. Results. A total of 4,414 patients (mean age: 77.3 years) were identified, of whom 15% received first-line bevacizumab. Among first-line-treated patients, bevacizumab receipt was associated with improved overall survival (hazard ratio: 0.85 [95% confidence interval: 0.75–0.97]; p = .013), and this benefit was limited to patients who received >1 month of bevacizumab therapy. Median and mean survival were greatest in patients treated with CTx plus bevacizumab relative to CTx alone (CTx plus bevacizumab median 19.4 months [mean 28.0 months] vs. CTx alone median 15.1 months [mean 22.9 months]; p < .001), as were mean lifetime costs (mean per patient cost $143,284 vs. $111,280). Compared with CTx alone, CTx plus bevacizumab was associated with a 5.1-month increase in mean survival and a $32,004 increase in mean lifetime treatment costs, with an incremental cost of $75,303 per life-year gained. Conclusion. Bevacizumab use is associated with longer survival than CTx alone in older patients treated in real-world clinical settings, at an incremental cost of $75,303 per life-year gained.

Little is known about how referrals to different cancer specialists influence cancer care for non-small-cell lung cancer (NSCLC). Among Medicare enrollees, we identified factors of patients and their primary care physician that were associated with referrals to cancer specialists, and how the types of cancer specialists seen correlated with delivery of guideline-based therapies (GBTs).Data from patients with stages III and IV NSCLC included in the SEER-Medicare database were linked to their physicians in the American Medical Association Masterfile database. Using logistic regression, we (1) identified patient and physician factors that were associated with referrals to cancer specialists (medical oncologists, radiation oncologists, and surgeons); (2) identified the types of referral to cancer specialists that predicted greater likelihood of receiving GBT (per National Comprehensive Cancer Network guidelines).A total of 28,977 patients with NSCLC diagnosed from January 1, 2000 to December 31, 2005 met eligibility criteria. Younger age, white race, higher income, and primary physician specialty other than family practice predicted higher likelihood of referrals to medical oncologists (P.01 for all predictors). Seeing the three types of cancer specialists predicted higher likelihood of GBT (stage IIIA: odds ratio [OR] = 20.6; P.001; IIIB: OR = 77.2; P.001; and IV: OR = 1.2; P = .011), compared with seeing a medical oncologist only. Use of GBTs increased over the study period (42% to 48% from 2000 to 2005; P.001).Referrals to all types of cancer specialists increased the likelihood of treatment with standard therapies, particularly in stage III patients. However, racial and income disparities still prevent optimal referrals to cancer specialists.

A recent randomized trial showed that low-dose CT (LDCT) screening reduces lung cancer mortality. Health care providers need an assessment of the national budget impact and cost-effectiveness of LDCT screening before this intervention is adopted in practice. Using data from the 2009 National Health Interview Survey, CMS, and the National Lung Screening Trial (NLST), the authors performed an economic analysis of LDCT screening that includes a budget impact model, an estimate of additional costs per lung cancer death avoided attributed to screening, and a literature search of cost-effectiveness analyses of LDCT screening. They conducted a one-way sensitivity analysis, reporting expenditures in 2011 U.S. dollars, and took the health care payer and patient perspectives. LDCT screening will add $1.3 to $2.0 billion in annual national health care expenditures for screening uptake rates of 50% to 75%, respectively. However, LDCT screening will avoid up to 8100 premature lung cancer deaths at a 75% screening rate. The prevalence of smokers who qualify for screening, screening uptake rates, and cost of LDCT scan were the most influential parameters on health care expenditures. The additional cost of screening to avoid one lung cancer death is $240,000. Previous cost-effectiveness analyses have not conclusively shown that LDCT is cost-effective. LDCT screening may add substantially to the national health care expenditures. Although LDCT screening can avoid more than 8000 lung cancer deaths per year, a cost-effectiveness analysis of the NLST will be critical to determine the value of this intervention and to guide decisions about its adoption.

Ventilation defect percent (VDP) measured in asthmatics with hyperpolarized helium-3 MRI was more strongly associated with ED visits and hospitalizations due to asthma exacerbation than were conventional biomarkers of lung function and inflammation.

Purpose Although American Society of Clinical Oncology guidelines discourage the use of tumor marker assessment for routine surveillance in nonmetastatic breast cancer, their use in practice is uncertain. Our objective was to determine use of tumor marker tests such as carcinoembryonic antigen and CA 15-3/CA 27.29 and associated Medicare costs in early-stage breast cancer survivors. Methods By using Surveillance, Epidemiology, and End Results-Medicare records for patients diagnosed with early-stage breast cancer between 2001 and 2007, tumor marker usage within 2 years after diagnosis was identified by billing codes. Logistic regression models were used to identify clinical and demographic factors associated with use of tumor markers. To determine impact on costs of care, we used multivariable regression, controlling for other factors known to influence total medical costs. Results We identified 39,650 eligible patients. Of these, 16,653 (42%) received at least one tumor marker assessment, averaging 5.7 tests over 2 years, with rates of use per person increasing over time. Factors significantly associated with use included age at diagnosis, diagnosis year, stage at diagnosis, race/ethnicity, geographic region, and urban/rural status. Rates of advanced imaging, but not biopsies, were significantly higher in the assessment group. Medical costs for patients who received at least one test were approximately 29% greater than costs for those who did not, adjusting for other factors. Conclusion Breast cancer tumor markers are frequently used among women with early-stage disease and are associated with an increase in both diagnostic procedures and total cost of care. A better understanding of factors driving the use of and the potential benefits and harms of surveillance-based tumor marker testing is needed.

Background: For uninsured American Indians and Alaskan Natives (AIAN) diagnosed with cancer, prompt enrollment in Medicaid may speed access to treatment and improve survival. We hypothesized that AIANs who were eligible for the Indian Health Service Care System (IHSCS) at cancer diagnosis may be enrolled in Medicaid sooner than other AIANs. Methods: Using Washington, Oregon, and California State Cancer Registries, we identified AIANs with a primary diagnosis of lung, breast, colorectal, cervical, ovarian, stomach, or prostate cancer between 2001 and 2007. Among AIANs enrolled in Medicaid within 365 days of a cancer diagnosis, we linked cancer registry records with Medicaid enrollment data and used a multivariate logistic regression model to compare the odds of delayed Medicaid enrollment between those with (n = 223) and without (n = 177) IHSCS eligibility. Results: Among AIANs who enrolled in Medicaid during the year following their cancer diagnosis, approximately 32% enrolled >1 month following diagnosis. Comparing those without IHSCS eligibility to those with IHSCS eligibility, the adjusted odds ratio (OR) for moderately late Medicaid enrollment (between 1 and 6 months after diagnosis) relative to early Medicaid enrollment (≤1 month after diagnosis) was 1.10 [95% confidence interval (CI), 0.62–1.95] and for very late Medicaid enrollment (>6 months to 12 months after diagnosis), OR was 1.14 (CI, 0.54–2.43). Conclusion: IHSCS eligibility at the time of diagnosis does not seem to facilitate early Medicaid enrollment. Impact: Because cancer survival rates in AIANs are among the lowest of any racial group, additional research is needed to identify factors that improve access to care in AIANs. Cancer Epidemiol Biomarkers Prev; 23(2); 362–4. ©2013 AACR.

Background The safety of bevacizumab in older mCRC patients is poorly understood. The purpose of this analysis was to determine the prevalence, incidence, and risk factors for treatment-related AEs in older bevacizumab recipients. Patients and Methods Patients age ≥65 were identified from SEER–Medicare and categorized by mCRC diagnosis pre and post bevacizumab approval (2001-2003 vs. 2005-2007). Preexisting conditions known to increase bevacizumab-related AE risk were identified in the year before diagnosis. Factors associated with bevacizumab receipt were identified using logistic regression. Incidence rates for all AEs and specific serious AEs were determined. Risk factors for first AE were determined by competing risks regression. Results Of 6821 patients, 3282 (48%) were diagnosed in 2005-2007 of whom 19% received first-line bevacizumab. Likelihood of bevacizumab receipt was lower in patients age ≥ 75 (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.36-0.47), nonwhite patients (OR, 0.67; 95% CI, 0.55-0.81), patients with higher comorbidity index (OR, 0.52; 95% CI, 0.43-0.62), and patients with preexisting cerebrovascular disease (OR, 0.49; 95% CI, 0.33-0.73). AE incidence rate was not increased among first-line bevacizumab recipients relative to first-line chemotherapy recipients. In a competing risk regression adjusting for potential confounders, bevacizumab receipt (2005-2007) was not associated with an increased risk of first AE compared with chemotherapy alone (2001-2007) (hazard ratio, 0.97; 95% CI, 0.87-1.08). Conclusion In an older mCRC population, bevacizumab receipt was less likely in older (age ≥ 75) nonwhite patients with preexisting cerebrovascular comorbidities. First-line bevacizumab was not associated with increased AE incidence or risk of first AE compared with chemotherapy alone.

Background The relative safety of BV in older mCRC pts is understudied. The objectives of this analysis are to investigate treatment-related AE incidence and to determine factors associated with AEs in a population-based sample of older mCRC pts. Methods Pts age ≥ 65 diagnosed (Dx) with mCRC in 2001-7 were identified from SEER-Medicare. First-line (1L) chemotherapy (CTx) was identified by claims within 3 months of Dx; pts were categorized as receiving no 1L CTx, 1L CTx alone, or 1L CTx + BV. Pts were also categorized by Dx period (2001-3 vs. 2005-7); pts Dx in 2004 were excluded as BV use could not be reliably identified in that year. Preexisting conditions (PCs) identified in the year prior to Dx were grouped into 5 categories (cardiovascular (CV), cerebrovascular (CNS), gastrointestinal (GI), tissue integrity (TI), and pulmonary (Pulm). Claims for these conditions between start of 1L CTx and end of follow-up were identified as AEs. AE incidence rates were determined by Dx year and 1L CTx cohort. We used a competing risks regression model to compare time to 1st AE for pts who received 1L CTx + BV in 2005-7 to pts who received 1L CTx alone in 2001-7. Similar models were constructed for specific serious AEs (stroke, DVT/PE, GI bleed, GI perforation). Results 6,899 pts (median age 77) were identified. In 2001-3, 37% of pts received 1L CTx alone; in 2005-7, 21% and 19% of pts received 1L CTx alone and 1L CTx + BV. AE incidence was similar between pts receiving 1L CTx alone in 2001-3 (135 AEs / 100,000 person-days (PD)) and 1L CTx + BV in 2005-7 (140 AEs / 100,000 PD). Time to 1st AE was not shorter in pts receiving 1L CTx + BV in 2005-7 compared with 1L CTx alone in 2001-7 (HR 0.99, p = 0.90). Similarly, receipt of 1L CTx + BV was not associated with a shorter time to specific AE. (Table) Conclusions Older pts who received 1L CTx + BV had neither increased AE incidence nor decreased time to 1st AE compared with pts who received 1L CTx alone. BV utilization may not increase AE risk among elderly mCRC pts. Time to 1st AE: BV vs. 1L CTx alone AE Type HR 95% CI Any AE 0.99 0.90-1.10 Stroke 1.04 0.95-1.15 DVT/PE 1.03 0.94-1.14 GI bleed 1.03 0.94-1.14 GI perforation 1.05 0.95-1.15 Models adjusted for: age, comorbidity, race, gender, CTx backbone, PC Disclosure V. Shankaran: This research activity received industry funding from Genentech, Inc. D. Mummy: This research activity received industry funding from Genentech, Inc. L. Koepl: This research activity received industry funding from Genentech, Inc. D. Blough: This research activity received industry funding from Genentech, Inc. Y.M. Yim: Financial interests include employment at Genentech, Inc. as as health economist and ownership in Genentech stocks. E. Yu: Financial interests include employment at Genentech, Inc. as Associate Director and stock ownership in Roche. S. Ramsey: This research activity received industry funding from Genentech, Inc.

e14068 Background: The relative safety of newer drugs in older pts with mCRC is understudied. The objective of this analysis is to determine factors associated with AEs in a population-based sample of older mCRC pts treated in real-world clinical settings. Methods: Pts ≥ age 65 Dx with mCRC in 2004-2007 were identified from SEER-Medicare, and excluded if they were enrolled in a Medicare HMO or lacked Medicare parts A and B. Pts who received 1st line (1L) chemotherapy (CTx) within 3 mo of Dx were dichotomized as 1L CTx alone and 1L CTx + bevacizumab (BV). Preexisting conditions (PCs) identified from claims in the 12 mo prior to start of 1L CTx were grouped into 5 categories (cardiovascular (CV), cerebrovascular (CNS), gastrointestinal (GI), tissue integrity (TI), and pulmonary (Pulm)). Claims for any of these same conditions between start of 1L CTx and end of follow-up were identified as AEs. Crude AE incidence rates were determined. Logistic regression was used to examine factors associated with BV use. Factors associated with time to 1st AE were identified in a Cox model. Results: 4,514 pts (median age 77) met inclusion, of whom 1,139 (25%) received 1L CTx only and 669 (15%) received 1L CTx + BV. BV use was less likely among pts age ≥ 75 (OR 0.35, pst AE with death as a competing risk, increased risk of AE was associated with age ≥ 75 (HR 1.13, p=0.02), CNS PC (HR 1.35, p=0.02), and CV PC (HR 1.13, p=0.05). Relative to 1L CTx alone, pts receiving 1L CTx + BV did not have a higher AE risk (HR 0.89, 95% CI 0.80-0.99). AE incidence was higher in pts receiving 1L CTx alone (without subsequent biologic) (185 events / 100,000 person-days (P-D) compared with pts receiving 1L CTx + BV (139 events / 100,000 P-D). Conclusions: In this cohort, pts who received 1L CTx + BV had neither increased AE incidence nor increased risk of 1st AE compared to pts who received 1L CTx alone. PCs were not associated with decreased BV use. These data suggests BV utilization may not increase AE risk among elderly mCRC pts tx in the community.

6007 Background: We identified the physicians initially involved in the management of stages III and IV NSCLC, and explored associations of patient and their initial physician factors with referrals to oncologists and subsequent receipt of guideline-based therapies (GBTs) endorsed by the National Comprehensive Cancer Network. Methods: Using a retrospective cohort design, we identified patients with a new diagnosis of stages III and IV NSCLC from 01/01/2000 to 12/31/2005 included in the Surveillance, Epidemiology, and End Results-Medicare database. After collecting patient sociodemographic, tumor, and treatment data, we linked Unique Physician Identifier Numbers (UPINs) from Medicare claims to the American Medical Association Masterfile database to identify the initial physicians and subsequent referrals to cancer specialists, defined as surgeons, radiation oncologists and oncologists. We used logistic regression to explore associations between: 1) patient and initial physician independent variables with referrals to oncologists; 2) referrals to different combinations of cancer specialists with receipt of stage-specific GBTs, adjusted for confounders. The follow-up period was 12 months or up to 12/31/2006. Results: For 28,977 patients, mean age was 75 years, 53% were male, 83% were white, 51% had stage IV, 37% initially saw an internal medicine doctor, 84% saw at least an oncologist, 31% saw all 3 types of cancer specialists, and 44% received GBTs. Younger age, white race, stage IV, higher income, lower co-morbidity index, initial physicians other than family practice doctors, and referral to pulmonologists were associated with higher likelihood of referral to oncologists (P