Citations

Abstract Importance Conventional Pulmonary Rehabilitation (PR) after a hospital admission for a COPD exacerbation reduces remission and improves quality of life and survival, but only 2% of hospitalized patients complete PR. New feasible and effective strategies for increasing adherence to rehabilitation in the post hospitalization period are needed. Objective Determine the effect of patient’s choice on adherence to rehabilitation and outcomes. Design, Setting, and Participants: Individuals discharged after a COPD-related hospitalization were randomized to home rehabilitation with health coaching (HRwHC) or the choicethe choice of conventional PR or HRwHC. Intervention The HRwHC program was asynchronous and included weekly health coaching calls for 12 weeks and remote monitoring of lifestyle activities including daily exercises, and steps measured by an activity tracker, the compliance with 24-minute daily exercise routine and a daily wellbeing assessment. Participants in the choice arm that elected for conventional PR were facilitated by the study team to attend the nearest PR center. Main Outcomes and Measures The primary outcomes were adherence and effect on health-related quality of life measured by the Chronic Respiratory Questionnaire. Secondarily Physical activity was measured with Actigraph®GX3T a validated triaxial accelerometry. Results Among 1905 potential participants identified, 296 were randomized (uptake 14%). Reasons for declining include No interest in research 556 (29%), Already in PR or in other monitoring or research program 125 (6.5%), too much going/still recovering 650 (34%), Felt not needed (content with care) 208 (11%), Hospice 12 (0.6%), Technology barrier 64 (3%). Arm baseline measures were not different between arms. Among participants in the choice group, 1 of 148 (0.6%) elected HRwHC instead of PR. Because all patients received the same intervention (except one), outcomes at 3 months showed no difference, result are presented as one group before -after analysis. Among 295 patients that chose or were randomized to HRwHC, adherence (completion) was 59%. CRQ physical and Emotional Summary as well as all individuals’ domains improved significantly and beyond the MCID at 3 months Table 1A. CRQ improvement was maintained at 6- and 12-months Table 1B-C. Linear mixed models for repeated measures confirmed the significant sustained improvement over one year after adjusting to age, FEV1%, Charlson comorbidity index (p < 0.001 for all three time point 3-6-12 months). Conclusions and Relevance Home rehabilitation may represent the preferred choice after a COPD-related hospital admission. HRwHC sustainably improved quality of life over one year making a feasible and effective rehabilitation option and opportunity for primary palliative care. This abstract is funded by: NIH

Abstract Rationale Alpha1-antitrypsin (AAT; gene name SERPINA1) is a critical antiprotease that protects the lung from neutrophil elastase-mediated injury. AAT deficiency predisposes to emphysema, which is further exacerbated by cigarette smoke (CS) exposure. We previously reported (PMID: 38325750) that a nebulized human platelet-derived exosome product (PEP) attenuated CS-induced emphysema in C57BL/6 mice. Given the presence of AAT protein in these platelet-derived exosomes (identified by proteomics), we hypothesized that PEP nebulization would significantly attenuate both spontaneous and CS-induced emphysema in SERPINA1 knockout (KO) mice. Methods Transgenic SERPINA1 KO C57BL/6 mice (both sexes) exposed to CS (10 cigarettes/day and 5 days/week) for 2 months were then randomized to receive nebulized PEP or 0.9% saline (placebo) twice weekly for 4 additional weeks, with continued CS exposure. PEP was reconstituted in 0.9% saline (22.7mg/mL; ∼3 × 10¹0 vesicles/mL) and administered via pressure- and humidity-controlled nose-only inhalation tower (2.25 mL of PEP or saline over 35 minutes). Lung static compliance (Cst), cutaneous O2 saturation, mean linear intercepts (Lm), and plethysmographic parameters were measured during and after the study. Results Histological analysis of the lung tissue sections revealed that PEP significantly attenuated the CS-induced increase in alveolar size, as determined by measurement of the mean linear intercepts (Lm, p < 0.001). Lung static compliance (Cst), which was increased in CS-exposed mice, was also significantly decreased in the PEP-treated group (p < 0.001) compared to placebo in the male and female combined group. Functional respiratory parameters further supported the protective effect of PEP in this AAT-deficient model. In female mice, PEP nebulization significantly improved several CS-impaired pulmonary function parameters, including minute volume (MV, p = 0.024), the flow at the point 50% of tidal volume is expired (EF50, p = 0.021), Peak Inspiratory Flow (PIF, p = 0.009), Peak Expiratory Flow (PEF, p = 0.018), and O2 saturation (p = 0.035). However, these improvements were not observed in male mice. Conclusions These findings extend prior observations and underscore the therapeutic potential of nebulized AAT-enriched PEP directly to the alveolar region, effectively attenuating injury and improving pulmonary function in AAT deficiency-related emphysema. This abstract is funded by: Department of Defense, Mayo Clinic Funding, The Young and Middle-aged Medical High-end Talents in Chongqing Program

Abstract Introduction We previously demonstrated that nebulized platelet-derived exosome product (PEP) alleviates cigarette smoke (CS)-induced murine emphysema. To elucidate the underlying molecular mechanisms, we conducted single-nucleus RNA sequencing of lung tissue, which initially revealed a shift in the cell source for TNF signaling (a critical regulator of inflammation in COPD lungs) from innate lymphoid cells (ILC) to alveolar macrophages (aMac) after chronic CS exposure. In this study, we conducted a more in-depth analysis of cellular communication to determine the mechanism by which PEP modulates CS-induced TNF signaling in the lung microenvironment. Methods Single-cell transcriptomics and cell-cell communication analyses were performed between CS-exposed placebo control lungs vs. sham control lungs and CS-exposed PEP-treated vs. placebo control lungs using R packages, including Seurat, CellChat, Patchwork, Future, and NMF. A comparative analysis of ligand-receptor interactions across these datasets was conducted using CellChat to infer intercellular signaling networks. Results Single-nuclear RNA-seq analysis revealed that the Thy1-ITGAX_ITGB2 signaling pathway was significantly upregulated by CS, acting as the adhesive and activating bridge that facilitates the switch in TNF production from ILC to aMac. Thy1 is a GPI-anchored ligand expressed on ILCs, and ITGAX_ITGB2 is its cognate receptor on aMacs. Concurrently, Ptprc-Mrc1 signaling, an inhibitory pathway in ILC-aMac crosstalk, was downregulated, contributing to sustained aMac activation by CS. Furthermore, analysis of aMac-aMac interactions revealed upregulated GRN/Sort1 signaling, which promotes the internalization of progranulin, an anti-inflammatory glycoprotein that competes for TNF/TNFR signaling. Ptprc-Mrc1 signaling was also downregulated within the aMac autocrine/paracrine network, further perpetuating a pro-inflammatory state. In contrast, treatment with PEP downregulated Thy1-ITGAX_ITGB2 signaling and upregulated Lamc1-Cd44 signaling, a hallmark of aMac deactivation, thereby inducing a phenotypic switch in inflammatory macrophages toward a reparative M2 state, promoting the resolution of CS-induced chronic inflammation. Conclusions These data suggest that the transition of TNF production from ILCs to aMacs under chronic CS stress is driven by increased Thy1-ITGAX_ITGB2 interactions and decreased Ptprc-Mrc1 signaling between ILCs and aMacs crosstalk within the local tissue. Enhancing the crosstalk between Lamc1-Cd44 and Ptprc-Mrc1 may suppress TNF production and attenuate CS induced aMac activation. Targeting these pathways, as demonstrated by nebulized PEP treatment, holds therapeutic potential to deactivate inflamed aMacs and promote homeostasis in the inflamed lung. This abstract is funded by: Department of Defense, Mayo Clinic Funding

Abstract Introduction Bronchiectasis is a chronic respiratory disease that increases fatigue, disability, and impairs quality of life. However, the impact of fatigue on patients with bronchiectasis, even in short-term follow-up, has not been sufficiently examined. We explored the association between fatigue and clinical outcomes among patients with bronchiectasis. Methods Adult bronchiectasis patients enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry were retrospectively analyzed. Patients with at least one annual follow-up visit in the 3-5 years post baseline and with fatigue data at both baseline and follow-up were included. Patients were grouped as experiencing fatigue versus not experiencing fatigue in the 2-years prior to baseline as reported at their baseline visit. We explored the relationship between baseline fatigue with patient demographics, co-existing conditions, components of the modified bronchiectasis severity index at baseline and follow-up. Wilcoxon, chi-square, and Fisher’s exact tests were used to assess the differences in continuous variables and associations between categorical variables, respectively. Stepwise multivariable logistic regression models explored the relationship of baseline fatigue with exacerbations and hospitalizations at follow-up. Model selection predictors were evaluated based on clinical relevance or p < 0.05 in univariable analyses. Results 1265 adults with bronchiectasis met the inclusion criteria. 563(45%) reported experiencing fatigue and 702 (55%) did not. The median age (interquartile range) was 70(62-78) years and patients were predominantly female (n = 1042, 83%). At baseline, patients experiencing fatigue had a higher proportion of co-existing diagnoses such as gastroesophageal reflux disease, chronic obstructive pulmonary disease, and rheumatologic disease, compared to those without fatigue (all p < 0.05). Furthermore, patients with fatigue had a higher prevalence of pulmonary-related hospitalizations (p < 0.001) at baseline and follow-up. Pseudomonas aeruginosa colonization and elevated dyspnea (modified Medical Research Council [mMRC] grade≥1) were more prevalent among those experiencing baseline fatigue compared to those without (all, p < 0.05). History of prior exacerbations (Odds Ratio [OR]:1.67, 95% CI:1.17-2.41) and baseline Pseudomonas aeruginosa colonization (OR:1.22, 95% CI:1.01-1.47) were significantly associated with increased odds of exacerbations at follow-up. In multivariable stepwise logistic regression, there was an increased odds of at least 1-hospitalization at follow-up among males (OR:2.23, 95% CI 1.12-4.42), patients with decreased Body Mass Index (OR:0.93, 95% CI: 0.87-1.0), and among patients with elevated dyspnea (mMRC grade ≥1) at baseline (OR:2.22, 95% CI: 1.16-4.24),[Table 1]. Conclusions Fatigue in bronchiectasis patients is associated with a more severe disease and greater healthcare utilization, although it may not independently predict future exacerbations or hospitalizations when accounting for other factors. This abstract is funded by: Bronchiectasis and NTM Association

Abstract Background Patients with chronic obstructive pulmonary disease (COPD) are particularly vulnerable to severe respiratory infections. While COVID-19 vaccination has demonstrated effectiveness in reducing severe disease in the general population, its real-world impact on clinical outcomes among COPD patients remains underexplored. Understanding these outcomes could strengthen vaccination advocacy and guide COPD management strategies. Research Question Does COVID-19 vaccination reduce the risk of mortality, COPD exacerbations, and mechanical ventilation in adults with COPD? Methods We conducted a retrospective, propensity-matched cohort study using the TriNetX US Collaborative Network, which aggregates de-identified electronic health records from 72 healthcare organizations. Adults with COPD were identified using ICD-10 code J44 and spirometric confirmation (FEV1/FVC ≤ 70%). Cohorts were divided by COVID-19 vaccination status, identified through CPT and RxNorm codes. The index date was defined as the earliest qualifying encounter, with outcomes assessed thereafter.Primary outcome was all-cause mortality; secondary outcomes included COPD exacerbation (J44.1) and mechanical ventilation (ICD-10-PCS 5A1945Z). Propensity-score matching (1:1) was performed on age, sex, race, comorbidities, and baseline clinical characteristics, yielding balanced cohorts (n = 3,969 each). Risk ratios (RR), hazard ratios (HR), and Kaplan-Meier survival analyses were calculated, with significance set at p < 0.05. Results After matching, median follow-up was 894 days for the unvaccinated group and 886 days for the vaccinated group. All-cause mortality 23.8% (942/3,954) in unvaccinated vs 11.1% (442/3,968) in vaccinated; RR 2.14 (95% CI 1.93-2.37); HR 1.80 (95% CI 1.60-2.02); p < 0.001. COPD exacerbations 31.3% (1,243/3,969) in unvaccinated vs 25.3% (1,006/3,969) in vaccinated; RR 1.24 (95% CI 1.15-1.33); HR 1.24 (95% CI 1.14-1.35); p < 0.001. Mechanical ventilation 1.8% (72/3,902) in unvaccinated vs 0.8% (30/3,928) in vaccinated; RR 2.42 (95% CI 1.58-3.69); HR 2.06 (95% CI 1.33-3.18); p = 0.001. Kaplan-Meier curves demonstrated consistently higher survival and event-free probabilities among vaccinated patients across all outcomes. Conclusions In this large, real-world analysis, COVID-19 vaccination was associated with significantly lower risks of all-cause mortality, COPD exacerbations, and need for mechanical ventilation. These findings emphasize the importance of vaccination as a key component of COPD care, supporting its inclusion in quality-improvement metrics and clinical counseling for patients with chronic lung disease. This abstract is funded by: None

Abstract Background Obesity contributes to worse symptoms and exacerbations in chronic obstructive pulmonary disease (COPD). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve weight and metabolic profiles and have emerging pulmonary benefits. However, their real-world impact on respiratory outcomes in patients with COPD and obesity is not well established. Research Question Among obese adults with COPD, is GLP-1 RA use associated with reduced risk of COPD exacerbations, acute respiratory failure, and all-cause mortality compared with those not receiving GLP-1 therapy? Methods We conducted a retrospective, propensity-matched cohort study using the TriNetX U.S. Collaborative Network. Adults aged ≥40 years with COPD (ICD-10 J44) and BMI ≥30 kg/m² were included. The exposed cohort comprised patients prescribed GLP-1 RAs (lixisenatide, albiglutide, dulaglutide, liraglutide, semaglutide, or exenatide), while comparators had no exposure. The index event was the first date meeting inclusion criteria. Outcomes were analyzed beginning 180 days after index to minimize reverse causation, excluding those with prior events. Propensity score matching (1:1) balanced demographics, comorbidities, laboratory data, and medication use, yielding 2,795 patients per group. Primary outcomes included the risk (≥1 event within window) of COPD exacerbation, acute respiratory hypoxic and/or hypercapnic failure leading to hospitalization, and all-cause mortality. Risk difference (RD), risk ratio (RR), and odds ratio (OR) were calculated; Kaplan-Meier and log-rank testing assessed time-to-event. Results After matching, baseline characteristics were well balanced. GLP-1 RA use was associated with significantly lower risk across all outcomes:COPD Exacerbation (J44.1): 18.2% (No GLP-1) vs 11.2% (GLP-1); RD 7.0%, RR 1.63 (95% CI 1.36-1.94); p = 0.042.Acute Hypoxic and/or Hypercapnic Respiratory Failure (J96.x): 19.2% vs 11.5%; RD 7.7%, RR 1.67 (1.42-1.96).All-Cause Mortality: 14.6% vs 7.6%; RD 7.0%, RR 1.92 (1.64-2.25); p = 0.010. Kaplan-Meier survival analysis demonstrated significantly improved survival in the GLP-1 group for mortality and COPD exacerbation outcomes. Conclusions In obese adults with COPD, GLP-1 RA therapy was associated with clinically and statistically significant reductions in COPD exacerbations, acute respiratory failure, and all-cause mortality. These findings suggest that GLP-1 RAs may offer dual metabolic and pulmonary benefits and warrant evaluation as adjunctive therapy in future prospective trials. This abstract is funded by: None

Abstract Rationale Alpha-1 antitrypsin (AAT) deficiency, primarily caused by homozygous SERPINA1 Z mutation, increases the risk of COPD. Individuals carrying one Z and one normal M allele (MZ) have higher COPD risk than MM individuals, although many never develop disease. COPD is a polygenic condition influenced by numerous genetic factors across the genome and by environmental exposures such as smoking. We aimed to examine how polygenic factors and smoking modify risk of airflow obstruction in MZ compared with MM. Methods We included participants with the MZ and MM genotypes from the Framingham Heart Study. We first tested the association between AAT genotype (MZ coded as 1 and MM as 0) and FEV1/FVC, stratified by ever-smoking status, and further evaluated interactions between AAT genotype and smoking pack-years. Next, for each participant we calculated a polygenic risk score (PRS) for FEV1/FVC, which was derived from external genome-wide association studies in the UK Biobank and SpiroMeta Consortium. To reflect risk for airflow limitation, higher PRSs correspond to lower FEV1/FVC. We then tested the interaction between the PRS and AAT genotype, stratified by ever-smoking. Models were adjusted for age, sex, height, current smoking, pack-years (among ever-smokers), familial relatedness, and in PRS models, principal components of genetic ancestry. Results Among 4,220 participants (mean age 53.7 years, 54.2% female, 50.2% ever-smokers, mean FEV1/FVC 74.6%), 133 (3.2%) had MZ genotype. In never-smokers, MZ individuals had 1.72% higher FEV1/FVC compared with MM (P = 0.032), whereas no difference was observed among ever-smokers (β= -0.39%; P = 0.65). Cumulative smoking modified the effect of MZ genotype on FEV1/FVC (interaction β= -0.13% per pack-year; P = 0.003); this interaction persisted among ever-smokers (β= -0.11% per pack-year; P = 0.044). A one-standard-deviation increase in the FEV1/FVC PRS was associated with lower FEV1/FVC in both never- (β= -2.37%; P < 0.0001) and ever-smokers (β= -2.46%; P < 0.0001). A higher PRS was disproportionately associated with reduced FEV1/FVC in MZ compared to MM (interaction β= -1.87% per standard-deviation PRS increase, P = 0.027) among ever-smokers, but not in never-smokers (P = 0.15). Conclusions In this community-based cohort, the AAT MZ genotype was associated with higher FEV1/FVC among non-smokers compared to MM. The interaction between MZ genotype and pack-years suggested a dose-dependent modifying effect of smoking on the MZ-related COPD risk. Among ever-smokers, higher polygenic risk further amplified susceptibility to airflow obstruction in MZ compared with MM. These findings highlight the roles of both polygenic and environmental risk factors in COPD susceptibility in MZ. Replication of the results is needed. This abstract is funded by: This work is supported by an Alpha-1 Foundation Grant and a Boston University Department of Medicine Career Investment Award

Abstract Background Muscle loss in COPD results from both disuse atrophy and systemic inflammation. We sought to identify inflammatory biomarkers associated with loss of pectoralis muscle area in COPD using serial CT scans and peripheral blood proteomics. Design We analyzed five-year longitudinal data from COPDGene, an ongoing observational cohort of current and former tobacco smokers with or without airflow obstruction. We quantified pectoralis major muscle (PMM) area on chest CT scans using a 3D convolutional neural network (CNN) trained on CT volumes and annotations provided by the TotalSegmentator project. We compared participants with CT PMM data and plasma proteins by SOMAScan (1K platform) from Phase 2 and 3 (paired n = 1,191). The correlation coefficient (r) between longitudinal changes in protein and in PMM area was plotted against the false discovery rate (FDR)-adjusted p-values. Proteins significantly associated with muscle loss (blue) or gain (red) were visualized using volcano plots. We then analyzed a subset (paired n = 500) of individuals with BMI>25 in Phase 2 whose BMI declined in Phase 3. Proteomic models were adjusted for age and clinical center. Pathway analysis utilized G:Profiler. Results Of the participants with paired proteomic and PMM data, mean PMM area was 21.7 ± 17.3 cm² at Phase 2 and 21.3 ± 17.9 cm² at Phase 3, with an annual change in PMM area of -0.31 + 0.99 cm². Multiple proteins were associated with muscle loss from Phase 2 to 3 (including leptin, FABP, and growth hormone receptor) and muscle gain (including F172A, GMEB2, and RNF41) (Fig 1a). Significant pathways were related to cancer, growth factor receptor dysregulation, and PI3K/AKT signaling. When restricting to those with BMI>25 who experienced BMI decline at Phase 3, muscle loss was associated with increased leptin and PACAP, versus association of gain with increased GDF118, EF1β, and FJF6 (Fig 1b). In the entire group, leptin declined between Phase 2 to Phase 3 in n = 571 participants and increased or was unchanged in n = 620. Compared with leptin decline, unchanged or increased leptin was associated with significantly greater interval PMM loss (−2.25 ± 9.75 cm² vs + 0.98 ± 9.43 cm²; p < 0.001) (Fig 1c). Conclusion Loss of PMM over five years was associated with several plasma proteins, including FABP and growth hormone receptor. The top biomarker, leptin, is a pleiotropic adipokine that regulates energy balance and inflammation. Integrating imaging and proteomics may identify future therapeutic targets to mitigate skeletal muscle loss in COPD. This abstract is funded by: This work was supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011

Abstract Rationale Sleep is an important dimension of COPD symptomology. Poor self-reported sleep quality has been independently associated with increased exacerbation risk and worse quality of life. There is limited evidence around the longitudinal sleep quality of patients with smoking-related lung disease. Methods Using the SPIROMICS longitudinal cohort of heavy smokers, we used group-based trajectory modeling to understand sleep quality over time as measured by serial retests of the Pittsburgh Sleep Quality Index (PSQI). We considered all participants of Black or Non-Hispanic White race who completed the PSQI in Visits 1-4, a span of 3 years. We considered race, gender, and social environmental exposures as time-stable risk factors for trajectory group membership. We adjusted for age, lung function, mood symptoms and self-reported COPD symptom severity were considered as time-varying factors. We selected the number of trajectory groups by minimizing Bayesian Information Criteria and polynomial order by maximizing the significance of exponential terms. For quality assurance we calculated average posterior probability of correct group assignment. Calculations were performed by complete case analysis and multiple imputation with chained equations. Results We analyzed 2,838 participants yielding 76,153 usable observations. Overall, 39.2% of participants had complete observations for all variables of interest at every measured visit, and 60.8% had at least one relevant observation missing. The largest single source of missingness in our dataset was the comorbidity count, for which 44% of participants had a missing observation. We identified two major trajectory groups. In one group, the PSQI was persistently high with little variation over time, containing 77.7% of the overall study population. The second group had low PSQI at baseline but experienced wide fluctuation over time. Risk factors for persistently poor sleep included female gender, Black race, and more adverse social conditions at either the neighborhood or individual level (Table). The average posterior probability of correct group assignment was 94.6% among the Low Variable group and 89.5% among the Persistent High group. Results were similar by complete case and imputed analysis, save that BMI did not independently predict group membership in the latter. Conclusion Historically underserved groups are at long term risk for poor sleep outcomes in smoking-related lung disease, even among those who are highly motivated and participate in clinical research. More work is needed to ensure equitable access to sleep medicine in order to improve the quality of care in COPD. This abstract is funded by: Nina Ireland Program for Lung Health

Abstract Background Daily physical activity (PA) is the strongest predictor of survival and is associated with the risk of hospitalization, poor quality of life 1-3 in people living with Chronic Obstructive Pulmonary Disease COPD.2 However, symptoms of breathlessness, functional limitations, and poor exercise tolerance may make it difficult to meet the conventional physical activity guidelines of 150 minutes of moderate intensity. There is a knowledge gap in the granular amount and intensity of daily PA that may provide a survival benefit for people living with COPD: specifically in light PA (1.5-3METs) and moderate (3-6 METs) PA, which are the intensities most achievable in moderate-severe disease. We aimed to determine whether different intensities of daily physical activity, accurately measured by a gold-standard activity monitor, were associated with a survival benefit in a large cohort of people living with moderate to severe COPD followed for six years. Methods Participants wore the Actigraph® GT3X-BT, a tri-axial wrist accelerometer, for 7 days. Survival at 72 months was assessed through the National Death Index Inquiry by Accurint® and confirmed by records. Analysis Participants in this cohort were randomly assigned to a training data set (70%) and 30% to a validation set. Classification and regression tree (CART) models were generated using the training data set. Bootstrapping with 3,000 iterations was conducted. 872 patients were part of this study: mean age 69+ 8, 54% female, mMRC score, (scale 0-4) was 2.6 + 0.8 and FEV1% was 46% +19. The mean follow-up was 42+ 21 months with a range of 1-72 months. At the end of the follow up 67.3% were alive, 32.7% were deceased. The bootstrapped CART analysis modeled cut points associated with survival as follows: 296 minutes for light PA, 17 minutes for moderate PA; and 3243 steps after adjusting for age, sex, FEV1% and mMRC score. Consistent with the 17 minutes of moderate PA providing 58% survival benefits, we also found that two 10-minute Freedson bouts of activity per day (2x10 min of PA in moderate intensity) the same provided the same survival benefit1. Cox models are presented in Table 1 Conclusion This report is the first to document the survival benefit of light physical activity in patients with COPD. In the context of most patients with moderate-severe COPD not able to achieve PA guidelines, our results represent a breath of fresh air, suggesting that simple and meaningful (to the patient) light activities may provide a survival benefit. This abstract is funded by: NIH