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Figure S1 shows that treprostinil exposure did not affect BAL cell number or BAL prostaglandin levels.

Prostacyclin (prostaglandin I2, PGI2) overproduction in FVB/N mice prevents the formation of carcinogen and tobacco smoke–induced adenomas, and administration of the oral prostacyclin analogue iloprost to wild-type mice also prevented carcinogen-induced mouse lung adenoma formation. Former smokers taking oral iloprost showed improved bronchial dysplasia histology compared with placebo. Next-generation oral prostacyclin analogues, like treprostinil, were developed for the treatment of pulmonary arterial hypertension (PAH). On the basis of our prior studies with iloprost, we performed preclinical studies examining the ability of treprostinil to chemoprevent urethane-induced murine lung adenocarcinoma. We determined the MTD in chow (prior studies had delivered treprostinil by gavage), and this dose produced serum levels in the experimental animals similar to those found in PAH patients treated with treprostinil. We then examined the chemopreventive efficacy of treprostinil exposure initiated both before (1 week) and after (6 weeks) urethane exposure to better model chemoprevention studies conducted in former smokers. Neither of these dosing strategies prevented murine lung cancer; however, we did detect changes in pulmonary inflammatory cell infiltrate and expression of CXCR4 (a chemokine receptor previously shown to increase in response to treprostinil exposure) in tumor-bearing, treprostinil-treated animals, indicating that the drug was bioavailable. One potential explanation stems from iloprost and treprostinil differentially activating cell surface prostaglandin receptors and intracellular peroxisome proliferator-activated receptors. When murine lung tumor cells were treated with treprostinil, their proliferation rate increased; in contrast, iloprost had no effect on proliferation. Future investigations comparing these two agents will provide insight into iloprost's chemopreventive mechanisms. Cancer Prev Res; 10(11); 671–9. ©2017 AACR.

Objective Lung cancer screening (LCS) efficacy is highly dependent on adherence to annual screening, but little is known about real-world adherence determinants. We used insurance claims data to examine associations between LCS annual adherence and demographic, comorbidity, health care usage, and geographic factors. Materials and Methods Insurance claims data for all individuals with an LCS low-dose CT scan were obtained from the Colorado All Payer Claims Dataset. Adherence was defined as a second claim for a screening CT 10 to 18 months after the index claim. Cox proportional hazards regression was used to define the relationship between annual adherence and age, gender, insurance type, residence location, outpatient health care usage, and comorbidity burden. Results After exclusions, the final data set consisted of 9,056 records with 3,072 adherent, 3,570 nonadherent, and 2,414 censored (unclassifiable) individuals. Less adherence was associated with ages 55 to 59 (hazard ratio [HR] = 0.80, 99% confidence interval [CI] = 0.67-0.94), 60 to 64 (HR = 0.83, 99% CI = 0.71-0.97), and 75 to 79 (HR = 0.79, 99% CI = 0.65-0.97); rural residence (HR = 0.56, 99% CI = 0.43-0.73); Medicare fee-for-service (HR = 0.45, 99% CI = 0.39-0.51), and Medicaid (HR = 0.50, 99% CI = 0.40-0.62). A significant interaction between outpatient health care usage and comorbidity was also observed. Increased outpatient usage was associated with increased adherence and was most pronounced for individuals without comorbidities. Conclusions This population-based description of LCS adherence determinants provides insight into populations that might benefit from specific interventions targeted toward improving adherence and maximizing LCS benefit. Quantifying population-based adherence rates and understanding factors associated with annual adherence are critical to improving screening adherence and reducing lung cancer death.

Background Lung cancer screening (LCS) implementation is complicated by the Centers for Medicare and Medicaid Services reimbursement requirements of shared decision-making and tobacco cessation counseling. LCS programs can utilize different structures to meet these requirements, but the impact of programmatic structure on provider behavior and screening outcomes is poorly described. Patients and Methods In a retrospective chart review of 624 patients in a hybrid structure, academic LCS program, we compared characteristics and outcomes of primary care provider (PCP)- and specialist-screened patients. We also assessed the impact of the availability of an LCS specialty clinic and best practice advisory (BPA) on PCP ordering patterns using electronic medical record generated reports. Results During the study period of July 1, 2014 through June 30, 2018, 48% of patients were specialist-screened and 52% were PCP-screened; there were no clinically relevant differences in patient characteristics or screening outcomes between these populations. PCPs demonstrate distinct practice patterns when offered the choice of specialist-driven or PCP-driven screening. Increased exposure to a LCS BPA is associated with increased PCP screening orders. The addition of a nurse navigator into the LCS program increased documentation of shared decision-making and tobacco cessation counseling to > 95% and virtually eliminated screening of ineligible patients. Conclusions Systematic interventions including a BPA and nurse navigator are associated with increased screening and improved program quality, as evidenced by reduced screening of ineligible patients, increased lung cancer risk of the screened population, and improved compliance with LCS guidelines. Individual PCPs demonstrate clear preferences regarding LCS that should be considered in program design.

Massive hemoptysis is a high-risk, low-frequency clinical scenario, and teaching the management of this emergency should extend beyond reliance on clinical exposure. Massive hemoptysis requires emergent intervention to avoid asphyxiation and death. Practitioners need both cognitive and procedural skills to intervene in a high-stress situation. Cognitive aids have demonstrated benefits in other emergency settings, but no such tool exists for massive hemoptysis. Using expert recommendations, we developed the ABCDE Approach for Massive Hemoptysis, a cognitively accessible, prioritized toolbox of interventions designed to assist learners in organizing an approach to these high-risk and time-sensitive patient cases. Herein we present the elements and use of the ABCDE approach. Providing a cognitive approach to massive hemoptysis is an important first step in improving education for this potentially fatal clinical scenario.

Lung cancer is the leading cause of cancer death worldwide and global burden could be reduced through targeted application of chemoprevention. The development of squamous lung carcinoma has been linked with persistent, high-grade bronchial dysplasia. Bronchial histology improved in former smokers in a chemoprevention trial with the prostacyclin analogue iloprost. Prostacyclin acts through peroxisome proliferator-activated receptor gamma (PPARγ) to reverse epithelial to mesenchymal transition and promote anticancer signaling. We hypothesized that the prostacyclin signaling pathway and EMT could provide response markers for prostacyclin chemoprevention of lung cancer. Human bronchial epithelial cells were treated with cigarette smoke condensate (CSC) or iloprost for 2 weeks, CSC for 16 weeks, or CSC for 4 weeks followed by 4 weeks of CSC and/or iloprost, and RNA was extracted. Wild-type or prostacyclin synthase transgenic mice were exposed to 1 week of cigarette smoke or one injection of urethane, and RNA was extracted from the lungs. We measured potential markers of prostacyclin and iloprost efficacy in these models. We identified a panel of markers altered by tobacco carcinogens and inversely affected by prostacyclin, including PPARγ, 15PGDH, CES1, COX-2, ECADHERIN, SNAIL, VIMENTIN, CRB3, MIR34c, and MIR221. These data introduce a panel of potential markers for monitoring interception of bronchial dysplasia progression during chemoprevention with prostacyclin. Chemoprevention is a promising approach to reduce lung cancer mortality in a high-risk population. Identifying markers for targeted use is critical for success in future clinical trials of prostacyclin for lung cancer chemoprevention. Cancer Prev Res; 11(10); 643–54. ©2018 AACR.

Prostacyclin (prostaglandin I2, PGI2) overproduction in FVB/N mice prevents the formation of carcinogen and tobacco smoke–induced adenomas, and administration of the oral prostacyclin analogue iloprost to wild-type mice also prevented carcinogen-induced mouse lung adenoma formation. Former smokers taking oral iloprost showed improved bronchial dysplasia histology compared with placebo. Next-generation oral prostacyclin analogues, like treprostinil, were developed for the treatment of pulmonary arterial hypertension (PAH). On the basis of our prior studies with iloprost, we performed preclinical studies examining the ability of treprostinil to chemoprevent urethane-induced murine lung adenocarcinoma. We determined the MTD in chow (prior studies had delivered treprostinil by gavage), and this dose produced serum levels in the experimental animals similar to those found in PAH patients treated with treprostinil. We then examined the chemopreventive efficacy of treprostinil exposure initiated both before (1 week) and after (6 weeks) urethane exposure to better model chemoprevention studies conducted in former smokers. Neither of these dosing strategies prevented murine lung cancer; however, we did detect changes in pulmonary inflammatory cell infiltrate and expression of CXCR4 (a chemokine receptor previously shown to increase in response to treprostinil exposure) in tumor-bearing, treprostinil-treated animals, indicating that the drug was bioavailable. One potential explanation stems from iloprost and treprostinil differentially activating cell surface prostaglandin receptors and intracellular peroxisome proliferator-activated receptors. When murine lung tumor cells were treated with treprostinil, their proliferation rate increased; in contrast, iloprost had no effect on proliferation. Future investigations comparing these two agents will provide insight into iloprost's chemopreventive mechanisms. Cancer Prev Res; 10(11); 671–9. ©2017 AACR.

Half of lung cancers are diagnosed in former smokers, leading to a significant treatment burden in this population. Chemoprevention in former smokers using the prostacyclin analogue iloprost reduces endobronchial dysplasia, a premalignant lung lesion. Iloprost requires the presence of the WNT receptor Frizzled 9 (Fzd9) for inhibition of transformed growth in vitro. To investigate the relationship between iloprost, cigarette smoke and Fzd9 expression, we used human samples, mouse models and in vitro studies. Fzd9 expression was low in human lung tumors and in progressive dysplasias. In mouse models and in vitro studies, tobacco smoke carcinogens reduced expression of Fzd9 while prostacyclin maintained or increased expression. Expression of miR-31 repressed Fzd9 expression, which was abrogated by prostacyclin. We propose a model where cigarette smoke exposure increases miR-31 expression, which leads to decreased Fzd9 expression and prevents response to iloprost. When smoke is removed miR-31 is reduced, prostacyclin can increase Fzd9 expression and progression of dysplasia is inhibited. Fzd9 and miR-31 are candidate biomarkers for precision application of iloprost and monitoring of treatment progress. As we continue to investigate the mechanisms of prostacyclin chemoprevention and identify biomarkers for its use, we will facilitate clinical trials and speed implementation of this valuable prevention approach.

Lung cancer remains the leading cause of cancer death in the United States, and chemoprevention offers an appealing area of investigation in the face of limited therapeutic success. Improvement in endobronchial histology was demonstrated in former smokers after oral iloprost chemoprevention in a phase II clinical trial. Of the 48 patients who received iloprost in the chemoprevention trial, 23 had regressive histology and 25 had stable or progressive histology. Identifying markers that predict which patients will respond to treatment will help refine target populations for future trials and clinical applications. Markers of drug activity will also facilitate clinical application by allowing monitoring during treatment. Preclinical studies indicate that iloprost, a prostacyclin analogue, acts through peroxisome proliferator activated receptor gamma (PPAR) to reduce transformed lung epithelial cell growth and markers of epithelial-to-mesenchymal transition (EMT). We hypothesize that PPAR expression status predicts response to prostacyclin chemoprevention and that expression changes in known downstream targets of PPAR and prostacyclin indicate response to prostacyclin treatment. Prostacyclin may also induce expression of PPAR, leading to increased antitumor signaling. We found that expression of PPAR and markers of prostacyclin signaling (15pgdh, CES1, and PTGS2) and EMT markers (Snail, Vimentin, Ecadherin, and CRB3) changed in cultured human bronchial epithelial cells (HBEC) in response to cigarette smoke condensate (CSC) and that iloprost reversed these changes. Expression in mice also changed in response to cigarette smoke carcinogens and prostacyclin. miR-34c is inversely correlated with bronchial histology grade and suppresses lung cancer progression. In our study, the level of miR-34c was lower in the NSCLC cell line H322 compared to HBEC. In H322, miR-34c increased with PPAR agonist treatment and decreased with PPAR antagonist treatment. In HBEC and mouse models of lung cancer chemoprevention, miR-34c increased with prostacyclin and decreased with cigarette smoke carcinogen exposure. In cultured primary progressive dysplastic bronchial epithelial cells, treatment with iloprost resulted in similar expression changes in Vimentin, Snail, Ecadherin, CRB3, CES1, and miR-34c. This study has the potential to improve iloprost lung cancer chemoprevention by allowing future trials to more effectively target high-risk patients, by providing a clinical biomarker for identification of chemoprevention candidates, and by identifying biomarkers for intermediate monitoring of response. Future studies will test expression of these markers in lung tissue biopsy and liquid biopsy samples from the oral and inhaled iloprost chemoprevention trials. Citation Format: Melissa New, Debbie McArthur, Lori Nield, Dan Merrick, Robert L. Keith, Meredith A. Tennis. Biomarkers for precision application of prostacyclin lung cancer chemoprevention [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B35.

Rationale: Lung cancer has a high mortality even when it is diagnosed at an early stage. Intercepting these early changes using chemoprevention could dramatically improve survival. Increased prostacyclin provides effective chemoprevention in multiple murine models and its oral analogue, iloprost, increased regression of dysplastic lesions in former smokers in clinical trials. MicroRNAs are short, noncoding RNA that are important post-transcriptional regulators during carcinogenesis. miRNA stability makes them attractive as potential biomarkers of premalignancy and response to chemoprevention. We hypothesize that alterations in the miRNA profile in early tumors and at-risk lung tissue are attenuated by increased levels of prostacyclin. Methods: Wild-type and transgenic prostacyclin synthase overexpressing (PGIS-OE) FVB/N mice were sacrificed at time = 0 as well as 8 and 16 weeks after intraperitoneal injection with urethane, which is known to induce Kras mutations resulting in adenocarcinoma. Transgenic mice and wild-type littermates were sacrificed at multiple timepoints (baseline, 8 weeks and 16 weeks post-urethane). Visible tumors were dissected and separated from remaining lung tissue. Tissue was lysed and homogenized and total RNA was extracted using the QIAGEN AllPrep DNA/RNA/miRNA Universal Kit. Samples from time = 0 and 16 weeks were analyzed using the Nanostring nCounter analysis system, which analyzed 550 murine miRNAs per sample. Quantitative real-time PCR (qRT-PCR) was performed using primers from QIAGEN. Results: miRNAs from lungs of naive WT and PGIS-OE mice were compared using Nanostring nCounter, without significant differences. From the 16-week group, miRNAs from tumors were compared with uninvolved lung tissue, with significant changes identified in over 80% of miRNAs tested. These data were cross-referenced with published human data, and a subset of biologically relevant miRNAs was chosen for further investigation with qRT-PCR in the earlier, 8-week timepoint: miR-143 (fold change=1.84), miR-146b (1.41), miR-154 (1.29), miR-410 (0.57), miR-429 (2.01), miR-451 (0.47). The miRNA fold-changes observed in the urethane-treated WT mice at 8 weeks were attenuated in the PGIS-OE mice. Conclusions: There are important changes to the miRNA profile in adenomas (early tumors) at 16 weeks, and these miRNAs are aberrant in the lungs at an even earlier time point when tumors have not yet developed (8 weeks). The changes to the miRNA profile in early carcinogenesis are attenuated by the presence of increased prostacyclin, even though prostacyclin does not cause significant changes to the miRNA profile at baseline. Ongoing investigation includes the evaluation of additional miRNAs in these samples, some from later time points (24 weeks), in cancer cell lines exposed to iloprost and in bronchial epithelial cells from a clinical trial of high-risk subjects treated with inhaled iloprost. Citation Format: Melissa L. New, Meredith A. Tennis, Lori D. Nield, Debbie McArthur, Robert L. Keith. Changes in miRNA profile in a murine model of lung adenocarcinoma are attenuated by increased prostacyclin levels [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A14.

Despite advances in targeted treatments, lung cancer remains a common and deadly malignancy, in part owing to its typical late presentation. Recent developments in lung cancer screening and ongoing efforts aimed at early detection, treatment, and prevention are promising areas to impact the mortality from lung cancer. In the past several years, lung cancer screening with low-dose chest computed tomography (CT) was shown to have mortality benefit, and lung cancer screening programs have been implemented in some clinical settings. Biomarkers for screening, diagnosis, and monitoring of response to therapy are under development. Prevention efforts aimed at smoking cessation are as crucial as ever, and there have been encouraging findings in recent clinical trials of lung cancer chemoprevention. Here we review advancements in the field of lung cancer prevention and early malignancy and discuss future directions that we believe will result in a reduction in the mortality from lung cancer.