Estimating the causal effect of filter ventilation levels in cigarettes on past 30-day smoking.

INTRODUCTION: Cigarettes with higher levels of filter ventilation are misperceived as less harmful and may be more appealing to consumers. Setting limits on filter ventilation has been considered as a policy, but a better understanding of any potential unintended consequences is needed. METHODS: Filter ventilation (0.2-61.1%) measured for 114 subbrands was merged with Wave 1 (2012-2013) of the Population Assessment of Tobacco Use and Health (PATH) data, restricted to adults 25+ years of age who smoked daily, and examined by quartiles. Inverse probability of exposure weights were used to estimate the causal effect of filter ventilation on past-30 day smoking at subsequent waves while accounting for potential confounders including demographics, menthol, heaviness of smoking and past quit attempts. RESULTS: Compared to those in the 1st (lowest) quartile of filter ventilation, those in the 2nd, 3rd and 4th quartiles had 1.02 (95% confidence interval: 0.57, 1.82), 0.86 (0.42, 1.73) and 1.52 (0.90, 2.56) times the odds of no past 30-day smoking at Wave 2 (approximately 1 year later, p=0.163), and 1.28 (0.80, 2.07), 1.11 (0.67, 1.83) and 1.65 (1.01, 1.24) times the odds of no past 30-day smoking at Wave 4 (3 years later, p = 0.238). CONCLUSIONS: This observational study found no strong evidence of a causal effect of filter ventilation on past 30-day smoking at approximately 1 and 3 years follow-up. However, our effect size estimates were not precise and thus an increase in the ability to quit smoking due to higher filter ventilation levels cannot be ruled out. IMPLICATIONS: Setting a maximum limit on filter ventilation (FV) in cigarettes could address the misperception that highly ventilated cigarettes are less harmful and the link between FV and lung adenocarcinoma. It is important to understand whether such a policy would have unintended consequences on longer-term smoking behavior. We found no strong evidence that FV affects past 30-day smoking 1-3 years later, but could not rule out the possibility that higher FV increases cessation rates. If future studies confirm these epidemiologic findings, this could mean that setting a limit on FV would not lead to reductions in the ability to quit smoking.

Selective Reduction of Socioeconomic Disparities in the Experimental Tobacco Marketplace: Effects of Cigarette and E-cigarette Flavor Restrictions.

INTRODUCTION: Cigarette smoking accounts for >30% of the socioeconomic gap in life expectancy. Flavored restrictions claim to promote equity; however, no previous studies have compared the effect of cigarette and e-cigarette flavor restrictions among individuals who smoke with lower and higher socioeconomic status (SES). AIMS AND METHODS: In a between-group within-subject design, individuals with lower (n = 155) and higher (n = 125) SES completed hypothetical purchasing trials in the experimental tobacco marketplace (ETM). Conditions were presented in a 2 × 2 factorial design (cigarette flavors restricted or unrestricted and e-cigarette flavors restricted or unrestricted) with increasing cigarette prices across trials. RESULTS: Results show (1) SES differences in cigarette, e-cigarette, and NRT purchases under unrestricted policies, with lower SES showing higher cigarette demand and lower e-cigarette and NRT substitution than higher SES, (2) cigarette restrictions decreased cigarette and increased NRT purchases among lower SES, but no significant changes among higher SES, (3) decreased SES differences in cigarette demand under cigarette restrictions, but persistence under e-cigarette restrictions or their combination, (4) persistence of SES differences in e-cigarette purchases when all restrictions were enforced, and (5) waning of SES differences in NRT purchasing under all restrictions. CONCLUSIONS: Flavor restrictions differentially affected individuals based on SES. Within-group comparisons demonstrated restrictions significantly impacted lower SES, but not higher SES. Between-group comparisons showed SES differences in cigarette purchasing decreased under cigarette restrictions, but persisted under e-cigarette-restrictions or their combination. Additionally, SES differences in NRT substitution decreased under flavor restrictions. These findings highlight the utility of the ETM to investigate SES disparities. IMPLICATIONS: With increasing trends of socioeconomic differences in smoking prevalence and cessation rates, smoking-related health disparities are expected to continue to widen. Restricting menthol flavor in cigarettes while enhancing the availability and affordability of NRT have the potential to alleviate SES disparities in tobacco use, therefore, positively impacting health equity. However, this effect may depend on flavor availability in other tobacco products.

COVID-19 or Cancer Stress? Anxiety and Depressive Symptoms in Patients with Advanced Lung Cancer.

BACKGROUND: Of all cancer patients, those with lung cancer are among the highest risk for infection, pneumonia, hospitalization, and early death from COVID-19. As cancer stress is ubiquitous, this exploratory study examines patients' COVID-19 stress and cancer stress in relation to their depressive and anxiety symptoms. METHOD: Newly diagnosed advanced lung cancer patients (N = 76) completed measures of cancer stress, COVID-19 illness perceptions and stress, and depressive and anxiety symptoms at a single monthly follow-up early in the pandemic (May 2020 to July 2020; Clinicaltrials.gov #NCT03199651). Hierarchical linear multiple regression analysis was used to identify the relationship of stressor variables to depressive and anxiety symptoms in this cross-sectional study. RESULTS: Hierarchical linear models revealed cancer stress was a significant predictor of both depressive symptoms (F(14,30) = 5.327, p < 0.001, R2 = 0.71, adjusted R2 = 0.58) and anxiety symptoms (F(14,30) = 4.513, p < 0.001, R2 = 0.68, adjusted R2 = 0.53) for patients at the start of the COVID-19 pandemic. By contrast, COVID-19 stress was not a significant predictor of depressive (F(13,31) = 1.415 p = .21, R2 = .37, adjusted R2 = .11) or anxiety symptoms (F(13,31) = 1.23, p = .30, R2 = .34, adjusted R2 = - .07). CONCLUSIONS: Advanced lung cancer patients during the early phase of the COVID-19 pandemic reported cancer stress as more important than COVID-19 stress in relation to their mental health. Empirically supported biobehavioral and cognitive behavioral treatments remain important to reducing psychological symptoms and enhancing patients' quality of life.

Sex-specific lung inflammation and mitochondrial damage in a model of electronic cigarette exposure in asthma.

The prevalence of electronic cigarette (EC) use among adult with asthma has continued to increase over time, in part due to the belief of being less harmful than smoking. However, the extent of their toxicity and the involved mechanisms contributing to the deleterious impact of EC exposure on patients with preexisting asthma have not been delineated. In the present project, we tested the hypothesis that EC use contributes to respiratory damage and worsening inflammation in the lungs of patients with asthma. To define the consequences of EC exposure in established asthma, we used a mouse model with/without preexisting asthma for short-term exposure to EC aerosols. C57/BL6J mice were sensitized and challenged with a DRA (dust mite, ragweed, Aspergillus fumigates, 200 µg/mL) mixture and exposed daily to EC with nicotine (2% nicotine in 30:70 propylene glycol: vegetable glycerin) or filtered air for 2 wk. The mice were evaluated at 24 h after the final EC exposure. After EC exposure in asthmatic mice, lung inflammatory cell infiltration and goblet cell hyperplasia were increased, whereas EC alone did not cause airway inflammation. Our data also show that mitochondrial DNA (mtDNA) content and a key mtDNA regulator, mitochondrial transcription factor A (TFAM), are reduced in asthmatic EC-exposed mice in a sex-dependent manner. Together, these results indicate that TFAM loss in lung epithelium following EC contributes to male-predominant sex pathological differences, including mitochondrial damage, inflammation, and remodeling in asthmatic airways.NEW & NOTEWORTHY Respiratory immunity is dysregulated in preexisting asthma, and further perturbations by EC use could exacerbate asthma severity. However, the extent of their toxicity and the involved mechanisms contributing to the deleterious impact of EC exposure on patients with preexisting asthma have not been delineated. We found that EC has unique biological impacts in lungs and potential sex differences with loss of TFAM, a key mtDNA regulator, in lung epithelial region from our animal EC study.

Vitamin E Acetate in Bronchoalveolar-Lavage Fluid Associated with EVALI.

BACKGROUND: The causative agents for the current national outbreak of electronic-cigarette, or vaping, product use-associated lung injury (EVALI) have not been established. Detection of toxicants in bronchoalveolar-lavage (BAL) fluid from patients with EVALI can provide direct information on exposure within the lung. METHODS: BAL fluids were collected from 51 patients with EVALI in 16 states and from 99 healthy participants who were part of an ongoing study of smoking involving nonsmokers, exclusive users of e-cigarettes or vaping products, and exclusive cigarette smokers that was initiated in 2015. Using the BAL fluid, we performed isotope dilution mass spectrometry to measure several priority toxicants: vitamin E acetate, plant oils, medium-chain triglyceride oil, coconut oil, petroleum distillates, and diluent terpenes. RESULTS: State and local health departments assigned EVALI case status as confirmed for 25 patients and as probable for 26 patients. Vitamin E acetate was identified in BAL fluid obtained from 48 of 51 case patients (94%) in 16 states but not in such fluid obtained from the healthy comparator group. No other priority toxicants were found in BAL fluid from the case patients or the comparator group, except for coconut oil and limonene, which were found in 1 patient each. Among the case patients for whom laboratory or epidemiologic data were available, 47 of 50 (94%) had detectable tetrahydrocannabinol (THC) or its metabolites in BAL fluid or had reported vaping THC products in the 90 days before the onset of illness. Nicotine or its metabolites were detected in 30 of 47 of the case patients (64%). CONCLUSIONS: Vitamin E acetate was associated with EVALI in a convenience sample of 51 patients in 16 states across the United States. (Funded by the National Cancer Institute and others.).

Mean platelet volume, thrombocytosis, and survival in non-small cell lung cancer patients treated with first-line pembrolizumab alone or with chemotherapy.

INTRODUCTION: Patients treated with immune checkpoint inhibitors (ICIs) may not response to treatment and are at risk for immune-related adverse events (irAEs). Platelet function has been linked to both oncogenesis and immune evasion. We studied the association between the change in mean platelet volume (MPV), platelet count, survival, and the risk of developing irAEs in patients with metastatic non-small cell lung cancer (NSCLC) who have received first-line ICI. METHODS: In this retrospective study, delta (∆) MPV was defined as the difference between cycle 2 and baseline MPV. Patient data were collected via chart review, and Cox proportional hazard and Kaplan-Meier method were used to assess the risk and estimate median overall survival. RESULTS: We identified 188 patients treated with first-line pembrolizumab, with or without concurrent chemotherapy. There were 80 (42.6%) patients received pembrolizumab monotherapy, and 108 (57.4%) received pembrolizumab in combination with platinum-based chemotherapy. Patients whose MPV (∆MPV ≤ 0) decreased had hazard ratio (HR) = 0.64 (95% CI 0.43-0.94) for death with p = 0.023. Patients with ∆MPV ≤ - 0.2 fL (median), there was a 58% increase in the risk of developing irAE (HR = 1.58, 95% CI 1.04-2.40, p = 0.031). Thrombocytosis at baseline and cycle 2 was associated with shorter OS with p = 0.014 and 0.039, respectively. CONCLUSION: Change in MPV after 1 cycle of pembrolizumab-based treatment was significantly associated with overall survival as well as the occurrence of irAEs in patients with metastatic NSCLC in the first-line setting. In addition, thrombocytosis was associated with poor survival.

Association Between Pretreatment Chest Imaging and Immune Checkpoint Inhibitor Pneumonitis Among Patients With Lung Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. METHODS: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. RESULTS: A total of 471 patients with lung cancer were included, of which 402 had non-small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69-16.92; P<.001; and HR, 2.81; 95% CI, 1.50-5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17-18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3-5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. CONCLUSIONS: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

Smoking Cessation, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

Although the harmful effects of smoking after a cancer diagnosis have been clearly demonstrated, many patients continue to smoke cigarettes during treatment and beyond. The NCCN Guidelines for Smoking Cessation emphasize the importance of smoking cessation in all patients with cancer and seek to establish evidence-based recommendations tailored to the unique needs and concerns of patients with cancer. The recommendations contained herein describe interventions for cessation of all combustible tobacco products (eg, cigarettes, cigars, hookah), including smokeless tobacco products. However, recommendations are based on studies of cigarette smoking. The NCCN Smoking Cessation Panel recommends that treatment plans for all patients with cancer who smoke include the following 3 tenets that should be done concurrently: (1) evidence-based motivational strategies and behavior therapy (counseling), which can be brief; (2) evidence-based pharmacotherapy; and (3) close follow-up with retreatment as needed.

Long-Term Impact of Daily E-cigarette Exposure on the Lungs of Asthmatic Mice.

INTRODUCTION: Although the greater popularity of electronic cigarettes (EC) among asthmatics is alarming, there is limited knowledge of the long-term consequences of EC exposure in asthmatics. AIMS AND METHODS: Mild asthmatic C57/BL6J adult male and female mice were established by intranasal insufflation with three combined allergens. The asthmatic and age and sex-matched' naïve mice were exposed to air, nicotine-free (propylene glycol [PG]/vegetable glycerin [VG]-only), or PG/VG+Nicotine, 4 hours daily for 3 months. The effects of EC exposure were accessed by measuring cytokines in bronchoalveolar lavage, periodic acid-schiff (PAS) staining, mitochondrial DNA copy numbers (mtCN), and the transcriptome in the lung. Significance was false discovery rate <0.2 for transcriptome and 0.05 for the others. RESULTS: In asthmatic mice, PG/VG+Nicotine increased PAS-positive cells and IL-13 compared to mice exposed to air and PG/VG-only. In naïve mice exposed to PG/VG+Nicotine and PG/VG-only, higher INF-γ was observed compared to mice exposed only to air. PG/VG-only and PG/VG+Nicotine had significantly higher mtCN compared to air exposure in asthmatic mice, while the opposite pattern was observed in non-asthmatic naïve mice. Different gene expression patterns were profoundly found for asthmatic mice exposed to PG/VG+Nicotine compared to PG/VG-only, including genes involved in mitochondrial dysfunction, oxidative phosphorylation, and p21-activated kinase (PAK) signaling. CONCLUSIONS: This study provides experimental evidence of the potential impact of nicotine enhancement on the long-term effects of EC in asthmatics compared to non-asthmatics. IMPLICATIONS: The findings from this study indicate the potential impact of EC in asthmatics by addressing multiple biological markers. The long-term health outcomes of EC in the susceptible group can be instrumental in supporting policymaking and educational campaigns and informing the public, healthcare providers, and EC users about the underlying risks of EC use.

Switching to cigarette brand variants with different filter ventilation levels: a descriptive analysis.

BACKGROUND: Regulation of filter ventilation (FV) has been proposed to reduce misperceptions that ventilation reduces the health risks of smoking. We describe smoking behaviour and exposure after switching to a cigarette brand variant (CBV) with a different FV level. METHODS: Wave 1 (2013-2014) of the Population Assessment of Tobacco Use and Health Study was merged with FV levels of participants' CBV and restricted to adults with a usual CBV, smoked daily and included in wave 4 (2016-2017; n=371). Generalised estimation equations method modelled changes in FV and cigarettes per day (CPD), quit interest, total nicotine equivalents (TNE) and total NNAL (biomarker of a tobacco-specific carcinogen). FV change was defined as a change in CBV resulting in a ≥20% increase or decrease in FV. Secondary analyses used FV change based on an increase from <5% to >10% or a decrease from >10% to <5%. RESULTS: A non-significant pattern indicating an increase of 0.97 and 0.49 CPD was observed among those who switched to a CBV and increased FV by ≥20% and from <5% to >10%, respectively. A non-significant pattern indicating a decrease of 1.31 and 1.97 CPD was observed among those who decreased FV by ≥20% and from >10% to <5%, respectively. Changes in quit interest and biomarkers were also non-significant with one exception: greater reduction in TNE among those who decreased from >10% to <5% FV versus no change (-8.51 vs -0.25 nmol/mg creatinine; p=0.0447). CONCLUSIONS: Switching to CBV with lower FV does not appear to increase exposure and may even reduce exposure for some. Additional investigations are recommended to confirm these descriptive findings.

Risk perceptions and continued smoking as a function of cigarette filter ventilation level among US youth and young adults who smoke.

BACKGROUND: While evidence demonstrates that the industry's marketing of cigarettes with higher filter ventilation (FV) misleads adults about their health risks, there is no research on the relationships between FV, risk perceptions and smoking trajectories among youth (ages 12-17) and young adults (ages 18-24). METHODS: Data on FV levels of major US cigarette brands/sub-brands were merged with the Population Assessment of Tobacco and Health Study to examine whether FV level in cigarettes used by wave 1 youth/young adults (n=1970) predicted continued smoking at waves 2-4, and whether those relationships were mediated by perceived risk of their cigarette brand. FV was modelled based on tertiles (0.2%-11.8%, low; 11.9%-23.2%, moderate; 23.3%-61.1%, high) to predict daily smoking, past 30-day smoking and change in number of days smoking at successive waves. RESULTS: The odds of perceiving one's brand as less harmful than other cigarette brands was 2.21 times higher in the high versus low FV group (p=0.0146). Relationships between FV and smoking outcomes at successive waves were non-significant (all p>0.05). CONCLUSION: Youth and young adults who use higher FV cigarettes perceived their brand as less harmful compared with other brands. However, level of FV was not associated with continued smoking.

Psychological Symptom Trajectories and Non-Small Cell Lung Cancer Survival: A Joint Model Analysis.

OBJECTIVE: Lung cancer remains the number one cause of cancer-related mortality worldwide, but less known is that lung cancer patients are among the most psychologically disabled of all cancer groups. Patients with stage IV non-small cell lung cancer (NSCLC) were studied to test the hypothesis that trajectories of depression and/or anxiety symptoms after diagnosis would show an adverse relationship with survival, beyond relevant controls. METHODS: Patients with stage IV NSCLC (n = 157) were enrolled (ClinicalTrials.gov Identifier: NCT03199651) at diagnosis and completed validated measures for depressive symptoms (Patient Health Questionnaire-9) and anxiety symptoms (Generalized Anxiety Disorder-7). Patients were reassessed every 1 to 2 months through 24 months (16 assessments; 80% average completion rate) and survival monitored. Joint statistical models provided simultaneous modeling of longitudinal (psychological) and time-to-event (survival) processes. Control variables were age, sex, marital status, education, smoking status, cancer type, and treatment received. RESULTS: Depression and anxiety symptoms significantly decreased with time since diagnosis. The 2-year trajectory of depressive symptoms was significantly associated with cancer survival after adjustment for covariates (hazard ratio = 1.09 per unit increase in the Patient Health Questionnaire-9, 95% confidence interval = 1.03-1.15, p = .002). Anxiety was marginally significant in the unadjusted (p = .053) but not the adjusted (p = .39) model. CONCLUSIONS: For the first time, joint model analyses test the interaction of a longitudinal trajectory of psychological symptoms, assessed from diagnosis to 24 months, and cancer survival. New data show the continuation of depressive and anxiety symptoms through treatment and thereafter. Immunotherapy and targeted therapies have dramatically improved survival for patients with advanced NSCLC; however, novel data suggest their benefit may be constrained by depressive symptoms.

Cancer Treatment During COVID-19: Resilience of Individuals With Advanced Non-Small Cell Lung Cancer Versus Community Controls.

BACKGROUND: Among all patients with cancer, those with advanced non-small cell lung cancer (NSCLC) experience the most distress. Although new therapies are improving survival, it is unknown whether receiving immunotherapy or targeted therapy during the COVID-19 pandemic increases patients' psychological vulnerability. To meet clinical needs, knowledge of patients' COVID-19 perceptions and safety behaviors is essential. Thus, this study compared patients' psychological responses at diagnosis and during COVID-19 and compared patients with similar individuals without cancer during the same period. PATIENTS AND METHODS: Patients with advanced NSCLC enrolled at diagnosis for cohort study participated (ClinicalTrials.gov identifier: NCT03199651). Those with follow-ups from April 28, 2020, through July 14, 2020 (n=76), were assessed again including COVID-19 measures. Simultaneously, community controls with similar sociodemographics and smoking histories were solicited (n=67). Measures were COVID-19 perceptions (Brief Illness Perception Questionnaire), social distancing, and depressive (Patient Health Questionnaire-9) and anxiety (Generalized Anxiety Disorder-7) symptoms. First, analyses evaluated differences in the psychological responses of patients with NSCLC at diagnosis and during COVID-19. Second, patients and controls were contrasted on COVID-19 perceptions, social distancing, and psychological symptoms. RESULTS: The depressive and anxious symptoms of patients with NSCLC were greater at diagnosis (P<.02) than during COVID-19, approximately 1 year later. Patients with NSCLC and controls did not differ in terms of sociodemographics, except those with NSCLC were more racially diverse and older, and had greater smoking history (P<.03). Groups did not differ regarding concern, understanding, or perceived control over COVID-19 (P>.406). Notably, controls anticipated the COVID threat would last longer, practiced more social distancing, were more concerned about family (P<.04), and reported worse psychological symptoms (P<.023). With less depression and anxiety, patients with NSCLC viewed COVID-19 as a shorter-term threat and had fewer COVID-19-related worries than did controls. For controls, COVID-19 was more salient, heightening worries and psychological symptoms. CONCLUSIONS: Despite multiple health stressors, patients with NSCLC demonstrated resilience when receiving cancer treatment during COVID-19. Nonetheless, this population remains psychologically vulnerable, requiring support at diagnosis and thereafter.

Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort. PATIENTS AND METHODS: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors. RESULTS: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs. CONCLUSIONS: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.

E-Cigarette or Vaping Product Use-associated Lung Injury: Developing a Research Agenda. An NIH Workshop Report.

The NHLBI convened a working group on October 23, 2019, to identify the most relevant and urgent research priorities and prevailing challenges in e-cigarette or vaping product use-associated lung injury (EVALI). Experts across multiple disciplines discussed the complexities of the EVALI outbreak, identified research priorities, and recommended strategies to address most effectively its causal factors and improve diagnosis, treatment, and prevention of this disease. Many research priorities were identified, including the need to create national and international registries of patients with EVALI, to track accurately those affected and assess outcomes. The group concluded that biospecimens from subjects with EVALI are urgently needed to help define EVALI pathogenesis and that vaping has disease risks that are disparate from smoking, with the occurrence of EVALI highlighting the importance of broadening e-cigarette research beyond comparators to smoking-related diseases.

Brief report: inhaled corticosteroid use and the risk of checkpoint inhibitor pneumonitis in patients with advanced cancer.

BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that may complicate treatment with immune checkpoint inhibitors (ICI) and can cause significant morbidity. We sought to identify predictors for the development of CIP, and whether the use of inhaled corticosteroids (ICS) at time of ICI may be protective. METHODS: Patients with advanced cancer treated with ICI from 2011 and 2018 were included in this study. CIP attribution to ICI was determined by treating physician at time of diagnosis. Predictors were assessed by univariate and multivariable Cox proportional hazard models. RESULTS: We identified 837 pts treated with ICI, of whom 30 (3.6%) developed grade 2 or higher CIP. 82 patients (9.8%) were receiving ICS at time of ICI and had increased risk of developing CIP with hazard ration (HR) of 4.22 (95% CI 1.93-9.21, p < 0.001) compared to those patients not receiving ICS. Patients with age ≥ 65 years had increased risk of developing CIP (HR 2.12, 95% CI 1.02-4.40, p = 0.044), as did 209 patients with lung cancer (198 NSCLC and 11 SCLC) compared to other types of cancers (HR 3.15, 95% CI 1.54-6.46, p = 0.002). In multivariable analysis, age ≥ 65 years, lung cancer diagnosis, and ICS use remained statistically associated with the development of CIP, with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009). CONCLUSIONS: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age ≥ 65 years and lung cancers as independent risk factors for CIP.

A Randomized Clinical Trial of Snus Examining the Effect of Complete Versus Partial Cigarette Substitution on Smoking-Related Behaviors, and Biomarkers of Exposure.

INTRODUCTION: This 8-week multisite, randomized controlled trial of snus examined the differential effects of instructions on (1) snus use, (2) smoking and smoking-related measures, and (3) exposure to tobacco-related constituents. METHOD: US adult daily cigarette smokers (n = 150; 43.3% female; Medianage = 43.5) were recruited from Minneapolis, Minnesota; Columbus and Coshocton, Ohio; and Buffalo, New York. Following a 1-week sampling phase of snus, participants who used at least 7 pouches were randomized to either (1) partial substitution (PS; "use snus as you like with your cigarettes"), (2) complete substitution (CS; "avoid cigarettes"), or (3) usual brand cigarettes (UB). Analyses included between-group analyses (eg, PS vs. CS) using Wilcoxon rank sum test of cigarettes per day and snus pouches per day, and a linear mixed model (biomarkers). RESULTS: Compared to the PS and UB groups, smokers assigned to CS reported greater reductions in cigarettes per day (ps < .001), using more snus pouches per day (p = .02), and more smoke-free days (CS median = 14.5, PS and UB medians = 0, p < .001). In addition, results demonstrated reductions in carbon monoxide (p < .001), total nicotine equivalents (p = .02), and four out of five measured volatile organic compounds (ps < .01) over time among the CS group. Exposure to N'-nitrosonornicotine increased by trial end only among the PS group (p < .04). Phenanthrene tetraol increased among all groups by trial end (p = .02) with no difference between groups. CONCLUSIONS: Instructions to completely switch from cigarettes to snus resulted in the greatest reduction in cigarettes and exposure to harmful constituents. IMPLICATIONS: Directly instructing smokers to switch completely to snus, rather than using ad libitum (with no instructions to avoid cigarettes), is necessary for reductions in smoking and subsequent exposure to harmful constituents.

A Randomized Clinical Trial Examining the Effects of Instructions for Electronic Cigarette Use on Smoking-Related Behaviors and Biomarkers of Exposure.

INTRODUCTION: Electronic cigarettes (e-cigarettes) have the potential to significantly reduce exposure to harmful constituents associated with cigarette smoking when smokers completely substitute cigarettes with e-cigarettes. This study examined patterns of e-cigarette and cigarette use, and extent of toxicant exposure, if smokers were instructed and incentivized to completely switch to e-cigarettes compared to instructions to use the product ad libitum. AIMS AND METHODS: US adult daily smokers (n = 264; 49.2% female; Mage = 47.0), uninterested in quitting smoking immediately, were recruited from Minneapolis, MN, Columbus, OH, and Buffalo, NY. Participants were randomized to 8 weeks of instructions for (1) ad libitum use of e-cigarettes (AD-E), (2) complete substitution of cigarettes with e-cigarettes (CS-E), (3) complete substitution of cigarettes with nicotine gum or lozenge (CS-NRT), or (4) continue smoking of usual brand cigarettes (UB). Participants were incentivized for protocol compliance, including complete switching in the CS-E and CS-NRT groups. Outcome variables were cigarette smoking rate and tobacco-related biomarkers of exposure. RESULTS: Smokers in the CS-E and CS-NRT groups showed lower rates of smoking and lower exposure to carbon monoxide, tobacco carcinogens, and other toxicants than smokers in the AD-E group. In general, no significant differences were observed between CS-E versus CS-NRT or between AD-E versus UB for most biomarkers. Significantly higher 7-day point prevalence smoke-free rates were observed for CS-E versus CS-NRT. CONCLUSIONS: Smokers instructed and incentivized to completely switch to e-cigarettes resulted in lower smoking rates and greater reductions in exposures to harmful chemicals than smokers instructed to use the product ad libitum. IMPLICATIONS: Smokers instructed to completely substitute e-cigarettes for cigarettes displayed significantly lower levels of smoking and biomarkers of exposure to carcinogens and toxicants, compared to smokers instructed to use e-cigarettes ad libitum and similar levels as smokers instructed to completely substitute with nicotine replacement therapies. Furthermore, a higher rate of complete switching was achieved with e-cigarettes versus nicotine replacement therapies. Approaches to maximize complete substitution with e-cigarettes are an important area for future research.

SMaSH: Sample matching using SNPs in humans.

BACKGROUND: Inadvertent sample swaps are a real threat to data quality in any medium to large scale omics studies. While matches between samples from the same individual can in principle be identified from a few well characterized single nucleotide polymorphisms (SNPs), omics data types often only provide low to moderate coverage, thus requiring integration of evidence from a large number of SNPs to determine if two samples derive from the same individual or not. METHODS: We select about six thousand SNPs in the human genome and develop a Bayesian framework that is able to robustly identify sample matches between next generation sequencing data sets. RESULTS: We validate our approach on a variety of data sets. Most importantly, we show that our approach can establish identity between different omics data types such as Exome, RNA-Seq, and MethylCap-Seq. We demonstrate how identity detection degrades with sample quality and read coverage, but show that twenty million reads of a fairly low quality RNA-Seq sample are still sufficient for reliable sample identification. CONCLUSION: Our tool, SMASH, is able to identify sample mismatches in next generation sequencing data sets between different sequencing modalities and for low quality sequencing data.

Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer.

BACKGROUND: A large collaborative analysis of data from 47 epidemiological studies concluded that longer duration of breastfeeding reduces the risk of developing breast cancer. Despite the strong epidemiological evidence, the molecular mechanisms linking prolonged breastfeeding to decreased risk of breast cancer remain poorly understood. METHODS: We modeled two types of breastfeeding behaviors in wild type FVB/N mice: (1) normal or gradual involution of breast tissue following prolonged breastfeeding and (2) forced or abrupt involution following short-term breastfeeding. To accomplish this, pups were gradually weaned between 28 and 31 days (gradual involution) or abruptly at 7 days postpartum (abrupt involution). Mammary glands were examined for histological changes, proliferation, and inflammatory markers by immunohistochemistry. Fluorescence-activated cell sorting was used to quantify mammary epithelial subpopulations. Gene set enrichment analysis was used to analyze gene expression data from mouse mammary luminal progenitor cells. Similar analysis was done using gene expression data generated from human breast samples obtained from parous women enrolled on a tissue collection study, OSU-2011C0094, and were undergoing reduction mammoplasty without history of breast cancer. RESULTS: Mammary glands from mice that underwent abrupt involution exhibited denser stroma, altered collagen composition, higher inflammation and proliferation, increased estrogen receptor α and progesterone receptor expression compared to those that underwent gradual involution. Importantly, when aged to 4 months postpartum, mice that were in the abrupt involution cohort developed ductal hyperplasia and squamous metaplasia. Abrupt involution also resulted in a significant expansion of the luminal progenitor cell compartment associated with enrichment of Notch and estrogen signaling pathway genes. Breast tissues obtained from healthy women who breastfed for < 6 months vs ≥ 6 months showed significant enrichment of Notch signaling pathway genes, along with a trend for enrichment for luminal progenitor gene signature similar to what is observed in BRCA1 mutation carriers and basal-like breast tumors. CONCLUSIONS: We report here for the first time that forced or abrupt involution of the mammary glands following pregnancy and lack of breastfeeding results in expansion of luminal progenitor cells, higher inflammation, proliferation, and ductal hyperplasia, a known risk factor for developing breast cancer.