Sex-related DNA methylation is associated with inflammation and gene expression in the lungs of healthy individuals.

Lung cancer exhibits sex-biased molecular characteristics and epidemiological trends, suggesting a need for sex-specific approaches to understanding its etiology and treatment. DNA methylation alterations play critical roles in lung carcinogenesis and may serve as valuable biomarkers for precision medicine strategies. We employed the Infinium MethylationEPIC array to identify autosomal sex-related differentially methylated CpG sites (DM-CpGs) in lung epithelium of healthy individuals (32 females and 37 males) while controlling for age, BMI, and tobacco use. We correlated DM-CpGs with gene expression in lung epithelium and immune responses in bronchoalveolar lavage. We validated these DM-CpGs in lung tumors and adjacent normal tissue from The Cancer Genome Atlas (TCGA). Among 522 identified DM-CpGs, 61% were hypermethylated in females, predominantly located in promoter regions. These DM genes were implicated in cell-to-cell signaling, cellular function, transport, and lipid metabolism. Correlation analysis revealed sex-specific patterns between DM-CpGs and gene expression. Additionally, several DM-CpGs were correlated significantly with cytokines (IL-1ß, IL-4, IL-12p70, and IFN-γ), macrophage, and lymphocyte counts. Also, some DM-CpGs were observed in TCGA lung adenocarcinoma, squamous cell carcinoma, and adjacent normal tissues. Our findings highlight sex-specific DNA methylation patterns in healthy lung epithelium and their associations with lung gene expression and lung immune biomarkers. These findings underscore the potential role of lung sex-related CpGs as epigenetic predispositions influencing sex disparities in lung cancer risk and outcomes, warranting further investigation for personalized lung cancer management strategies.

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.

A Phase 2 Trial of Primary Tumor Stereotactic Body Radiation Therapy Boost Before Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: Primary tumor failure is common in patients treated with chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control (PTC) in early-stage NSCLC. This trial tested an SBRT boost to the primary tumor before the start of CRT to improve PTC. METHODS AND MATERIALS: Patients with LA-NSCLC received an SBRT boost in 2 fractions (central location 12 Gy, peripheral location 16 Gy) to the primary tumor, followed by standard CRT (60 Gy in 30 fractions). The primary objective was PTC rate at 1 year, and the hypothesis was that the 1-year PTC rate would be ≥90%. Secondary objectives included objective response rate, regional and distant control, disease-free survival (DFS), and overall survival (OS). Correlative studies included functional magnetic resonance imaging and blood-based miRNA analysis. RESULTS: The study enrolled 21 patients (10 men and 11 women); the median age was 62 years (range, 52-78). The median pretreatment primary tumor size was 5.0 cm (range, 1.0-8.3). The most common nonhematologic toxicities were pneumonitis, fatigue, esophagitis/dysphagia, dyspnea, and cough. Only 1 treatment-related grade 4 nonhematologic toxicity occurred (respiratory failure/radiation pneumonitis), and no grade 5 toxicities occurred. The objective response rate at 3 and 6 months was 72.7% and 80.0%, respectively, and PTC at 1 and 2 years was 100% and 92.3%, respectively. The 2-year regional and distant control rates were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 years were 46.1% and 50.3%, respectively, and median survival was 37.8 months. Functional magnetic resonance imaging detected a mean relative decrease in blood oxygenation level-dependent signal of -87.1% (P = .05), and miR.142.3p was correlated with increased risk of grade ≥3 pulmonary toxicity (P = .01). CONCLUSIONS: Dose escalation to the primary tumor using upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably to standard treatment. Functional magnetic resonance imaging suggested changes in oxygenation with the first SBRT boost dose, and miR.142.3p was correlated with pulmonary toxicity.

mRNA vaccines against SARS-CoV-2 induce divergent antigen-specific T-cell responses in patients with lung cancer.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is highly transmissible and evades pre-established immunity. Messenger RNA (mRNA) vaccination against ancestral strain spike protein can induce intact T-cell immunity against the Omicron variant, but efficacy of booster vaccination in patients with late-stage lung cancer on immune-modulating agents including anti-programmed cell death protein 1(PD-1)/programmed death-ligand 1 (PD-L1) has not yet been elucidated. METHODS: We assessed T-cell responses using a modified activation-induced marker assay, coupled with high-dimension flow cytometry analyses. Peripheral blood mononuclear cells (PBMCs) were stimulated with various viral peptides and antigen-specific T-cell responses were evaluated using flow cytometry. RESULTS: Booster vaccines induced CD8+ T-cell response against the ancestral SARS-CoV-2 strain and Omicron variant in both non-cancer subjects and patients with lung cancer, but only a marginal induction was detected for CD4+ T cells. Importantly, antigen-specific T cells from patients with lung cancer showed distinct subpopulation dynamics with varying degrees of differentiation compared with non-cancer subjects, with evidence of dysfunction. Notably, female-biased T-cell responses were observed. CONCLUSION: We conclude that patients with lung cancer on immunotherapy show a substantial qualitative deviation from non-cancer subjects in their T-cell response to mRNA vaccines, highlighting the need for heightened protective measures for patients with cancer to minimize the risk of breakthrough infection with the Omicron and other future variants.

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.

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.

Illegal product purchasing in the experimental tobacco marketplace: Effects of menthol cigarette and cigarette ventilation ban.

BACKGROUND: Tobacco regulations may increase demand for illegal cigarettes. We use the Experimental Tobacco Marketplace to estimate the impact of banning menthol cigarettes (Experiment 1) and decreasing allowable cigarette filter ventilation levels (Experiment 2). METHODS: Crowdsourced participants were randomized into one of four groups (2×2 factorial design). Experiment 1 included menthol availability (yes/no) by purchasing option (legal only vs illegal available). Experiment 2 included filter-vented cigarettes availability (yes/no) by purchasing option (legal only vs illegal available). Participants were given an individualized budget to purchase tobacco. Percent budget spent was the outcome measure. RESULTS: Experiment 1, with a legal marketplace only, non-menthol cigarette purchasing was lower (p=0.010) and electronic-cigarette purchasing was higher (p=0.016), when cigarettes were banned compared to when they were available. With an illegal marketplace, switching to legal non-menthol cigarettes was less likely (p<0.001) and purchasing illegal menthol cigarettes was higher (p<0.001), when cigarettes were banned compared to when they were available. Experiment 2, with a legal marketplace only, cigarette purchasing was lower (p=0.010), when the participant's filtered vented cigarettes were banned compared to when they were available. With an illegal marketplace, purchasing the legal low-ventilated cigarette option was lower (p<0.001) and significant differences in illegal filter-vented cigarette purchasing were not observed, when their filter-vented cigarettes were banned compared to when they were available legally. CONCLUSIONS: Without an illegal option, both restrictions decreased cigarette purchasing, but the menthol ban increased e-cigarette purchasing. With an illegal option, a menthol ban increased illegal cigarette purchasing, but decreasing filter ventilation did not.

Accelerated epigenetic age, inflammation, and gene expression in lung: comparisons of smokers and vapers with non-smokers.

BACKGROUND: Cigarette smoking and aging are the main risk factors for pulmonary diseases, including cancer. Epigenetic aging may explain the relationship between smoking, electronic cigarette vaping, and pulmonary health. No study has examined smoking and vaping-related epigenetic aging in relation to lung biomarkers. METHODS: Lung epigenetic aging measured by DNA methylation (mAge) and its acceleration (mAA) was assessed in young (age 21-30) electronic cigarette vapers (EC, n = 14, including 3 never-smoking EC), smokers (SM, n = 16), and non-EC/non-SM (NS, n = 39). We investigated relationships of mAge estimates with chronological age (Horvath-mAge), lifespan/mortality (Grim-mAge), telomere length (TL-mAge), smoking/EC history, urinary biomarkers, lung cytokines, and transcriptome. RESULTS: Compared to NS, EC and SM had significantly older Grim-mAge, shorter TL-mAge, significantly accelerated Grim-mAge and decelerated TL-mAge. Among SM, Grim-mAA was associated with nicotine intake and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). For EC, Horvath-mAA was significantly correlated with puffs per day. Overall, cytokines (IL-1ß, IL-6, and IL-8) and 759 transcripts (651 unique genes) were significantly associated with Grim-mAA. Grim-mAA-associated genes were highly enriched in immune-related pathways and genes that play a role in the morphology and structures of cells/tissues. CONCLUSIONS: Faster lung mAge for SM is consistent with prior studies of blood. Faster lung mAge for EC compared to NS indicates possible adverse pulmonary effects of EC on biological aging. Our findings support further research, particularly on epigenetic markers, on effects of smoking and vaping on pulmonary health. Given that most EC are former smokers, further study is needed to understand unique effects of electronic cigarettes on biological aging.

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.

Untargeted Metabolomics and Body Mass in Adolescents: A Cross-Sectional and Longitudinal Analysis.

Obesity in children and adolescents has increased globally. Increased body mass index (BMI) during adolescence carries significant long-term adverse health outcomes, including chronic diseases such as cardiovascular disease, stroke, diabetes, and cancer. Little is known about the metabolic consequences of changes in BMI in adolescents outside of typical clinical parameters. Here, we used untargeted metabolomics to assess changing BMI in male adolescents. Untargeted metabolomic profiling was performed on urine samples from 360 adolescents using UPLC-QTOF-MS. The study includes a baseline of 235 subjects in a discovery set and 125 subjects in a validation set. Of them, a follow-up of 81 subjects (1 year later) as a replication set was studied. Linear regression analysis models were used to estimate the associations of metabolic features with BMI z-score in the discovery and validation sets, after adjusting for age, race, and total energy intake (kcal) at false-discovery-rate correction (FDR) ≤ 0.1. We identified 221 and 16 significant metabolic features in the discovery and in the validation set, respectively. The metabolites associated with BMI z-score in validation sets are glycylproline, citrulline, 4-vinylsyringol, 3'-sialyllactose, estrone sulfate, carnosine, formiminoglutamic acid, 4-hydroxyproline, hydroxyprolyl-asparagine, 2-hexenoylcarnitine, L-glutamine, inosine, N-(2-Hydroxyphenyl) acetamide glucuronide, and galactosylhydroxylysine. Of those 16 features, 9 significant metabolic features were associated with a positive change in BMI in the replication set 1 year later. Histidine and arginine metabolism were the most affected metabolic pathways. Our findings suggest that obesity and its metabolic outcomes in the urine metabolome of children are linked to altered amino acids, lipid, and carbohydrate metabolism. These identified metabolites may serve as biomarkers and aid in the investigation of obesity's underlying pathological mechanisms. Whether these features are associated with the development of obesity, or a consequence of changing BMI, requires further study.

Role of untargeted omics biomarkers of exposure and effect for tobacco research.

Tobacco research remains a clear priority to improve individual and population health, and has recently become more complex with emerging combustible and noncombustible tobacco products. The use of omics methods in prevention and cessation studies are intended to identify new biomarkers for risk, compared risks related to other products and never use, and compliance for cessation and reinitation. to assess the relative effects of tobacco products to each other. They are important for the prediction of reinitiation of tobacco use and relapse prevention. In the research setting, both technical and clinical validation is required, which presents a number of complexities in the omics methodologies from biospecimen collection and sample preparation to data collection and analysis. When the results identify differences in omics features, networks or pathways, it is unclear if the results are toxic effects, a healthy response to a toxic exposure or neither. The use of surrogate biospecimens (e.g., urine, blood, sputum or nasal) may or may not reflect target organs such as the lung or bladder. This review describes the approaches for the use of omics in tobacco research and provides examples of prior studies, along with the strengths and limitations of the various methods. To date, there is little consistency in results, likely due to small number of studies, limitations in study size, the variability in the analytic platforms and bioinformatic pipelines, differences in biospecimen collection and/or human subject study design. Given the demonstrated value for the use of omics in clinical medicine, it is anticipated that the use in tobacco research will be similarly productive.

A Pilot Cross-Sectional Study of Immunological and Microbiome Profiling Reveals Distinct Inflammatory Profiles for Smokers, Electronic Cigarette Users, and Never-Smokers.

Smokers (SM) have increased lung immune cell counts and inflammatory gene expression compared to electronic cigarette (EC) users and never-smokers (NS). The objective of this study is to further assess associations for SM and EC lung microbiomes with immune cell subtypes and inflammatory gene expression in samples obtained by bronchoscopy and bronchoalveolar lavage (n = 28). RNASeq with the CIBERSORT computational algorithm were used to determine immune cell subtypes, along with inflammatory gene expression and microbiome metatranscriptomics. Macrophage subtypes revealed a two-fold increase in M0 (undifferentiated) macrophages for SM and EC users relative to NS, with a concordant decrease in M2 (anti-inflammatory) macrophages. There were 68, 19, and 1 significantly differentially expressed inflammatory genes (DEG) between SM/NS, SM/EC users, and EC users/NS, respectively. CSF-1 and GATA3 expression correlated positively and inversely with M0 and M2 macrophages, respectively. Correlation profiling for DEG showed distinct lung profiles for each participant group. There were three bacteria genera-DEG correlations and three bacteria genera-macrophage subtype correlations. In this pilot study, SM and EC use were associated with an increase in undifferentiated M0 macrophages, but SM differed from EC users and NS for inflammatory gene expression. The data support the hypothesis that SM and EC have toxic lung effects influencing inflammatory responses, but this may not be via changes in the microbiome.

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.

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.

Depression in association with neutrophil-to-lymphocyte, platelet-to-lymphocyte, and advanced lung cancer inflammation index biomarkers predicting lung cancer survival.

Lung cancer is a product of inflammation and a dysfunctional immune system, and depression has similar dysregulation. Depression disproportionately affects lung cancer patients, having the highest rates of all cancers. Systemic inflammation and depression are both predictive of non-small cell lung cancer (NSCLC) survival, but the existence and extent of any co-occurrence is unknown. Studied is the association between systemic inflammation ratio (SIR) biomarker levels and patients' depressive symptoms, with the hypothesis that depression severity would be significantly associated with prognostically poor inflammation. Newly diagnosed stage-IV non-small cell lung cancer (NSCLC; N = 186) patients were enrolled (ClinicalTrials.gov Identifier: NCT03199651) and blood draws and depression self-reports (Patient Health Questionnaire-9) were obtained. For SIRs, cell counts of neutrophils (N), lymphocytes (L), and platelets (P) were abstracted for ratio (R) calculations for NLR, PLR, and the Advanced Lung cancer Inflammation Index (ALI). Patients were followed and biomarkers were tested as predictors of 2-year overall survival (OS) to confirm their relevance. Next, multivariate linear regressions tested associations of depression with NLR, PLR, and ALI. Overall 2-year mortality was 61% (113/186). Cox model analyses confirmed higher NLR [hazard ratio (HR) = 1.91; p = 0.001] and PLR (HR = 2.08; p<0.001), along with lower ALI (HR = 0.53; p = 0.005), to be predictive of worse OS. Adjusting for covariates, depression was reliably associated with biomarker levels (p ≤ 0.02). Patients with moderate/severe depressive symptoms were 2 to 3 times more likely to have prognostically poor biomarker levels. Novel data show patients' depressive symptoms were reliably associated with lung-relevant systemic inflammation biomarkers, all assessed at diagnosis/pretreatment. The same SIRs were found prognostic for patients' 2-year OS. Intensive study of depression, combined with measures of cell biology and inflammation is needed to extend these findings to discover mechanisms of depression toxicity for NSCLC patients' treatment responses and survival.

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.

Selective suppression of de novo SARS-CoV-2 vaccine antibody responses in patients with cancer on B cell-targeted therapy.

We assessed vaccine-induced antibody responses to the SARS-CoV-2 ancestral virus and Omicron variant before and after booster immunization in 57 patients with B cell malignancies. Over one-third of vaccinated patients at the pre-booster time point were seronegative, and these patients were predominantly on active cancer therapies such as anti-CD20 monoclonal antibody. While booster immunization was able to induce detectable antibodies in a small fraction of seronegative patients, the overall booster benefit was disproportionately evident in patients already seropositive and not receiving active therapy. While ancestral virus- and Omicron variant-reactive antibody levels among individual patients were largely concordant, neutralizing antibodies against Omicron tended to be reduced. Interestingly, in all patients, including those unable to generate detectable antibodies against SARS-CoV-2 spike, we observed comparable levels of EBV- and influenza-reactive antibodies, demonstrating that B cell-targeting therapies primarily impair de novo but not preexisting antibody levels. These findings support rationale for vaccination before cancer treatment.

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.

Is perception reality? Associations among "light" cigarettes and number of cigarettes smoked per day.

INTRODUCTION: Cigarette filter ventilation and light descriptors are associated with lowered perceptions of risk and smoking more cigarettes per day (CPD). This study examined the relationship between usual cigarette ventilation, perception, and CPD. METHODS: A crowdsourced sample (N = 995) of individuals who smoke higher-ventilated (=>20% ventilation) or lower-ventilated (=<10% ventilation) cigarettes identified their usual cigarette as "light" or "full flavor", and reported their average CPD. RESULTS: We found: 1) no association between ventilation status and perception of light versus full flavor (AUC=0.58), with the inaccurate perception being more prevalent in younger individuals (p = 0.041) and those who smoke L&M (73%, p < 0.001) and Camel (61%, p = 0.006) brands; and 2) perception, but not ventilation of usual cigarette, was significantly associated with CPD (p = 0.006), with individuals who perceived their cigarettes as light reporting an average of 13% more cigarettes per day (2.6 CPD), compared to those who perceived their cigarette as full flavor. CONCLUSIONS: Perceptions of light versus full-flavor, but not ventilation status, predicted CPD. These findings may inform anti-smoking health communication strategies and smoking cessation interventions. IMPLICATIONS: Tobacco control policies should eradicate the perception of cigarettes as light or full-flavored. Future research investigating the associations between cigarette filter ventilation and smoking behavior should consider the confounding effects that may lie in an individual's perceptions of their cigarettes.

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.