Publications by authors named "Stephen Lam"

373 Publications

The relationship between the epigenetic aging biomarker "grimage" and lung function in both the airway and blood of people living with HIV: An observational cohort study.

EBioMedicine 2022 Aug 6;83:104206. Epub 2022 Aug 6.

Centre for Heart Lung Innovation, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada; Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Background: Age-related comorbidities such as chronic obstructive pulmonary disease (COPD) are common in people living with human immunodeficiency virus (PLWH). We investigated the relationship between COPD and the epigenetic age of the airway epithelium and peripheral blood of PLWH.

Methods: Airway epithelial brushings from 34 PLWH enrolled in the St. Paul's Hospital HIV Bronchoscopy cohort and peripheral blood from 378 PLWH enrolled in The Strategic Timing of Antiretroviral Treatment (START) study were profiled for DNA methylation. The DNA methylation biomarker of age and healthspan, GrimAge, was calculated in both tissue compartments. We tested the association of GrimAge with COPD in the airway epithelium and airflow obstruction as defined by an FEV/FVC<0.70, and FEV decline over 6 years in blood.

Findings: The airway epithelium of PLWH with COPD was associated with greater GrimAge residuals compared to PLWH without COPD (Beta=3.18, 95%CI=1.06-5.31, P=0.005). In blood, FEV/FVC
Interpretation: GrimAge may reflect lung and systemic epigenetic changes that occur with advanced airflow obstruction and may help to identify PLWH with a higher risk of developing COPD.

Funding: Canadian Institutes of Health Research and the British Columbia Lung Association. The START substudy was funded by NIH grants: UM1-AI068641, UM1-AI120197, and RO1HL096453.
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http://dx.doi.org/10.1016/j.ebiom.2022.104206DOI Listing
August 2022

Deep neural network based quantum simulations and quasichemical theory for accurate modeling of molten salt thermodynamics.

Chem Sci 2022 Jul 15;13(28):8265-8273. Epub 2022 Jun 15.

National Center for Computational Sciences, Oak Ridge National Laboratory Oak Ridge TN 37830 USA

With dual goals of efficient and accurate modeling of solvation thermodynamics in molten salt liquids, we employ molecular dynamics (AIMD) simulations, deep neural network interatomic potentials (NNIP), and quasichemical theory (QCT) to calculate the excess chemical potentials for the solute ions Na and Cl in the molten NaCl liquid. NNIP-based molecular dynamics simulations accelerate the calculations by 3 orders of magnitude and reduce the uncertainty to 1 kcal mol. Using the Density Functional Theory (DFT) level of theory, the predicted excess chemical potential for the solute ion pair is -178.5 ± 1.1 kcal mol. A quantum correction of 13.7 ± 1.9 kcal mol is estimated higher-level quantum chemistry calculations, leading to a final predicted ion pair excess chemical potential of -164.8 ± 2.2 kcal mol. The result is in good agreement with a value of -163.5 kcal mol obtained from thermo-chemical tables. This study validates the application of QCT and NNIP simulations to the molten salt liquids, allowing for significant insights into the solvation thermodynamics crucial for numerous molten salt applications.
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http://dx.doi.org/10.1039/d2sc02227cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9297527PMC
July 2022

Airway Eosinophilia on Bronchoalveolar Lavage and the Risk of Exacerbations in COPD.

Biomedicines 2022 Jun 15;10(6). Epub 2022 Jun 15.

Centre for Heart Lung Innovation, St Paul's Hospital, The University of British Columbia, Vancouver, BC V6Z 1Y6, Canada.

The associations between airway eosinophilia, measured in sputum or peripheral blood, and acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are inconsistent. We therefore aimed to determine the association between eosinophilia in bronchoalveolar lavage (BAL) fluid and AECOPD in a clinical cohort. We analyzed differential cell counts from baseline BAL fluid in participants in the DISARM clinical trial (Clinicaltrials.gov #NCT02833480) and classified participants by the presence or absence of BAL eosinophilia (>1% of total leukocytes). We determined the association between BAL eosinophilia and AECOPD over 1 year of follow-up using negative binomial regression and Cox proportional hazards test. N = 63 participants were randomized, and N = 57 had BAL differential cell counts available. Participants with BAL eosinophilia (N = 21) had a significantly increased rate of acute exacerbations (unadjusted incidence rate ratio (IRR) 2.0, = 0.048; adjusted IRR 2.24, = 0.04) and a trend toward greater probability of acute exacerbation (unadjusted hazard ratio (HR) 1.74, = 0.13; adjusted HR 2.3, = 0.1) in the year of follow-up compared to participants without BAL eosinophilia (N = 36). These associations were not observed for BAL neutrophilia (N = 41 participants), BAL lymphocytosis (N = 27 participants) or peripheral blood eosinophilia at various threshold definitions (2%, N = 37; 3%, N = 27; 4%, N = 16). BAL may therefore be a sensitive marker of eosinophilic inflammation in the distal lung and may be of benefit for risk stratification or biomarker-guided therapy in COPD.
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http://dx.doi.org/10.3390/biomedicines10061412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220207PMC
June 2022

Inhaled Corticosteroids Selectively Alter the Microbiome and Host Transcriptome in the Small Airways of Patients with Chronic Obstructive Pulmonary Disease.

Biomedicines 2022 May 11;10(5). Epub 2022 May 11.

Centre for Heart Lung Innovation, The University of British Columbia, St. Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada.

Background: Patients with chronic obstructive pulmonary disease (COPD) are commonly treated with inhaled corticosteroid/long-acting ß2-agonist combination therapy. While previous studies have investigated the host-microbiome interactions in COPD, the effects of specific steroid formulations on this complex cross-talk remain obscure.

Methods: We collected and evaluated data from the Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota (DISARM), a randomized controlled trial. Bronchoscopy was performed on COPD patients before and after treatment with salmeterol/fluticasone, formoterol/budesonide or formoterol-only. Bronchial brush samples were processed for microbial 16S rRNA gene sequencing and host mRNA sequencing. Longitudinal changes in the microbiome at a community, phylum and genus level were correlated with changes in host gene expression using a Spearman's rank correlation test.

Findings: In COPD patients treated with salmeterol/fluticasone, the expression levels of 676 host genes were significantly correlated to changes in the alpha diversity of the small airways. At a genus level, the expression levels of 122 host genes were significantly related to changes in the relative abundance of . Gene enrichment analyses revealed the enrichment of pathways and biological processes related to innate and adaptive immunity and inflammation. None of these changes were evident in patients treated with formoterol/budesonide or formoterol alone.

Interpretation: Changes in the microbiome following salmeterol/fluticasone treatment are related to alterations in the host transcriptome in the small airways of patients with COPD. These data may provide insights into why some COPD patients treated with inhaled corticosteroids may be at an increased risk for airway infection, including pneumonia.

Funding: The Canadian Institute of Health Research, the British Columbia Lung Association, and an investigator-initiated grant from AstraZeneca.
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http://dx.doi.org/10.3390/biomedicines10051110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138653PMC
May 2022

Regulation of proton partitioning in kinase-activating acute myeloid leukemia and its therapeutic implication.

Leukemia 2022 08 27;36(8):1990-2001. Epub 2022 May 27.

Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China.

Gain-of-function kinase mutations are common in AML and usually portend an inferior prognosis. We reported a novel mechanism whereby kinase mutants induced intracellular alkalization characteristic in oncogenesis. Thirteen kinases were found to activate sodium/hydrogen exchanger (NHE1) in normal hematopoietic progenitors, of which FLT3-ITD, KRAS, and BTK phosphorylated NHE1 maintained alkaline intracellular pH (pHi) and supported survival of AML cells. Primary AML samples with kinase mutations also showed increased NHE1 phosphorylation and evidence of NHE1 addiction. Amiloride enhanced anti-leukemic effects and intracellular distribution of kinase inhibitors and chemotherapy. Co-inhibition of NHE1 and kinase synergistically acidified pHi in leukemia and inhibited its growth in vivo. Plasma from patients taking amiloride for diuresis reduced pHi of leukemia and enhanced cytotoxic effects of kinase inhibitors and chemotherapy in vitro. NHE1-mediated intracellular alkalization played a key pathogenetic role in transmitting the proliferative signal from mutated-kinase and could be exploited for therapeutic intervention in AML.
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http://dx.doi.org/10.1038/s41375-022-01606-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343251PMC
August 2022

Software development to optimize the minimal detectable difference in human airway images captured using optical coherence tomography.

Clin Physiol Funct Imaging 2022 Sep 25;42(5):308-319. Epub 2022 May 25.

School of Kinesiology, Faculty of Education, University of British Columbia, Vancouver, Canada.

Optical coherence tomography (OCT) is an imaging methodology that can be used to assess human airways. OCT avoids the harmful effects of ionizing radiation and has a high spatial resolution making it well suited for imaging the structure of small airways. Analysis of OCT airway images has typically been performed manually by tracing the airway with a relatively high coefficient of variation. The purpose of this study was to develop an analysis tool to reduce the inter- and intra-observer reproducibility of OCT and improve the ability to detect differences in airways. OCT images from healthy, young human volunteers were used to develop and test the OCT software. Measurement software was developed to allow the conversion of the original image into a grayscale image and was followed by an enhancement operation to brighten the image, and contour measurement. A total of 140 OCT images, 70 small (<2 mm) and 70 medium (2-4 mm) sized airways were analyzed. The inter- and intraobserver reproducibility of airway measurements ranged for strong to very strong in the small-sized airways. For medium-sized airways the reproducibility was considered moderate. Bland-Altman bias was low between observers and observations for all measures. The minimal detectable differences in the airway measurements with our semi-automated software were lower relative to manual tracing in medium-sized airways. Our software improves the ability to perform quantitative OCT analysis and may help to quantify the extent of airway remodelling in respiratory disease or elite athletes in future studies.
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http://dx.doi.org/10.1111/cpf.12762DOI Listing
September 2022

Peppermint protocol: first results for gas chromatography-ion mobility spectrometry.

J Breath Res 2022 05 26;16(3). Epub 2022 May 26.

Centre for Analytical Science, Department of Chemistry, Loughborough University, Loughborough, United Kingdom.

Theseeks to inform the standardisation of breath analysis methods. Fivewith gas chromatography-ion mobility spectrometry (GC-IMS), operating in the positive mode with a tritiumH 5.68 keV, 370 MBq ionisation source, were undertaken to provide benchmarkdata for this technique, to support its use in breath-testing, analysis, and research. Headspace analysis of a peppermint-oil capsule by GC-IMS with on-column injection (0.5 cm) identified 12 IMS responsive compounds, of which the four most abundant were: eucalyptol;-pinene;-pinene; and limonene. Elevated concentrations of these four compounds were identified in exhaled-breath following ingestion of a peppermint-oil capsule. An unidentified compound attributed as a volatile catabolite of peppermint-oil was also observed. The most intense exhaled peppermint-oil component was eucalyptol, which was selected as a peppermint marker for benchmarking GC-IMS. Twenty-five washout experiments monitored levels of exhaled eucalyptol, by GC-IMS with on-column injection (0.5 cm), at= 0 min, and then at+ 60,+ 90,+ 165,+ 285 and+ 360 min from ingestion of a peppermint capsule resulting in 148 peppermint breath analyses. Additionally, thedata was used to evaluate clinical deployments with a further five washout tests run in clinical settings generating an additional 35 breath samples. Regression analysis yielded an average extrapolated time taken for exhaled eucalyptol levels to return to baseline values to be 429 ± 62 min (±95% confidence-interval). The benchmark value was assigned to the lower 95% confidence-interval, 367 min. Further evaluation of the data indicated that the maximum number of volatile organic compounds discernible from a 0.5 cmbreath sample was 69, while the use of an in-line biofilter appeared to reduce this to 34.
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http://dx.doi.org/10.1088/1752-7163/ac6ca0DOI Listing
May 2022

A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians.

J Thorac Oncol 2022 Aug 30;17(8):974-990. Epub 2022 Apr 30.

Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.

Introduction: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

Methods: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers.

Results: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828 and rs204999, OR = 1.17, p = 6.57 × 10; rs3135369 and rs2858859, OR = 1.17, p = 2.43 × 10; rs2858859 and rs9275572, OR = 1.15, p = 2.84 × 10; rs2853668 and rs62329694, OR = 0.73, p = 2.70 × 10). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828 and rs204999, OR = 1.13, p = 0.008; rs3135369 and rs2858859, OR = 1.11, p = 5.23 × 10; rs3135369 and rs9271300, OR = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification.

Conclusions: Important G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.
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http://dx.doi.org/10.1016/j.jtho.2022.04.011DOI Listing
August 2022

CCL5 production in lung cancer cells leads to an altered immune microenvironment and promotes tumor development.

Oncoimmunology 2022 30;11(1):2010905. Epub 2021 Dec 30.

Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada.

Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumor-derived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRAS or EGFR expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (T), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.
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http://dx.doi.org/10.1080/2162402X.2021.2010905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9038050PMC
December 2021

Airway Aging and Methylation Disruptions in HIV-associated Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2022 07;206(2):150-160

Centre for Heart Lung Innovation, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.

Age-related diseases like chronic obstructive pulmonary disease (COPD) occur at higher rates in people living with human immunodeficiency virus (PLWH) than in uninfected populations. To identify whether accelerated aging can be observed in the airways of PLWH with COPD, manifest by a unique DNA methylation signature. Bronchial epithelial brushings from PLWH with and without COPD and HIV-uninfected adults with and without COPD ( = 76) were profiled for DNA methylation and gene expression. We evaluated global Alu and LINE-1 methylation and calculated the epigenetic age using the Horvath clock and the methylation telomere length estimator. To identify genome-wide differential DNA methylation and gene expression associated with HIV and COPD, robust linear models were used followed by an expression quantitative trait methylation (eQTM) analysis. Epigenetic age acceleration and shorter methylation estimates of telomere length were found in PLWH with COPD compared with PLWH without COPD and uninfected patients with and without COPD. Global hypomethylation was identified in PLWH. We identified 7,970 cytosine bases located next to a guanine base (CpG sites), 293 genes, and 9 expression quantitative trait methylation-gene pairs associated with the interaction between HIV and COPD. Actin binding LIM protein family member 3 () was one of the novel candidate genes for HIV-associated COPD highlighted by our analysis. Methylation age acceleration is observed in the airway epithelium of PLWH with COPD, a process that may be responsible for the heightened risk of COPD in this population. Their distinct methylation profile, differing from that observed in patients with COPD alone, suggests a unique pathogenesis to HIV-associated COPD. The associations warrant further investigation to establish causality.
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http://dx.doi.org/10.1164/rccm.202106-1440OCDOI Listing
July 2022

Distinct bronchial microbiome precedes clinical diagnosis of lung cancer.

Mol Cancer 2022 03 7;21(1):68. Epub 2022 Mar 7.

Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada.

Resident microbial populations have been detected across solid tumors of diverse origins. Sequencing of the airway microbiota represents an opportunity for establishing a novel omics approach to early detection of lung cancer, as well as risk prediction of cancer development. We hypothesize that bacterial shifts in the pre-malignant lung may be detected in non-cancerous airway liquid biopsies collected during bronchoscopy. We analyzed the airway microbiome profile of near 400 patients: epithelial brushing samples from those with lung cancer, those who developed an incident cancer, and those who do not develop cancer after 10-year follow-up. Using linear discriminate analysis, we define and validate a microbial-based classifier that is able to predict incident cancer in patients before diagnosis with no clinical signs of cancer. Our results demonstrate the potential of using lung microbiome profiling as a method for early detection of lung cancer.
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http://dx.doi.org/10.1186/s12943-022-01544-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8900294PMC
March 2022

Identifying the limitations of cardiopulmonary exercise testing prior to esophagectomy using a pooled analysis of patient-level data.

Dis Esophagus 2022 Feb 9. Epub 2022 Feb 9.

Department of Surgery, The University of Melbourne, Melbourne, Australia.

Preoperative cardiopulmonary exercise testing (CPET) provides an objective assessment of aerobic fitness in patients undergoing surgery. While peak oxygen uptake during exercise (VO2peak) and anaerobic threshold have demonstrated a moderate correlation with the development of complications following esophagectomy, no clinically useful threshold values have been defined. By pooling patient level data from existing studies, we aimed to define optimal thresholds for preoperative CPET parameters to predict patients at high risk of postoperative complications. Studies reporting on the relationship between preoperative CPET variables and post-esophagectomy complications were determined from a comprehensive literature search. Patient-level data were obtained from six contributing centers for pooled-analyses. Outcomes of interest included cardiopulmonary and non-cardiopulmonary complications, unplanned intensive care unit readmission, and 90-day and 12-month all-cause mortality. Receiver operating characteristic curves and logistic regression models estimated the predictive value of CPET parameters for each individual outcome of interest. This analysis comprised of 621 patients who underwent CPET prior to esophagectomy during the period from January 2004 to March 2017. For both anaerobic threshold and VO2peak, none of the receiver operating characteristic curves achieved an area under the curve value > 0.66 for the outcomes of interest. The discriminatory ability of CPET for determining high-risk patients was found to be poor in patients undergoing an esophagectomy. CPET may only carry an adjunct role to clinical decision-making.
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http://dx.doi.org/10.1093/dote/doac005DOI Listing
February 2022

Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk.

Hum Mol Genet 2022 Feb 9. Epub 2022 Feb 9.

Departments of Epidemiology and Community and Family Medicine, Dartmouth College, Hanover, NH.

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 (OR = 0.71, p = 4.29x10-8); rs79942605 (OR = 2.17, p = 2.81x10-8); and rs208908 (OR = 0.70, p = 4.54x10-8), were identified with different risk effect of lung cancer between men and women. Further eQTL and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of CXADR (Coxsackie Virus And Adenovirus Receptor) gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.
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http://dx.doi.org/10.1093/hmg/ddac030DOI Listing
February 2022

Gene-gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer.

Eur J Med Res 2022 Jan 31;27(1):14. Epub 2022 Jan 31.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility.

Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent.

Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups.

Results: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR  = 1.20; 95% CI 1.13-1.27; p  = 5.6 × 10) and never smokers (e.g., maker rs1133683 Axin2; OR  = 1.27; 95% CI 1.19-1.35; p  = 1.0 × 10). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants.

Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.
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http://dx.doi.org/10.1186/s40001-022-00638-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8805279PMC
January 2022

Breath collection protocol for SARS-CoV-2 testing in an ambulatory setting.

J Breath Res 2022 03 4;16(2). Epub 2022 Mar 4.

Integrative Oncology, BC Cancer Research Centre, Vancouver, Canada.

. The SARS-CoV-2 pandemic changed the way the society functioned. The race to develop a rapid, non-invasive, widely available test resulted in multiple studies examining the potential of breath to be that 'game changing test'. Breath sampling is a non-invasive point of care test, but SAR-CoV-2 has introduced a level of danger into collection and analysis that requires a change in workflow to keep staff and participants safe. We developed a SARS-CoV 2 breath test work flow for collection and processing of breath samples in an ambulatory care setting and prospectively evaluated the protocol. Protocol development included testing the effect of respiratory filters on the integrity and reproducibility of breath samples.. Prospective, observational study conducted at community COVID-19 testing sites, collecting breath samples from patients presenting for RT-PCR testing. Breath was collected via Tedlar®, and/or BioVOC-2™ as well as an environmental sample for all participants. Samples were transferred to Tenex tubes, dry purged and analyzed using a Centri automated sample introduction machine, GC, and a Bench-ToF-HD.. We successfully collected and processed 528 breath samples from 393 participants at community-based ambulatory COVID-19 test sites. The majority of samples were collected before vaccines were available and throughout the emergence of the Delta Variant. No staff member was infected.. We demonstrated a safe workflow for the collection, handling, transport, storage, and analysis of breath samples during the pandemic collecting highly infectious SARS-CoV-2 positive breath samples. This was done without filters as they added complexity to the breath matrix, jeopardizing the sample integrity.
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http://dx.doi.org/10.1088/1752-7163/ac4e2cDOI Listing
March 2022

Blood-Based Biomarker Panel for Personalized Lung Cancer Risk Assessment.

J Clin Oncol 2022 03 7;40(8):876-883. Epub 2022 Jan 7.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: To investigate whether a panel of circulating protein biomarkers would improve risk assessment for lung cancer screening in combination with a risk model on the basis of participant characteristics.

Methods: A blinded validation study was performed using prostate lung colorectal ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the performance of a four-marker protein panel (4MP) consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in combination with a lung cancer risk prediction model (PLCO) compared with current US Preventive Services Task Force (USPSTF) screening criteria. The 4MP was assayed in 1,299 sera collected preceding lung cancer diagnosis and 8,709 noncase sera.

Results: The 4MP alone yielded an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.77 to 0.82) for case sera collected within 1-year preceding diagnosis and 0.74 (95% CI, 0.72 to 0.76) among the entire specimen set. The combined 4MP + PLCO model yielded an area under the receiver operating characteristic curve of 0.85 (95% CI, 0.82 to 0.88) for case sera collected within 1 year preceding diagnosis. The benefit of the 4MP in the combined model resulted from improvement in sensitivity at high specificity. Compared with the USPSTF2021 criteria, the combined 4MP + PLCO model exhibited statistically significant improvements in sensitivity and specificity. Among PLCO participants with ≥ 10 smoking pack-years, the 4MP + PLCO model would have identified for annual screening 9.2% more lung cancer cases and would have reduced referral by 13.7% among noncases compared with USPSTF2021 criteria.

Conclusion: A blood-based biomarker panel in combination with PLCO significantly improves lung cancer risk assessment for lung cancer screening.
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http://dx.doi.org/10.1200/JCO.21.01460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906454PMC
March 2022

Clinical and Endoscopic Characteristics Associated With Post-Endoscopy Upper Gastrointestinal Cancers: A Systematic Review and Meta-analysis.

Gastroenterology 2022 04 25;162(4):1123-1135. Epub 2021 Dec 25.

Norwich Medical School, University of East Anglia, Norwich, UK; Department of General Surgery, Norfolk & Norwich University Hospital NHS Foundation Trust, Norwich, UK.

Background & Aims: Ten percent of patients with an upper gastrointestinal cancer will have received an esophagogastroduodenoscopy (EGD) within 3 years before diagnosis, termed post-endoscopy upper gastrointestinal cancers (PEUGIC). We aimed to determine the characteristics of PEUGIC, and compare these with detected cancers.

Methods: We searched MEDLINE and Embase from inception for studies comparing the characteristics of PEUGIC and detected upper gastrointestinal cancers, and reported findings at the initial "cancer-negative" endoscopy. We synthesized results using random effects meta-analysis. This review is registered on PROSPERO, CRD42019125780.

Results: A total of 2696 citations were screened and 25 studies were included, comprising 81,184 UGI cancers, of which 7926 were considered PEUGIC. For PEUGIC assessed within 6 to 36 months of a "cancer-negative" EGD, the mean interval was approximately 17 months. Patients with PEUGIC were less likely to present with dysphagia (odds ratio [OR] 0.37) and weight loss (OR 0.58) and were more likely to present with gastroesophageal reflux (OR 2.64) than detected cancers. PEUGICs were more common in women in Western populations (OR 1.30). PEUGICs were typically smaller at diagnosis and associated with less advanced disease staging compared with detected cancers (OR 2.87 for stage 1 vs 2-4). Most EGDs (>75%) were abnormal preceding diagnosis of PEUGIC.

Conclusions: There is a substantial delay in the diagnosis of PEUGIC. They are less likely to present with alarm symptoms than detected cancers. PEUGICs are overall less advanced at diagnosis. Most patients with PEUGIC have abnormalities reported at the preceding "cancer-negative" EGD. The epidemiology of PEUGIC may inform preventive strategy.
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http://dx.doi.org/10.1053/j.gastro.2021.12.270DOI Listing
April 2022

USPSTF2013 versus PLCOm2012 lung cancer screening eligibility criteria (International Lung Screening Trial): interim analysis of a prospective cohort study.

Lancet Oncol 2022 01 11;23(1):138-148. Epub 2021 Dec 11.

Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Background: Lung cancer is a major health problem. CT lung screening can reduce lung cancer mortality through early diagnosis by at least 20%. Screening high-risk individuals is most effective. Retrospective analyses suggest that identifying individuals for screening by accurate prediction models is more efficient than using categorical age-smoking criteria, such as the US Preventive Services Task Force (USPSTF) criteria. This study prospectively compared the effectiveness of the USPSTF2013 and PLCOm2012 model eligibility criteria.

Methods: In this prospective cohort study, participants from the International Lung Screening Trial (ILST), aged 55-80 years, who were current or former smokers (ie, had ≥30 pack-years smoking history or ≤15 quit-years since last permanently quitting), and who met USPSTF2013 criteria or a PLCOm2012 risk threshold of at least 1·51% within 6 years of screening, were recruited from nine screening sites in Canada, Australia, Hong Kong, and the UK. After enrolment, patients were assessed with the USPSTF2013 criteria and the PLCOm2012 risk model with a threshold of at least 1·70% at 6 years. Data were collected locally and centralised. Main outcomes were the comparison of lung cancer detection rates and cumulative life expectancies in patients with lung cancer between USPSTF2013 criteria and the PLCOm2012 model. In this Article, we present data from an interim analysis. To estimate the incidence of lung cancers in individuals who were USPSTF2013-negative and had PLCOm2012 of less than 1·51% at 6 years, ever-smokers in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO) who met these criteria and their lung cancer incidence were applied to the ILST sample size for the mean follow-up occurring in the ILST. This trial is registered at ClinicalTrials.gov, NCT02871856. Study enrolment is almost complete.

Findings: Between June 17, 2015, and Dec 29, 2020, 5819 participants from the International Lung Screening Trial (ILST) were enrolled on the basis of meeting USPSTF2013 criteria or the PLCOm2012 risk threshold of at least 1·51% at 6 years. The same number of individuals was selected for the PLCOm2012 model as for the USPSTF2013 criteria (4540 [78%] of 5819). After a mean follow-up of 2·3 years (SD 1·0), 135 lung cancers occurred in 4540 USPSTF2013-positive participants and 162 in 4540 participants included in the PLCOm2012 of at least 1·70% at 6 years group (cancer sensitivity difference 15·8%, 95% CI 10·7-22·1%; absolute odds ratio 4·00, 95% CI 1·89-9·44; p<0·0001). Compared to USPSTF2013-positive individuals, PLCOm2012-selected participants were older (mean age 65·7 years [SD 5·9] vs 63·3 years [5·7]; p<0·0001), had more comorbidities (median 2 [IQR 1-3] vs 1 [1-2]; p<0·0001), and shorter life expectancy (13·9 years [95% CI 12·8-14·9] vs 14·8 [13·6-16·0] years). Model-based difference in cumulative life expectancies for those diagnosed with lung cancer were higher in those who had PLCOm2012 risk of at least 1·70% at 6 years than individuals who were USPSTF2013-positive (2248·6 years [95% CI 2089·6-2425·9] vs 2000·7 years [1841·2-2160·3]; difference 247·9 years, p=0·015).

Interpretation: PLCOm2012 appears to be more efficient than the USPSTF2013 criteria for selecting individuals to enrol into lung cancer screening programmes and should be used for identifying high-risk individuals who benefit from the inclusion in these programmes.

Funding: Terry Fox Research Institute, The UBC-VGH Hospital Foundation and the BC Cancer Foundation, the Alberta Cancer Foundation, the Australian National Health and Medical Research Council, Cancer Research UK and a consortium of funders, and the Roy Castle Lung Cancer Foundation for the UK Lung Screen Uptake Trial.
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http://dx.doi.org/10.1016/S1470-2045(21)00590-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716337PMC
January 2022

Deep Learning for Lung Cancer Detection on Screening CT Scans: Results of a Large-Scale Public Competition and an Observer Study with 11 Radiologists.

Radiol Artif Intell 2021 Nov 27;3(6):e210027. Epub 2021 Oct 27.

Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Nijmegen, the Netherlands (C.J., A.A.A.S., E.T.S., P.K.G., H.B., M.B., B.G., S.S., B.v.G.); Department of Digital Technology & Innovation, Siemens Healthineers, Erlangen, Germany (A.A.A.S.); Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands (F.A.M.H., P.A.d.J.); ETZ (Elisabeth-TweeSteden Ziekenhuis), Tilburg, the Netherlands (E.R.); Section of Radiology, Department of Medicine and Surgery (DiMeC), University of Parma, Parma, Italy (M.S.); Department of Radiology, Meander Medical Center, Amersfoort, the Netherlands (K.C., S.S.); Department of Radiology, AZ Zeno, Knokke-Heist, Belgium (J.M.); Department of Imaging, Royal Brompton Hospital, London, England (A.D.); Division of Cancer Prevention (P.F.P.) and Center for Biomedical Informatics & Information Technology (K.F.), National Cancer Institute, National Institutes of Health, Bethesda, Md; British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada (S.C.L.); and Fraunhofer MEVIS, Bremen, Germany (B.v.G.).

Purpose: To determine whether deep learning algorithms developed in a public competition could identify lung cancer on low-dose CT scans with a performance similar to that of radiologists.

Materials And Methods: In this retrospective study, a dataset consisting of 300 patient scans was used for model assessment; 150 patient scans were from the competition set and 150 were from an independent dataset. Both test datasets contained 50 cancer-positive scans and 100 cancer-negative scans. The reference standard was set by histopathologic examination for cancer-positive scans and imaging follow-up for at least 2 years for cancer-negative scans. The test datasets were applied to the three top-performing algorithms from the Kaggle Data Science Bowl 2017 public competition: grt123, Julian de Wit and Daniel Hammack (JWDH), and Aidence. Model outputs were compared with an observer study of 11 radiologists that assessed the same test datasets. Each scan was scored on a continuous scale by both the deep learning algorithms and the radiologists. Performance was measured using multireader, multicase receiver operating characteristic analysis.

Results: The area under the receiver operating characteristic curve (AUC) was 0.877 (95% CI: 0.842, 0.910) for grt123, 0.902 (95% CI: 0.871, 0.932) for JWDH, and 0.900 (95% CI: 0.870, 0.928) for Aidence. The average AUC of the radiologists was 0.917 (95% CI: 0.889, 0.945), which was significantly higher than grt123 ( = .02); however, no significant difference was found between the radiologists and JWDH ( = .29) or Aidence ( = .26).

Conclusion: Deep learning algorithms developed in a public competition for lung cancer detection in low-dose CT scans reached performance close to that of radiologists. Lung, CT, Thorax, Screening, Oncology © RSNA, 2021.
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http://dx.doi.org/10.1148/ryai.2021210027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637223PMC
November 2021

Lung Cancer Screening Considerations During Respiratory Infection Outbreaks, Epidemics or Pandemics: An International Association for the Study of Lung Cancer Early Detection and Screening Committee Report.

J Thorac Oncol 2022 02 3;17(2):228-238. Epub 2021 Dec 3.

Department of Integrative Oncology, BC Cancer and Department of Medicine, University of British Columbia, Vancouver, Canada.

After the results of two large, randomized trials, the global implementation of lung cancer screening is of utmost importance. However, coronavirus disease 2019 infections occurring at heightened levels during the current global pandemic and also other respiratory infections can influence scan interpretation and screening safety and uptake. Several respiratory infections can lead to lesions that mimic malignant nodules and other imaging changes suggesting malignancy, leading to an increased level of follow-up procedures or even invasive diagnostic procedures. In periods of increased rates of respiratory infections from severe acute respiratory syndrome coronavirus 2 and others, there is also a risk of transmission of these infections to the health care providers, the screenees, and patients. This became evident with the severe acute respiratory syndrome coronavirus 2 pandemic that led to a temporary global stoppage of lung cancer and other cancer screening programs. Data on the optimal management of these situations are not available. The pandemic is still ongoing and further periods of increased respiratory infections will come, in which practical guidance would be helpful. The aims of this report were: (1) to summarize the data available for possible false-positive results owing to respiratory infections; (2) to evaluate the safety concerns for screening during times of increased respiratory infections, especially during a regional outbreak or an epidemic or pandemic event; (3) to provide guidance on these situations; and (4) to stimulate research and discussions about these scenarios.
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http://dx.doi.org/10.1016/j.jtho.2021.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639478PMC
February 2022

Plasma obtained following murine hindlimb ischemic conditioning protects against oxidative stress in zebrafish models through activation of nrf2a and downregulation of duox.

PLoS One 2021 24;16(11):e0260442. Epub 2021 Nov 24.

Zebrafish Centre for Advanced Drug Discovery, The Keenan Research Centre for Biomedical Science Toronto, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Ontario, Canada.

Ischemia/reperfusion of organ systems in trauma patients with resuscitated hemorrhagic shock (HSR) contributes to tissue injury and organ dysfunction. Previous studies using a murine model of HSR showed that remote ischemic preconditioning (RIC) protected against organ injury and that the plasma was able to prevent neutrophil migration in a zebrafish tailfin-cut inflammation model. In this study, we hypothesized that RIC plasma inhibits neutrophil function through a decrease in reactive oxygen species (ROS) production via the upregulation of the transcription factor Nrf2 and downstream antioxidative genes. Plasma from mice subjected to RIC (4 cycles of 5-min hindlimb ischemia/reperfusion) was microinjected into zebrafish. The results show that RIC plasma caused a reduction of ROS generation in response to tail injury. In addition, RIC plasma protected the fish larvae in the survival studies when exposed to either H2O2 or LPS. Oxidative stress PCR Array showed that RIC plasma treatment led to upregulation of antioxidative related genes including hsp70, hmox1a, nqo1 as well as downregulation of duox, the producer of H2O2. To explore the role of nrf2 in RIC, RIC plasma from Nrf2 KO mice were injected to the zebrafish and showed no inhibitory effect on neutrophil migration. Moreover, knockdown of nrf2a attenuated the anti-inflammatory and protective effect of RIC plasma. The downregulation of duox and upregulation of hmox1a were confirmed to require the activation of nrf2a. Therefore, we show that the protective effect of RIC may be related to the elaboration of humoral factors which counter injury-induced ROS generation in a nrf2-dependent fashion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260442PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612579PMC
January 2022

ABC du dépistage du cancer du poumon: Information clé pour les médecins de première ligne.

Can Fam Physician 2021 Nov;67(11):823-829

Professeur de médecine à l'Université de la Colombie-Britannique à Vancouver (C.-B.), pneumologue à BC Cancer, Scientifique distingué et titulaire de la chaire Leon Judah Blackmore de recherche sur le cancer du poumon, et directeur médical du BC Lung Screening Program au BC Cancer Research Centre.

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http://dx.doi.org/10.46747/cfp.6711823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589131PMC
November 2021

Lung cancer screening primer: Key information for primary care providers.

Can Fam Physician 2021 11;67(11):817-822

Professor of Medicine at the University of British Columbia in Vancouver, a respirologist at BC Cancer, and Distinguished Scientist Leon Judah Blackmore Chair in Lung Cancer Research and Medical Director of the BC Lung Screening Program at the BC Cancer Research Centre.

Objective: To review new evidence reported since the 2016 publication of the Canadian Task Force on Preventive Health Care recommendations and to summarize key facets of lung cancer screening to better equip primary care providers (PCPs) in anticipation of wider implementation of the recommendations.

Quality Of Evidence: A new, large randomized controlled trial has been published since 2016, as have updates from 4 other trials. PubMed was searched for studies published between January 1, 2004, and December 31, 2020, using search words including , and . All information from peer-reviewed articles, reference lists, books, and websites was considered.

Main Message: Lung cancers diagnosed at stage 4 have a 5-year survival rate of only 5% and have a disproportionate impact on those with lower socioeconomic status, rural populations, and Indigenous populations. By , or diagnosing lung cancers at an earlier and more treatable stage, lung cancer screening reduces mortality with a number needed to screen of 250 to prevent 1 death. Practical aspects of lung cancer screening are reviewed, including criteria to screen, appropriate low-dose computed tomography screening, and management of findings. Harms of screening, such as overdiagnosis and incidental findings, are discussed to allow PCPs to appropriately counsel their patients in the face of ongoing implementation of new lung cancer screening programs.

Conclusion: Lung cancer screening, with its embedded emphasis on smoking cessation, is an excellent addition to PCPs' preventive health care tools. The implementation of formal and pilot lung cancer screening programs across Canada means that PCPs will be increasingly required to counsel their patients around the uptake of lung cancer screening.
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http://dx.doi.org/10.46747/cfp.6711817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589127PMC
November 2021

Thermodynamic and Transport Properties of LiF and FLiBe Molten Salts with Deep Learning Potentials.

ACS Appl Mater Interfaces 2021 Nov 12;13(46):55367-55379. Epub 2021 Nov 12.

Department of Mechanical Engineering, University of South Carolina, Columbia, South Carolina 29208, United States.

Molten salts have attracted interest as potential heat carriers and/or fuel solvents in the development of new Gen IV nuclear reactor designs, high-temperature batteries, and thermal energy storage. In nuclear engineering, salts containing lithium fluoride-based compounds are of particular interest due to their ability to lower the melting points of mixtures and their compatibility with alloys. A machine learning potential (MLP) combined with a molecular dynamics study is performed on two popular molten salts, namely, LiF (50% Li) and FLiBe (66% LiF and 33% BeF), to predict the thermodynamic and transport properties, such as density, diffusion coefficients, thermal conductivity, electrical conductivity, and shear viscosity. Due to the large possibilities of atomic environments, we employ training using Deep Potential Smooth Edition (DPSE) neural networks to learn from large datasets of 141,278 structures with 70 atoms for LiF and 238,610 structures with 91 atoms for FLiBe molten salts. These networks are then deployed in fast molecular dynamics to predict the thermodynamic and transport properties that are only accessible at longer time scales and are otherwise difficult to calculate with classical potentials, molecular dynamics, or experiments. The prospect of this work is to provide guidance for future works to develop general MLPs for high-throughput thermophysical database generation for a wide spectrum of molten salts.
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http://dx.doi.org/10.1021/acsami.1c17942DOI Listing
November 2021

Airway luminal area and the resistive work of breathing during exercise in healthy young females and males.

J Appl Physiol (1985) 2021 12 28;131(6):1750-1761. Epub 2021 Oct 28.

School of Kinesiology, University of British Columbia, Vancouver, British Columbia, Canada.

We examined the relationship between the work of breathing (W) during exercise and in vivo measures of airway size in healthy females and males. We hypothesized that sex differences in airway luminal area would explain the larger resistive W during exercise in females. Healthy participants ( = 11 females and = 11 males; 19-30 yr) completed a cycle exercise test to exhaustion where W was assessed using an esophageal balloon catheter. On a separate day, each participant underwent a bronchoscopy procedure for optical coherence tomography measures of seven airways. In vivo measures of luminal area were made for the fourth to eighth airway generations. A composite index of airway size was calculated as the sum of the luminal area for each generation, and the total area was calculated based on Weibel's model. We found that index of airway size (males: 37.4 ± 6.3 mm vs. females: 27.5 ± 7.4 mm) and airway area calculated based on Weibel's model (males: 2,274 ± 557 mm vs. females: 1,594 ± 389 mm) were significantly larger in males (both = 0.003). When minute ventilation was greater than ∼60 L·min, the resistive W was higher in females. At the highest equivalent flow achieved by all subjects, resistance to inspired flow was larger in females and significantly associated with two measures of airway size in all subjects: index of airway size ( = 0.524, = 0.012) and Weibel area ( = 0.525, = 0.012). Our findings suggest that innate sex differences in luminal area result in a greater resistive W during exercise in females compared with males. We hypothesized that the higher resistive work of breathing in females compared with males during high-intensity exercise is due to smaller airways. In vivo measures of the fourth to eighth airway generations made using optical coherence tomography show that females tend to have smaller airway luminal areas of the fourth to sixth airway generations. Sex differences in airway luminal area result in a greater resistive work of breathing during exercise in females compared with males.
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http://dx.doi.org/10.1152/japplphysiol.00418.2021DOI Listing
December 2021

Two-Year Follow-Up of a Randomized Controlled Study of Integrated Smoking Cessation in a Lung Cancer Screening Program.

JTO Clin Res Rep 2021 Feb 15;2(2):100097. Epub 2020 Sep 15.

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Introduction: Smoking cessation activities incorporated into lung cancer screening programs have been broadly recommended, but studies to date have not exhibited increased quit rates associated with cessation programs in this setting. We aimed to determine the long-term effectiveness of smoking cessation counseling in smokers presenting for lung cancer screening.

Methods: This was a randomized control trial of an intensive, telephone-based smoking cessation counseling intervention incorporating lung cancer screening results versus usual care (information pamphlet). This analysis reports on the long-term impact (24-mo) of the intervention on abstinence from smoking.

Results: A total of 337 active smokers who participated in the screening study were randomized to active smoking cessation counseling (n = 171) or control arm (n = 174) and completed a 24-month assessment. The 30-day smoking abstinence rates at 24 months postrandomization was 18.3% and 21.4% in the control and intervention arms, respectively-a 3.1% difference (95% confidence interval: -5.4 to 11.6,  = 0.48). No statistically significant differences in the 7-day abstinence, the use of pharmacologic cessation aids, nicotine replacement therapies, nor intent to quit in the following 30 days were noted ( > 0.05). The abstinence rates at 24-months were higher overall than at 12-months (19.9% versus 13.3%, < 0.001), and smoking intensity was lower than at baseline for ongoing smokers.

Conclusions: A telephone-based smoking cessation counseling intervention incorporating lung cancer screening results did not result in increased long-term cessation rates versus written information alone in unselected smokers undergoing lung cancer screening. Overall, quit rates were high and continued to improve throughout participation in the screening program. (ClinicalTrials.govNCT02431962).
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http://dx.doi.org/10.1016/j.jtocrr.2020.100097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474430PMC
February 2021

The oesophageal microbiome and cancer: hope or hype?

Trends Microbiol 2022 04 4;30(4):322-329. Epub 2021 Sep 4.

University of East Anglia, Norwich Research Park, Norwich, UK; Quadram Institute Bioscience, Norwich Research Park, Norwich, UK; School of Veterinary Medicine, University of Surrey, Guildford, Surrey, UK. Electronic address:

The human oesophagus is home to a complex microbial community, the oesophageal microbiome. Despite decades of work, we still have only a poor, low-resolution view of this community, which makes it hard to distinguish hope from hype when it comes to assessing links between the oesophageal microbiome and cancer. Here we review the potential importance of this microbiome and discuss new approaches, including culturomics, metagenomics, and recovery of whole-genome sequences, that bring renewed hope for an in-depth characterisation of this community that could deliver translational impact.
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http://dx.doi.org/10.1016/j.tim.2021.08.007DOI Listing
April 2022

Effects of Inhaled Corticosteroid/Long-Acting β-Agonist Combination on the Airway Microbiome of Patients with Chronic Obstructive Pulmonary Disease: A Randomized Controlled Clinical Trial (DISARM).

Am J Respir Crit Care Med 2021 11;204(10):1143-1152

Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.

Inhaled corticosteroids (ICS) are commonly prescribed with long-acting β-agonists (LABA) in chronic obstructive pulmonary disease (COPD). To date, the effects of ICS therapy on the airway microbiome in COPD are unknown. To determine the effects of ICS/LABA on the airway microbiome of patients with COPD. Clinically stable patients with COPD were enrolled into a 4-week run-in period during which ICS was discontinued and all participants were placed on formoterol (Form) 12 μg twice daily (BID). The participants were then randomized to budesonide/formoterol (Bud + Form; 400/12 μg BID), fluticasone/salmeterol (Flu + Salm; 250/50 μg BID), or formoterol only (12 μg BID) for 12 weeks. Participants underwent bronchoscopy before and after the 12-week treatment period. The primary endpoint was the comparison of changes in the airway microbiome over the trial period between the ICS/LABA and LABA-only groups. Sixty-three participants underwent randomization: Bud + Form ( = 20), Flu + Salm ( = 22), and Form ( = 21) groups; 56 subjects completed all visits. After the treatment period, changes in α-diversity were significantly different across groups, especially between Flu + Salm and Form groups (Δrichness:  = 0.02; ΔShannon index:  = 0.03). Longitudinal differential abundance analyses revealed more pronounced microbial shifts from baseline in the fluticasone (vs. budesonide or formoterol only) group. Fluticasone-based ICS/LABA therapy modifies the airway microbiome in COPD, leading to a relative reduction in α-diversity and a greater number of bacterial taxa changes. These data may have implications in patients who develop pneumonia on ICS. Clinical trial registered with www.clinicaltrials.gov (NCT02833480).
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http://dx.doi.org/10.1164/rccm.202102-0289OCDOI Listing
November 2021

Screening for Lung Cancer in Individuals Who Never Smoked: An International Association for the Study of Lung Cancer Early Detection and Screening Committee Report.

J Thorac Oncol 2022 01 27;17(1):56-66. Epub 2021 Aug 27.

Division of Respiratory Medicine and Thoracic Oncology, Department of Internal Medicine V Thoracic Oncology Centre Munich University of Munich-Campus Innenstadt Munich, Germany, member of the German Center for Lung Research (DZL - CPC-M).

Screening with low-dose computed tomography of high-risk individuals with a smoking history reduces lung cancer mortality. Current screening guidelines and eligibility criteria can miss more than 50% of lung cancers, and in some geographic areas, such as East Asia, a large proportion of the missed lung cancers are in never-smokers. Although randomized trials revealed the benefits of screening for people who smoke, these trials generally excluded never-smokers. Thus, the feasibility and effectiveness of lung cancer screening of individuals who never smoked are uncertain. Several known and suspected risk factors for lung cancers in never-smokers such as exposure to secondhand smoke, occupational carcinogens, radon, air pollution, and pulmonary diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases, and intrinsic factors, such as age, are well noted. In this regard, knowledge of risk factors may make possible quantification and prediction of lung cancer risk in never smokers. It is worth considering if and how never smokers could be included in population-based screening programs. As the implementation of these programs is challenging in many countries owing to multiple factors and the epidemiologic differences by global regions, these issues will need to be evaluated in each country taking into account various factors, including accuracy of risk assessment and cost-effectiveness of screening in never smokers. This report aims to outline current knowledge on risk factors for lung cancer in never smokers to propose research strategies for this topic and initiate a broader discussion on lung cancer screening of never smokers. Similar considerations can be made in current and ex-smokers, which do not fulfill the current screening inclusion criteria, but otherwise are at increased risk. Although screening of never smokers may in the future be effectively conducted, current evidence to support widespread implementation of this practice is lacking.
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http://dx.doi.org/10.1016/j.jtho.2021.07.031DOI Listing
January 2022
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