A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease.
Levels ...of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models.
Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin IL-15, IL-1RA, IL-1β, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval CI = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1β, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking.
Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time.
Low-dose chest CT screening for lung cancer has become a standard of care in the United States, in large part because of the results of the National Lung Screening Trial (NLST). Additional evidence ...supporting the net benefit of low-dose chest CT screening for lung cancer, and increased experience in minimizing the potential harms, has accumulated since the prior iteration of these guidelines. Here, we update the evidence base for the benefit, harms, and implementation of low-dose chest CT screening. We use the updated evidence base to provide recommendations where the evidence allows, and statements based on experience and expert consensus where it does not.
Approved panelists reviewed previously developed key questions using the Population, Intervention, Comparator, Outcome format to address the benefit and harms of low-dose CT screening, and key areas of program implementation. A systematic literature review was conducted using MEDLINE via PubMed, Embase, and the Cochrane Library on a quarterly basis since the time of the previous guideline publication. Reference lists from relevant retrievals were searched, and additional papers were added. Retrieved references were reviewed for relevance by two panel members. The quality of the evidence was assessed for each critical or important outcome of interest using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Meta-analyses were performed when enough evidence was available. Important clinical questions were addressed based on the evidence developed from the systematic literature review. Graded recommendations and ungraded statements were drafted, voted on, and revised until consensus was reached.
The systematic literature review identified 75 additional studies that informed the response to the 12 key questions that were developed. Additional clinical questions were addressed resulting in seven graded recommendations and nine ungraded consensus statements.
Evidence suggests that low-dose CT screening for lung cancer can result in a favorable balance of benefit and harms. The selection of screen-eligible individuals, the quality of imaging and image interpretation, the management of screen-detected findings, and the effectiveness of smoking cessation interventions can impact this balance.
Decision curve analysis (DCA) is a popular approach for assessing biomarkers and risk models, but does not require costs and thus cannot identify optimal risk thresholds for actions. Full decision ...analyses can identify optimal thresholds, but typically used methods are complex and often difficult to understand. We develop a simple framework to calculate the incremental net benefit for a single‐time screen as a function of costs (for tests and treatments) and effectiveness (life‐years gained). We provide simple expressions for the optimal cost‐effective risk threshold and, equally importantly, for the monetary value of life‐years gained associated with the risk threshold. We consider the controversy over the risk threshold to screen women for mutations in BRCA1/2. Importantly, most, and sometimes even all, of the thresholds identified by DCA are infeasible based on their associated dollars per life‐year gained. Our simple framework facilitates sensitivity analyses to cost and effectiveness parameters. The proposed approach estimates optimal risk thresholds in a simple and transparent manner, provides intuition about which quantities are critical, and may serve as a bridge between DCA and a full decision analysis.
Despite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating ...inflammation markers with lung cancer.
We conducted a nested case-control study (n = 526 lung cancer patients and n = 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median = 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively.
Of 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk (P trend across marker categories < .05), including acute-phase proteins (C-reactive protein CRP, serum amyloid A SAA), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 sTNFRII), anti-inflammatory cytokines (interleukin 1 receptor antagonist IL-1RA), lymphoid differentiation cytokines (interleukin 7 IL-7), growth factors (transforming growth factor alpha TGF-A), and chemokines (epithelial neutrophil-activating peptide 78 ENA 78/CXCL5, monokine induced by gamma interferon MIG/CXCL9, B cell-attracting chemokine 1 BCA-1/CXCL13, thymus activation regulated chemokine TARC/CCL17, macrophage-derived chemokine MDC/CCL22). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR = 0.71; 95% confidence interval = 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile Q 1 = 1.1% vs Q4 = 3.1%) and current smokers (Q1 = 2.3% vs Q4 = 7.9%) even after adjustment for smoking.
Some circulating inflammation marker levels are associated with prospective lung cancer risk.
Although risk-based selection of ever-smokers for screening could prevent more lung cancer deaths than screening according to the U.S. Preventive Services Task Force (USPSTF) guidelines, it ...preferentially selects older ever-smokers with shorter life expectancies due to comorbidities.
To compare selection of ever-smokers for screening based on gains in life expectancy versus lung cancer risk.
Cohort analyses and model-based projections.
U.S. population of ever-smokers aged 40 to 84 years.
130 964 National Health Interview Survey participants, representing about 60 million U.S. ever-smokers during 1997 to 2015.
Annual computed tomography (CT) screening for 3 years versus no screening.
Estimated number of lung cancer deaths averted and life-years gained after development of a mortality model.
Using the calibrated and validated mortality model in U.S. ever-smokers aged 40 to 84 years and selecting 8.3 million ever-smokers to match the number selected by the USPSTF criteria in 2013 to 2015, the analysis estimated that life-gained-based selection would increase the total life expectancy from CT screening (633 400 vs. 607 800 years) but prevent fewer lung cancer deaths (52 600 vs. 55 000) compared with risk-based selection. The 1.56 million persons selected by the life-gained-based strategy but not the risk-based strategy were younger (mean age, 59 vs. 75 years) and had fewer comorbidities (mean, 0.75 vs. 3.7).
Estimates are model-based and assume implementation of lung cancer screening with short-term effectiveness similar to that from trials.
Life-gained-based selection could maximize the benefits of lung cancer screening in the U.S. population by including ever-smokers who have both high lung cancer risk and long life expectancy.
Intramural Research Program of the National Cancer Institute, National Institutes of Health.
Background
The incidence of breast cancer increased in the United States until circa 2000 then decreased, mostly among women with estrogen receptor (ER)-positive cancers. Time trends provide ...important clues for cancer etiology and prevention; however, the observed trends of ER-positive and ER-negative breast cancers can be biased by missing ER data.
Methods
We developed a simple imputation method to correct invasive female breast cancer incidence for missing or unknown ER expression, using nationally representative data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program during 1980-2008, including 588 720 invasive female breast cancer patients with 471 336 233 woman-years of follow-up. Corrected rates of ER-positive and ER-negative breast cancers were used to calculate age-standardized incidence rates, estimated annual percentage changes, and projections derived from age-period-cohort models.
Results
The recent decrease in the incidence of breast cancer overall stabilized near 200 per 100 000 woman-years by 2007-2008, reflecting a transient decrease in ER-positive cancers and a steady decrease in ER-negative cancers. The projected incidence rate for breast cancer overall through the year 2016 was similar to the incidence rate during 2007-2008. In contrast, rates of ER-positive breast cancers were projected to increase 5.3% (95% confidence interval = 5.2% to 5.4%), whereas rates of ER-negative breast cancers were projected to decrease 11.4% (95% confidence interval = 11.3% to 11.6%) during 2009-2016.
Conclusion
Recent changes in breast cancer incidence overall reflect the superimposition of divergent trends in ER-positive and ER-negative cancers. If current trends continue, the incidence of ER-positive breast cancers will increase, the incidence of ER-negative breast cancers will continue to decrease, and the incidence of breast cancer overall will remain similar to its current level.
We examined whether draft 2020 United States Preventive Services Task Force (USPSTF) lung cancer screening recommendations "partially ameliorate racial disparities in screening eligibility" compared ...with the 2013 guidelines, as claimed. Using data from the 2015 National Health Interview Survey, USPSTF-2020 increased eligibility by similar proportions for minorities (97.1%) and Whites (78.3%). Contrary to the intent of USPSTF-2020, the relative disparity (differences in percentages of model-estimated gainable life-years from National Lung Screening Trial-like screening by eligible Whites vs minorities) actually increased from USPSTF-2013 to USPSTF-2020 (African Americans: 48.3%-33.4% = 15.0% to 64.5%-48.5% = 16.0%; Asian Americans: 48.3%-35.6% = 12.7% to 64.5%-45.2% = 19.3%; Hispanic Americans: 48.3%-24.8% = 23.5% to 64.5%-37.0% = 27.5%). However, augmenting USPSTF-2020 with high-benefit individuals selected by the Life-Years From Screening with Computed Tomography (LYFS-CT) model nearly eliminated disparities for African Americans (76.8%-75.5% = 1.2%) and improved screening efficiency for Asian and Hispanic Americans, although disparities were reduced only slightly (Hispanic Americans) or unchanged (Asian Americans). The draft USPSTF-2020 guidelines increased the number of eligible minorities vs USPSTF-2013 but may inadvertently increase racial and ethnic disparities. LYFS-CT could reduce disparities in screening eligibility by identifying ineligible people with high predicted benefit regardless of race and ethnicity.
A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 ...American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The group's goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillomavirus-negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up.
Background
Previous studies that were based primarily on small numbers of patients suggested that certain circulating proinflammatory cytokines may be associated with lung cancer; however, large ...independent studies are lacking.
Methods
Associations between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and lung cancer were analyzed among 270 case patients and 296 control subjects participating in the National Cancer Institute-Maryland (NCI-MD) case-control study. Results were validated in 532 case patients and 595 control subjects in a nested case-control study within the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Association with C-reactive protein (CRP), a systemic inflammation biomarker, was also analyzed. Associations between biomarkers and lung cancer were estimated using logistic regression models adjusted for smoking, stage, histology, age, and sex. The 10-year standardized absolute risks of lung cancer were estimated using a weighted Cox regression model.
Results
Serum IL-6 and IL-8 levels in the highest quartile were associated with lung cancer in the NCI-MD study (IL-6, odds ratio OR = 3.29, 95% confidence interval CI = 1.88 to 5.77; IL-8, OR = 2.06, 95% CI = 1.19 to 3.57) and with lung cancer risk in the PLCO study (IL-6, OR = 1.48, 95% CI = 1.04 to 2.10; IL-8, OR = 1.57, 95% CI = 1.10 to 2.24), compared with the lowest quartile. In the PLCO study, increased IL-6 levels were only associated with lung cancer diagnosed within 2 years of blood collection, whereas increased IL-8 levels were associated with lung cancer diagnosed more than 2 years after blood collection (OR = 1.57, 95% CI = 1.15 to 2.13). The 10-year standardized absolute risks of lung cancer in the PLCO study were highest among current smokers with high IL-8 and CRP levels (absolute risk = 8.01%, 95% CI = 5.77% to 11.05%).
Conclusions
Although increased levels of both serum IL-6 and IL-8 are associated with lung cancer, only IL-8 levels are associated with lung cancer risk several years before diagnosis. Combination of IL-8 and CRP are more robust biomarkers than either marker alone in predicting subsequent lung cancer.
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