Impact of Reduced Tobacco Smoking on Lung Cancer Mortality in the United States During 1975–2000

Background: Considerable effort has been expended on tobacco control strategies in the United States since the mid-1950s. However, we have little quantitative information on how changes in smoking behaviors have impacted lung cancer mortality. We quantified the cumulative impact of changes in smoking behaviors that started in the mid-1950s on lung cancer mortality in the United States over the period 1975–2000. Methods: A consortium of six groups of investigators used common inputs consisting of simulated cohort-wise smoking histories for the birth cohorts of 1890 through 1970 and independent models to estimate the number of US lung cancer deaths averted during 1975–2000 as a result of changes in smoking behavior that began in the mid-1950s. We also estimated the number of deaths that could have been averted had tobacco control been completely effective in eliminating smoking after the Surgeon General’s first report on Smoking and Health in 1964. Results: Approximately 795,851 US lung cancer deaths were averted during the period 1975–2000: 552,574 among men and 243,277 among women. In the year 2000 alone, approximately 70,218 lung cancer deaths were averted: 44,135 among men and 26,083 among women. However, these numbers are estimated to represent approximately 32% of lung cancer deaths that could have potentially been averted during the period 1975–2000, 38% of the lung cancer deaths that could have been averted in 1991–2000, and 44% of lung cancer deaths that could have been averted in 2000. Conclusions: Our results reflect the cumulative impact of changes in smoking behavior since the 1950s. Despite a large impact of changing smoking behaviors on lung cancer deaths, lung cancer remains a major public health problem. Continued efforts at tobacco control are critical to further reduce the burden of this disease

Performance of the Adapted Diabetes Complications Severity Index Translated to ICD-10

OBJECTIVES: To assess the performance of the adapted Diabetes Complications Severity Index (aDCSI) translated to International Classification of Diseases, Tenth Revision (ICD-10) in predicting hospitalizations, mortality, and healthcare-associated costs. STUDY DESIGN: Retrospective closed cohort study based on secondary data analysis. METHODS: We translated the aDCSI to ICD-10 and calculated aDCSI scores based on health insurance claims data. To assess predictive performance, we used multivariate regression models to calculate risk ratios (RRs) of hospitalizations and mortality and linear predictors of cost. RESULTS: We analyzed a sample of 157,115 patients with diabetes mellitus. RRs of hospitalizations (total and cause specific) rose with increasing aDCSI scores. Predicting total hospitalizations over a 4-year period, unadjusted RRs were 1.22 for an aDCSI score of 1 (compared with a score of 01, 1.55 for a score of 2, 1.77 fora score of 3, 2.11 fora score of 4, and 2.72 for scores of 5 and higher. Cause-specific hospitalizations and mortality showed similar results. Costs clearly increased in each successive score category. CONCLUSIONS: Our study supports the validity of the aDCSI as a severity measure for complications of diabetes, as it correlates to and predicts total and cause-specific hospitalizations, mortality, and costs. The aDCSI's performance in ICD-10-coded data is comparable with that in international Classification of Diseases, Ninth Revision-coded data

Natural resistance to cancers: a Darwinian hypothesis to explain Peto’s paradox

<p>Abstract</p> <p>Background</p> <p>Peto's paradox stipulates that there is no association between body mass (a surrogate of number of cells and longevity) and cancer prevalence in wildlife species. Resolving this paradox is a very promising research direction to understand mechanisms of cancer resistance. As of present, research has been focused on the consequences of these evolutionary pressures rather than of their causes.</p> <p>Discussion</p> <p>Here, we argue that evolution through natural selection may have shaped mechanisms of cancer resistance in wildlife species and that this can result in a threshold in body mass above which oncogenic and tumor suppressive mechanisms should be increasingly purified and positively selected, respectively.</p> <p>Summary</p> <p>We conclude that assessing wildlife species in their natural ecosystems, especially through theoretical modeling, is the most promising way to understand how evolutionary processes can favor one or the other pathway. This will provide important insights into mechanisms of cancer resistance.</p

Epigenetic dysregulation from chromosomal transit in micronuclei.

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1-4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer

Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma

Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative 'enhancer rewiring' events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA