Cancer Incidence and Survival Among Patients Following an Acute Coronary Syndrome.

To examine the role of acute coronary syndrome (ACS) in subsequent cancer incidence and survival, 2 cohorts of patients hospitalized with ACS were matched 1:1 by gender and age (±3 years) to cardiovascular disease (CVD)-free patients from 2 cycles of the Israeli National Health and Nutrition Surveys. Data on all-cause mortality were retrieved from national registries. Cancer incidence with death treated as a competing event, overall survival, and mortality risk associated with incident cancer as a time-dependent variable were compared between the groups. Our cohort included 2,040 cancer-free matched pairs (mean age of 60±14 years, 42.5% women). Despite higher rates of smokers and patients with hypertension and diabetes mellitus, 10-year cumulative cancer incidence was significantly lower in the ACS group compared with CVD-free group (8.0% vs 11.4%, p = 0.02). This decreased risk was more pronounced in women than men (pinteraction = 0.05). Although being free of CVD meant a significant (p <0.001) survival advantage in the general cohort, this advantage faded once a cancer diagnosis was made (p = 0.80). After adjustment for sociodemographic and clinical covariates, the hazard ratios for mortality associated with a cancer diagnosis were 2.96 (95% confidence interval: 2.36 to 3.71) in the ACS group versus 6.41 (95% confidence interval: 4.96 to 8.28) in the CVD-free group (Pinteraction<0.001). In conclusion, in this matched cohort, ACS was associated with a lower risk of cancer and mitigated the excess risk of mortality associated with cancer incidence.

An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination.

Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiologic data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor. SIGNIFICANCE: Exercise protects against cancer progression and metastasis by inducing a high nutrient demand in internal organs, indicating that reducing nutrient availability to tumor cells represents a potential strategy to prevent metastasis. See related commentary by Zerhouni and Piskounova, p. 4124.

Preexisting coronary heart disease and susceptibility to long-term effects of traffic-related air pollution: A matched cohort analysis.

BACKGROUND: Individuals with coronary heart disease are considered susceptible to traffic-related air pollution exposure. Yet, cohort-based evidence on whether preexisting coronary heart disease modifies the association of traffic-related air pollution with health outcomes is lacking. AIM: Using data of four Israeli cohorts, we compared associations of traffic-related air pollution with mortality and cancer between coronary heart disease patients and matched controls from the general population. METHODS: Subjects hospitalized with acute coronary syndrome from two patient cohorts (inception years: 1992-1993 and 2006-2014) were age- and sex-matched to coronary heart disease-free participants of two cycles of the Israeli National Health and Nutrition Surveys (inception years: 1999-2001 and 2005-2006). Ambient concentrations of nitrogen oxides at the residential place served as a proxy for traffic-related air pollution exposure across all cohorts, based on a high-resolution national land use regression model (50 m). Data on all-cause mortality (last update: 2018) and cancer incidence (last update: 2016) were retrieved from national registries. Cox-derived stratum-specific hazard ratios with 95% confidence intervals were calculated, adjusted for harmonized covariates across cohorts, including age, sex, ethnicity, neighborhood socioeconomic status, smoking, diabetes, hypertension, prior stroke and prior malignancy (the latter only in the mortality analysis). Effect-modification was examined by testing nitrogen oxides-by-coronary heart disease interaction term in the entire matched cohort. RESULTS: The cohort (mean (standard deviation) age 61.5 (14) years; 44% women) included 2393 matched pairs, among them 2040 were cancer-free at baseline. During a median (25th-75th percentiles) follow-up of 13 (10-19) and 11 (7-17) years, 1458 deaths and 536 new cancer cases were identified, respectively. In multivariable-adjusted models, a 10-parts per billion nitrogen oxides increment was positively associated with all-cause mortality among coronary heart disease patients (hazard ratio = 1.13, 95% confidence interval 1.05-1.22), but not among controls (hazard ratio = 1.00, 0.93-1.08) (pinteraction = 0.003). A similar pattern was seen for all-cancer incidence (hazard ratioCHD = 1.19 (1.03-1.37), hazard ratioCHD-Free = 0.93 (0.84-1.04) (pinteraction = 0.01)). Associations were robust to multiple sensitivity analyses. CONCLUSIONS: Coronary heart disease patients might be at increased risk for traffic-related air pollution-associated mortality and cancer, irrespective of their age and sex. Patients and clinicians should be more aware of the adverse health effects on coronary heart disease patients of chronic exposure to vehicle emissions.

Leisure-Time Physical Activity and Cancer Risk Among Older Adults: A Cohort Study.

OBJECTIVE: To examine the association between leisure-time physical activity (LTPA) and long-term cancer risk in a nationwide cohort of older adults. PARTICIPANTS AND METHODS: The cohort comprised participants of a national survey conducted between July 2005 and December 2006, constituting a random sample of Israeli community-dwelling adults aged 65 years or older. Based on self-reported LTPA habits, participants were classified as sufficiently active, insufficiently active, or inactive according to published guidelines. Cancer diagnosis was assessed via the Israeli National Cancer Registry through September 2015. Inverse probability weighted hazard ratios for incident cancer, based on propensity score, were estimated for LTPA categories. RESULTS: Analysis included 1542 participants with no history of cancer at baseline (median [25th-75th percentile] age, 73 years [69-78 years]; 826 [53.6%] women). Inactive participants (n=641 [41.6%]) were more likely to be female, of lower socioeconomic status, and with higher body mass index and poorer perceived health compared with their insufficiently active (n=443 [28.7%]) and sufficiently active (n=458 [29.7%]) counterparts. In the propensity score-weighted synthetic sample, the distribution of measured baseline covariates was similar across LTPA categories. Over a median follow-up of 9 years, 254 new cancer cases (16.5%) were diagnosed. Leisure-time physical activity was inversely associated with incident cancer, with adjusted hazard ratios (95% CIs) of 0.66 (0.46-0.93) in insufficiently active and 0.59 (0.42-0.82) in sufficiently active participants compared with inactive individuals (P value for trend = .002). CONCLUSION: Among older adults, engaging in LTPA, even at lower levels than officially recommended, may have a beneficial effect on primary prevention of cancer.

Cancer and mortality in relation to traffic-related air pollution among coronary patients: Using an ensemble of exposure estimates to identify high-risk individuals.

BACKGROUND: Moderate correlations were previously observed between individual estimates of traffic-related air pollution (TRAP) produced by different exposure modeling approaches. This induces exposure misclassification for a substantial fraction of subjects. AIM: We used an ensemble of well-established modeling approaches to increase certainty of exposure classification and reevaluated the association with cancers previously linked to TRAP (lung, breast and prostate), other cancers, and all-cause mortality in a cohort of coronary patients. METHODS: Patients undergoing percutaneous coronary interventions in a major Israeli medical center from 2004 to 2014 (n = 10,627) were followed for cancer (through 2015) and mortality (through 2017) via national registries. Residential exposure to nitrogen oxides (NOx) -a proxy for TRAP- was estimated by optimized dispersion model (ODM) and land use regression (LUR) (rPearson = 0.50). Mutually exclusive groups of subjects classified as exposed by none of the methods (high-certainty low-exposed), ODM alone, LUR alone, or both methods (high-certainty high-exposed) were created. Associations were examined using Cox regression models. RESULTS: During follow-up, 741 incident cancer cases were diagnosed and 3051 deaths occurred. Using a ≥25 ppb cutoff, compared with high-certainty low exposed, the multivariable-adjusted hazard ratios (95% confidence intervals) for lung, breast and prostate cancer were 1.56 (1.13-2.15) in high-certainty exposed, 1.27 (0.86-1.86) in LUR-exposed alone, and 1.13 (0.77-1.65) in ODM-exposed alone. The association of the former category was strengthened using more extreme NOx cutoffs. A similar pattern, albeit less strong, was observed for mortality, whereas no association was shown for cancers not previously linked to TRAP. CONCLUSIONS: Use of an ensemble of TRAP exposure estimates may improve classification, resulting in a stronger association with outcomes.

Chronic exposure to traffic-related air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study.

Background Exposure to traffic-related air pollution (TRAP) is considered to have a carcinogenic effect. The authors previously reported a nonsignificant association between TRAP and cancer risk in a relatively small cohort of myocardial infarction survivors. This study assessed whether TRAP exposure is associated with subsequent cancer in a large cohort of coronary patients. Methods & results Consecutive patients undergoing percutaneous coronary interventions in a major medical centre in central Israel from 2004 to 2014 were followed for cancer through 2015. Residential levels of nitrogen oxides (NOx) - a proxy for TRAP - were estimated based on a high-resolution national land use regression model. Cox proportional hazards models were constructed to study relationships with cancer. Among 12,784 candidate patients, 9816 had available exposure data and no history of cancer (mean age, 68 years; 77% men). During a median (25th-75th percentiles) follow-up of 7.0 (3.9-9.3) years, 773 incident cases of cancer (8%) were diagnosed. In a multivariable-adjusted model, a 10-ppb increase in mean NOx exposure was associated with hazard ratios (HRs) of 1.07 (95% confidence interval [CI] 1.00-1.15) for all-site cancer and 1.16 (95% CI 1.05-1.28) for cancers previously linked to TRAP (lung, breast, prostate, kidney and bladder). A stronger association was observed for breast cancer (HR = 1.43; 95% CI 1.12-1.83). Associations were slightly strengthened after limiting the cohort to patients with more precise exposure assessment. Conclusion Coronary patients exposed to TRAP are at increased risk of several types of cancer, particularly lung, prostate and breast. As these cancers are amenable to prevention strategies, identifying highly exposed patients may provide an opportunity to improve clinical care.

Long-term exposure to traffic-related air pollution and cancer among survivors of myocardial infarction: A 20-year follow-up study.

BACKGROUND: Previous studies suggested a carcinogenic effect of exposure to traffic-related air pollution. Recently, higher rates of cancer incidence were observed among myocardial infarction survivors compared with the general population. We examined the association between chronic exposure to nitrogen oxides, a proxy measure for traffic-related air pollution, and cancer incidence and mortality in a cohort of myocardial infarction patients. METHODS: Patients aged ≤65 years admitted to hospital in central Israel with a first myocardial infarction in 1992-1993 were followed to 2013 for cancer incidence and cause-specific mortality. Data on sociodemographic and cancer risk factors were obtained, including time-varying information on smoking. Using land use regression models, annual averages of nitrogen oxides during follow-up were estimated individually according to home addresses. Cox proportional hazards models were constructed to study the relationships with cancer outcomes. RESULTS: During a mean follow-up of 16 (SD 7) years, 262 incident cancers and 105 cancer deaths were identified among 1393 cancer-free patients at baseline (mean age 54 years; 81% men). In adjusted models, a 10 ppb increase in mean nitrogen oxide exposure was associated with a hazard ratio (HR) of 1.06 (95% confidence interval (CI) 0.96-1.18) for cancer incidence and HR of 1.08 (95% CI 0.93-1.26) for cancer mortality. The association with lung, bladder, kidney or prostate cancer (previously linked to air pollution) was stronger (HR 1.16; 95% CI 1.00-1.33). CONCLUSIONS: Chronic exposure to traffic-related air pollution may constitute an environmental risk factor for cancer post-myocardial infarction. Variation in the strength of association between specific cancers needs to be explored further.