2nd Tertile Research Articles

Immune characterization of breast cancer metastases: prognostic implications

BackgroundTumor-infiltrating lymphocytes (TILs) evaluated in primary breast cancer (BC) convey prognostic information. Limited data in the metastatic setting are available.MethodsSecondary lesions from 94 BC patients, 43 triple-negative (TN) and 51 HER2-positive, were evaluated for TILs and expression of CD8, FOXP3, and PD-L1 by immunohistochemistry.ResultsTILs levels on metastasis were generally low (median 5%) and did not differ between TN and HER2+ tumors. Younger patients showed significantly lower TILs (p = 0.002). In HER2+ patients, TILs were higher in lung metastases as compared to other sites (p = 0.038). TILs composition was different across metastatic sites: skin metastases presented higher FOXP3 (p = 0.002) and lower CD8/FOXP3 ratio (p = 0.032). Patients treated for metastatic BC prior to biopsy had lower CD8 (overall: p = 0.005, HER2+: p = 0.011, TN: p = 0.075).In TN patients, median overall survival (OS) was 11.8 and 62.9 months for patients with low and high TILs, respectively (HR 0.29, 95%CI 0.11–0.76, log-rank p = 0.008). CD8/FOXP3 ratio was also prognostic in TN patients (median OS 8.0, 13.2, and 54.0 months in 1st, 2nd and 3th tertile, log-rank p = 0.019). Both TILs and CD8/FOXP3 ratio were independent factors at multivariate analysis. Counterintuitively, in HER2+ BC, low TILs tumors showed better prognosis (median OS 53.7 vs 39.9 months in TILs low and TILs high, not statistically significant).ConclusionsOur findings indicate the relevance of TILs as prognostic biomarker for TNBC even in the advanced setting and provide novel hypothesis-generating data on potential sources of immune heterogeneity of metastatic BC.

Decreasing trend in passive tobacco smoke exposure and association with asthma in U.S. children

In this study, we assessed trends of serum cotinine levels over time among US children ages 3–11 years and compared the risk of asthma in groups exposed to passive tobacco smoke. We utilized National Health and Nutrition Examination Survey (NHANES) data collected from 2003 to 2014 (n = 8064). Serum cotinine level, household smoker status, asthma status, and sociodemographic information were extracted for multiple regression analyses. The adjusted biannual change in log (cotinine) in comparison to earlier NHANES survey cycles was − 0.196 (p < 0.001) overall, − 0.055 (p = 0.089) among children with household smoker(s), and − 0.129 (p < 0.001) among children without. The proportion of children living with household smokers decreased from 24.9% in the 2003–2004 cycle to 11.4% in the 2013–2014 cycle. The adjusted odds ratios (ORs) for asthma were 1.34 (95% confidence interval (CI): 1.00–1.80; 2nd tertile vs 1st tertile) and 1.69 (95%CI: 1.25–2.29; 3rd tertile vs1st tertile), respectively. Highly exposed asthmatic children, in the 3rd cotinine tertile (>0.13 ng/mL), were primarily Non-Hispanic Black (61.0%) and whose family incomes were below poverty guidelines. Overall results reveal passive smoke exposure level among children ages 3–11 in the US decreased over the study period. Nevertheless, higher exposure to passive smoke is still associated with higher odds of childhood asthma. Targeted smoking cessation interventions in clinical practices are needed to reduce tobacco smoke exposure and related asthma risk in children, particularly in low-income and minority groups.

Lower Plasma Klotho Concentrations Are Associated with Vascular Dementia but Not Late-Onset Alzheimer’s Disease

Background: The protein Klotho is involved in biological processes related to longevity, cardiovascular health, and cognition. Serum Klotho levels have been associated with better cognition in animal models; moreover, lower Klotho concentrations in cerebrospinal fluid from subjects with late-onset Alzheimer’s disease (LOAD) have been reported. Objective: Our study aimed to examine the possible relationship between Klotho plasma concentrations and cognitive status in the elderly. Methods: We evaluated plasma Klotho levels in a sample of 320 elderly patients admitted to a Memory Clinic. Four groups of subjects were enrolled, including cognitively intact individuals complaining about memory loss (controls) and patients affected by LOAD, mild cognitive impairment, or vascular dementia (VD). The sample was stratified by plasma Klotho tertiles. Results: Lower levels of plasma Klotho (1st tertile) were associated with older age, higher prevalence of VD, single/multiple lacunar infarcts and leukoaraiosis, coronary heart disease and stroke, and higher levels of creatinine, homocysteine, and high-sensitivity C-reactive protein. On multivariate logistic regression analysis, the risk of VD was 3- and 4-fold in subjects belonging to the 1st tertile (≤514.8 pg/mL, OR 3.54, 95% CI 1.05–11.93) and 2nd tertile (> 514.8, < 659.1 pg/mL, OR 4.28, 95% CI 1.30–14.06) compared to the 3rd tertile (≥659.1 pg/mL). A significantly increased VD risk was found for Klotho values < 680 pg/mL. Conclusion: In a sample of elderly individuals, we found a significant association between low plasma Klotho levels and VD, but not LOAD. This finding suggests that, although these 2 forms of dementia might overlap, some physiopathological mechanisms related to VD and LOAD remain distinct.

Association of change in total cholesterol level with mortality: A population-based study.

BackgroundHypercholesterolemia is a well-established risk factor for coronary heart disease, but the association between cholesterol level change and mortality is not fully understood. We aimed to investigate the association of 2 year (2002–2003 to 2004–2005) change in cholesterol with all-cause and cause-specific mortality in a population-based cohort study.Methods and findingsThe study population consisted of 269,391 participants aged more than 40 years who were free of myocardial infarction, stroke and cancer using the Korean National Health Insurance Service—National Health Screening Cohort. Cholesterol levels were classified into 1st, 2nd and 3rd tertiles during each of the first and second health examinations, respectively. The participants were followed-up for all-cause and cause-specific mortality from 1 January 2006 to 31 December 2013. Compared to participants who stayed within the 2nd tertile group for cholesterol during both the first and second examinations, participants who became or maintained cholesterol levels to the 1st tertile during the second examination had increased risk of all-cause mortality [adjusted hazard ratio (aHR) with 95% confidence interval (95% CI) = 1.28 (1.18–1.38) in 1st/1st, 1.16 (1.07–1.26) in 2nd/1st and 1.47 (1.32–1.64) in 3rd/1st tertile levels, respectively]. In addition, increased or persistent high cholesterol levels to the 3rd tertile was associated with elevated risk for all-cause mortality [aHR (95% CI) = 1.10 (1.01–1.20) in 1st/2nd, 1.16(1.03–1.31) in 1st/3rd and 1.15(1.05–1.25) in 3rd/3rd tertile levels].ConclusionsChanges in cholesterol levels in either direction to low cholesterol or persistently low cholesterol levels were associated with higher risk of mortality. Particularly, spontaneous decline in cholesterol levels may be a marker for worsening health conditions.

Valor de la puntuación SYNTAX II para la predicción de eventos clínicos en pacientes sometidos a implante percutáneo de válvula aórtica

Introduction and objectivesThe predictive value of the SYNTAX score (SS) for clinical outcomes after transcatheter aortic valve implantation (TAVI) is very limited and could potentially be improved by the combination of anatomic and clinical variables, the SS-II. We aimed to evaluate the value of the SS-II in predicting outcomes in patients undergoing TAVI. MethodsA total of 402 patients with severe symptomatic aortic stenosis undergoing transfemoral TAVI were included. Preprocedural TAVI angiograms were reviewed and the SS-I and SS-II were calculated using the SS algorithms. Patients were stratified in 3 groups according to SS-II tertiles. The coprimary endpoints were all-cause death and major adverse cardiovascular events (MACE), a composite of all-cause death, cerebrovascular event, or myocardial infarction at 1 year. ResultsIncreased SS-II was associated with higher 30-day mortality (P=.036) and major bleeding (P=.015). The 1-year risk of death and MACE was higher among patients in the 3rd SS-II tertile (HR, 2.60; P=.002 and HR, 2.66; P<.001) and was similar among patients in the 2nd tertile (HR, 1.27; P=.507 and HR, 1.05; P=.895) compared with patients in the 1st tertile. The highest SS-II tertile was an independent predictor of long-term mortality (P=.046) and MACE (P=.001). ConclusionsThe SS-II seems more suited to predict clinical outcomes in patients undergoing TAVI than the SS-I. Increased SS-II was associated with poorer clinical outcomes at 1 and 4 years post-TAVI, independently of the presence of coronary artery disease.Full English text available from: www.revespcardiol.org/en

Liver fibrosis marker, 7S domain of collagen type IV, in patients with pre-capillary pulmonary hypertension

BackgroundPulmonary hypertension (PH) causes right ventricular dysfunction and central venous congestion, and may lead to congestive hepatopathy. The serum 7S domain of collagen type IV (P4NP 7S) is an established marker of liver fibrosis in chronic liver disease. We aimed to determine whether P4NP 7S is related to hemodynamic parameters, and assessed the potential values of P4NP 7S to predict mortality. MethodsConsecutive 76 pre-capillary PH patients were divided into tertiles based on their serum P4NP 7S levels. We compared right-heart catheterization, echocardiographic findings, and mortality among the tertiles, and compared P4NP 7S with other known biomarkers of mortality. ResultsCardiac index, mean pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular fractional area change did not differ among the three groups. In contrast, compared to 1st and 2nd tertiles, the 3rd tertile had higher levels of right atrial pressure, right atrial area, and right ventricular area (P<0.05, respectively). In the Kaplan-Meier analysis, mortality progressively increased from the 1st to 2nd and 3rd tertiles (log-rank, P=0.002). In the Cox proportional hazard analysis, P4NP 7S was a predictor of mortality. ROC analysis demonstrated that a P4NP 7S concentration of 4.75ng/ml predicted mortality (AUC 0.85, 95% CI 0.75–0.94; P<0.001), and that the prognostic value of P4NP 7S was comparable or superior to that of other biomarkers (total bilirubin, creatinine, uric acid, C-reactive protein, B-type natriuretic peptide, and troponin I). ConclusionsSerum P4NP 7S is associated with higher central venous pressure, right-sided volume overload, and mortality in PH patients.

Association between serum zinc level and hypercholesterolemia and insulin resistance in Brazilian children

The objective of the study was to assess the association between serum zinc level and cardiometabolic factors in prepubertal Brazilian children. This was a cross-sectional study in a representative sample of schoolchildren 8 to 9 years of age in public and private urban schools in Viçosa, Minas Gerais State, Brazil. Body composition was assessed with dual-energy x-ray absorptiometry. The study measured serum glucose, insulin, total cholesterol, high and low density lipoprotein cholesterol, triglycerides, apolipoproteins A (Apo A) and B, uric acid, leptin, homocysteine, ultrasenstive C-reactive protein, and serum zinc. Arterial pressure was measured with automatic inflation equipment. Zinc deficiency was observed in 1.3% of the children. Girls showed the worst cardiometabolic profile, with higher prevalence of increased android fat, triglycerides, insulin resistance, leptin, zinc, and Apo A. In the first tertile of serum zinc concentration, prevalence of insulin resistance was 96% higher (PR = 1.96; 95%CI: 1.04-3.66) and hypercholesterolemia was 23% lower (PR = 0.77; 95%CI: 0.61-0.96) than in the reference category (grouped 2nd and 3rd tertiles of serum zinc concentration). Despite the low prevalence of zinc deficiency, insulin resistance was more prevalent in children in the lowest third of serum zinc concentration. It is important to prevent cardiometabolic alterations in childhood, especially insulin resistance, with an emphasis on serum zinc level.

Factors that influence the redox state in children: An exploratory study

OBJECTIVE:The aim of the present study was to investigate the association of the redox state via malondialdehyde (MDA) as a lipid peroxidation biomarker and hydrophilic antioxidant capacity (HAC) with dietary, anthropometric, demographic, socio-economic and clinical variables as well as the serum concentrations of vitamins in children aged 20-36 months. This cross-sectional study was conducted from May 2013 to May 2014 and included a total of 100 children.METHODS:The variables studied included anthropometric measurements, dietary intake by the Food Frequency Questionnaire (FFQ), socio-demographic features, clinical attributes, serum redox status, and serum vitamin concentrations.RESULTS:Children with a family income above the minimum wage and adequate body mass index (BMI) presented higher HAC. The MDA concentration was higher in children older than 24 months. Breastfeeding for up to 120 days provided greater antioxidant capacity. Children classified in the 2nd tertile for “fruit and vegetables” and “milk and dairy products” consumption showed lower levels of MDA. There was a positive correlation of MDA with serum vitamin A levels. These results show that among children in the 20-36 months age group, family income, breastfeeding, BMI and intake of fruits and vegetables can have an influence on the imbalance of the redox state.CONCLUSION:One strategy to prevent the imbalance between oxidants and antioxidants could be for health professionals to raise awareness among families, as such knowledge could repress/prevent the progression/initiation of several diseases in adult life.

The Value of the SYNTAX Score II in Predicting Clinical Outcomes in Patients Undergoing Transcatheter Aortic Valve Implantation

Introduction and objectivesThe predictive value of the SYNTAX score (SS) for clinical outcomes after transcatheter aortic valve implantation (TAVI) is very limited and could potentially be improved by the combination of anatomic and clinical variables, the SS-II. We aimed to evaluate the value of the SS-II in predicting outcomes in patients undergoing TAVI. MethodsA total of 402 patients with severe symptomatic aortic stenosis undergoing transfemoral TAVI were included. Preprocedural TAVI angiograms were reviewed and the SS-I and SS-II were calculated using the SS algorithms. Patients were stratified in 3 groups according to SS-II tertiles. The coprimary endpoints were all-cause death and major adverse cardiovascular events (MACE), a composite of all-cause death, cerebrovascular event, or myocardial infarction at 1 year. ResultsIncreased SS-II was associated with higher 30-day mortality (P=.036) and major bleeding (P=.015). The 1-year risk of death and MACE was higher among patients in the 3rd SS-II tertile (HR, 2.60; P=.002 and HR, 2.66; P<.001) and was similar among patients in the 2nd tertile (HR, 1.27; P=.507 and HR, 1.05; P=.895) compared with patients in the 1st tertile. The highest SS-II tertile was an independent predictor of long-term mortality (P=.046) and MACE (P=.001). ConclusionsThe SS-II seems more suited to predict clinical outcomes in patients undergoing TAVI than the SS-I. Increased SS-II was associated with poorer clinical outcomes at 1 and 4 years post-TAVI, independently of the presence of coronary artery disease.

Postprocedural high-sensitivity troponin T and prognosis in patients with non-ST-segment elevation myocardial infarction treated with early percutaneous coronary intervention.

The association of postprocedural high-sensitivity troponin T (hs-TnT) with prognosis of non-ST-segment elevation myocardial infarction (NSTEMI) patients is incompletely investigated. To assess the prognostic value of hs-TnT in NSTEMI patients undergoing early percutaneous coronary intervention (PCI). This study included 3783 patients with NSTEMI undergoing early PCI. Preprocedural and peak postprocedural hs-TnT was measured. Patients were divided into 3 groups: a group with postprocedural hs-TnT in the 1st tertile (hs-TnT <105ng/L; n=1264), a group with postprocedural hs-TnT in the 2nd tertile (hs-TnT ≥105ng/L to 470ng/L; n=1258) and a group with postprocedural hs-TnT in the 3rd tertile (hs-TnT >470ng/L; n=1261). The primary outcome was 1-year all-cause mortality. Overall, there were 299 deaths: 59 (5.5%), 98 (8.2%) and 142 deaths (12.6%) among patients of the 1st, 2nd and 3rd postprocedural hs-TnT tertiles (unadjusted hazard ratio [HR]=1.65, 95% confidence interval [CI] 1.20 to 2.67; P=0.002 for tertile 2 vs tertile 1 and unadjusted HR=2.41 [1.79-3.25]; P<0.001 for tertile 3 vs tertile 1). After adjustment postprocedural hs-TnT was independently associated with the risk of all-cause mortality (adjusted [HR]=1.22 [1.13-1.33], P<0.001 for 1 unit higher log hs-TnT). Postprocedural hs-TnT improved the risk prediction of the model of all-cause mortality (the C statistic of the model without [with baseline variables only] and with incorporation of postprocedural hs-TnT was 0.759 [0.732-0.782] and 0.772 [0.746-0.794], respectively; P<0.001). In patients with NSTEMI undergoing early PCI, postprocedural hs-TnT is independently associated with increased risk of mortality up to 1year after PCI.

Changes in high-sensitivity troponin after drug-coated balloon angioplasty for drug-eluting stent restenosis.

The success of drug-coated balloon therapy might be compromised by intraprocedural particulate embolisation of matrix coating, which may cause downstream microvascular obstruction. We aimed to investigate whether drug-coated balloon therapy was associated with an increase in markers of myocardial necrosis compared with drug-eluting stents or plain balloon angioplasty. In the ISAR-DESIRE-3 trial, patients with limus-eluting stent restenosis were randomised to treatment with a paclitaxel-coated balloon (PCB), paclitaxel-eluting stent (PES) or balloon angioplasty. We included enrolled patients who had pre- and post-intervention high-sensitivity troponin (hs-TnT) levels available. The delta (peak post-procedure minus baseline) troponin was compared between treatment arms. The association between delta troponin tertiles and three-year mortality was also evaluated. Three hundred and forty-three (343) patients were included, comprising patients treated with PCB (n=115), PES (n=112) and balloon angioplasty (n=116). Groups were well matched in terms of baseline characteristics. There was no difference in delta troponin in patients treated with PCB, PES and balloon angioplasty (36±65, 70±183, and 51±124 ng/L, respectively, p=0.16). Three-year mortality was 7.7%, 8.8% and 14.3% for the 1st, 2nd and 3rd tertiles of delta troponin, respectively, p=0.23. In patients with drug-eluting stent restenosis, there was no difference in subclinical myocardial necrosis among patients treated with PCB, PES, and balloon angioplasty.

Relation of elevated serum uric acid levels to first-degree heart block and other cardiac conduction defects in hospitalized patients with type 2 diabetes

AimsSeveral studies have reported that moderately elevated serum uric acid levels are associated with an increased risk of tachyarrhythmias (mainly atrial fibrillation) in patients with and without type 2 diabetes mellitus (T2DM). It is currently unknown whether an association also exists between elevated serum uric acid levels and cardiac conduction defects in patients with T2DM. MethodsWe retrospectively analyzed a hospital-based sample of 967 patients with T2DM discharged from our Division of Endocrinology over the years 2007–2014. Standard electrocardiograms were performed on all patients and were interpreted by expert cardiologists. ResultsOverall, 267 (27.6%) patients had some type of conduction defects on electrocardiograms (defined as at least one block among first-degree atrio-ventricular block, second-degree block, third-degree block, left bundle branch block, right bundle branch block, left anterior hemi-block or left posterior hemi-block). Patients in the 3rd serum uric acid tertile had a higher prevalence of any cardiac conduction defects than those belonging to 2nd or 1st tertile, respectively (35.8% vs. 25.0% vs. 22.6%; p<0.0001). Elevated serum uric acid levels were associated with a nearly twofold increased risk of cardiac conduction defects after adjustment for age, sex, hemoglobin A1c, diabetes duration, metabolic syndrome, chronic kidney disease, chronic obstructive pulmonary disease, ischemic heart disease, valvular heart disease and medication use (adjusted-odds ratio 1.84, 95% confidence intervals 1.2–2.9; p=0.009). ConclusionsModerately elevated serum uric acid levels are associated with an increased prevalence of any cardiac conduction defects in hospitalized patients with T2DM, independent of multiple risk factors and potential confounding variables.

O51-4 - Presepsin, Soluble CD14 Subtype, Is a Novel Marker of Short-term Mortality in Patients Hospitalized for Worsening Heart Failure

Presepsin, a subtype of soluble CD14, is an inflammatory marker, which largely reflects monocytic activation. We prospectively investigated the prognostic value of plasma presepsin concentration in 506 patients (mean age, 71 years) hospitalized for worsening heart failure. Results: Presesin levels significantly (P < .0001) correlated with estimated glomerular filtration rate (r = −0.42), N-terminal pro-B-type natriuretic peptide (r = 0.34), and high-sensitivity C-reactive protein (r = 0.36). During 6-month follow-up period, 53 deaths occurred, including 42 cardiovascular deaths. Using a multivariate Cox regression analysis including clinical, biochemical, and echocardiographic parameters, presepsin concentration was an independent predictor of 6-month mortality (P = .01). Patients with 3rd presepsin tertile had a higher risk for 6-month mortality than those with 1st or 2nd presepsin tertile (Figure). Conclusion: Presepsin may be a novel marker of short-term mortality in patients hospitalized for worsening heart failure.

Alanine Aminotransferase and Total Bilirubin Are Synergistically Associated with Metabolic Syndrome Among Middle-Aged and Elderly Japanese Women.

Metabolic syndrome (MetS) is associated with an increased risk of major cardiovascular events. Alanine aminotransferase (ALT) at high levels and total bilirubin (T-BiL) at low levels were oxidative potentials, but it was uncertain whether ALT and T-BiL had an additive interaction for the risk of MetS. From a single community, we recruited 864 women (70 ± 8 years) during their annual health examination. We cross-sectionally investigated whether ALT and T-BiL are associated with MetS and its components based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report. Of these subjects, 415 women (48.0%) had MetS. Participants with MetS had a higher ALT and lower T-BiL level than those without MetS. The adjusted-odds ratios (OR) (95% confidence interval [CI]) for MetS across tertiles of ALT and T-BiL were 1.00, 1.19 (0.78-1.81), and 1.86 (1.24-2.80) and 1.00, 0.96 (0.65-1.43), and 0.54 (0.36-0.81), respectively. When ALT and T-BiL were categorized into three binary characteristics by tertiles of ALT and T-BiL, high T-BiL was associated with decreased risk for MetS in a multivariable model (OR: 0.55, 95% CI: 0.37-0.82), especially among those with 1st tertile ALT. Similarly, high ALT was also associated with increased risk for MetS in a multivariate model (OR: 1.81, 95% CI: 1.20-2.71), especially among those with 2nd & 3rd tertiles of T-BiL. In the formal testing of addictive interaction between ALT and T-BiL for MetS, presence of T-BiL <0.72 mg/dL (1st and 2nd tertile) alone was not associated with increased risk of MetS in a multivariate analysis, and presence of ALT ≥16 IU/L (2nd and 3rd tertile) alone was not associated with increased risk of MetS. These results suggested that higher ALT and lower T-BiL levels were synergistically associated with MetS, independent of other confounding factors among Japanese women.

Forward flexion of trunk in Parkinson's disease patients is affected by subjective vertical position.

PurposeNo method has been established to evaluate the dissociation between subjective and objective vertical positions with respect to the self-awareness of postural deformity in patients with Parkinson’s disease (PD). The purpose of this study was to demonstrate, from the relationship between an assessment of the dissociation of subjective and objective vertical positions of PD patients and an assessment based on established PD clinical evaluation scales, that the dissociation regarding vertical position is a factor in the severity of the forward flexion of trunk (FFT).MethodsSubjects were 39 PD patients and 15 age-matched healthy individuals (control group). Posture was evaluated with measurement of FFT angle during static standing and the subjective vertical position (SV) of the patient. For evaluation of motor function, the Modified Hoehn & Yahr scale, Unified Parkinson’s Disease Rating Scale (UPDRS), 3-m Timed Up and Go Test (TUG), and Functional Reach Test (FRT) were used.ResultsIn PD patients, FFT angle in the 3rd tertile of patients was 13.8±9.7°, significantly greater than those in the control group and the 1st and 2nd tertiles of PD patients (control group vs 3rd tertile, p = 0.008; 1st tertile vs 3rd tertile, p<0.001; 2nd vs 3rd tertile, p = 0.008). In multiple regression analysis for factors in the FFT angle, significant factors were SV, disease duration, and the standard deviation of each SV angle measurement.ConclusionThe dissociation between SV and objective vertical position affects the FFT of PD patients, suggesting an involvement of non-basal ganglia pathologies.

Abstract 2299: Toxic metals in private well water and bladder and kidney cancer incidence in North Carolina

Abstract Introduction: There are a limited number of studies conducted in the US that have related metals in well water with kidney and bladder cancer. We investigated levels of arsenic (As), cadmium (Cd), manganese (Mn), and lead (Pb) in private well water and the association with incidence of bladder and kidney cancer in 100 counties in North Carolina, a state that has among the highest proportion of well water consumers in the country. Methods: Between 1998-2010, private wells across 100 NC counties were analyzed for levels of As, Cd, Mn and Pb (n=63,836, n=22,915, n=70,675 and n=65,535 measurements, respectively) and geocoded. Bladder and kidney cancer incidence for each county between 1990 and 2011 were obtained from the North Carolina Department of Health and Human Services. County-level data on potential confounders were obtained from US Census Bureau data (2010) and the Behavioral risk factor surveillance study (2003, 2005). For each county, the mean concentration of each metal and the incidence rate of kidney and bladder cancer were calculated separately. Using counties as the unit of analysis, we used Poisson regression to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) between mean concentration of the four metals and kidney and bladder cancer incidence, adjusting for age, gender, race, education, physical activity, smoking, diabetes, hypertension and residential well water supply. County mean metal levels were analyzed in tertiles. Counties with less than 10 cases or fewer than 10 well measurements for any metal were excluded from the analysis. Results: Ninety-eight counties were included in the final analysis. In the fully adjusted model, elevated IRRs for kidney cancer were observed in counties with the highest tertile of As (3rd tertile: 0.99-11.44 ppb, IRR=1.05 (95% CI 1.00, 1.11)). Similarly, elevated IRRs for kidney cancer were observed for both the 2nd and 3rd tertiles of Cd (3rd tertile 0.61-2.98 ppb: IRR=1.05 (95% CI 1.00, 1.10)) and the 2nd tertile of Pb (3.88-5.05 ppb, IRR=1.05 (95% CI 1.00, 1.10)). A dose response was observed for kidney cancer incidence and Mn (2nd tertile: 37.33-51.74 pbb; IRR =1.06 (95% CI 1.02, 1.11); 3rd tertile: 52.95-146.60 ppb: IRR=1.13 (95% CI 1.08, 1.19)). For bladder cancer, no relationship was observed with As but IRRs were elevated for the other metals including potential dose-response trend with Cd and Mn (Pb 2nd tertile 3.88-5.05 ppb: IRR=1.03 (95% CI 1.00, 1.07); Cd 3rd tertile 0.61-2.98 ppb: IRR=1.10 (95% CI 1.06, 1.15); Mn 3rd tertile 52.95-146.60 ppb: IRR=1.12 (95% CI 1.08, 1.16)). Conclusion: In North Carolina, counties with higher mean private well metal levels had elevated kidney and bladder cancer incidence rates. The conclusions are limited by the ecological approach, but the consistency of the associations suggests that the influence of metals in private well water in North Carolina on health outcome deserves additional investigation. Citation Format: Deepika Shrestha, Selin Cronkrite, Alison Sanders, Rebecca Fry, Katie M. Applebaum. Toxic metals in private well water and bladder and kidney cancer incidence in North Carolina [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2299. doi:10.1158/1538-7445.AM2017-2299

The maturation stage of tumoral tertiary lymphoid structures to predict recurrence risk in localized colorectal cancer.

e15083 Background: The tumor immune infiltrate and organized lymphocytic aggregates within the tumor microenvironment, known as tertiary lymphoid structures (TLS), play a critical role in cancer. We hypothesize that the maturation stage of TLS harbors prognostic information on recurrence risk in patients (pts) with non-metastatic colorectal cancer (nmCRC). Methods: In a comprehensive immunofluorescence and clinical analysis of 111 pts with UICC stage II &amp; III nmCRC (median age: 65 yrs; female: n = 53 (48%); stage III: n = 69 (62%)), we quantified the number and maturation status of tumor-associated TLS in baseline surgical specimens:[1] Early TLS (E-TLS, composed of dense lymphocytic aggregates without follicular dendritic cells (FDCs), [2] Primary follicle-like TLS (PFL-TLS, having FDCs but no germinal center (GC) reaction), and [3] Secondary follicle-like TLS (SFL-TLS, having an active GC reaction). The 3-year incidence of recurrence was the primary endpoint of this study, which occurred in 19 pts (3-year recurrence risk = 18.3%). Results: Most TLS formed in tissue adjacent to the tumor. The median number of TLS/mm of tumor perimeter was 1.0 [25th-75th percentile: 0.5-1.7]. The average proportions of different TLS maturation stages were 56% of E-TLS [40-78], 20% of PFL-TLS [6-37], and 16% of SFL-TLS [0-32]. A structural equation model was fitted to summarize the TLS counts and maturation stages into a TLS maturation immunoscore for predicting recurrence. 3-year recurrence risks were 31.7% (95%CI: 17.2-47.3), 15.9% (5.7-30.5), and 9.4% (2.4-22.4) in pts in the 1st, 2nd, and 3rd tertile of the score (Gray’s test p = 0.05). A higher score was significantly associated with a lower recurrence risk (Hazard ratio (HR) for 10 units increase = 0.76, 95%CI: 0.59-0.97, p = 0.03), and this association prevailed in multivariable analysis adjusting for age, ECOG performance status, stage, and adjuvant chemotherapy (Adjusted HR = 0.73, 0.54-0.99, p = 0.05). Conclusions: Tumors of nmCRC pts with a very low risk of recurrence are characterized by an increased fraction of mature TLS comprising FDCs and GCs. If confirmed prospectively, adjuvant chemotherapy may be avoided in nmCRC pts with a high TLS maturation score.

Alkaline phosphatase and prognosis in patients with coronary artery disease.

The evidence on the association between alkaline phosphatase (ALP) and prognosis of patients with coronary artery disease (CAD) is limited. The aim of this study was to assess the association of ALP with the risk of mortality or coronary events in patients with CAD. The study included 5540 patients with angiography-proven CAD treated with catheter-based coronary revascularization. Baseline ALP measurements were available for analysis in all patients. Patients were divided into three groups: a group with an ALP activity in the 1st tertile (ALP ≤ 65·5 U/L; n = 1855), a group with an ALP activity in the 2nd tertile (ALP > 65·5 to 85·7 U/L; n = 1839) and a group with an ALP in the 3rd tertile (ALP > 85·7 U/L; n = 1846). The primary outcome was all-cause mortality at 3-year follow-up. All-cause deaths (number [Kaplan-Meier estimates]) occurred in 443 patients: 117 (7·2%), 130 (8·1%) and 196 deaths (11·8%) among patients of the 1st, 2nd and 3rd ALP tertiles (unadjusted hazard ratio [HR] = 1·33, 95% confidence interval [CI]: 1·19 to 1·50; P < 0·001, calculated per tertile increment in the ALP activity). After adjustment in multivariable Cox proportional hazards model, ALP was independently associated with the risk of all-cause mortality (adjusted HR = 1·33 [1·18-1·51], P < 0·001, calculated per unit increment in log ALP). The multivariable model for all-cause mortality with baseline variables without ALP had a C statistic of 0·820 [0·797-0·843] which increased to 0·825 [0·804-0·849] after ALP inclusion; delta C statistic 0·005 [0·001-0·011]; P < 0·001. In patients with CAD, elevated ALP activity was independently associated with the risk of 3-year all-cause mortality.

Cysteinylated transthyretin as a discriminator of cardiovascular risk in patients with diabetes mellitus

BackgroundThe cysteine residue on transthyretin (TTR) is susceptible to be oxidized, and serum cysteinylated TTR (Cys-TTR) level is thought to reflect oxidative stress. The purpose of this study was to elucidate the relationship between Cys-TTR and arterial stiffness, a known predictor of cardiovascular disease, in patients with type 2 diabetes. MethodsThe subjects were 105 male outpatients with type 2 diabetes. Arterial stiffness was evaluated by measuring cardio-ankle vascular index (CAVI). The relationship between CAVI and ratio of Cys-TTR to total TTR (Cys-TTR ratio) was analyzed. ResultsCys-TTR ratio was significantly correlated with CAVI (Pearson's correlation coefficient: 0.316, p<0.01), and CAVI was significantly higher in the 3rd tertile group for Cys-TTR ratio than in its 1st tertile group. These relationships were also significant after adjusting for age, smoking, alcohol drinking, body mass index, mean arterial pressure, hemoglobin A1c, LDL cholesterol-to-HDL cholesterol ratio and eGFR. Prevalence of high CAVI (≥10.0) was significantly higher in the 3rd tertile for Cys-TTR ratio than in its 1st tertile and tended to be higher with an increase in tertile (28.6% in the 1st tertile, 42.9% in the 2nd tertile and 60.0% in the 3rd tertile). Odds ratio (OR) for high CAVI of the 3rd vs. 1st tertile groups for Cys-TTR ratio was significantly higher than the reference level of 1.00 both before and after adjustment for the above cardiovascular risk factors (crude OR, 3.75 [1.38–10.17]; adjusted OR, 5.09 [1.39–18.64]). ConclusionsCys-TTR ratio is associated with arterial stiffness in patients with diabetes and is proposed as a new discriminator of cardiovascular risk.

Leukocyte telomere length and mortality among U.S. adults: Effect modification by physical activity behaviour

ABSTRACTThe purpose of this study was to examine the association between leukocyte telomere length (LTL) and mortality (outcome variable), with consideration by physical activity behaviour. Data from the 1999–2002 National Health and Nutrition Examination Survey were employed (N = 6,611; 20–85 yrs), with follow-up mortality assessment through 31 December 2006. DNA was extracted from whole blood to assess LTL via quantitative polymerase chain reaction. Compared to those in the first LTL tertile, the adjusted hazard ratio for all-cause mortality for those in the 2nd and 3rd LTL tertiles, respectively, was 0.82 (95% CI: 0.60–1.12; P = .22) and 0.76 (95% CI: 0.50–1.14; P = .18). However, after adjustments, LTL tertile 3 (vs. 1) was associated with all-cause mortality (HR = 0.37; 95% CI: 0.14–0.93; P = .03) for those who engaged in moderate-intensity exercise. Similarly, LTL was associated with CVD-specific mortality for those who engaged in moderate-intensity exercise (HR = 0.17; 95% CI: 0.04–0.73; P = .02). Longer telomeres are associated with increased survival, particularly among men and those who are active, underscoring the importance of promotion of physical activity behaviour.