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Retinopathy is a microvascular complication of diabetes mellitus (DM); however, it is also increasingly recognized in persons without DM. The microvascular diseases may play a prominent role in coronary heart disease (CHD) development in individuals with DM. We performed the study to evaluate the relation between non-DM retinopathy and CHD and also the association between baseline retinopathy and incidence and progression of CHD in individuals with and without DM. We included 5709 subjects with and without DM from the Multi-Ethnic Study of Atherosclerosis, who had retinal photos and coronary artery calcium score (CACS) available. We studied the association between baseline retinopathy and incidence and progression of coronary artery calcification (CAC) in subjects with and without DM. In DM group, the presence of retinopathy was significantly associated with an increased rate of CAC (RR 1.3 (95% CI [1.02, 1.66]) after adjusting for age, sex, race, follow-up time, and CHD risk factors. In non-DM group, the presence of retinopathy was not significantly associated with increased risk of CAC, however, the interaction between presence of retinopathy and DM status was not statistically significant. Within the DM group with CAC present at baseline, the presence of retinopathy was significantly associated with greater CAC progression (113 Agatson units (AU) greater, (95% CI [51-174]). In the non-DM group with present CAC at baseline; the presence of retinopathy was associated with 24 (95% CI [-0.69, 48.76]) AU higher CAC progression. All findings were adjusted for CHD risk factors. In conclusion, after adjustment for major CHD risk factors, retinopathy was associated with progression of CAC in both DM and non-DM individuals. However, the association was stronger in those with DM.

Background Age and human immunodeficiency virus (HIV) treatment may affect the association of HIV infection with atherosclerosis. Methods We used identical carotid artery B-mode ultrasonographic methods in 5 cohorts participating in the National Heart, Lung, and Blood Institute HIV-CVD Collaborative to measure intima-media thickness of the right far wall of the common carotid artery (CCA-IMT) and carotid artery bifurcation (BIF-IMT) between 2010 and 2013. Participants aged 6-75 years were either HIV infected or uninfected. Linear regression assessed associations of CCA-IMT and BIF-IMT with HIV infection and cardiovascular disease risk factors, within age and HIV treatment groups. Adjustment variables included sex, race/ethnicity, smoking, height, weight, and use of antihypertensive and lipid-lowering drugs. Results We studied 867 HIV-infected and 338 HIV-uninfected male and 696 HIV-infected and 246 HIV-uninfected female participants. Among both middle-aged (30-49 years) and older adults (50-75 years), HIV-infected participants had CCA-IMT and BIF-IMT values that were similar to or lower than those in HIV-uninfected participants. In contrast, among those aged 6-29 years, HIV infection was associated with higher CCA-IMT and BIF-IMT values. Among HIV-infected participants, associations of higher systolic blood pressure and lower high-density lipoprotein cholesterol with Carotid artery intima-media thickness strengthened with age. Conclusions The effects of HIV on carotid artery structure may differ across the lifespan, with traditional determinants of cardiovascular disease burden playing a larger role and HIV playing a lesser role in older adults than in young adults and children.

Rationale and Objectives Vascular calcification independently predicts cardiovascular disease (CVD), and computed tomography (CT) is a useful tool to evaluate and quantify not only coronary but also thoracic aortic calcification (TAC). Previous TAC progression reports were limited to dialysis and renal transplant patients. This is the first study to evaluate TAC progression in a large multiethnic cohort without clinically evident CVD at entry. Methods Non–contrast-enhanced cardiac CTs were obtained in 5886 of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants (mean age, 62 years; 48% males; 40% white, 27% black, 21% Hispanic, and 12% Chinese). Baseline and follow-up TAC scores were derived. Results Overall, 4308 (73%) participants had no detectable baseline TAC. Mean follow-up duration was 2.4 ± 0.8 years, during which 12% developed TAC. The overall incidence rate was 4.8%/year and was greater with age across gender and ethnic groups; TAC incidence was significantly lower in blacks than whites. After adjustment for follow-up duration, regression analyses showed age, systolic blood pressure, antihypertensives, and smoking were associated with incident TAC. A total of 1578 (27%) participants had TAC at baseline with a positive association between average annual TAC change and baseline age. Although the overall median change was 32.9 (−1.4 to 112.2) Agatston units, 27% showed an annual score change of ≥100 and blacks showed the lowest median across ethnic groups; 22.7 (−3 to 86.8). Age, systolic blood pressure, lipid-lowering medication, diabetes, and smoking were associated with TAC progression. Conclusions In MESA, traditional CV risk factors were related to both TAC incidence and progression. Blacks had the lowest incidence and median change across ethnic groups, consistent with previous findings for coronary calcification.

© 2015 Society of Cardiovascular Computed Tomography. Background: Cardiovascular calcification outside of the coronary tree, known as extracoronary calcification (ECC), is highly prevalent, often occurs concurrently in multiple sites, and yet its prognostic value is unclear. Objective: To determine whether multisite ECC is associated with coronary heart disease (CHD) events, CHD mortality, and all-cause mortality. Methods: We evaluated 5903 participants from the Multi-Ethnic Study of Atherosclerosis without diabetes who underwent CT imaging for calcification of the aortic valve, aortic root, mitral valve, and thoracic aorta. Participants were followed for 10.3years. Multivariable adjusted hazard ratios estimated risk of outcomes for increasing numbers of ECC sites (0, 1, 2, 3, and 4), and receiver operator characteristic analysis assessed model discrimination. Results: Prevalence of any ECC was 45%; median age was 62 years. Compared with those without ECC, those with ECC in 4 sites had increased hazards of 4.5, 7.1 and 2.3 for CHD events, CHD mortality, and all-cause mortality, respectively, independent of traditional risk factors (TRF; all P ≤ .05), and had ≥2-fold increased hazards for outcomes independent of coronary artery calcification (CAC). Each additional site of ECC was positively associated with each outcome in a graded fashion. When added to TRF, ECC significantly increased the area under the receiver operator characteristic curve for all outcomes and modestly increased the area under the curve for mortality beyond TRF+ CAC (0.799 to 0.802; P= .03). Conclusion: Increasing multisite ECC has a graded association with higher CHD and mortality risk, contributing information beyond TRF. Multisite ECC incidentally identified on imaging can be used to improve individualized risk prediction.

F-18-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been used to evaluate the metabolic response of metastatic brain tumors to treatment by comparing their tumor glucose metabolism before and after treatment. The standard analysis based on regions-of-interest has the advantage of simplicity. However, it is by definition restricted to those regions and is subject to observer variability. In addition, the observed changes in tumor metabolism are often confounded by normal changes in the tissue background, which can be heterogenous. We propose an analysis pipeline for automatically detecting the change at each voxel in the entire brain of a single subject, while adjusting for changes in the background. The complete analysis includes image registration, segmentation, a hierarchical model for background adjustment and voxelwise statistical comparisons. We demonstrate the method’s ability to identify areas of tumor response and/or progression in two subjects enrolled in a clinical trial using FDG-PET to evaluate lapatinib for the treatment of brain metastases in breast cancer patients.

Objective: This study was carried out to examine the efficacy of a 12-week, low-intensity (1-hour/wk of therapist contact), parent-delivered intervention for toddlers at risk for autism spectrum disorders (ASD) aged 14 to 24 months and their families. Method: A randomized controlled trial involving 98 children and families was carried out in three different sites investigating the efficacy of a parent delivery of the Early Start Denver Model (P-ESDM), which fosters parental use of a child-centered responsive interaction style that embeds many teaching opportunities into play, compared to community treatment as usual. Assessments were completed at baseline and 12 weeks later, immediately after the end of parent coaching sessions. Results: There was no effect of group assignment on parent‐child interaction characteristics or on any child outcomes. Both groups of parents improved interaction skills, and both groups of children demonstrated progress. Parents receiving P-ESDM demonstrated significantly stronger working alliances with their therapists than did the community group. Children in the community group received significantly more intervention hours than those in the P-ESDM group. For the group as a whole, both younger child age at the start of intervention and a greater number of intervention hours were positively related to the degree of improvement in children’s behavior for most variables. Conclusions: Parentimplemented intervention studies for early ASD thus far have not demonstrated the large effects seen in intensive-treatment studies. Evidence that both younger age and more intervention hours positively affect developmental rates has implications for clinical practice, service delivery, and public policy. J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(10): 1052‐1065. Key Words: Early Start Denver Model (ESDM), early intervention, toddler, parent‐child interaction, autism

Background Vascular endothelial growth factor (VEGF)-targeted therapy has become standard treatment for patients with metastatic renal cell cancer (mRCC). Since these therapies can induce tumor necrosis and minimal tumor shrinkage, Response Evaluation Criteria in Solid Tumors (RECIST) may not be optimal for predicting clinical outcome. Objective To systematically determine the optimal early posttherapy imaging changes (EPTIC) to separate responders and nonresponders at the first posttreatment follow-up computed tomography (CT). Design, setting, and participants Seventy mRCC patients with 155 target lesions treated with first-line sunitinib, sorafenib, or bevacizumab at academic medical centers underwent contrast-enhanced thoracic and abdominal CT at baseline and first follow-up after therapy initiation (median: 78 d after therapy initiation; range: 31–223 d). Measurements Evaluations were performed according to (1) RECIST 1.0; (2) Choi criteria; (3) tumor shrinkage (TS) of ≥10% decrease in sum of the longest unidimensional diameter (SLD); and (4) 15% or 20% decrease in mean CT tumor density. Correlation with time to treatment failure (TTF) and overall survival (OS) were compared and stratified by response to each of the radiologic criteria. Results and limitations Eleven patients were considered responders by RECIST 1.0; 49 based on Choi criteria; 31 patients had ≥10% decrease in the SLD; and 36 and 32 patients had ≥15% and ≥20% decrease, respectively, in mean tumor density on CT. Only the threshold of 10% decrease in the SLD was statistically significant in predicting TTF (10.4 vs 5.1 mo; p =0.02) and OS (32.5 vs 15.8 mo; p =0.002). Receiver operating characteristic analysis yielded a 10% decrease in SLD as the optimal size change threshold for responders. The retrospective nature of the study and measurements by a single oncoradiologist are inherent limitations. Conclusions In the retrospectively analyzed study population of mRCC patients receiving VEGF-targeted agents, a 10% reduction in the SLD on the first follow-up CT was an optimal early predictor of outcome.

Rationale and Objectives Determine inter- and intraobserver variability of computed tomography (CT) tumor volume measurements in advanced non-small-cell lung cancer (NSCLC) patients treated in a Phase II clinical trial using chest CT. Materials and Methods Twenty-three advanced NSCLC patients with a total of 53 measurable lung lesions enrolled in a Phase II, multicenter, open-label clinical trial of erlotinib were retrospectively studied with institutional review board approval. Two radiologists independently measured the tumor size, volume, and CT attenuation coefficient using commercially available volume analysis software. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess inter- and intraobserver agreement. Results High CCCs (0.949–0.990) were observed in all types of measurements for interobserver agreement. The 95% limits of agreements for volume, unidimensional, and bidimensional measurements were (−26.0%, 18.6%), (−23.1%, 24.4%), and (−34.0%, 48.6%), respectively. Volume measurement had slightly higher CCC and narrower 95% limits of agreement compared to uni- and bidimensional measurements. CCCs for intraobserver agreement were high (range, 0.946–0.996) with CCC for volume being slightly higher than CCCs of uni- and bidimensional measurements. The smaller the tumor volume was, the larger the interobserver difference of CT attenuation. Location, morphology, or adjacent atelectasis had no significant impact on inter- or intraobserver variability. Conclusion CT tumor volume measurement in advanced NSCLC patients using clinical chest CT and commercially available software demonstrated high inter- and intraobserver agreement, indicating that the method may be used routinely in clinical practice.

To examine the role of brachytherapy in the treatment of cholangiocarcinomas in a relatively large group of patients.Using the Surveillance, Epidemiology and End Results database, a total of 193 patients with cholangiocarcinoma treated with brachytherapy were identified for the period 1988-2003. The primary analysis compared patients treated with brachytherapy (with or without external-beam radiation) with those who did not receive radiation. To try to account for confounding variables, propensity score and sensitivity analyses were used.There was a significant difference between patients who received radiation (n = 193) and those who did not (n = 6859) with regard to surgery (p0.0001), race (p0.0001), stage (p0.0001), and year of diagnosis (p0.0001). Median survival for patients treated with brachytherapy was 11 months (95% confidence interval [CI] 9-13 months), compared with 4 months for patients who received no radiation (p0.0001). On multivariable analysis (hazard ratio [95% CI]) brachytherapy (0.79 [0.66-0.95]), surgery (0.50 [0.46-0.53]), year of diagnosis (1998-2003: 0.66 [0.60-0.73]; 1993-1997: (0.96 [0.89-1.03; NS], baseline 1988-1992), and extrahepatic disease (0.84 [0.79-0.89]) were associated with better overall survival.To the authors' knowledge, this is the largest dataset reported for the treatment of cholangiocarcinomas with brachytherapy. The results of this retrospective analysis suggest that brachytherapy may improve overall survival. However, because of the limitations of the Surveillance, Epidemiology and End Results database, these results should be interpreted cautiously, and future prospective studies are needed.

Introduction The potential benefits and long-term complications of radiotherapy treatment for malignant thymoma are unclear. This is a retrospective analysis of outcome in patients with malignant thymoma from the Surveillance, Epidemiology, and End Results database between 1973 and 2005. Methods Of the 1987 patients identified, 1334 were analyzed. Patients were categorized according to the Masaoka staging system as stage I to IIA, IIB or III to IV. The primary end points were overall survival, cardiac mortality, and the development of secondary malignancies. Results Patients received surgery and radiation (50%), surgery alone (26%), radiation alone (12%), or no treatment (12%). The median follow-up time for survivors was 65 months (range, 1–361 months). There was no significant increase in the 12-year cumulative incidence rate of death from heart disease (10.2% radiation versus 7.5% no radiation, p = 0.83) or incidence of secondary malignancies (11.7% versus 12.4%, p = 0.70) with radiation. Compared with surgery alone, adjuvant radiation significantly improved overall survival in patients with stage III to IV disease ( p = 0.04) and demonstrated a nonsignificant trend in patients with stage IIB disease ( p = 0.09). However, after excluding patients surviving less than 4 months to account for surgical mortality, the benefit with radiation was no longer significant (stage IIB: p = 0.45, stage III–IV: p = 0.44). Conclusions Radiation does not seem to increase the risk of cardiac mortality or secondary malignancy in patients with malignant thymoma. Although the routine use of postoperative radiotherapy in malignant thymoma does not appear warranted, high-risk patients may benefit from adjuvant radiation. This study can help to design prospective trials to further establish the role of radiotherapy in malignant thymoma.

S UMMARY When testing multiple hypotheses simultaneously, there is a need to adjust the levels of the individual tests to effect control of the family-wise error rate (FWER). Standard frequentist adjustments control the error rate but are typically both conservative and oblivious to prior information. We propose a Bayesian testing approach—multiplicity-calibrated Bayesian hypothesis testing—that sets individual critical values to reflect prior information while controlling the FWER via the Bonferroni inequality. If the prior information is specified correctly, in the sense that those null hypotheses considered most likely to be false in fact are false, the power of our method is substantially greater than that of standard frequentist approaches. We illustrate our method using data from a pharmacogenetic trial and a preclinical cancer study. We demonstrate its error rate control and power advantage by simulation.

The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.

Extrahepatic cholangiocarcinomas (EHC) are rare tumors of the biliary tree because of their low incidence, large randomized studies examining radiotherapy (RT) for EHC have not been performed. The purpose of this study was to examine the role of adjuvant and palliative RT in the treatment of EHC in a large patient population.This was a retrospective analysis of 4,758 patients with EHC collected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was overall survival.Patients underwent surgery (28.8%), RT (10.0%), surgery and RT (14.7%), or no RT or surgery (46.4%). The median age of the patient population was 73 years (range, 23-104), 52.5% were men, and 80.7% were white. The median overall survival time was 16 months (95% confidence interval [CI] 15-17), 9 months (95% CI 9-11), 9 months (95% CI 9-10), and 4 months (95% CI 3-4) for surgery and RT, surgery, RT, and no RT or surgery, respectively. The overall survival was significantly different between the surgery and surgery and RT groups (p.0001) and RT and no RT or surgery groups (p.0001) on the log-rank test. The propensity score-adjusted analyses of surgery and RT vs. surgery (hazard ratio, 0.94; 95% CI, 0.84-1.05) were not significantly different, but that for RT vs. no RT or surgery (hazard ratio, 0.61; 95% CI, 0.54-0.70) was significantly different.These results suggest that palliative RT prolongs survival in patients with EHC. The benefit associated with surgery and RT was significant on univariate analysis but not after controlling for potential confounders using the propensity score. Future studies should evaluate the addition of chemotherapy and biologic agents for the treatment of EHC.

Pharmacogenetic clinical trials seek to identify genetic modifiers of treatment effects. When a trial has collected data on many potential genetic markers, a first step in analysis is to screen for evidence of pharmacogenetic effects by testing for treatment-by-marker interactions in a statistical model for the outcome of interest. This approach is potentially problematic because (i) individual significance tests can be overly sensitive, particularly when sample sizes are large; and (ii) standard significance tests fail to distinguish between markers that are likely, on biological grounds, to have an effect, and those that are not. One way to address these concerns is to perform Bayesian hypothesis tests [Berger (1985) Statistical decision theory and Bayesian analysis. New York: Springer; Kass and Raftery (1995) J Am Stat Assoc 90:773-795], which are typically more conservative than standard uncorrected frequentist tests, less conservative than multiplicity-corrected tests, and make explicit use of relevant biological information through specification of the prior distribution. In this article we use a Bayesian testing approach to screen a panel of genetic markers recorded in a randomized clinical trial of bupropion versus placebo for smoking cessation. From a panel of 59 single-nucleotide polymorphisms (SNPs) located on 11 candidate genes, we identify four SNPs (one each on CHRNA5 and CHRNA2 and two on CHAT) that appear to have pharmacogenetic relevance. Of these, the SNP on CHRNA5 is most robust to specification of the prior. An unadjusted frequentist test identifies seven SNPs, including these four, none of which remains significant upon correction for multiplicity. In a panel of 43 randomly selected control SNPs, none is significant by either the Bayesian or the corrected frequentist test.

Myocardial scarring leads to cardiac dysfunction and poor prognosis. The prevalence of and factors associated with unrecognized myocardial infarction and scar have not been previously defined using contemporary methods in a multiethnic US population.To determine prevalence of and factors associated with myocardial scar in middle- and older-aged individuals in the United States.The Multi-Ethnic Study of Atherosclerosis (MESA) study is a population-based cohort in the United States. Participants were aged 45 through 84 years and free of clinical cardiovascular disease (CVD) at baseline in 2000-2002. In the 10th year examination (2010-2012), 1840 participants underwent cardiac magnetic resonance (CMR) imaging with gadolinium to detect myocardial scar. Cardiovascular disease risk factors and coronary artery calcium (CAC) scores were measured at baseline and year 10. Logistic regression models were used to estimate adjusted odds ratios (ORs) for myocardial scar.Cardiovascular risk factors, CAC scores, left ventricle size and function, and carotid intima-media thickness.Myocardial scar detected by CMR imaging.Of 1840 participants (mean [SD] age, 68 [9] years, 52% men), 146 (7.9%) had myocardial scars, of which 114 (78%) were undetected by electrocardiogram or by clinical adjudication. In adjusted models, age, male sex, body mass index, hypertension, and current smoking at baseline were associated with myocardial scar at year 10. The OR per 8.9-year increment was 1.61 (95% CI, 1.36-1.91; P .001); for men vs women: OR, 5.76 (95% CI, 3.61-9.17; P .001); per 4.8-SD body mass index: OR, 1.32 (95% CI, 1.09-1.61, P = .005); for hypertension: OR, 1.61 (95% CI, 1.12-2.30; P = .009); and for current vs never smokers: 2.00 (95% CI, 1.22-3.28; P = .006). Age-, sex-, and ethnicity-adjusted CAC scores at baseline were also associated with myocardial scar at year 10. Compared with a CAC score of 0, the OR for scores from 1 through 99 was 2.4 (95% CI, 1.5-3.9); from 100 through 399, 3.0 (95% CI, 1.7-5.1), and 400 or higher, 3.3 (95% CI, 1.7-6.1) (P ≤ .001). The CAC score significantly added to the association of myocardial scar with age, sex, race/ethnicity, and traditional CVD risk factors (C statistic, 0.81 with CAC vs 0.79 without CAC, P = .01).The prevalence of myocardial scars in a US community-based multiethnic cohort was 7.9%, of which 78% were unrecognized by electrocardiography or clinical evaluation. Further studies are needed to understand the clinical consequences of these undetected scars.

Objectives— To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). Approach and Results— MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%–90.3%) compared with intermittent asthmatics 91.1% (88.5%–93.8%) and nonasthmatics 90.2% (89.4%–91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01–2.5]; P =0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Conclusions— In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics.

Background: Chronic asthma and cardiovascular disease (CVD) share a common inflammatory pathophysiology. We hypothesized that chronic asthma requiring daily controller medications is associated with higher CVD risk. Methods: Presence of chronic asthma and use of controller medications (CM; inhaled corticosteroids, leukotriene inhibitors, oral corticosteroids) were assessed in the MESA at Exam 1. Participants were followed for a mean (standard deviation) 9.1 (2.8) years for development of CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of chronic asthma and CVD. Results: The 6792 MESA participants were 62.2 (10.2) years old: 47% male, 28% African-American, 22% Hispanic and 2% Chinese. The 156 asthmatics that were on CM were compared with the 511 who were asthmatic but not on CM and the 6125 non-asthmatics. Asthmatics on CM, compared to those not on CM and non-asthmatics, respectively had higher age-adjusted levels of C-reactive protein (1.2 [1.2] vs 0.9 [1.2] vs 0.6 [1.2] mg/L) and fibrinogen (379 [88] vs 356 [80] vs 345 [73] mg/dL) (both p Discussion: In this large multi-ethnic cohort, asthmatics on CM had a higher CVD event rate compared to non-asthmatics. Increased CVD risk among asthmatics may be related to increased inflammatory stress.

Vascular calcification independently predicts cardiovascular disease (CVD), and computed tomography (CT) is a useful tool to evaluate and quantify not only coronary but also thoracic aortic calcification (TAC). Previous TAC progression reports were limited to dialysis and renal transplant patients. This is the first study to evaluate TAC progression in a large multiethnic cohort without clinically evident CVD at entry.Non-contrast-enhanced cardiac CTs were obtained in 5886 of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants (mean age, 62 years; 48% males; 40% white, 27% black, 21% Hispanic, and 12% Chinese). Baseline and follow-up TAC scores were derived.Overall, 4308 (73%) participants had no detectable baseline TAC. Mean follow-up duration was 2.4 ± 0.8 years, during which 12% developed TAC. The overall incidence rate was 4.8%/year and was greater with age across gender and ethnic groups; TAC incidence was significantly lower in blacks than whites. After adjustment for follow-up duration, regression analyses showed age, systolic blood pressure, antihypertensives, and smoking were associated with incident TAC. A total of 1578 (27%) participants had TAC at baseline with a positive association between average annual TAC change and baseline age. Although the overall median change was 32.9 (-1.4 to 112.2) Agatston units, 27% showed an annual score change of ≥100 and blacks showed the lowest median across ethnic groups; 22.7 (-3 to 86.8). Age, systolic blood pressure, lipid-lowering medication, diabetes, and smoking were associated with TAC progression.In MESA, traditional CV risk factors were related to both TAC incidence and progression. Blacks had the lowest incidence and median change across ethnic groups, consistent with previous findings for coronary calcification.

ObjectiveWe develop a new diabetes CHD risk estimator using traditional risk factors plus coronary artery calcium (CAC), ankle-brachial index (ABI), high sensitivity C-reactive protein, family history of CHD, and carotid intima-media thickness and compared it with United Kingdom Prospective Diabetes study (UKPDS), Framingham risk and the NCEP/ATP III risk scores in type 2 diabetes mellitus (T2DM).Methods and resultsWe combined data from T2DM without clinical CVD in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (N=1343). After a mean follow-up of 8.5 years, 85 (6.3%) participants had incident CHD. Among the novel risk markers, CAC best predicted CHD independent of the FRS [hazard ratio: HR (95% CI): log (CAC+25):1.69 (1.45-1.97), p25 and ≤125:2.29 (0.87-5.95), >125 and ≤400: 3.87 (1.57-9.57), >400: 5.97 (2.57-13.84), respectively). The MESA-HNR diabetes CHD risk score has better accuracy for the main outcome versus the FRS or UKPDS [area under curve (AUC) of 0.76 vs. 0.70 and 0.69, respectively; all p&nbsp

Capecitabine produces an objective response rate of up to 25 % in anthracycline-treated, taxane-resistant metastatic breast cancer (MBC). The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has clinical activity when used alone in MBC. The objective of this study was to determine the efficacy and safety of tipifarnib–capecitabine combination in MBC patients who were previously treated with an anthracycline and progressed on taxane therapy. Eligible patients received oral capecitabine 1,000 mg/m2 twice daily plus oral tipifarnib 300 mg twice daily on days 1–14 every 21 days. The primary endpoint was ORR. The trial was powered to detect an improvement in response rate from 25 to 40 %. Among 63 eligible, partial response occurred in six patients (9.5 %; 90 % CI 4.2–17.9 %), median progression-free survival was 2.6 months (95 % CI 2.1–4.4), and median overall survival was 11.4 months (95 % CI 7.7–14.0). Dose modifications were required for 43 patients (68 %) for either tipifarnib and/or capecitabine. Grades 3 and 4 toxicities were seen in 30 patients (44 %; 90 % CI 44.4–67.0 %) and 11 patients (16 %; 90 % CI 10.8–29.0 %), respectively. The most common grade 3 toxicities included neutropenia, nausea, and vomiting; and the most common grade 4 toxicity was neutropenia (8 out of 11 cases). The tipifarnib–capecitabine combination is not more effective than capecitabine alone in MBC patients who were previously treated with an anthracycline and taxane therapy.

The association between metabolic syndrome and electrocardiographic (ECG) abnormalities is not well established.ECG tracings of 6,765 men and women aged 45-84 years, free of clinical cardiovascular disease, from the Multi-Ethnic Study of Atherosclerosis were obtained (2000-2002) and classified as normal or having major or minor abnormalities. We evaluated the associations of metabolic syndrome and its components with ECG abnormalities, adjusting for age, ethnicity, and gender and testing for effect modification by ethnicity and gender.The associations of metabolic syndrome, hypertension, and high triglycerides with ECG abnormalities varied significantly by gender. In males, metabolic syndrome and hypertension were significantly associated with major ECG abnormality [1.69 (1.33-2.13), and 2.22 (1.72-2.86), respectively] after adjusting for ethnicity and gender. Hypertension was also associated significantly with minor ECG abnormality in males after adjusting for age and ethnicity. In females, metabolic syndrome and hypertension were significantly associated with major [1.84 (1.44-2.37), and 1.68 (1.27-2.22), respectively] and minor [1.38 (1.19-1.59), and 1.53 (1.32-1.79), respectively] ECG abnormalities after adjusting for age and ethnicity. High triglycerides were only significantly associated with major ECG abnormality in females after adjusting for age and ethnicity. After adjusting for age, ethnicity, and gender, central obesity and high fasting blood glucose were significantly associated with major and minor ECG abnormalities, whereas low high-density lipoprotein cholesterol was significantly associated with major ECG abnormality only.Metabolic syndrome and its components are associated with major and/or minor ECG abnormalities. The relationship of metabolic syndrome, hypertension, and high triglycerides with ECG abnormalities varied according to gender.

The current study examined the impact of re-excision and residual disease on local recurrence after breast conservation treatment for patients with negative margins. Patients with residual disease on re-excision had a higher local recurrence rate than other patients. However, with reasonably low local recurrence rates in all subgroups, neither re-excision nor residual disease on re-excision are contraindications for breast conservation treatment.To evaluate the impact of re-excision and the presence of residual disease on local recurrence for patients who underwent breast conservation treatment (BCT) with negative final resection margins.The records of 902 patients with stage I or II unilateral invasive breast cancer who had BCT were reviewed. The study cohort consisted of patients with negative final resection margins and was divided into 3 subgroups: (a) single excision (n = 332 [37%]), (b) re-excision with no residual disease in the re-excision specimen (n = 440 [49%]), and (c) re-excision with residual disease in the re-excision specimen (n = 130 [14%]). The median follow-up was 6.75 years.At 15 years, the rates of local failure were 10% for patients with a single excision, 10% for patients with a re-excision without residual disease, and 16% for patients with a re-excision with residual disease (P = .033). There were no significant differences between the 3 groups for overall survival, cause-specific survival, relapse-free survival, or freedom from distant metastases (all P ≥ .082). Multivariate analysis demonstrated an increased risk of local failure for patients with residual disease in the re-excision specimen that was borderline statistically significant (hazard ratio, 2.16; P = .061).Despite achieving negative final resection margins, the patients with residual disease in the re-excision specimen had a higher rate of local recurrence than patients who underwent single excision or patients without residual disease on re-excision. However, local recurrence was reasonably low in all 3 subgroups, and, therefore, neither re-excision nor residual disease represent contraindications for BCT.

BACKGROUND: Incidence of pulmonary embolism (PE) for different cancer types in oncology outpatients is unknown. The purposes of the current study is to determine the incidence of PE in oncology outpatients and to investigate whether the incidence for PE is higher in certain cancers. METHODS: A cohort of oncology outpatients who had imaging studies at Dana-Farber Cancer Institute, a tertiary outpatient cancer institute, from January 2004 through December 2009 was identified using research patient data registry. Radiology reports were reviewed to identify patients who developed PE. Incidences of PE in the total population and in each of 16 predefined cancer groups were calculated. Risk of PE for each cancer was compared using Fisher exact test. RESULTS: A total of 13,783 patients was identified, of which 395 (2.87%; 95% confidence interval [CI], 2.59-3.16) developed PE. The incidence of PE was highest in the central nervous system ([CNS] 12.90%; 95% CI, 8.45-18.59), hepatobiliary (6.85%; 95% CI, 3.33-12.24), pancreatic (5.81%; 95% CI, 3.59-8.84), and upper gastrointestinal (5.81%; 95% CI, 3.96-8.20) malignancies. The risk of PE was significantly higher for CNS (P < .0001; odds ratio [OR], 5.28), pancreatic (P = .0027; OR, 2.15), upper gastrointestinal (P = .0002; OR, 2.18), and lung/pleural malignancies (P = .0028; OR, 1.45). There was significantly lower risk of PE for hematologic (incidence, 1.16%; 95% CI, 0.79-1.64; P < .0001; OR, 0.35) and breast malignancies (incidence, 1.50%; 95% CI, 1.02-2.11; P < .0001; OR, 0.47). CONCLUSIONS: The incidence of PE in oncology outpatients in a tertiary cancer center during a 6-year period was 2.87%. CNS, pancreatic, upper gastrointestinal, and lung/pleural malignancies had a significantly higher risk for PE than other malignancies, whereas hematologic and breast malignancies had a significantly lower risk. Cancer 2011. © 2011 American Cancer Society.

Determine inter- and intraobserver variability of computed tomography (CT) tumor volume measurements in advanced non-small-cell lung cancer (NSCLC) patients treated in a Phase II clinical trial using chest CT.Twenty-three advanced NSCLC patients with a total of 53 measurable lung lesions enrolled in a Phase II, multicenter, open-label clinical trial of erlotinib were retrospectively studied with institutional review board approval. Two radiologists independently measured the tumor size, volume, and CT attenuation coefficient using commercially available volume analysis software. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess inter- and intraobserver agreement.High CCCs (0.949-0.990) were observed in all types of measurements for interobserver agreement. The 95% limits of agreements for volume, unidimensional, and bidimensional measurements were (-26.0%, 18.6%), (-23.1%, 24.4%), and (-34.0%, 48.6%), respectively. Volume measurement had slightly higher CCC and narrower 95% limits of agreement compared to uni- and bidimensional measurements. CCCs for intraobserver agreement were high (range, 0.946-0.996) with CCC for volume being slightly higher than CCCs of uni- and bidimensional measurements. The smaller the tumor volume was, the larger the interobserver difference of CT attenuation. Location, morphology, or adjacent atelectasis had no significant impact on inter- or intraobserver variability.CT tumor volume measurement in advanced NSCLC patients using clinical chest CT and commercially available software demonstrated high inter- and intraobserver agreement, indicating that the method may be used routinely in clinical practice.

Objective The purpose of this analysis is to determine the pathologic prognostic factors and treatment outcome of patients with carcinosarcoma of the uterus. Methods A retrospective analysis of data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute between January 1, 1988 and November 1, 2003 was conducted. A total of 1855 with AJCC Stages I–III disease were identified who received primary surgical treatment. Overall survival curves were constructed using Kaplan–Meier curves. Cox proportional hazards model was used to identify factors predictive of overall survival. Results AJCC stage of all patients was as follows: 65% Stage I ( n =1099), 14% Stage II ( n =245), 21% Stage III ( n =353). 57% ( n =965) patients underwent LND. The median number of lymph nodes removed was 12 (SD=10.2); 119 (14%) patients had positive lymph nodes. Five-year overall survival (OS), disease free survival, and median survival were significantly improved for patients receiving lymph node dissection (LND) as compared to patients that received no LND, irrespective of radiotherapy. Adjuvant radiation therapy had no improvement on overall survival regardless of LND. There was no overall survival benefit to the addition of radiotherapy regardless of whether patients underwent a lymph node dissection or not. Age, race, marital status, lymph node dissection and stage were predictive of survival on multivariate analysis. Conclusions Lymphadenectomy is significantly associated with improved overall survival in patients with Stage I–III uterine carcinosarcoma compared to no lymphadenectomy. The use of adjuvant radiotherapy conferred no overall survival benefit.

OBJECTIVES Recent studies have demonstrated that the percentage of positive prostate needle biopsies (PPBs) is an independent predictor of biochemical failure (BF) after radical prostatectomy and external beam radiotherapy. Few studies have confirmed this phenomenon in patients treated with permanent interstitial brachytherapy. We conducted an analysis to determine the clinical utility of the PPBs in predicting BF after permanent interstitial brachytherapy for patients with clinically localized prostate cancer. METHODS The clinical and pathologic data from 245 hormone-naive patients with clinical Stage T1c-T2cNxM0 prostate cancer who had undergone permanent prostate brachytherapy from 1992 to 2002 at our institution were retrospectively evaluated. The PPBs, preimplant prostate-specific antigen, and biopsy Gleason score were evaluated as predictors of BF after brachytherapy. The risk of BF was calculated using logistic regression models. The time to BF was assessed using Cox proportional hazard models and Kaplan-Meier estimates. RESULTS The median PPBs in our study cohort was 27%. The risk of BF was 10.9% for those with a PPBs less than the median versus 26.2% for those with a PPBs greater than the median. A PPBs greater than the median was an independent predictor of BF on multivariate analysis (relative risk 2.3, 95% confidence interval 1.21 to 4.39, P = 0.011). In the time-to-failure models, the PPBs, prostate-specific antigen level, and Gleason score were significantly associated with BF. CONCLUSIONS Our data suggest that the PPBs is significantly associated with BF in patients undergoing permanent interstitial brachytherapy. The PPBs, along with the pretreatment prostate-specific antigen level and Gleason biopsy score, is a useful preoperative parameter in predicting for BF and the time to failure for patients treated with interstitial brachytherapy.