Survival outcomes for lung neuroendocrine tumors in California differ by sociodemographic factors.

Lung neuroendocrine tumors (NETs) have few known predictors of survival. We investigated associations of sociodemographic, clinicopathologic, and treatment factors with overall survival (OS) and lung cancer-specific survival (LCSS) for incident lung NET cases (typical or atypical histology) in the California Cancer Registry (CCR) from 1992 to 2019. OS was estimated with the Kaplan-Meier method and compared by sociodemographic and disease factors univariately with the log-rank test. We used sequential Cox proportional hazards regression for multivariable OS analysis. LCSS was estimated using Fine-Gray competing risks regression. There were 6038 lung NET diagnoses (5569 typical, 469 atypical carcinoid); most were women (70%) and non-Hispanic White (73%). In our multivariable model, sociodemographic factors were independently associated with OS, with better survival for women (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.57-0.68, P < 0.001), married (HR 0.76, 95% CI 0.70-0.84, P < 0.001), and residents of high socioeconomic status (SES) neighborhoods (HRQ5vsQ1 0.73, 95% CI 0.62-0.85, P < 0.001). Compared to cases with private insurance, OS was worse for cases with Medicare (HR 1.24, 95% CI 1.10-1.40, P < 0.001) or Medicaid/other public insurance (HR 1.45, 95% CI 1.24-1.68, P < 0.001). In our univariate model, non-Hispanic Black Californians had worse OS than other racial/ethnic groups, but differences attenuated after adjusting for stage at diagnosis. In our LCSS models, we found similar associations between sex and marital status on survival, but no differences in outcomes by SES or insurance. By race/ethnicity, American Indian cases had worse LCSS. In summary, beyond disease-related and treatment variables, sociodemographic factors were independently associated with survival in lung NETs.

Emerging Precision Medicine Approaches for Lung Neuroendocrine Tumors.

Well-differentiated lung neuroendocrine tumors (LNETs) are heterogeneous cancers that are increasing in incidence. Treatment options for LNETs have expanded in recent years, and our knowledge of the molecular subtypes has also advanced. Multidisciplinary teams have an established role in personalizing the best treatment for individual patients. Other precision medicine approaches for the treatment of LNETs have lagged behind those for non-small-cell lung cancer, with only rare actionable molecular alterations identified and few established predictive factors to guide therapy selection. However, as summarized in this review, there is increasing potential for personalized treatment of patients with LNETs. In particular, advances in radiotheragnostics may allow us to tailor the treatment of individual patients with NETs in the coming years. These advances may soon deliver the promise of more effective, less toxic treatments and better outcomes for patients with these increasingly common cancers.

Osimertinib-induced biventricular cardiomyopathy with abnormal cardiac MRI findings: a case report.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) inhibitor that is currently the first-line treatment for metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) due to its favorable efficacy and tolerability profile compared to previous generations of EGFR inhibitors. However, it can cause uncommon, yet serious, cardiovascular adverse effects. CASE PRESENTATION: We present the case of a 63-year-old man with EGFR-mutated NSCLC treated with osimertinib who developed new-onset non-ischemic cardiomyopathy with biventricular dysfunction and heart failure in the context of an enlarging pericardial effusion. For the first time, we demonstrate cardiac MR imaging findings associated with osimertinib-associated cardiomyopathy, including focal late gadolinium enhancement and myocardial edema. The patient's biventricular function normalized after initiation of goal-directed medical therapy for heart failure and holding osimertinib. The patient was subsequently started on afatinib, a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), without recurrence of cardiomyopathy. CONCLUSIONS: This case highlights the need to better understand osimertinib-induced cardiotoxicity and strategies to optimize oncologic care in patients who develop severe cardiac toxicities from cancer therapy. It further underlines the importance of specialized multidisciplinary care of cancer patients who develop cardiotoxicities to optimize their oncologic outcomes.

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas.

BACKGROUND: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. PRIMARY ENDPOINT: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.

Periprocedural Management of Patients Undergoing Liver Resection or Embolotherapy for Neuroendocrine Tumor Metastases.

OBJECTIVES: The objective of this study was to describe the periprocedural management of patients with well-differentiated neuroendocrine tumors with hepatic metastases who underwent liver-directed procedures. METHODS: We performed a retrospective review of patients with metastatic neuroendocrine tumors who underwent liver resection, ablation, or embolotherapy at a single center from 2012 to 2016. The primary outcome was occurrence of documented carcinoid crisis (CC) or hemodynamic instability (HDI), defined as 10 minutes or more of systolic blood pressure less than 80 or greater than 180 mm Hg, or pulse greater than 120 beats per minute. RESULTS: We identified 75 patients who underwent liver resection/ablation (n = 38) or embolotherapy (n = 37). Twenty-four patients (32%) experienced CC or HDI (CC/HDI); CC occurred in 3 patients. No clinicopathologic or procedural factors, including procedure type, octreotide or long-acting somatostatin analog use, and history of carcinoid syndrome, were associated with CC/HDI. Grades 2 to 4 complications were reported in 42% of patients who experienced CC/HDI versus in 16% of patients who did not experience CC/HDI (P < 0.05). CONCLUSIONS: A significant portion of patients developed CC/HDI, and these patients were more likely to develop severe postprocedural complications. Periprocedural octreotide use was not associated with lower CC/HDI occurrence, but continued use is advised given its safety profile until additional studies definitively demonstrate lack of benefit.

Complicated Case Presentation: Management of Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an inherited predisposition to tumors of the parathyroid glands, anterior pituitary, and pancreatic islet cells. In this review, we discuss the clinical case of a 45-year-old woman with MEN1 that was presented at the 2015 North American Neuroendocrine Tumor Society Symposium. In our review of this patient's complicated clinical course and subsequent operative management, we highlight controversies in the diagnosis and management of pancreatic neuroendocrine tumors in MEN1. In particular, this case illustrates the lack of consensus regarding the optimal biochemical and radiologic screening for pancreatic neuroendocrine tumors and absence of guidelines about the appropriate surgical approach for treatment. We review these controversies and discuss possible approaches to management.

Selective association of electrocardiographic abnormalities with insulin sensitivity and beta-cell function in type 2 diabetes mellitus: a cross-sectional analysis.

BACKGROUND: We investigated the association of electrocardiographic (ECG) abnormalities with markers of insulin resistance and pancreatic beta-cell dysfunction in a cross-sectional study of type 2 diabetes patients. METHODS: Electrocardiographic criteria were evaluated in the Penn Diabetes Heart Study participants (n = 1671; 64% male; 61% Caucasian), including a sub-sample (n = 710) that underwent oral glucose tolerance testing. The Matsuda Insulin Sensitivity Index and homeostasis model assessment of insulin resistance (HOMA-IR) estimated insulin sensitivity; Insulinogenic Index and homeostasis model assessment of beta-cell function assessed beta-cell function. Multivariable regression modelling was used to analyse associations of ECG changes with these indices. RESULTS: In unadjusted analyses, subjects in the highest quartile of Matsuda index had the lowest prevalence of Q-waves (6.3% versus 15.3%, p = 0.005). In adjusted models, an inverse association was seen between Q-waves and log Matsuda index [one standard deviation increase; OR = 0.59 (95% CI 0.43-0.87 p = 0.001)]. In the full Penn Diabetes Heart Study, there was a direct association between Q-waves and HOMA-IR [one standard deviation increase; OR = 1.43 (95% CI 1.13-1.81, p = 0.003)]. In adjusted models, left ventricular hypertrophy also was inversely associated with Matsuda index and directly with HOMA-IR. Higher Insulinogenic Index scores were associated with a lower prevalence of nonspecific ST changes [OR = 0.78 (95% CI 0.62-0.98, p = 0.032)]. CONCLUSIONS: In type 2 diabetic patients, both oral glucose tolerance testing-derived and HOMA-derived measures of insulin resistance were associated with pathologic Q-waves and left ventricular hypertrophy on ECGs. Copyright © 2016 John Wiley & Sons, Ltd.

Systemic Therapies for Advanced Gastrointestinal Carcinoid Tumors.

Well-differentiated gastrointestinal neuroendocrine tumors (GINETs) tend to be slow growing, but treatment of advanced disease remains a challenge. Somatostatin analogues (SSAs) are considered standard therapy for carcinoid syndrome. SSAs delay tumor progression in advanced well-differentiated gastroenteropancreatic NETs. Cytotoxic chemotherapy and interferon play a limited role in the treatment of nonpancreatic GINETs. There is no standard approach to treatment of patients with disease progression. Identification of systemic agents with antitumor activity in advanced disease remains an unmet medical need. Enrollment to clinical trials is encouraged; potential therapeutic targets include the vascular endothelial growth factor and mammalian target of rapamycin signaling pathways.

Ascending and descending thoracic aorta calcification in type 2 diabetes mellitus.

BACKGROUND: Calcification of the thoracic aorta is a risk factor for cardiovascular disease and peripheral arterial disease but has not been well studied in diabetics. In addition, many studies consider aortic calcium as a single anatomic entity, whereas calcification of the ascending and descending portions of the thoracic aorta may represent separate phenotypes. We sought to characterize the prevalence of ascending and descending aortic calcium among diabetics and to assess their associations with cardiovascular risk factors, coronary artery calcium, and peripheral arterial disease. METHODS: Within the Penn Diabetes Heart Study, a cross-sectional study of subjects with type 2 diabetes mellitus but without coronary or renal disease, we quantified Agatston scores of the ascending and descending thoracic aorta in 1739 subjects (63% male, 61% Caucasian). Multivariate logistic and Tobit regressions were used to assess associations with cardiovascular risk factors, coronary calcium, and peripheral arterial disease. RESULTS: Of all subjects, 54% had thoracic aortic calcium; of these, 37% had calcium solely in the ascending thoracic aorta and 20% solely in the descending thoracic aorta. In multivariate regression, age, Caucasian race, systolic blood pressure, low-density lipoprotein cholesterol, smoking, and diabetes duration were independently associated with calcium of both the ascending and descending thoracic aorta (P < .001 for all). Ascending and descending aortic calcium were each independently associated with coronary calcium in multivariate regression, but only calcification of the descending thoracic aortic was associated with low ankle-brachial index. CONCLUSION: Ascending and descending thoracic aortic calcium have similar associations with traditional cardiovascular risk factors in diabetics and are independently associated with coronary artery calcium. Only calcium in the descending aorta is associated with peripheral arterial disease. Delineation of both phenotypes may provide information about the individualized vascular disease and risk profile of patients with type 2 diabetes mellitus.

Very low density lipoprotein cholesterol associates with coronary artery calcification in type 2 diabetes beyond circulating levels of triglycerides.

OBJECTIVE: While recent genomic studies have focused attention on triglyceride (TG) rich lipoproteins in cardiovascular disease (CVD), little is known of very low-density lipoprotein cholesterol (VLDL-C) relationship with atherosclerosis and CVD. We examined, in a high-risk type-2 diabetic population, the association of plasma VLDL-C with coronary artery calcification (CAC). METHODS: The Penn Diabetes Heart Study (PDHS) is a cross-sectional study of CVD risk factors in type-2 diabetics (n = 2118, mean age 59.1 years, 36.5% female, 34.1% Black). Plasma lipids including VLDL-C were calculated (n = 1879) after ultracentrifugation. RESULTS: In Tobit regression, VLDL-C levels were positively associated with increasing CAC after adjusting for age, race, gender, Framingham risk score, body mass index, C-reactive protein, exercise, medication and alcohol use, hemoglobin A1c, and diabetes duration [Tobit ratio (TR) and 95% confidence interval (CI) 0.38 (0.12-0.65), P = 0.005] and even after inclusion of apolipoprotein B data [TR 0.31 (0.03-0.58), P = 0.030]. Approximately 3-fold stronger effect was observed in women [TR 0.75 (0.16-1.34), P = 0.013] than men [TR 0.20 (-0.10-0.50), P = 0.189; gender interaction P = 0.034]. Plasma VLDL-C was related more strongly to CAC scores than TG levels (e.g., Akaike information criteria of 7263.65 vs. 7263.94) and had stronger CAC association in individuals with TGs >150 mg/dl (TR 0.80, P = 0.010) vs. those with TGs <150 mg/dl (TR 0.27, P = 0.185). CONCLUSIONS: In PDHS, VLDL-C is associated with CAC independent of established CVD risk factors, particularly in women, and may have value even beyond apolipoprotein B levels and in patients with elevated TGs.

Omega-3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers.

SCOPE: Fish oil-derived n-3 PUFA may improve cardiometabolic health through modulation of innate immunity. However, findings in clinical studies are conflicting. We hypothesized that n-3 PUFA supplementation would dose-dependently reduce the systemic inflammatory response to experimental endotoxemia in healthy humans. METHODS AND RESULTS: The Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) study was an 8-wk randomized double-blind trial of placebo or n-3 PUFA supplementation (Lovaza 465 mg eicosapentaenoic acid (EPA) + 375 mg docosahexaenoic acid (DHA)) at "low" (1/day, 900 mg) or "high" (4/day, 3600 mg) dose in healthy individuals (N = 60; age 18-45; BMI 18-30; 43% female; 65% European-, 20% African-, 15% Asian-ancestry) before a low-dose endotoxin challenge (LPS 0.6 ng/kg intravenous bolus). The endotoxemia-induced temperature increase was significantly reduced with high-dose (p = 0.03) but not low-dose EPA + DHA compared to placebo. Although there was no statistically significant impact of EPA + DHA on individual inflammatory responses (tumor necrosis factor-α (TNF-α), IL-6, monocyte chemotactic protein (MCP-1), IL-1 receptor agonist (IL-1RA), IL-10, C-reactive protein (CRP), serum amyloid A (SAA)), there was a pattern of lower responses across all biomarkers with high-dose (nine of nine observed), but not low-dose EPA + DHA. CONCLUSION: EPA + DHA at 3600 mg/day, but not 900 mg/day, reduced fever and had a pattern of attenuated LPS induction of plasma inflammatory markers during endotoxemia. Clinically and nutritionally relevant long-chain n-3 PUFA regimens may have specific, dose-dependent, anti-inflammatory actions.

Differential associations of oral glucose tolerance test-derived measures of insulin sensitivity and pancreatic ß-cell function with coronary artery calcification and microalbuminuria in type 2 diabetes.

OBJECTIVE We evaluated relationships of oral glucose tolerance testing (OGTT)-derived measures of insulin sensitivity and pancreatic ß-cell function with indices of diabetes complications in a cross-sectional study of patients with type 2 diabetes who are free of overt cardiovascular or renal disease. RESEARCH DESIGN AND METHODS A subset of participants from the Penn Diabetes Heart Study (n = 672; mean age 59 ± 8 years; 67% male; 60% Caucasian) underwent a standard 2-h, 75-g OGTT. Insulin sensitivity was estimated using the Matsuda Insulin Sensitivity Index (ISI), and ß-cell function was estimated using the Insulinogenic Index. Multivariable modeling was used to analyze associations between quartiles of each index with coronary artery calcification (CAC) and microalbuminuria. RESULTS The Insulinogenic Index and Matsuda ISI had distinct associations with cardiometabolic risk factors. The top quartile of the Matsuda ISI had a negative association with CAC that remained significant after adjusting for traditional cardiovascular risk factors (Tobit ratio -0.78 [95% CI -1.51 to -0.05]; P = 0.035), but the Insulinogenic Index was not associated with CAC. Conversely, the highest quartile of the Insulinogenic Index, but not the Matsuda ISI, was associated with lower odds of microalbuminuria (OR 0.52 [95% CI 0.30-0.91]; P = 0.022); however, this association was attenuated in models that included duration of diabetes. CONCLUSIONS Lower ß-cell function is associated with microalbuminuria, a microvascular complication, while impaired insulin sensitivity is associated with higher CAC, a predictor of macrovascular complications. Despite these pathophysiological insights, the Matsuda ISI and Insulinogenic Index are unlikely to be translated into clinical use in type 2 diabetes beyond established clinical variables, such as obesity or duration of diabetes.

Non-compressible arterial disease and the risk of coronary calcification in type-2 diabetes.

OBJECTIVE: Ankle-brachial index (ABI) screening is recommended for the detection of asymptomatic peripheral arterial disease (PAD) in at-risk populations, including diabetics. A low ABI identifies obstructive lower extremity vascular disease and predicts CVD events and increased mortality. A high ABI represents non-compressible arterial disease (NCAD), and is also associated with increased mortality and vascular events. Our objective is to investigate whether low and high ABI have distinct patterns of association with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis in individuals with type-II diabetes mellitus. METHODS: The Penn Diabetes Heart Study (PDHS) is a prospective observational cohort of diabetic individuals without clinically evident CVD. Multivariate logistic and Tobit linear regression were used to compare CVD risk factors and coronary artery (CAC) among 1863 subjects with PAD (ABI ≤ 0.9), NCAD (ABI ≥ 1.4 or non-compressible) or normal ABI (0.91-1.39). RESULTS: Compared to those with normal ABI, PAD was associated with smoking, obesity, and lower HDL-c; while diabetes duration and reduced renal function were associated with NCAD. Both PAD and NCAD were independently associated with increased CAC compared to those with normal ABI, and these relationships were not attenuated in multiply adjusted models. CONCLUSION: NCAD bears a distinct relationship to traditional CVD risk factors among diabetics, though like PAD is independently associated with increased CAC. These findings support the recognition of NCAD as a high-risk phenotype and provide additional relevance to ABI screening in diabetics.

Race and gender variation in response to evoked inflammation.

BACKGROUND: Race- and gender-variation in innate immunity may contribute to demographic differences in inflammatory and cardiometabolic disease; yet their influence on dynamic responses during inflammatory stress is poorly understood. Our objective was to examine race and gender influence on the response to experimental endotoxemia. METHODS: The Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) study was designed to investigate regulation of inflammatory and metabolic responses during low-grade endotoxemia (LPS 1 ng/kg intravenously) in healthy individuals (median age 24, IQR=7) of European (EA; n=193, 47% female) and African ancestry (AA; n=101, 59% female). RESULTS: Baseline clinical, metabolic, and inflammatory biomarkers by race and gender were consistent with epidemiological literature; pre-LPS cytokines (e.g. median (IQR) IL-6, 2.7 (2) vs.2.1 (2) pg/ml, P=0.001) were higher in AA than EA. In contrast, acute cytokine responses during endotoxemia were lower in AA than EA (e.g. median (IQR) peak IL-1RA, 30 (38) vs.43 (45) ng/ml P=0.002) as was the induction of hepatic acute-phase proteins (e.g. median (IQR) peak CRP 12.9 (9) vs.17.4 (12) mg/L P=0.005). Further, baseline levels of cytokines were only weakly correlated with peak inflammatory responses (all r(s) <0.2) both in AA and in EA. There were less pronounced and less consistent differences in the response by gender, with males having a higher AUC for CRP response compared to females (median (IQR) AUC: 185 (112) vs. 155 (118), P=0.02). CONCLUSIONS: We observed lower levels of evoked inflammation in response to endotoxin in AA compared with EA, despite similar or higher baseline levels of inflammatory markers in AA. Our data also suggest that levels of inflammatory biomarkers measured in epidemiological settings might not predict the degree of acute stress-response or risk of diseases characterized by activation of innate immunity. TRIAL REGISTRATION: FDA clinicaltrials.gov registration number NCT00953667.

Cardiovascular risk factors and mitral annular calcification in type 2 diabetes.

OBJECTIVE: Mitral annular calcification (MAC) is a degenerative process of the mitral annulus associated with cardiac disease and stroke. Although thought to be more prevalent in type 2 diabetes (T2DM), MAC remains poorly characterized in this population, due to confounding by renal and cardiac disease. Our goal was to study the risk factors for MAC in a sample of T2DM subjects without renal and cardiac disease. METHODS: The Penn Diabetes Heart Study (PDHS) is a cross-sectional study of diabetic individuals without clinical cardiovascular or renal disease. We quantified and analyzed MAC Agatston scores in baseline cardiac CTs from 1753 individuals. Logistic and tobit regression were used to assess MAC's relationship with risk factors and coronary artery calcium (CAC). RESULTS: MAC was present in 12.0% of subjects, with a median Agatston score of 72.3 [Interquartile range (22.2-256.9)]. Older age, female gender, Caucasian race, and longer diabetes duration were independently associated with both the presence and extent MAC even after controlling for CAC; however, hypertension, hyperlipidemia, tobacco use, CRP levels, and other comorbidities were not associated. CAC was strongly associated with MAC [OR of 4.0 (95% CI 2.4-6.6)] in multivariable models. CONCLUSIONS: Age, female gender, Caucasian race, and diabetes duration were associated with the presence and extent of MAC in T2DM subjects, independent of CAC, which was also strongly associated with MAC. These data suggest that additional mechanisms for MAC formation in diabetics may exist which are distinct from those related to generalized atherosclerosis and deserve further investigation.

Peroxisome Proliferator-Activated Receptor-α Agonism With Fenofibrate Does Not Suppress Inflammatory Responses to Evoked Endotoxemia.

BACKGROUND: Data conflict with regard to whether peroxisome proliferator-activated receptor-α agonism suppresses inflammation in humans. We hypothesized that in healthy adults peroxisome proliferator-activated receptor-α agonism with fenofibrate would blunt the induced immune responses to endotoxin (lipopolysaccharide [LPS]), an in vivo model for the study of cardiometabolic inflammation. METHODS AND RESULTS: In the Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) trial, 36 healthy volunteers (mean age 26±7 years, mean body mass index 24±3 kg/m(2), 44% female, 72% white) were randomized to fenofibrate 145 mg or placebo daily. After 6 to 8 weeks of treatment, subjects underwent a low-dose LPS challenge. Clinical and blood measurements were collected at randomization, before LPS administration, and serially for 24 hours after LPS administration. We examined area under the curve for evoked responses by treatment group. Compared to placebo, but before LPS challenge, fenofibrate reduced total cholesterol and tended to decrease triglycerides, consistent with achieved therapeutic plasma levels of fenofibric acid. In the placebo group, LPS induced a modest inflammatory response with increased cytokines and chemokines (2- to 4-hour post-LPS 8-fold increase in tumor necrosis factor-α, 9-fold increase in interleukin-6, 9-fold increase in interleukin-10, and 10-fold increase in monocyte chemotactic protein-1; all P<0.001) and acute-phase reactants (24-hour post-LPS 15-fold increase in serum amyloid A and 9-fold increase in C-reactive protein; both P<0.001). Compared to placebo, however, fenofibrate did not significantly attenuate LPS-induced levels of plasma cytokines, chemokines, or acute-phase proteins. CONCLUSIONS: These data suggest a lack of systemic antiinflammatory properties of fenofibrate at clinically relevant dosing in humans. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/ct2/show/NCT01048502. Unique identifier: NCT01048502. (J Am Heart Assoc. 2012;1:e002923 doi: 10.1161/JAHA.112.002923.).