Biomarker Substudy Research Articles

The Renal Effects of Aggressive Volume Removal in Heart Failure Patients with Preexisting Worsening Renal Function

Introduction Accumulating data suggests that worsening renal function (WRF) during decongestion of acute decompensated heart failure (ADHF) patients is a benign and transient finding. However, it is unknown if continued aggressive volume removal in patients with preexisting WRF is harmful. Hypothesis Aggressive volume removal in ADHF patients with preexisting WRF will be associated with renal tubular injury. Methods We used data from the multicenter CARRESS-HF trial that randomized patients with ADHF and pre-existing WRF to aggressive volume removal with stepped pharmacologic therapy (SPT) versus fixed rate ultrafiltration (UF). Patients in the urinary renal tubular injury biomarker (NAG, KIM-1, and NGAL) sub-study were evaluated ( N =105). Results The severity of pre-randomization increase in creatinine was unrelated to baseline levels of renal tubular injury biomarkers (r=0.1, P =0.31). During randomized aggressive volume removal, creatinine further worsened in 53% of patients. Those with post-randomization WRF were highly likely to have a concurrent increase in renal tubular injury biomarkers (OR=12.6, P =0.004). This finding did not differ by mode of volume removal (SPT vs. UF, P interaction =0.47). Increase in renal tubular injury biomarkers during decongestion was associated with a higher incidence of hemoconcentration (OR=3.1, P =0.015), and paradoxically, better recovery of creatinine at 60 days ( P =0.01). Post-randomization WRF ( P =0.63) and worsening tubular injury biomarkers ( P =0.91) were not associated with death or rehospitalization at 60 days. Conclusions Aggressive volume removal in the setting of ADHF with preexisting WRF was associated with continued increase of creatinine in approximately half of patients. Worsened creatinine in this setting was accompanied by evidence of renal tubular injury. However, decongestion and renal function recovery at 60 days was superior in patients with worsening tubular injury markers. This suggests that increases in creatinine with effective decongestion may be clinically benign and transient, even when accompanied by renal tubular injury.

P823Multiple biomarkers and cause-specific mortality in patients with acute coronary syndromes - Insights from the PLATO biomarker substudy

P823Multiple biomarkers and cause-specific mortality in patients with acute coronary syndromes - Insights from the PLATO biomarker substudy

Detection of IL-36γ through noninvasive tape stripping reliably discriminates psoriasis from atopic eczema

This project was mainly supported by a 2014 Pfizer Inflammation Competitive Research Programme (ICRP). In addition, assay development support was received by MRC grant MR/M01942X/1. GDB and DMR were funded by the Wellcome Trust (102705, 97377), the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). Some of the samples included in the atopic dermatitis comparator group were acquired in the context of the National Institute for Health Research (NIHR) funded ALPHA trial (EUDRACT 2014-004741-27) – explorative biomarker substudy. The ALPHA trial was developed in collaboration with the Clinical Trials Research Unit at the University of Leeds with support from the UK Dermatology Clinical Trials Network (UK DCTN). The UK DCTN is grateful to the British Association of Dermatologists and the University of Nottingham for financial support of the Network. This research is also supported by the NIHR Leeds Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 TARGET study

IntroductionInterleukin-6 (IL-6) orchestrates formation of an inflammatory pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a human monoclonal antibody blocking the IL-6Rα. In TARGET (NCT01709578), a phase...

Interaction of Body Mass Index on the Association Between N-Terminal-Pro-b-Type Natriuretic Peptide and Morbidity and Mortality in Patients With Acute Heart Failure: Findings From ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure).

BackgroundHigher body mass index (BMI) is associated with lower circulating levels of N‐terminal‐pro‐b‐type natriuretic peptide (NT‐proBNP). The Interaction between BMI and NT‐proBNP with respect to clinical outcomes is not well characterized in patients with acute heart failure.Methods and ResultsA total of 686 patients from the biomarker substudy of the ASCEND‐HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HF ) clinical trial with documented NT‐proBNP levels at baseline were included in the present analysis. Patients were classified by the World Health Organization obesity classification (nonobese: BMI <30 kg/m2, Class I obesity: BMI 30–34.9 kg/m2, Class II obesity BMI 35–39.9 kg/m2, and Class III obesity BMI ≥40 kg/m2). We assessed baseline characteristics and 30‐ and 180‐day outcomes by BMI class and explored the interaction between BMI and NT‐proBNP for these outcomes. Study participants had a median age of 67 years (55, 78) and 71% were female. NT‐proBNP levels were inversely correlated with BMI (P<0.001). Higher NT‐proBNP levels were associated with higher 180‐day mortality (adjusted hazard ratio for each doubling of NT‐proBNP, 1.40; 95% confidence interval, 1.16, 1.71; P<0.001), but not 30‐day outcomes. The effect of NT‐proBNP on 180‐day death was not modified by BMI class (interaction P=0.24).ConclusionsThe prognostic value of NT‐proBNP was not modified by BMI in this acute heart failure population. NT‐proBNP remains a useful prognostic indicator of long‐term mortality in acute heart failure even in the obese patient.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.

Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation: study protocol for a registry-based randomised controlled trial

BackgroundOral anticoagulation therapy is recommended for the prevention of recurrent ischemic stroke in patients with atrial fibrillation (AF). Current guidelines do not provide evidence-based recommendations on optimal time-point to start anticoagulation therapy after an acute ischemic stroke. Non-vitamin K antagonist oral anticoagulants (NOACs) may offer advantages compared to warfarin because of faster and more predictable onset of action and potentially a lower risk of intracerebral haemorrhage also in the acute phase after an ischemic stroke. The TIMING study aims to establish the efficacy and safety of early vs delayed initiation of NOACs in patients with acute ischemic stroke and AF.Methods/DesignThe TIMING study is a national, investigator-led, registry-based, multicentre, open-label, randomised controlled study. The Swedish Stroke Register is used for enrolment, randomisation and follow-up of 3000 patients, who are randomised (1:1) within 72 h from ischemic stroke onset to either early (≤ 4 days) or delayed (≥ 5–10 days) start of NOAC therapy. The primary outcome is the composite of recurrent ischemic stroke, symptomatic intracerebral haemorrhage, or all-cause mortality within 90 days after randomisation. Secondary outcomes include: individual components of the primary outcome at 90 and 365 days; major haemorrhagic events; functional outcome by the modified Rankin Scale at 90 days; and health economics. In an optional biomarker sub-study, blood samples will be collected after randomisation from approximately half of the patients for central analysis of cardiovascular biomarkers after study completion. The study is funded by the Swedish Medical Research Council. Enrolment of patients started in April 2017.ConclusionThe TIMING study addresses the ongoing clinical dilemma of when to start NOAC after an acute ischemic stroke in patients with AF. By the inclusion of a randomisation module within the Swedish Stroke Register, the advantages of a prospective randomised study design are combined with the strengths of a national clinical quality register in allowing simplified enrolment and follow-up of study patients. In addition, the register adds the possibility of directly assessing the external validity of the study findings.Trial registrationClinicalTrials.gov, NCT02961348. Registered on 8 November 2016.

Platelet-related biomarkers and their response to inhibition with aspirin and p2y12-receptor antagonists in patients with acute coronary syndrome.

The PLATelet inhibition and patient Outcomes (PLATO) trial showed that treatment with ticagrelor reduced the rate of death due to vascular causes, myocardial infarction and stroke when compared to clopidogrel in patients with ST-elevation or non-ST-elevation acute coronary syndrome (ACS). While the comparative benefit of ticagrelor over clopidogrel increased over time, event rates accrued in both groups during the study period. The purpose of our biomarker-based exploratory analysis was to determine whether long-term platelet inhibition may be associated with platelet adaptation. A sample of 4000 participants from the PLATO trial also consented to participate in a prospectively designed biomarker substudy. Blood samples were procured at baseline, immediately prior to hospital discharge and at 1 and 6months. Markers of platelet activity, including platelet count, serum CD40-ligand and soluble P-selectin were analyzed. Mean levels were compared at discharge, 1 and 6months following study drug initiation-first for all patients and subsequently stratified by treatment group. A linear mixed model was used to estimate the short-term change rate (baseline to 1month) and long-term change rate (1-6months) for each biomarker. A Cox proportional hazards model was used to calculate hazard ratios for each change in biomarker over the two time periods examined: baseline to 1month and 1 to 6months. Prior to randomized treatment (baseline), sCD40 ligand and sP-selectin levels were elevated above the normal range of the assay (0.39 and 33.5µg/L, respectively). The mean level of each biomarker was significantly different at 1month compared to baseline (p < 0.0001). When stratified by treatment group, at 1month patients treated with ticagrelor had a larger increase in platelet count compared to those treated with clopidogrel (p < 0.0001). Similarly, when comparing biomarker levels for all patients at 6months with those at 1month, each differed significantly (p < 0.05). There was no significant difference between treatment groups during this time period. The rate of change for both platelet count and sP-selectin were significantly different between baseline and 1month when compared to the 1 to 6-month time period (p < 0.0001). When comparing treatment groups, the rate of increase in platelets from baseline to 1month was greater for patients treated with ticagrelor (p < 0.0001). This was no longer observed in the 1 to 6-month interval. Using a Cox proportional hazard model, the increase in platelet count from 1 to 6months was associated with ischemic-thrombotic events, while sCD40 ligand decrease from 1 to 6months was associated with hemorrhagic events. There were no differences between treatment groups for the associations with clinical endpoints. Dynamic changes in platelet count, sCD-40 ligand and sP-selectin occur over time among patients with ACS. Platelet-directed therapy with a P2Y12 receptor inhibitor in combination with aspirin modestly impacts the expression of these biomarkers. Platelet count and sCD40 ligand may offer modest overall predictive value for future ischemic-thrombotic or hemorrhagic clinical events, respectively. The existence of a platelet adaptome and its overall clinical significance among patients at risk for thrombotic events will require a more in-depth and platelet-biology specific investigation.

Rationale for nebivolol/valsartan combination for hypertension: review of preclinical and clinical data.

To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin–angiotensin–aldosterone system inhibitors, when combined, have been deemed ‘less effective’ based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg – a vasodilatory β1-selective antagonist/β3 agonist – and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I–II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension.

Abstract P1-02-14: Circulating cell-free DNA (CFD) measured by a simple fluorescent assay to predict relapse in triple negative breast cancer patients receiving neoadjuvant chemotherapy: A biomarker substudy of prospective observational study (NCT02001519, NCT02001506)

Abstract Background: Prior technique to measure cell free DNA(CFD) is labor-intensive and expensive, while, recently developed fluorescent CFD assay is more simple and convenient.The aim of this study was to evaluate the role of CFD measured by a fluorescent assay as a biomarker of patients with triple negative breast cancer (TNBC) received neoadjuvant chemotherapy Methods: We prospectively enrolled patients with TNBC, clinical stage II or III (T&amp;gt;1.5cm or lymph node &amp;gt; 1.5cm), who were scheduled for neoadjuvant chemotherapy. Patients received 4 cycles of adriamycin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (AC) followed by 4 cycles of cisplatin or docetaxel, and surgery. Plasma samples were obtained from patients before initial chemotherapy (baseline-CFD) and after 4 cycles of AC neoadjuvant chemotherapy (AC-CFD). Results: This study included 72 patients who met the inclusion criteria. The mean levels of baseline-CFD and AC-CFD were 239±68 ng/mL and 210±66 ng/mL, respectively, and the CFD level was significantly decreased after AC chemotherapy.( p=0.001) The baseline-CFD was not associated with initial tumor characteristics. (T stage 1-2 vs. 3, p=0.313; N stage 0 vs. 1-3, p=0.317) There was no statistically significant difference between patients with response (CR or PR) to AC chemotherapy and those without response in terms of baseline-CFD, AC-CFD, and change of CFD between two values. (p=0.814, p=0.839, p=0.927) With 33.6 months of median follow up, there were 18 cases of relapse. Relapsed group showed numerically higher level of baseline-CFD, although it was not statistically significant. (relapse, 259 ng/mL; non-relapse, 233 ng/mL; p=0.161) We performed a ROC curve analysis of baseline-CFD for relapse, and found an area under the curve of 0.62 (95% CI, 0.46-0.78) at 222 ng/mL. Patients with baseline-CFD above 222 showed higher relapses than those below 222. (HR, 2.75; 95% CI, 0.96-7.84; p = 0.059) Conclusions: The baseline-CFD obtained using a simple and convenient fluorescent assay could predict relapse, suggesting baseline-CFD as a potential biomarker for risk stratification of TNBC. Citation Format: Park K, Woo M, Kim JE, Ahn J-H, Jung KH, Kim S-B. Circulating cell-free DNA (CFD) measured by a simple fluorescent assay to predict relapse in triple negative breast cancer patients receiving neoadjuvant chemotherapy: A biomarker substudy of prospective observational study (NCT02001519, NCT02001506) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-14.

A phase Ib/II study of second-line therapy with panitumumab, irinotecan and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT): Biomarker substudy.

643 Background: Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This phase Ib/II study evaluated the efficacy and safety of irinotecan, panitumumab and everolimus (Townsend et al. ESMO 2016).These are the results of the biomarker substudy. Methods: Patients with KRAS exon 2 WT mCRC after failure of fluoropyrimidine based therapy received IV irinotecan (200mg/m2) and panitumumab (6mg/kg) 2 weekly. Everolimus dose was 5mg orally alternate days for dose level 1/expansion, and 5mg daily for level 2. Survival outcomes were calculated using Kaplan-Meier method. DNA was isolated from FFPE tumour sections for whole exome sequencing. Reads were mapped to hg19 reference genome and variants called using GATK tool. RAS/RAF mutations (MT) identified were correlated with response (Fishers exact test), progression free survival (PFS) and overall survival (OS). Filtering for variants in genes associated with progressive disease (PD) was performed. Results: 48 patients were enrolled. 33 had adequate tissue and outcome data for analysis (29 dose level 1, 4 level 2). Median age 63 yrs (41-82), M/F 23/10, ECOG 0/1 17/16. 14 (42%) had partial response (PR), 15 (45%) stable disease (SD) as best response. Median PFS was 5.3 ms and OS 11.1 ms. Three patients had RAS MTs (KRAS exon 2 G12V, KRAS exon 3 Q61H, NRAS exon 2 G12D) and 5 BRAF V600E MT. 2/3 RAS MT had SD and 1/3 PR. 3/5 BRAF MT had SD and 2/5 PD. 13/25 all WT had PR (52%) and 10/25 (40%) SD. BRAF V600E was associated with poorer PFS v WT (median 2.7 v 6.1 ms; P &lt; 0.0001). In all WT patients median PFS was 5.8 ms and OS 12.2 ms. In exploratory analysis 4 patients were heterozygous for PPP1R17 L12V variant (rs3735422) which correlated with PD in 3/4 (P = 0.003) and worse PFS (P = 0.0001). On multivariate analysis (COX regression) BRAF V600E MT and PPP1R17 L12V remained associated with worse PFS (p = 0.005 &amp; p = 0.001 respectively). Conclusions: No responses were seen in patients with BRAF MT. One of 3 with RAS MT had a PR suggesting mTOR inhibition may overcome resistance in this group however this may represent purely a chemotherapy effect. PPP1R17 L12V variant should be validated in larger cohorts. Clinical trial information: NCT01139138.

Inflammatory Biomarkers Predict Heart Failure Severity and Prognosis in Patients With Heart Failure With Preserved Ejection Fraction

Background— Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis. Methods and Results— In 86 stable patients with HF and EF ≥45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay. Orthogonal projection to latent structures by partial least square analysis was performed on 87 biomarkers and 240 clinical variables, ranking biomarkers associated with New York Heart Association (NYHA) Functional class and the composite outcome (all-cause mortality and HF hospitalization). Biomarkers significantly correlated with outcome were analyzed by multivariable Cox regression and correlations with echocardiographic measurements performed. The orthogonal partial least square outcome-predicting biomarker pattern was run against the Ingenuity Pathway Analysis (IPA) database, containing annotated data from the public domain. The orthogonal partial least square analyses identified 32 biomarkers correlated with NYHA class and 28 predicting outcomes. Among outcome-predicting biomarkers, growth/differentiation factor-15 was the strongest and an additional 7 were also significant in Cox regression analyses when adjusted for age, sex, and N-terminal probrain natriuretic peptide: adrenomedullin (hazard ratio per log increase 2.53), agouti-related protein; (1.48), chitinase-3–like protein 1 (1.35), C–C motif chemokine 20 (1.35), fatty acid–binding protein (1.33), tumor necrosis factor receptor 1 (2.29), and TNF-related apoptosis-inducing ligand (0.34). Twenty-three of them correlated with diastolic dysfunction (E/e′) and 5 with left atrial volume index. The IPA suggested that increased inflammation, immune activation with decreased necrosis and apoptosis preceded poor outcome. Conclusions— In HF with preserved ejection fraction, novel biomarkers of inflammation predict HF severity and prognosis that may complement or even outperform traditional markers, such as N-terminal probrain natriuretic peptide. These findings lend support to a hypothesis implicating global systemic inflammation in HF with preserved ejection fraction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov ; Unique identifier: NCT00774709.

Relevance of angiopoietin-2 and soluble P-selectin levels in patients with pulmonary arterial hypertension receiving combination therapy with oral treprostinil: a FREEDOM-C2 biomarker substudy.

Clinicaltrials.gov identifier NCT00887978.

49P The role of circulating cell-free DNA measured by a simple fluorescent assay to predict relapse in triple negative breast cancer receiving neoadjuvant chemotherapy

Background Prior technique to measure cell free DNA(CFD) is labor-intensive and expensive, while, recently developed fluorescent CFD assay is more simple and convenient. The aim of this study was to evaluate the role of CFD measured by a fluorescent assay as a biomarker of patients with triple negative breast cancer (TNBC) received neoadjuvant chemotherapy Methods This study is a biomarker substudy of prospective observational study (NCT02001519, NCT02001506). We prospectively enrolled patients with TNBC, clinical stage II or III (T > 1.5cm or lymph node > 1.5cm), who were scheduled for neoadjuvant chemotherapy. Patients received 4 cycles of adriamycin 60 mg/m2 plus cyclophosphamide600mg/m2(AC)followedby4cyclesofcisplatinordocetaxel,and surgery. Plasma samples were obtained from patients before initial chemotherapy (baseline-CFD) andafter4 cyclesof ACneoadjuvantchemotherapy(AC-CFD). Results This study included 72 patients who met the inclusion criteria. The mean levels of baseline-CFD and AC-CFD were 239668 ng/mL and 210666 ng/mL, respectively, and the CFD level was significantly decreased after AC chemotherapy. (p = 0.001) The baseline-CFD was not associated with initial tumor characteristics. (T stage 1-2 vs. 3, p=0.313;Nstage0vs.1-3,p=0.317)Therewasnostatisticallysignificantdifference betweenpatientswithresponse(CRorPR) toACchemotherapyandthosewithout response in terms of baseline-CFD, AC-CFD, and change of CFD between two values. (p=0.814,p=0.839,p=0.927)With33.6monthsofmedianfollowup,therewere18 cases of relapse. Relapsed group showed numerically higher level of baseline-CFD, although itwas not statistically significant. (relapse, 259 ng/mL; non-relapse, 233 ng/ mL;p=0.161)WeperformedaROCcurveanalysisofbaseline-CFDforrelapse,and foundanareaunderthecurveof0.62(95%CI,0.46-0.78)at222ng/mL.Patientswith baseline-CFD above222 showedhigherrelapses thanthosebelow222.(HR, 2.75; 95% CI,0.96-7.84;p=0.059) Conclusions The baseline-CFD obtained using a simple and convenient fluorescent assay could predict relapse, suggesting baseline-CFD as a potential biomarker for risk stratification of TNBC. Clinical trial indentification A biomarker substudy of prospective observational study (NCT02001519,NCT02001506) Legal entity responsible for the study The study was approved by the institutional review board of Asan Medical Center and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines Funding N/A Disclosure All authors have declared no conflicts of interest.

Abstract 13144: MicroRNA Sequencing Highlights Regulatory Networks Upstream of Osteopontin and B-type Natriuretic Peptide in Acute Coronary Sydrome

Introduction: The genomic regulatory networks underlying the pathogenesis of acute coronary syndrome (ACS) are incompletely understood. As intermediate traits, circulating protein biomarkers report on underlying disease severity and are powerfully prognostic in ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with measurement of biomarkers would highlight potential regulatory pathways. Methods: We studied 186 patients enrolled in the biomarker substudy of the TRILOGY clinical trial of ACS. MiRNA sequencing was performed on RNA extracted from whole blood, and seven known prognostic protein biomarkers were measured from plasma (N-terminal pro B-type natriuretic peptide [NT-proBNP], C-reactive protein, osteopontin [OPN], myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein 1, and neopterin). MiRNAs were tested for association with these biomarkers using generalized linear models. Target genes putatively regulated by the associated miRNAs were examined using pathway analysis. Results: Fourteen miRNAs, including cardiac-related miRs 20b-5p and 320a,b and d, were associated with OPN levels (min. p=1.1x10 -4 ), and five miRNAs, including cardiac-related miRs 25-3p and 423-3p, were associated with NT-proBNP levels (min. p=3.4x10 -4 ); no other biomarkers showed significant associations. Sixty-three KEGG pathways were enriched in the target genes of either NT-proBNP- or OPN-associated miRNAs, with five pathways found in the top ten for both biomarkers: prion diseases, fatty acid biosynthesis, lysine degradation, protein processing in endoplasmic reticulum, and viral carcinogenesis. Conclusions: By integrating large-scale microRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRs with two prognostic biomarkers (OPN and NT-proBNP), and identified potential genomic regulatory networks underlying these biomarkers. We further identified novel non-cardiac genomic pathways associated with these biomarkers. These results may inform future studies delineating genomic pathways underlying ACS outcomes.

Catalytic iron in acute myocardial infarction complicated by cardiogenic shock — A biomarker substudy of the IABP-SHOCK II-trial

BackgroundCatalytic iron (CI) is unbound ferric iron with the potential to generate reactive oxygen species with further deleterious vascular effects. In acute coronary syndromes, high levels of CI are linked to all-cause mortality. The prognostic impact of CI and iron metabolism in cardiogenic shock (CS) is currently undetermined. Aims of this study were to investigate the prognostic impact of CI and to identify predictors of high CI levels in patients with CS complicating acute myocardial infarction. MethodsThe Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial randomized 600 patients with CS to either therapy with intraaortic balloon pump or control. In 185 of these patients, blood samples were systematically collected at baseline and day 3. CI levels were measured using a modified bleomycin detectable iron assay. Furthermore, levels of free hemoglobin, total serum iron, transferrin, total iron binding capacity, ferritin, hepcidin, and transferrin saturation were assessed. ResultsPatients with baseline CI levels in the highest quartile had a worse outcome in comparison to patients with lower CI (day 1: HR 1.91 [1.11–3.31], p=0.005; day 3: HR 2.15 [1.06–4.34], p=0.01). In multivariable Cox-regression analysis baseline CI remained an independent predictor of 30-day mortality (HR per 10LOG 2.08 [1.25–3.47], p=0.005). Predictors of CI levels on day 3 were baseline CI, bleeding events, and baseline troponin T. ConclusionsCI levels were associated with increased short-term mortality in CS complicating acute myocardial infarction. High levels of CI at day 3 were associated with bleeding and high troponin levels.

Cardiovascular Biomarker Score and Clinical Outcomes in Patients With Atrial Fibrillation

Treatment decisions in atrial fibrillation (AF) are based on clinical assessment of risk. The CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes mellitus, and stroke, transient ischemic attack or thromboembolism [2 points]-vascular disease, and sex category [female]) risk score is pragmatic and widely used but has only moderate discrimination. To develop and test a cardiovascular biomarker score for indication of risk in patients with AF. The ENGAGE AF-TIMI 48 trial was a randomized, double-blind, double-dummy clinical trial comparing 2 once-daily edoxaban dose regimens with warfarin in 21 105 patients with AF at moderate to high risk of stroke. This prespecified subanalysis was performed in 4880 patients enrolled at randomization in the biomarker substudy. Cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and d-dimer levels were measured at baseline. A multimarker risk score was developed to determine the probability of stroke, systemic embolic events, or death by assigning tiered points for higher concentrations of the biomarkers. Risk score and clinical outcomes based on cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and d-dimer levels at baseline. Of the 5002 patients enrolled in the biomarker substudy of the ENGAGE AF-TIMI 48 trial, 4880 patients (97.6%) had all 3 biomarkers available at randomization (1820 [37.3%] were women; median [interquartile range] age, 71 [64-77] years). After adjustment for the CHA2DS2-VASc score, each biomarker was associated with a 2.8-fold to 4.2-fold gradient of risk comparing the highest vs lowest concentrations across groups of increasing concentrations (P < .001 for trend for each). The multimarker risk score identified a more than 15-fold gradient of risk after adjustment for CHA2DS2-VASc score. When added to the CHA2DS2-VASc score, the biomarker score significantly enhanced prognostic accuracy by improving the C statistic from 0.586 (95% CI, 0.565-0.607) to 0.708 (95% CI, 0.688-0.728) (P < .001) and reclassification with a net reclassification improvement of 59.4% (P < .001). A prototype multimarker risk score significantly enhanced risk assessment for stroke, systemic embolic events, or death compared with traditional clinical risk stratification. Incorporation of biomarkers into clinical decision making to define therapeutic management in AF warrants consideration. clinicaltrials.gov Identifier: NCT00781391.

Mibefradil Dihydrochloride With Hypofractionated Radiation for Recurrent Glioblastoma: Preliminary Results of a Phase 1 Dose Expansion Trial

ATNT-15. MIBEFRADIL DIHYDROCHORIDE WITH HYPOFRACTIONATED RADIATION FOR RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS OF A PHASE I DOSE EXPANSION TRIAL Nataniel H. Lester-Coll1, Jeannie Kluytenaar1, Kira F. Pavlik2, James B. Yu1, Joseph N. Contessa1, Jennifer Moliterno3, Joseph M. Piepmeier3, Kevin P. Becker4, Joachim M. Baehring4, Anita J. Huttner5, Alexander O. Vortmeyer5, Ramachandran Ramani6, Rachel J. Lampert7, Xiaopan Yao8, and Ranjit S. Bindra1; Departmentof TherapeuticRadiology, YaleUniversity School of Medicine, New Haven, CT, USA; Yale University School of Medicine, New Haven, CT, USA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA; Department of Cardiology, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Analytical Sciences, Yale University School of Medicine, New Haven, CT, USA BACKGROUND: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Our group recently performed a high-throughput drug screen for novel DNA repair inhibitors which identified mibefradil dihydrochloride, a T-type calcium channel blocker. Follow-up studies by our group and others subsequently revealed that mibefradil is active as a glioma radiosensitizer. Based on these findings, we sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and hypofractionated radiation (RT), in a Phase I study of patients with recurrent GBM. A subset of patients are enrolled on a molecular biomarker sub-study, in which the drug is administered prior to surgical re-resection, and the tissue is analyzed for tumor penetration and in situ activity. METHODS: The inclusion criteria are histologically proven GBM progressive or recurrent following RT and temozolomide treatment. Patients receive mibefradil, in escalating dose from 150mg/day until the maximum tolerated dose (MTD) or a dose of 350 mg/day is reached using a standard 3 + 3 design. RT consists of 5 fractions of 600 cGy each, delivered over 2 weeks for a total of 3,000 cGy using stereotactic, intensity-modulated RT. RESULTS: To date, eight patients have been enrolled including two patients on the molecular biomarker sub-study, and seven have been successfully treated. The first dose level cohort has completed accrual. Median progression-free survival was 2.5 months. One patient experienced a complete radiographic response on MRI and one had grade 3 or higher drug-related toxicity. CONCLUSIONS: This Phase I dose-escalation study assesses the safety and determines the MTD of mibefradildihydrochlorideas anovel radiosensitizer inpatientswith recurrent GBM. Our preliminary data suggest that mibefradil and RT can be safely co-administered with the potential to improve disease response as a novel radiosensitizer. Neuro-Oncology 17:v10–v17, 2015. doi:10.1093/neuonc/nov205.15 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Perceived Weight Discrimination and 10-Year Risk of Allostatic Load Among US Adults.

Discrimination promotes multisystem physiological dysregulation termed allostatic load, which predicts morbidity and mortality. It remains unclear whether weight-related discrimination influences allostatic load. The aim of this study was to prospectively examine 10-year associations between weight discrimination, allostatic load, and its components among adults 25-75years in the Midlife Development in the US Biomarker Substudy. Participants with information on weight discrimination were analyzed (n=986). At both timepoints, participants self-reported the frequency of perceived weight discrimination across nine scenarios as "never/rarely" (scored as 0), "sometimes" (1), or "often" (2). The two scores were averaged and then dichotomized as "experienced" versus "not experienced" discrimination. High allostatic load was defined as having ≥3 out of 7 dysregulated systems (cardiovascular, sympathetic/parasympathetic nervous systems, hypothalamic pituitary axis, inflammatory, lipid/metabolic, and glucose metabolism), which collectively included 24 biomarkers. Relative risks (RR) were estimated from multivariate models adjusted for sociodemographic and health characteristics, other forms of discrimination, and BMI. Over 41% of the sample had obesity, and 6% reported weight discrimination at follow-up. In multivariable-adjusted analyses, individuals who experienced (versus did not experience) weight discrimination had twice the risk of high allostatic load (RR, 2.07; 95% CI, 1.21; 3.55 for baseline discrimination; 2.16, 95% CI, 1.39; 3.36 for long-term discrimination). Weight discrimination was associated with lipid/metabolic dysregulation (1.56; 95% CI 1.02, 2.40), glucose metabolism (1.99; 95% CI 1.34, 2.95), and inflammation (1.76; 95% CI 1.22, 2.54), but no other systems. Perceived weight discrimination doubles the 10-year risk of high allostatic load. Eliminating weight stigma may reduce physiological dysregulation, improving obesity-related morbidity and mortality.

A community-engaged randomized controlled trial of an integrative intervention with HIV-positive, methamphetamine-using men who have sex with men.

BackgroundContingency management (CM) is an evidence-based intervention providing tangible rewards as positive reinforcement for abstinence from stimulants such as methamphetamine. Integrative approaches targeting affect regulation could boost the effectiveness of CM in community-based settings and optimize HIV/AIDS prevention efforts.Methods/DesignThis randomized controlled trial with HIV-positive, methamphetamine-using men who have sex with men (MSM) is examining the efficacy of a 5-session, individually delivered positive affect regulation intervention – Affect Regulation Treatment to Enhance Methamphetamine Intervention Success (ARTEMIS). ARTEMIS is designed to sensitize individuals to non-drug-related sources of reward as well as assist with managing depression and other symptoms of stimulant withdrawal during CM. HIV-positive, methamphetamine-using MSM who are enrolled in a community-based, 12-week CM program are randomized to receive ARTEMIS or an attention-matched control condition. Follow-up assessments are conducted at 3, 6, 12, and 15 months after enrollment in CM. Four peripheral venous blood samples are collected over the 15-month follow-up with specimen banking for planned biomarker sub-studies. The primary outcome is mean HIV viral load. Secondary outcomes include: sustained HIV viral suppression, T-helper cell count, psychological adjustment, stimulant use, and potentially amplified transmission risk behavior.DiscussionImplementation of this randomized controlled trial highlights the importance of delineating boundaries between research activities and community-based service provision. It also provides insights into best practices for integrating the distinct agendas of academic and community partners in clinical research. This trial is currently enrolling and data collection is anticipated to be completed in September of 2018.Trial registrationThis trial was registered on clinicaltrials.gov (NCT01926184) on August 16, 2013.

Usefulness of Serum B-Type Natriuretic Peptide Levels in Comatose Patients Resuscitated from Out-of-Hospital Cardiac Arrest to Predict Outcome

N-terminal pro-B-type natriuretic (NT-proBNP) is expressed in the heart and brain, and serum levels are elevated in acute heart and brain diseases. We aimed to assess the possible association between serum levels and neurological outcome and death in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). Of the 939 comatose OHCA patients enrolled and randomized in the Targeted Temperature Management (TTM) trial to TTM at 33°C or 36°C for 24hours, 700 were included in the biomarker substudy. Of these, 647 (92%) had serum levels of NT-proBNP measured 24, 48, and 72hours after return of spontaneous circulation (ROSC). Neurological outcome was evaluated by the Cerebral Performance Category (CPC) score and modified Rankin Scale (mRS) at 6months. Six hundred thirty-eight patients (99%) had serum NT-proBNP levels ≥125 pg/ml. Patients with TTM at 33°C had significantly lower NT-proBNP serum levels (median 1,472 pg/ml) than those in the 36°C group (1,914 pg/ml) at 24 hours after ROSC, p <0.01 but not at 48 and 72 hours. At 24 hours, an increase in NT-proBNP quartile was associated with death (Plogrank <0.0001). In addition, NT-proBNP serum levels > median were independently associated with poor neurological outcome (odds ratio, ORCPC 2.02, CI 1.34 to 3.05, p <0.001; ORmRS 2.28, CI 1.50 to 3.46, p <0.001) adjusted for potential confounders. The association was diminished at 48 and 72 hours after ROSC. In conclusion, NT-proBNP serum levels are increased in comatose OHCA patients. Furthermore, serum NT-proBNP levels are affected by level of TTM and are associated with death and poor neurological outcome.