Serial Biomarker Research Articles

Updated systematic review and meta-analysis of the predictive value of serum biomarkers in the assessment and management of fever during neutropenia in children with cancer.

Routinely measurable biomarkers as predictors for adverse outcomes in febrile neutropenia could improve management through risk stratification. This systematic review assesses the predictive role of biomarkers in identifying events such as bacteraemia, clinically documented infections, microbiologically documented infection, severe sepsis requiring intensive care or high dependency care and death. This review collates 8319 episodes from 4843 patients. C-reactive protein (CRP), interleukin (IL)-6, IL-8 and procalcitonin (PCT) consistently predict bacteraemia and severe sepsis; other outcomes have highly heterogeneous results. Performance of the biomarkers at admission using different thresholds demonstrates that PCT>0.5ng/mL offers the best compromise between sensitivity and specificity: sensitivity 0.67 (confidence interval [CI] 0.53-0.79) specificity 0.73 (CI 0.66-0.77). Seventeen studies describe the use of serial biomarkers, with PCT having the greatest discriminatory role. Biomarkers, potentially with serial measurements, may predict adverse outcomes in paediatric febrile neutropenia and their role in risk stratification is promising.

Biomarker Predictors of Adverse Acute Kidney Injury Outcomes in Critically Ill Patients: The Dublin Acute Biomarker Group Evaluation Study

Background: The Dublin Acute Biomarker Group Evaluation (DAMAGE) Study is a prospective 2-center observational study investigating the utility of urinary biomarker combinations for the diagnostic and prognostic assessment of acute kidney injury (AKI) in a heterogeneous adult intensive care unit (ICU) population. The objective of this study is to evaluate whether serial urinary biomarker measurements, in combination with a simple clinical model, could improve biomarker performance in the diagnostic prediction of severe AKI and clinical outcomes such as death and need for renal replacement therapy (RRT). Methods: Urine was collected daily from patients admitted to the ICU, for a total of 7 post-admission days. Urine biomarker concentrations (neutrophil gelatinase-associated lipocalin [NGAL], α-glutathione S-transferase [GST], π-GST, kidney injury molecule-1 [KIM-1], liver-type fatty acid-binding protein [L-FABP], Cystatin C, creatinine, and albumin) were measured. Urine biomarkers were combined with a clinical prediction of AKI model, to determine ability to predict AKI (any stage, within 2 days or 7 days of ICU admission), or a ­30-day composite clinical outcome (RRT – or death). Results: A total of 257 (38%) patients developed AKI within 7 days of ICU admission. Of those who developed AKI, 106 (41%) patients met stage 3 AKI within 7 days of ICU admission and 208 patients of the entire study cohort (31%) met the composite clinical endpoint of in-hospital mortality or RRT within 30 days of ICU admission. The addition of urinary NGAL/albumin to the clinical model modestly improved the prediction of AKI, in particular severe stage 3 AKI (area under the curve [AUC] of 0.9 from 0.87, p = 0.369) and the prediction of 30-day RRT or death (AUC 0.83 from 0.79, p = 0.139). Conclusion: A clinical model incorporating severity of illness, patient demographics, and chronic illness with currently available clinical biomarkers of renal function was strongly predictive of development of AKI and associated clinical outcomes in a heterogeneous adult ICU population. The addition of urinary NGAL/albumin to this simple clinical model improved the prediction of severe AKI, need for RRT and death, but not at a statistically or clinically significant level, when compared to the clinical model alone.

Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs

Abstract Mechanisms of resistance to immunotherapies are multiple and complex with components intrinsic to the tumor cell and within the immune microenvironment. We review evidence of the interaction of tumor cell signaling pathways with immune pathways and the role this plays in de novo and acquired resistance. The mitogen-activated protein kinase (MAPK) pathway activation and effects on T-cell function are discussed. Phosphoinositide 3-kinase (PI3K) pathway activation (including PTEN loss of function) correlates with T-cell inhibition and immunotherapy resistance. Wnt signaling has been implicated in T-cell function suppression. Key evidence from preclinical models exists for the role of these signaling pathways and is described. Clinical evidence is less advanced though correlation of mutations in key nodes with immune resistance provides a limited clinical correlation. Serial biomarker analysis in patients receiving targeted drugs has been attempted with notable examples including BRAF inhibition in melanoma patients resulting in dynamic changes in programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes. Drug combinations aim to overcome mechanisms of resistance, and recent years have seen numerous combinations of targeted therapies and immune checkpoint inhibitors proposed. However, clear biological rationale and thoughtful trial designs with a translational focus are required to allow such combinations to achieve their full potential.

Biological variation of cardiac markers in patients with aortic valve stenosis

ObjectiveCardiac biomarkers hold promise for follow-up and management of aortic valve stenosis (AVS). When interpreting serial biomarker measurements of patients with AVS, it can be challenging to distinguish ‘real changes’...

Postoperative ‘STEMI’ in Intracerebral Hemorrhage due to Arteriovenous Malformation: A Case Report and Review of Literature

Electrocardiogram (ECG) changes suggestive of cardiac ischemia are frequently demonstrated in patients with ischemic stroke and subarachnoid hemorrhage. However, little is known of such changes particularly acute ST segment myocardial infarction (STEMI) in patients with intracerebral hemorrhage (ICH), especially after neurosurgery. We present a patient with intraparenchymal hemorrhage due to cerebral arteriovenous malformation (AVM) who exhibited acute STEMI after neurosurgery. Serial cardiac biomarkers and echocardiograms were performed which did not reveal any evidence of acute myocardial infarction. The patient was managed conservatively from cardiac stand point with no employment of anticoagulants, antiplatelet therapy, fibrinolytic agents, or angioplasty and recovered well with minimal neurological deficit. This case highlights that diffuse cardiac ischemic signs on the ECG can occur in the setting of an ICH after neurosurgery, potentially posing a difficult diagnostic and management conundrum.

3424 Serial Biomarker Monitoring Predicts Long Term Outcomes in Acute Graft Versus Host Disease

OBJECTIVES/SPECIFIC AIMS: The first aim of the study is to evaluate the accuracy of serum biomarkers of acute GVHD measured after four weeks of corticosteroid therapy to predict 6 month NRM. The second aim of this study is to compare the accuracy of the biomarker algorithm to that of clinical response to corticosteroids after four weeks. The third aim of the study is to develop a novel regression model that uses weekly biomarker measurements over the first month of corticosteroid therapy to predict 6 month NRM. METHODS/STUDY POPULATION:. Patients who received HCT at one of 22 IRB-approved centers and provided blood samples to the Mount Sinai Acute GVHD International Consortium (MAGIC) biorepository and developed GVHD between January 2008 to May 2018 are included in this study. Patients were divided by time into a training set (Jan 2008-Dec 2015, n=233) for model development and a validation set (Jan 2015-May 2018, n=357) to evaluate the predictive performance of the model. The later time of the validation set was chosen deliberately to model contemporaneous GVHD treatment practices. The size of each group was designed so that there would be roughly equal numbers of deaths in both groups. RESULTS/ANTICIPATED RESULTS:. Serum concentrations of GVHD biomarkers after one month of corticosteroid therapy were measured in the validation set, and the predicted probability of NRM ($\hat{\rm p}$) was computed according to the previously published algorithm: $\log[-\log(1 - \hat{\rm p})]=-11.263 + 1.844({\rm logST}2)+ 0.577({\rm logREG}3\alpha)$. The performance of the biomarker algorithm was evaluated by creating receiver operating characteristic (ROC) curves and calculating the area under the curve (AUC) in the validation set. The AUC of the biomarker algorithm was a significantly better predictor of 6 month NRM than clinical response to treatment after four weeks of corticosteroids (0.84 vs. 0.64, p<0.001), which is a clinically relevant improvement in accuracy. To evaluate serial biomarker monitoring, serum biomarker concentrations will be measured weekly at five time points from treatment initiation to one month after corticosteroid therapy. We will use these values in the training set to develop a regression model for 6 month NRM that accounts for repeated biomarker measurements. The performance of this model will be tested in the validation set and the accuracy of the serial biomarker measurements will be compared to the accuracy of measuring biomarkers at the single time point after four weeks of corticosteroid therapy. An AUC improvement of 0.05 would be considered clinically significant. DISCUSSION/SIGNIFICANCE OF IMPACT: Clinical response to treatment after four weeks has been the standard endpoint in GVHD interventional trials for decades. If biomarkers measured at the same time more accurately predict long term mortality, this study would provide the basis for a novel endpoint in GVHD trials and enable more accurate determination of effect size of experimental interventions. An accurate biomarker algorithm will prove useful in guiding immunosuppressive treatment decisions for patients with GVHD. Patients identified by the algorithm as low-risk may benefit from reduced-dose corticosteroid therapy, potentially reducing lethal opportunistic infections. Patients identified as high-risk will be candidates for more intensive immunosuppression or investigational therapies. This precision medicine approach tailors therapy to the individual patient’s biology.

Temporal Patterns of 14 Blood Biomarker candidates of Cardiac Remodeling in Relation to Prognosis of Patients With Chronic Heart Failure-The Bio- SH i FT Study.

BackgroundRemodeling biomarkers carry high potential for predicting adverse events in chronic heart failure (CHF) patients. However, temporal patterns during the course of CHF, and especially the trajectory before an adverse event, are unknown. We studied the prognostic value of temporal patterns of 14 cardiac remodeling biomarker candidates in stable patients with CHF from the Bio‐SHiFT (Serial Biomarker Measurements and New Echocardiographic Techniques in Chronic Heart Failure Patients Result in Tailored Prediction of Prognosis) study.Methods and ResultsIn 263 CHF patients, we performed trimonthly blood sampling during a median follow‐up of 2.2 years. For the analysis, we selected all baseline samples, the 2 samples closest to the primary end point (PE), or the last sample available for end point–free patients. Thus, in 567 samples, we measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2, 3, and 9, tissue inhibitor metalloproteinase‐4, perlecan, aminopeptidase‐N, caspase‐3, cathepsin‐D, cathepsin‐Z, and cystatin‐B. The PE was a composite of cardiovascular mortality, heart transplantation, left ventricular assist device implantation, and HF hospitalization. Associations between repeatedly measured biomarker candidates and the PE were investigated by joint modeling. Median age was 68 (interquartile range: 59–76) years with 72% men; 70 patients reached the PE. Repeatedly measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2 and 9, tissue inhibitor metalloproteinase‐4, perlecan, cathepsin‐D, and cystatin‐B levels were significantly associated with the PE, and increased as the PE approached. The slopes of biomarker trajectories were also predictors of clinical outcome, independent of their absolute level. Associations persisted after adjustment for clinical characteristics and pharmacological treatment. Suppression of tumorigenicity‐2 was the strongest predictor (hazard ratio: 7.55 per SD difference, 95% CI: 5.53–10.30), followed by growth differentiation factor‐15 (4.06, 2.98–5.54) and matrix metalloproteinase‐2 (3.59, 2.55–5.05).ConclusionsTemporal patterns of remodeling biomarker candidates predict adverse clinical outcomes in CHF.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01851538.

Acute HIV Infection in Youth: Protocol for the Adolescent Trials Network 147 (ATN147) Comprehensive Adolescent Research and Engagement Studies (CARES) Study.

BackgroundEarly treatment studies have shown that prompt treatment of HIV with combination antiretroviral therapy (cART) can limit the size of latent viral reservoirs, thereby providing clinical and public health benefits. Studies have demonstrated that adolescents have a greater capacity for immune reconstitution than adults. Nevertheless, adolescents who acquired HIV through sexual transmission have not been included in early treatment studies because of challenges in identification and adherence to cART.ObjectiveThis study aimed to identify and promptly treat with cART youth aged 12 to 24 years in Los Angeles and New Orleans who have acute, recent, or established HIV infection, as determined by Fiebig stages 1 to 6 determined by viral RNA polymerase chain reaction, p24 antigen presence, and HIV-1 antigen Western blot. The protocol recommends treatment on the day of diagnosis when feasible. Surveillance and dedicated behavioral strategies are used to retain them in care and optimize adherence. Through serial follow-up, HIV biomarkers and response to antiretroviral therapy (ART) are assessed. The study aims to assess viral dynamics, decay and persistence of viral reservoirs over time, and correlate these data with the duration of viral suppression.MethodsA total of 72 youth (36 acutely infected and 36 treatment naïve controls) are enrolled across clinical sites using a current community-based strategy and direct referrals. Youth are prescribed ART according to the standard of care HIV-1 management guidelines and followed for a period of 2 years. Assessments are conducted at specific time points throughout these 2 years of follow-up for monitoring of adherence to ART, viral load, magnitude of HIV reservoirs, and presence of coinfections.ResultsThe study began enrolling youth in July 2017 across study sites in Los Angeles and New Orleans. As of September 30, 2018, a total of 37 youth were enrolled, 12 with recently acquired, 16 with established HIV infection as determined by Fiebig staging, and 9 pending determination of Fiebig status. Recruitment and enrollment are ongoing.ConclusionsWe hypothesize that the size of the HIV reservoir and immune activation markers will be different across groups treated with cART, that is, those with acute or recent HIV infection and those with established infection. Adolescents treated early who are virally suppressed will have diminished HIV reservoirs than those with established infection. These youth may be potential candidates for a possible HIV vaccine and additional HIV remission intervention trials. Our study will inform future studies of viral remission strategies.International Registered Report Identifier (IRRID)DERR1-10.2196/10807

Clinical significance of serial biomarkers activity determination after acute heart failure decompensation: sST2 NT-proBNP role during long-term follow-up

Monitoring of concentrations of modern biomarkers to evaluate the efficacy of long‑term treatment of patients after acute decompensated HF (ADHF). The study included 100 patients with severe decompensated FC II-IV CHF and LV EF <40 % due to IHD, DCMP or AH. At discharge from the hospital, patients were divided into groups of low (NT‑proBNP<1400 pg / ml) (control, n=30) and high (NT‑proBNP≥1400 pg / ml) risk (n=70). Patients at high risk were randomized to two treatment groups, a group of NT‑proBNP monitoring (NPM) (n=35) and a group of standard therapy (n=35). At the end of the study, noncompliant patients were isolated from these two groups into a separate group (n=10). The aim of the treatment was decreasing theNT‑proBNP concentration to less than 1000 pg / ml and / or ≥50 % of the baseline level. In addition to the soluble suppression of tumorigenicity2(sST2) receptor, concentrations of copeptin, neutrophil gelatinase associated lipocalin (NCAL), galectin 3, and high‑sensitivity troponin T were measured at discharge from the hospital (baseline) and at three and 6 months of treatment. Thestrongest correlations were found between changes in concentrations (Δ%) of NT‑proBNP, copeptin, and sST2 and changes in CHF FC, 6‑min walk distance, CCS, quality of life, LV EF, and Е / Е' (р<0.001). The incidence of cardiovascular events was directly related with thedegree of decrease and / or increase in biomarker concentration. Patients of the NPM group had the lowest risk of adverse clinical outcome upon a decrease in NT‑proBNP <988.5 pg / ml at 6 months of treatment or > 50 % of the baseline level at discharge from the hospital. For these patients, the mean Δ% was 60.7±8.5 % for NT‑proBNP, 34.03±17.6 % for sST2, and 32.41±8.8 % for copeptin [OR at 95 % CI 0.08 (0.02-0.36), р <0.0001]. A significant increase in the risk for cardiovascular events was observed only at a considerable increase in NT‑proBNP >50 % [OR at 95 % CI 3.8 (1.13-13.0), р=0.03], and the highest incidence of cardiovascular events was observed in the group of noncompliant patients (110 %). Besides NT‑proBNP, to significantly decrease the risk of cardiovascular events, it was necessary to achieve a decrease in sST2 concentration to less than 30 ng / ml or by more than 24.9 % (Δ%) at the end offollowup [ОR (95 % CI: 0.1 (0.02-0.5), р=0.004]. Among the modern biomarkers, changes inNT‑proBNP, sST2, and copeptin concentrations most accurately reflect changes in the clinical and functional status, quality of life, and EchoCG parameters in HF patients during long‑term monitoring. The lowest risk for adverse clinical outcomes was observed in post‑decompensation patients with a decrease in NT‑proBNP <988.5 pg / ml after 6 months of treatment or ≥50 % of baseline upon discharge from the hospital. The sST2 concentration has to be reduced by more than 24.9 % of baseline and less than 30 ng / ml in the course of long‑term treatment after decompensated HF.

Achieving a Difference in Involved and Uninvolved Light Chains (dFLC) of Less Than 10mg/L Is the New Goal of Therapy in Systemic AL Amyloidosis: Analysis of 916 Patients Treated Upfront with Bortezomib-Based Therapy

BackgroundBased on international consensus criteria (ICC), the treatment goal in AL amyloidosis (AL) is at least a very good partial response (VGPR, defined by dFLC<40mg/L), associated with better organ responses and overall survival (OS). In patients presenting with low dFLC (<50mg/L), a low-dFLC partial response (PR, dFLC<10mg/L) predicts better renal and OS. Given emerging data on the impact of minimal residual disease in AL, we posited that a target of dFLC<10mg/L may be important in all AL patients, irrespective of baseline light chain levels. We therefore report outcomes in the largest cohort treated with upfront bortezomib-based therapy and explore the impact of dFLC<10mg/L as a potential therapy goal in AL.MethodsAll patients from a prospective observational study of newly diagnosed AL treated with upfront bortezomib regimes from 2010-2017 were included. All underwent serial organ function assessment and biomarkers. Organ responses were defined by ICC. Survival was calculated by Kaplan-Meier analysis. All outcomes are reported on an intention-to-treat (ITT) basis. Haematologic responses were assessed by ICC and absolute dFLC. Patients with presentation dFLC 20-50mg/L were regarded as achieving a low-dFLC PR if dFLC<10mg/L after treatment. Progression-free survival (PFS) was defined as time to death or progression to next therapy. Time-to-next-treatment (TNT) was defined as time from first-line therapy to second-line.Results916 patients were included. Median age was 66 years (29-89), M:F 59%:41%. The number of patients with cardiac, renal, liver, peripheral nerve and autonomic involvement was: 71%, 68%, 14%, 6% and 6%. The number of patients with Mayo Stage 1, 2 and 3 disease was 16%, 33% and 51%. The median NT-proBNP and dFLC were 2228ng/L (range 29-93776) and 180mg/L (0-15898), respectively. All received bortezomib-based therapy: CyBorD 95%, bortezomib-dexamethasone 3%, bortezomib-thalidomide-dexamethasone 1.3%, bortezomib-melphalan-prednisolone 0.3%, bortezomib-lenalidomide-dexamethasone 0.3% and bortezomib-melphalan-thalidomide-dexamethasone 0.1%. The median number of chemotherapy cycles was 5 (1-9).ITT haematologic responses by ICC at 6 months were: complete haematologic response (CR) 15%, VGPR 30%, partial response (PR) 16%, low-dFLC PR 4%, non-response 35% (including deaths 25%). Evaluable haematologic responses were: CR 21%, VGPR 40%, PR 21%, low-dfLC PR 5% and non-response 13%. Absolute dFLC responses were: dFLC <10 mg/L 30%; dFLC 10-20mg/L 11%; dFLC 20-30mg/L 6%; dFLC 30-40mg/L 5%, dFLC 40-50mg/L 3%, dFLC>50mg/L 20% and deaths 25%.Median OS, PFS and TNT were 72 months, 22 months and not reached (55% of evaluable patients not having progressed to next treatment at 7 years). Median OS was not reached in patients in a CR, VGPR or low-dFLC PR; median OS was 71 and 39 months in patients in a PR and non-response, respectively. Median OS in patients with 6 month dFLC<10mg/L, dFLC 10-40mg/L, and dFLC>40mg/L was not reached (86% alive at 6 years), not reached (61% alive at 6 years) and 53 months, respectively. Median PFS was not reached in patients in a CR or low-dFLC PR, and it was 48, 17 and 13 months in patients in a VGPR, PR and non-response, respectively. Median PFS in patients with 6 month dFLC<10mg/L, 10-40mg/L and dFLC> 40mg/L was not reached, 33 and 14 months, respectively. Median TNT in patients in a CR, VGPR and “low-dFLC” response was not reached; it was 16 and 13 months in those in a PR and non-response, respectively (Fig. 1A). Median TNT in patients with a 6 month dFLC<10mg/L, 10-40mg/L and dFLC>40mg/L was not reached, 38 months and 13 months (Fig. 1B).Median OS, PFS and TNT at 3 and 5 years in patients achieving CR vs dFLC<10mg/L was: 76% vs 82%, and 67% vs 76%. 32% achieved cardiac responses in total, compared to 61% in those with 6 month dFLC<10mg/L (p<0.0001). 15.4% achieved renal responses overall, compared to 27.4% in the 6 month dFLC<10mg/L group (p=0.0003).ConclusionIn this study, we report the largest cohort of AL patients treated with upfront bortezomib. On an evaluable basis, 66% of patients achieved CR/VGPR/low-dFLC response. The OS, PFS and TNT in patients in a CR are akin to those previously reported in ASCT. Strikingly, PFS, TNT and organ responses are markedly better in patients with dFLC<10mg/L after treatment, even compared to patients in a standard CR. We propose that dFLC<10mg/L should be evaluated in an international collaboration as the new therapy goal in AL. [Display omitted] DisclosuresWechalekar:Janssen: Honoraria.

Serial Biomarker Monitoring Early after HCT Identifies Different Risks for Relapse and Graft-Vs-Host Disease

Relapse of malignancy and lethal graft versus host disease (GVHD) are the principal causes of failure of allogeneic hematopoietic cell transplant (HCT). Recently we have shown that at seven days after HCT an algorithm using two serum biomarkers (ST2 and REG3α) can predict severe GVHD (Hartwell et al. JCI Insight 2017). We determined whether serial testing (in the first month following HCT) of patients with low probability biomarkers would improve the predictive accuracy of the algorithm and identify patients with different risks of relapse and lethal GVHD. Patients who received an HCT at 18 centers in the Mount Sinai Acute GVHD International Consortium (MAGIC) for hematologic malignancy and who supplied three blood samples were divided into a training set and validation set with equal numbers of lethal GVHD events, which was defined as death from GVHD or infection during treatment for GVHD. Patients in the training set (n=702) underwent HCT from January 1, 2006 until June 30, 2015, whereas patients in the validation set (n=906) underwent HCT from July 1, 2015 to May 1, 2017. Serum samples were analyzed using the previously published algorithm of two biomarkers up to three times (day 7, day 14, day 28 or GVHD onset, if onset occurred within the first 28 days). The algorithm generates a predicted probability of lethal GVHD between 0 and 1 for each patient. Patients were categorized as either low probability (LP) or high probability (HP) for lethal GVHD. HP thresholds of 0.20 and 0.16 were used to classify patients with and without GVHD symptoms, respectively (once categorized as HP, patients remained in that category and were not retested). All results were similar between training and validation sets, and we present here the validation set results. Serial testing identified 28% of patients as HP with a three-fold greater cumulative incidence of lethal GVHD at one year (13% vs 4%, p Early development of GVHD (by day 28) is a risk factor for lethal GVHD. Therefore, we next plotted RFS (dashed line), relapse (solid line), and lethal GVHD (dotted line) rates in patients who developed GVHD by day 28. 25% of patients with GVHD were categorized as HP and had a cumulative incidence of lethal GVHD more than four times higher (28%) than that of relapse (6%); however the risks were reversed for the 75% of patients who were LP, where relapse (15%) occurred twice as often as lethal GVHD (7%) (Figure 3B). In patients who did not develop GVHD in the first month, this reversal of risks was even more dramatic. Approximately half (53%) of the entire validation cohort did not develop GVHD by day 28 and was LP at all three evaluations. These patients had an exceptionally low risk of lethal GVHD and thus they relapsed (25%) much more often than they died from GVHD (3%). When malignancies were classified according to risk for relapse by the disease risk index (DRI) (Figure 3C), the probability of relapse was three fold higher than lethal GVHD in malignancies with a low DRI (12%), six fold higher for intermediate DRI (20%), and eleven fold higher for high/very high DRI (33%). We conclude that a serial monitoring strategy using GVHD biomarkers for one month after HCT is able to identify two groups of patients with very different risks of lethal GVHD and relapse. For these patients, the intensity of immunosuppression after day 28 could be tailored according to the probabilities of developing lethal GVHD and relapse in the context of clinical trials. Disclosures Aziz:Doris Duke Charitable Foundation: Research Funding. Ayuk:Therakos (Mallinckrodt): Honoraria; Novartis: Honoraria; Celgene: Consultancy; Gilead: Consultancy. Chen:REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Merli:Neovii Biotech: Honoraria; AMGEN: Honoraria. Roesler:Sanofi: Other: Travel, Accommodations, Expenses; Amgen: Equity Ownership; Jazz Pharmaceuticals: Other: Travel, Accommodations, Expenses; Immunomedics: Equity Ownership; Biogen: Equity Ownership; Merck: Consultancy; Pfizer: Consultancy. Kitko:Novartis: Consultancy, Honoraria; Mallinckrodt: Honoraria, Other: Travel, Accommodations, Expenses. Qayed:Novartis: Consultancy. Wolfl:Bristol-myers Squibb: Equity Ownership; Novartis: Equity Ownership; Taheda: Equity Ownership; Juno: Equity Ownership; Neovii: Other: Travel, Accommodations, Expenses. Mielke:Celgene: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau; Kiadis Pharma: Speakers Bureau; Miltenyi: Speakers Bureau. Wudhikarn:Takeda Oncology: Other: Travel, Accommodations, Expenses. Nakamura:Celgene: Honoraria; Molmed: Honoraria; Merck: Consultancy; Pharmacyclics: Consultancy; Atara: Consultancy; Jazz Pharmaceuticals: Consultancy. Pulsipher:CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding; Amgen: Honoraria. Reshef:Pfizer: Consultancy; Atara Biotherapeutics: Consultancy; Kite Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy. Levine:Therakos: Consultancy; Novartis: Consultancy; Bluebird: Consultancy; Incyte: Consultancy; Kamada: Research Funding; Viracor: Patents & Royalties. Ferrara:Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Xenikos: Consultancy, Other: Travel, Accommodations, Expenses; Kamada: Consultancy, Research Funding; Viracor: Consultancy, Patents & Royalties.

Serial circulating omega 3 polyunsaturated fatty acids and healthy ageing among older adults in the Cardiovascular Health Study: prospective cohort study

ObjectiveTo determine the longitudinal association between serial biomarker measures of circulating omega 3 polyunsaturated fatty acid (n3-PUFA) levels and healthy ageing.DesignProspective cohort study.SettingFour communities in the United States (Cardiovascular Health...

Real-world use of procalcitonin and other biomarkers among sepsis hospitalizations in the United States: A retrospective, observational study.

BackgroundSepsis management guidelines endorse use of biomarkers to support clinical assessment and treatment decisions in septic patients. The impact of biomarkers on improving patient outcomes remains uncertain.MethodsRetrospective observational study of adult sepsis discharges between January 1, 2012, and December 31, 2015, from Premier Healthcare Database hospitals. Sepsis was defined by an All Patients Refined Diagnosis-Related Group code of 720 (septicemia and disseminated infections). Use of four biomarker strategies was evaluated based on hospital records: (i) >1 procalcitonin (PCT), (ii) 1 PCT, (iii) no PCT but ≥1 C-reactive protein (CRP) and/or lactate and (iv) no sepsis biomarkers. Associations between biomarker use and clinical and cost outcomes were examined. The primary outcome was impact of biomarker strategy on hospital costs per day.ResultsAmong 933,591 adult sepsis discharges during the study period, 731,392 (78%) had biomarker tests ordered. In multivariable analyses, discharges with >1 PCT had higher hospital costs per day ($1,904; 95% confidence interval [CI] $1,896–$1,911) compared with discharges with no sepsis biomarkers ($1,606; 95% CI $1,658–$1,664). Discharges with >1 PCT also had greater illness severity and antimicrobial exposure compared with other biomarker-use groups. The adjusted odds of dying during hospital stay compared with being discharged were significantly lower for sepsis discharges with >1 PCT (0.64; 95% CI 0.61–0.67) and 1 PCT (0.88; 95% CI 0.85–0.91) compared with no sepsis biomarker use. The proportion of discharges with ≥1 PCT increased almost six-fold during the study; use of other biomarkers remained constant.ConclusionsBetween 2012 and 2015, PCT use among sepsis discharges increased six-fold while lactate and CRP use remained unchanged. PCT use was associated with decreased odds of in-hospital mortality but increased hospital costs per day. Serial biomarker monitoring may be associated with improved patient outcomes in the most critically ill septic patients.

P3607Can high-dose statin therapy given before off-pump CABG “recapture” cardioprotection in patients already on chronic statin therapy: Assessment by serial cardiac biomarker assay

P3607Can high-dose statin therapy given before off-pump CABG “recapture” cardioprotection in patients already on chronic statin therapy: Assessment by serial cardiac biomarker assay

Early Changes in Serial CBCT-Measured Parotid Gland Biomarkers Predict Chronic Xerostomia After Head and Neck Radiation Therapy

To determine whether serial cone beam computed tomography (CBCT) images taken during head and neck radiation therapy (HNR) can improve chronic xerostomia prediction. In a retrospective analysis, parotid glands (PGs) were delineated on daily kV CBCT images using deformable image registration for 119 HNR patients (60 or 70Gy in 2Gy fractions over 6 or 7weeks). Deformable image registration accuracy for a subset of deformed contours was quantified using the Dice similarity coefficient and mean distance to agreement in comparison with manually drawn contours. Average weekly changes in CBCT-measured mean Hounsfield unit intensity and volume were calculated for each PG relative to week 1. Dose-volume histogram statistics were extracted from each plan, and interactions among dose, volume, and intensity were investigated. Univariable analysis and penalized logistic regression were used to analyze association with observer-rated xerostomia at 1year after HNR. Models including CBCT delta imaging features were compared with clinical and dose-volume histogram-only models using area under the receiver operating characteristic curve (AUC) for grade ≥1 and grade ≥2 xerostomia prediction. All patients experienced end-treatment PG volume reduction with mean (range) ipsilateral and contralateral PG shrinkage of 19.6% (0.9%-58.4%) and 17.7% (4.4%-56.3%), respectively. Midtreatment volume change was highly correlated with mean PG dose (r=-0.318, P<1e-6). Incidence of grade ≥1 and grade ≥2 xerostomia was 65% and 16%, respectively. For grade ≥1 xerostomia prediction, the delta-imaging model had an AUC of 0.719 (95% confidence interval [CI], 0.603-0.830), compared with 0.709 (95% CI, 0.603-0.815) for the dose/clinical model. For grade ≥2 xerostomia prediction, the dose/clinical model had an AUC of 0.692 (95% CI, 0.615-0.770), and the addition of contralateral PG changes modestly improved predictive performance, with an AUC of 0.776 (0.643-0.912). The rate of CBCT-measured PG image feature changes improves prediction over dose alone for chronic xerostomia prediction. Analysis of CBCT images acquired for treatment positioning may provide an inexpensive monitoring system to support toxicity-reducing adaptive radiation therapy.

Net reclassification improvement with serial biomarkers and bed-sided spirometry to early predict the need of organ support during the early post-transplantation in-hospital stay in allogeneic HCT recipients.

To predict the need of intensive care unit admission with organ support during the transplantation hospital stay in 101 consecutives allogeneic hematopoietic cell transplantation (allo-HCT) recipients the added predictive utility of three times per week Copeptin, MR-proADM, MR-proANP, NT-proBNP, IL-6, Procalcitonin, D-dimer and three times per week bed-sided pulmonary function test was determined in comparison with an index model. The index model was calculated by multivariate regression analysis out of the patients' routine laboratory parameters. To calculate the added predictive utility of the investigated markers the Δ-AUC and the continuous net reclassification improvement (cNRI + 2 to - 2), splitted for events and non-events were calculated for each marker in comparison with the index model. According to the Δ-AUC, none of the parameters improved risk prediction. In contrast, the cNRI was significantly improved for events and non-events by Copeptin (event 0.75, p value 0.0013; non-event 0.4, p value 0.000079) and for events by NT-proBNP (0.6, p value 0.018). D-dimer and PCT significantly predicted the non-event. Of the spirometry parameters, the FEF50% improved prediction of event and non-event according to the cNRI model. Our data support the additional serial analysis of Copeptin and NT-proBNP in allo-HCT recipients during the transplantation hospital stay.

Use of integrated imaging and serum biomarker profiles to identify subclinical dysfunction in pediatric cancer patients treated with anthracyclines

BackgroundAnthracycline induced cardiomyopathy is a major cause of mortality and morbidity among pediatric cancer survivors. It has been postulated that oxidative stress induction and inflammation may play a role in the pathogenesis of this process. Accordingly, the present study performed an assessment of biomarker profiles and functional imaging parameters focused upon potential early determinants of anthracycline induced cardiomyopathy.MethodsPatients (10–22 years) were prospectively enrolled between January 2013 and November 2014. Thirteen subjects completed the study and underwent serial cardiac magnetic resonance imaging and plasma biomarker profiling performed 24–48 h after the first anthracycline dose and at set dose intervals. In addition, we collected plasma samples from 62 healthy controls to examine normal plasma biomarker profiles.ResultsLeft ventricular ejection fraction (LVEF) decreased from 64.3 ± 6.2 at the first visit to 57.5 ± 3.3 (p = 0.004) 1 year after chemotherapy. A decline in longitudinal strain magnitude occurred at lower cumulative doses. A differential inflammatory/matrix signature emerged in anthracycline induced cardiomyopathy patients compared to normal including increased interleukin-8 and MMP levels. With longer periods of anthracycline dosing, MMP-7, a marker of macrophage proteolytic activation, increased by 165 ± 54% whereas interleukin-10 an anti-inflammatory marker decreased by 75 ± 13% (both p < 0.05). MMP7 correlated with time dependent changes in EF.ConclusionsAsymptomatic pediatric patients exposed to anthracycline therapy develop abnormal strain parameters at lower cumulative doses when compared to changes in EF. A differential biomarker signature containing both inflammatory and matrix domains occur early in anthracycline treatment. Dynamic changes in these domains occur with increased anthracycline doses and progression to anthracycline induced cardiomyopathy. These findings provide potential prognostic and mechanistic insights into the natural history of anthracycline induced cardiomyopathy.Trial registration numberNCT03211520 Date of Registration February 13, 2017, retrospectively registered.

Abstract MP06: Circulating Fatty Acids in the De Novo Lipogenesis Pathway and Total and Cause-Specific Mortality Among Older Adults: The Cardiovascular Health Study

De novo lipogenesis (DNL) is a crucial metabolic pathway that convert excess carbohydrates to fatty acids (FA) for energy and storage. Both DNL and the synthesized FA have biologic effects that may affect cardiometabolic risk. Yet, the association between DNL FA and mortality and CVD are not well-established in older adults, especially using serial biomarkers which objectively allow more accurate estimates of long-term FA exposure, as well as changes over time. We investigated the longitudinal association between serial levels of circulating DNL FA and total mortality, cause-specific mortality, and total CVD among 3,869 older U.S. adults (mean age 75 y) free of prevalent CVD at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n-7), stearic (18:0), and oleic acid (18:1n-9) were quantified at baseline, year 6, and year 13. Outcomes were centrally adjudicated using multiple sources. Risk was assessed in multivariable-adjusted Cox models with time-varying FA and covariates. During 46,974 person-years, 3,227 deaths (including 1,131 from CVD, 2,096 from non-CVD causes) and 1,754 incident total CVD events occurred. After multivariable-adjustment, cumulative levels of 16:0, 16:1n-7 and 18:1n-9 were each positively, while 18:0 was inversely, associated with total mortality ( Table ). Associations were generally similar for CVD vs. non-CVD mortality, and vs. total incident CVD (not shown). Among non-CVD deaths, associations for dementia and pulmonary deaths were generally similar to total mortality; while only 16:0 and 18:1n-9 were positively associated with cancer mortality. Higher long-term levels of circulating 16:0, 16:1n-7 and 18:1n-9 were positively, while 18:0 was inversely, associated with total mortality in older adults. Novel findings highlight the potential relevance of DNL later in life, and the need for further experimental research and interventions on the relevant underlying physiology and long-term health effects of DNL FA. Findings for FA changes over time to be presented.

Comparison of Magnetic Resonance Analysis of Myocardial Scarring With Biomarker Release Following S-T Elevation Myocardial Infarction

Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) is commonly assumed to represent myocardial fibrosis; however, comparative human histological data are limited, and there is no consensus on the most accurate method for LGE quantitation. We evaluated the relationship between CMR assessment of regional fibrosis and infarct size assessment using serial biomarkers after ST elevation acute myocardial infarction (STEMI). Ninety-three patients treated for STEMI (59±10 years, 86% male) underwent CMR 6 months after infarction. Infarct size was quantified by CMR-LGE using manual and range of semi-automated thresholds (range: 2-10 standard deviations [SD]) above reference myocardium and the full width-half maximum (FWHM) technique, and compared with the rise in serum biomarkers. The agreement between CMR and biomarker in the identification of large infarcts based on peak troponin (TnI) levels was also analysed. Quantification methods had a strong influence on the infarct size assessment with CMR-LGE. Significant correlations were observed between LGE and biomarkers across all of the signal intensity thresholds. Whilst there was a wide variation with respect to the estimation of total LGE size (from 6.8±7.7 to 32.1±11.3 grams), the variation in the correlation with peak troponin level was much smaller (r-values ranging from 0.670 to 0.876). There was good agreement between CMR-LGE and biomarker assessment of infarct size; the best agreement between CMR-LGE and large infarction using a threshold of 8SD for peak TnI>50ng/mL (Cohen's kappa (κ)=0.722), and a threshold of 4SD for peak TnI >95ng/mL (κ=0.761). The correlation between CMR-LGE quantification of infarct size and biomarker release following STEMI at a range of semi-automated thresholds was consistently strong, with good agreement between measures across a range of thresholds.

A phase 2 and biomarker study of sorafenib combined with FOLFOX in patients with advanced hepatocellular carcinoma (HCC).

270 Background: Sorafenib is the standard first line treatment for advanced HCC and showed a median time to progression (TTP) of 5.5 months and an overall response rate (ORR) of 2% in the phase III SHARP trial. FOLFOX has shown modest activity in HCC with a progression free survival (PFS) of 2.9 months and ORR of 8% in a phase III trial. In this single-arm, multicenter phase 2 and biomarker study, sorafenib plus FOLFOX was evaluated in the first line treatment of advanced HCC. Methods: Patients with histologically proven advanced HCC, Child Pugh A liver function, and no prior systemic therapies received sorafenib 400mg orally twice daily during a 2-week lead-in, followed by concurrent modified FOLFOX (5-FUCI 1200mg/m2/day for 46 hours and LV 400mg/m2 bolus, Oxaliplatin 85mg/m2) on day 1 and 15 of each 28-day cycle. The primary endpoint was TTP, calculated from date of study entry to date of radiological or clinical disease progression. Serial plasma anti-angiogenic and anti-inflammatory biomarkers were evaluated. Results: The study enrolled 40 patients with advanced HCC: median age, 65 years; male 85%; Child Pugh A5, 70%; BCLC stage C, 95%; HCC etiology, HCV 40%, HBV 13%, alcohol 13%. Grade 3/4 adverse events were notable for AST (23%), ALT (15%), bilirubin (10%), diarrhea (10%), anemia (10%), hypertension (5%), hand-foot syndrome (5%), and thrombocytopenia (5%). Dose reductions for sorafenib and FOLFOX were done in 73% and 65% of patients, respectively. The median TTP was 8.8 months (95%CI, 6.5-11.2). The ORR was 18%, and the stable disease rate was 55%. Among 36 patients with a baseline AFP ≥ 5 ng/mL, 10 (28%) had a ≥ 50% drop in AFP. Low baseline plasma levels of sVEGFR1, VEGF-C, and bFGF and high levels of s-cMET and IL-12 tended to associate with longer TTP (p &lt; 0.10). Decreased s-cMET at day 15 and decreased s-cMET and IL-2 at day 43 were associated with longer TTP (p &lt; 0.05). Conclusions: Sorafenib+FOLFOX demonstrated encouraging clinical efficacy with moderate toxicity in the first line treatment of advanced HCC. Initial biomarker evaluation suggested a correlation between TTP and baseline angiogenic markers as well as changes in IL-2 and s-cMET. Complete biomarker analysis will be presented at the meeting. Clinical trial information: NCT01775501.