Baseline Biomarkers Research Articles

Patient-Reported Outcomes after Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphomas

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy has shown clinical efficacy in refractory and relapsed large B-cell lymphomas, but is associated with serious acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As part of a larger study evaluating baseline biomarkers in prospective patients receiving CAR-T therapy at the Juravinski Hospital and Cancer Centre, we are reporting preliminary data on patient-reported health-related quality of life (HRQoL). Objective: To measure longitudinal HRQoL in patients receiving CAR-T therapy. We expected HRQoL to worsen in the first 30 days, but improve long term. Methods: A prospective cohort observational study was conducted. Patients with relapsed or refractory large B-cell lymphoma, who were eligible for CAR-T therapy, tisagenlecleucel, were consecutively approached to participate. Demographic data and disease characteristics were collected. Patients received lymphodepleting chemotherapy on days -5 to -3. CAR-T cells were infused on Day 0. CRS and ICANS were assessed using ASTCT criteria. HRQoL was measured using FACT-Lym (Hlubocky et al., Leuk. Lymphoma 2013); a validated 42-item questionnaire answered by the patient on a 5-point Likert scale on days 0 (baseline), day 30, and months 3, 6 and 12. FACT-Lym includes FACT-G (physical, social, emotional and functional well-being domains), plus a lymphoma specific subscale (Lym-S). A score of 0 represents worst HRQoL and higher scores indicate an improvement (score range, 0-168). FACT-Lym Trial Outcome Index (TOI) is a combination of physical and functional well-being and Lym-S. Minimal important differences have been estimated using anchor (performance status and disease progression) and distribution methods for FACT-Lym (Carter et al., Blood 2008). Results: Among 34 patients registered to the study between January 2020 and June 2021, two did not receive their infusion due to progressive disease. Baseline demographics and disease characteristics are described in Table 1. Twenty-one (21/32, 65.7%) patients required bridging therapy prior to CAR-T infusion. Of the 32 patients who received CAR-T infusion, 22 (68.8%) received an outpatient CAR-T infusion; 18/22 (81.8%) were admitted to hospital. 26/32 (81.2%) developed any grade CRS; 6/32 (18.8%) developed grade 3 or 4 CRS. 6/32 (18.8%) developed grade 1 or 2 ICANS and no one developed grade 3 or 4 ICANS. Ten patients died and one withdrew. The remaining 23 patients were followed for one year. Ethics approval for the FACT-Lym questionnaire administration was pending when the first four patients were recruited. Of the 28 patients approached to complete the FACT-lym questionnaire, 26 (92.9%) completed a baseline and at least one follow-up. Fifteen (15/26, 57.7%) completed the 12-month questionnaire. Two remain on study protocol. Attrition was due to death in six patients, two were unknown, and one was due to withdrawal. The median (IQR) FACT-Lym score at baseline was 129 (106, 146), then worsened at day 30, 117.5 (97, 142), and unexpectedly did not improve beyond baseline by month 3, 128 (108, 156). Scores improved by month 6, 136 (114, 154) and month 12, 141.5 (100, 158). Figure 1 illustrates median change from baseline for FACT-Lym total scores and domains. Median change in FACT-Lym total scores at month 12 and FACT-TOI score at months 6 and 12 surpassed a minimal important difference. Conclusions: After initial worsening of HRQoL in patients who received CAR-T therapy, improvements were seen at 6 and 12 months. Future analyses will explore associations between HRQoL and baseline markers, toxicity and treatment response. These results will help enrich our understanding of the patient CAR-T experience and aid in complex and shared decision-making. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A public resource of baseline data from the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial.

The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Trial evaluated the anti-oligomeric amyloid beta (Aβ) antibody therapy crenezumab in cognitively unimpaired members of the Colombian presenilin 1 (PSEN1) E280A kindred. We report availability, methods employed to protect confidentiality and anonymity of participants, and process for requesting and accessing baseline data. We developed mechanisms to share baseline data from the API ADAD Trial in consultation with experts and other groups sharing data from Alzheimer's disease (AD) prevention trials, balancing the need to protect anonymity and trial integrity with making data broadly available to accelerate progress in the field. We pressure-tested deliberate and inadvertent potential threats under specific assumptions, employed a system to suppress or mask both direct and indirect identifying variables, limited and firewalled data managers, and put forth specific principles requisite to receive data. Baseline demographic, PSEN1 E280A and apolipoprotein E genotypes, florbetapir and fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, clinical, and cognitive data can now be requested by interested researchers. Baseline data are publicly available; treatment data and biological samples, including baseline and treatment-related blood-based biomarker data will become available in accordance with our original trial agreement and subsequently developed Collaboration for Alzheimer's Prevention principles. Sharing of these data will allow exploration of important questions including the differential effects of initiating an investigational AD prevention therapy both before as well as after measurable Aβ plaque deposition.

Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration.

Dementia is a growing socioeconomic challenge that requires early intervention. Identifying biomarkers that reliably predict clinical progression early in the disease process would better aid selection of individuals for future trial participation. Here, we compared the ability of baseline, single time-point biomarkers (CSF amyloid 1-42, CSF ptau-181, white matter hyperintensities (WMH), cerebral microbleeds, whole-brain volume, and hippocampal volume) to predict decline in cognitively normal individuals who later converted to mild cognitive impairment (MCI) (CNtoMCI) and those with MCI who later converted to an Alzheimer disease (AD) diagnosis (MCItoAD). Standardized baseline biomarker data from AD Neuroimaging Initiative 2 (ADNI2)/GO and longitudinal diagnostic data (including ADNI3) were used. Cox regression models assessed biomarkers in relation to time to change in clinical diagnosis using all follow-up time points available. Models were fit for biomarkers univariately and together in a multivariable model. Hazard ratios (HRs) were compared to evaluate biomarkers. Analyses were performed separately in CNtoMCI and MCItoAD groups. For CNtoMCI (n = 189), there was strong evidence that higher WMH volume (individual model: HR 1.79, p = 0.002; fully adjusted model: HR 1.98, p = 0.003) and lower hippocampal volume (individual: HR 0.54, p = 0.001; fully adjusted: HR 0.40, p < 0.001) were associated with conversion to MCI individually and independently. For MCItoAD (n = 345), lower hippocampal (individual model: HR 0.45, p < 0.001; fully adjusted model: HR 0.55, p < 0.001) and whole-brain volume (individual: HR 0.31, p < 0.001; fully adjusted: HR 0.48, p = 0.02), increased CSF ptau (individual: HR 1.88, p < 0.001; fully adjusted: HR 1.61, p < 0.001), and lower CSF amyloid (individual: HR 0.37, p < 0.001; fully adjusted: HR 0.62, p = 0.008) were most strongly associated with conversion to AD individually and independently. Lower hippocampal volume was a consistent predictor of clinical conversion to MCI and AD. CSF and brain volume biomarkers were predictive of conversion to AD from MCI, whereas WMH were predictive of conversion to MCI from cognitively normal. The predictive ability of WMH in the CNtoMCI group may be interpreted as some being on a different pathologic pathway, such as vascular cognitive impairment.

Plasma thrombomodulin levels are associated with acute kidney injury in patients with acute heart failure

Cardiorenal syndrome type I (CRS I) is defined as the development of acute kidney injury (AKI) following acute decompensated heart failure (ADHF). The clinical significance of endothelial markers in ADHF-associated AKI has yet to be clarified. This study therefore investigated the biological processes linking ADHF and AKI with the aim of determining whether the plasma markers of endothelial injury and activation are associated with AKI in patients with ADHF. The study prospectively recruited 125 consecutive patients admitted to a coronary critical unit due to ADHF. Patients with and without AKI were compared in terms of soluble thrombomodulin (sTM), angiopoietin (Ang)-1 and −2 plasma levels as well as baseline characteristics. Among the study population, 14 (11.2%) patients developed CRS within 7 days after admission. The hemoglobin levels (median [IQR]11.3[10.8–12.6] vs. 13.5 [12.2–15.0] g/dL, p = 0.003) and baseline eGFR (66.5[35.7–87.9] vs. 78.5 [64.9–107.5] mL/minute/1.73m2, p = 0.044) of patients with CRS were lower than those of patients without CRS. Patients with CRS also presented elevated plasma levels of BNP (1317.5 [222.6–3375.5] vs. 258.2 [63.2–925.8] pg/mL, p = 0.008), Ang-2 (3993.0 [1561.3–15722.7] vs. 1805.9 [1196.9–3302.3] pg/mL, p = 0.006), and sTM (6665.7 [4707.1–11947.3] vs. 4132.2 [3338.0–5531.8] ng/mL, p < 0.001), compared to patients without CRS. Multivariate logistic regression analysis based on forward stepwise method identified that log sTM was the only independent risk factor for AKI (OR, 13.83; 3.02–63.28, p = 0.001). Furthermore, higher sTM levels were associated with AKI in patients with ADHF. These findings suggest a novel approach to dealing with kidney injury in the context of ADHF, involving the use of baseline biomarker profiles to identify individuals at risk of developing AKI. KEY MESSAGES The clinical significance of endothelial markers in acute decompensated heart failure (ADHF)-associated acute kidney injury (AKI) has not previously been clarified. This study revealed that markers of endothelial injury (i.e. plasma soluble thrombomodulin (sTM) levels) were higher in ADHF patients with AKI than in those without AKI. Multivariate analysis identified sTM level > cutoff value of 4,855.2 pg/mL as an independent factor associated with the development of AKI. sTM could potentially be used as a biomarker to predict the development of AKI in patients with heart failure. These findings suggest a novel approach to dealing with kidney injury in the context of ADHF, involving the use of baseline biomarker profiles to identify individuals at risk of developing AKI.

Abstract 11933: Cardiac and Fibrosis-Related Biomarker Levels Do Not Predict Disease Development in Presymptomatic Phospholamban Cardiomyopathy

Introduction: Phospholamban (PLN) cardiomyopathy is an inherited cardiomyopathy with malignant arrhythmias and/or heart failure due to fibrosis. There is no proven treatment against disease progression. The i-PHORECAST trial investigated whether the antifibrotic properties of eplerenone prevent disease development in presymptomatic mutation carriers using late gadolinium enhancement (LGE) as a measure of cardiac fibrosis. As part of this study, several biomarkers linked to cardiac damage and fibrosis were measured to investigate their prognostic use. Hypothesis: We assessed if biomarkers linked to cardiac damage and fibrosis enable early detection of overt PLN cardiomyopathy. Methods: Presymptomatic PLN mutation carriers (N=84, age 39 [27-50] years, 44% male) were randomized to receive eplerenone or no treatment. Biomarkers (NT-pro-BNP, troponin, TP1NP, GDF-15, and IL-6) were measured from blood samples at baseline (N=84) and after a three year follow up (N=57, age 37 [26-46] years, 49% male). Composite endpoints included changes in LVEDV/RVEDV/LVEF/RVEF, new LGE, QRS voltage, symptoms requiring treatment, ventricular ectopy, and cardiovascular death. Results: No clinically relevant and statistically significant differences between treatment groups, Table 1 . No significant association between baseline biomarker measurements and LVEF decrease or the development of new LGE, Figure 1 . Conclusions: Levels of NT-pro-BNP, troponin, TP1NP, GDF-15, and IL-6 are not associated with development of cardiac fibrosis or left ventricular dysfunction in presymptomatic PLN mutation carriers, thus do not enable early detection of overt PLN cardiomyopathy.

Abstract 14726: Serial Assessment of Cardiac Biomarkers and Risk of Cardiovascular Death or Hospitalization for Heart Failure in DECLARE-TIMI 58

Introduction: Circulating cardiovascular (CV) biomarkers, including N-terminal pro-B type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT), are associated with risk of heart failure (HF) events in patients (pts) with type 2 diabetes (T2D). Less is known about the prognostic significance of changes in these biomarkers over time or the early effects of the SGLT2i dapagliflozin (dapa) on these markers. Methods: DECLARE-TIMI 58 was a randomized, placebo-controlled trial of dapa in 17,160 pts with T2D (median f/u = 4.2y). NT-proBNP &amp; hsTnT (Roche) were measured at baseline &amp; 6 mo. The outcome of interest was CV death (CVD) or hosp for HF (HHF). Outcome analyses were performed from a landmark of the 6-mo study visit with pts categorized by change in each biomarker over the first 6 mo. Hazard ratios were adjusted for baseline biomarker value, randomized treatment, age, sex, race, smoking, eGFR, prior HF, BMI, T2D duration, insulin use, CAD, prior MI, ischemic stroke, PAD, dyslipidemia, &amp; hypertension. Linear mixed models were used to assess the effect of dapa on log-transformed NT-proBNP &amp; hsTnT. Results: Serial NT-proBNP &amp; hsTnT values were available in 13,459 pts (78%). Among pts allocated to placebo (n=6,698), NT-proBNP was more dynamic than hsTnT (≥20% change from baseline in 71% vs. 33% of pts; p&lt;0.001). In the full cohort, independent of randomized treatment, there was a stepwise graded relationship between change in NT-proBNP &amp; hsTnT and risk of CVD/HHF, whereby increases in either biomarker were associated with higher risk and decreases in either biomarker were associated with lower risk (p-trend for adj-HR &lt;0.001 for each). Considered together, changes in the 2 markers were complementary ( Fig ; p&lt;0.001). Dapa significantly reduced NT-proBNP (relative LS mean change, -6% [-4% to -8%]; p&lt;0.001) but not hsTnT (0% [-1% to +1%]; p=0.92) over 6 mo. Conclusions: Early changes in hsTnT &amp; NT-proBNP are associated with subsequent risk of CVD/HHF in pts with T2D.

Early Diagnosis of Chemotherapy-Linked Cardiotoxicity in Breast Cancer Patients Using Conventional Biomarker Panel: A Prospective Study Protocol

The prognosis of cancer treatment depends on, among other aspects, the cardiotoxicity of chemotherapy. This research aims to create a feasible algorithm for the early diagnosis of antitumor therapy cardiotoxicity in breast cancer patients. The paper represents a protocol for a prospective cohort study with N 120 eligible participants admitted for treatment with anthracyclines and/or trastuzumab. These patients will be allocated into four risk groups regarding potential cardiotoxic complications. Patients will be examined five times every three months for six biomarkers,: cardiac troponin I (cTnI), brain natriuretic peptide (BNP), C-reactive protein (CRP), myeloperoxidase (MPO), galectin-3 (Gal-3), and D-dimer, simultaneously with echocardiographic methods, including speckle tracking. The adjusted relative risk (aOR) of interrupting an entire course of chemotherapy due to cardiotoxic events will be assessed using multiple analyses of proportional Cox risks. The Cox model will also assess associations between baseline biomarker values and time to cardiotoxic events. Moreover, partly conditional survival models will be applied to determine associations between repeated assessments of changes in biomarkers from baseline and time to cancer therapy-related cardiac dysfunction. All models will be adjusted for cancer therapy regimen, baseline LVEF, groups at risk, baseline biomarker values, and age. The decision-tree and principal component analysis (PCA) methods will also be applied. Thus, feasible patterns will be detected.

EFFECT OF TEZEPELUMAB ON ASTHMA INFLAMMATORY BIOMARKER LEVELS VARIES BY BASELINE BIOMARKER LEVELS

<h3>Introduction</h3> In the phase 3 NAVIGATOR study, tezepelumab reduced exacerbations irrespective of baseline biomarkers, and substantially reduced levels of inflammatory biomarkers (blood eosinophil count [BEC], fractional exhaled nitric oxide [FeNO], and serum total immunoglobulin E [IgE]) in patients with severe, uncontrolled asthma. This <i>post hoc</i> analysis assessed the effect of tezepelumab on biomarker levels in patients grouped by baseline biomarker levels. <h3>Methods</h3> NAVIGATOR (NCT03347279) was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12–80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Changes from baseline to week 52 in BEC, FeNO levels and serum total IgE levels were assessed in patients grouped by baseline levels of the respective biomarker. <h3>Results</h3> Overall, 1059 patients received either tezepelumab (n=528) or placebo (n=531). At week 52, tezepelumab reduced BEC, FeNO levels and serum total IgE levels in those with elevated biomarkers at baseline (<b>Figure</b>). Mean relative reductions from baseline with tezepelumab were generally greater in those with higher baseline biomarker levels versus those with lower baseline biomarker levels. For the lowest baseline BEC and FeNO level subgroups, small decreases from baseline were observed with tezepelumab, while placebo recipients demonstrated an increase from baseline at week 52. <h3>Conclusion</h3> Tezepelumab reduced levels of all key inflammatory biomarkers in patients with severe, uncontrolled asthma, with greater reductions in patients with higher baseline levels of the respective biomarker. These data further support the anti-inflammatory effects of tezepelumab in patients with severe asthma.

High Baseline TNF-α Levels may Associate with Poor Outcomes after Total Neoadjuvant Therapy for Gastroesophageal Cancer: Initial Biomarker Analysis from a Prospective Study

<h3>Purpose/Objective(s)</h3> We previously reported the feasibility and early efficacy of neoadjuvant FOLFIRINOX followed by CRT for gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, response to neoadjuvant therapies in these cancers is heterogenous and response biomarkers are needed. We previously identified candidate blood inflammatory and angiogenesis biomarkers in gastric and GEJ adenocarcinoma patients. Here, we investigated circulating inflammatory and angiogenesis cytokines as biomarkers of response to neoadjuvant chemoradiation. <h3>Materials/Methods</h3> We enrolled patients on an NCI-sponsored, prospective, single arm study (NCT03279237). Key eligibility criteria included: histologically confirmed T3/4 or lymph node (LN) positive gastric or GEJ adenocarcinoma, and ECOG PS ≤1. Extensive LN disease beyond the surgical field (supraclavicular or para-aortic) was permitted if deemed able to be encompassed within the radiotherapy field. Patients received neoadjuvant FOLFIRINOX x 8 cycles, restaging, CRT (45 Gy for gastric, 50.4 Gy for GEJ) with concurrent C/T, restaging, followed by surgical resection. We collected blood samples at baseline and at pre-defined time-points during chemoradiation, including C1D1, C1D8, restaging, and at time of disease progression. For this analysis, we measured baseline levels of proinflammatory markers, including IFN-ɣ, IL-10, IL-12p70, IL-4, IL-6, IL-8, and TNF-α; growth factors and soluble receptors including bFGF, sFLT1, PlGF, VEGF-A, VEGF-C, VEGF-D; HGF, TGF-β, and Ang-2. Baseline biomarker levels were correlated with clinical endpoints: pathologic complete response (pCR) and progression-free survival (PFS). Given the exploratory nature of this analysis, p≤0.10 was considered statistically significant. <h3>Results</h3> From October 2017 to June 2018, 25 pts were enrolled, with baseline assays available on 24 pts. With a median follow up of 43.1 months (range: 36.6-50.2), there were 7 patients who had a pCR, 11 patients with disease progression, and 11 patients who have died. In our initial exploratory analysis, none of the candidate biomarkers was different between patients who showed a pCR after chemoradiation versus those who did not (p-value: range 0.28-1.00). However, we found that a plasma TNF-α level above median was associated with worse PFS rates at 12 months (42% versus 83%) and at 24 months (33% versus 75%) (n=12, p=0.06). <h3>Conclusion</h3> Prior studies have suggested associations between inflammation biomarkers and outcomes. Among patients with gastroesophageal adenocarcinoma treated with total neoadjuvant therapy, higher baseline of circulating TNF-α may be associated with worse PFS. Further exploration of TNF-a as a biomarker or therapeutic target in model systems may be warranted to further understand our observations.

Use of serial changes in biomarkers vs. baseline levels to predict left ventricular remodelling after STEMI.

Cellular communication network factor 1 (CCN1) is an independent predictor of MACE after ACS and elevated levels correlated with infarct size after STEMI. We compared the prognostic accuracy of baseline levels of CCN1, NT-proBNP, hsTnT, and ST2 and changes in levels over time to predict the development of structural and functional alterations typical of LV remodelling. Serial 3-T cMRI scans were performed to determine LVEF, LVEDV, LVESV, infarct size, and relative infarct size, which were correlated with serial measurements of the four biomarkers. The prognostic significance of these biomarkers was assessed by multiple logistic regression analysis by examining their performance in predicting dichotomized cardiac MRI values 12months after STEMI based on their median. For each biomarker three models were created using baseline (BL), the Δ value (BL to 6months), and the two values together as predictors. All models were adjusted for age and renal function. Receiver operator curves were plotted with area under the curve (AUC) to discriminate the prognostic accuracy of individual biomarkers for MRI-based structural or functional changes. A total of 44 predominantly male patients (88.6%) from the ETiCS (Etiology, Titre-Course, and Survival) study were identified at a mean age of 55.5±11.5 (SD) years treated by successful percutaneous coronary intervention (97.7%) at a rate of 95.5% stent implantation within a median pain-to-balloon time of 260min (IQR 124-591). Biomarkers hsTnT and ST2 were identified as strong predictors (AUC>0.7) of LVEDV and LVEF. BL measurement to predict LVEF [hsTnT: AUC 0.870 (95% CI: 0.756-0.983), ST2: AUC 0.763 (95% CI: 0.615-0.911)] and the Δ value BL-6M [hsTnT: AUC 0.870 (95% CI: 0.756-0.983), ST2: AUC 0.809 (95% CI: 0.679-0.939)] showed a high prognostic value without a significant difference for the comparison of the BL model vs. the Δ-value model (BL-6M) for hsTnT (P=1) and ST2 (P=0.304). The combined model that included baseline and Δ value as predictors was not able to improve the ability to predict LVEF [hsTnT: AUC 0.891 (0.791-0.992), P=0.444; ST2: AUC 0.778 (0.638-0.918), P=0.799]. Baseline levels of CCN1 were closely associated with LVEDV at 12months [AUC 0.708 (95% CI: 0.551-0.865)] and infarct size [AUC 0.703 (95% CI: 0.534-0.872)]. Baseline biomarker levels of hsTnT and ST2 were the strongest predictors of LVEF and LVEDV at 12months after STEMI. The association of CCN1 with LVEDV and infarct size warrants further study into the underlying pathophysiology of this novel biomarker.

The effect of microbiome-modulating probiotics, prebiotics and synbiotics on glucose homeostasis in type 2 diabetes: A systematic review, meta-analysis, and meta-regression of clinical trials

Aim/hypothesisThe globally escalating diabetes epidemic is responsible for significant morbidity and mortality. Microbiome-modulating nutraceuticals have been investigated for their potential to restore metabolic and floral homeostasis in type 2 diabetic patients MethodsA systematic review, meta-analyses and meta-regressions were conducted to investigate the effect of probiotics, prebiotics, and synbiotics on various biomarkers of glucose homeostasis based on a multi-database search of clinical trials published through April 10, 2022. Data was pooled using random effects meta-analyses and reported as mean differences with 95% confidence intervals (CIs), followed by univariate linear model meta-regression. ResultsData from 68 trial comparisons across 58 studies (n = 3835) revealed that, compared to placebo/control group, administration of pro/pre/synbiotics was associated with statistically significant changes in fasting plasma glucose (−12.41 mg/dl [95% CI: −15.94; −8.88], p 0.0001), glycated hemoglobin (−0.38% [95% CI: −0.47; −0.30], p 0.0001), fasting insulin (−1.49 µU/mL [95% CI: −2.12; −0.86], p 0.0001), HOMA-IR (−0.69 [95% CI: −1.16; −0.23], p = 0.0031) and QUICKI (0.0148 [95% CI: 0.0052; 0.0244], p = 0.0025), but not C-peptide (−0.0144 ng/mL [95% CI: −0.2564; −0.2275], p = 0.9069). Age, baseline BMI, baseline biomarker value, pro/prebiotic dosage, trial duration, nutraceutical type, and recruitment region significantly affected the potential of pro/pre/synbiotics use as personalized diabetes adjunct therapy. Lastly, we discuss unexplained observations and directives for future trials, with the aim of maximizing our understanding of how microbiome-modulating nutraceuticals can treat various metabolic diseases ConclusionsPro/pre/synbiotic supplementation improved glucose homeostasis in diabetic patients. Our results support their potential use as adjunct therapy for improving glycemia and insulinemia alongside pharmacological therapeutics.

Serum Tau, Neurofilament Light Chain, Glial Fibrillary Acidic Protein, and Ubiquitin Carboxyl-Terminal Hydrolase L1 Are Associated with the Chronic Deterioration of Neurobehavioral Symptoms after Traumatic Brain Injury.

The purpose of this study was to examine the association of serum tau, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L1 (UCHL-1) concentrations evaluated within the first 12 months after a military-related TBI, with longitudinal changes in neurobehavioral functioning extending two or more years post-injury. Participants were 84 United States service members and veterans (SMVs) prospectively enrolled in the Defense and Veterans Brain Injury Center of Excellence/Traumatic Brain Injury Center 15-Year Longitudinal TBI Study, separated into three discreet groups: (a) uncomplicated mild TBI (MTBI; n = 28), (b) complicated mild, moderate, severe, and penetrating TBI combined (STBI; n = 29], and (c) non-injured controls (NIC, n = 27). Participants completed a battery of self-report neurobehavioral symptom measures (e.g., depression, post-traumatic stress disorder [PTSD], post-concussion, anxiety, somatic, cognitive, and neurological symptoms) within 12 months of injury (baseline), and then again at two or more years post-injury (follow-up). At baseline, participants also completed a blood draw to determine serum concentrations of tau, NFL, GFAP, and UCHL-1 using an ultra-sensitivity assay method. In the MTBI and STBI groups (using hierarchical regression analyses), (1) baseline tau concentrations predicted the deterioration of neurobehavioral symptoms from baseline to follow-up on measures of anxiety, PTSD, depression, post-concussion, somatic, and neurological symptoms (accounting for 10-28% of the variance); (2) NFL predicted the deterioration of depression, post-concussion, somatic, cognitive, and neurological symptoms (10-32% variance); (3) GFAP predicted the deterioration of post-concussion, PTSD, depression, anxiety, somatic, neurological, and cognitive symptoms (11-43% variance); and (4) UCHL-1 predicted the deterioration of anxiety, somatic, and neurological symptoms (10-16% variance). In the NIC group, no meaningful associations were found between baseline biomarker concentrations and the deterioration of neurobehavioral symptoms on the majority of measures. This study reports that elevated tau, NFL, GFAP, and UCHL-1 concentrations within the first 12 months of injury are associated with the deterioration of neurobehavioral symptoms that extends to the chronic phase of recovery after a TBI. These findings suggest that a blood-based panel including these biomarkers could be a useful prognostic tool to identifying those individuals at risk of poor future outcome after TBI.

CSF Alzheimer Disease Biomarkers: Time-Varying Relationships With MCI Symptom Onset and Associations With Age, Sex, and ApoE4.

This study aimed to examine whether baseline CSF measures of Alzheimer disease (AD)-related pathology are associated with the time to onset of mild cognitive impairment (MCI) and whether these associations differ by age, sex, Apolipoprotein E (ApoE4) status, and proximal (≤7 years) vs distal (>7 years) time to symptom onset. Measures of amyloid (Aβ1-42 and Aβ1-40), phospho-tau (ptau181), and total tau (t-tau) were determined from CSF samples obtained at baseline from participants in an ongoing longitudinal project, known as the Biomarkers for Older Controls at Risk for Alzheimer Disease study (BIOCARD) study. The fully automated, Lumipulse G immunoassay was used to analyze the specimens. Cox regression models were used to examine the relationship of baseline biomarker levels with time to symptom onset of MCI and interactions with age, sex, and ApoE allelic status in subjects who progressed from normal cognition to MCI. Analyses included 273 participants from the BIOCARD cohort, who were cognitively normal and predominantly middle-aged at baseline, and have been followed for an average of 16 years (max = 23.6). During follow-up, 94 progressed to MCI (median time to symptom onset = 6.9 years). In Cox regression models, elevated ptau181 and t-tau levels were associated with time to MCI symptom onset if it occurred within 7 years of baseline (HR 1.386 and 1.329; p = 0.009 and 0.017, respectively), while a lower Aβ42/Aβ40 ratio was associated with symptom onset if it occurred >7 years from baseline (HR 0.596, p = 0.003). There were also significant 3-way CSF × age × sex interactions for ptau181 and Aβ42/Aβ40, with follow-up analyses indicating that associations between these biomarkers and progression to MCI were stronger among men than among women, but this difference between sexes diminished with increasing age. The lengthy follow-up of BIOCARD participants permitted an examination of time-varying associations between CSF AD biomarkers with MCI symptom onset and the influence of sex, baseline age, and ApoE4 genotype on these associations. These factors may inform clinical trial enrollment strategies, or trial duration and outcomes, which may use these measures as surrogate markers of treatment response.

Determinants of post-operative atrial fibrillation in 1613 patients undergoing coronary artery bypass grafting in the Statin Therapy In Cardiac Surgery (STICS) trial

Abstract Introduction Post-operative atrial fibrillation (POAF) occurs in 20–40% of patients in the first week after cardiac surgery, and is associated with longer hospital stay, higher stroke risk, and worse overall prognosis. The surgery-related inflammatory response has been strongly implicated in POAF pathogenesis; however, lower CRP levels resulting from perioperative rosuvastatin therapy in the Statin Therapy In Cardiac Surgery (STICS) randomized trial were not associated with a reduced incidence of POAF. Furthermore, POAF independently predicts subsequent clinical AF and as such may reflect the presence of a subclinical cardiomyopathic substrate. We tested this hypothesis by investigating determinants of POAF in 1613 patients who underwent isolated coronary artery bypass grafting in China in the STICS trial. Methods Clinical data included age, sex, body mass index, medical history, medications, and type of surgery (on-pump vs off-pump). Blood taken prior to surgery was assayed for troponin I, N-terminal pro–brain natriuretic peptide (NT-proBNP), creatinine, low-density lipoprotein (LDL) cholesterol, and serum CD40 ligand. The biomarkers growth differentiation factor 15, interleukin-6, procalcitonin, and placental growth factor were measured at baseline and at 6 hours after surgery. Echocardiography evaluated left ventricular ejection fraction (LVEF) and left atrial (LA) size. POAF was detected by continuous Holter electrocardiographic monitoring for 5 days after surgery. Results POAF occurred in 314 of 1613 patients (19%). As expected, age was the single strongest predictor of POAF (C-statistic 0.66 [95% CI 0.62–0.70]). After adjustment for age, NT-proBNP, LA size, Troponin, LVEF, sex, calcium-channel blocker use, and prior myocardial infarction were all significantly associated with POAF when assessed individually (all P&amp;lt;0.05). In multivariate analysis, a basic model incorporating only age, NT-proBNP, and LA size had a C-statistic of 0.69 (95% CI 0.66–0.73). This performance was not significantly different to that of models including all available variables, irrespective of whether baseline or post-surgery biomarker results were used (all C-statistics 0.71 [95% CI 0.68–0.75]; Table 1). The basic model numerically outperformed more complex risk prediction scores including CHARGE-AF (0.66, 95% CI 0.63–0.70; Figure 1), POAF score (0.64, 95% CI 0.61–0.68), CHA2DS2-VASc (0.60, 95% CI 0.57–0.63), and AF risk index (0.57, 95% CI 0.54–0.60). Conclusions A basic model requiring only age, NT-proBNP, and LA size has good predictive value for POAF in this population, comparing well to more complex risk prediction scores. More broadly, these results suggest that systemic inflammation and perioperative myocardial injury may be less relevant to the pathogenesis of POAF than the effects of aging and cardiac structural and functional changes. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

PASSAGE: A PHASE 4, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE THE EFFECTIVENESS AND SAFETY OF TEZEPELUMAB IN PATIENTS WITH SEVERE ASTHMA, INCLUDING UNDER-REPRESENTED GROUPS

PASSAGE: A PHASE 4, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE THE EFFECTIVENESS AND SAFETY OF TEZEPELUMAB IN PATIENTS WITH SEVERE ASTHMA, INCLUDING UNDER-REPRESENTED GROUPS

788O Association of pre-treatment ctDNA with disease recurrence and clinical and translational factors in patients with stage IIIB-D/IV melanoma treated with adjuvant immunotherapy (CheckMate 915)

In patients (pts) with resectable melanoma, circulating tumor DNA (ctDNA) detection post-resection may be useful to inform disease state and recurrence risk. Post-resection pre-treatment plasma from 1127 pts with stage IIIB-D/IV resected melanoma treated with nivolumab + ipilimumab vs nivolumab in the phase 3 CheckMate 915 study (NCT03068455) was retrospectively evaluated for ctDNA status and level, using a tumor-guided, pt-specific panel of up to 200 variants (Invitae Personalized Cancer MonitoringÔ). Kaplan-Meier and Cox regression models were used to evaluate the association between ctDNA status and recurrence-free survival (RFS), alone and combined with baseline clinical factors and biomarkers, including interferon-γ, TMB, tumor PD-L1, CD8+ T cells, tumor thickness, ulceration, and lymph node involvement. Overall pre-treatment ctDNA prevalence was ∼16% (95% CI: 14%–18%) and similar across most baseline demographics. A trend of greater ctDNA+ prevalence in higher stage III substages of melanoma was observed (IIIB = 11% [35/333], IIIC = 18% [110/596], IIID = 41% [13/32]). Pre-treatment ctDNA was associated with an increased risk of recurrence (HR 1.87, 95% CI: 1.48–2.36; Table). No significant interaction between ctDNA status and treatment arm was seen (ratio of hazard ratios: 0.99, 95% CI: 0.63–1.57). Patients with ctDNA present exhibited a greater rate of recurrence, seen as early as week 13 of therapy (Table). Distant metastasis-free survival results were similar. In composite analyses, improved RFS prediction was observed after combining ctDNA with clinical factors and biomarkers.Table: 788ORFS probability by pre-treatment ctDNA status in CheckMate 915 treated patientsStatusNumber of pts (n)13-week RFS (95% CI)12-month RFS (95% CI)24-month RFS (95% CI)ctDNA+18372.3% (65–78.3)58.4% (50.7–65.3)45.5% (37.9–52.8)ctDNA-94491.7% (89.7–93.3)75.1% (72.1–77.8)65.4% (62.1–68.4) Open table in a new tab Pre-treatment ctDNA was associated with increased risk of early recurrence across treatment arms. ctDNA is a useful biomarker for combined analyses predicting outcome for adjuvant melanoma.

Abstract P120: Left Ventricular Hypertrophy Is Associated With Higher Cardiac Biomarkers In Patients With Covid-19

Introduction: Left ventricular hypertrophy (LVH) is a risk factor for adverse cardiovascular outcomes such as heart failure and arrhythmia. LVH is characterized by increased left ventricular mass with myocardial fibrosis and may contribute to COVID-19-induced cardiac injury. Hypothesis: LVH is a predictor of poor outcomes in patients with COVID-19. Methods: We conducted a two-center retrospective study of 415 adult patients hospitalized with COVID-19 from March 2020 to September 2021 who had an echocardiogram performed while inpatient. Baseline characteristics, biomarkers, and hospitalization outcomes were described. LVH was diagnosed by linear measurements with echocardiography. Statistical analyses were performed using SAS 9.4 and SPSS 28. Differences between groups were determined by one-way ANOVA, Wilcoxon rank-sum, or Fisher exact test. Results: LVH was present in 34.2% (142/415) of patients. Compared to those without LVH, those with LVH were older (64 vs 68 years, p=0.02), heavier (84.4 vs 89.6 kg, p=0.03), and more likely to be diabetic (39.6% vs 50.0%, p=0.04), hypertensive (61.5% vs 71.8%, p=0.04), and smokers (5.1% vs 12.0%, p=0.02). NT-proBNP (1342 vs 721, p=0.02) and peak troponin I (0.03 vs 0.01, p=0.002) levels were higher in the LVH group. The LVH group had increased rates of myocardial infarction (7% vs 4%), new-onset heart failure (8.5% vs 7.3%), and mortality (35.9% vs 30%), although these findings were not statistically significant. Similarly, logistic regression models showed a sustained effect of age (OR 1.17 [CI 1.02-1.34], for every 10 years), diabetes (OR 1.53 [CI 1.02-2.29]), hypertension (OR 1.59 [CI 1.03-2.4]), and smoking (OR 2.52 [CI 1.2-5.3]) in patients with LVH; however, there was no difference between groups for all outcomes measured. Conclusion: LVH was significantly associated with other cardiovascular risk factors and increased cardiac biomarkers, suggesting a higher degree of cardiac injury in LVH patients with COVID-19. Although there was a higher rate of cardiovascular events and mortality in patients with LVH, these findings were not statistically significant. Studies with a larger sample size are needed to determine whether LVH is an independent predictor of COVID-19-induced cardiac injury.

Abstract IA12: Prognostic and predictive biomarkers for cabozantinib in HCC

Abstract In recent years, the therapeutic landscape for patients with advanced/unresectable hepatocellular carcinoma (HCC) has become more complex, novel immunotherapy combinations have demonstrated their activity and represent a new standard of care, such as atezolizumab plus bevacizumab, or will soon be included in the treatment algorithm, such as durvalumab plus tremelimumab. For other combinations such as cabozantinib plus atezolizumab, a progression-free survival (PFS) benefit not associated with an improvement in overall survival (OS) was shown. However, tyrosine kinase inhibitors, including cabozantinib, still remain important therapeutic options in the management of patients with advanced HCC. In this field there is a lack of prognostic and predictive biomarkers and alpha-fetoprotein (AFP) remains the most widely used prognostic biomarker in clinical practice and the only predictive biomarker available only for ramucirumab. Cabozantinib inhibits receptor tyrosine kinases implicated in HCC progression, tumor immunosuppression, and resistance to antiangiogenic therapy, including VEGF receptors 1–3, MET, and the TAM family kinases TYRO3, AXL, and MER. Cabozantinib significantly improved OS and PFS compared to placebo in patients with previously treated advanced HCC in the phase 3 CELESTIAL trial. In the presented exploratory analyses, outcomes were evaluated according to baseline plasma biomarker levels and changes during treatment at week 4 or 8. Biomarkers chosen for the study included AFP, cabozantinib targets and their ligands, and other plasma proteins with prognostic significance in HCC. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at week 4 or 8 as continuous variables; multivariable analyses adjusted for clinical covariates were also performed. Finally, outcomes were also evaluated based on clinical factors as ALBI grade and adverse events. Several biomarkers or clinical factors at baseline or during treatment were identified as prognostic and associated with different OS and/or PFS. Low baseline levels of AFP, MET, HGF, GAS6, IL-8, ANG2, high levels of IGF-1, and ALBI grade 1 were identified as potential favorable prognostic biomarkers/factors in previously treated advanced HCC. However, hazard ratios for OS and PFS favored cabozantinib over placebo at low and high baseline levels for all biomarkers, and no baseline biomarkers predicted treatment benefit. Cabozantinib induced pharmacodynamic changes in several biomarkers, but these changes were not associated with OS or PFS, except for AFP response which correlated with improved OS and PFS. The occurrence of some adverse events during treatment has been associated with longer OS and PFS with cabozantinib. Future studies should explore both circulating and tumor biomarkers related to angiogenic signaling, inflammation, and immune-cell function, in order to identify prognostic and predictive biomarkers to guide clinical decision-making and improve outcomes for patients with advanced HCC. Citation Format: Lorenza Rimassa. Prognostic and predictive biomarkers for cabozantinib in HCC [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA12.

Development of a Hybrid-Imaging-Based Prognostic Index for Metastasized-Melanoma Patients in Whole-Body 18F-FDG PET/CT and PET/MRI Data.

Besides tremendous treatment success in advanced melanoma patients, the rapid development of oncologic treatment options comes with increasingly high costs and can cause severe life-threatening side effects. For this purpose, predictive baseline biomarkers are becoming increasingly important for risk stratification and personalized treatment planning. Thus, the aim of this pilot study was the development of a prognostic tool for the risk stratification of the treatment response and mortality based on PET/MRI and PET/CT, including a convolutional neural network (CNN) for metastasized-melanoma patients before systemic-treatment initiation. The evaluation was based on 37 patients (19 f, 62 ± 13 y/o) with unresectable metastasized melanomas who underwent whole-body 18F-FDG PET/MRI and PET/CT scans on the same day before the initiation of therapy with checkpoint inhibitors and/or BRAF/MEK inhibitors. The overall survival (OS), therapy response, metastatically involved organs, number of lesions, total lesion glycolysis, total metabolic tumor volume (TMTV), peak standardized uptake value (SULpeak), diameter (Dmlesion) and mean apparent diffusion coefficient (ADCmean) were assessed. For each marker, a Kaplan–Meier analysis and the statistical significance (Wilcoxon test, paired t-test and Bonferroni correction) were assessed. Patients were divided into high- and low-risk groups depending on the OS and treatment response. The CNN segmentation and prediction utilized multimodality imaging data for a complementary in-depth risk analysis per patient. The following parameters correlated with longer OS: a TMTV < 50 mL; no metastases in the brain, bone, liver, spleen or pleura; ≤4 affected organ regions; no metastases; a Dmlesion > 37 mm or SULpeak < 1.3; a range of the ADCmean < 600 mm2/s. However, none of the parameters correlated significantly with the stratification of the patients into the high- or low-risk groups. For the CNN, the sensitivity, specificity, PPV and accuracy were 92%, 96%, 92% and 95%, respectively. Imaging biomarkers such as the metastatic involvement of specific organs, a high tumor burden, the presence of at least one large lesion or a high range of intermetastatic diffusivity were negative predictors for the OS, but the identification of high-risk patients was not feasible with the handcrafted parameters. In contrast, the proposed CNN supplied risk stratification with high specificity and sensitivity.

Serologic phenotypes distinguish systemic lupus erythematosus patients developing interstitial lung disease and/or myositis.

ObjectivesTo determine if serologic phenotypes could be identified in systemic lupus erythematosus patients developing interstitial lung disease (ILD) and/or myositis.MethodsAdult SLE patients (without myositis/ILD at baseline) had annual assessments and serum sampling between 2000 and 2017. New-onset ILD was identified using the SDI pulmonary fibrosis item. New-onset myositis was identified using the SLICC Damage Index muscle atrophy/weakness item, the SLEDAI-2K item for myositis, and annual creatinine kinase testing. Chart review confirmed ILD/myositis cases and randomly sampled SLE patients from baseline formed our sub-cohort (N = 72). Cases and sub-cohort were compared regarding myositis-related biomarkers at baseline and at a randomly selected follow-up between baseline and end of observation (date of ILD/myositis diagnosis or Dec. 31, 2017). Descriptive analyses and hazards ratios (HRs) were generated for ILD/myositis incidence, focusing on baseline serology and adjusting for sex, race/ethnicity, age at SLE diagnosis, and SLE duration.ResultsFourteen SLE patients developed ILD (N = 9), myositis (N = 3), and/or both (N = 2). Thirteen of those (92.9%) developing ILD/myositis had at least one biomarker at baseline, versus 47 (65.3%) SLE patients who never developed myositis/ILD. The most common biomarkers in myositis/ILD were KL-6, anti-Ro52, and anti-Ku. Baseline biomarkers tended to remain positive in follow-up. In multivariate Cox regressions, SLE patients had higher risk of developing myositis/ILD with elevated baseline KL-6 (adjusted hazard ratio 3.66; 95% confidence interval 1.01, 13.3). When updating biomarkers over time, we also saw correlations between anti-Smith and ILD/myositis.ConclusionsBaseline myositis-related biomarkers were highly associated with ILD/myositis incidence. This is the first identification of biomarker phenotypes with ILD/myositis risk in SLE.