Determinants Of Adverse Outcomes Research Articles

Effect of levothyroxine supplementation in extremely low birth weight infants with transient hypothyroxinemia of prematurity

This study aimed to determine the short- and/or long-term outcomes of levothyroxine replacement therapy in extremely low birth weight (ELBW) infants with transient hypothyroxinemia of prematurity (THOP). The medical records of 335 ELBW infants with THOP were reviewed retrospectively to identify whether levothyroxine treatment affects short- and/or long-term outcomes at a corrected age of 2 years. The infants were arbitrarily grouped based on thyroxine (T4) (free T4 [fT4]) levels into group 1 (n = 142), which included infants with T4 (fT4) levels < 2.5 (0.5) ng/dl, and group 2 (n = 193), which included those with T4 (fT4) levels ranging from ≥ 2.5 (0.5) ng/dl to < 4.5 (0.9) ng/dl. Levothyroxine replacement therapy was not associated with beneficial short- or long-term outcomes in ELBW infants with THOP. Short-term outcomes, such as mortality and composite morbidities, and long-term outcomes, such as failure to achieve catch-up height at a corrected age of 2 years, were significantly higher in group 1 than in group 2, regardless of levothyroxine treatment status. Levothyroxine replacement therapy is not associated with short-or long-term advantages in ELBW infants with THOP. This study suggests that the severity of THOP may be the major determinant of adverse outcomes in ELBW infants with THOP, rather than levothyroxine treatment.

Determinants of mortality after stereotactic radio-ablation for ventricular tachycardia. Results from the international MUSIC consortium

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council Background SBRT is currently restrained to the most severe patients with drug- and catheter ablation-refractory VT, often associated with advanced heart failure. Purpose To analyze the determinants of mortality after SBRT for VT. Methods Patients with drug- and catheter ablation-refractory VT underwent imaging prior to SBRT. The inHEART technology was used to create image-based 3D models of substrate, cardiac anatomy, and organs at risk (coronaries, phrenic nerve, GI tract, AV node). In MUSIC software (IHU Liryc-Inria), 3D models were fused with prior EP maps, and SBRT targets were interactively drawn in 3D by the referring EP cardiologist. Transmural target volumes and organs at risk were fused with a 4D planning CT and used to plan SBRT in Eclipse (Varian). SBRT was delivered with either Truebeam or Edge systems (Varian), at a total dose of 25 Gy in a single session. The determinants of adverse outcomes after SBRT were analyzed. Results 30 pts from 7 centers were included (age 70±10, 90% men). Mean LVEF was 26±9%. The VT etiology was ischemic in 67%, and non-ischemic or mixed in 47%. Patients had undergone a mean of 1.7±1.2 prior failed catheter ablation procedures. SBRT was delivered on median planning treatment volumes (PTVs) of 96[63-149] mL. Complications attributed to SBRT were observed in 2/30 (7%), none of which were fatal (heart failure and pneumonitis, both managed with steroids). Over a median FU of 4[2-8] months, death or heart transplant occurred in 11(37%) pts, attributed to VT recurrence in 4(13%), and heart failure in 7(23%). On univariate analysis, patients experiencing death or transplant after SBRT were older (77±6 vs. 66±9 years, P=0.001) and showed lower LVEF (22±6 vs. 29±10%, P=0.03). In contrast, mortality or transplant did not relate to the underlying VT etiology (P=0.30), the number of prior catheter ablations (P=0.20), the pre-SBRT VT burden (P=0.20) and the SBRT treatment volume (P=0.18). Conclusion In patients with severe drug- and catheter ablation-refractory VT undergoing cardiac SBRT, mortality is most often due to non-arrhythmic causes, and is more driven by age and LV dysfunction than by the VT substrate, pre-SBRT arrhythmia burden, and SBRT treatment volume.

Patient Sex and Postoperative Outcomes after Inpatient Intraabdominal Surgery: A Population-based Retrospective Cohort Study.

Intraabdominal surgeries are frequently performed procedures that lead to a high volume of unplanned readmissions and postoperative complications. Patient sex may be a determinant of adverse outcomes in this population, possibly due to differences in biology or care delivery, but it is understudied. The authors hypothesized that there would be no association between patient sex and the risk of postoperative adverse outcomes in intraabdominal surgery. This retrospective, population-based cohort study involved adult inpatients aged 18 yr or older who underwent intraabdominal surgeries in Ontario, Canada, between April 2009 and March 2016. The authors studied the association of patient sex on the primary composite outcome of all-cause death, hospital readmission, or major postoperative complications, all within 30 postoperative days. Inverse probability of exposure weighting based on propensity scores (computed using demographic characteristics such as rural residence status and median neighborhood income quintile, common comorbidities, and surgery- and hospital-specific characteristics) was used to estimate the adjusted association of sex on outcomes. The cohort included 215,846 patients (52.3% female). The primary outcome was observed in 24,712 (21.9%) females and 25,486 (24.7%) males (unadjusted risk difference, 2.8% [95% CI, 2.5 to 3.2%]; P < 0.001). After adjustment, the association between the male sex and the primary outcome was not statistically significant (adjusted risk difference, -0.2% [95% CI, -0.5 to 0.2%]; P = 0.378). In a large population of intraabdominal surgical patients, there was no differential risk between sexes in the composite outcome of all-cause death, hospital readmission, or major postoperative complications, all within 30 postoperative days.

Abstract 12969: Community-Level Socioeconomic Distress, Race, and Risk of Adverse Outcomes Following Heart Failure Hospitalization Among Medicare Beneficiaries

Background: Socioeconomic (SE) disadvantage is a strong determinant of adverse outcomes in patients with HF. The contribution of SE disparities to adverse outcomes in HF may differ among Black vs. White patients and has not been well studied. Methods: Using the 100% CMS MedPAR data, Black and White patients hospitalized with HF between 2014 and 2017 were identified and stratified based on the distressed community index (DCI)—a measure of the SE disadvantage of residential ZIP codes on a continuous scale (range 0-100, see Fig. legend)—into two groups: SE distressed (Q5) vs. non-distressed (Q1-4). The rates of 30-day and 1-year mortality and readmission were compared across the distressed vs. non-distressed race groups. The adjusted association between DCI and risk of adverse outcomes was assessed separately across the race groups using adjusted hierarchical logistic regression models with restricted cubic splines. Results: The study included 1,238,537 White (14.8% distressed) and 190,721 Black (44.4% distressed) patients. White patients living in SE distressed communities had a significantly higher risk of adverse outcomes at 30-days and 1-year f/u (Fig. A). In contrast, among Black patients, the risk of adverse outcomes among those living in distressed vs. non-distressed communities were not meaningfully different at 30-days and became more prominent by 1-year f/u. Similar results were noted in the restricted cubic spline analysis with stronger and more graded association between DCI score and risk of adverse outcomes in White (vs. Black) patients (Fig. B). Conclusion: SE distress is strongly associated with risk of adverse outcomes in White patients with HF. Among Black patients, SE distress is more common, but its adverse effects are less evident during short-term f/u and are better highlighted in the long-term. Other societal factors such as structural racism and poor access to care may be important prognostic determinants in Black patients with HF.

Abstract 9534: Proteomic Signature of Right Ventricular Failure in Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease leading to pulmonary artery pressure elevation and right ventricular (RV) failure. RV failure is the principal determinant of adverse outcomes in PAH patients and represents a major unmet medical need. Thus, a better understanding the pathogenesis of RV failure is mandatory. In this study, we used an unbiased proteomics approach to identify the molecular players engaged in RV failure development caused by PAH. Methods and Results: Proteomics analysis (nano-LC-MS/MS) was performed using control (autopsy, normal RV function, n=10), compensated (cRV, patients with RV hypertrophy and preserved cardiac index&gt;2.2L/min/m 2 , n=10), and decompensated RV (dRV, PAH patients who died from RV failure, n=10). We identified 424 differentially expressed proteins between the dRV and control patients (p&lt;0.05). Of these 424 proteins, 245 were upregulated and 179 were downregulated in the dRV. Using GO enrichment analysis and protein-protein interaction network, we found that upregulated proteins were significantly enriched in pathways involved in immune system and extracellular matrix organization, whereas downregulated proteins were mainly involved in muscle structure development, metabolism, and RNA splicing. To confirm the robustness and sensitivity of the expression changes observed in our proteomic data sets, expression levels of 3 selected proteins implicated in RNA splicing, namely heterogeneous ribonucleoprotein particle (HNRNP)-A1, -C1/C2 and -U, were measured by Western blotting. Consistent with the results of proteomics, these HNRNP proteins were markedly downregulated in dRV compared to cRV or controls (p&lt;0.05). Similar results were observed in RV tissue samples from monocrotaline-injected and pulmonary artery banding-subject rats (n=7-10, p&lt;0.05). In vitro , we demonstrated that knockdown of HNRNPA1 using siRNA prevents phenylephrine-induced cardiomyocyte (H9c2) hypertrophy, as assessed by immunostaining of F-actin and expression of Nppb . Further experiments are currently performed to decipher the role of HNRNPs in RV failure. Conclusions: Our data open novel perspectives for understanding molecular mechanisms of RV failure progression in PAH.

Incidence and determinants of adverse outcomes among women who were managed for eclampsia in the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia

BackgroundThe incidence of eclampsia and its adverse maternal outcomes are very high in developing countries, particularly in Subsaharan African Countries. Identifying predictors for adverse maternal outcomes of eclampsia has paramount importance for helping health care providers to optimize their management outcomes. Therefore, this study aimed to assess the incidence of adverse maternal outcomes of eclampsia and its determinant factors.MethodsA retrospective follow-up study design was applied. The data were extracted from patient charts using a structured, pre-tested, questionnaire. Descriptive analyses (frequencies, means, and standard deviation) were calculated, and bi-variable and multivariable logistic regression models were used to testing the association between independent variables and an outcome variable. After the data were coded and entered into Epi-Info Version 7.2 Software, the data were analyzed using STATA Version 14 Statistical Software.ResultsThe magnitude of eclampsia was 5.36 per 1000 pregnancies (95% CI: 4.72, 6.10). The incidence of adverse maternal outcomes in eclamptic mothers was 53.7% (95% CI: 47.02, 60.24%). After adjusting for covariates maternal age 30–34, AOR 5.4 [95% CI = 1.02, 28.6]; age above 34, AOR 10.5 [95% CI = 1.3, 88.6]; gravidity 2–4, AOR 0.3 [95% CI = 0.1, 0.9]; 10 or more convulsions, AOR 4.6 [95% CI = 1.4, 14.9]; mild pyrexia, AOR 20.4 [95% CI = 3.7, 112.7]; moderate pyrexia, AOR 14.6 [95% CI = 1.7125.1]; platelet count below 50,000 cells/mm3, AOR 34.9 [95% CI = 3.6, 336.2]; platelet count between 50,000 and 99,000 cells/mm3, AOR 24.5 [95%CI = 5.4111.6]; and stillbirth of the current pregnancy, AOR 23.2 [95%CI = 2.1257.5] were strong predictors of adverse maternal outcomes in eclamptic mothers.ConclusionsThe incidence of adverse maternal outcomes of eclampsia was found to be high compared to similar studies discussed in this study. This study recommends early identification of patients with the risk factors (having many convulsions, high body temperature, low platelet count, patient age above 30 years, and 2–4 pregnancies), strengthening the referral system, and advocation of research on the area of adverse maternal outcomes and thereby encourage evidence-based medicine.

YBX1 mediates translation of oncogenic transcripts to control cell competition in AML

Persistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.

Cardiac resynchronization therapy improves left atrial reservoir function through resynchronization of the left atrium in patients with heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Background The structural remodeling of the left atrium (LA) has been proposed as an important determinant of adverse outcomes in patients with heart failure (HF). However, little is known about the potential impact of LA mechanical dyssynchrony on its reservoir function and the prognosis of patients with HF. In addition, it has not been fully investigated whether cardiac resynchronization therapy (CRT) is also beneficial to LA function. Purposes The purposes of this study were to test whether left ventricular (LV) dyssynchrony may negatively affect LA synchronicity and reservoir function, and to assess whether residual LA dyssynchrony after CRT affects the prognosis in patients with HF with reduced ejection fraction (HFrEF). Methods This study included total of 90 subjects: 40 HFrEF with a wide-QRS complex (≧130 ms), 28 HFrEF with a narrow-QRS, and 22 age- and sex-matched normal controls. LA global longitudinal strain (LA-GLS) and LA dyssynchrony were quantified using speckle-tracking strain analysis. LA dyssynchrony was defined as the maximal difference of time-to-peak strain (LA time-diff). All wide-QRS HFrEF received CRT, and event-free survival was tracked for 24 months. Results At baseline, HFrEF patients showed significant LA remodeling coupled with the reduced LA reservoir function, as evidenced by larger LA volume index (LAVi: 46 ± 16 vs. 30 ± 14 mL/m², P &amp;lt; 0.01) and smaller LA-GLS (13.0 ± 4.8 vs. 30.6 ± 10.7%, P &amp;lt; 0.01). Of note was that, not only LV dyssynchrony (381 ± 178 vs. 177 ± 62 ms, P &amp;lt; 0.01) but also LA dyssynchrony (298 ± 136 vs. 186 ± 78 ms, P &amp;lt; 0.01) were significantly larger in patients with HFrEF compared to normal subjects and this applied even more to patients with a wide-QRS complex. All patients with a wide-QRS complex underwent CRT, and only responders exhibited the significant decrease in LA time-diff (from 338 ± 123 to 245 ± 141 ms, P &amp;lt; 0.05) and increase in LA-GLS (from 11.9 ± 4.7 to 19.6 ± 10.1%, P &amp;lt; 0.05) in parallel with the reduction in LAVi (from 48 ± 17 to 37 ± 18 mL/m², P &amp;lt; 0.05) at 6 months after CRT. Receiver operating characteristic curve analysis identified the optimal cut-off value of LA time-diff at 6 months after CRT as 202 ms (P &amp;lt; 0.05) and that of LA-GLS as 14.6% (P &amp;lt; 0.05) for predicting adverse cardiac events. The patients whose LA time-diff reduced &amp;lt;202 ms after CRT showed significantly favorable event-free survival than the others. Similarly, the patients whose LA-GLS improved &amp;gt;14.6% after CRT exhibited significantly favorable event-free survival than the others (P &amp;lt; 0.05, respectively). Of note was that, when the patients were restricted to CRT responders only, those who showed LA time-diff less than 202 ms at 6 months after CRT almost never experienced cardiac events (P &amp;lt; 0.05). Conclusions The improved LV coordination by CRT also resulted in resynchronization of discoordinated LA wall motion and a consecutive improvement of LA reservoir function, which ultimately lead to the favorable outcome for HFrEF patients with wide-QRS complex. Abstract Figure.

Determination of scar area using native and post contrast T1 mapping: a validation study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Goethe University Hospital Introduction Late gadolinium enhancement (LGE) with Full Width Half Maximum (FWHM) is the standard imaging method for the measurement of the scar area in ischemic heart disease, a major determinant of adverse outcome. T1 mapping techniques have become increasingly applied in everyday clinical practice. Agreement in area quantification between T1 mapping and LGE for the scar extent has not been systematically assessed. Purpose This study aims to ascertain concordance between the area determined by native and post contrast T1 mapping against LGE to determine scar area in patients with a prior myocardial infarction. It also examines intra and inter-observer reproducibility for these two methods. Methods Subendocardial scar was evaluated in 132 patients with ischemic heart disease using LGE, native and post contrast T1 mapping in 3 short axis slices. Native and postcontrast T1 mapping was performed using GoetheCVI®MOLLI sequence (Gadovist® 0.1mmol/kg). FWHM method was applied for LGE and compared with the manually delineated area of scar in native and postcontrast T1 mapping acquisitions within the identical slices. The presence of the scar was defined as LGE &amp;gt;3% of the myocardial mass. Bland-Altman methods were employed to assess concordance between techniques and reproducibly between observers. Results In comparison to LGE, area measurements in native T1 acquisitions underestimated infarct size (9,1% vs 12,6%, p = 0.01), while postcontrast T1 overestimated it (19,4% vs 12,6%, p &amp;lt; 0.001). The disparity between the measurements was accentuated with larger scar areas (Figure 1). Intraobserver reproducibility (native T1: intra/inter MD ± SD, CoV, postcontrast T1: intra/inter) was similar with both methods, whereas interobserver variability for native T1 mapping acquisition was worse. Conclusions We demonstrate that measurements of the area of myocardial scar by T1 mapping acquisitions yield considerably different results in comparison to the standard LGE-based FWHM method. High observer agreement indicates that these differences are genuinely related to the type of the underlying acquisition and the differences in detected signal. The approaches are not interchangeable. However, the importance of these results for predicting patient outcome is yet to be elucidated. Nonetheless, these results were consistent in the inter and intraobserver analysis for post contrast T1 mapping, although native T1 mapping failed to show similar consistency. Figure 1: Bland-Altmann plot of differences (mean ± upper and lower limit of agreement-LOA) in scar area extent (percentage) between LGE and native T1 mapping (A), LGE and post contrast T1 mapping (B). The difference increases linearly for larger scar areas when using post contrast mapping, which does not apply for native mapping. Abstract Figure 1

Long-term prognostic significance of dispersion of ventricular repolarization in patients with cardiac sarcoidosis

Abstract Background Although the presence of cardiac involvement is recognised as a determinant of worse clinical outcomes in sarcoidosis patients, the determinants of adverse outcomes in patients with cardiac sarcoidosis (CS) have not been well understood. T-peak to T-end interval (TpTe) on the surface electrocardiogram (ECG) was proposed as a marker of dispersion of ventricular repolarisation. Prolonged TpTe to QT interval ratio (TpTe/QT) represents a period of potential vulnerability to reentrant ventricular arrhythmias. Notably, prolonged TpTe/QT has been associated with increased risk of mortality in hypertrophic cardiomyopathy, congenital long-QT syndrome, and Brugada syndrome. However, its prognostic implication in patients with CS is unclear. Purpose We sought to investigate whether TpTe/QT was associated with long-term clinical outcomes in patients with CS. Methods A total of 108 consecutive CS patients between August 1986 and March 2019 in two academic hospitals who had ECG data before initiation of immunosuppressive therapy were examined. We excluded patients who received pacemaker (n=15) or cardiac resynchronization therapy (n=3) at the time of ECG. Ultimately, 90 CS patients were included in this study. All standard 12-lead ECGs were recorded at 25 mm/s with an amplification of 10 mm/mV. TpTe was measured from the peak of T wave to the end of T wave which defined as the intersection of the tangent to the down slope of the T wave and the isoelectric line. Lead V5 was selected for the analyses. If V5 is not suitable for analyses, V4 was selected. The primary outcome was the composite of advanced atrioventricular block (AVB), ventricular tachycardia or ventricular fibrillation (VT/VF), heart failure hospitalisation and all-cause death. Results During a median follow-up period of 4.70 (interquartile range [IQR] 2.06–7.23) years, adverse events occurred in 21 patients (23.3%), including 2 advanced AVB, 12 VT/VF, 4 heart failure hospitalisation and 3 all-cause death. Events group had higher TpTe/QT compared to no events group (0.231 [IQR 0.193–0.261] vs. 0.282 [IQR 0.263–0.304] P&amp;lt;0.001). Kaplan-Meier analyses revealed that the primary outcome, especially VT/VF or sudden cardiac death more frequently occurred in patients with higher TpTe/QT (≥0.242, the median) compared to those with lower TpTe/QT (Figure 1). Multivariable Cox regression analysis showed that higher TpTe/QT was independently associated with increased subsequent risk of adverse events (hazard ratio 1.09, 95% confidence interval [CI] 1.02–1.17, P=0.014) even after adjustment for age, sex and left ventricular ejection fraction. Furthermore, the optimal cut-off value of TpTe/QT for the discriminatory of primary outcome was 0.257, and c-index was 0.77 (95% CI 0.64–0.89). Conclusions Higher TpTe/QT was associated with worse long-term clinical outcomes in patients with CS. Our findings indicate the importance of assessing TpTe/QT for risk stratification in patients with CS. Figure 1 Funding Acknowledgement Type of funding source: None

Abstract A21: Longitudinal analysis of cell-free DNA for therapy monitoring of ALK-positive non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) patients with ALK rearrangements are routinely treated with tyrosine kinase inhibitors (TKIs), leading to improved survival. However, clinical courses vary widely and the disease remains incurable. Therefore, early detection and molecular characterization of treatment failure is important for therapy guidance. To identify indicators of therapy response and resistance, we performed genotyping of circulating cell-free DNA (cfDNA), including panel-based deep sequencing (&amp;gt;4,200x coverage) and shallow whole-genome sequencing (sWGS; 0.5x coverage) from serial plasma samples (n=282) of 73 patients with ALK rearrangements. Variable mutation levels were marked in all patients and correlated with clinical features. At progression, individual dynamics of resistance mutations were seen: while some mutations became undetectable upon therapy switch, variant fractions of other alterations further increased. We also found mutated TP53 at the time of progression in patients with initially TP53 wild-type tumors. The progression-free survival of patients with acquired TP53 mutations was comparable to that of primarily TP53 mutated and shorter than that of persistently TP53 wild-type cases. Shallow WGS of cfDNA identified copy number variations (CNVs), some of which might contribute to disease progression. To quantitatively assess CNVs, trimmed median absolute deviation from copy number neutrality (t-MAD) scores were calculated from sWGS data. Longitudinal t-MAD assessment reflected the kinetics of mutant allele frequencies in cfDNA and allowed disease monitoring with increasing t-MAD and mutation levels at tumor progression. Moreover, EML4-ALK fusion variant 3 (V3) and TP53 mutations define molecular determinants of adverse outcome in ALK+ NSCLC. Shallow WGS of cfDNA identified increased t-MAD levels in patients with EML4-ALK V3 compared to those with fusion V1. Similarly, patients with TP53 mutations showed a higher t-MAD than TP53 wild-type cases. In summary, overall survival of patients with detectable mutations in plasma DNA at any time point during clinical follow-up was shorter than that of patients without detectable mutations in cfDNA. Similarly, overall survival time from the first detection of mutations cfDNA until death/end of follow-up was shorter than in cases without detectable mutations. Our data suggest that liquid biopsies could help to improve the care of ALK+ NSCLC patients through early detection of disease progression and tailored treatment of resistant tumors. Although individual courses were seen, rising mutation levels could indicate the need of radiologic reassessment earlier than scheduled. Detection of CNVs as surrogate for genomic instability and acquired TP53 mutations in liquid identified high-risk cases and suggests the potential clinical utility of cfDNA monitoring for this disease beyond profiling of ALK resistance mutations. Citation Format: Steffen Dietz, Petros Christopoulos, Lisa Gu, Volker Endris, Zhao Yuan, Simon J. Ogrodnik, Tomasz Zemojtel, Marc A. Schneider, Anna-Lena Volckmar, Michael Meister, Thomas Muley, Martin Reck, Matthias Schlesner, Michael Thomas, Albrecht Stenzinger, Holger Sültmann. Longitudinal analysis of cell-free DNA for therapy monitoring of ALK-positive non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A21.

P2634Prognostic value of admission left ventricular outflow tract velocity time integral in hospitalized heart failure patients with preserved ejection fraction: a report from the JASPER registry

Abstract Background There are little effective treatment strategies for heart failure with preserved ejection fraction (HFpEF) to achieve a reduction of morbidity and mortality. Thus, accurate prognostication of patients with HFpEF could help improve their outcomes by identifying high-risk patients who might potentially benefit from intensive inpatient and outpatient monitoring and early referral for advanced HFpEF therapy. The left ventricular outflow tract velocity time integral (LVOT-VTI) is a representative non-invasive parameter for evaluating stroke volume, which can be a determinant of adverse outcomes in hospitalized patients with heart failure. However, the prognostic implication of admission LVOT-VTI for hospitalized HFpEF patients is undetermined. Purpose The aim of the present study was to investigate whether admission LVOT-VTI could predict poor clinical outcomes in hospitalized patients with HFpEF. Methods We examined consecutive 535 hospitalized HFpEF patients (left ventricular ejection fraction ≥50%) due to acute decompensated heart failure from the JASPER (JApanese heart failure Syndrome with Preserved Ejection fRaction) multicenter registry, obtained between November 2012 and March 2015. Patients without accessible LVOT-VTI data on admission were excluded. Finally, 214 patients were examined. The primary outcome of interest was composite of all-cause death and rehospitalization due to heart failure. Results Mean age was 78±11 years, 100 were male, and median plasma brain-type natriuretic peptide level was 400 (interquartile range [IQR] 223–711) pg/ml. During a median follow-up period of 688 (IQR 162–810) days, adverse events occurred in 83 patients (39%), including 47 (22%) all-cause death, 51 (24%) rehospitalization due to heart failure. The c-index of LVOT-VTI for predicting the composite of adverse events was 0.59 (95% CI 0.51 to 0.67), and the optimal cut-off value of LVOT-VTI was 15.8 cm. Low LVOT-VTI (≤15.8 cm) was significantly associated with higher adverse events compared to high LVOT-VTI (&gt;15.8 cm) (Figure). Multivariable Cox regression analysis revealed that lower LVOT-VTI was an independent determinant of adverse events (HR 0.94, 95% CI 0.91 to 0.98, P=0.005) even after adjustment for pre-specified confounders including age, sex, systolic blood pressure, serum sodium, albumin, plasma brain-type natriuretic peptide and renal function. Figure 1 Conclusions Lower admission LVOT-VTI was an independent determinant of worse clinical outcomes in hospitalized HFpEF patients, indicating that LVOT-VTI on admission could be a useful marker for risk stratification in these patients.

Long-term Prognostic Significance of Admission Tricuspid Regurgitation Pressure Gradient in Hospitalized Patients With Heart Failure With Preserved Ejection Fraction: A Report From the Japanese Real-World Multicenter Registry

BackgroundDoppler-estimated peak systolic tricuspid regurgitation pressure gradient (TRPG) is a representative noninvasive parameter for evaluating pulmonary artery systolic pressure, which can be a determinant of adverse outcomes in chronic heart failure with preserved ejection fraction (HFpEF). However, the prognostic implications of TRPG at admission for hospitalized patients with HFpEF are undetermined. Methods and ResultsWe examined 469 consecutive hospitalized patients with decompensated HFpEF (left ventricular ejection fraction ≥ 50%) who underwent TRPG measurement at admission in our HFpEF multicenter registry. The primary outcome of interest was all-cause death. Admission TRPG was significantly correlated with estimated pulmonary capillary wedge pressure and left atrial dimension (r = 0.24, P < 0.001 and r = 0.21, P < 0.001, respectively). During a median follow-up period of 748 (IQR 540–820) days, 83 patients died. Higher TRPG was significantly associated with higher mortality compared to lower TRPG (log-rank; P = 0.007). Multivariable analysis revealed that elevated TRPG was an independent determinant of mortality (HR 1.02, 95% CI 1.01–1.04, P = 0.008) after adjustment for prespecified confounders and renal function. ConclusionsElevated TRPG at admission was an independent determinant of mortality in hospitalized patients with HFpEF, indicating that TRPG at admission could be a useful marker for risk stratification in these patients.

LONG-TERM PROGNOSTIC SIGNIFICANCE OF ADMISSION TRICUSPID REGURGITANT PRESSURE GRADIENT IN HOSPITALIZED HEART FAILURE PATIENTS WITH PRESERVED EJECTION FRACTION: A REPORT FROM JAPANESE REAL-WORLD MULTICENTER REGISTRY

The Doppler-estimated peak systolic tricuspid regurgitant pressure gradient (TRPG) is a representative noninvasive method for the evaluation of pulmonary artery systolic pressure, which can be a determinant of adverse outcomes in chronic heart failure with preserved ejection fraction (HFpEF).

Prognostic Biomarkers Converge on a Germinal Centre Dark Zone Phenotype As a Determinant of Adverse Outcome in Follicular Lymphoma Patients Treated with Rituximab and Chemotherapy

Introduction: Follicular lymphoma (FL) is a clinically and genetically heterogeneous disease with highly variable patient outcomes. Recently, Huet et al. proposed a 23-gene expression-based risk score for predicting progression-free survival (PFS) in FL patients treated with rituximab and chemotherapy (Huet et al. Lancet Oncology 2018). The m7-FLIPI risk score has also been described as a clinico-genetic model predicting patient outcomes (Pastore et al. Lancet Oncology 2015). Moreover, EZH2 wild-type status and high expression of the FOXP1 transcription factor are associated with increased risk of lymphoma progression (Mottok et al. Blood 2018). This multitude of prognostic tools in FL raises the question whether they identify common biology. The aims of this study were to assess whether the 23-gene predictor score identifies a poor risk group of patients in our own gene expression dataset, and whether commonality exists between the 23-gene score, the m7-FLIPI, EZH2 mutation status and FOXP1 expression.Methods: In our previous work, we generated Illumina DASL microarray expression profiles for 137 FL patients who were treated with rituximab and CVP chemotherapy (cyclophosphamide, vincristine and prednisone). Using genes from the 23-gene linear risk predictor, we determined each patient's risk score by setting coefficients at -1 and +1 for genes associated with favorable and unfavorable PFS, respectively. We dichotomized the distribution of scores using the maximally selected log-rank statistic. We also performed unsupervised, hierarchical clustering to identify underlying subgroups in an unbiased fashion. Survival analyses were performed using the log-rank test and Cox regression analyses. We used gene set enrichment analysis to identify concordant differences of relevant gene signatures between specimens with either low or high expression of FOXP1.Results: Twenty genes from the 23-gene predictor (87%) were identified in the DASL gene expression dataset. The coefficients from univariate Cox regression analysis from our data were correlated with coefficients from Huet et al. (Pearson r = .7, P < .001; Spearman r = .44, P = .051). All poor-risk genes from the 23-gene predictor were associated with poor PFS in our data, and vice versa. Concordantly, calculated risk scores were significantly associated with PFS in the univariate Cox regression analysis (P = .007). Dichotomizing the distribution of risk scores identified 68% of cases with high risk score who had inferior PFS and OS compared to 32% of cases with low risk score (5-year PFS 54% vs. 77%, P = .004; 5-year OS 73% vs. 86%, P = .04). Hence, the risk score stratified patients into groups with diverging outcomes. This association was found to be independent of the Follicular Lymphoma Prognostic Index (FLIPI). In addition, the mean risk score was significantly higher in cases with high expression of FOXP1 (P < .001) and in cases with high m7-FLIPI risk score (P = .023). Unsupervised hierarchical clustering identified two main clusters (“cluster 1” and “cluster 2”) that were characterized by low and high expression of genes associated with poor outcome, respectively. Patients from “cluster 2” experienced worse PFS compared to patients in “cluster 1” (P = .046; 5-year PFS 54% vs. 68%). The 5-year OS was 72% for patients in “cluster 2”, vs. 81% in “cluster 1” (P = .13).We have previously reported that a germinal centre dark zone signature is enriched in cases with high FOXP1 expression, and the ICA13 signature reported by Huet et al. has been described as being highly expressed in centroblasts. Using gene set enrichment analysis, we found that genes with positive weight and coefficients in the ICA13 and the 23-gene predictor score, respectively, were enriched in the FOXP1-high phenotype (adjusted P = .009 and .005, respectively). GeneMANIA illustrated co-expression interconnectivity among ORAI2, TCF4, AFF3, FOXO1, CXCR4 and FOXP1, suggesting that genes with prognostic significance operate in tightly regulated networks.Conclusions: Our results exemplify the robustness of the predictor model by Huet et al. Further, we demonstrate biomarker convergence on a common phenotype: FOXP1 expression, EZH2 wild-type status and expression of dark zone-related genes, which characterize a subset of FL cases with adverse outcome following rituximab and chemotherapy. DisclosuresSarkozy:Roche/Genentech: Consultancy. Sehn:Roche/Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Weigert:Novartis: Research Funding; Roche: Research Funding. Steidl:Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Seattle Genetics: Consultancy; Nanostring: Patents & Royalties: patent holding.

Stroke Outcome and Determinants among Patients with and without Diabetes in a Tertiary Hospital in Ghana.

Background Diabetes mellitus, a well-established independent risk factor for stroke, has varied association with stroke outcome from previous studies. This study investigated stroke outcome and determinants among patients with and without diabetes in a tertiary hospital in Ghana. Methods A prospective study conducted among stroke patients with and without diabetes admitted in a Ghanaian tertiary hospital. Baseline clinical and biochemical data were documented. Functional stroke outcome was evaluated at 1, 3, and 6 months after stroke using the modified Rankin Scale. Results Number of participants enrolled were 326 and 105 (32.20%) had diabetes. Higher proportions of diabetes patients had poor functional stroke outcome at 1, 3, and 6 months (79%, 75.23%, 73.33%) compared with those without diabetes (70.13%, 65.16, 61.99) (p>0.05). Stroke patients with diabetes had lower survival compared with those without diabetes (p=0.0745). Mortality at 6 months was more likely among ischaemic stroke patients with diabetes compared with those without diabetes (Odds Ratio 2.037; CI: 1.058-3.923). Determinants of poor functional stroke outcome for diabetes patients were older age (Adjusted Odds Ratio (AOR)-1.07; CI-1.03-1.12), female gender (AOR-3.74; CI-1.26-12.65), and pneumonia (AOR-11.32; CI-1.93-220.05) whereas the determinants for those without diabetes were unemployment (AOR-4.19; CI-1.24-19.50), speech abnormalities (AOR-1.99; CI1.08-3.73), and pneumonia (AOR-4.05; CI-1.83-9.77). High fasting plasma glucose (HR-1.15; CI-1.07-1.23), elevated temperature (HR-1.41; CI-1.11-1.79), and pneumonia (HR-2.25; CI-1.44-3.50) were determinants of low survival among all stroke patients. Conclusion Trends towards poorer functional outcome and reduced survival were found among Ghanaian stroke patients with diabetes compared with those without diabetes. Older age, female gender, pneumonia, elevated temperature, and fasting plasma glucose were determinants of adverse outcome in stroke patients with diabetes.

Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury: An Operation Brain Trauma Therapy Study.

Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), markers of glial and neuronal cell body injury, respectively, have been previously selected by the Operation Brain Trauma Therapy (OBTT) pre-clinical therapy and biomarker screening consortium as drug development tools. However, traumatic axonal injury (TAI) also represents a major consequence and determinant of adverse outcomes after traumatic brain injury (TBI). Thus, biomarkers capable of assessing TAI are much needed. Neurofilaments (NFs) are found exclusively in axons. Here, we evaluated phospho-neurofilament-H (pNF-H) protein as a possible new TAI marker in serum and cerebrospinal fluid (CSF) across three rat TBI models in studies carried out by the OBTT consortium, namely, controlled cortical impact (CCI), parasagittal fluid percussion (FPI), and penetrating ballistics-like brain injury (PBBI). We indeed found that CSF and serum pNF-H levels are robustly elevated by 24 h post-injury in all three models. Further, in previous studies by OBTT, levetiracetam showed the most promising benefits, whereas nicotinamide showed limited benefit only at high dose (500 mg/kg). Thus, serum samples from the same repository collected by OBTT were evaluated. Treatment with 54 mg/kg intravenously of levetiracetam in the CCI model and 170 mg/kg in the PBBI model significantly attenuated pNF-H levels at 24 h post-injury as compared to respective vehicle groups. In contrast, nicotinamide (50 or 500 mg/kg) showed no reduction of pNF-H levels in CCI or PBBI models. Our current study suggests that pNF-H is a useful theranostic blood-based biomarker for TAI across different rodent TBI models. In addition, our data support levetiracetam as the most promising TBI drug candidate screened by OBTT to date.

Circulating Progenitor Cells and Racial Differences.

Blacks compared with whites have a greater risk of adverse cardiovascular outcomes. Impaired regenerative capacity, measured as lower levels of circulating progenitor cells (CPCs), is a novel determinant of adverse outcomes; however, little is known about racial differences in CPCs. To investigate the number of CPCs, PC-mobilizing factors, PC mobilization during acute myocardial infarction and the predictive value of CPC counts in blacks compared with whites. CPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34+, CD133+, VEGF2R+, and CXCR4+ epitopes in 1747 subjects, mean age 58.4±13, 55% male, and 26% self-reported black. Patients presenting with acute myocardial infarction (n=91) were analyzed separately. Models were adjusted for relevant clinical variables. SDF-1α (stromal cell-derived factor-1α), VEGF (vascular endothelial growth factor), and MMP-9 (matrix metallopeptidase-9) levels were measured (n=561), and 623 patients were followed for median of 2.2 years for survival analysis. Blacks were younger, more often female, with a higher burden of cardiovascular risk, and lower CPC counts. Blacks had fewer CD34+ cells (-17.6%; [95% confidence interval (CI), -23.5% to -11.3%]; P<0.001), CD34+/CD133+ cells (-15.5%; [95% CI, -22.4% to -8.1%]; P<0.001), CD34+/CXCR4+ cells (-17.3%; [95% CI, -23.9% to -10.2%]; P<0.001), and CD34+/VEGF2R+ cells (-27.9%; [95% CI, -46.9% to -2.0%]; P=0.04) compared with whites. The association between lower CPC counts and black race was not affected by risk factors or cardiovascular disease. Results were validated in a separate cohort of 411 patients. Blacks with acute myocardial infarction had significantly fewer CPCs compared with whites ( P=0.02). Blacks had significantly lower plasma MMP-9 levels ( P<0.001) which attenuated the association between low CD34+ and black race by 19% (95% CI, 13%-33%). However, VEGF and SDF-1α levels were not significantly different between the races. Lower CD34+ counts were similarly predictive of mortality in blacks (hazard ratio, 2.83; [95% CI, 1.12-7.20]; P=0.03) and whites (hazard ratio, 1.79; [95% CI, 1.09-2.94]; P=0.02) without significant interaction. Black subjects have lower levels of CPCs compared with whites which is partially dependent on lower circulating MMP-9 levels. Impaired regenerative capacity is predictive of adverse outcomes in blacks and may partly account for their increased risk of cardiovascular events.

Determinants of Adverse Outcomes After Systemic-To-Pulmonary Shunts in Biventricular Circulation

Systemic-to-pulmonary shunts are useful palliative procedures, although many teams have been deterred by high mortality and morbidity. We aimed to identify predictors of adverse outcomes after shunts in biventricular lesions. From 2004 to 2014, 173 children had shunt procedures. Morphologies included: tetralogy of Fallot, pulmonary atresia with ventricular septal defect (VSD) with and without major aortopulmonary collaterals (MAPCAs), transposition of great arteries with pulmonary stenosis, and double outlet right ventricle. Median age was 22 days (range, 3 to 3,438 days) and median weight 3.2 kg (range, 1.7 to 20 kg). Shunt sizes ranged from 3 to 5 mm with median shunt size/weight ratio 1.03 mm/kg (range, 0.3 to 2.5 mm/kg). In-hospital mortality was 5.2% for the initial shunt procedure. Inter-stage mortality was 3.6%. Overall, 86% of patients progressed to corrective surgery. Acute events were observed in 41 patients, leading to 6 deaths. Events included 30 emergency chest openings, 16 shunt thrombosis, and 17 pulmonary overcirculation. Independent predictors of acute events or in-hospital mortality were genetic or extracardiac anomalies (hazard ratio [HR]= 1.9, p= 0.04), and preoperative shock/acidosis (HR= 2.73, p=0.003). Diagnosis of pulmonary atresia with VSD and MAPCAs was protective (HR= 0.23, p=0.042). Weight, shunt size, and size/weight ratios were not significant risk factors. Shunt thrombosis occurred at a median 3 hours (range, 0 to 46 hours) postoperatively, leading to 33% of in-hospital deaths. Low postoperative oxygen saturation and higher platelet counts in intensive care were independent predictors of thrombosis (p= 0.022, p=0.005 respectively). Early adverse events contribute to mortality and morbidity for the shunt procedure. Patients with lower oxygen saturation and higher platelet counts in the postoperative period are at higher risk of shunt thrombosis.

Clinical Application of Grace Risk Score in Patients with Acute Coronary Syndrome

Objectives: To determine clinical application of GRACE risk score in patients with acute coronary syndrome (ACS).Patients and Methods: It was an observational analytical study conducted in the Cardiology ward of Mayo hospital, Lahore from April to July 2015. Patients with Acute STEMI, NSTEMI or Unstable angina (UA) were selected on the basis of typical chest pain, ECG changes or cardiac biomarkers .For all eligible cases, at presentation GRS was calculated using online calculator. Also, GRACE risk categories and predicted in-hospital mortality were determined. Patients with previous episodes of STEMI/ NSTEMI, old Left Bundle Branch Block (LBBB), stable angina pectoris, acute pericarditis, myocarditis, acute rheumatic fever or pulmonary embolism were excluded. Data was analyzed on SPSS 20 and the R project for statistical computing. Individual components of GRS were compared among discharged and expired cases using t-test. A p-value of &lt;0.05 was considered significant.Results: A total of 165 patients with STEMI and ACS were included. The mean GRS among males andfemales was 137.4 ± 39 and 151.5 ± 50.6. The observed in-hospital mortality was 12.12% with 60% patients of STEMI. Among expired cases, 90% patients had high GRS, predominantly from STEMI group. Important determinants of adverse outcome were advanced age, tachycardia, low systolic blood pressure and presence of cardiac failure.Conclusion: STEMI was the major acute cardiac event. The mean GRS of expired patients was significantly higher than discharged group. GRS accurately identified low risk cases with low probability of in-hospital death. GRS over estimate probability of in-hospital death among STEMI high risk cases that had higher scores and discharged uneventfully. Grace Risk Score is a reliable predictor of risk category and adverse outcomes and its use by clinicians should be strongly recommended.