Deliverable D4.4 Simulated coherent scattering data from plasma and non–plasma samples

Deliverable D4.4 of work package 4 (SIMEX) in EUCALL

Cardiovascular Magnetic Resonance Imaging-Based Right Atrial Strain Analysis of Cardiac Amyloidosis

Background: Cardiac amyloidosis (CA) manifests in a hypertrophic phenotype with a poor prognosis, making differentiation from hypertrophic cardiomyopathy (HCM) challenging and delaying early treatment. The extent to which magnetic resonance imaging (MRI) quantifies the right atrial strain (RAS) and strain rate (RASR), providing valuable diagnostic information, is not yet clinically established. Aims: This study assesses diagnostic differences in the longitudinal RAS and RASR between CA and HCM patients, control subjects (CTRL) and CA subtypes in addition to the impact of atrial fibrillation (AF) on the right atrial function in CA patients. The RAS and RASR of tricuspid regurgitation (TR) patients are used to assess the potential for diagnostic overlap. Methods: RAS and RASR quantification was conducted via MRI feature-tracking for biopsy-confirmed CA patients with subtypes identified. Strain parameters were compared for CTRL, HCM and TR patients. Post hoc testing identified intergroup differences. Results: In total, 41 CA patients were compared to 47 CTRL, 20 HCM and 31 TR patients. Reservoir (R), conduit and booster RAS and RASRs allow for significant differentiation (p < 0.001) between CA and HCM patients (R: 10.6 ± 14.3% vs. R: 33.5 ± 16.3%) and CTRL (R: 44.6 ± 15.7%). Booster and reservoir RAS and RASRs qualified as reliable diagnostic tests (AUC > 0.8). CA patients with AF, in contrast to sinus rhythm, demonstrated a significantly impaired reservoir RAS and RASR and booster RASR. The discriminative power of RAS for CA vs. TR was insufficient (R: 10.6% ± 14.3% vs. 7.0% ± 6.0%, p = 0.069). Differentiation between 21 transthyretin and 20 light-chain amyloidosis subtypes was not achievable (R: 0.7% ± 1.0% vs. 0.7% ± 1.0%, p = 0.827). Conclusion: The MRI-derived RAS and RASR are impaired in CA patients and may support noninvasive differentiation between CA, HCM and CTRL

Magnetic-Resonance-Imaging-Based Left Atrial Strain and Left Atrial Strain Rate as Diagnostic Parameters in Cardiac Amyloidosis

Aims: The present study aims to evaluate magnetic-resonance-imaging (MRI)-assessed left atrial strain (LAS) and left atrial strain rate (LASR) as potential parameters for the diagnosis of cardiac amyloidosis (CA), the distinction of clinical subtypes and differentiation from other cardiomyopathies. Methods and results: LAS and LASR were assessed by MRI feature tracking in patients with biopsy-proven CA. LAS and LASR of patients with CA were compared to healthy subjects and patients with hypertrophic cardiomyopathy. LAS and LASR were also analyzed concerning differences between patients with transthyretin (ATTR) and light chain amyloidosis (AL). A total of 44 patients with biopsy-proven CA, 19 patients with hypertrophic cardiomyopathy and 24 healthy subjects were included. In 22 CA patients (50%), histological examination identified ATTR as CA subtype and AL in the remaining patients. No significant difference was observed for reservoir, conduit or booster LAS in patients with AL or ATTR. Reservoir LAS, conduit LAS and booster LAS were significantly reduced in patients with CA and HCM as compared to healthy subjects (p < 0.001). Reservoir LAS and booster LAS were significantly reduced in CA as compared to HCM patients (p < 0.001). A linear correlation was observed between LA global reservoir strain and LA-EF (p < 0.001, r = 0.5), conduit strain and global longitudinal LV strain (p < 0.001, r = 0.5), global booster strain rate and LA-EF (p < 0.001, r = 0.6) and between global booster strain rate and LA area at LVED (p < 0.0001, 0.5). Conclusions: LAS and LASR are severely impaired in patients with CA. The MRI-based assessment of LAS and LASR might allow non-invasive diagnosis and categorization of CA and its distinct differentiation from other hypertrophic phenotypes

CMR-based right ventricular strain analysis in cardiac amyloidosis and its potential as a supportive diagnostic feature

$\it Background:$ Right ventricular (RV) strain has provided valuable prognostic information for patients with $\underline {cardiac amyloidosis}$ (CA). However, the extent to which RV strain and strain rate can differentiate CA is not yet clinically established. CA underdiagnosis delays treatment strategies and exacerbates patient prognosis. $\it Aims:$ Evaluation of $\underline {cardiac magnetic resonance}$ (CMR) quantified RV global and regional strain of CA and $\underline {HCM}$ patients along with CA subtypes. $\it Methods:$ CMR feature tracking attained longitudinal, radial and circumferential global and regional strain in 47 control subjects (CTRL), 43 CA-, 20 hypertrophic cardiomyopathy- (HCM) patients. CA patients were subdivided in 21 transthyretin-related amyloidosis (ATTR) and 20 acquired immunoglobulin light chain (AL) patients. Strain data and baseline clinical parameters were statistically analysed with respect to $\underline {diagnostic performance}$ and discriminatory power between the different clinical entities. $\it Results:$ Effective differentiation of CA from HCM patients was achieved utilizing global longitudinal (GLS: 16.5 $\pm$ 3.9% vs. −21.3 $\pm$ 6.7%, p = 0.032), radial (GRS: 11.7 $\pm$ 5.3% vs. 16.5 $\pm$ 7.1%, p < 0.001) and circumferential (GCS: -7.6 $\pm$ 4.0% vs. −9.4 $\pm$ 4.4%, p = 0.015) right ventricular strain. Highest strain-based hypertrophic phenotype differentiation was attained using GRS (AUC = 0.86). Binomial regression found right $\underline {ventricular ejection fraction}$ (RV-EF) (p = 0.017) to be a significant predictor of CA-HCM differentiation. CA subtypes had comparable cardiac strains. $\it Conclusion:$ CMR-derived RV global strains and various regional longitudinal strains provide discriminative radiological features for CA-HCM differentiation. However, in terms of feasibility, cine-derived RV-EF quantification may suffice for efficient differential diagnostic support

Machine-learning-based diagnostics of cardiac sarcoidosis using multi-chamber wall motion analyses

Background: Hindered by its unspecific clinical and phenotypical presentation, cardiac sarcoidosis (CS) remains a challenging diagnosis. Objective: Utilizing cardiac magnetic resonance imaging (CMR), we acquired multi-chamber volumetrics and strain feature tracking for a support vector machine learning (SVM)-based diagnostic approach to CS. Method: Forty-five CMR-negative (CMR(−), 56.5(53.0;63.0)years), eighteen CMR-positive (CMR(+), 64.0(57.8;67.0)years) sarcoidosis patients and forty-four controls (CTRL, 56.5(53.0;63.0)years)) underwent CMR examination. Cardiac parameters were processed using the classifiers of logistic regression, KNN(K-nearest-neighbor), DT (decision tree), RF (random forest), SVM, GBoost, XGBoost, Voting and feature selection. Results: In a three-cluster analysis of CTRL versus vs. CMR(+) vs. CMR(−), RF and Voting classifier yielded the highest prediction rates (81.82%). The two-cluster analysis of CTRL vs. all sarcoidosis (All Sarc.) yielded high prediction rates with the classifiers logistic regression, RF and SVM (96.97%), and low prediction rates for the analysis of CMR(+) vs. CMR(−), which were augmented using feature selection with logistic regression (89.47%). Conclusion: Multi-chamber cardiac function and strain-based supervised machine learning provides a non-contrast approach to accurately differentiate between healthy individuals and sarcoidosis patients. Feature selection overcomes the algorithmically challenging discrimination between CMR(+) and CMR(−) patients, yielding high accuracy predictions. The study findings imply higher prevalence of cardiac involvement than previously anticipated, which may impact clinical disease management

Cardiovascular magnetic resonance imaging-based right atrial strain analysis of cardiac amyloidosis

$\bf Background:$ Cardiac amyloidosis (CA) manifests in a hypertrophic phenotype with a poor prognosis, making differentiation from hypertrophic cardiomyopathy (HCM) challenging and delaying early treatment. The extent to which magnetic resonance imaging (MRI) quantifies the right atrial strain (RAS) and strain rate (RASR), providing valuable diagnostic information, is not yet clinically established. $\bf Aims:$ This study assesses diagnostic differences in the longitudinal RAS and RASR between CA and HCM patients, control subjects (CTRL) and CA subtypes in addition to the impact of atrial fibrillation (AF) on the right atrial function in CA patients. The RAS and RASR of tricuspid regurgitation (TR) patients are used to assess the potential for diagnostic overlap. $\bf Methods:$ RAS and RASR quantification was conducted via MRI feature-tracking for biopsy-confirmed CA patients with subtypes identified. Strain parameters were compared for CTRL, HCM and TR patients. Post hoc testing identified intergroup differences. $\bf Results:$ In total, 41 CA patients were compared to 47 CTRL, 20 HCM and 31 TR patients. Reservoir (R), conduit and booster RAS and RASRs allow for significant differentiation ($\it p$ 0.8). CA patients with AF, in contrast to sinus rhythm, demonstrated a significantly impaired reservoir RAS and RASR and booster RASR. The discriminative power of RAS for CA vs. TR was insufficient (R: 10.6% $\pm$ 14.3% vs. 7.0% $\pm$ 6.0%, $\it p$ = 0.069). Differentiation between 21 transthyretin and 20 light-chain amyloidosis subtypes was not achievable (R: 0.7% $\pm$ 1.0% vs. 0.7% $\pm$ 1.0%, $\it p$ = 0.827). $\bf Conclusion:$ The MRI-derived RAS and RASR are impaired in CA patients and may support noninvasive differentiation between CA, HCM and CTRL

Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: results from a large multicenter study

Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes

Erratum : Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

This corrects the article DOI: 10.1038/nm.4484