Additional Prognostic Information Research Articles

Long-term follow-up of IgA nephropathy: clinicopathological features and predictors of outcomes.

The establishment of the Oxford classification and newly developed prediction models have improved the prognostic information for immunoglobulin A nephropathy (IgAN). Considering new treatment options, optimizing prognostic information and improving existing prediction models are favorable. We used random forest survival analysis to select possible predictors of end-stage kidney disease among 37 candidate variables in a cohort of 232 patients with biopsy-proven IgAN retrieved from the Norwegian Kidney Biopsy Registry. The predictive value of variables with relative importance >5% was assessed using concordance statistics and the Akaike information criterion. Pearson's correlation coefficient was used to identify correlations between the selected variables. The median follow-up period was 13.7 years. An isolated analysis of histological variables identified six variables with relative importance >5%: T %, segmental glomerular sclerosis without characteristics associated with other subtypes (not otherwise specified, NOS), normal glomeruli, global sclerotic glomeruli, segmental adherence and perihilar glomerular sclerosis. When histopathological and clinical variables were combined, estimated glomerular filtration rate (eGFR), proteinuria and serum albumin were added to the list. T % showed a better prognostic value than tubular atrophy/interstitial fibrosis (T) lesions with C-indices at 0.74 and 0.67 and was highly correlated with eGFR. Analysis of the subtypes of segmental glomerulosclerosis (S) lesions revealed that NOS and perihilar glomerular sclerosis were associated with adverse outcomes. Reporting T lesions as a continuous variable, normal glomeruli and subtypes of S lesions could provide clinicians with additional prognostic information and contribute to the improved performance of the Oxford classification and prognostic tools.

INTELLIGENCE ANALYSIS OF EMPIRICAL DATA BASED ON TIME SERIES

Context. The problem of intelligent data analysis for assessing the stability of operators’ functioning as a component of safety management is considered.The object of the study was to verify estimates of the complexity and chaotic nature of physiological processes based on nonlinear dynamics methods.
 Objective. The goal of work is intelligent data analysis for assessing the stability of the functioning of a dynamic system based on the methods of non-linear dynamics.
 Method. Data intelligence to obtain additional useful information to avoid wrong decisions when deciding on the current state of the operator to be able to perform professional duties. Quantitative assessment of the complexity of physiological dynamics to determine the stability of feedback control processes of body subsystems and their constant adaptation to changes in environmental conditions. The presence of significant nonlinearities in the biomedical signals of the body is associated with the appearance of a chaotic component that describes the chaotic nature of the body’s processes. Due to the fact that biomedical signals have both a periodic and a chaotic component, the study of the latter makes it possible to determine the informational component of the nature of the internal organization of the organism and provide information about the possible destabilization of the functional state of the operator. The use of nonlinear dynamics methods to study changes in the operator’s body and provide additional independent prognostic information complementing traditional data analysis in the time and frequency domains. Several indices obtained by the methods of nonlinear dynamics are proposed, which contribute to the expansion of the diagnostic solution based on the available data.
 Results. The results of the study can be used during the construction of mathematical methods of non-linear dynamics to describe empirical data of this kind.
 Conclusions. Experimental studies have suggested recommending the use of non-linear methods dynamics as an an additional independent component that allows analyzing the chaotic component of biomedical signals to avoid wrong decisions during professional selection and assessment of the current state of aviation industry operators as one of the causes of adverse events in aviation. Prospects for further research may include the creation of a methodology based on nonlinear dynamics methods that will allow to increase the reliability of predicting a malfunction of the cardiovascular system as an indicator of a change in the balance of the functional state of the operator based on additional informative parameters, which can be used to assess triggers that may cause an adverse event in aviation, as well as an experimental study of the proposed mathematical approaches for a wide range of diagnostic problems.

Effects of anthropometric changes on hospitalization and mortality among patients on hemodialysis.

Low values for anthropometric indicators are risk factors for adverse clinical outcomes among patients on hemodialysis. Nonetheless, little is known about the association between the trajectory of anthropometric indicators and prognosis. We examined theassociation between a one-year change in anthropometric indicators and hospitalization and mortality in patients undergoing hemodialysis. This retrospective cohort study collected data on five anthropometric indicators from patients undergoing maintenance hemodialysis: body mass index, mid-upper arm circumference, triceps skinfold, mid-arm muscle circumference, and calf circumference. We calculated their trajectories over one year. The outcomes were all-cause death and the number of all-cause hospitalizations. Negative binomial regressions were used to examine these associations. We included 283 patients (mean age, 67.3years; 60.4% males). During the follow-up period (median, 2.7years), 30 deaths and 200 hospitalizations occurred. Body mass index (incident rate ratio [IRR]: 0.87; 95% confidence interval [CI] 0.85-0.90), mid-upper arm circumference (IRR: 0.94; 95% CI 0.88-0.99), triceps skinfold (IRR: 0.92; 95% CI 0.84-0.99), and mid-arm muscle circumference (IRR: 0.99; 95% CI 0.98-0.99) increases over one year were associated with a lower risk of all-cause hospitalizations and death regardless of their value at any one point in time. However, the calf circumference trajectory was not associated with clinical events (IRR: 0.94; 95% CI 0.83-1.07). Body mass index, mid-upper arm circumference, triceps skinfold, and mid-arm muscle circumference trajectories were independently associated with clinical events. Routinely assessing these simple measures in clinical practice may provide additional prognostic information for managing patients undergoing hemodialysis.

Deep learning-based quantification of epicardial adipose tissue volume in cardiac magnetic resonace predicts major adverse cardiovascular events in patients with known or suspected CAD

Abstract Funding Acknowledgements Type of funding sources: None. Background Increased epicardial adipose tissue (EAT) volume quantified with cardiac magnetic resonance (CMR) has been associated with the development of major adverse cardiac events (MACE). We sought to investigate the additional prognostic role EAT volume in patients with known or suspected coronary artery disease (CAD) undergoing CMR imaging. Methods 702 consecutive patients (age: 63±10 y, male 84%) with known or suspected CAD underwent clinically indicated CMR. Using a new DL algorithm, EAT volume was quantified on short-axis stack steady state free precession (SSFP) images. Firstly, a training set of 300 patients with manually traced EAT (ground truth) was randomly split (patient-wise) into development (n=240, 80%) and held-out testing (n=60, 20%) cohorts. Secondly, we applied our segmentation network on a validation set of 402 patients with unlabeled data for automated EAT segmentations. Finally, we applied the algorith to the entire population (702 patients) to quantify EAT. EAT volume, normalized for the body mass index (EAT index), was compared to standard clinical and imaging variables for the prediction of MACE defined as non-fatal myocardial infarction and cardiac deaths. Results 52 patients (7.4%) developed MACE during a follow-up of 5.8±1.2 years. Left ventricular ejection fraction (LVEF) < 50% (HR 2.271 [95% CI 1.117–4.616]), p = 0.023, late gadolinium enhancement (LGE) presence (HR 2.456 [95% CI 1.077–5.602]), p = 0.033 and EAT index ≥ 1,8 (HR 6.187 [95% CI 1.879–20.372]), p = 0.003 were independent predictors of MACE. Adding EAT index in a model including LVEF and LGE provided a significant improvement in predicting the endpoint with a Harrell C statistic of 0.75. Conclusions In patients with known or suspected CAD undergoing CMR, fully automated EAT volume quantification provides additional prognostic information on top of standard clinical and imaging parameters.

Determinants of left atrial reservoir strain in a large healthy population

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Centre for Innovative Ultrasound Solutions Nord-Trøndelag Hospital Trust. Background Echocardiographic evaluation of the left atrium (LA) has until recently been done by assessment of LA end-systolic volume (LAESV) or Doppler measurements. While these measurements provide prognostic information, they indirectly measure LA function. LA reservoir strain, however, is a direct measurement of LA function and provides additional prognostic information but is affected by the left ventricle (LV) through movement of the atrioventricular plane. Purpose By evaluation of echocardiograms from a large healthy population we aimed to study the associations of LA reservoir strain with age, LA-, and LV volumes, and LV global longitudinal strain (LV GLS). Methods Echocardiographic acquisitions and analyses were performed according to current recommendations. All study personnel were experienced and affiliated with a European Association of Cardiovascular Imaging accredited echocardiographic laboratory. The associations of LA reservoir strain as outcome variable with age, LAESV, LV end-diastolic volume (LVEDV) and LV GLS were assessed by multiple linear regression analyses. Results In total 1412 subjects (56% females) with mean (SD) age 57 (12) years were included. Mean LVEF was 60.4% in females and 59.6% in males. Totally, 39% of the variance in LA reservoir strain between subjects was explained by age, LAESV, LVEDV and LV GLS (Table 1). All four characteristics were significantly associated with LA reservoir strain (all p<0.001). Age and LV GLS were the two most important characteristics for determining LA reservoir strain, indicating lower LA reservoir strain with higher age and lower absolute LV GLS. Six years of higher age had a similar effect as one percent lower absolute LV GLS. Similarly, 28 mL larger LAESV and 35mL smaller LVEDV corresponded to one percent lower absolute LV GLS. Conclusion In this large healthy population, almost 40% of the variance in LA reservoir strain between subjects was explained by age, LV GLS, and the volumes of LA and LV. The most important determinants were age and GLS, contributing equally to a reduction of LA reservoir strain with higher age and lower absolute LV GLS. Correspondingly, the size of LA and LV contributed less to the variability of LA reservoir strain. In conclusion, both age and LV function should be considered when interpreting LA reservoir strain.

Correlating MRI features with additional genetic markers and patient survival in histological grade 2-3 IDH-mutant astrocytomas

PurposeThe increasing importance of molecular markers for classification and prognostication of diffuse gliomas has prompted the use of imaging features to predict genotype (“radiogenomics”). CDKN2A/B homozygous deletion has only recently been added to the diagnostic paradigm for IDH[isocitrate dehydrogenase]-mutant astrocytomas; thus, associated radiogenomic literature is sparse. There is also little data on whether different IDH mutations are associated with different imaging appearances. Furthermore, given that molecular status is now generally obtained routinely, the additional prognostic value of radiogenomic features is less clear. This study correlated MRI features with CDKN2A/B status, IDH mutation type and survival in histological grade 2-3 IDH-mutant brain astrocytomas.MethodsFifty-eight grade 2–3 IDH-mutant astrocytomas were identified, 50 with CDKN2A/B results. IDH mutations were stratified into IDH1-R132H and non-canonical mutations. Background and survival data were obtained. Two neuroradiologists independently assessed the following MRI features: T2-FLAIR mismatch (<25%, 25–50%, >50%), well-defined tumour margins, contrast-enhancement (absent, wispy, solid) and central necrosis.Results8/50 tumours with CDKN2A/B results demonstrated homozygous deletion; slightly shorter survival was not significant (p=0.571). IDH1-R132H mutations were present in 50/58 (86%). No MRI features correlated with CDKN2A/B status or IDH mutation type. T2-FLAIR mismatch did not predict survival (p=0.977), but well-defined margins predicted longer survival (HR 0.36, p=0.008), while solid enhancement predicted shorter survival (HR 3.86, p=0.004). Both correlations remained significant on multivariate analysis.ConclusionMRI features did not predict CDKN2A/B homozygous deletion, but provided additional positive and negative prognostic information which correlated more strongly with prognosis than CDKN2A/B status in our cohort.

Longitudinal Assessment of Circulating Tumor Cells and Outcome in Small Cell Lung Cancer: A Sub-Study of RASTEN-A Randomized Trial with Low Molecular Weight Heparin.

Circulating tumor cells (CTCs) may provide a liquid biopsy approach to disease monitoring in small cell lung cancer (SCLC), a particularly aggressive tumor subtype. Yet, the prognostic role of CTCs during and after treatment in relation to baseline remains ill-defined. Here, we assessed the value of longitudinal CTC analysis and the potential of low-molecular-weight heparin (LMWH) to reduce CTC abundance in SCLC patients from a randomized trial (RASTEN). Blood samples were collected at baseline, before chemotherapy Cycle 3, and at 2-month follow-up from 42 patients in total, and CTCs were quantified using the FDA-approved CellSearch system. We found a gradual decline in CTC count during and after treatment, independently of the addition of LMWH to standard therapy. Detectable CTCs at baseline correlated significantly to reduced survival compared to undetectable CTCs (unadjusted hazard ratio (HR) of 2.75 (95% CI 1.05-7.20; p = 0.040)). Furthermore, a persistent CTC count at 2-month follow-up was associated with a HR of 4.22 (95% CI 1.20-14.91; p = 0.025). Our findings indicate that persistently detectable CTCs during and after completion of therapy offer further prognostic information in addition to baseline CTC, suggesting a role for CTC in the individualized management of SCLC.

Association Between Lipoprotein(A), LPA Genetic Risk Score, Aortic Valve Disease, and Subsequent Major Adverse Cardiovascular Events

Cohort studies have demonstrated associations between calcific aortic valve disease (CAVD) and lipoprotein(a) [Lp(a)]. As Lp(a) is almost entirely genetically determined, with the increasing clinical availability of genetic information, this study aimed to determine whether Lp(a), when predicted from genetic data, is associated with CAVD and major adverse cardiovascular events (MACE). Consecutive patients undergoing coronary angiography were invited to participate in the study. Of 752 analysable participants, 446 had Lp(a) measured and 703 had a calculable LPA genetic risk score (GRS). Calcific aortic valve disease was categorised as absent/present and by severity. The primary outcomes were presence of CAVD at baseline, and MACE over 7 years of follow-up. The GRS explained 45% of the variation in Lp(a). After adjustment for cardiac risk factors and coronary artery disease, the odds of CAVD increased with Lp(a) (OR 1.039 per 10-unit increase, 95% CI 1.022–1.057; p<0.001) and GRS (OR 1.054 per 10-unit increase, 95% CI 1.024–1.086; p<0.001). Lp(a) and the GRS as continuous variables were not associated with subsequent MACE. Dichotomised GRS (>54) was associated with MACE, but this relationship became non-significant when coronary artery disease classification was added into the model (OR 1.33, 95% CI 0.93–1.91; p=0.12). An LPA GRS can explain 45% of the variation in Lp(a) levels. Both Lp(a) and an LPA GRS are associated with CAVD. An elevated GRS appears to be associated with future cardiac events in a secondary risk setting, but, if coronary artery disease status is known, it does not provide additional prognostic information.

Identifying osteosarcoma signatures in cell free DNA using 5-hydroxymethylcytosine profiling.

10022 Background: Osteosarcoma is the most common primary bone tumor in children and adolescents. Prognostic biomarkers are limited, and post-treatment surveillance relies heavily on radiologic imaging. Capture and analysis of cell-free DNA (cfDNA) from the bloodstream is an emerging technique that could be used to provide additional prognostic information and track residual disease following treatment. 5-hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression, and tumor specific patterns of global 5-hmC deposition are identifiable in several cancers and vary according to disease burden. We profiled 5-hmC using plasma-derived cfDNA from osteosarcoma patients and healthy children to assess its utility as a biomarker of disease status. Methods: cfDNA was isolated from patients diagnosed with osteosarcoma and well child controls. Nano-hmC-Seal, a technique developed to isolate 5-hmC-modified DNA fragments, was used to generate sequencing libraries of cfDNA. Genomic DNA from osteosarcoma cell lines was serially diluted with healthy donor-derived cfDNA. DESeq2 was used to identify genes with high 5-hmC deposition in osteosarcoma cell line DNA relative to serial dilutions. In patient cfDNA samples, the relative abundance of 5-hmC deposition on these osteosarcoma genes was determined using gene set variation analysis (GSVA). GSVA returns a score ranging from -1 to 1, with positive values indicating a relative abundance of 5-hmC deposition on osteosarcoma genes. Results: The cohort consisted of 33 healthy children and 17 patients with osteosarcoma including 53 serially collected samples from these patients. 139 osteosarcoma genes were identified and used for GSVA analysis. Patients with osteosarcoma had significantly higher GSVA scores than well children (0.26 vs -0.38; p &lt; 0.001). Hierarchal clustering identified two clusters of samples from children with osteosarcoma. Cluster 1 contained samples with scores correlating with osteosarcoma-derived DNA compared to Cluster 2 (0.14 vs -0.18; p &lt; 0.001). Furthermore, Cluster 1 contained 17 of 23 samples from patients with active disease on clinical imaging (sensitivity = 74%, specificity = 57%). High 5-hmC deposition on MYC was readily identified in one sample obtained at diagnosis from the only patient with a MYC amplified tumor. Additional samples from this patient during treatment showed decreasing 5-hmC deposition on MYC, consistent with a treated tumor shedding less DNA into the blood. Additionally, decreased disease burden following surgical resection was identifiable in 5-hmC profiles (presurgical GSVA score 0.22 vs postsurgical -0.08; p = 0.004). Conclusions: Osteosarcoma 5-hmC signatures can identify patients with active disease. Monitoring cfDNA in osteosarcoma using 5-hmC profiling is a promising technique that warrants further investigation with larger patient cohorts.

The role of blood neutrophil lymphocyte ratio in predicting the initial response to anti-VEGF treatment in neovascular AMD patients.

Vascular endothelial growth factor (VEGF) has a critical role in age-related macular degeneration (AMD), and intravitreal injection of anti-VEGF drugs is the mainstay of neovascular AMD treatment. Blood neutrophil-to-lymphocyte ratio (NLR) is shown to be a biomarker of inflammation in AMD. We aimed to investigate the role of NLR in predicting favorable short-term anti-VEGF treatment results in neovascular AMD patients. A total of 112 patients diagnosed with exudative AMD and had taken 3 monthly intravitreal bevacizumab injections were analyzed retrospectively. Medical records were reached to obtain neutrophil and lymphocyte values to calculate NLR. Best-corrected visual acuity and central macular thickness (CMT) measurements were recorded at each visit. T test or Mann-Whitney U test was used to compare continuous variables, and chi-square test was used to compare categorical variables. Receiver operating characteristics curve (ROC) analysis was performed to determine cut-off, sensitivity, and specificity values. P value of ≤ 0.05 was considered statistically significant. The mean age was 68.1 ± 7.2years, and the mean NLR was 2.11 ± 0.81. The ROC analysis revealed a cut off value of 2.0 for NLR to predict at least 100μm CMT change (sensitivity 87.1%; specificity 87.8%) and a cut off value of 2.4 for NLR to predict at least 0.1 logMAR visual improvement (sensitivity 77.2%; specificity 64.8%) after 3 monthly IVT bevacizumab injections. NLR can provide additional prognostic information for the identification of patients with a good initial response to anti-VEGF therapy.

Prognostic value of nutritional status in post-implant CRT outcomes in patients with chronic heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Introduction There’s a close relationship between chronic heart failure (CHF) and malnutrition, and their main pathophysiological modifications are well known. Cardiac resynchronization therapy (CRT) has proven to be a promising therapy in symptomatic heart failure (HF) patients with broad QRS complexes and impaired systolic function with optimized medical therapy. However, there is still a considerable amount of non-responder patients. The role of nutritional status in CRT therapy response has yet still not been well assessed. Purpose Assess the prognostic value of nutritional status in post-op outcomes in patients with Chronic Heart Failure and (CRT) Methods Single-center retrospective study of patients submitted to CRT implantation between January 2007 and march 2021. Inclusion criteria were patients meeting criteria for CRT implantation, QRS duration ≥ 120ms, FEVE ≤ 35%, NYHA class II–IV and no adverse events during the follow up. Primary outcomes measured were all-cause mortality, cardiovascular mortality, and hospitalizations due to HF in a 1-year follow-up. To evaluate patient's nutritional status the CONUT score was used with patients being categorized in 2 groups: Low CONUT (Score 0-4: normal/low malnutrition) and Hight CONUT (Score 5-12: moderate/severe malnutrition). Results 198 patients (83%) exhibited Low CONUT status, and 41 patients (17%) exhibited High CONUT status. Patients with Hight CONUT were older (72.9 yrs vs 65.9 yrs, p&amp;lt;0.001), and exhibited higher percentage of chronic obstructive pulmonary disease (43.9% vs 27.3%, p=0.004), atrial fibrillation (72.9%, vs 25.3%, p&amp;lt;0.001), hypertension (78.1% vs 60.6%, p=0.038), chronic kidney disease (39.1% vs 21.2%, p=0.016) and NYHA IV (19.5% vs 5.1%, p&amp;lt;0.001). Cardiovascular mortality was 3.7% in the low CONUT group vs 29.3% in the Hight CONUT group (p&amp;lt;0.001; HR, 0.12; 95% CI, 0.05-0.29) and total HF hospitalizations were 16 and43, respectively (p=0.013; HR, 0.482, 95% CI, 0.27 to 0.86). The nutritional status prior to CRT assessed by the CONUT score showed to be an independent predictor of cardiovascular mortality (p=0.007; HR, 0.16 95% CI, 0.04-0,60). Conclusion Malnutrition was a common condition in our CRT patients showing that deficient nutrition status remains highly underdiagnosed. Patients with worse nutritional status before CRT device implantation presented higher morbidity and were more prone to worst outcomes such as cardiovascular mortality and mortality by all causes as well as higher incidence of hospitalizations secondary to HF decompensation. Assessment of nutritional status using screening tools may provide additional prognostic information in patients with HF and help early identification of those who may benefit from further assessment and nutritional intervention.

Development and testing of a polygenic risk score for breast cancer aggressiveness

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS’s association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06–1.21, p = 4.0 × 10–4). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRSER-/ER+). Furthermore, its effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention.

Ultrasensitive NGS MRD assessment in Ph+ ALL: Prognostic impact and correlation with RT-PCR for BCR::ABL1.

Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, RT-PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay (sensitivity of 10-6 ) and its correlation with RT-PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT-PCR and NGS, and 31% of patients who achieved NGS MRD negativity were PCR+ at the same timepoint. Among eight patients with long-term detectable BCR::ABL1 by PCR, six were PCR+/NGS-. These patients generally had stable PCR levels that persisted despite therapeutic interventions, and none subsequently relapsed; in contrast, patients who were PCR+/NGS+ had more variable PCR values that responded to therapeutic intervention. In a separate cohort of prospectively collected clinical samples, 11 of 65 patients (17%) with Ph+ ALL who achieved NGS MRD negativity had detectable BCR::ABL1 by PCR, and none of these patients relapsed. Relapse-free survival and overall survival were similar in patients who were PCR+/NGS- and PCR-/NGS-, suggesting that PCR for BCR::ABL1 did not provide additional prognostic information in patients who achieved NGS MRD negativity. NGS-based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low-level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.

Prognostic contribution of left ventricular myocardial work assessment in mitral valve prolapse

Mitral Valve Prolapse (MVP) is the leading cause of primary mitral regurgitation (MR). Due to volume overload-induced changes in severe MR, assessment of left ventricular systolic function, an important marker to refer patients to surgery, is difficult. The aim of our study was to assess cardiac mechanics based on the non-invasive evaluation of myocardial work, by analysing the left ventricular pressure-strain loop, taking into account loading conditions. In total, 321 patients (63% male) with MVP (with or without severe MR), who underwent a comprehensive echocardiography and cardiac magnetic resonance (CMR) between 2010 and 2021, were included. Myocardial work parameters were assessed using a dedicated software. The primary endpoint associated cardiovascular death, sustained ventricular arrhythmia, heart failure, new onset atrial fibrillation, or arterial embolism. Of the 321 patients 186 (58%) had a GWW (global wasted work) < 120 mmHg% and 135 (42%) a GWW ≥ 120 mmHg%. GWW < 120 mmHg% was associated with echographic and CMR parameters of abnormal filling, volume overload and more severe regurgitation. During a mean follow-up of 4.5 ± 2.8 years, censored at the time of mitral valve surgery, 36 cardiovascular events were recorded in the GWW < 120 mmHg% group versus 14 in the GWW ≥ 120 mmHg% group (19% vs. 10%; P = 0.028). Heart failure (15 vs. 6%; P = 0.011) and mitral valve intervention (69 vs. 59%; P = 0.045) rates were higher in the GWW < 120 mmHg% group. Five-year cardiovascular event-free survival was decreased in patients with GWW < 120 mmHg% (46.6 ± 7.7% vs. 59.1 ± 12.4%; P = 0.023). In multivariable analysis, MR severity, the presence of late enhancement on CMR, and GWW < 120 mmHg% (HR 1.76; 95% CI 0.93–3.34; P = 0.085) were associated with impaired event-free survival. Myocardial work-up provides additional diagnostic and prognostic information to echocardiography and cardiac MRI in MV.

Cardiac Magnetic Resonance in myocarditis: besides the diagnosis?

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Patients with acute myocarditis (AM) can be at increased risk of adverse cardiac events after the index episode. Beyond its undoubted role in diagnosis, Cardiac Magnetic Resonance (CMR) can also provide additional prognostic information and contribute to the patients risk stratification. Methods Retrospective study with patients admitted with the clinical suspicion of myocarditis in our center from February/2018 to September/2021, in whom CMR was performed. A total of 48 patients were included and divided into two groups based on the number of segments with late gadolinium enhancement (LGE). The threshold (&amp;gt; or &amp;lt; than 5 segments) was determined according to ROC curve analysis. The primary outcome was a composite of all-cause mortality, heart failure and myocarditis recurrence. Results We included 48 patients (95,8% males; mean age 37,0±16,1 years old), 93,8% presenting with chest pain and 63,2% presenting with st-segment elevation on electrocardiogram. During hospitalization, 3 patients needed ionotropic support, 7 had supraventricular tachycardia, 9 non-sustained ventricular tachycardia, 1 sustained ventricular tachycardia, 1 needed extracorporeal membrane oxygenation and 9 had heart failure. CMR (performed 6 days (median) after admission) showed LGE in 45 patients (93,8%) and mean left ventricular ejection fraction (LVEF) of 55,5±8,7%. Both groups had similar age (35,0±13,7 vs 38,5±17,6 years, p=0,45), cardiovascular risk factors, st-segment elevation at admission (61,9% vs 63,0%, p=0,38), pro-BNP levels at admission [286 (IQR 144-699) mg/dl vs 522 (IQR 222-1253) mg/dl, p = 0,20] and peak C-reactive protein [5,7 (IQR 4-12) vs 5,2 (IQR 2,6-12,5),p=0,77]. Patients with LGE in ≥5 segments (56,3%) had lower LVEF (53,2±9,6 vs 58,2±6,6, p=0,02), had more non-sustained ventricular tachycardia episodes (29,6% vs 4,8%, p=0,03), incidence of heart failure during hospitalization (25,9% VS 9,6%, p=0,19) and higher peak troponin levels [1,54 (IQR0,64-2,45) vs 0,594 (IQR 0,374-1,07), p=0,002]. During a median follow-up of 21,5 (IQR 8–35,2) months, 11 patients (22,9%) experienced the primary outcome (6 for heart failure, 4 for AM recurrence, 1 death). The incidence of the primary endpoint increased by 1,20 (95% CI 1,08-1,60) for each segment involved. Patients with ≥ 5 segments had a higher incidence of this outcome (25,7 vs 5,1 per 100 patient/year, log rank p=0,02). After adjusting for possible cofounders, LGE≥ 5 segments on CMR was an independent predictor of all-cause mortality, heart failure and myocarditis recurrence (HR 7,22, 95% CI 1,33-39,16). Conclusion In this study, LGE involving 5 or more segments by LGE was correlated with adverse cardiovascular events among patients with suspected myocarditis. These data suggest that cardiac resonance imaging might add value to currently existing diagnostic tools for risks assessment in AM.

Risk factors and 180-day mortality of acute kidney disease in critically ill patients: A multi-institutional study.

Critically ill patients with acute kidney injury (AKI) have a poor prognosis. Recently, the Acute Disease Quality Initiative (ADQI) proposed to define acute kidney disease (AKD) as acute or subacute damage and/or loss of kidney function post AKI. We aimed to identify the risk factors for the occurrence of AKD and to determine the predictive value of AKD for 180-day mortality in critically ill patients. We evaluated 11,045 AKI survivors and 5,178 AKD patients without AKI, who were admitted to the intensive care unit between 1 January 2001 and 31 May 2018, from the Chang Gung Research Database in Taiwan. The primary and secondary outcomes were the occurrence of AKD and 180-day mortality. The incidence rate of AKD among AKI patients who did not receive dialysis or died within 90 days was 34.4% (3,797 of 11,045 patients). Multivariable logistic regression analysis indicated that AKI severity, underlying early CKD, chronic liver disease, malignancy, and use of emergency hemodialysis were independent risk factors of AKD, while male gender, higher lactate levels, use of ECMO, and admission to surgical ICU were negatively correlated with AKD. 180-day mortality was highest among AKD patients without AKI during hospitalization (4.4%, 227 of 5,178 patients), followed by AKI with AKD (2.3%, 88 of 3,797 patients) and AKI without AKD (1.6%, 115 of 7,133 patients). AKI with AKD had a borderline significantly increased risk of 180-day mortality (aOR 1.34, 95% CI 1.00-1.78; p = 0.047), while patients with AKD but no preceding AKI episodes had the highest risk (aOR 2.25, 95% CI 1.71-2.97; p < 0.001). The occurrence of AKD adds limited additional prognostic information for risk stratification of survivors among critically ill patients with AKI but could predict prognosis in survivors without prior AKI.

Effect of C-reactive protein on the risk of Heart failure: a mendelian randomization study

BackgroundTraditional observational studies have shown positive associations between c-reactive protein (CRP) and heart failure (HF) risk. However, this association has not been fully elucidated. Therefore, Mendelian randomization was used to examine CRP’s possible etiological roles with HF.MethodsWe implemented a two-sample Mendelian randomization framework to examine the causality of the association between CRP and HF based on summary statistics by large-scale genome-wide association studies (GWAS) datasets of European ancestry through inverse-variance weighted, weighted median, MREgger regression, and MR-PRESSO methods. The summary statistics dataset on the association of genetic variants with CRP was used from the published GWAS of European descent in UK Biobank participants (N = 427,367) and the CHARGE consortium (N = 575,531). The GWAS dataset used to identify genetic variants underlying HF from the HERMES consortium includes 977,323 participants (47,309 cases and 930,014 controls). The odds ratio (OR) with 95% confidence intervals (CIs) was employed to examine this association.ResultsThe results of our IVW indicated that CRP was strongly associated with HF (OR = 4.18, 95% CI = 3.40–5.13, p < 0.001). The Cochran heterogeneity test showed significant heterogeneity among SNPs of CRP (Q = 317.55, p < 0.001; I2 = 37.6%), and no considerable pleiotropy was detected for the association of CRP with HF [intercept = 0.003; p = 0.234]. This finding remained consistent using different Mendelian randomization methods and sensitivity analyses.ConclusionOur MR study did identify convincing evidence to support CRP associated with HF risk. Human genetic data suggest that CRP is a causative factor in HF. Hence, CRP assessment may offer additional prognostic information as an adjuvant to overall risk assessment in HF patients. These findings prompt significant questions about the function of inflammation in the progression of HF. More research into the role of inflammation in HF is needed to guide trials of anti-inflammation management.

Automated Ki-67 labeling index assessment in prostate cancer using artificial intelligence and multiplex fluorescence immunohistochemistry.

The Ki-67 labeling index (Ki-67 LI) is a strong prognostic marker in prostate cancer, although its analysis requires cumbersome manual quantification of Ki-67 immunostaining in 200-500 tumor cells. To enable automated Ki-67 LI assessment in routine clinical practice, a framework for automated Ki-67 LI quantification, which comprises three different artificial intelligence analysis steps and an algorithm for cell-distance analysis of multiplex fluorescence immunohistochemistry (mfIHC) staining, was developed and validated in a cohort of 12,475 prostate cancers. The prognostic impact of the Ki-67 LI was tested on a tissue microarray (TMA) containing one 0.6mmsample per patient. A 'heterogeneity TMA' containing three to six samples from different tumor areas in each patient was used to model Ki-67 analysis of multiple different biopsies, and 30 prostate biopsies were analyzed to compare a 'classical' bright field-based Ki-67 analysis with the mfIHC-based framework. The Ki-67 LI provided strong and independent prognostic information in 11,845 analyzed prostate cancers (p< 0.001 each), and excellent agreement was found between the framework for automated Ki-67 LI assessment and the manual quantification in prostate biopsies from routine clinical practice (intraclass correlation coefficient: 0.94 [95% confidence interval: 0.87-0.97]). The analysis of the heterogeneity TMA revealed that the Ki-67 LI of the sample with the highest Gleason score (area under the curve [AUC]: 0.68) was as prognostic as the mean Ki-67 LI of all six foci (AUC: 0.71 [p= 0.24]). The combined analysis of the Ki-67 LI and Gleason score obtained on identical tissue spots showed that the Ki-67 LI added significant additional prognostic information in case of classical International Society of Urological Pathology grades (AUC: 0.82 [p= 0.002]) and quantitative Gleason score (AUC: 0.83 [p= 0.018]). The Ki-67 LI is a powerful prognostic parameter in prostate cancer that is now applicable in routine clinical practice. In the case of multiple cancer-positive biopsies, the sole automated analysis of the worst biopsy was sufficient. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Identification of distinct tumor cell patterns with single-cell RNA sequencing integrating primary lung adenocarcinoma and brain metastasis tumor.

Lung adenocarcinoma (LUAD) is the most common form of lung cancer and is often accompanied by brain metastasis (BM). The heterogeneity of the tumor renders all current conventional treatments less effective. This study aims to dissect tumor cell heterogeneity and identify potential therapeutic targets. We conducted single-cell RNA-sequencing (scRNA-seq) in 8 patients with treatment-naïve LUAD BM and included scRNA-seq data of 10 primary LUAD samples and their matched adjacent normal tissue from GSE131907 to determine the tumor cell heterogeneity. Our analyses revealed tumor cells derived from brain metastases were more heterogeneous. Tumor cells from BM harbored significantly more copy number variants (CNVs), and cells of magnoid subtype were the critical source of malignant cells both in BM and the primary lung tumor. Pseudo-time trajectory analysis revealed that malignant cells had upregulated genes enriched for cell cycle and cell division. Integrated analysis of tumor cells revealed 2 distinct malignant cell clusters (cluster 4 and cluster 6) and their marker genes. The signatures identified in the single-cell profile had prognostic value in the bulk tumor profiles. Moreover, the signature of cluster 4 had significant prognostic value in predicting patients surviving longer than 3.5 years, while the signature of cluster 6 showed better predictive ability within 1 year. Magnoid-type cells are most likely to develop into the riskiest cell type and potentially promote tumor progression. scRNA profiling that integrates LUAD BM and primary LUAD can provide information on those malignant cells with BM potential, offering additional prognostic information at cellular level, and may serve as a foundational resource for further tumor cell dissection and therapeutic target exploration.

Abstract OT2-05-01: FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols

Abstract FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols BACKGROUND: Genomic signatures, such as the 70-gene MammaPrint, provide additional prognostic information for early-stage breast cancer (EBC), such as tumor metastatic potential, and expand the available information clinicians and patients require for shared treatment decision making beyond the standard clinicopathologic factors. EBC tumors are further stratified into clinically actionable subtypes by molecular assays such as the 80-gene molecular profiling assay BluePrint, improving pathological complete response rates (pCR) and outcomes as evidenced by a number of recent trials. The ongoing FLEX Study (NCT03053193) is designed to expand the genomic information available for EBC cases, and to increase the speed of data generation for rare and underserved research areas. To date, FLEX is the largest international multicenter real-world evidence (RWE) EBC registry, with more than 10,000 patients enrolled in fewer than five years since opening. FLEX pairs full genome data with more than 800 clinical data points collected over 10 years of follow up to provide the most comprehensive big data database available for early-stage breast cancer. The FLEX enrollment has a goal of a minimum of 30,000 patients within 10 years. METHODS: The FLEX study is a multicenter, prospective, observational trial for patients ≥18 years old with histologically proven stage I-III invasive breast cancer that is node negative or positive (up to three nodes) who receive MammaPrint, with or without BluePrint as standard of care management. Patients consent to the collection of clinically annotated full transcriptome data. Additionally, this study protocol allows physicians to investigate targeted populations or clinical trial investigator-initiated studies (IIS) upon approval by a peer-driven Scientific Review Committee. As patients enrolled in the FLEX study meet all eligibility criteria for inclusion no additional consent is required. The FLEX enrollment has already surpassed 1/3 of set target goal. As of April 2022, the trial has surpassed 10,000 patients enrolled at nearly 100 trial sites across the US and Europe, Middle East and Africa (EMEA). To date, there have been 36 publications in international scientific congresses with 39 FLEX IIS and in progress. With over 250 active and collaborating physicians leveraging the shared infrastructure, the IIS have enabled the ability to address disparities in treatment to underrepresented populations, rare subtypes, age, and patient centered specific topics. Current and future questions investigated via this platform will continue to strive to improve outcomes for early-stage breast cancer patients. Citation Format: Alejandra Perez, Hannah Linden, Nathalie Johnson, Sami Diab, Chirag Jani, Chelsea D. Gawryletz, Richard Fine, Laura Lawson, Megan Baker, Victoria Poillucci, Lisa E. Blumencranz, William Audeh. FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-05-01.