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Epigenetic Features of cfDNA Progress in cfDNA research has been driven forward rapidly by systematic characterizations of specific DNA mutations across basic and clinical research settings. This momentum has promise to not only accelerate the advent of personalized cancer care based on cfDNA assays but to also unlock the potential of cfDNA as a biomarker for various other diseases and clinical conditions. Oberhofer et al. also discuss cfDNA fragmentomics, but they also explore exciting and rapidly expanding research showing that various other epigenetic and physico-chemical features of cfDNA, such as various types of DNA methylation patterns, post-translational histone modifications, and nucleosome compaction patterns, are often cell- and disease-specific, which can be leveraged to trace the origins of cfDNA molecules. They found a high concordance in the mutational profiles between cfDNA and tissue analysis, indicating that cfDNA may be an ideal biomarker and potentially an alternative method to tissue analysis for the management of PMBL cases [[20]]. [Extracted from the article]

Background: The association of aspartate aminotransferase to alanine aminotransferase ratio (De Ritis ratio) with clinical outcomes in patients with chronic coronary syndromes (CCS) remains unclear. This study aims to assess the association of De Ritis ratio with adverse cardiovascular events in patients with CCS. Materials and Methods: The study included 5020 patients with CCS undergoing percutaneous coronary intervention. Patients were categorized into groups according to tertiles of the De Ritis ratio: tertile 1 (De Ritis ratio: <.75; n = 1688 patients), tertile 2 (De Ritis ratio:.75–1.08; n = 1666 patients) and tertile 3 (De Ritis ratio: >1.08; n = 1666 patients). The primary endpoint was 3‐year mortality. Results: At 3 years, there were 384 deaths, 176 myocardial infarctions and 61 strokes. In groups with De Ritis in the 1st, 2nd and 3rd tertiles, deaths occurred in 5.0%, 7.5% and 14.5% of the patients, respectively (adjusted hazard ratio = 1.09, 95% confidence interval [1.06–1.12], p <.001); myocardial infarctions occurred in 2.6%, 3.5% and 5.1% of the patients, respectively (p <.001); strokes occurred in 1.0%, 1.2% and 1.9% of the patients, respectively (p =.030); bleeding at 30 days (n = 112) occurred in 1.4%, 1.6% and 3.7% of the patients, respectively (p <.001). The C‐statistic of the Cox proportional hazards model for all‐cause mortality with baseline data without the De Ritis ratio was.815 [.794–.836] and.818 [.797–.838] after the inclusion of the De Ritis ratio (delta C‐statistic =.003; p =.005). Conclusions: In patients with CCS undergoing percutaneous coronary intervention, an elevated De Ritis ratio was associated with long‐term major adverse cardiovascular events. [ABSTRACT FROM AUTHOR]

• Elevated De Ritis ratio with AST and ALT activity in the reference range has prognostic value. • De Ritis ratio with AST and ALT activity in the reference range predicts 3-year all-cause, cardiac and noncardiac mortality. • De Ritis ratio provides prognostic information on top of cardiovascular risk factors. Whether aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (De Ritis ratio) with AST and ALT activities within the reference range has prognostic value is unknown. This study included 3392 patients with stable coronary artery disease and AST and ALT activities within the reference range. Patients are categorized in groups according to tertiles of the De Ritis ratio: a group with De Ritis ratio in the 1st tertile (De Ritis ratio: 0.22 to 0.81; n = 1131), a group with De Ritis ratio in the 2nd tertile (De Ritis ratio: >0.81 to 1.09; n = 1130) and a group with De Ritis ratio in the 3rd tertile (De Ritis ratio: >1.09 to 3.40; n = 1131). The primary endpoint was 3-year mortality. The mean value of De Ritis ratio was 1.00 ± 0.39 (range: 0.22–3.40). Overall, there were 234 deaths at 3 years: 43 deaths in patients of 1st tertile, 75 deaths in patients of 2nd tertile and 116 deaths in patients of 3rd tertile of De Ritis ratio (Kaplan-Meier estimates of 3-year mortality, 4.4 %, 7.8 % and 12.5 %, respectively; (adjusted hazard ratio = 1.24, 95 % confidence interval 1.12 to 1.38; P < 0.001 for 1 unit higher De Ritis ratio). The C-statistic of the risk prediction model for mortality with baseline demographical and clinical variables without De Ritis ratio was 0.803 [0.774–0.832] and it increased to 0.810 [0.782–0.839] after inclusion of De Ritis ratio into the model (P = 0.038). An elevated De Ritis ratio with aminotransferase levels within the reference range was associated with the increased risk of mortality. [ABSTRACT FROM AUTHOR]

• De Ritis ratio predicts 3-year all-cause mortality after acute myocardial infarction. • De Ritis ratio predicts 3-year cardiac mortality after acute myocardial infarction. • De Ritis ratio predicts 30-day risk of bleeding after percutaneous coronary intervention. • De Ritis ratio has a moderate sensitivity regarding prediction of mortality. The association between aspartate aminotransferase to alanine aminotransferase ratio (De Ritis ratio) and prognosis of patients with acute myocardial infarction (AMI) remains poorly investigated. This study included 3000 patients with AMI undergoing percutaneous coronary intervention. Patients were categorized in groups according to tertiles of the De Ritis ratio: tertile 1 (De Ritis ratio < 1.11; 905 patients), tertile 2 (De Ritis ratio 1.11 to 1.95; 1003 patients) and tertile 3 (De Ritis ratio > 1.95; 1002 patients). The primary endpoint was 3-year all-cause mortality. At 3 years, all-cause deaths occurred in 487 patients: 119 deaths (13.2%) in patients of 1st tertile, 164 deaths (17.8%) in patients of 2nd tertile and 204 deaths (21.9%) in patients of 3rd tertile of the De Ritis ratio (adjusted hazard ratio [HR] = 1.16, 95% confidence interval [CI] 1.02 to 1.31], P = 0.023 per unit increment in the logarithmic scale of the De Ritis ratio); cardiac deaths occurred in 328 patients: 76 deaths (8.2%) in patients of 1st tertile, 110 deaths (12.0%) in patients of 2nd tertile and 142 deaths (15.4%) in patients of 3rd tertile of the De Ritis ratio (adjusted HR = 1.20 [1.04–1.40], P = 0.014 per unit increment in the logarithmic scale of De Ritis ratio). The C-statistic of the multivariable model(s) with baseline data without and with De Ritis ratio was 0.822 [0.805–0.839] and 0.823 [0.805–0.840], (P = 0.419) for all-cause mortality and 0.831[0.811–0.852] and 0.832 [0.811–0.853], P = 0.621) for cardiac mortality. In patients with AMI, elevated De Ritis ratio was associated with increased risk of 3-year mortality. [ABSTRACT FROM AUTHOR]

• ALP predicts 3-year mortality in patients with diabetes mellitus and ischemic heart disease. • Low and high ALP activity levels were associated with increased risk of mortality. • Impaired renal function and elevated C-reactive protein correlated with higher ALP activity. The association between alkaline phosphatase (ALP) and mortality in patients with diabetes mellitus (DM) and ischemic heart disease (IHD) remains poorly investigated. The study included 1426 patients with DM and IHD who underwent percutaneous coronary intervention. Patients were divided in groups according to tertiles of ALP activity: a group with ALP activity in 1st tertile (ALP activity: 20.8–65.0 U/L; n = 478), a group with ALP activity in 2nd tertile (ALP activity: 65.1–87.0 U/L; n = 473) and a group with ALP activity in 3rd tertile (ALP activity: 87.1–1520 U/L; n = 475). The primary endpoint was 3-year all-cause mortality. At 3 years, all-cause deaths occurred in 182 patients: 50 deaths (12.4%) in patients of 1st tertile, 47 deaths (11.7%) in patients of 2nd tertile and 85 deaths (20.8%) in patients of 3rd tertile of ALP activity (adjusted hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.02 to 1.42, P = 0.031); cardiac deaths occurred in 110 patients: 28 deaths (7.0%) in patients of 1st tertile, 30 deaths (7.6%) in patients of 2nd tertile and 52 deaths (12.7%) in patients of 3rd tertile of ALP activity (adjusted HR = 1.27 [1.04–1.56], P = 0.021, with both risk estimates calculated for unit increment in the log scale of ALP activity). The C-statistic of the multivariable model with baseline data without and with ALP was 0.787 [0.750–0.818] and 0.804 [0.757–0.851], (P = 0.575) for all-cause mortality and 0.832 [0.798–0.864] and 0.876 [0.833–0.918], (P = 0.115) for cardiac mortality. In patients with DM and IHD, elevated ALP activity was associated with increased risk of 3-year mortality. [ABSTRACT FROM AUTHOR]

• Cockcroft-Gault creatinine clearance and EKFC equations predict mortality better than MDRD-4 and CKD-EPI equations. • Cockcroft-Gault creatinine clearance and EKFC equations predict bleeding better than MDRD-4 and CKD-EPI equations. • All four eGFR equations failed to improve risk prediction for myocardial infarction. It remains unknown which equation used to assess the glomerular function is better for risk stratification in patients with acute coronary syndrome (ACS). This study included 3985 patients with ACS. Glomerular function was assessed using 4 equations: the Cockcroft-Gault creatinine clearance (C-G CrCl), Modification of Diet in Renal Disease-4 (MDRD-4), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) equations. The primary outcome was one-year all-cause mortality. For each 30 ml/min decrement, the adjusted hazard ratio [HR] with 95% confidence interval [CI] for one-year mortality was 1.67 [1.27–2.25] for C-G CrCl , 1.45 [1.16–1.81] for MDRD-4, 1.76 [1.35–2.30] for CKD-EPI and 1.94 [1.44–2.63] for EKFC equation. Area under the receiver operating characteristic curve (AUC) for one-year mortality was 0.748 [0.709–0.788] for C-G CrCl , 0.670 [0.621–0.718] for estimated glomerular filtration rate (eGFR) calculated by MDRD-4 equation, 0.725 [0.684–0.765] for eGFR calculated by CKD-EPI equation and 0.741 [0.703–0.779] for eGFR calculated by EKFC equation (P = 0.342 for C-G CrCl , vs. EKFC equation and P ≤ 0.009 for all other AUC comparisons). In patients with ACS, C-G CrCl and EKFC equations showed a similar discriminatory power regarding prediction of one-year mortality. Both equations were better than MDRD-4 and CKD-EPI equations for risk discrimination for mortality. Clinical Trial Registration: NCT01944800. [ABSTRACT FROM AUTHOR]

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is frequently used as a valuable prognostic biomarker in cardiac diseases. In children, however, it has not been established because of its strong age dependency. To overcome this obstacle, we recently introduced the zlog value of N-terminal pro-B-type natriuretic peptide (zlog-proBNP) as an age-adjusted reference.Objectives: This study evaluates the prognostic power of zlog-proBNP for the occurrence of major adverse cardiovascular events (MACE) throughout childhood in patients with congenital heart diseases (CHD).Methods: A total of 910 children with CHD (median age 5 months; range 0.0-18.0 years) were included. MACE was defined as death, resuscitation, mechanical circulatory support, or hospitalization caused by cardiac decompensation. Because the physiological NT-proBNP concentration decreases significantly during childhood, zlog values were applied for an age-independent evaluation.Results: MACE occurred in 138 children during a median follow-up of 6 months (range 1 day to 7.6 years). High zlog-proBNP values (>+3.0) were most strongly associated with adverse events (n = 93; adjusted HR: 21.1; 95% CI: 2.9-154.2; P < 0.001). Among all evaluated indicators, zlog-proBNP was the best predictor for MACE (adjusted HR: 1.52; 95% CI: 1.31-1.76; P < 0.001) along with age and predictively superior to absolute NT-proBNP values. A cutoff value of +1.96 (age-independent upper limit of the physiological NT-proBNP concentration) achieved a negative predictive value of >96%.Conclusions: Zlog-proBNP overcomes the strong age dependency of NT-proBNP and is a powerful prognostic marker for age-independent exclusion and prediction of MACE in children with CHD. We therefore expect zlog-proBNP to play a pivotal role in the future management of children with heart diseases. [ABSTRACT FROM AUTHOR]

Background: The association between elevated creatine kinase (CK) and bleeding in patients with acute coronary syndrome (ACS) remains incompletely investigated. We undertook this study to assess whether there is an association between elevated CK activity and the risk for bleeding in contemporary patients with ACS. Materials and Methods: This post hoc analysis of a randomized trial included 3368 patients with ACS undergoing percutaneous coronary intervention. CK was measured serially in all patients until hospital discharge. The main outcome was 30‐day incidence of major bleeding (type 3 to 5 bleeding according to the Bleeding Academic Research Consortium criteria). Results: Patients were categorized in groups according to the peak CK tertiles: 1st tertile (CK ≤259 U/L; n = 1127 patients), 2nd tertile (CK ≥260 to 990 U/L; n = 1119 patients), and 3rd tertile (CK ≥ 991 U/L; n = 1122 patients). Peak CK activity was higher in patients with bleeding than those without bleeding (771 [316‐1845] U/L vs. 496 [190‐1357] U/L; P <.001). Bleeding occurred in 26 patients (2.3%) with peak CK within 1st tertile, 39 patients (3.5%) with peak CK within 2nd tertile, and 54 patients (4.8%) with peak CK within 3rd tertile (univariable hazard ratio [HR]=1.39, 95% confidence interval [CI] 1.08 to 1.81, P =.012, per tertile increment in CK values). After adjustment, peak CK activity remained significantly associated with the 30‐day bleeding (HR = 1.67 [1.16‐2.41]; P =.006 per unit increment in logarithmic CK values). The C statistic of the multivariable model with CK activity was 0.807 [0.770‐0.842]. Conclusions: In patients with ACS, peak CK activity was independently associated with increased 30‐day incidence of bleeding. [ABSTRACT FROM AUTHOR]

Zielgerichtete Therapien (Targeted Therapies) mit Antikörpern oder sog. Small Molecules sind eine wirksame Behandlungsstrategie bei Tumorerkrankungen, wenn im Tumorgewebe spezifische Mutationen auf den Zielmolekülen vorhanden sind. Während der Therapie kann sich die Klonalität des Tumors verändern, d. h. Mutationen können verschwinden oder neue Mutationen können entstehen. Deshalb ist für eine echte „Companion Diagnostic“ nicht nur die molekulare Testung vor Beginn der Therapie, sondern auch wiederholt während der Therapie oder im weiteren Krankheitsverlauf sinnvoll. Mit der Liquid Profiling- bzw. Liquid Biopsy-Diagnostik steht eine nicht-invasive und sehr sensitive Methode zur Verfügung, mit der eine Aussage über den Mutationsstatus eines Tumors getroffen werden kann. Dies schafft die Grundlage für individuelle Anpassungen der Therapie an den jeweils aktuellen Bedarf. [ABSTRACT FROM AUTHOR]

Bei NT-proBNP zeigt sich eine besonders ausgeprägte Altersabhängigkeit der Referenzintervalle im Kindesalter. Kontinuierliche Referenzintervalle und ein NT-proBNP-spezifischer zlog-Wert ermöglichen in der Kinderkardiologie erstmals Verlaufskontrollen und unterstützen die Risikostratifizierung bei schwerwiegenden kardialen Ereignissen. Dies erhöht den Stellenwert dieses Biomarkers für den klinischen Einsatz deutlich. [ABSTRACT FROM AUTHOR]

Extrazelluläre Vesikel sind eine heterogene Gruppe von subzellulären Partikeln, die durch verschiedene Mechanismen von den Ursprungszellen freigesetzt werden. Sie transportieren spezifische Informationen und sind für eine effiziente interzelluläre Kommunikation verantwortlich, die für viele physiologische Prozesse sowie für die Pathogenese und das Fortschreiten verschiedener Erkrankungen von großer Bedeutung ist. In Zukunft könnten sie für den gezielten Transport von Medikamenten genutzt werden oder als empfindliche Biomarker für das „Liquid Profiling“ dienen. [ABSTRACT FROM AUTHOR]

Data regarding the association between alanine aminotransferase (ALT) and prognosis of patients with coronary artery disease (CAD) are limited. The aim of this study was to assess the association of ALT with the prognosis of patients with CAD. The study included 9523 patients with angiography-proven CAD who underwent percutaneous coronary intervention. Baseline ALT activity measurements were available for analysis in all patients. The primary outcome was 3-year cardiac mortality. Patients were divided into three groups: a group with ALT within the 1st tertile (ALT 2.0 U/L to ≤17.0 U/L; n = 3276 patients), a group with ALT within the 2nd tertile (ALT >17.0 U/L to ≤26.0 U/L; n = 3075 patients) and a group with ALT within 3rd tertile (>26 U/L to ≤50.0 U/L; n = 3172 patients). Cardiac death (primary outcome) occurred in 441 patients: 201 (7.1%), 126 (4.7%) and 114 (4.0%) of these occurring in patients in the 1st, 2nd and 3rd ALT tertiles, respectively (with percentages representing Kaplan–Meier estimates of 3-year cardiac mortality); adjusted hazard ratio = 1.43, 95% confidence interval 1.11 to 1.85, P = 0.006 calculated for 1 unit decrement in the logarithmic scale of ALT. The multivariable model for cardiac mortality with baseline variables without ALT had a C-statistic of 0.827 [0.801–0.853], P < 0.001, which increased to 0.832 [0.806–0.857], P < 0.001 after incorporation of ALT (P = 0.020). In patients with CAD, ALT was inversely and independently associated with the risk of 3-year cardiac mortality. Low ALT may reflect cardiovascular risk that is poorly mediated by traditional cardiovascular risk factors. • Alanine aminotransferase (ALT) is inversely associated with 3-year cardiac mortality • ALT improves the risk prediction for cardiac mortality • Low ALT mediates cardiovascular risk poorly presented by cardiovascular risk factors [ABSTRACT FROM AUTHOR]

Eine frühzeitige Erkennung gilt als Schlüssel für eine bestmögliche Behandlung von Tumorerkrankungen. Ein neuer Ansatz zum umfassenden Tumor-Screening ist die Charakterisierung von zellfreier Tumor-DNA (ctDNA) im Blutplasma durch massive Sequenzierung in Form eines molekularen Profiling der Mutationen, der Methylierungsmuster sowie einer Fragmentanalyse der ctDNA. Dadurch ist die zielgenaue Erkennung von Tumoren im frühen Stadium wie auch deren Lokalisation möglich. Studien mit echten Screening-Populationen müssen die Anwendbarkeit in der Praxis noch klären. [ABSTRACT FROM AUTHOR]

Objectives The objective of the study was to investigate the association between alkaline phosphatase (AP) activity and prognosis of patients with acute coronary syndrome (ACS). Design and methods The study included 2134 patients with ACS undergoing percutaneous coronary intervention. All included patients had baseline AP measurements available. The receiver operating characteristic curve analysis showed that the best cut-off of AP for mortality prediction was 98.0 U/L. Using this cut-off, patients were divided into two groups: a group with AP > 98.0 U/L ( n = 493) and a group with AP ≤ 98.0 U/L ( n = 1641). The primary endpoint was 3-year mortality. Results Overall, there were 229 deaths over the follow-up: 90 deaths among patients with an AP > 98.0 U/L and 139 deaths among patients with an AP ≤ 98.0 U/L (Kaplan-Meier estimates of 3-year total mortality, 19.5% and 9.3%, respectively; adjusted hazard ratio [HR] = 1.37, 95% confidence interval [CI] 1.10–1.70, P = 0.004 for each unit higher log AP). Cardiac deaths occurred in 157 patients: 66 deaths among patients with an AP > 98.0 U/L and 91 deaths among patients with an AP ≤ 98.0 U/L (Kaplan-Meier estimates of 3-year cardiac mortality, 14.3% and 6.0%, respectively; adjusted HR = 1.32 [1.02–1.70], P = 0.033, for each unit higher log AP). The C-statistic of the multivariable model with baseline variables was 0.836 [0.807–0.866] and it increased to 0.842 [0.814–0.874] after inclusion of AP ( P = 0.045). Conclusions In patients presenting with an ACS and treated with percutaneous coronary intervention, elevated AP activity is associated with increased risk of subsequent mortality. [ABSTRACT FROM AUTHOR]

Background: This meta-analysis evaluated whether pretherapy serum levels of carcinoembryonic antigen (CEA) and cytokeratin-19 fragments (CYFRA 21-1) are predictive of response to therapy in non-small cell lung cancer (NSCLC) and whether changes in these markers during vs pretherapy are indicative of response.Methods: Original peer-reviewed studies enrolling adults with untreated advanced NSCLC were identified using PubMed. Two reviewers independently extracted data from eligible studies and assessed study heterogeneity and the risk of study bias.Results: Fourteen studies were eligible; 11 had objective response as an end point and three evaluated clinical benefit (i.e., response and stable disease). Study bias was relatively low. Both markers showed comparable modest predictive value across studies, with baseline CYFRA 21-1 numerically better in predicting treatment benefit. A good performance in identifying objective response during treatment was seen (AUC 0.724 (95% CI 0.667-0.785) for CYFRA 21-1 and 0.728 (95% CI, 0.599-0.871) for CEA). A decline in CYFRA 21-1 levels during treatment was highly indicative for objective response (sensitivity 79.1% (95% CI 71.5-85.1)).Conclusions: Comprehensive analysis of study heterogeneity and bias provides a high level of evidence for the clinical utility of CEA and CYFRA 21-1 for the prediction and monitoring of response in NSCLC. [ABSTRACT FROM AUTHOR]

The article reports on highly sensitive troponin as an effective cardiac biomarker. The troponins and natriuretic peptides that have significantly improved the specificity of cardiology diagnostics. Methodological advancements and new parameters now focus on rapid exclusion diagnostics and the early detection of severe outcomes.

Before the introduction of modern imaging techniques and the recent developments in molecular diagnosis, tumor markers (TMs) were among the few available diagnostic tools for the management of cancer patients. Easily obtained from serum or plasma samples, TMs are minimally invasive and convenient, and the associated costs are low. Single TMs were traditionally used but these have come under scrutiny due to their low sensitivity and specificity when used, for example, in a screening setting. However, recent research has shown superior performance using a combination of multiple TMs as a panel for assessment, or as part of validated algorithms that also incorporate other clinical factors. In addition, newer TMs have been discovered that have an increased sensitivity and specificity profile for defined malignancies. The aim of this review is to provide a concise overview of the appropriate uses of both traditional and newer TMs and their roles in diagnosis, prognosis, and the monitoring of patients in current clinical practice. We also look at the future direction of TMs and their integration with other diagnostic modalities and other emerging serum based biomarkers, such as circulating nucleic acids, to ultimately advance diagnostic performance and improve patient management. [ABSTRACT FROM AUTHOR]

In der Laboratoriumsmedizin kann maschinelles Lernen eingesetzt werden, um in den reichlich vorhandenen Daten verborgene Strukturen und Zusammenhänge zu entdecken oder die Diagnosefindung zu unterstützen. Am Beispiel eines Datensatzes aus der Onkologie werden die einzelnen Prozessschritte von den Rohdaten bis zum fertigen Ergebnis demonstriert. Dabei verursacht die Datenaufbereitung den höchsten Aufwand. [ABSTRACT FROM AUTHOR]

The global burden of colorectal cancer (CRC)-associated morbidity and mortality is increasing, in part due to a lack of early detection. Direct structural examination techniques, such as colonoscopy, are invasive and can therefore affect the willingness of patients to participate in screening. Recently, the use of “liquid biopsy” has gained considerable attention as a novel source of biomarkers. Blood-based biomarkers could prove to be practical tools for CRC detection, as the monitoring of biomarkers in biological fluids offers many advantages, including minimal invasiveness and easy accessibility. Biomarkers with high specificity and sensitivity can enable the detection of CRC at an early stage, thereby improving prognosis, prediction of treatment response, and recurrence risk. In this review, we summarize that the biomarkers currently thought to have potential for the early detection and monitoring of CRC, including circulating tumor cells, DNA, RNA and proteins. [ABSTRACT FROM AUTHOR]

High molecular group box 1 (HMGB1) is a highly conserved member of the HMG-box-family; abundantly expressed in almost all human cells and released in apoptosis; necrosis or by activated immune cells. Once in the extracellular space, HMGB1 can act as a danger associated molecular pattern (DAMP), thus stimulating or inhibiting certain functions of the immune system; depending on the "combinatorial cocktail" of the surrounding milieu. HMGB1 exerts its various functions through binding to a multitude of membrane-bound receptors such as TLR-2; -4 and -9; IL-1 and RAGE (receptor for advanced glycation end products); partly complex-bound with intracellular fragments like nucleosomes. Soluble RAGE in the extracellular space, however, acts as a decoy receptor by binding to HMGB1 and inhibiting its effects. This review aims to outline today's knowledge of structure, intraand extracellular functions including mechanisms of release and finally the clinical relevance of HMGB1 and RAGE as clinical biomarkers in therapy monitoring, prediction and prognosis of malignant and autoimmune disease. [ABSTRACT FROM AUTHOR]

Background We performed a multicenter evaluation of the Elecsys® progastrin-releasing peptide (ProGRP) immunoassay in Europe and China. Methods The assay was evaluated at three European and two Chinese sites by imprecision, stability, method comparison and differentiation potential in lung cancer. Results Intermediate imprecision across five analyte concentrations ranged from 2.2% to 6.0% coefficient of variation. Good stability for plasma and serum samples was shown for various storage conditions. There was excellent correlation between the Elecsys® and ARCHITECT assays in plasma (slope 1.02, intercept − 2.72 pg/mL). The Elecsys® assay also showed good correlation between serum and plasma samples (slope 0.93, intercept 2.35 pg/mL; correlation coefficient 0.97). ProGRP differentiated small-cell and non-small-cell lung cancer (NSCLC; area under the curve 0.90, 95% CI 0.87–0.93; 78.3% sensitivity, 95% specificity; at 84 pg/mL), with no relevant effects of ethnicity, age, gender or smoking. Median ProGRP concentrations were low in benign diseases (38 pg/mL), other malignancies (40 pg/mL) or NSCLC (39 pg/mL), except chronic kidney disease above stage 3 (> 100 pg/mL). Conclusions Increased stability of the Elecsys® ProGRP assay in serum and plasma offers clear benefits over existing assays. This first evaluation of a ProGRP assay in China demonstrated comparable differentiation potential among different ethnicities. [ABSTRACT FROM AUTHOR]

Laboratory information systems typically contain hundreds or even thousands of reference limits stratified by sex and age. Since under these conditions a manual plausibility check is hardly feasible, we have developed a simple algorithm that facilitates this check. An open-source R tool is available as a Shiny application at github.com/SandraKla/Zlog_AdRI. Based on the zlog standardization, we can possibly detect critical jumps at the transitions between age groups, regardless of the analytical method or the measuring unit. Its advantage compared to the standard z-value is that means and standard deviations are calculated from the reference limits rather than from the underlying data itself. The purpose of the tool is illustrated by the example of reference intervals of children and adolescents from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER). The Shiny application identifies the zlog values, lists them in a colored table format and plots them additionally with the specified reference intervals. The algorithm detected several strong and rapid changes in reference intervals from the neonatal period to puberty. Remarkable jumps with absolute zlog values of more than five were seen for 29 out of 192 reference limits (15.1%). This might be attenuated by introducing shorter time periods or mathematical functions of reference limits over age. Age-partitioned reference intervals will remain the standard in laboratory routine for the foreseeable future, and as such, algorithmic approaches like our zlog approach in the presented Shiny application will remain valuable tools for testing their plausibility on a wide scale. [ABSTRACT FROM AUTHOR]

The article reports that Raiko Krüger and colleagues describe lean management solutions that can be used in hospital laboratories in order to guarantee the shortest possible throughput times from the laboratory order to the transmission of findings.

Breast cancer is the most common cancer affecting women worldwide. It is a malignant and heterogeneous disease with distinct molecular subtypes, which has prognostic and predictive implications. Circulating tumor DNA (ctDNA), cell-free fragmented tumor-derived DNA in blood plasma, is an invaluable source of specific cancer-associated mutations and holds great promise for the development of minimally invasive diagnostic tests. Furthermore, serial monitoring of ctDNA over the course of systemic and targeted therapies not only allows unparalleled efficacy assessments but also enables the identification of patients who are at risk of progression or recurrence. Droplet digital PCR (ddPCR) is a powerful technique for the detection and monitoring of ctDNA. Due to its relatively high accuracy, sensitivity, reproducibility, and capacity for absolute quantification, it is increasingly used as a tool for managing cancer patients through liquid biopsies. In this review paper, we gauge the clinical utility of ddPCR as a technique for mutational profiling in breast cancer patients and focus on HER2, PIK3CA, ESR1, and TP53, which represent the most frequently mutated genes in breast cancers. [ABSTRACT FROM AUTHOR]

Data on systemic inflammatory response syndrome (SIRS) after transcatheter aortic valve implantation (TAVI) are scarce and limited to small cohorts. We aimed to investigate its incidence and mid-term impact in a large cohort of TAVI patients. From January 2018 to December 2020, 717 patients with severe aortic valve stenosis undergoing TAVI were included. SIRS was defined as fulfilling at least two of the following criteria within 48 h from the procedure: leucocyte count >12.0 or <4.0 × 109/l, respiratory rate > 20 breaths per minute or PaCO 2 ≤ 4.3 kPa/32 mmHg, heart rate > 90 beats per minute and temperature > 38.0 °C or <36.0 °C. Clinical endpoints were 1-year rehospitalization for chronic heart failure (CHF) and 2-years all-cause mortality. Event rates during follow-up were calculated as Kaplan-Meier estimates. SIRS developed in 56.3 % (404/717) of patients after TAVI. SIRS occurred more frequently in patients with post-dilatation (SIRS 34.7 % (140/404) vs. no SIRS 23.3 % (73/313); p < 0.001) and major vascular complications (SIRS 16.1 % (65/404) vs. no SIRS 8.6 % (27/313); p = 0.004). Further, ICU days were more in patients who developed SIRS (SIRS 1.56 ± 1.50 days vs. no SIRS 1.22 ± 1.02 days; p = 0.001). At 2-years, all-cause mortality in the entire population was 23.9 %. However, there was no difference in CHF at 1-year (5.9 % vs. 4.1 %; log-rank = 0.347) nor in all-cause mortality at 2-years (22.0 % vs. 26.2 %; log-rank = 0.690) between the groups. SIRS is a common finding after TAVI, which may prolong hospital stay but is without effect on mortality during 2-years follow-up. • SIRS is a common finding after TAVI, occurring in more than half of patients. • SIRS occurs more often in patients with post-dilatation and major vascular complications. • Inflammatory markers after TAVI increase, irrespective of SIRS development. • The occurrence of SIRS after TAVI is without effect on 2-years mortality. [ABSTRACT FROM AUTHOR]

Liquid biopsy is a broad term that refers to the testing of body fluids for biomarkers that correlate with a pathological condition. While a variety of body-fluid components (e.g., circulating tumor cells, extracellular vesicles, RNA, proteins, and metabolites) are studied as potential liquid biopsy biomarkers, cell-free DNA (cfDNA) has attracted the most attention in recent years. The total cfDNA population in a typical biospecimen represents an immensely rich source of biological and pathological information and has demonstrated significant potential as a versatile biomarker in oncology, non-invasive prenatal testing, and transplant monitoring. As a significant portion of cfDNA is composed of repeat DNA sequences and some families (e.g., pericentric satellites) were recently shown to be overrepresented in cfDNA populations vs their genomic abundance, it holds great potential for developing liquid biopsy-based biomarkers for the early detection and management of patients with cancer. By outlining research that employed cell-free repeat DNA sequences, in particular the ALU and LINE-1 elements, we highlight the clinical potential of the repeat-element content of cfDNA as an underappreciated marker in the cancer liquid biopsy repertoire. [ABSTRACT FROM AUTHOR]

Die prognostische Bedeutung von NT-proBNP bei Kindern mit angeborenen Herzfehlern konnte wegen der vor allem im ersten Lebensjahr ausgeprägten Altersdynamik bislang nur unzureichend untersucht werden. Abhilfe schafft die altersangepasste Standardisierung der Absolutwerte mithilfe des kürzlich eingeführten NT-proBNP-spezifischen zlog-Wertes, der analog zu einem Z-Score interpretiert wird. Wir zeigen, dass die Wahrscheinlichkeit schwerer kardialer Ereignisse bei Kindern mit angeborenen Herzfehlern stark zunimmt, je höher dieser Wert liegt. [ABSTRACT FROM AUTHOR]

Background: Severity of lung hypoplasia, pulmonary hypertension (PH) and cardiac dysfunction are major contributors to mortality in congenital diaphragmatic hernia (CDH). Therefore, early assessment and management is important to improve outcome. NT-proBNP is an established cardiac biomarker with only limited data for early postnatal risk assessment in CDH newborns.Aims: To investigate the correlation of NT-proBNP at birth, 6 h, 12 h, 24 h, and 48 h with PH and cardiac dysfunction and the prognostic information of NT-proBNP for the use of ECMO support or mortality.Subjects: 44 CDH newborns treated at our institution (December 2014-October 2017) were prospectively enrolled.Outcome Measures: Primary clinical endpoint was either need for ECMO or death within the first 48 h (group A). Infants not receiving ECMO support were allocated to group B. Mortality was tested as secondary endpoint.Results: NT-proBNP levels measured at 6 h, 12 h, 24 h and 48 h postpartum correlated significantly with PH severity following NICU admission and at 24 h, and with severity of cardiac dysfunction at birth, 24 h, 48 h and after 7 days of life. There was no difference in NT-proBNP levels between survivors and non-survivors. NT-proBNP levels were significantly higher in group A at 6 h (p = 0.007), 12 h (p = 0.036), and 24 h (p = 0.007), but not at birth (p = 0.785) or 48 h (p = 0.15) compared to group B.Conclusion: NT-proBNP analysis in the first 48 h of life may be useful to assess PH and cardiac dysfunction in CDH newborns and to predict the need for ECMO support. [ABSTRACT FROM AUTHOR]

Background: The association between hypocholesterolaemia and outcome of patients with coronary artery disease (CAD) remains controversial. We undertook this study to investigate whether there is an association between spontaneous or under statin therapy occurring hypocholesterolaemia and mortality in patients with CAD. Materials and Methods: This study included 14 952 patients with CAD undergoing percutaneous coronary intervention (PCI). Hypocholesterolaemia was defined as a total cholesterol (TC) <157 mg/dL (the upper limit of 1st quintile of TC). The study outcome was all‐cause mortality at 30 days and 3 years after PCI. Results: Patients are categorized in four groups according to TC and statin therapy on admission: statin‐naïve patients with hypocholesterolaemia (n = 1102), statin‐naïve patients without hypocholesterolaemia (n = 7490), statin‐treated patients with hypocholesterolaemia (n = 1824) and statin‐treated patients without hypocholesterolaemia (n = 4536). In these groups, 30‐day all‐cause deaths occurred in 3.7%, 1.4%, 1.2% and 0.6% of the patients, respectively; 3‐year deaths occurred in 18.0%, 8.4%, 10.9% and 7.2%, of the patients, respectively. After adjustment, hypocholesterolaemia remained independently associated with 30‐day (adjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] 1.07 to 2.09; P < 0001) and 3‐year (HR = 1.29 [1.12‐1.47]; P <.001) mortality. Statin therapy on admission was independently associated with 30‐day (HR = 0.61 [0.43‐0.86]; P =.012) and 3‐year (HR = 0.82 [0.72‐0.94]; P =.017) mortality with no statin‐by‐cholesterol interaction with respect to 30‐day (adjusted Pint = 0.669) or 3‐year (adjusted Pint = 0.767) all‐cause mortality suggesting that statins reduce the risk of mortality irrespective of cholesterol level. Conclusions: In patients with CAD, hypocholesterolaemia on admission was independently associated with increased risk of all‐cause mortality at 30 days and 3 years after PCI. [ABSTRACT FROM AUTHOR]

Liquid biopsies are revolutionizing the detection and management of malignant diseases. While repetitive DNA sequences, such as LINE-1 and ALU are established in cell-free DNA (cfDNA) research, their clinical applications remain limited. In this study, we explore human satellite 2 (HSATII), a prevalent repeat DNA sequence in plasma that exhibits increased levels in cancer patients, thereby positioning it as a potential pan-cancer biomarker. We employed targeted sequencing and copy number variation (CNV) analysis using two primer pairs to assess the differential abundance of HSATII sequences in the plasma of breast cancer patients compared to healthy individuals. PCR amplicons of HSATII from 10 patients and 10 control subjects were sequenced, generating 151 bp paired-end reads. By constructing a pooled reference dataset, HSATII copy ratios were estimated in the patients. Our analysis revealed several significant CNVs in HSATII, with certain sequences displaying notable gains and losses across all breast cancer patients, suggesting their potential as biomarkers. However, we observed pronounced fragmentation of cfDNA in cancer, leading to the loss of longer PCR amplicons (>180 bp). While not all observed losses can be attributed to fragmentation artifacts, this phenomenon does introduce complexity in interpreting CNV data. Notably, this research marks the first instance of targeted HSATII sequencing in a liquid biopsy context. Our findings lay the groundwork for developing sequencing-based assays to detect differentially represented HSATII sequences, potentially advancing the field of minimally-invasive cancer screening. [ABSTRACT FROM AUTHOR]

Intense physical exercise is known to increase cardiac biomarkers; however, it is unclear, whether this phenomenon is physiological, or if it indicates myocardial tissue injury. The aim of our study was to investigate the effects of seven consecutive days of excessive endurance exercise on continuous assessment of cardiac biomarkers, function, and tissue injury. During a 7‐day trail‐running competition (Transalpine Run, distance 267.4 km, altitude ascent/descent 15556/14450 m), daily blood samples were obtained for cardiac biomarkers (hs‐TnT, NT‐proBNP, and suppression of tumorigenicity‐2 protein (ST2)) at baseline, after each stage and 24–48 h post‐race. In addition, echocardiography was performed every second day, cardiac magnetic resonance imaging (CMR) before (n = 7) and after (n = 16) the race. Twelve (eight males) out of 17 healthy athletes finished all seven stages (average total finish time: 43 ± 8 h). Only NT‐proBNP increased significantly (3.6‐fold, p = 0.009) during the first stage and continued to increase during the race. Hs‐TnT revealed an incremental trend during the first day (2.7‐fold increase, p = 0.098) and remained within the pathological range throughout the race. ST2 levels did not change during the race. All cardiac biomarkers completely returned to physiological levels post‐race. NT‐proBNP kinetics correlated significantly with mild transient reductions in right ventricular function (assessed by TAPSE, tricuspid annular plane systolic function; r = −0.716; p = 0.014). No significant echocardiographic changes in LV dimensions, LV function, or relevant alterations in CMR were observed post‐race. In summary, this study shows that prolonged, repetitive, high‐volume exercise induced a transient, significant increase in NT‐proBNP associated with right ventricular dysfunction without corresponding left ventricular functional or structural impairment. [ABSTRACT FROM AUTHOR]

Children with congenital heart disease (CHD) undergoing cardiac surgery on cardiopulmonary bypass (CPB) are at risk for systemic inflammation leading to endothelial dysfunction associated with increased morbidity. Bioactive adrenomedullin (bio-ADM) is a peptide regulating vascular tone and endothelial permeability. The aim of this study was to evaluate the dynamics of plasma bio-ADM in this patient cohort and its role in capillary leak. Plasma samples from 73 pediatric CHD patients were collected for bio-ADM measurement at five different timepoints (TP) in the pre-, intra-, and post-operative period. The primary endpoint was a net increase in bio-ADM levels after surgery on CPB. Secondary endpoints included association of bio-ADM levels with clinical signs for endothelial dysfunction. Bio-ADM levels increased after surgery on CPB from pre-operative median of 12 pg/mL (IQR [interquartile range] 12.0–14.8 pg/mL) to a maximum post-operative median of 48.8 pg/mL (IQR 34.5–69.6 pg/mL, p<0.001). Bio-ADM concentrations correlated positively with post-operative volume balance, (r=0.341; p=0.005), increased demand for vasoactive medication (duration: r=0.415; p<0.001; quantity: TP3: r=0.415, p<0.001; TP4: r=0.414, p<0.001), and hydrocortisone treatment for vasoplegia (bio-ADM median [IQR]:129.1 [55.4–139.2] pg/mL vs. 37.9 [25.2–64.6] pg/mL; p=0.034). Patients who required pleural effusion drainage revealed higher bio-ADM levels compared to those who did not (median [IQR]: 66.4 [55.4–90.9] pg/mL vs. 40.2 [28.2–57.0] pg/mL; p<0.001). Bio-ADM is elevated in children after cardiac surgery and higher levels correlate with clinical signs of capillary leakage. The peptide should be considered as biomarker for endothelial dysfunction and as potential therapeutic target in this indication. [ABSTRACT FROM AUTHOR]

Simple Summary: In oncology, the identification of early predictors of response/survival is of particular interest. C-reactive protein (CRP) concentrations have been associated with advanced non-small-cell lung cancer and poor prognosis. We characterized the association between anticancer drug exposure, tumor size as a marker of tumor dynamics, and CRP as a marker of inflammation and derived different predictors. CRP at the beginning of treatment cycle 3 (day 42) was identified as the strongest predictor of both progression-free survival and overall survival, and the inflammatory status, monitored by CRP concentration, emerged as a promising prognostic marker. The high significance of longitudinal CRP concentrations compared to baseline concentrations provided a true reflection of the patient status. This framework could be applied to other treatment modalities such as immunotherapies or targeted therapies, allowing the identification of patients at risk of early progression and/or short survival to spare them unnecessary toxicities and offer alternative treatment decisions. In oncology, longitudinal biomarkers reflecting the patient's status and disease evolution can offer reliable predictions of the patient's response to treatment and prognosis. By leveraging clinical data in patients with advanced non-small-cell lung cancer receiving first-line chemotherapy, we aimed to develop a framework combining anticancer drug exposure, tumor dynamics (RECIST criteria), and C-reactive protein (CRP) concentrations, using nonlinear mixed-effects models, to evaluate and quantify by means of parametric time-to-event models the significance of early longitudinal predictors of progression-free survival (PFS) and overall survival (OS). Tumor dynamics was characterized by a tumor size (TS) model accounting for anticancer drug exposure and development of drug resistance. CRP concentrations over time were characterized by a turnover model. An x-fold change in TS from baseline linearly affected CRP production. CRP concentration at treatment cycle 3 (day 42) and the difference between CRP concentration at treatment cycles 3 and 2 were the strongest predictors of PFS and OS. Measuring longitudinal CRP allows for the monitoring of inflammatory levels and, along with its reduction across treatment cycles, presents a promising prognostic marker. This framework could be applied to other treatment modalities such as immunotherapies or targeted therapies allowing the timely identification of patients at risk of early progression and/or short survival to spare them unnecessary toxicities and provide alternative treatment decisions. [ABSTRACT FROM AUTHOR]

Paclitaxel/platinum chemotherapy, the backbone of standard first‐line treatment of advanced non‐small cell lung cancer (NSCLC), exhibits high interpatient variability in treatment response and high toxicity burden. Baseline blood biomarker concentrations and tumor size (sum of diameters) at week 8 relative to baseline (RS8) are widely investigated prognostic factors. However, joint analysis of data on demographic/clinical characteristics, blood biomarker levels, and chemotherapy exposure‐driven early tumor response for improved prediction of overall survival (OS) is clinically not established. We developed a Weibull time‐to‐event model to predict OS, leveraging data from 365 patients receiving paclitaxel/platinum combination chemotherapy once every three weeks for ≤six cycles. A developed tumor growth inhibition model, combining linear tumor growth and first‐order paclitaxel area under the concentration‐time curve‐induced tumor decay, was used to derive individual RS8. The median model‐derived RS8 in all patients was a 20.0% tumor size reduction (range from −78% to +15%). Whereas baseline carcinoembryonic antigen, cytokeratin fragments, and thyroid stimulating hormone levels were not significantly associated with OS in a subset of 221 patients, and lactate dehydrogenase, interleukin‐6 and neutrophil‐to‐lymphocyte ratio levels were significant only in univariate analyses (p value < 0.05); C‐reactive protein (CRP) in combination with RS8 most significantly affected OS (p value < 0.01). Compared to the median population OS of 11.3 months, OS was 128% longer at the 5th percentile levels of both covariates and 60% shorter at their 95th percentiles levels. The combined paclitaxel exposure‐driven RS8 and baseline blood CRP concentrations enables early individual prognostic predictions for different paclitaxel dosing regimens, forming the basis for treatment decision and optimizing paclitaxel/platinum‐based advanced NSCLC chemotherapy. [ABSTRACT FROM AUTHOR]

Fragments of cell-free DNA (cfDNA) in human body fluids often carry disease-specific alterations and are now widely recognized as ideal biomarkers for the detection and monitoring of genomic disorders, especially cancer, that are normally difficult to examine noninvasively. However, the conversion of promising research findings into tools useful in routine clinical testing of cancer has been a slow-moving process. A major reason is that the diagnostic sensitivity and specificity of cfDNA-based clinical assays are negatively impacted by a combination of suboptimal and inter-institutional differences in preanalytical procedures. The most prominent factors include: (i) a poor understanding of the biological factors that determine the characteristics of the cfDNA population in a biospecimen prior to collection, (ii) inattention to how cfDNA with different structures and physical properties are affected differently by a given preanalytical step, and (iii) the sheer number of possible conditions that can be selected from for each preanalytical step along with a continually expanding menu of commercial products that often show varying degrees of bias and efficiency. The convergence of these variables makes it difficult for research groups and institutions to reach a consensus on optimal preanalytical procedures and a challenging task to establish widely applied standards, which ultimately hamper the development of cfDNA assays that are fit for broad clinical implementation. In this review, we follow a systematic approach to explore the most confounding preanalytical factors that affect the outcome of cfDNA measurements. [ABSTRACT FROM AUTHOR]

The article reports that the concept of reference intervals celebrates a big birthday in 2020. It notes that International founded 50 years ago Federation of Clinical Chemistry (IFCC) an "Expert Panel on Reference Values" that help assess laboratory values in health and illness. It adds that no manufacturer could successfully market a test today, without specifying reference limits, and no laboratory may transmit analytical results, checked without these limits too.

Simple Summary: Ovarian cancer is often diagnosed only in advanced stages, which limits therapeutic options and prognosis. Therefore, better and easily accessible methods for the early diagnosis of ovarian cancer are needed. In particular, blood-based biomarkers seem to be promising candidates for the accurate detection of ovarian cancer. We determined the concentrations of the two proteins HMGB1 and sRAGE in the sera of 231 women with ovarian cancer, benign diseases and without known gynecologic disease. In the analyses of receiver operating characteristics, both HMGB1 and sRAGE could distinguish patients with ovarian cancer from healthy women (area under the curve (AUC) 0.77 and 0.65), benign diseases (AUC 0.72 and 0.61) or all non-malignant cases (AUC 0.74 and 0.63). Moreover, the ratio of HMGB1/sRAGE differentiated even better between malignancies and other cases (AUC 0.78, 0.74 and 0.76, respectively). In conclusion, HMGB1 and sRAGE are potential candidates for the development of assays for early diagnosis of ovarian cancer and warrant inclusion in further validation studies. Background: High mobility group box 1 (HMGB1), soluble receptor of advanced glycation end products (sRAGE) and programmed cell death markers PD-1 and PD-L1 are immunogenic serum biomarkers that may serve as novel diagnostic tools for cancer diagnosis. Methods: We investigated the four markers in sera of 231 women, among them 76 with ovarian cancer, 87 with benign diseases and 68 healthy controls, using enzyme immunoassays. Discrimination between groups was calculated using receiver operating characteristic (ROC) curves and sensitivities at fixed 90% and 95% specificities. Results: HMGB1 levels were significantly elevated and sRAGE levels were decreased in cancer patients as compared to benign and healthy controls. In consequence, the ratio of HMGB1 and sRAGE discriminated best between diagnostic groups. The areas under the curve (AUCs) of the ROC curves for differentiation of cancer vs. healthy were 0.77 for HMGB1, 0.65 for sRAGE and 0.78 for the HMGB1/sRAGE ratio, and slightly lower for the differentiation of cancer vs. benigns with 0.72 for HMGB1, 0.61 for sRAGE and 0.74 for the ratio of both. The highest sensitivities for cancer detection at 90% specificity versus benign diseases were achieved using HMGB1 with 41.3% and the HMGB1/sRAGE ratio with 39.2%, followed by sRAGE with 18.9%. PD-1 showed only minor and PD-L1 no power for discrimination between ovarian cancer and benign diseases. Conclusion: HMGB1 and sRAGE have differential diagnostic potential for ovarian cancer detection and warrant inclusion in further validation studies. [ABSTRACT FROM AUTHOR]

Background: Severe coronavirus disease 2019 (COVID-19) disease courses are characterized by immuno-inflammatory, thrombotic, and parenchymal alterations. Prediction of individual COVID-19 disease courses to guide targeted prevention remains challenging. We hypothesized that a distinct serologic signature precedes surges of IL-6/D-dimers in severely affected COVID-19 patients. Methods: We performed longitudinal plasma profiling, including proteome, metabolome, and routine biochemistry, on seven seropositive, well-phenotyped patients with severe COVID-19 referred to the Intensive Care Unit at the German Heart Center. Patient characteristics were: 65 ± 8 years, 29% female, median CRP 285 ± 127 mg/dL, IL-6 367 ± 231 ng/L, D-dimers 7 ± 10 mg/L, and NT-proBNP 2616 ± 3465 ng/L. Results: Based on time-series analyses of patient sera, a prediction model employing feature selection and dimensionality reduction through least absolute shrinkage and selection operator (LASSO) revealed a number of candidate proteins preceding hyperinflammatory immune response (denoted ΔIL-6) and COVID-19 coagulopathy (denoted ΔD-dimers) by 24–48 h. These candidates are involved in biological pathways such as oxidative stress/inflammation (e.g., IL-1alpha, IL-13, MMP9, C-C motif chemokine 23), coagulation/thrombosis/immunoadhesion (e.g., P- and E-selectin), tissue repair (e.g., hepatocyte growth factor), and growth factor response/regulatory pathways (e.g., tyrosine-protein kinase receptor UFO and low-density lipoprotein receptor (LDLR)). The latter are host- or co-receptors that promote SARS-CoV-2 entry into cells in the absence of ACE2. Conclusions: Our novel prediction model identified biological and regulatory candidate networks preceding hyperinflammation and coagulopathy, with the most promising group being the proteins that explain changes in D-dimers. These biomarkers need validation. If causal, our work may help predict disease courses and guide personalized treatment for COVID-19. [ABSTRACT FROM AUTHOR]

Despite recent advances in the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance to targeted therapy remains a major obstacle. Epithelial-mesenchymal transition (EMT) has been identified as a key resistance mechanism in NSCLC. Here, we investigated the mechanistic role of key EMT-regulating small non-coding microRNAs (miRNAs) in sublines of the NSCLC cell line HCC4006 adapted to afatinib, erlotinib, gefitinib, or osimertinib. The most differentially expressed miRNAs derived from extracellular vesicles were associated with EMT, and their predicted target ZEB1 was significantly overexpressed in all resistant cell lines. Transfection of a miR-205-5p mimic partially reversed EMT by inhibiting ZEB1, restoring CDH1 expression, and inhibiting migration in erlotinib-resistant cells. Gene expression of EMT-markers, transcription factors, and miRNAs were correlated during stepwise osimertinib adaptation of HCC4006 cells. Temporally relieving cells of osimertinib reversed transition trends, suggesting that the implementation of treatment pauses could provide prolonged benefits for patients. Our results provide new insights into the contribution of miRNAs to drug-resistant NSCLC harboring EGFR-activating mutations and highlight their role as potential biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Tumor marker determinations are valuable tools for the guidance of breast cancer patients during the course of disease. They are assessed on diverse analytical platforms that may be associated with differences according to the methods applied and the clinical performance. To investigate the method dependency and clinical significance of breast cancer protein tumor markers, CEA, CA 15-3, CA 125, CA 19-9 and AFP were measured in a total of 154 biobanked samples from 77 patients with breast cancer, 10 with DCIS, 31 with benign breast diseases and 36 healthy controls using a Millipore multiplex biomarker panel (MP) and an automized version of the routinely used Vista LOCI technology. The markers were compared between methods and investigated for diagnostic performance. CEA, CA 15-3 and AFP showed good correlations between both platforms with correlation coefficients of R = 0.85, 0.85 and 0.92, respectively, in all samples, but similarly also in the various subgroups. CA 125 and CA 19-9 showed only moderate correlations (R = 0.71 and 0.56, respectively). Absolute values were significantly higher for CEA, CA 15-3, CA 125 and AFP in the Vista LOCI as compared with the MP method and vice versa for CA 19-9. The diagnostic performance for discrimination of breast cancer from healthy controls was similar for both methods with AUCs in ROC curves for CEA (MP 0.81, 95% CI 0.72–0.91; LOCI 0.81; 95% CI 0.72–0.91) and CA-15-3 (MP 0.75, 95% CI 0.65–0.86; LOCI 0.67, 95% CI 0.54–0.79). Similar results were obtained for the comparison of breast cancer with benign breast diseases regarding CEA (AUC MP 0.62, 95% CI 0.51–0.73; LOCI 0.64, 95% CI 0.53–0.74) and CA-15-3 (MP 0.70, 95% CI 0.6–0.81; LOCI 0.66, 95% CI 0.54–0.77). Both platforms show moderate to good method comparability for tumor markers with similar clinical performance. However, absolute levels in individual patients should be interpreted with care. [ABSTRACT FROM AUTHOR]

Blood-based biomarkers are valuable diagnostic tools for the management of lung cancer patients. They support not only differential diagnosis and histological subtyping, but are also applied for estimation of prognosis, stratification for specific therapies, monitoring of therapy response, surveillance monitoring and early detection of residual or progressive disease. Early diagnosis of lung cancer in high risk populations (screening) is a promising future indication but poses high medical and economic challenges to marker performance. The five mostly used classical ‘tumor markers’ show characteristic profiles of sensitivity and specificity for non-small cell lung cancer (NSCLC) like cytokeratin 19-fragments (CYFRA 21-1), carcino-embryonic antigen (CEA) and squamous cancer cell antigen (SCCA) as well as for small cell lung cancer (SCLC) like progastrin-releasing peptide (ProGRP) and neuron-specific enolase (NSE). Combined use and pattern recognition approaches enable highly accurate diagnosis, subtyping and therapy monitoring. For the interpretation of serial measurements on an individual level, marker-specific algorithms have to be developed. So-called companion diagnostics identify druggable molecular changes in signaling pathways of tumor tissue that can be addressed by targeted therapies. New highly sensitive technologies enable the convenient and serial molecular characterization on circulating tumor DNA (ctDNA) in the blood, too. This approach is helpful when biopsies are not available and to overcome tumor molecular heterogeneity and plasticity. As only a portion of patients have such druggable molecular changes, future strategies will imply the combined use of classical and new ctDNA-based biomarkers to optimize the management of lung cancer patients during the course of disease. [ABSTRACT FROM PUBLISHER]

Notwithstanding some improvement in the earlier detection of patients with lung cancer, most of them still present with a late-stage disease at the time of diagnosis. Next to the most frequently utilized factors affecting the prognosis of lung cancer patients (stage, performance, and age), the recent application of biomarkers obtained by liquid profiling has gained more acceptance. In our study, we aimed to answer these questions: (i) Is the quantification of free-circulating methylated PTGER4 and SHOX2 plasma DNA a useful method for therapy monitoring, and is this also possible for patients treated with different therapy regimens? (ii) Is this approach possible when blood-drawing tubes, which allow for a delayed processing of blood samples, are utilized? Baseline values for mPTGER4 and mSHOX2 do not allow for clear discrimination between different response groups. In contrast, the combination of the methylation values for both genes shows a clear difference between responders vs. non-responders at the time of re-staging. Furthermore, blood drawing into tubes stabilizing the sample allows researchers more flexibility. [ABSTRACT FROM AUTHOR]

The glycoproteins alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) have long been approved as biomarkers for diagnosing and monitoring tumors. International Reference Preparations (IRPs) have been around since 1975. Nevertheless, manufacturer-dependent differences have been reported, indicating a lack of harmonization. This paper analyzes data from 15 external quality assessment (EQA) surveys conducted worldwide between 2018 and 2022. The aim was to gain insight into the longitudinal development of manufacturer-dependent differences for CEA and AFP. In each survey, participating laboratories received two samples with different tumor marker levels. Inter- and intra-assay variability was analyzed and the mean 80% and 90% of the manufacturer collectives were compared to the evaluation criteria of the German Medical Association (RiliBÄK). The median EQA results for CEA revealed manufacturer-dependent differences between the highest and lowest collective of up to 100%; for AFP, the median differences mostly remained below 40%. The coefficients of variation were predominantly low for both markers. We concluded that the current assays for AFP and CEA detection are better harmonized than previously reported. The assays displayed a good robustness; however, a narrowing of the current assessment limits in EQA schemes could further enhance the quality of laboratory testing. [ABSTRACT FROM AUTHOR]

Purpose: Novel biomarkers to better predict outcome and select the best therapeutic strategy for the individual patient are necessary for pancreatic ductal adenocarcinoma (PDAC). Methods: Using a panel assay, multiple biomarkers (IFN-γ, IL-10, IL-6, IL-8, TNF-α, CEA, CA 19–9, CYFRA 21–1, HE4, PD-1 and PD-L1 levels) were measured in serum samples of 162 patients with resected, locally advanced and metastatic PDAC in this retrospective single-center study. Optimal cut-off values to differentiate prognostic subgroups with significantly different overall survival (OS) were determined by receiver operator characteristics and Youden Index analysis. Marker levels were assessed before the start of chemotherapy and correlated with OS by univariate and multivariate Cox analysis. Results: Median OS for resected patients was 28.2 months, for locally advanced patients 17.9 months and for patients with metastatic disease 8.6 months. CYFRA 21–1 and IL-8 discriminated metastatic from locally advanced patients best (AUC 0.85 and AUC 0.81, respectively). In univariate analyses, multiple markers showed prognostic relevance in the various subgroups. However, multivariate Cox models comprised only CYFRA 21–1 in the resected group (HR 1.37, p = 0.015), IL-10 in locally advanced PDAC (HR 10.01, p = 0.014), as well as CYFRA 21–1 and CA 19–9 in metastatic PDAC (p = 0.008 and p = 0.010) as an independent prognostic marker for overall survival. Conclusion: IL-10 levels may have independent prognostic value in locally advanced PDAC, whereas CYFRA 21–1 levels are prognostic after PDAC surgery. CYFRA 21–1 and IL-8 have been identified to best discriminate metastatic from locally advanced patients. [ABSTRACT FROM AUTHOR]

Excellent pre-analytical stability is an essential precondition for reliable molecular profiling of circulating tumor DNA (ctDNA) in oncological diagnostics. Therefore, in vitro degradation of ctDNA and the additional release of contaminating genomic DNA from lysed blood cells must be prevented. Streck Cell-Free DNA blood collection tubes (cfDNA BCTs) have proposed advantages over standard K2EDTA tubes, but mainly have been tested in healthy individuals. Blood was collected from cancer patients (n = 53) suffering from colorectal (n = 21), pancreatic (n = 11), and non-small-cell lung cancer (n = 21) using cfDNA BCT tubes and K2EDTA tubes that were processed immediately or after 3 days (BCTs) or 6 hours (K2EDTA) at room temperature. The cfDNA isolated from these samples was characterized in terms of yield using LINE-1 qPCR; the level of gDNA contamination; and the mutation status of KRAS, NRAS, and EGFR genes using BEAMing ddPCR. CfDNA yield and gDNA levels were comparable in both tube types and were not affected by prolonged storage of blood samples for at least 3 days in cfDNA BCTs or 6 hours in K2EDTA tubes. In addition, biospecimens collected in K2EDTA tubes and cfDNA BCTs stored for up to 3 days demonstrated highly comparable levels of mutational load across all respective cancer patient cohorts and a wide range of concentrations. Our data support the applicability of clinical oncology specimens collected and stored in cfDNA BCTs for up to 3 days for reliable cfDNA and mutation analyses. [ABSTRACT FROM AUTHOR]

Background: Trauma is still a major cause of mortality in people < 50 years of age. Biomarkers are needed to estimate the severity of the condition and the patient outcome. Methods: Cell-free DNA (cfDNA) and further laboratory markers were determined in plasma and serum of 164 patients at time of admission to the emergency room. Among them were 64 patients with severe trauma (Injury Severity Score (ISS) ≥ 16), 51 patients with moderate trauma (ISS < 16) and 49 patients with single fractures (24 femur neck and 25 ankle fractures). Disease severity was objectified by ISS and Glasgow Coma Scale (GCS). Results: cfDNA levels in plasma and serum were significantly higher in patients with severe multiple trauma (SMT) than in those with moderate trauma (p = 0.002, p = 0.003, respectively) or with single fractures (each p < 0.001). CfDNA in plasma and serum correlated very strongly with each other (R = 0.91; p < 0.001). The AUC in ROC curves for identification of SMT patients was 0.76 and 0.74 for cfDNA in plasma and serum, respectively—this was further increased to 0.84 by the combination of cfDNA and hemoglobin. Within the group of multiple trauma patients, cfDNA levels were significantly higher in more severely injured patients and patients with severe traumatic brain injury (GCS ≤ 8 versus GCS > 8). Thirteen (20.3%) of the multiple trauma patients died during the first week after trauma. Levels of cfDNA were significantly higher in non-surviving patients than in survivors (p < 0.001), reaching an AUC of 0.81 for cfDNA in both, plasma and serum, which was further increased by the combination with hemoglobin and leukocytes. Conclusions: cfDNA is valuable for estimation of trauma severity and prognosis of trauma patients. [ABSTRACT FROM AUTHOR]

Background: COVID-19 might pose a risk for adults with congenital heart disease (ACHD). However, data regarding the rate of infection as well as myocardial involvement in ACHD patients are currently lacking. Methods: During the study period from January to June 2021, all consecutive outpatients from our ACHD clinic were eligible to participate. Clinical data were collected. An antibody test for COVID-19 was performed in all patients. Cardiovascular magnetic resonance imaging (CMR) was offered to those with a positive antibody test. Results: Overall, 420 patients (44.8% female, mean age 36.4 ± 11.6 years) participated. Congenital heart defect (CHD) complexity was simple in 96 (22.9%), moderate in 186 (44.3%), complex in 117 (27.9%), and miscellaneous in 21 (5.0%) patients. Altogether, 28 (6.7%) patients had a positive antibody test. Out of these, 14 had an asymptomatic course. The others had mainly mild symptoms and were managed as outpatients. Furthermore, 11 patients (39.3%) had even not been aware of their infection. Fourteen patients underwent a CMR without signs of myocardial involvement in any of them. Conclusions: We observed a number of undetected cases of COVID-19 infections in our ACHD population. Reassuringly, in all cases, the infection had a mild clinical course. [ABSTRACT FROM AUTHOR]

Plasma cell-free DNA (cfDNA) originates from various tissues and cell types and can enable minimally invasive diagnosis, treatment and monitoring of cancer and other diseases. Proper extraction of cfDNA is critical to obtain optimal yields and purity. The goal of this study was to compare the performance of six commercial cfDNA kits to extract pure, high-quality cfDNA from human plasma samples and evaluate the quantity and size profiles of cfDNA extracts—among them, two spin-column based, three magnetic bead-based and two automatic magnetic bead-based methods. Significant differences were observed in the yield of DNA among the different extraction kits (up to 4.3 times), as measured by the Qubit Fluorometer and Bioanalyzer. All kits isolated mostly small fragments corresponding to mono-nucleosomal sizes. The highest yield and reproducibility were obtained by the manual QIAamp Circulating Nucleic Acid Kit and automated MagNA Pure Total NA Isolation Kit. The results highlight the importance of standardizing preanalytical conditions depending on the requirements of the downstream applications. [ABSTRACT FROM AUTHOR]