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Background: Children with univentricular hearts (UVH) undergo up to three palliative surgical procedures to achieve complete circulatory separation (Fontan circulation). As a marker of cardiac wall stress, NT-proBNP is a promising tool to assess systemic ventricular load in these patients. However, different reference intervals (RI) apply to each stage, as NT-proBNP is highly age-dependent., Methods: Children undergoing systemic-to-pulmonary (SP) shunt placement (stage 1), bidirectional cavopulmonary shunt (BCPS, stage 2) or total cavopulmonary connection (TCPC, stage 3) between 2011 and 2021 with NT-proBNP measurement within 7 days before surgery were included. Furthermore, outpatients after TCPC with NT-proBNP measurement were enrolled. Biomarker levels were evaluated using its age-adjusted z-score ("zlog-NT-proBNP"; age-independent RI, -1.96 to +1.96), allowing comparison between different stages and revealing changes in systemic ventricular load independent of the marked physiological decline in RI with age., Results: Overall, 289 children (227 before, 62 after TCPC) met the eligibility criteria. Median time between blood sampling and surgery (SP shunt/BCPS/TCPC) was 2 [1-3] days and 3.2 [2.0-4.5] years after TCPC. Age-adjusted zlog-NT-proBNP levels were 3.47 [2.79-3.93] in children with native UVH (before SP shunt), 3.10 [1.89-3.58] at stage 1 (before BCPS), 1.08 [0.51-1.88] at stage 2 (before TCPC), and 1.09 [0.72-1.75] at stage 3 (after TCPC/Fontan completion). Consequently, BCPS revealed the strongest decrease (median - 2.02 logarithmized standard deviations, p < 0.001)., Conclusions: In children with UVH undergoing staged Fontan palliation, zlog-NT-proBNP is a highly promising tool for course assessment of systemic ventricular load, independent of the age-related decline in physiological NT-proBNP concentration., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Invasive mechanical ventilation and oxygen toxicity are postnatal contributors to chronic lung disease of prematurity, also known as bronchopulmonary dysplasia (BPD). Cyfra 21-1 is a soluble fragment of cytokeratin 19, which belongs to the cytoskeleton stabilizing epithelial intermediate filaments. As a biomarker of structural integrity, Cyfra 21-1 might be associated with airway injury and lung hypoplasia in neonates. Serum Cyfra 21-1 concentrations for 80 preterm and 80 healthy term newborns were measured within 48 h after birth. Preterm infants with the combined endpoint BPD/mortality had significantly higher Cyfra 21-1 levels compared with those without fulfilling BPD/mortality criteria ( P = 0.01). Also, severe RDS (>grade III) was associated with higher Cyfra levels ( P = 0.01). Total duration of oxygen therapy was more than five times longer in neonates with high Cyfra 21-1 levels ( P = 0.01). Infants with higher Cyfra 21-1 values were more likely to receive mechanical ventilation (50% vs. 17.5%). However, the duration of mechanical ventilation was similar between groups. The median Cyfra value was 1.93 ng/mL (IQR: 1.68-2.53 ng/mL) in healthy term neonates and 8.5 ng/mL (IQR: 3.6-16.0 ng/mL) in preterm infants. Using ROC analysis, we calculated a Cyfra cutoff > 8.5 ng/mL to predict BPD/death with an AUC of 0.795 ( P = 0.004), a sensitivity of 88.9%, and a specificity of 55%. Mortality was predicted with a cutoff > 17.4 ng/mL (AUC: 0.94; P = 0.001), a sensitivity of 100%, and a specificity of 84%. These findings suggest that Cyfra 21-1 concentration might be useful to predict poor outcome in premature infants.

Introduction: Alterations in cell-free DNA concentration (cfDNA) over time have been studied in diseased or injured patients or analyzed in athletes during exhaustive exercise. However, no fluctuations have been examined over a short time course in healthy humans at rest so far, wherefore the aim of this study was to examine individual variations at different time points within 75 min., Methods: Serial blood drawing was performed in 14 healthy female volunteers at rest within 75 min. Plasma DNA was quantified by real-time qPCR, and absolute levels were analyzed together with relative variations. cfDNA alterations were moreover analyzed in consideration of potential volunteer-related impact factors (e.g., pulse) and were compared to alterations of plasma CK and AST., Results: Absolute cfDNA concentration ranged from 0.6 to 3.4 ng/ml. Regarding alterations over time, positive and negative variations were identified, whereby the interdecile range of fold changes was from 0.5 to 1.4. The maximum fold change was determined at 10 min. No relations were found between cfDNA levels and the analyzed individual factors., Conclusion: We evidenced the variability of cfDNA in healthy humans at rest within a short time course. The determined variations should serve in future studies to distinguish small cfDNA increases after minor trauma from natural fluctuations. Without such reference of intra-individual variation at rest, it would not be feasible to distinguish an injury from a fluctuation with certainty. Thus, a basis was established for the application of cfDNA as biomarker for the detection of mild injuries in forensic biomechanics.

Background: Up to 50% of the patients still die or have to be rehospitalized during the first year after transcatheter aortic valve replacement (TAVR). This emphasizes the need for more strategic patient selection. The aim of this prospective observational cohort study was to compare the prognostic value of risk scores and circulating biomarkers to predict all-cause mortality and rehospitalization in patients undergoing TAVR., Methods: We calculated the hazard ratios and C-statistics (area under the curve [AUC]) of 4 risk scores (logistic European System for Cardiac Operative Risk Evaluation [EuroSCORE], EuroSCORE II, Society of Thoracic Surgeons predicted risk of mortality, and German aortic valve score) and 5 biomarkers of inflammation and/or myocardial dysfunction (high-sensitivity C-reactive protein, growth differentiation factor (GDF)-15, interleukin-6, interleukin-8, and N-terminal pro-B-type natriuretic peptide) for the risk of death (n = 80) and the combination of death or rehospitalization (n = 132) during the first year after TAVR in 310 consecutive TAVR patients., Results: The EuroSCORE II and GDF-15 had the strongest predictive value for 1-year mortality (EuroSCORE II, AUC 0.711; GDF-15, AUC 0.686) and for the composite end point (EuroSCORE II, AUC 0.690; GDF-15, AUC 0.682). When added to the logistic EuroSCORE and EuroSCORE II, GDF-15 enhanced the prognostic performance of the score and enabled substantial reclassification of patients. Combinations of increasing tertiles of the logistic EuroSCORE or EuroSCORE II and GDF-15 allowed the stratification of the patients into subgroups with mortality rates ranging from 4.0% to 49.1% and death/rehospitalization rates ranging from 15.3% to 68.4%., Conclusions: Our study identified GDF-15 in addition to the logistic EuroSCORE and the EuroSCORE II as the most promising predictors of a poor outcome after TAVR., (Copyright © 2015 Elsevier Inc. All rights reserved.)

BackgroundThis 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.MethodsOriginal 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.ResultsFourteen 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)).ConclusionsComprehensive 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.

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.

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]

Auf den zweijährig stattfindenden Konferenzen über „circulating nucleic acids in plasma and serum“ (CNAPS) treffen sich regelmäßig zahlreiche renommierte Forschende aus aller Welt, um die neuesten Erkenntnisse und Erfahrungen auf diesem jungen Forschungszweig auszutauschen. Diese umfassen grundlegende Fragen der Struktur und Biologie von zirkulierenden Nukleinsäuren (CNAs), technologische Neuerungen zum hochsensitiven und spezifischen Nachweis im Blut sowie deren Applikationen als diagnostische Biomarker für eine Vielzahl von klinischen Indikationen. In diesem Bericht sind Eindrücke vom 13th International Symposium on Circulating Nucleic Acids in Plasma and Serum (CNAPS) vom 04. bis 06.03.2024 in Graz, Österreich, zusammengefasst. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lung cancer is a major burden to global health and is still among the most frequent and most lethal malignant diseases. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in a variety of processes including tumorigenesis, formation of a tumor microenvironment and metastasis. It is therefore a potential prognostic biomarker in malignant diseases. OBJECTIVE: In this study, we investigated the applicability of MIF in serum samples as a biomarker in lung cancer. METHODS: In a retrospective approach, we analyzed the sera of 79 patients with non-small-cell lung cancer (NSCLC) and 14 patients with small-cell lung cancer (SCLC) before the start of chemotherapy, as well as before the second and third chemotherapy cycle, respectively. Serum MIF levels were measured using a sandwich immunoassay with a sulfo-tag-labelled detection antibody, while pro-gastrin releasing peptide (proGRP) levels were determined with an enzyme-linked immunosorbent assay. RESULTS: No difference in serum MIF levels between responders and non-responders to chemotherapy was observed at all time points, while proGRP levels were significantly lower in responders before the second chemotherapy cycle (p = 0.012). No differences in biomarker levels depending on the histopathological classification of NSCLC patients was found. Moreover, in ROC curve analyses MIF was not able to distinguish between responders and non-responders to therapy. proGRP could differentiate between responders and non-responders before the second chemotherapy cycle (p = 0.015) with sensitivities of 43% at 90% and 95% specificity, respectively. Likewise, proGRP yielded significantly longer survival times of patients with low proGRP concentrations before the second chemotherapy cycle (p = 0.015) in Kaplan-Meier analyses, yet MIF showed no significant differences in survival times at all time points. Comparison with the biomarkers CEA and CYFRA 21-1 in the same cohort showed that these established biomarkers clearly performed superior to MIF and proGRP. CONCLUSIONS: From the present results, there is no indication that serum MIF may serve as a biomarker in prognosis and monitoring of response to therapy in lung cancer. Limitations of this study include its retrospective design, the inclusion of a larger NSCLC and a smaller SCLC subgroup, the classical chemotherapeutic treatment, the use of a non-diagnostic immunoassay (RUO-test) for MIF measurement and the lack of a validation cohort. Strengths of the study are its highly standardized procedures concerning sample collection, preanalytic treatment, measurements and quality control of the laboratory assays. [ABSTRACT FROM AUTHOR]

Clinical laboratories are responsible for performing lung cancer tumor marker testing as part of routine clinical care. It is their responsibility to guarantee that the reported tumor marker results are reliable and meet the necessary quality standards for proper clinical use. During the different laboratory phases, pre-analytical, analytical and post-analytical, specific steps and processes can introduce errors and generate incorrect clinical interpretation. This editorial briefly outlines critical laboratory issues related to lung cancer tumor markers, specific for each of these three laboratory phases. [ABSTRACT FROM AUTHOR]

Blood-based diagnostics for lung cancer support the diagnosis, estimation of prognosis, prediction, and monitoring of therapy response in lung cancer patients. The clinical utility of serum tumor markers has considerably increased due to developments in serum protein tumor markers analytics and clinical biomarker studies, the exploration of preanalytical and influencing conditions, the interpretation of biomarker combinations and individual biomarker kinetics, as well as the implementation of biostatistical models. In addition, circulating tumor DNA (ctDNA) and other liquid biopsy markers are playing an increasingly prominent role in the molecular tumor characterization and the monitoring of tumor evolution over time. Thus, modern lung cancer biomarkers may considerably contribute to an individualized companion diagnostics and provide a sensitive guidance for patients throughout the course of their disease. In this special edition on Tumor Markers in Lung Cancer, experts summarize recent developments in clinical laboratory diagnostics of lung cancer and give an outlook on future challenges and opportunities. [ABSTRACT FROM AUTHOR]

BACKGROUND: Protein tumor markers are released in high amounts into the blood in advanced non-small cell lung cancer (NSCLC). OBJECTIVE: To investigate the relevance of serum tumor markers (STM) for prognosis, prediction and monitoring of therapy response in NSCLC patients receiving chemotherapy. METHODS: In a biomarker substudy of a prospective, multicentric clinical trial (CEPAC-TDM) on 261 advanced NSCLC patients, CYFRA 21-1, CEA, SCC, NSE, ProGRP, CA125, CA15-3 and HE4 were assessed in serial serum samples and correlated with radiological response after two cycles of chemotherapy and overall (OS) and progression-free survival (PFS). RESULTS: While pretherapeutic STM levels at staging did not discriminate between progressive and non-progressive patients, CYFRA 21-1, CA125, NSE and SCC at time of staging did, and yielded AUCs of 0.75, 0.70, 0.69 and 0.67 in ROC curves, respectively. High pretherapeutic CA15-3 and CA125 as well as high CYFRA 21-1, SCC, CA125 and CA15-3 levels at staging were prognostic for shorter PFS and OS –also when clinical variables were added to the models. CONCLUSIONS: STM at the time of first radiological staging and pretherapeutic CA15-3, CA125 are predictive for first-line treatment response and highly prognostic in patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

BACKGROUND: Therapeutic possibilities for non-small cell lung cancer (NSCLC) have considerably increased during recent decades. OBJECTIVE: To summarize the prognostic relevance of serum tumor markers (STM) for early and late-stage NSCLC patients treated with classical chemotherapies, novel targeted and immune therapies. METHODS: A PubMed database search was conducted for prognostic studies on carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA 21-1), neuron-specific enolase, squamous-cell carcinoma antigen, progastrin-releasing-peptide, CA125, CA 19-9 and CA 15-3 STMs in NSCLC patients published from 2008 until June 2022. RESULTS: Out of 1069 studies, 141 were identified as meeting the inclusion criteria. A considerable heterogeneity regarding design, patient number, analytical and statistical methods was observed. High pretherapeutic CYFRA 21-1 levels and insufficient decreases indicated unfavorable prognosis in many studies on NSCLC patients treated with chemo-, targeted and immunotherapies or their combinations in early and advanced stages. Similar results were seen for CEA in chemotherapy, however, high pretherapeutic levels were sometimes favorable in targeted therapies. CA125 is a promising prognostic marker in patients treated with immunotherapies. Combinations of STMs further increased the prognostic value over single markers. CONCLUSION: Protein STMs, especially CYFRA 21-1, have prognostic potential in early and advanced stage NSCLC. For future STM investigations, better adherence to comparable study designs, analytical methods, outcome measures and statistical evaluation standards is recommended. [ABSTRACT FROM AUTHOR]

BACKGROUND: The value of serum tumor markers (STMs) in the current therapeutic landscape of lung cancer is unclear. OBJECTIVE: This scoping review gathered evidence of the predictive, prognostic, and monitoring value of STMs for patients with advanced lung cancer receiving immunotherapy (IT) or targeted therapy (TT). METHODS: Literature searches were conducted (cut-off: May 2022) using PubMed and Cochrane CENTRAL databases. Medical professionals advised on the search strategies. RESULTS: Study heterogeneity limited the evidence and inferences from the 36 publications reviewed. While increased baseline levels of serum cytokeratin 19 fragment antigen (CYFRA21-1) and carcinoembryonic antigen (CEA) may predict IT response, results for TT were less clear. For monitoring IT-treated patients, STM panels (including CYFRA21-1, CEA, and neuron-specific enolase) may surpass the power of single analyses to predict non-response. CYFRA21-1 measurement could aid in monitoring TT-treated patients, but the value of CEA in this context requires further investigation. Overall, baseline and dynamic changes in individual or combined STM levels have potential utility to predict treatment outcome and for monitoring of patients with advanced lung cancer. CONCLUSIONS: In advanced lung cancer, STMs provide additional relevant clinical information by predicting treatment outcome, but further standardization and validation is warranted. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) and stable disease (SD) have an unmet clinical need to help guide early treatment adjustments. OBJECTIVE: To evaluate the potential of tumor biomarkers to inform on survival outcomes in NSCLC SD patients. METHODS: This post hoc analysis included 480 patients from the IMpower150 study with metastatic NSCLC, treated with chemotherapy, atezolizumab and bevacizumab combinations, who had SD at first CT scan (post-treatment initiation). Patients were stratified into high- and low-risk groups (overall survival [OS] and progression-free survival [PFS] outcomes) based on serum tumor biomarker levels. RESULTS: The CYFRA 21-1 and CA 125 biomarker combination predicted OS and PFS in patients with SD. Risk of death was ~4-fold higher for the biomarker-stratified high-risk versus low-risk SD patients (hazard ratio [HR] 3.80; 95% confidence interval [CI] 3.02–4.78; p < 0.0001). OS in patients with the low- and high-risk SD was comparable to that in patients with the CT-defined partial response (PR; HR 1.10; 95% CI 0.898–1.34) and progressive disease (PD) (HR 1.05; 95% CI 0.621–1.77), respectively. The findings were similar with PFS, and consistent across treatment arms. CONCLUSIONS: Biomarker testing shows potential for providing prognostic information to help direct treatment in NSCLC patients with SD. Prospective clinical studies are warranted. ClinicalTrials.gov: NCT02366143 [ABSTRACT FROM AUTHOR]

BACKGROUND: Serum tumor markers (STM) may complement imaging and provide additional clinical information for patients with non-small cell lung cancer (NSCLC). OBJECTIVE: To determine whether STMs can predict outcomes in patients with stable disease (SD) after initial treatment. METHODS: This single-center, prospective, observational trial enrolled 395 patients with stage III/IV treatment-naïve NSCLC; of which 263 patients were included in this analysis. Computed Tomography (CT) scans were performed and STMs measured before and after initial treatment (two cycles of chemotherapy and/or an immune checkpoint inhibitor or tyrosine kinase inhibitor); analyses were based on CT and STM measurements obtained at first CT performed after cycle 2 only PFS and OS were analyzed by Kaplan-Meier curves and Cox-proportional hazard models. RESULTS: When patients with SD (n = 100) were split into high- and low-risk groups based on CYFRA 21-1, CEA and CA 125 measurements using an optimized cut-off, a 4-fold increase risk of progression or death was estimated for high- vs low-risk SD patients (PFS, HR 4.17; OS, 3.99; both p < 0.0001). Outcomes were similar between patients with high-risk SD or progressive disease (n = 35) (OS, HR 1.17) and between patients with low-risk SD or partial response (n = 128) (PFS, HR 0.98; OS, 1.14). CONCLUSIONS: STMs can provide further guidance in patients with indeterminate CT responses by separating them into high- and low-risk groups for future PFS and OS events. [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]

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]

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]

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]

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]

The interaction between programmed death-1 receptor PD-1 and its ligands PD-L1 and PD-L2 is involved in self-tolerance, immune escape of cancer, cardiovascular diseases, and COVID-19. As blood-based protein markers they bear great potential to improve oncoimmunology research and monitoring of anti-cancer immunotherapy. A variety of preanalytical conditions were tested to assure high quality plasma sample measurements: (i) different time intervals and storage temperatures before and after blood centrifugation; (ii) fresh samples and repeated freeze–thaw-cycles; (iii) different conditions of sample preparation before measurement. Concerning short-term stability, acceptable recoveries for PD-1 between 80 and 120% were obtained when samples were kept up to 24 h at 4 and 25 °C before and after blood centrifugation. Similarly, recoveries for PD-L2 were acceptable for 24 h at 4 °C and 6 h at 25 °C before blood centrifugation and up to 24 h at 4 and 25 °C after centrifugation. Variations for PD-L1 were somewhat higher, however, at very low signal levels. Sample concentrations (ng/mL) were neither affected by the freezing process nor by repeated freeze–thaw cycles with coefficients of variation for PD-1: 9.1%, PD-L1 6.8%, and PD-L2 4.8%. All three biomarkers showed good stability regarding preanalytic conditions of sample handling enabling reliable and reproducible quantification in oncoimmunology research and clinical settings of anti-cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Acute type A aortic dissection (ATAAD) constitutes a life-threatening aortic pathology with significant morbidity and mortality. Without surgical intervention the usual mortality rate averages between 1 and 2% per hour. Thus, an early diagnosis of ATAAD is of pivotal importance to direct the affected patients to the appropriate treatment. Preceding tests to find an appropriate biomarker showed among others an increased aggrecan (ACAN) mRNA expression in aortic tissue of ATAAD patients. As a consequence, we investigated whether ACAN is a potential biomarker for diagnosing ATAAD. Mean ACAN protein concentration showed a significantly higher plasma concentration in ATAAD patients (38.59 ng/mL, n = 33) compared to plasma of patients with thoracic aortic aneurysms (4.45 ng/mL, n = 13), patients with myocardial infarction (11.77 ng/mL, n = 18) and healthy volunteers (8.05 ng/mL, n = 12). Cardiac enzymes like creatine kinase MB and cardiac troponin T showed no correlation with ACAN levels in ATAAD patients. Receiver-operator characteristics (ROC) curve analysis for ATAAD patients versus control subjects an optimum discrimination limit of ACAN plasma levels at 14.3 ng/mL with a corresponding sensitivity of 97% and specificity of 81%. According to our findings ACAN is a reliable potential biomarker in plasma samples to detect ATAAD with high sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Keywords: evidence based-medicine; reference change value; tumor biomarker EN evidence based-medicine reference change value tumor biomarker 553 555 3 03/11/22 20220301 NES 220301 To the Editor, A word of caution on using biomarker reference change values (RCV) to guide medical decisions: In a recent study from the EFLM working group on biological variation, the biological variation of tumor markers has been investigated and estimates of the within and between subject biological variations were obtained [[1]]. Also, cancer treatment itself has a significant effect on the tumor and therefore tumor biomarker dynamics. [Extracted from the article]

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]

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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]

Multiple factors contribute to the development and progression of breast cancer. Markers of tumor growth and invasion, cell death, immune activation, and angiogenesis can be assessed in parallel by a novel multiplex immunoassay panel. The diagnostic performance of a multiplex cancer biomarker magnetic bead panel comprising 24 tumor associated parameters was evaluated in sera of 154 women including 77 patients with breast cancer, 10 with precancerous lesions, 31 with benign breast diseases, and 36 healthy controls. Marker levels were log-transformed for variance stabilization. Significance testing was done using t-test or Wilcoxon rank-sum test with correction of p values for multiple testing. Furthermore, receiver operating characteristic analyses were performed. Serum levels of several biomarkers were significantly (p = 0.001) higher in cancer patients than in healthy controls, particularly alpha-fetoprotein, cancer antigen 15-3, cancer antigen 19-9, migration inhibitory factor, carcinoembryonic antigen, cancer antigen 125, hepatocyte growth factor, soluble Fas, tumor necrosis factor-a, stem cell factor, and osteopontin. As most markers were also elevated in benign breast diseases, only cancer antigen 15-3 showed significant differences to cancer patients (p = 0.001). The resulting areas under the curve in receiver operating characteristic curves for discrimination between benign and malignant breast diseases achieved 0.71 with a sensitivity of 33.8% at 95% specificity. Multiplexing enables parallel analysis of different biomarker classes for cancer detection. Established cancer antigen 15-3 proved to be most relevant for differential diagnosis. [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, markerspecific 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 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]

Circulating nucleic acids (CNAs) are under investigation as a liquid biopsy in cancer as potential non-invasive biomarkers, as stable structure in circulation nucleosomes could be valuable sources for detection of cancer-specific alterations in histone modifications. Our interest is in histone methylation marks with a focus on colorectal cancer, one of the leading cancers respective the incidence and mortality. Our previous work included the analysis of trimethylations of lysine 9 on histone 3 (H3K9me3) and of lysine 20 on histone 4 (H4K20me3) by chromatin immuno- precipitation-related PCR in circulating nucleosomes. Here we asked whether global immunologic measurement of histone marks in circulation could be a suitable approach to show their potential as biomarkers. In addition to H3K9me3 and H4K20me3 we also measured H3K27me3 in plasma samples from CRC patients (n = 63) and cancer free individuals (n = 40) by ELISA-based methylation assays. Our results show that of three marks, the amounts of H3K27me3 (p = 0.04) and H4K20me3 (p < 0.001) were significantly lower in CRC patients than in healthy controls. For H3K9me3 similar amounts were measured in both groups. Areas under the curve (AUC) in receiver operating characteristic (ROC) curves indicating the power of CRC detection were 0.620 for H3K27me3, 0.715 for H4K20me3 and 0.769 for the combination of both markers. In conclusion, findings of this preliminary study reveal the potential of blood-based detection of CRC by quantification of histone methylation marks and the additive effect of the marker combination. [ABSTRACT FROM AUTHOR]

Background: The innate immune receptor RIG-I detects viral RNA within the cytosol of infected cells. Activation of RIG-I leads to the induction of antiviral cytokines, in particular type I interferon, the inhibition of a T(H)17 response as well as to the suppression of tumor growth. Therefore, RIG-I is a promising drug target for the treatment of cancer as well as multiple sclerosis. A specific ligand for RIG-I is currently in preclinical testing. The first-in-human trial will need to be carefully designed to avoid an overshooting cytokine response. Therefore, the ResI study was set up to analyze the human immune response to standard treatment with recombinant interferon-beta to establish biomarkers for safety and efficacy of the upcoming first-in-human trial investigating the RIG-I ligand. Methods/Design: ResI is a single center, prospective, open label, non-randomized phase I clinical trial. Three different cohorts (20 healthy volunteers, 20 patients with RRMS and ongoing interferon-beta treatment and 10 patients starting on interferon-beta) will receive standard interferon-beta-1a therapy for nine days. The study will be conducted according to the principles of the german medicinal products act, ICH-GCP, and the Declaration of Helsinki on the phase I unit of the Institute of Clinical Chemistry and Clinical Pharmacology and in the Department of Neurology, both University Hospital Bonn. Interferon-beta-induced cytokine levels, surface marker on immune cells, mRNA- and miRNA-expression as well as psychometric response will be investigated as target variables. Discussion: The ResI study will assess biomarkers in response to interferon-β treatment to guide the dose steps within the first-in-human trial with a newly developed RIG-I ligand. Thus, ResI is a biomarker study to enhance the safety of the clinical development of a first-in-class compound. The data can additionally be used for the development of other therapies based on type I interferon induction such as TLR ligands. Moreover, it will help to understand the interferon-beta induced immune response in a controlled in vivo setting in the human system. [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]

Aim Hepatic apoptosis is involved in the pathogenesis of immune-mediated liver diseases such as autoimmune hepatitis ( AIH), primary biliary cirrhosis ( PBC) and primary sclerosing cholangitis ( PSC). The aim of our study was to quantify distinct markers of apoptosis in sera of patients with AIH, PBC and PSC, and to evaluate correlation with markers of disease activity and prognosis. Methods Sera of patients with AIH, PBC and PSC, and of healthy controls were collected and distinct cell death markers were quantified using a bead-based multiplex enzyme linked immunosorbent assay (soluble intracellular adhesion molecule [ sICAM], macrophage migration inhibitory factor [ MIF], soluble Fas [s Fas], plasminogen activator inhibitor 1 [ PAI-1]) or single enzyme-linked immunosorbent assays ( DNAse, M30, M65). Results In comparison with healthy controls, the apoptotic markers sFas, sICAM (only in PSC patients), M30 and the cell death marker M65 were substantially elevated in sera of patients with immune-mediated liver diseases, whereas DNAse activity was reduced. Interestingly, patients with advanced PSC presented with higher levels of sICAM, M30 and M65 than patients with mild PSC. Regression analysis revealed correlations between serum levels of sICAM, M30 and M65 with the Mayo Risk Score for PSC, and of M65 with the Mayo Risk Score for PBC. Conclusion Concentrations of the serum markers of apoptosis sFas and M30 and of the marker of total cell death M65 are elevated in patients with immune-mediated liver diseases, whereas activity of DNAse is reduced. In patients with PSC, sICAM, M30 and M65 may serve as indicators for disease activity and prognosis. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are one of the important regulators of cellular functions fundamental for healthy pregnancy processes, including angiogenesis and differentiation of trophoblast cells, and their deregulation could be implicated in the pathogenesis of pregnancy complications, including preeclampsia (PE). The aim of this study was to assess the association of miRNA expression in plasma samples with PE, its onset, and severity. Our study enrolled 59 pregnant women, 27 in the preeclamptic study group and 32 in the control group with physiological pregnancy. Preeclamptic pregnancies were divided into subgroups based on the severity and onset of disease. Relative expression of miR-21-5p, miR-155-5p, miR-210-5p, miR-16-5p, and miR-650 isolated from plasma samples was analysed by quantitative real-time PCR and normalised to experimentally established reference genes. Our results revealed upregulation of miR-21-5p (1.16-fold change, p = 0.0015), miR-155-5p (1.62-fold change, p = 0.0005) in preeclamptic pregnancies, compared to controls. Overexpression of these two miRNAs was observed, especially in subgroups of severe and late-onset PE compared to healthy pregnancies. Although we hypothesised that the expression level of studied miRNAs could vary between PE subtypes (mild vs. severe, early onset vs. late-onset), no obvious differences were detected. In conclusion, our study could contribute to the large-scale studies for the identification of non-invasive biomarkers for PE detection to improve outcomes for women and their new-borns. [ABSTRACT FROM AUTHOR]

• Available cancer biomarkers are associated with low diagnostic performance. • Satellite 2 DNA amount is higher in the blood circulation of patients with cancer. • Satellite 2 DNA may be a universal biomarker for the detection of cancer. Currently, cancer biomarkers are associated with low diagnostic performance, and the notion of using cell-free DNA (cfDNA) as a surrogate cancer biomarker is a subject of ongoing research efforts. Pericentromeric satellite repeats were shown to expand in tumor cells. Here, we hypothesized that the increased release of satellite DNA into the circulation might be a basis for developing a biomarker for the detection of cancer. The study included patients with different cancer types, and controls without cancer. Human satellite 2 repeat (HSATII) from chromosomes 1, 10, or 16 was amplified using extracted DNA from plasma or direct application of diluted plasma in PCR. We first showed that HSATII DNA levels were higher in patients with cancer than in controls relative to LINE1 element, with chr10-HSATII being the most relevant. Absolute quantification in digital PCR showed much higher levels of chr10-HSATII in patients with breast cancer compared with healthy individuals. Subsequently, employing diluted plasma also revealed that HSATII DNA was present in increased levels in patients with cancer including breast, gastric, lung or bile cancers, sarcoma or Hodgkin's lymphoma than in controls with an AUC of 94% in the ROC curve. This proof-of-concept study reveals the high potential of HSATII DNA as a surrogate cancer biomarker. [ABSTRACT FROM AUTHOR]