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Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense., Innate immunity represents an early defense mechanism against invading pathogens. Whereas in mammals this is complemented by adaptive immunity, host defenses in many other animal species, including arthropods--the largest phylum [...]

Background: Despite the significance of colonoscopy for early diagnosis of colorectal adenocarcinoma (CRC), population-wide screening remains challenging, mainly because of low acceptance rates. Herein, exosomal (exo-miR) and free circulating microRNA (c-miR) may be used as liquid biopsies in CRC to identify individuals at risk. Direct comparison of both compartments has shown inconclusive results, which is why we directly compared a panel of 10 microRNAs in this entity. Methods: Exo-miR and c-miR levels were measured using real-time quantitative PCR after isolation from serum specimens in a cohort of 69 patients. Furthermore, results were compared to established tumor markers CEA and CA 19-9. Results: Direct comparison of exo- and c-miR biopsy results showed significantly higher microRNA levels in the exosomal compartment (p < 0.001). Exo-Let7, exo-miR-16 and exo-miR-23 significantly differed between CRC and healthy controls (all p < 0.05), while no c-miR showed this potential. Sensitivity and specificity can be further enhanced using combinations of multiple exosomal miRNAs. Conclusions: Exosomal microRNA should be considered as a promising biomarker in CRC for future studies. Nonetheless, results may show interference with common comorbidities, which must be taken into account in future studies. [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]

Background Heterozygous familial hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce. Methods In the VRONI study, children aged 5–14 years in Bavaria are invited to participate in an FH screening program during regular pediatric visits. The screening is based on low-density lipoprotein cholesterol measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first-degree relatives, reverse cascade screening is recommended to identify and treat affected family members. Results Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data safety, legal and organizational aspects, which will be outlined in this article. Recruitment started in early 2021, within the first months, more than 380 pediatricians screened over 5200 children. Approximately 50 000 children are expected to be enrolled in the VRONI study until 2024. Conclusions VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nationwide FH screening infrastructure. Furthermore, we aim to validate genetic variants of unclear significance, detect novel causative mutations and contribute to polygenic risk indices (DRKS00022140; August 2020). [ABSTRACT FROM AUTHOR]

Although prostate-specific antigen-based prostate cancer screening had a positive impact in reducing prostate cancer mortality, it also led to overdiagnosis, overtreatment and a significant number of unnecessary biopsies. In the post-prostate-specific antigen era, new biomarkers have emerged that can complement the information given by prostate-specific antigen, towards a better cancer diagnostic specificity, and also allowing a better estimate of the aggressiveness of the disease and its clinical outcome. That means those markers have the potential to assist the clinician in the decision-making processes, such as whether or not to perform a biopsy, and to make the best treatment choice among the new therapeutic options available, including active surveillance in lower risk disease. In this article, we will review several of those more recent diagnostic markers (4Kscore®, [-2]proPSA and Prostate Health Index, SelectMDx®, ConfirmMDx®, Progensa® Prostate Cancer Antigen 3, Mi-Prostate Score, ExoDx™ Prostate Test, the Stockholm3 test and ERSPC risk calculators) and prognostic markers (OncotypeDX® Genomic Prostate Score, Prolaris®, Decipher® and ProMark®). We will also address some new liquid biopsy approaches – circulating tumour cells and cell-free DNA – with a potential role in metastatic castration-resistant prostate cancer and will briefly give some future perspectives, mostly outlooking epigenetic markers. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of in‐hospital haemoglobin drop in patients with acute coronary syndrome (ACS) undergoing invasive therapy remains insufficiently investigated. Materials and Methods: This observational study included 3838 patients with ACS with admission and in‐hospital nadir haemoglobin values available. Haemoglobin drop was defined as a positive difference between admission and nadir haemoglobin values. The primary endpoint was one‐year all‐cause mortality. Results: In‐hospital haemoglobin drop occurred in 3142 patients (82%). Patients were categorized into 4 groups: no haemoglobin drop (n = 696 patients), <3 g/dl haemoglobin drop (n = 2703 patients), 3 to <5 g/dl haemoglobin drop (n = 344 patients) and ≥5 g/dl haemoglobin drop (n = 95 patients). The primary endpoint occurred in 156 patients: 17 patients (2.5%) in the group with no haemoglobin drop, 81 patients (3.0%) in the group with <3g/dl haemoglobin drop, 37 patients (10.9%) in the group with 3 to <5 g/dl haemoglobin drop and 21 patients (22.2%) in the group with ≥5 g/dl haemoglobin (adjusted hazard ratio [HR] = 1.30, 95% confidence interval 1.17 to 1.45; p <.001 for one g/dl haemoglobin drop). The association of haemoglobin drop with one‐year mortality remained significant after exclusion of patients with in‐hospital overt bleeding (adjusted HR = 1.27 [1.11–1.46]; p <.001 for one g/dl haemoglobin drop). The lowest haemoglobin drop associated with mortality was 1.23 g/dl in all patients (HR = 1.03 [1.02–1.04]) and 1.13 g/dl in patients without overt bleeding (HR = 1.03 [1.01–1.04]). Conclusions: In patients with ACS, in‐hospital haemoglobin drop was associated with higher risk of one‐year mortality even in the absence of overt bleeding. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aim: Lack of interchangeability between prostate-specific antigen (PSA) assays could have a clinical impact. We compared PSA assays from different manufacturers and calibrations. Patients and Methods: A total of 233 men who underwent prostate biopsy (PSA: 2-10 ng/ml; Beckman Coulter Access® Hybritech® as reference) were enrolled. Total (tPSA) and free PSA (fPSA) were also measured using the Roche cobas® and the Abbott Architect® methods. Results: Roche tPSA values were ≈1% higher than Beckman, while Abbott values were ≈5% lower. Roche had the highest diagnostic sensitivity (92%) compared to Beckman Coulter (87%) and Abbott (85%). Roche fPSA was ≈3% lower and Abbott ≈17% higher than that of Beckman. For the percentage of fPSA, Roche had the highest sensitivity (98%). Conclusion: Roche cobas® and Beckman Coulter Access® Hybritech® tPSA were almost interchangeable. While the agreement was acceptable for tPSA, this did not happen with fPSA and greater efforts for harmonization are required. [ABSTRACT FROM AUTHOR]

To evaluate the diagnostic performance of the prostate health index (PHI) and of the percentage of [-2]proPSA (%[-2]proPSA) calculated with total and free PSA from non-Beckman Coulter manufacturers (Roche and Abbott), and compare it with the fully Beckman Coulter [-2]proPSA derivatives. In this study, 237 men (PSA: 2–10 μg/L) scheduled for prostate biopsy were enrolled. %[-2]proPSA and PHI were calculated with total and free PSA from three manufacturers. Beckman Coulter PSA and [-2]proPSA were performed on the Access 2 analyzer (Hybritech calibration). Roche PSA was performed on the cobas e411 and the Abbott PSA on the Architect i2000sr. Statistical analysis was performed, considering prostate cancer (PCa) as the outcome. Univariate analysis showed that all indices were predictors of cancer, irrespective of the manufacturer (p<0.001). The AUC was similar for all manufacturers, both for %[-2]proPSA (Beckman Coulter: 0.756; Roche: 0.770; Abbott: 0.756) and PHI (Beckman Coulter: 0.776; Roche: 0.785; Abbott: 0.778). When considering the cutoffs that allowed 90% sensitivity, [-2]proPSA derivatives calculated with Roche and Abbott PSA had similar specificities and predictive values when compared to Beckman Coulter. The percentage of missed cancers (8–9%) was the same between manufacturers. The percentage of spared biopsies was significantly higher with Roche's PHI (21.0%) and Abbott's PHI (20.6%) than with Beckman Coulter's PHI (17.2%). In the PSA range between 2 and 10 μg/L, [-2]proPSA derivatives maintain their diagnostic performance in PCa detection when calculated with PSA from Roche and Abbott. This can lead to a broader implementation of these indices in clinical laboratories worldwide. [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]

Background/Aim: Evasion from cell death occurs in prostate cancer (PCa). We verified whether serum levels of cell death markers can have diagnostic value in PCa. Patients and Methods: A total of 233 men scheduled for prostate biopsy [prostate specific antigen (PSA) level: 2-10 ng/ml] were enrolled. Serum nucleosomes, nucleosomes containing the H3 histone (H3), high mobility group box 1 (HMGB1), and soluble receptor for advanced glycation end products (sRAGE) were analyzed by enzyme immunoassays. Results: There were no differences (p>0.05) in nucleosomes, H3, and sRAGE levels between patients with and without PCa or clinically significant PCa (csPCa). HMGB1 had lower levels in PCa patients (p=0.023) and was a predictor of PCa (p=0.047), but not of csPCa (p=0.180). Conclusion: In patients with critical PSA levels between 2-10 ng/ml, HMGB1 had some diagnostic value for overall PCa detection, but it was not predictive of csPCa. Nucleosomes, H3 and sRAGE did not discriminate between PCa or csPCa and controls. [ABSTRACT FROM AUTHOR]

Abstract Background Selective Internal Radiation Therapy (SIRT) is a new and effective locoregional anticancer therapy for colorectal cancer patients with liver metastases. Markers for prediction of therapy response and prognosis are needed for the individual management of those patients undergoing SIRT. Methods Blood samples were prospectively and consecutively taken from 49 colorectal cancer patients with extensive hepatic metastases before, three, six, 24 and 48 h after SIRT to analyze the concentrations of nucleosomes and further laboratory parameters, and to compare them with the response to therapy regularly determined 3 months after therapy and with overall survival. Results Circulating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), C-reactive protein (CRP) and various liver markers increased already 24 h after SIRT. Pretherapeutical levels of CYFRA 21-1, CEA, cancer antigen 19-9 (CA 19-9), asparate-aminotransferase (AST) and lactate dehydrogenase (LDH) as well as 24 h values of nucleosomes were significantly higher in patients suffering from disease progression (N = 35) than in non-progressive patients (N = 14). Concerning overall survival, CEA, CA 19-9, CYFRA 21-1, CRP, LDH, AST, choline esterase (CHE), gamma-glutamyl-transferase, alkaline phosphatase, and amylase (all 0 h, 24 h) and nucleosomes (24 h) were found to be prognostic relevant markers in univariate analyses. In multivariate Cox-Regression analysis, the best prognostic model was obtained for the combination of CRP and AST. When 24 h values were additionally included, nucleosomes (24 h) further improved the existing model. Conclusion Panels of biochemical markers are helpful to stratify pretherapeutically colorectal cancer patients for SIR-therapy and to early estimate the response to SIR-therapy.

Abstract Background Transarterial chemoembolization (TACE) therapy is an effective locoregional treatment in hepatocellular cancer (HCC) patients. For early modification of therapy, markers predicting therapy response are urgently required. Methods Here, sera of 50 prospectively and consecutively included HCC patients undergoing 71 TACE therapies were taken before and 3 h, 6 h and 24 h after TACE application to analyze concentrations of circulating nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), alpha fetoprotein (AFP), C-reactive protein (CRP) and several liver biomarkers, and to compare these with radiological response to therapy. Results While nucleosomes, CYFRA 21-1, CRP and some liver biomarkers increased already 24 h after TACE, percental changes of nucleosome concentrations before and 24 h after TACE and pre- and posttherapeutic values of AFP, gamma-glutamyl-transferase (GGT) and alkaline phosphatase (AP) significantly indicated the later therapy response (39 progression versus 32 no progression). In multivariate analysis, nucleosomes (24 h), AP (24 h) and TACE number were independent predictive markers. The risk score of this combination model achieved an AUC of 81.8% in receiver operating characteristic (ROC) curves and a sensitivity for prediction of non-response to therapy of 41% at 97% specificity, and of 72% at 78% specificity. Conclusion Circulating nucleosomes and liver markers are valuable tools for early estimation of the efficacy of TACE therapy in HCC patients.

Gaps in the translation of research findings to clinical management have been recognized for decades. They exist for the diagnosis as well as the management of cancer. The international standards for cancer diagnosis are contained within the World Health Organization (WHO) Classification of Tumours, published by the International Agency for Research on Cancer (IARC) and known worldwide as the WHO Blue Books. In addition to their relevance to individual patients, these volumes provide a valuable contribution to cancer research and surveillance, fulfilling an important role in scientific evidence synthesis and international standard setting. However, the multidimensional nature of cancer classification, the way in which the WHO Classification of Tumours is constructed, and the scientific information overload in the field pose important challenges for the translation of research findings to tumour classification and hence cancer diagnosis. To help address these challenges, we have established the International Collaboration for Cancer Classification and Research (IC3R) to provide a forum for the coordination of efforts in evidence generation, standard setting and best practice recommendations in the field of tumour classification. The first IC3R meeting, held in Lyon, France, in February 2019, gathered representatives of major institutions involved in tumour classification and related fields to identify and discuss translational challenges in data comparability, standard setting, quality management, evidence evaluation and copyright, as well as to develop a collaborative plan for addressing these challenges. What's new? The World Health Organization Classification of Tumours has been informing cancer research and clinical practice by providing an international consensus on the tumour criteria for cancer diagnosis. In a new initiative coordinated by the International Agency for Research on Cancer, major institutions are now joining forces to address the remaining challenges in translational research and facilitate the application of research results to clinical practice. The newly‐established International Collaboration for Cancer Classification and Research (IC3R) aims to provide a forum for the coordination of efforts in generating evidence, setting standards, and providing best practice recommendations for tumor classification and cancer research. [ABSTRACT FROM AUTHOR]

Abstract Background Elevated levels of nucleosomal DNA fragments can be detected in plasma and sera of patients with malignant diseases. Methods We investigated the course of nucleosomal DNA, thymidine kinase, lactate dehydrogenase and leukocytes in sera of 25 patients with acute myeloid leukemia during the first cycle of induction chemotherapy and tested their power to distinguish between patients with complete remission and those with no remission. Results Almost all patients showed strongly decreasing levels of nucleosomal DNA during the first week, in some cases after initial peaks. In overall analysis of variance, DNA levels could clearly distinguish between patients with complete remission, who had higher DNA values, and those with insufficient response (p = 0.017). The area under the curve of DNA values of days 2–4 after start of therapy (AUC 2–4) discriminated between both groups with a sensitivity of 56% at a specificity of 100%. Further, pretherapeutic levels and AUC 2–4 of nucleosomal DNA correlated significantly with blast reduction after 16 days. A tendency to higher levels in patients with complete response was also found for thymidine kinase, lactate dehydrogenase and leukocytes, however the difference did not reach the level of significance (p = 0.542, p = 0.260, and p = 0.144, respectively). Conclusion Our results indicate that nucleosomal DNA fragments are valuable markers for the early prediction of therapeutic efficacy in patients with acute myeloid leukemia.

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]

Background and Aims: Evidence on the association between aspartate aminotransferase (AST) activity and mortality of patients with ischemic heart disease (IHD) is limited. We investigated whether there is an association between AST activity and mortality in IHD patients.Methods and Results: The study included 6857 patients with coronary angiography-proven IHD and AST activity within the reference range. AST activity measurements were available in all patients. The primary outcome was 3-year cardiac mortality. Patients were categorized in groups according to the AST activity tertiles: a group with AST within the 1st tertile (AST < 17.0 U/L), a group with AST within the 2nd tertile (AST > 17-24.5 U/L) and a group with AST within the 3rd tertile (AST > 24.5 U/L). Cardiac death (n = 297) occurred in 109, 69 and 119 patients in the 1st to 3rd AST tertiles (Kaplan-Meier estimates of mortality: 5.3%, 3.6% and 5.9%; univariable hazard ratio [HR] = 1.75, 95% confidence interval [CI] 1.30-2.36, P < 0.001 for tertile 3 vs. 2; HR = 1.13 [0.87-1.46], P = 0.370 for tertile 3 vs. 1; and HR = 0.65 [0.48-0.87], P = 0.004 for tertile 2 vs. 1). The association between AST and cardiac mortality was U-shaped. AST values <15 U/L (HR = 1.118 [1.009-1.238]) and >23 U/L (HR = 1.029 [1.003-1.056]) were associated with higher cardiac mortality compared with the reference value (21 U/L). After adjustment, the association between AST and cardiac mortality was attenuated (P = 0.133) but remained non-linear (P = 0.047).Conclusions: In patients with IHD, AST activity was associated with the risk of cardiac mortality with a U-shaped relationship. After adjustment, the association between AST and mortality was attenuated. [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]