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CA 15-3 and CEA are tumor markers used in routine clinical care for breast cancer and colorectal cancer, among others. Current measurement procedures (MP) for these tumor markers are considered to be insufficiently harmonized. This study investigated the achievable harmonization for CA 15-3 and CEA by using an in silico simulation of external quality assessment (EQA) data from multiple EQA programs using patient-pool based samples.CA 15-3 and CEA data from SKML (2021), UK NEQAS (2020–2021) and KEQAS (2020–2021) were used. A harmonization protocol was defined in which MPs that were considered equivalent were used to value assign EQA samples, and recalibration was only required if the MP had a bias of >5 % with value assigned EQA. Harmonization status was assessed by determining the mean level of agreement and residual variation by CV (%).Only MPs from Abbott, Beckman, Roche and Siemens were available in all EQA programs. For CA 15-3, recalibration was proposed for Beckman MP only and for CEA, recalibration was proposed for Siemens MP only. When the harmonization procedures were applied, for CA 15-3 the pre-harmonization mean bias range per MP was reduced from −29.28 to 9.86 %, into −0.09–0.12 % after harmonization. For CEA, the mean bias range per MP was reduced from −23.78 to 2.00 % pre-harmonization to −3.13–1.42 % post-harmonization.The present study suggests that a significant improvement in the harmonization status of CA 15-3 and CEA may be achieved by recalibration of a limited number of MPs. [ABSTRACT FROM AUTHOR]

The article discusses the use of circulating tumor DNA (ctDNA) in blood tests to improve the personalized treatment of colorectal cancer by providing more accurate prognosis and monitoring therapy response, especially in early-stage disease detection and post-operative care. It highlights the role of ctDNA in liquid biopsies and its potential for revolutionizing cancer management by predicting treatment outcomes and identifying minimal residual disease.

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]

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]

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]

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]

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]

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]

Purpose: Recent studies indicate that circulating microRNAs in serum/plasma are a novel class of non-invasive biomarkers with diagnostic and prognostic information. So far, circulating microRNAs have not been analyzed in patients with bladder cancer. Methods: We collected serum from patients with non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and non-malignant urological disease. Total RNA was isolated from 400 μl of serum using the mirVana PARIS Kit; the artificial cel-miR-39 was spiked-in prior to RNA isolation to control different RNA isolation efficiencies. Quantitative real-time PCR was applied to measure the levels of 22 microRNAs upregulated in BCA tissue (miR-15a, miR-18a, miR-21, miR-93, miR-96, miR-103, miR-130b, miR-135b, miR-141, miR-182, miR-183, miR-190, miR-191, miR-200b, miR-422b, miR-425, miR-449b, miR-601, miR-639, miR-644, miR-649 and miR-1233) in the marker identification cohort (NMIBC, n = 11, MIBC, n = 10; controls, n = 10). The most promising serum microRNAs were tested in a validation cohort (NMIBC, n = 65, MIBC, n = 61; controls, n = 105). Results: The RNA recovery was similar in patients with NMIBC, MIBC and control subjects. The analysis of serum microRNA levels in the marker identification cohort indicated that serum miR-141 and miR-639 levels were increased in bladder cancer patients compared to CTRL. The analysis of these miR-141 and miR-639 in the validation cohort demonstrated that microRNA levels were similar in bladder cancer patients and control subjects. Furthermore, microRNA levels were not correlated with clinicopathological parameters (pT-stage, metastasis, grading). Conclusions: The analysis of serum miR-141 and miR-639 levels does not seem to be helpful in the diagnosis or prognosis of BCA. [ABSTRACT FROM AUTHOR]

Objectives: To identify an appropriate reference gene for the analysis of circulating micro-ribonucleic acid in patients with urological malignancies. Methods: Serum from patients with prostate cancer ( n = 24), bladder cancer ( n = 24), renal cell carcinoma ( n = 24) and control subjects ( n = 48) was spiked with cel-miR-39, and then ribonucleic acid was isolated. Quantitative real-time polymerase chain reaction was used to determine the levels of candidate reference genes ( RNU1-4, RNU6-2, SNORD43, SNORD44, SNORD48, S NORA74A, miR-let-7a-1, miR-106a). Reference gene stability was determined using the NormFinder, geNorm and comparative delta-Ct algorithm. The effect of normalization was tested with miR-21 as the target gene, as this was previously suggested to be upregulated in cancer patients' serum. Results: Recovery of cel-miR-39 (mean 11.6%, range 1-56%) was similar in control subjects and cancer patients. SNORD44 and SNORD74A levels were around the detection limit of the assay and were thus omitted. All remaining candidates showed satisfying stability; SNORD43 was the most stable reference gene using all three algorithms. A combination of two genes ( SNORD43, RNU1-4) increases the stability somewhat. The level of miR-21 was similar in cancer patients and healthy controls, irrespective of the normalization strategy. Conclusions: SNORD43 is a suitable reference gene for the analysis of circulating micro-ribonucleic acid in patients with urological malignancies. Our study questions the suitability of miR-21 as a biomarker for uro-oncological patients. [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]

We performed method comparison for the tumor markers CA 15-3, CA 19-9, and CA 125 measured by luminescent oxygen channeling immunoassay technology on the Dimension Vista 1500 and by classic luminescence technology on the Immulite 2000 XPI. Within-day and total imprecision were determined according to Clinical and Laboratory Standards Institute (CLSI) guidelines using three serum pools at different clinically relevant levels. In addition, parallel measurements on both systems were performed in a total of 738 routine serum samples (133 CA 15-3, 395 CA 19-9, and 210 CA 125). Total imprecision of serum pools for CA 15-3 ranged between 4.6% and 5.9%, for CA 19-9 between 4.4% and 7.8%, and for CA 125 between 3.3% and 4.3%. Marker values determined within the measurement range of both systems correlated well with each other (R = 0.88 for CA 15-3, R = 0.93 for CA 19-9, and R = 0.96 for CA 125). Slopes between the Vista and the Immulite method were 0.96 for CA 125, 0.72 for CA 15-3, and 0.87 for CA 19-9, indicating lower values for CA 15-3 and CA 19-9 when measured by the Vista method. This was particularly obvious for CA 19-9 levels in the lower measuring range of <100 U/mL (R = 0.85; slope 0.73). [ABSTRACT FROM PUBLISHER]

Differential diagnosis of suspicious lung masses is essential for the selection of the appropriate therapy strategy. While non-small cell lung cancer (NSCLC) in early stages and single lung metastases from other cancers mostly are resected by surgery, late stage NSCLC, small cell lung cancers (SCLC) and multiple lung metastases are treated by systemic chemo- and/or radiotherapeutic approaches. In many patients, biopsies for the histopathological subtyping can not be taken due to multimorbidity and instable clinical conditions of the patient or unfavourable localisation of the tumor. In addition, heterogeneity of lung tumors may imply the presence of different malignant cell types in one suspicious lesion. As tumor-related biomarkers in blood reflect the biochemical properties of cancer cells, their release or non-release may be helpful to support the clinical decision making. This review summarizes the current knowledge about the potential and the role of serum-based biomarkers for the differential diagnosis of lung cancer which is also mirrored in the new recommendations of the National Academy of Clinical Biochemistry (NACB). [ABSTRACT FROM AUTHOR]

Prognostic information on the course of cancer disease is highly relevant for the accurate decision of the most effective treatment strategy for an individual patient. In early stage disease, the application of adjuvant chemo- or radiotherapy after surgery depends on the risk of the patient to early suffer from tumor recurrence. In advanced stage disease, risk stratification of the patients influences the choice of more aggressive or mild therapy alternatives. Besides tumor related parameters like tumor stage and individual factors, additional information by biomarkers is needed to better characterize patients prognosis in both situations. Although there are plenty of studies dealing on the prognostic relevance of diverse biomarkers in non-small cell lung cancer (NSCLC), the results are quite heterogeneous and sometimes conflicting. Reasons for this situation may be found in the design, the performance, the evaluation and the quality of result reporting of the studies. In this review, we focus on the prerequisites of informative prognostic trials, spot on the general shortcomings of studies published so far, and summarize the results of the prognostic studies available for early and advanced stages of NSCLC. [ABSTRACT FROM AUTHOR]

The dysregulation of proliferating and apoptotic processes is a common feature in cancerogenesis. Thus, apoptotic products released into blood circulation are suggested as promising markers for the early cancer detection. However though sensitive assays are available, the lack of organ- and tumor-specificity limits the usefulness of most apoptotic parameters for screening purposes. However, they seem to be valuable for the prognosis and the prediction of response to systemic chemo- or radiotherapy in cancer disease. Here, the relevance of diverse circulating apoptotic markers is reviewed for the clinical management of patients with lung cancer. Among those promising markers are ligands and receptors of the FAS-system, members of the intracellular caspase cascade, cleaved apoptosis substrates such as cytokeratines, nucleosomal DNA, and apoptosis modulators like survivin. The review discusses their role for diagnosis, prognosis and therapy monitoring of lung cancer disease. [ABSTRACT FROM AUTHOR]

As the release and amount of circulating biomarkers show considerable variations between individuals, single value determinations are often difficult to be interpreted on their diagnostic or prognostic significance on the individual level. However, changes of the biomarker levels in a specific person during the disease course are quite informative for the estimation of the efficacy of therapy or the early detection of recurrent disease because they consider only intraindividual variations. If methods for marker determination are maintained, preanalytical and analytical standard prerequistits are respected, thresholds for each marker have to be defined which exceeds the normal, intraindividual biological variation. Then continuous biomarker increases may be indicative for disease activity in terms of inefficient therapy response or tumor recurrence while decreasing values often are associated with activity reduction of cancer disease. Here, we review the current knowledge on biomarker kinetics in patients with non-small cell lung cancer (NSCLC) and discuss the conditions and pitfalls of their relevance for the estimation efficacy of therapy and the early detection of recurrent disease. Further, we suggest a scenario to reveal the power of the defined biomarker use in future and to include those markers into the individual management of NSCLC patients. [ABSTRACT FROM AUTHOR]

The article looks at developments in the study of lung cancer biomarkers. According to the authors, circulating biochemical markers are important and informative tools for managing lung cancer. Biomarkers are considered vital for follow-up investigations because biochemical changes in the blood manifest early the possibility of increasing tumor activity. Information on the release of biochemical markers by various benign and malignant diseases has been limited.

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.

Nucleosomes, complexes of DNA and histone proteins, are released from dying and stressed cells into the blood circulation. Concentrations of circulating nucleosomes in plasma and serum are frequently found to be elevated in various cancers, and also in such acute conditions as stroke, trauma, and sepsis as well as in autoimmune diseases. The first part of this review focuses on the structural and functional properties of nucleosomes, the potential sources of nucleosome release into the circulation, the metabolism of circulating nucleosomes, and their pathophysiological role in disease. It goes on to describe the relevance of circulating nucleosomes in the diagnosis and prognosis of non-malignant conditions such as sepsis, stroke, and autoimmune disease. Finally, it describes the clinical value of nucleosomes in the diagnosis, staging, prognosis, and monitoring of therapy in cancer; in particular, their potential as a new diagnostic tool for the early estimation of response to cytotoxic cancer therapy is emphasized. [ABSTRACT FROM AUTHOR]

Summary: The increasing panel of systemic therapies enables the individual management of cancer patients, even in advanced stages. However, diagnostic tools indicating early the efficacy of therapy are still needed. In prospectively collected sera of 161 patients with recurrent non-small cell lung cancer (NSCLC) receiving second-line chemotherapy, the courses of nucleosomes, cytokeratin-19 fragments (CYFRA 21-1), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and progastrin-releasing peptide (ProGRP) were investigated and correlated with therapy response. At high specificity for detection of progressive disease, most sensitive biomarkers were identified and included in a combination model. High levels and insufficient decreases of nucleosomes and CYFRA 21-1 during the first cycle of therapy indicated poor outcome. Combination of nucleosome concentrations at day 8 and CYFRA 21-1 before start of the second cycle enabled the early detection of progressive disease with a sensitivity of 34.4% at 95% specificity (AUC 0.79) prior to imaging techniques. When cutoffs were fixed at the 90th percentile of responding patients, the combination model achieved sensitivities of 19% at 100% specificity and of 52% at 88% specificity. Thus, nucleosomes and CYFRA 21-1 showed to be valuable for the individual management of patients with recurrent NSCLC. [Copyright &y& Elsevier]

Nucleosomes, complexes of DNA and histone proteins, are released during cell death into the blood circulation. Elevated serum and plasma levels have been found in various forms of cancer, but also in autoimmune diseases and acute situations such as stroke, trauma, and during sepsis. Here, the clinical relevance of circulating nucleosomes for diagnosis, staging, prognosis, and therapeutic monitoring of cancer is reviewed. Several studies have shown that levels of nucleosomes are significantly higher in serum and plasma of cancer patients in comparison to healthy controls. However, because of elevations of nucleosome levels in patients with benign diseases relevant for differential diagnosis, they are not suitable for cancer diagnosis. Concerning tumor staging, nucleosome levels correlate with tumor stage and presence of metastases in gastrointestinal cancer, but not in other tumor types. Prognostic value of circulating nucleosomes is found in lung cancer in univariate analyses, but not in multivariate analyses. Circulating nucleosomes are most informative for the monitoring of cytotoxic therapy. Strongly decreasing levels are mainly found in patients with remission of disease, whereas constantly high or increasing values are associated with progressive disease during chemo- and radiotherapy. In addition, therapy outcome is already indicated by the nucleosomal course during the first week of chemo- and radiotherapy in patients with lung, pancreatic, and colorectal cancer as well as in hematologic malignancies. Despite their non-tumor-specificity, kinetics of nucleosomes are valuable markers for the early estimation of therapeutic efficacy and may be helpful to adapting early cancer therapy in the future. [ABSTRACT FROM AUTHOR]

This study aimed to test the diagnostic utility of the DNA integrity index for detection of cancer. Matched serum and plasma samples of 42 patients with various forms of cancer and 17 patients with corresponding benign diseases were analyzed. DNA was isolated from 1 mL serum and plasma using the MagNA Pure LC system. Cell-free DNA was quantified by real-time PCR using the reference gene of the LightCycler t(14;18) kit. Subsequently, the DNA integrity index was calculated as the ratio in relative abundance of 347-bp versus 137-bp PCR products. We found that DNA concentrations were not different in plasma (median: 4.5 ng/mL) and serum (67.1 ng/mL) of patients with benign diseases when compared with values in plasma (5.1 ng/mL) and serum (65.4 ng/mL) of cancer patients. Similarly, the DNA integrity index in plasma (0.38), and serum of patients with benign diseases (0.29) was comparable to values in plasma (0.33) and serum (0.37) of cancer patients. Diagnostic sensitivity of DNA (AUC 0.53) and DNA integrity (AUC 0.45) was poor in plasma, and was increased only slightly by the combination of both (AUC 0.57). In serum, sensitivity of DNA (AUC 0.52) and DNA integrity (AUC 0.64) was higher and was further improved by the combination of both (AUC 0.72) reaching a sensitivity of 30% at 100% specificity. In conclusion, we could not confirm a high diagnostic utility of the DNA integrity index. However, a combination with other markers such as DNA may enhance sensitivity for cancer detection. [ABSTRACT FROM AUTHOR]

Background: Cancer antigen CA125 is known as a valuable marker for the management of ovarian cancer. Methods: The analytical and clinical performance of the Access OV Monitor Immunoassay System (Beckman Coulter) was evaluated at five different European sites and compared with a reference system, defined as CA125 on the Elecsys System (Roche Diagnostics). Results: Total imprecision (%CV) of the OV Monitor ranged between 3.1% and 8.8%, and inter-laboratory reproducibility between 4.7% and 5.0%. Linearity upon dilution showed a mean recovery of 100% (SD+8.1%). Endogenous interferents had no influence on OV Monitor levels (mean recoveries: hemoglobin 107%, bilirubin 103%, triglycerides 103%). There was no high-dose hook effect up to 27,193 kU/L. Clinical performance investigated in sera from 1811 individuals showed a good correlation between the Access OV Monitor and Elecsys CA125 (R=0.982, slope=0.921, intercept=+1.951). OV Monitor serum levels were low in healthy individuals (n=267, median=9.7 kU/L, 95th percentile=30.8 kU/L), higher in individuals with various benign diseases (n=549, medians=10.9–16.4 kU/L, 95th percentiles=44.2–355 kU/L) and even higher in individuals suffering from various cancers (n=995, medians=12.4–445 kU/L; 95th percentiles=53.4–4664 kU/L). Optimal diagnostic accuracy for cancer detection against the relevant benign control group by the OV Monitor was found for ovarian cancer [area under the curve (AUC) 0.898]. Results for the reference CA125 assay were comparable (AUC 0.899). Conclusions: The Access OV Monitor provides very good methodological characteristics and demonstrates an excellent analytical and clinical correlation with Elecsys CA125. The best diagnostic accuracy for the OV Monitor was found in ovarian cancer. Our results also suggest a clinical value of the OV Monitor in other cancers. Clin Chem Lab Med 2008;46:588–99. [ABSTRACT FROM AUTHOR]

The prognostic relevance of blood markers in cerebral stroke is still a matter of controversial debate. In sera of 63 patients, nucleosomes, neuronspecific enolase (NSE), S100 protein, and C-reactive protein (CRP) were determined daily during the first week after cerebral stroke. Infarction volume was quantified by CT or MRI and the clinical status by Barthel Index (BI) at admission, discharge, and after 12 months (prognosis). All markers were evaluated by univariate and multivariate analysis on their prognostic relevance. During observation time (12 months), three patients died and 33 reached complete recovery. Infarction volume, nucleosomes, NSE, S100, and CRP correlated significantly with clinical status at admission. The same markers except CRP and initial BI correlated with recovery after 12 months. Almost all patients with initial BI ‡ 50 reached complete recovery. In patients with initially severe defects (BI < 50), nucleosomes and S100, both at day 3, were found to be prognostically relevant. At 100%-specificity for non-recovery, only nucleosomes maintained their prognostic power (sensitivity 52.6%; p = 0.014), whereas S100 did not (sensitivity 16.7%; p = 0.25). In multivariate analysis, nucleosomes and BI at admission showed independent prognostic relevance (p = 0.039). Circulating nucleosomes and clinical scores provide independent prognostic information concerning the later outcome in patients with initially severe defects after stroke. [ABSTRACT FROM AUTHOR]

Expression of ligands of the immunoreceptor NKG2D such as MICA and MICB has been proposed to play an important role in the immunosurveillance of tumors. Proteolytic shedding of NKG2D ligands from cancer cells therefore constitutes an immune escape mechanism impairing anti-tumor reactivity by NKG2D-bearing cytotoxic lymphocytes. Serum levels of sMICA have been shown to be of diagnostic significance in malignant diseases of various origins. Here, we investigated the potential of soluble MICB, the sister molecule of MICA, as a marker in cancer and its correlation with soluble MICA. Analysis of MICB in sera of 512 individuals revealed slightly higher MICB levels in patients with various malignancies ( N = 296; 95th percentile 216 pg/ml; P = 0.069) than in healthy individuals ( N = 62; 95th percentile 51 pg/ml). Patients with benign diseases ( N = 154; 95th percentile 198 pg/ml) exhibited intermediate MICB levels. In cancer patients, elevated MICB levels correlated significantly with cancer stage and metastasis ( P = 0.007 and 0.007, respectively). Between MICB and MICA levels, only a weak correlation was found ( r = 0.24). Combination of both markers resulted only in a slightly higher diagnostic power in the high specificity range. The reduction of MICA and MICB surface expression on cells by shedding and the effects of sMICA and sMICB in serum on host lymphocyte NKG2D expression might play a role in late stages of tumor progression by overcoming the confining effect of NK cells and CD8 T cells. While MICB levels are not suited for the diagnosis of cancer in early stages, they may provide additional information for the staging of cancer disease. [ABSTRACT FROM AUTHOR]

Facing an era of promising new antitumor therapies, predictors of therapy response are needed for the individual management of treatment. In sera collected prospectively from 311 patients with advanced non-small cell lung cancer receiving first-line chemotherapy, changes in nucleosomal DNA fragments, cytokeratin-19 fragments (CYFRA 21–1), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and progastrin-releasing peptide (ProGRP) were investigated and correlated with therapy response. In univariate analysis, high levels, slower and incomplete decline in nucleosomal DNA, CYFRA 21–1, and CEA predicted poor outcome. DNA concentrations at day 8 of the first therapeutic cycle and CYFRA 21–1 before start of the second cycle were identified as best predictive variables. In multivariate analysis, they predicted progression with a specificity of 100% in 29% of the cases earlier than imaging techniques. Thus, nucleosomal DNA and CYFRA 21–1 specifically identify a subgroup of patients with insufficient therapy response at the early treatment phase and showed to be valuable for disease management. [ABSTRACT FROM AUTHOR]

The inadequate response of immune cells to circulating apoptotic products, such as nucleosomal DNA fragments, is assumed to be a potent stimulus for the production of autoantibodies during the pathogenesis and progression of systemic lupus erythematosus (SLE). Here, we analyzed the levels of circulating nucleosomes, caspases, and C-reactive protein in sera of 244 individuals with various autoimmune diseases (155 with autoimmune hepatic disorders, 25 with ANCA-associated vasculitis, and 64 with various connective tissue diseases), and 32 healthy controls. Nucleosomes and caspase activities were significantly elevated in sera of patients with hepatic autoimmune diseases, connective tissue diseases, and particularly in ANCA-associated vasculitis when compared with healthy individuals. Nucleosomes showed a correlation with caspases, and caspases with C-reactive protein, but nucleosomes did not correlate with C-reactive protein. Serum levels of the apoptotic products, nucleosomes, and caspases are increased in various autoimmune diseases but may not be solely responsible for antinucleosome antibody production in SLE patients. It remains to be clarified whether qualitative changes in nucleosomes are linked with pathogenesis and disease progression in SLE. [ABSTRACT FROM AUTHOR]

Background: Nucleosomes are cell death products that are elevated in serum of patients with diseases that are associated with massive cell destruction. We investigated the kinetics of circulating nucleosomes after cerebral stroke and their correlation with the clinical status. Methods: In total, we analyzed nucleosomes by ELISA in sera of 63 patients with early stroke daily during the first week after onset. For correlation with the clinical pathology, patients were grouped into those with medium to slight functional impairment (Barthel Index BI ≥50) and those with severe functional impairment (BI <50). Results: Patients with BI ≥50 showed a continuous increase in nucleosomes until day 5 (median: 523 arbitrary units, AU) followed by a slow decline. In contrast, patients with BI <50 showed a steeper initial increase reaching a maximum already on day 3 (869 AU). Both, days after stroke (p < 0.001) and BI (p < 0.001), had a significant influence on nucleosome concentrations, respectively. Consistently, patients with BI <50 had a significantly larger area under the curve (AUC/day) of nucleosome values during the first week after stroke (800 AU) than patients with BI ≥50 (497 AU; p = 0.031). Concerning the infarction volume, nucleosomes showed significant correlations for the concentrations on day 3 (r = 0.43; p = 0.001) and for the area under the curve (r = 0.34; p = 0.016). Conclusion: Even if nucleosomes are nonspecific cell death markers, their release into serum after cerebral stroke correlates with the gross functional status as well as with the infarction volume and can be considered as biochemical correlative to the severity of stroke. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Determination of plasma 24S-hydroxycholesterol, which is produced almost exclusively in the brain and is released only in small amounts into circulation under physiological conditions, might be a marker to monitor non-invasively the time course and the extent of the disintegration of the blood–brain barrier after cerebral ischemia. We investigated the plasma concentrations for 4 to 10 days of 24S-hydroxycholesterol, and compared the concentration with the liver-specific oxysterol 7α-hydroxycholesterol, the ubiquitously produced 27-hydroxycholesterol, and cholesterol itself in six patients who were admitted to the hospital within 24h after symptoms of stroke. Quantification of oxysterols was performed by isotope dilution mass spectrometry and cholesterol by gas–liquid chromatography. Initial concentrations of cholesterol, 24S-, 7α-, and 27-hydroxycholesterol in stroke patients were not different from data of healthy controls given in the literature. During the following days, no changes could be observed in the concentrations of cholesterol nor in the other oxysterols. Particularly the brain specific 24S-hydroxycholesterol was very constant and showed only minimal changes. Furthermore, comparison of patients with extended or small lesions did not reveal any differences in the concentrations of oxysterols. Therefore, circulating levels of 24S-hydroxycholesterol are supposed to be only of limited value for monitoring the brain–blood barrier function in patients with acute ischemic stroke. [Copyright &y& Elsevier]

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]

Background/Objectives: We present a software package called reflimR (Version 1.0.6), which enables rapid and transparent verification of reference intervals from routine laboratory measurements. Our method makes it easy to compare the results with specified target values and facilitates the interpretation of deviations using traffic light colors. Methods: The algorithm includes three procedural steps: (a) definition of an appropriate distribution model, based on Bowley's quartile skewness, (b) iterative truncation, based on a modified boxplot method to obtain the central 95% of presumably inconspicuous results, and (c) extrapolation of reference limits from a truncated normal quantile–quantile plot. Results: All algorithms have been combined into one consolidated library, which can be called in the R environment with a single command reflim (x). Using an example dataset included in the package, we demonstrate that our method can be applied to mixed data containing a substantial proportion of pathological values. It leads to similar results as the direct guideline approach as well as the more sophisticated indirect refineR software package. As compared to the latter, reflimR works much faster and needs smaller datasets for robust estimates. For the interpretation of the results, we present an intuitive color scheme based on tolerance ranges (permissible uncertainty of laboratory results). We show that a relatively high number of published reference limits require careful reevaluation. Conclusions: The reflimR package closes the gap between direct guideline methods and the more sophisticated indirect refineR method. We recommend reflimR for the rapid routine verification of large amounts of reference limits and refineR for a careful analysis of unclear or doubtful results from this check. [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]

An editorial about the challenges in the detection of non-small cell lung cancer (NSCLC) is presented. The authors addressed the prevalence of lung cancer worldwide. They discussed the involvement of circulating biomarkers in the management of lung cancer. They explained the difference between small and non-small cell lung cancer.

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]