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• 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]

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]

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]

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]

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]

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]

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

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]

Children with univentricular hearts (UVH) undergo up to three palliative surgical procedures to achieve complete circulatory separation (Fontan circulation). As a marker of cardiac wall stress, NT-proBNP is a promising tool to assess systemic ventricular load in these patients. However, different reference intervals (RI) apply to each stage, as NT-proBNP is highly age-dependent. Children undergoing systemic-to-pulmonary (SP) shunt placement (stage 1), bidirectional cavopulmonary shunt (BCPS, stage 2) or total cavopulmonary connection (TCPC, stage 3) between 2011 and 2021 with NT-proBNP measurement within 7 days before surgery were included. Furthermore, outpatients after TCPC with NT-proBNP measurement were enrolled. Biomarker levels were evaluated using its age-adjusted z-score ("zlog-NT-proBNP"; age-independent RI, −1.96 to +1.96), allowing comparison between different stages and revealing changes in systemic ventricular load independent of the marked physiological decline in RI with age. Overall, 289 children (227 before, 62 after TCPC) met the eligibility criteria. Median time between blood sampling and surgery (SP shunt/BCPS/TCPC) was 2 [1–3] days and 3.2 [2.0–4.5] years after TCPC. Age-adjusted zlog-NT-proBNP levels were 3.47 [2.79–3.93] in children with native UVH (before SP shunt), 3.10 [1.89–3.58] at stage 1 (before BCPS), 1.08 [0.51–1.88] at stage 2 (before TCPC), and 1.09 [0.72–1.75] at stage 3 (after TCPC/Fontan completion). Consequently, BCPS revealed the strongest decrease (median − 2.02 logarithmized standard deviations, p < 0.001). In children with UVH undergoing staged Fontan palliation, zlog-NT-proBNP is a highly promising tool for course assessment of systemic ventricular load, independent of the age-related decline in physiological NT-proBNP concentration. • Age-adjusted zlog-NT-proBNP helps to quantify ventricular stress in children with UVH. • Strongest decrease of zlog-NT-proBNP was observed with bidirectional cavopulmonary shunt. • Children after TCPC mostly reveal physiological zlog-NT-proBNP levels. [ABSTRACT FROM AUTHOR]

• PHI density has a better diagnostic performance than PHI in overall prostate cancer. • For clinically significant cancer PHI and its density perform almost equally. • PSA density performs better than PHI density in detecting significant cancer. Overdiagnosis of prostate cancer (PCa) should be minimized. We wanted to evaluate the diagnostic performance of the prostate health index density (PHID) and compare it with that of the prostate health index (PHI) alone and of the prostate-specific antigen density (PSAD). 232 men scheduled for a prostate biopsy (prostate-specific antigen level: 2–10 µg/L), were enrolled. PHI, PHID and PSAD were evaluated considering PCa and clinically significant PCa (csPCa) as the outcomes. For PCa, the area under the curve (AUC) was higher for PHID (0.823) than for PHI (0.779) and PSAD (0.776). For csPCa, the AUC was also higher for PHID (0.851) but closer to that of PSAD (0.819) and PHI (0.813). For equal sensitivities (90%) for PCa, PHID and PSAD offered the highest specificities (37%), missing the same number of cancers (n = 11). Considering csPCa, PHI and PHID had similar specificities. PSAD reached the highest specificity (50.0%), sparing 32.8% of biopsies, while missing 9 cases of csPCa. PHID has a better diagnostic performance than PHI for overall PCa detection, but very close to the PSAD performance. Considering csPCa, PHI and PHID perform almost equally, but PSAD has a better diagnostic performance. [ABSTRACT FROM AUTHOR]

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

Abstract: Background: In breast cancer patients undergoing neoadjuvant chemotherapy before surgery, biomarkers for predicting response to therapy are urgently required. Patients and methods: In 65 patients with locally confined breast cancer who had completed the course of chemotherapy until surgery, plasma DNA biomarkers obtained before and during therapy were evaluated concerning (early) estimation of therapy response. Levels of repetitive ALU 115 and ALU 247 elements as well as DNA integrity calculated according the formulas of Umetani (1) and Wang (2) were correlated with changes in histopathological staging at surgery and compared with conventional tumor markers CEA and CA 15-3. Results: At surgery, 13 patients presented complete remission (CR), 32 partial remission (PR) and 20 no change of disease (NC). Pretherapeutic Her2/neu status was positively correlated with therapy response (p =0.019). DNA biomarkers before onset of therapy cycles 1, 2 and 6 did not indicate outcome after therapy. However, kinetics of ALU 115 from cycle 1 to 6 showed decreases in CR patients, while in NC patients, an increase was observed (p =0.033). Similar tendencies were found for ALU 247 fragments. DNA integrity index as well as CEA and CA 15-3 were not informative for therapy outcome. Conclusion: Kinetics of plasma DNA (ALU 115) is associated with response to neoadjuvant chemotherapy in patients with locally confined breast cancer. [Copyright &y& Elsevier]

Highlights: [•] Circulating nucleosomes and survivin are elevated in sera of patients with locally confined and metastatic breast cancer. [•] Cytokeratin-18 fragments (M30-antigen) and breast tumor markers CEA and CA 15-3 are only elevated in metastatic disease. [•] High pretherapeutic nucleosome levels indicate poor response to neoadjuvant chemotherapy. [•] Apoptotic biomarkers bear valuable information for diagnosis and therapy response in breast cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: Extracellular nucleic acids are present in plasma, serum, and other body fluids and their analysis has gained increasing attention during recent years. Because of the small quantity and highly fragmented nature of cell-free DNA in plasma and serum, a fast, efficient, and reliable isolation method is still a problem and so far there is no agreement on a standardized method. We used spin columns from commercial suppliers (QIAamp DNA Blood Midi Kit from Qiagen; NucleoSpin Kit from Macherey-Nagel; MagNA Pure isolation system from Roche Diagnostics) to isolate DNA from 44 plasma samples in parallel at laboratories in Berlin and Munich. DNA in all samples was quantified by real-time PCR on a LightCycler 480 using three different targets (GAPDH, ß-globin, ERV). The quantities of cell-free DNA for the different isolation methods and genes varied between medians of 1.6ng/mL and 28.1ng/mL. This considerable variation of absolute DNA values was mainly caused by the use of different isolation methods (p<0.0001). Comparable results were achieved by the use of the genes GAPDH and ERV while higher values were obtained by use of ß-globin. The laboratory site had only minor influence on DNA yield when manual extraction methods were used. [Copyright &y& Elsevier]

Abstract: Background: We evaluated the utility of post-treatment plasma levels of the circulating bone-morphogenetic protein-6-specific mRNA (cBMP6 mRNA), cell-free DNA (cf-DNA), apoptotic nucleosomes and Histone H3 lysine 27 trimethylation (H3K27me3), in discriminating metastatic prostate cancer (PCa) from organ confined, locally controlled disease. Methods: Peripheral blood was taken from the patients at the end of therapy, and quantitative PCR was performed to amplify cBMP6 mRNA or cf-DNA from plasma while apoptotic nucleosomes and H3K27me3 were determined by ELISA-based approaches. Following blinded measurements, the markers were compared between the patients with local (n=22), local advanced (n=11) or metastatic disease (n=28). Results: Of the four markers investigated, the cBMP6 mRNA and H3K27me3 levels revealed significant differences between the three subgroups. We found higher levels of cBMP6 mRNA in the patients with metastases than in those with localized (p=0.001) or local advanced disease (p=0.05). When compared to cBMP6, H3K27me3 displayed an inverse distribution and was significantly lower in the patients with metastatic disease than in those with localized (p=0.05) or local advanced disease (p=0.024). There was no correlation between the different markers and total PSA levels or Gleason score at diagnosis. Conclusion: Our study provides evidence that post-treatment analysis of cBMP6 mRNA and H3K27me3 may be used to distinguish metastatic PCa from organ confined, locally controlled disease. [Copyright &y& Elsevier]

• Generalized convulsive seizures concur with increased inflammatory markers in blood. • HMGB1, S100 and leukocytes rise immediately after the seizure. • Elevations of MMP9 and CRP can be found later on. • This indicates irritations of the blood brain barrier and a systemic inflammatory response. • Markers of metabolic stress are correlated with these inflammatory changes. Neuroinflammation and disruption of blood brain barrier (BBB) are important players in epileptogenesis, ictogenesis and pharmacoresistance. In this context, we investigated blood levels of HMGB1 and other inflammatory and BBB markers after generalized and focal to bilateral tonic-clonic seizures in serum, summarized under the term generalized convulsive seizures (GCS). We included consenting adults who were admitted to the epilepsy monitoring unit. Blood samples were drawn at baseline and immediately after a GCS as well as after 2, 6 and 24 h. We measured leukocytes, c-reactive protein (CRP), the danger-associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1) and S100, receptor of advanced glycation end products (RAGE) alongside the BBB markers intercellular adhesion molecule-1 (ICAM1) and matrix metalloproteinase 9 (MMP9). Noradrenaline and lactate measurements were available from a previous study. P-levels <0.05 were regarded as significant. Twenty-eight patients with 28 GCS were included. Leukocytosis occurred immediately after GCS and normalized within two hours (p < 0.001). S100 and HMGB1 both increased by ∼80 % (p < 0.001). MMP9 peaked after six hours with levels at 48.6 % above baseline. RAGE decreased by 17.6 % with a nadir at 24 h. CRP increased by 118 % with a peak at 24 h. ICAM1 remained stable (p = 0.068). Postictal HMGB1 correlated with postictal leukocytosis (r = 0.42; p = 0.025) and with MMP9 levels six hours later (r = 0.374; p = 0.05). Postictal lactate levels correlated with MMP9 at 6 h (r = 0.48; p = 0.01) and CRP at 24 h (r = 0.39; p = 0.04). Postictal noradrenaline correlated with lactate (r = 0.57; p = 0.02) and leukocytes (r = 0.39; p = 0.047). The serum level of the DAMPs HMGB1 and S100 increase immediately after GCS. The hypothetical mechanism includes central nervous processes, such as glutamate toxicity and ROS release from seizing neurons but also muscular tissues. BBB breakdown is marked by the release of MMP9. Further research is needed to understand the complex interactions between electrical and metabolic stress, neuroinflammation and BBB mechanics in seizures and epilepsy. Our study reveals signs of inflammation, neuronal damage and transitory disruption of BBB following single GCS, underscoring the widespread and possibily detrimental effects of recurrent seizures on brain properties. The long term impact on the disease course, however, is unclear. [ABSTRACT FROM AUTHOR]