Moving forward on tumor pathology research reporting: a guide for pathologists from the WHO Classification of Tumors EVI MAP Group.

Evidence-based medicine (EBM) can be unfamiliar territory for those working in tumor pathology research and there is a great deal of uncertainty about how to undertake an EBM approach to planning and reporting histopathology-based studies. In this article, endorsed by the WHO International Agency for Research on Cancer's (IARC) International Collaboration for Cancer Classification and Research (IC3R), we aim to help pathologists and researchers to understand the basics of planning an evidence-based tumor pathology research study, as well as our recommendations on how to report the findings from these. We introduce some basic EBM concepts, the PICO model, thoughts on study design, and emphasize the concept of reporting standards. There are many study-specific reporting guidelines available, and we provide an overview of these. However, existing reporting guidelines perhaps do not always fit tumor pathology research papers, and so here we collate the key reporting dataset together into one generic checklist that we think will simplify the task for pathologists. The article aims to complement our recent Hierarchy of Evidence for Tumor Pathology and Glossary of Evidence (study) Types in tumor pathology. Together, these articles should help any researcher get to grips with the basics of EBM for planning and publishing research in tumor pathology, as well as encourage an improved standard of the reports available to us all in the literature.

Influence of a 7-day Transalpine Trail Run on cardiac biomarkers and myocardial function.

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

PATHFINDER-CHD: prospective registry on adults with congenital heart disease, abnormal ventricular function, and/or heart failure as a foundation for establishing rehabilitative, prehabilitative, preventive, and health-promoting measures: rationale, aims, design and methods.

BACKGROUND: Adults with congenital heart defects (ACHD) globally constitute a notably medically underserved patient population. Despite therapeutic advancements, these individuals often confront substantial physical and psychosocial residua or sequelae, requiring specialized, integrative cardiological care throughout their lifespan. Heart failure (HF) is a critical challenge in this population, markedly impacting morbidity and mortality. AIMS: The primary aim of this study is to establish a comprehensive, prospective registry to enhance understanding and management of HF in ACHD. Named PATHFINDER-CHD, this registry aims to establish foundational data for treatment strategies as well as the development of rehabilitative, prehabilitative, preventive, and health-promoting interventions, ultimately aiming to mitigate the elevated morbidity and mortality rates associated with congenital heart defects (CHD). METHODS: This multicenter survey will be conducted across various German university facilities with expertise in ACHD. Data collection will encompass real-world treatment scenarios and clinical trajectories in ACHD with manifest HF or at risk for its development, including those undergoing medical or interventional cardiac therapies, cardiac surgery, inclusive of pacemaker or ICD implantation, resynchronization therapy, assist devices, and those on solid organ transplantation. DESIGN: The study adopts an observational, exploratory design, prospectively gathering data from participating centers, with a focus on patient management and outcomes. The study is non-confirmatory, aiming to accumulate a broad spectrum of data to inform future hypotheses and studies. PROCESSES: Regular follow-ups will be conducted, systematically collecting data during routine clinical visits or hospital admissions, encompassing alterations in therapy or CHD-related complications, with visit schedules tailored to individual clinical needs. ASSESSMENTS: Baseline assessments and regular follow-ups will entail comprehensive assessments of medical history, ongoing treatments, and outcomes, with a focus on HF symptoms, cardiac function, and overall health status. DISCUSSION OF THE DESIGN: The design of the PATHFINDER-CHD Registry is tailored to capture a wide range of data, prioritizing real-world HF management in ACHD. Its prospective nature facilitates longitudinal data acquisition, pivotal for comprehending for disease progression and treatment impacts. CONCLUSION: The PATHFINDER-CHD Registry is poised to offer valuable insights into HF management in ACHD, bridging current knowledge gaps, enhancing patient care, and shaping future research endeavors in this domain.

Targeted Sequencing of Human Satellite 2 Repeat Sequences in Plasma cfDNA Reveals Potential Breast Cancer Biomarkers.

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

Lung cancer tumor marker analysis: A clinical laboratory perspective.

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

Lung cancer biomarkers: Raising the clinical value of the classical and the new ones.

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

Quantification of ventricular stress in univentricular hearts during early childhood using age-independent zlog-NT-proBNP.

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

Relevance of tumor markers for prognosis and predicting therapy response in non-small cell lung cancer patients: A CEPAC-TDM biomarker substudy.

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

Investigating the Current Harmonization Status of Tumor Markers Using Global External Quality Assessment Programs: A Feasibility Study.

BACKGROUND: The harmonization status of most tumor markers (TMs) is unknown. We report a feasibility study performed to determine whether external quality assessment (EQA) programs can be used to obtain insights into the current harmonization status of the tumor markers α-fetoprotein (AFP), prostate specific antigen (PSA), carcinoembryonic antigen (CEA), cancer antigen (CA)125, CA15-3 and CA19-9. METHODS: EQA sample results provided by 6 EQA providers (INSTAND [Germany], Korean Association of External Quality Assessment Service [KEQAS, South Korea], National Center for Clinical Laboratories [NCCL, China], United Kingdom National External Quality Assessment Service [UK NEQAS, United Kingdom], Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek [SKML, the Netherlands], and the Royal College of Pathologists of Australasia Quality Assurance Programs [RCPAQAP, Australia]) between 2020 and 2021 were used. The consensus means, calculated from the measurement procedures present in all EQA programs (Abbott Alinity, Beckman Coulter DxI, Roche Cobas, and Siemens Atellica), was used as reference values. Per measurement procedure, the relative difference between consensus mean for each EQA sample and the mean of all patient-pool-based EQA samples were calculated and compared to minimum, desirable, and optimal allowable bias criteria based on biological variation. RESULTS: Between 19040 (CA15-3) and 25398 (PSA) individual results and 56 (PSA) to 76 (AFP) unique EQA samples were included in the final analysis. The mean differences with the consensus mean of patient-pool-based EQA samples for all measurement procedures were within the optimum bias criterion for AFP, the desirable bias for PSA, and the minimum bias criterion for CEA. However, CEA results <8 µg/L exceeded the minimum bias criterion. For CA125, CA15-3, and CA19-9, the harmonization status was outside the minimum bias criterion, with systematic differences identified. CONCLUSIONS: This study provides relevant information about the current harmonization status of 6 tumor markers. A pilot harmonization investigation for CEA, CA125, CA15-3, and CA19-9 would be desirable.

Missing prognostic value of soluble PD-1, PD-L1 and PD-L2 in lung cancer patients undergoing chemotherapy - A CEPAC-TDM biomarker substudy.

BACKGROUND: Programmed cell death receptors and ligands in cancer tissue samples are established companion diagnostics for immune checkpoint inhibitor (ICI) therapies. OBJECTIVE: To investigate the relevance of soluble PD-1, PD-L1 and PD-L2 for estimating therapy response and prognosis in non-small cell lung cancer patients (NSCLC) undergoing platin-based combination chemotherapies. METHODS: In a biomarker substudy of a prospective, multicentric clinical trial (CEPAC-TDM) on advanced NSCLC patients, soluble PD-1, PD-L1 and PD-L2 were assessed in serial serum samples by highly sensitive enzyme-linked immunosorbent assays and correlated with radiological response after two cycles of chemotherapy and with overall survival (OS). RESULTS: Among 243 NSCLC patients, 185 achieved response (partial remission and stable disease) and 58 non-response (progression). The distribution of PD-1, PD-L1 and PD-L2 at baseline (C1), prior to staging (C3) and the relative changes (C3/C1) greatly overlapped between the patient groups with response and non-response, thus hindering the discrimination between the two groups. None of the PD markers had prognostic value regarding OS. CONCLUSIONS: Neither soluble PD-1, PD-L1 nor PD-L2 did provide clinical utility for predicting response to chemotherapy and prognosis. Studies on the relevance of PD markers in ICI therapies are warranted.

Improvement of differential diagnosis of lung cancer by use of multiple protein tumor marker combinations.

BACKGROUND: Differential diagnosis of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in hospitalized patients is crucial for appropriate treatment choice. OBJECTIVE: To investigate the relevance of serum tumor markers (STMs) and their combinations for the differentiation of NSCLC and SCLC subtypes. METHODS: Between 2000 and 2003, 10 established STMs were assessed retrospectively in 311 patients with NSCLC, 128 with SCLC prior systemic first-line therapy and 51 controls with benign lung diseases (BLD), by automatized electrochemiluminescence immunoassay technology. Receiver operating characteristic (ROC) curves and logistic regression analyses were used to evaluate the diagnostic efficacy of both individual and multiple STMs with corresponding sensitivities at 90% specificity. Standards for Reporting of Diagnostic Accuracy (STARD guidelines) were followed. RESULTS: CYFRA 21-1 (cytokeratin-19 fragment), CEA (carcinoembryonic antigen) and NSE (neuron specific enolase) were significantly higher in all lung cancers vs BLD, reaching AUCs of 0.81 (95% CI 0.76-0.87), 0.78 (0.73-0.84), and 0.88 (0.84-0.93), respectively. By the three marker combination, the discrimination between benign and all malignant cases was improved resulting in an AUC of 0.93 (95% CI 0.90-0.96). In NSCLC vs. BLD, CYFRA 21-1, CEA and NSE were best discriminative STMs, with AUCs of 0.86 (95% CI 0.81-0.91), 0.80 (0.74-0.85), and 0.85 (0.79-0.91). The three marker combination also improved the AUC: 0.92; 95% CI 0.89-0.96). In SCLC vs. BLD, ProGRP (pro-gastrin-releasing peptide) and NSE were best discriminative STMs, with AUCs of 0.89 (95% CI 0.84-0.94) and 0.96 (0.93-0.98), respectively, and slightly improved AUC of 0.97 (95% CI 0.95-0.99) when in combination. Finally, discrimination between SCLC and NSCLC was possible by ProGRP (AUC 0.86; 95% CI 0.81-0.91), NSE (AUC 0.83; 0.78-0.88) and CYFRA 21-1 (AUC 0.69; 0.64-0.75) and by the combination of the 3 STMs (AUC 0.93; 0.91-0.96), with a sensitivity of 88% at 90% specificity. CONCLUSIONS: The results confirm the power of STM combinations for the differential diagnosis of lung cancer from benign lesions and between histological lung cancer subtypes.

CYFRA 21-1, CA 125 and CEA provide additional prognostic value in NSCLC patients with stable disease at first CT scan.

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

A pocket companion to cell-free DNA (cfDNA) preanalytics.

The cumulative pool of cell-free DNA (cfDNA) molecules within bodily fluids represents a highly dense and multidimensional information repository. This "biological mirror" provides real-time insights into the composition, function, and dynamics of the diverse genomes within the body, enabling significant advancements in personalized molecular medicine. However, effective use of this information necessitates meticulous classification of distinct cfDNA subtypes with exceptional precision. While cfDNA molecules originating from different sources exhibit numerous genetic, epigenetic, and physico-chemical variations, they also share common features that complicate analyses. Considerable progress has been achieved in mapping the landscape of cfDNA features, their clinical correlations, and optimizing extraction procedures, analytical approaches, bioinformatics pipelines, and machine learning algorithms. Nevertheless, preanalytical workflows, despite their profound impact on cfDNA measurements, have not progressed at a corresponding pace. In this perspective article, we emphasize the pivotal role of robust preanalytical procedures in the development and clinical integration of cfDNA assays, highlighting persistent obstacles and emerging challenges.

Prognostic value of tumor markers ProGRP, NSE and CYFRA 21-1 in patients with small cell lung cancer and chemotherapy-induced remission.

BACKGROUND: Despite successful response to first line therapy, patients with small-cell lung cancer (SCLC) often suffer from early relapses and disease progression. OBJECTIVE: To investigate the relevance of serum tumor markers for estimation of prognosis at several time points during the course of disease. METHODS: In a prospective, single-center study, serial assessments of progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), cytokeratin-19 fragments (CYFRA 21-1) and carcino-embryogenic antigen (CEA) were performed during and after chemotherapy in 232 SCLC patients, and correlated with therapy response and overall survival (OS). RESULTS: ProGRP, NSE and CYFRA 21-1 levels decreased quickly after the first chemotherapy cycle and correlated well with the radiological response. Either as single markers or in combination they provided valuable prognostic information regarding OS at all timepoints investigated: prior to first-line therapy, after two treatment cycles in patients with successful response to first-line therapy, and prior to the start of second-line therapy. Furthermore, they were useful for continuous monitoring during and after therapy and often indicated progressive disease several months ahead of radiological changes. CONCLUSIONS: The results indicate the great potential of ProGRP, NSE and CYFRA 21-1 for estimating prognosis and monitoring of SCLC patients throughout the course of the disease.

Serum tumor markers for response prediction and monitoring of advanced lung cancer: A review focusing on immunotherapy and targeted therapies.

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

Plasma Soluble Glycoprotein VI, Platelet Function, Bleeding, and Ischemic Events in Patients Undergoing Elective Percutaneous Coronary Intervention.

BACKGROUND AND AIMS: Glycoprotein VI (GPVI) is the major platelet-specific collagen receptor. GPVI shedding with generation of soluble GPVI (sGPVI) is an endogenous feedback mechanism preventing platelet overstimulation. sGPVI has not been investigated in patients with chronic coronary syndrome (CCS) undergoing percutaneous coronary intervention (PCI), especially regarding its potential value as a predictor of ischemic and bleeding risk. METHODS: Baseline plasma sGPVI levels were available in 318 patients with CCS undergoing PCI. Platelet function was assessed by measuring both adenosine diphosphate (ADP) and collagen-induced platelet aggregation. Co-primary endpoints were a composite of death or myocardial injury at 48 hours after PCI, and Bleeding Academic Research Consortium (BARC) type 1 to 5 bleeding at 30 days. RESULTS: There was no significant correlation between sGPVI and platelet function at baseline or at 48 hours after PCI and loading with antiplatelet drugs. Baseline plasma sGPVI levels were not associated with the ischemic risk: the incidence of the ischemic endpoint was 25.0% in the lower, 22.9% in the middle, and 26.7% in the upper sGPVI tertile (p = 0.82). There was a significant nonlinear relationship between sGPVI and the risk of bleeding: the incidence of the bleeding endpoint was 11.8% in the lower, 12.6% in the middle, and 26.4% in the upper sGPVI tertile (p = 0.006). CONCLUSION: In patients with CCS undergoing PCI, plasma levels of sGPVI did not correlate with ADP- or collagen-induced platelet aggregation. Patients with higher baseline levels of sGPVI may carry an increased risk of bleeding at 30 days after PCI but no excess risk of ischemic events.

Bioactive adrenomedullin (bio-ADM) is associated with endothelial dysfunction in infants and children with complex congenital heart disease undergoing open-heart surgery on cardiopulmonary bypass.

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

Combined use of CYFRA 21-1 and CA 125 predicts survival of patients with metastatic NSCLC and stable disease in IMpower150.

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

Lack of clinical utility of serum macrophage migration inhibitory factor (MIF) for monitoring therapy response and estimating prognosis in advanced lung cancer.

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