Validation of disease-specific biomarkers for the early detection of bronchopulmonary dysplasia.

OBJECTIVE: To demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding Ig-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants. METHODS AND RESULTS: Proteome screening in first-week-of-life plasma samples of n = 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic®, Olink-Proteomics®) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease. CONCLUSION: While successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD. TRIAL REGISTRATION: Deutsches Register Klinische Studien (DRKS) No. 00004600; https://www.drks.de . IMPACT: The urgent need for biomarkers that enable early decision making and personalized monitoring strategies in preterm infants with BPD is challenged by targeted marker analyses, cohort size, and disease heterogeneity. We demonstrate the potential of the plasma proteins BCAM, SIGLEC-14, and ANGPTL-3 to identify infants with BPD early after birth while improving the predictive power of clinical variables, confirming the robustness toward proteome assays and proving disease specificity. Our comprehensive analysis enables a phase-III clinical trial that allows full implementation of the biomarkers into clinical routine to enable early risk stratification in preterms with BPD.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

A pressing need for research to reduce nutritional uncertainties in preterm infant care: Findings from a European roundtable discussion with parent representatives.

INTRODUCTION: Other than for agreement that own mother's milk is the optimum feed, nutritional practice for very preterm babies varies widely. As part of the development of a randomised controlled trial to address preterm nutrition uncertainties, and with the help of the European Foundation for the Care of Newborn Infants (EFCNI), we sought the views of parents across Europe. METHODS: We held two roundtable discussions about the proposed trial, inviting the participation of parents and preterm adults through EFCNI. We sought their views and prior knowledge of preterm nutrition uncertainties, treatment comparisons and opinions on specific aspects of design such as cluster versus individual randomisation. We used thematic Framework Analysis to explore the data. RESULTS: There were 11 participants (two men and nine women) from six European countries. Nine were parents and two were preterm adults. Participants strongly supported the need for research to improve care. However, we found little knowledge of methods to resolve uncertainties in care, and wide variation in information provided to parents during their baby's neonatal unit stay. No parent recalled a member of the clinical staff having told them about nutrition uncertainties. CONCLUSIONS: Present-day best practice is to involve parents, patients, and the public in all stages of clinical research from design to dissemination and implementation. To strengthen involvement and participation we suggest there is need to improve knowledge of research methods. Clinicians may find it helpful to receive training on how to explain clinical uncertainties, and methods to resolve these.

Outcomes from the other side.

Parents and individuals who were born preterm rarely contribute to research study design in order to ensure that outcomes are reported that are of relevance to them. In this article we explore aspects of the measures we use and the lived experiences of three individuals with experience of having a very preterm birth or being very preterm themselves. Their experiences tell us that follow up needs to be more than 2 years, that prematurity needs to be more widely acknowledged in education and that adult services need to consider the consequences of being born early. There are encouraging signs that these important issues are becoming recognised. Individuals designing outcome studies should ensure that these important voices are heard, and their perspectives captured in such studies.

The relation between deoxycytidine kinase activity and the radiosensitising effect of gemcitabine in eight different human tumour cell lines.

BACKGROUND: Gemcitabine (dFdC) is an active antitumour agent with radiosensitising properties, shown both in preclinical and clinical studies. In the present study, the relation between deoxycytidine kinase (dCK) activity and the radiosensitising effect of gemcitabine was investigated in eight different human tumour cell lines. METHODS: Tumour cells were treated with dFdC (0-100 nM) for 24 h prior to radiotherapy (RT) (gamma-Co60, 0-6 Gy, room temperature). Cell survival was determined 7, 8, or 9 days after RT by the sulforhodamine B test. dCK activity of the cells was determined by an enzyme activity assay. RESULTS: A clear concentration-dependent radiosensitising effect of dFdC was observed in all cell lines. The degree of radiosensitisation was also cell line dependent and seemed to correlate with the sensitivity of the cell line to the cytotoxic effect of dFdC. The dCK activity of our cell lines varied considerably and differed up to three fold from 5 to 15 pmol/h/mg protein between the tested cell lines. In this range dCK activity was only weakly related to radiosensitisation (correlation coefficient 0.62, p = 0.11). CONCLUSION: Gemcitabine needs to be metabolised to the active nucleotide in order to radiosensitise the cells. Since dFdCTP accumulation and incorporation into DNA are concentration dependent, the degree of radiosensitisation seems to be related to the extent of dFdCTP incorporated into DNA required to inhibit DNA repair. The activity of dCK does not seem to be the most important factor, but is clearly a major factor. Other partners of the intracellular metabolism of gemcitabine in relation to the cell cycle effects and DNA repair could be more responsible for the radiosensitising effect than dCK activity.