Genetic and Non-genetic Determinants and Clinical Consequences of Impaired Lung Function

Lung function tests and genetics are important to understand lung health and to investigate pathways that lead to an impaired lung function. The aim of this thesis was to study the epidemiology of impaired lung function including COPD, to unravel the genetic and non-genetic determinants, and finally to study the impact of impaired lung function on adverse health outcomes

Pulmonary disease, its risk factors and necessity for long-term follow-up care in childhood cancer survivors.

Treatment for childhood cancer puts the young patients at risk to develop adverse health outcomes. These adverse health outcomes can develop acute, already during treatment, or slowly over years to decades after completion of treatment. They can be of transient nature or long-lasting and chronic. Adverse health outcomes can potentially affect every organ system, including the lung. The term late effects is used to describe this heterogeneity of adverse health outcomes. Pulmonary late effects contribute to a higher morbidity and mortality in childhood cancer survivors compared to siblings or the general population

Radiogenomics in non-small-cell lung cancer

Ο μη μικροκυτταρικός καρκίνος του πνεύμονα είναι ο πιο συχνά συναντώμενος υποτύπος καρκίνου του πνεύμονα, ο οποίος αποτελείται από ένα φάσμα υποτύπων. Το NSCLC είναι ένας θανατηφόρος, ετερογενής συμπαγής όγκος με μια εκτεταμένη σειρά μοριακών χαρακτηριστικών. Η πάθηση έχει γίνει ένα αξιοσημείωτο παράδειγμα ιατρικής ακριβείας καθώς το ενδιαφέρον για το θέμα συνεχίζει να επεκτείνεται. Ο απώτερος στόχος της τρέχουσας έρευνας είναι να χρησιμοποιήσει συγκεκριμένα γονίδια ως βιοδείκτες για την πρόγνωση, την έγκαιρη διάγνωση και την εξατομικευμένη θεραπεία, τα οποία διευκολύνονται από τη χρήση εξελισσόμενων τεχνικών αλληλούχισης επόμενης γενιάς που επιτρέπουν την ταυτόχρονη ανίχνευση μεγάλου αριθμού γενετικές ανωμαλίες. Γνωστές μεταλλάξεις ενός αριθμού γονιδίων, όπως τα EGFR, ALK και KRAS, επηρεάζουν ήδη τις αποφάσεις θεραπείας και νέα βασικά γονίδια και μοριακές υπογραφές διερευνώνται για την προγνωστική τους αξία καθώς και για την πιθανή συμβολή τους στην ανοσοθεραπεία και τη θεραπεία της υποτροπής στην αντίσταση στις υπάρχουσες θεραπείες. Οι τύποι δειγμάτων που χρησιμοποιούνται για μελέτες NGS, όπως αναρροφήσεις με λεπτή βελόνα, ιστός ενσωματωμένος σε παραφίνη σταθεροποιημένος με φορμαλίνη και DNA χωρίς κύτταρα, έχουν ο καθένας τα δικά του πλεονεκτήματα και μειονεκτήματα που πρέπει να ληφθούν υπόψηNon-small cell lung cancer is the most often encountered subtype of lung cancer, which consists of a spectrum of subtypes. NSCLC is a lethal, heterogeneous solid tumor with an extensive array of molecular features. The condition has become a notable example of precision medicine as interest in the topic continues to expand. The ultimate goal of the current research is to use specific genes as biomarkers for its prognosis, timely diagnosis, and personalized therapy, all of which are facilitated by the use of evolving next-generation sequencing techniques that permit the simultaneous detection of a large number of genetic abnormalities. Known mutations of a number of genes, such as EGFR, ALK, and KRAS, already influence treatment decisions, and new key genes and molecular signatures are being investigated for their prognostic value as well as their potential contribution to immunotherapy and the treatment of recurrence due to resistance to existing therapies. The sample types utilized for NGS studies, such as fine-needle aspirates, formalin-fixed paraffin-embedded tissue, and cell-free DNA, each have their own advantages and disadvantages that must be taken into accoun

Macrolide maintenance treatment for bronchiectasis

Bronchiectasis, pathological widening of the small and medium sized bronchi, may result from various disorders with one common trait; a faltering airway defence system. This allows for persistent bacterial infection and an augmented airway inflammatory response. Patients’ suffering is often considerable and is characterized by a chronic, productive cough and intermittent infectious exacerbations. In case of failure of non-pharmaceutical treatment options, bronchiectasis patients with frequent exacerbations have frequently been treated with long term, low dose antibiotic treatment, more specifically, the macrolide antibiotic azithromycin. This medical practice has not been based on solid evidence to confirm the efficacy of macrolide maintenance treatment and surprisingly little was known about the potential downsides of this treatment modality. In this thesis, we provide an overview of the current knowledge on bronchiectasis, its diagnostic challenges and the available treatment options. A structured clinical workup is advocated, for which a diagnostic flow chart is offered. We investigate efficacy and safety of macrolide maintenance treatment in a randomised controlled trial, describe radiological responses to treatment and some of azithromycin’s pharmacokinetic properties. We conclude by expressing our concerns on indiscriminate use of azithromycin maintenance treatment, because of its important downsides; the induction of microbial resistance, besides other detrimental effects. Ideally, azithromycin maintenance treatment should be reserved for a ‘macrolide-responsive’ phenotype of bronchiectasis patients and in this thesis we give directions for further research in this area by proposing patient characteristics which might be predictive for a beneficial response to this treatment modality