Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease

Background No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. Results 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O 2 -saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O 2 -saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. Conclusions Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013)

Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program

Abstract Background To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program. Methods Afatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3 + 3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades. Results Overall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications. 30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, −D, leptin and sEGFR in their sera. Conclusions Afatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, −D and leptin might show promising results in future studies. Clinical trials registration NCT01679405 August, 2012

Additional file 1: of Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program

Table S1. Main inclusion and exclusion criteria. Contains the main inclusion and exclusion criteria for patient selection in this study. (DOC 35 kb

Additional file 2: of Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program

Table S2. Predefined disease limited toxicities. List with the disease limited toxicities associated with afatinib in this study. (DOC 36 kb

Latitudinal gradient in avian insectivory: complementary effects of climate, habitat and bird diversity

AbstractAimAccording to the Latitudinal Biotic Interaction Hypothesis (LBIH), the general increase in biodiversity towards lower latitudes can be partially explained by an increase in the intensity of biotic interactions. While LBIH received some support for plant-herbivores interactions, much less is known about how higher trophic levels may contribute to shape biotic interactions across latitudinal gradients. We hypothesized that the diversity of insectivorous birds increases towards lower latitude, leading to higher predation rates on insect herbivores.LocationEurope.TaxonInsectivorous birds and pedunculate oaks.MethodsWe deployed plasticine caterpillars in 138 oak trees in 47 sites along a 19° latitudinal gradient in Europe to quantify bird insectivory through predation attempts. In addition, we used passive acoustic monitoring to (i) characterize the acoustic diversity of surrounding soundscapes; and (ii) infer both taxonomic and functional diversity of insectivorous birds from recordings.ResultsThe functional diversity of insectivorous birds increased towards lower latitude. Bird predation increased with latitude, forest cover and bird acoustic diversity but decreased with mean annual temperature and functional richness of insectivorous birds. Contrary to our predictions, latitudinal clines in bird predation attempts were not directly mediated by changes in insectivorous bird diversity or acoustic diversity, but latitude and habitat still had independent effects on predation attempts.Main conclusionsOur study does not fully support the predictions of the LBIH of more biotic interactions southwards and advocates for better accounting for activity and abundance of insectivorous birds when studying the large-scale variation in insect-tree interactions.</jats:sec

Decomposing drivers in avian insectivory: Large‐scale effects of climate, habitat and bird diversity

International audienceAim Climate is a major driver of large‐scale variability in biodiversity, as a likely result of more intense biotic interactions under warmer conditions. This idea fuelled decades of research on plant‐herbivore interactions, but much less is known about higher‐level trophic interactions. We addressed this research gap by characterizing both bird diversity and avian predation along a climatic gradient at the European scale. Location Europe. Taxon Insectivorous birds and pedunculate oaks. Methods We deployed plasticine caterpillars in 138 oak trees in 47 sites along a 19° latitudinal gradient in Europe to quantify bird insectivory through predation attempts. In addition, we used passive acoustic monitoring to (i) characterize the acoustic diversity of surrounding soundscapes; (ii) approximate bird abundance and activity through passive acoustic recordings; and (iii) infer both taxonomic and functional diversity of insectivorous birds from recordings. Results The functional diversity of insectivorous birds increased with warmer climates. Bird predation increased with forest cover and bird acoustic activity but decreased with mean annual temperature and functional richness of insectivorous birds. Contrary to our predictions, climatic clines in bird predation attempts were not directly mediated by changes in insectivorous bird diversity or acoustic activity, but climate and habitat still had independent effects on predation attempts. Main Conclusions Our study supports the hypothesis of an increase in the diversity of insectivorous birds towards warmer climates but refutes the idea that an increase in diversity would lead to more predation and advocates for better accounting for activity and abundance of insectivorous birds when studying the large‐scale variation in insect‐tree interactions.Objectif Le climat est l'un des principaux facteur structurant de la variabilité à grande échelle de la biodiversité, possiblement en raison d'interactions biotiques plus intenses dans des conditions de température plus élevées. Cette idée a alimenté des décennies de recherche sur les interactions plantes‐herbivores, mais on en sait beaucoup moins sur les interactions impliquant les niveaux trophiques supérieurs. Nous avons comblé cette lacune en caractérisant à la fois la diversité des oiseaux et leur activité de prédation le long d'un gradient climatique à l'échelle européenne. Localisation Europe. Taxon Oiseaux insectivores et chênes pédonculés. Méthodes Nous avons déployé des leurres en pâte à modeler mimant des chenilles sur 138 chênes dans 47 sites le long d'un gradient latitudinal de 19° en Europe pour quantifier l'insectivorie avienne par le biais de tentatives de prédation. De plus, nous avons utilisé la surveillance acoustique passive pour (i) caractériser la diversité acoustique des paysages sonores environnants; (ii) estimer l'abondance et l'activité des oiseaux à travers des enregistrements acoustiques passifs et (iii) déduire à la fois la diversité taxonomique et fonctionnelle des oiseaux insectivores à partir des enregistrements. Résultats Nous avons montré une augmentation de la diversité fonctionnelle des oiseaux insectivores avec la température moyenne. La prédation avienne augmentait avec la couverture forestière et l'activité acoustique des oiseaux, mais diminuait avec la température annuelle moyenne et la richesse fonctionnelle des oiseaux insectivores. Contrairement à nos prédictions, la variation de la diversité des oiseaux n'était pas le lien mécaniste entre le climat et la variation des tentatives de prédation sur les leurres, laquelle était directement influencée par le climat et la couverture forestière. Conclusions Principales Notre étude confirme l'hypothèse d'une augmentation de la diversité des oiseaux insectivores vers des climats plus chauds, mais ne corrobore pas l'idée qu'une augmentation de la diversité conduirait à davantage de predation. Elle plaide en faveur d'une meilleure prise en compte de l'activité et de l'abondance des oiseaux insectivores lors de l'étude de la variation à grande échelle des interactions entre insectes et arbres

Latitudinal gradient in avian insectivory: complementary effects of climate, habitat and bird diversity

According to the Latitudinal Biotic Interaction Hypothesis (LBIH), the general increase in biodiversity towards lower latitudes can be partially explained by an increase in the intensity of biotic interactions. While LBIH received some support for plant-herbivores interactions, much less is known about how higher trophic levels may contribute to shape biotic interactions across latitudinal gradients. We hypothesized that the diversity of insectivorous birds increases towards lower latitude, leading to higher predation rates on insect herbivores. Location Europe. Taxon Insectivorous birds and pedunculate oaks. Methods We deployed plasticine caterpillars in 138 oak trees in 47 sites along a 19° latitudinal gradient in Europe to quantify bird insectivory through predation attempts. In addition, we used passive acoustic monitoring to (i) characterize the acoustic diversity of surrounding soundscapes; and (ii) infer both taxonomic and functional diversity of insectivorous birds from recordings. Results The functional diversity of insectivorous birds increased towards lower latitude. Bird predation increased with latitude, forest cover and bird acoustic diversity but decreased with mean annual temperature and functional richness of insectivorous birds. Contrary to our predictions, latitudinal clines in bird predation attempts were not directly mediated by changes in insectivorous bird diversity or acoustic diversity, but latitude and habitat still had independent effects on predation attempts. Main conclusions Our study does not fully support the predictions of the LBIH of more biotic interactions southwards and advocates for better accounting for activity and abundance of insectivorous birds when studying the large-scale variation in insect-tree interactions