Search

Background: Novel anticancer agents are initially evaluated in a palliative setting in phase I studies. The benefit-risk applying the selected dose from these phase I studies can be considered acceptable at time of registration, however, it is unknown if the optimal dose has been selected during drug development., Methods: The European Medicines Agency (EMA) European Public Assessment Reports (EPARs) overview was used to select anticancer agents evaluated between 2015 and 2020. The dose selection and tolerability data of EMA assessed anticancer agents was analysed to evaluate dose selection., Results: Sixty EPARs were included for analysis. A dose-response relation was identified in five dossiers (8%). The maximum tolerated dose (MTD) was the selected dose for 15 anticancer agents (25%). The MTD was not determined in 27 out of 60 cases (59%). When the MTD was determined but not applied as final dose, the most frequently used dose selection criteria were the combination of toxicity, exposure response, pharmacokinetic data and pharmacodynamic data (in 7 out of 18 cases). Data on tolerability were analysed separately for protein kinase inhibitors and monoclonal antibodies as the dosing interval and mitigation of adverse events (AEs) differs. The median discontinuation, dose reduction and dose interruption rates due to AEs of protein kinase inhibitors were 10%, 26% and 45% for monotherapy and 13%, 47% and 55% for combination therapy, respectively. The median discontinuation rates due to AEs for monoclonal antibodies were 8% for monotherapy and 26% for combination therapy., Conclusion: The dose-response relationship has not been established for the majority of the registered anticancer agents. The selected posology is often poorly tolerable as reflected by the high discontinuation and dose reduction rates. Due to the absence of dose-response data, it is often unknown if the optimal dose has been selected for anticancer agents., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Syndromic craniosynostosis is a congenital disorder characterised by premature fusion of calvarial sutures combined with other anomalies. The facial appearance is different and patients may show physical impairment, mental or developmental disabilities, elevated intracranial pressure and obstructive sleep apnoea. The impact of this condition on daily functioning has not been studied before. The aim of this study is to assess the health-related quality of life in children and adolescents with syndromic or complex craniosynostosis and to determine the impact of these syndromes on parents. A prospective study was performed in 111 children. Health-related quality of life was measured by international standardised quality-of-life questionnaires, the Infant Toddler Quality of Life Questionnaire (ITQoL), Child Health Questionnaire Parental Form 50 (CHQ-PF50), Child Health Questionnaire Child Form 87 (CHQ-CF87) and Short-Form Health Survey (SF-36). For comparison, we used Dutch population norms of health-related quality-of-life-scores. Parents' scores for patients with syndromic or complex craniosynostosis were significantly lower than those for the norm population. Apert syndrome had the largest impact on the different domains. Scores on the CHQ-PF50 scales for 'physical functioning', 'parental impact emotional' and 'family activities' for these patients were significantly lower than scores for patients with other syndromes, possibly due to the complexity of the syndrome, which includes complex syndactyly, cognitive impairment and behaviour problems. Parents reported a reduced health-related quality of life for themselves, mostly psychosocial with clearly significantly lower general health perceptions. In conclusion, syndromic craniosynostosis has a large impact on the health-related quality of life of these children and their parents, both physical and psychosocial., (Copyright © 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

To allow more sensitive, selective, and routine analyses of platinum(Pt)-GG and -AG intrastrand cross-links we have significantly improved our quantitative (32)P-postlabeling assay (M. J. P. Welters et al. Carcinogenesis 18, 1767-1774, 1997). Instead of off-line scintillation counting we introduced an on-line flow radioisotope detector into the HPLC system. Furthermore, the isolation protocol for the adducts was significantly modified and optimized to reduce interfering background peaks that prevented quantification of low levels of the cisplatin-DNA adducts in white blood cells obtained from patients. Reduction of background signals was obtained by boiling the samples, followed by phenol/chloroform/isoamylethanol extraction after the DNA digestion step. The labeling efficiency for the adducts was increased by 40% by using Na-formate instead of NH(4)-formate for elution of the adducts from the strong cation-exchange columns. Finally, a calibration curve and quality controls were implemented. The labeling efficiencies were not different between the dinucleotides. The between- and within-run precision for the Pt-GG and Pt-AG adducts measured at the lower limit of quantification of 87 and 53 amol/microg DNA, respectively, was less than 20% CV. The adducts were stable in DNA stored for a 2-month time period at -80 degrees C. The assay is now routinely used for high-precision analyses of patient and cell line samples containing very low adduct levels., (Copyright 1999 Academic Press.)