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Tamoxifen is widely used in patients with hormone receptor‐positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z‐endoxifen. The Z‐endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z‐endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z‐endoxifen concentration and tamoxifen treatment outcomes, and identify a Z‐endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed‐effect (NLME) model for tamoxifen and Z‐endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z‐endoxifen. The final parent‐metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co‐medication with CYP2D6 inhibitors, on Z‐endoxifen pharmacokinetics. Future work will use the model to simulate Z‐endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long‐term survival to identify the Z‐endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor‐positive breast cancer. [ABSTRACT FROM AUTHOR]

To examine parent-professional agreement in proxy-reports of child quality of life (QoL) and the factors associated with low child QoL in children with cerebral palsy (CP) and associated intellectual impairment. Professional (teacher, therapist, or residential carer) and parent reports of QoL for 204 children (127 males, 77 females, mean age 10y 4mo [SD 1y 6mo]; range 8-12y) with CP and IQ less than or equal to 70 were obtained in 2004 to 2005 in nine European regions, using the KIDSCREEN questionnaire. Parent-professional agreement was studied using correlation and mean differences; multilevel logistic regression was used to determine factors influencing QoL reports and agreement. The mean parent-reported scores of child QoL were significantly higher than the professional reports in the Psychological well-being domain and significantly lower for Social support. The average frequency of disagreement (parent-professional difference greater than 0.5SD of scores) over all domains was 62%. High levels of stress in parenting negatively influenced parent reports of child QoL compared with professional reports, while child pain was associated with professionals rating lower than parents. Proxies do not always agree when reporting the QoL of children with severe disabilities. Parental well-being and child pain should be taken into account in the interpretation of QoL reports in such children. (Contains 3 tables and 1 figure.)

Objectives: To describe psychological symptoms in 8-12-year-old children with cerebral palsy; to investigate predictors of these symptoms and their impact on the child and family. Design: A cross-sectional multi-centre survey. Participants: Eight hundred and eighteen children with cerebral palsy, aged 8-12 years, identified from population-based registers of cerebral palsy in eight European regions and from multiple sources in one further region. Main outcome measures: The Strengths and Difficulties Questionnaire (SDQ)[superscript P4-16] and the Total Difficulties Score (TDS) dichotomised into normal/borderline (TDS less than or equal to 16) versus abnormal (TDS greater than 16). Statistical analysis: Multilevel, multivariable logistic regression to relate the presence of psychological symptoms to child and family characteristics. Results: About a quarter of the children had TDS greater than 16 indicating significant psychological symptoms, most commonly in the domain Peer Problems. Better gross motor function, poorer intellect, more pain, having a disabled or ill sibling and living in a town were independently associated with TDS greater than 16. The risk of TDS greater than 16 was odds ratio (OR) = 0.2 (95% CI: 0.1 to 0.3) comparing children with the most and least severe functional limitations; OR = 3.2 (95% CI: 2.1 to 4.8) comparing children with IQ less than 70 and others; OR = 2.7 (95% CI: 1.5 to 4.6) comparing children in severe pain and others; OR = 2.7 (95% CI:1.6 to 4.6) comparing children with another disabled sibling or OR = 1.8 (95% CI: 1.2 to 2.8) no siblings and others; OR = 1.8 (95% CI: 1.1 to 2.8) comparing children resident in a town and others. Among parents who reported their child to have psychological problems, 95% said they had lasted over a year, 37% said they distressed their child and 42% said they burdened the family at least "quite a lot". Conclusions: A significant proportion of children with cerebral palsy have psychological symptoms or social impairment sufficiently severe to warrant referral to specialist services. Care must be taken in the assessment and management of children with cerebral palsy to ensure psychological problems are not overlooked and potentially preventable risk factors like pain are treated effectively. The validity of the SDQ for children with severe disability warrants further assessment.

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration‐time data for TAM and 6 metabolites come from a prospective, multicenter, 3‐year follow‐up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7‐compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra‐rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N‐desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose‐adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient's CYP2D6 phenotype for TAM dose adaptation. [ABSTRACT FROM AUTHOR]

Objective To evaluate the psychometric performance of the Child Health Questionnaire (CHQ) in children with cerebral palsy (CP). Method 818 parents of children with CP, aged 8-12 from nine regions of Europe completed the CHQ (parent form 50 items). Functional abilities were classified using the five-level Gross Motor Function Classification Scheme (Levels I-Ill as ambulant; Level IV-V as nonambulant CP). Results Ceiling effects were observed for a number of subscales and summary scores across all Gross Motor Function Classification System levels, whilst floor effects occurred only in the physical functioning scale (Level V CP). Reliability was satisfactory overall. Confirmatory factor analysis (CFA) revealed a seven-factor structure for the total sample of children with CP but with different factor structures for ambulant and nonambulant children. Conclusion The CHQ has limited applicability in children with CP, although with judicious use of certain domains for ambulant and nonambulant children can provide useful and comparable data about child health status for descriptive purposes. [ABSTRACT FROM AUTHOR]

Anti-PDL1 is a monoclonal antibody targeting the programmed death-cell ligand (PD-L1) by blocking the programmed death-cell (PD-1)/PD-L1 axis. It restores the immune system response in several tumours, such as non-small cell lung cancer (NSCLC). Anti-PDL1 or anti-PD1 treatments rely on PD-L1 tumoural expression assessed by immunohistochemistry on biopsy tissue. However, depending on the biopsy extraction site, PD-L1 expression can vary greatly. Non-invasive imaging enables whole-body mapping of PD-L1 sites and could improve the assessment of tumoural PD-L1 expression., Methods: Pharmacokinetics (PK), biodistribution and dosimetry of a murine anti-PDL1 radiolabelled with zirconium-89, were evaluated in both healthy mice and immunocompetent mice with lung cancer. Preclinical PET (μPET) imaging was used to analyse [ 89 Zr]DFO-Anti-PDL1 distribution in both groups of mice. Non-compartmental (NCA) and compartmental (CA) PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in humans., Results: Organ distribution was correctly estimated using PK modelling in both healthy mice and mice with lung cancer. Tumoural uptake occurred within 24 h post-injection of [ 89 Zr]DFO-Anti-PDL1, and the best imaging time was at 48 h according to the signal-to-noise ratio (SNR) and image quality. An in vivo blocking study confirmed that [ 89 Zr]DFO-anti-PDL1 specifically targeted PD-L1 in CMT167 lung tumours in mice. AUC in organs was estimated using a 1-compartment PK model and extrapolated to human (using allometric scaling) in order to estimate the radiation exposure in human. Human-estimated effective dose was 131 μSv/MBq., Conclusion: The predicted dosimetry was similar or lower than other antibodies radiolabelled with zirconium-89 for immunoPET imaging., Competing Interests: Employment: CF and YB are employees of General Electric-Zionexa laboratory. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Krache, Fontan, Pestourie, Bardiès, Bouvet, Payoux, Chatelut, White-Koning and Salabert.)