Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort

Breast cancer; Circadian rhythm; RadiotherapyCáncer de mama; Ritmo circadiano; RadioterapiaCàncer de mama; Ritme circadià; RadioteràpiaBackground Circadian rhythm impacts broad biological processes, including response to cancer treatment. Evidence conflicts on whether treatment time affects risk of radiotherapy side-effects, likely because of differing time analyses and target tissues. We previously showed interactive effects of time and genotypes of circadian genes on late toxicity after breast radiotherapy and aimed to validate those results in a multi-centre cohort. Methods Clinical and genotype data from 1690 REQUITE breast cancer patients were used with erythema (acute; n=340) and breast atrophy (two years post-radiotherapy; n=514) as primary endpoints. Local datetimes per fraction were converted into solar times as predictors. Genetic chronotype markers were included in logistic regressions to identify primary endpoint predictors. Findings Significant predictors for erythema included BMI, radiation dose and PER3 genotype (OR 1.27(95%CI 1.03-1.56); P < 0.03). Effect of treatment time effect on acute toxicity was inconclusive, with no interaction between time and genotype. For late toxicity (breast atrophy), predictors included BMI, radiation dose, surgery type, treatment time and SNPs in CLOCK (OR 0.62 (95%CI 0.4-0.9); P < 0.01), PER3 (OR 0.65 (95%CI 0.44-0.97); P < 0.04) and RASD1 (OR 0.56 (95%CI 0.35-0.89); P < 0.02). There was a statistically significant interaction between time and genotypes of circadian rhythm genes (CLOCK OR 1.13 (95%CI 1.03-1.23), P < 0.01; PER3 OR 1.1 (95%CI 1.01-1.2), P < 0.04; RASD1 OR 1.15 (95%CI 1.04-1.28), P < 0.008), with peak time for toxicity determined by genotype. Interpretation Late atrophy can be mitigated by selecting optimal treatment time according to circadian genotypes (e.g. treat PER3 rs2087947C/C genotypes in mornings; T/T in afternoons). We predict triple-homozygous patients (14%) reduce chance of atrophy from 70% to 33% by treating in mornings as opposed to mid-afternoon. Future clinical trials could stratify patients treated at optimal times compared to those scheduled normally.EU-FP7

What is the health status of girls and boys in the COVID-19 pandemic? Selected results of the KIDA study

Background: It is well known that there are gender differences in the health behaviour and physical and mental health of children. The COVID-19 pandemic influenced the health and lifestyles of children and adolescents by changing their living conditions. The present work investigates whether gender differences in selected health indicators are evident more than two years after the onset of the pandemic. Methods: In the study Kindergesundheit in Deutschland aktuell (KIDA) (German Children’s Health Update), cross-sectional telephone surveys were conducted with parents of 3- to 15-year-olds (n=3,478). Parental information on the general and mental health of the child, on increased need for health care and mental health services, as well as on physical activity and utilisation of sports activities were queried in standardised manner. Gender differences were assessed using Chi2 tests. Results: A total of 91% of the girls and 92% of the boys had their general health assessed as being (very) good by their parents (difference not significant, n.s.). An increased need for care and support was indicated for 10.6% of the 3- to 15-year-olds (girls: 9%, boys: 12%, n.s.). Boys met the physical activity recommendations of the WHO significantly more often (60%) than girls (54%). Good to excellent mental health was reported for 93% of both boys and girls. When changes during the pandemic were reported, no differences were found in the responses for girls compared to boys. Conclusions: Gender differences were found for individual parameters and age groups. These differences must be assessed in the context of other social determinants of health, and need to be considered when planning preventive measures

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types

Meta-genome; Toxicities; CancerMetagenoma; Toxicidades; CáncerMetagenoma; Toxicitats; CàncerBackground This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). Methods A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV—formerly SNP)–based heritability of rSTATacute in all patients and for each cancer type. Results Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified ‘RNA splicing via endonucleolytic cleavage and ligation’ (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). Conclusions There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta–genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.E.N. was supported by a scholarship for a PhD from the University of Groningen, Groningen, The Netherlands. T.D. is funded as an Academic Clinical Fellow by the National Institute for Health Research, UK. D.J.T. is supported by a grant from The Taylor Family Foundation and Cancer Research UK [C19941/A30286]. M.L.K.C. is supported by the National Medical Research Council Singapore Clinician Scientist Award (NMRC/CSA-INV/0027/2018), National Research Foundation Proton Competitive Research Program (NRF-CRP17-2017-05), Ministry of Education Tier 3 Academic Research Fund (MOE2016-T3-1-004), the Duke-NUS Oncology Academic Program Goh Foundation Proton Research Programme, NCCS Cancer Fund, and the Kua Hong Pak Head and Neck Cancer Research Programme. G.C.B. is supported by Cancer research UK RadNet Cambridge [C17918/A28870]. RADIOGEN research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (INT20/00071, INT15/00070, INT17/00133, INT16/00154; PI19/01424; PI16/00046; PI13/02030; PI10/00164); by AECC grant PRYES211091VEGA and through the Autonomous Government of Galicia (Consolidation and structuring program: IN607B). C.N.A. and L.M.H.S. received funding from the Danish Cancer Society (grant R231-A14074-B2537). T.R. was funded by a National Institutes of Health Research (NIHR) Clinical Lectureship (CL 2017-11-002) and is supported by the NIHR Leicester Biomedical Research Centre. This publication presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. REQUITE received funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement No. 601826. S.G.E. is supported by the government of Catalonia 2021SGR01112. L.D. was supported by the European Union Horizon 2020 research and innovation programs BRIDGES (grant No. 634935)

Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families

Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias. Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes. Results: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling. Conclusion: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families

Wie steht es um die Gesundheit von Mädchen und Jungen in der COVID-19-Pandemie? Ausgewählte Ergebnisse der KIDA-Studie

Hintergrund: Es ist bekannt, dass es bei Kindern geschlechterbezogene Unterschiede im Gesundheitsverhalten sowie in der körperlichen und psychischen Gesundheit gibt. Die COVID-19-Pandemie beeinflusste durch veränderte Lebensbedingungen die Gesundheit und die Lebensweisen von Kindern und Jugendlichen. Die vorliegende Arbeit untersucht, ob sich mehr als zwei Jahre nach Pandemiebeginn Geschlechterunterschiede bei ausgewählten Gesundheitsindikatoren zeigen. Methode: In der Studie Kindergesundheit in Deutschland aktuell (KIDA) wurden telefonische Querschnittsbefragungen mit Eltern von 3- bis 15-Jährigen (n = 3.478) durchgeführt. Elternangaben zur allgemeinen und psychischen Gesundheit des Kindes, zu erhöhten Versorgungs- oder Unterstützungsbedarfen sowie zur körperlichen Aktivität und Nutzung von Sportangeboten wurden standardisiert erfragt. Geschlechterunterschiede wurden mit Chi2-Tests bewertet. Ergebnisse: Für 91 % der Mädchen und 92 % der Jungen wurde die allgemeine Gesundheit durch ihre Eltern als (sehr) gut eingeschätzt (Unterschied nicht signifikant). Erhöhte Versorgungs- und Unterstützungsbedarfe wurden für 10,6 % der 3- bis 15-Jährigen angegeben (Mädchen: 9 %, Jungen 12 %, n. s.). Jungen erreichten mit 60 % signifikant häufiger die WHO-Bewegungsempfehlungen als Mädchen (54 %). Für je 93 % der Jungen und Mädchen wurde eine gute bis ausgezeichnete psychische Gesundheit angegeben. Bei Veränderungen der psychischen Gesundheit im Vergleich zum vorpandemischen Zeitraum fanden sich keine Unterschiede in den Antworten zu Mädchen im Vergleich zu Jungen. Schlussfolgerungen: Für einzelne Parameter und Altersgruppen fanden sich Geschlechterunterschiede, die zusammen mit anderen sozialen Determinanten der Gesundheit bewertet und bei präventiven Maßnahmen berücksichtigt werden müssen

What is the health status of girls and boys in the COVID-19 pandemic? Selected results of the KIDA study

Background: It is well known that there are gender differences in the health behaviour and physical and mental health of children. The COVID-19 pandemic influenced the health and lifestyles of children and adolescents by changing their living conditions. The present work investigates whether gender differences in selected health indicators are evident more than two years after the onset of the pandemic. Methods: In the study Kindergesundheit in Deutschland aktuell (KIDA) (German Children’s Health Update), cross-sectional telephone surveys were conducted with parents of 3- to 15-year-olds (n=3,478). Parental information on the general and mental health of the child, on increased need for health care and mental health services, as well as on physical activity and utilisation of sports activities were queried in standardised manner. Gender differences were assessed using Chi2 tests. Results: A total of 91% of the girls and 92% of the boys had their general health assessed as being (very) good by their parents (difference not significant, n.s.). An increased need for care and support was indicated for 10.6% of the 3- to 15-year-olds (girls: 9%, boys: 12%, n.s.). Boys met the physical activity recommendations of the WHO significantly more often (60%) than girls (54%). Good to excellent mental health was reported for 93% of both boys and girls. When changes during the pandemic were reported, no differences were found in the responses for girls compared to boys. Conclusions: Gender differences were found for individual parameters and age groups. These differences must be assessed in the context of other social determinants of health, and need to be considered when planning preventive measures

SARS-CoV-2 Transmissibility Within Day Care Centers—Study Protocol of a Prospective Analysis of Outbreaks in Germany

Introduction: Until today, the role of children in the transmission dynamics of SARS-CoV-2 and the development of the COVID-19 pandemic seems to be dynamic and is not finally resolved. The primary aim of this study is to investigate the transmission dynamics of SARS-CoV-2 in child day care centers and connected households as well as transmission-related indicators and clinical symptoms among children and adults. Methods and Analysis: COALA (“Corona outbreak-related examinations in day care centers”) is a day care center- and household-based study with a case-ascertained study design. Based on day care centers with at least one reported case of SARS-CoV-2, we include one- to six-year-old children and staff of the affected group in the day care center as well as their respective households. We visit each child's and adult's household. During the home visit we take from each household member a combined mouth and nose swab as well as a saliva sample for analysis of SARS-CoV-2-RNA by real-time reverse transcription polymerase chain reaction (real-time RT-PCR) and a capillary blood sample for a retrospective assessment of an earlier SARS-CoV-2 infection. Furthermore, information on health status, socio-demographics and COVID-19 protective measures are collected via a short telephone interview in the subsequent days. In the following 12 days, household members (or parents for their children) self-collect the same respiratory samples as described above every 3 days and a stool sample for children once. COVID-19 symptoms are documented daily in a symptom diary. Approximately 35 days after testing the index case, every participant who tested positive for SARS-CoV-2 during the study is re-visited at home for another capillary blood sample and a standardized interview. The analysis includes secondary attack rates, by age of primary case, both in the day care center and in households, as well as viral shedding dynamics, including the beginning of shedding relative to symptom onset and viral clearance. Discussion: The results contribute to a better understanding of the epidemiological and virological transmission-related indicators of SARS-CoV-2 among young children, as compared to adults and the interplay between day care and households.Peer Reviewe

High weekly integral dose and larger fraction size increase risk of fatigue and worsening of functional outcomes following radiotherapy for localized prostate cancer

IntroductionWe hypothesized that increasing the pelvic integral dose (ID) and a higher dose per fraction correlate with worsening fatigue and functional outcomes in localized prostate cancer (PCa) patients treated with external beam radiotherapy (EBRT). MethodsThe study design was a retrospective analysis of two prospective observational cohorts, REQUITE (development, n=543) and DUE-01 (validation, n=228). Data were available for comorbidities, medication, androgen deprivation therapy, previous surgeries, smoking, age, and body mass index. The ID was calculated as the product of the mean body dose and body volume. The weekly ID accounted for differences in fractionation. The worsening (end of radiotherapy versus baseline) of European Organisation for Research and Treatment of Cancer EORTC) Quality of Life Questionnaire (QLQ)-C30 scores in physical/role/social functioning and fatigue symptom scales were evaluated, and two outcome measures were defined as worsening in >= 2 (WS2) or >= 3 (WS3) scales, respectively. The weekly ID and clinical risk factors were tested in multivariable logistic regression analysis. ResultsIn REQUITE, WS2 was seen in 28% and WS3 in 16% of patients. The median weekly ID was 13.1 L center dot Gy/week [interquartile (IQ) range 10.2-19.3]. The weekly ID, diabetes, the use of intensity-modulated radiotherapy, and the dose per fraction were significantly associated with WS2 [AUC (area under the receiver operating characteristics curve) =0.59; 95% CI 0.55-0.63] and WS3 (AUC=0.60; 95% CI 0.55-0.64). The prevalence of WS2 (15.3%) and WS3 (6.1%) was lower in DUE-01, but the median weekly ID was higher (15.8 L center dot Gy/week; IQ range 13.2-19.3). The model for WS2 was validated with reduced discrimination (AUC=0.52 95% CI 0.47-0.61), The AUC for WS3 was 0.58, ConclusionIncreasing the weekly ID and the dose per fraction lead to the worsening of fatigue and functional outcomes in patients with localized PCa treated with EBRT

Development and Optimization of a Machine-Learning Prediction Model for Acute Desquamation After Breast Radiation Therapy in the Multicenter REQUITE Cohort.

Some patients with breast cancer treated by surgery and radiation therapy experience clinically significant toxicity, which may adversely affect cosmesis and quality of life. There is a paucity of validated clinical prediction models for radiation toxicity. We used machine learning (ML) algorithms to develop and optimise a clinical prediction model for acute breast desquamation after whole breast external beam radiation therapy in the prospective multicenter REQUITE cohort study. Using demographic and treatment-related features (m = 122) from patients (n = 2058) at 26 centers, we trained 8 ML algorithms with 10-fold cross-validation in a 50:50 random-split data set with class stratification to predict acute breast desquamation. Based on performance in the validation data set, the logistic model tree, random forest, and naïve Bayes models were taken forward to cost-sensitive learning optimisation. One hundred and ninety-two patients experienced acute desquamation. Resampling and cost-sensitive learning optimisation facilitated an improvement in classification performance. Based on maximising sensitivity (true positives), the "hero" model was the cost-sensitive random forest algorithm with a false-negative: false-positive misclassification penalty of 90:1 containing m = 114 predictive features. Model sensitivity and specificity were 0.77 and 0.66, respectively, with an area under the curve of 0.77 in the validation cohort. ML algorithms with resampling and cost-sensitive learning generated clinically valid prediction models for acute desquamation using patient demographic and treatment features. Further external validation and inclusion of genomic markers in ML prediction models are worthwhile, to identify patients at increased risk of toxicity who may benefit from supportive intervention or even a change in treatment plan. [Abstract copyright: © 2022 The Authors.