Survival of European adolescents and young adults diagnosed with cancer in 2010-2014.

BACKGROUND: We used the comprehensive definition of AYA (age 15 to 39 years) to update 5-year relative survival (RS) estimates for AYAs in Europe and across countries and to evaluate improvements in survival over time. METHODS: We used data from EUROCARE-6. We analysed 700,000 AYAs with cancer diagnosed in 2000-2013 (follow-up to 2014). We focused the analyses on the 12 most common cancers in AYA. We used period analysis to estimate 5-year RS in Europe and 5-year RS differences in 29 countries (2010-2014 period estimate) and over time (2004-06 vs. 2010-14 period estimates). FINDINGS: 5-year RS for all AYA tumours was 84%, ranging from 70% to 90% for most of the 12 tumours analysed. The exceptions were acute lymphoblastic leukaemia, acute myeloid leukaemia, and central nervous system tumours, presenting survival of 59%, 61%, and 62%, respectively. Differences in survival were observed among European countries for all cancers, except thyroid cancers and ovarian germ-cell tumours. Survival improved over time for most cancers in the 15- to 39-year-old age group, but for fewer cancers in adolescents and 20- to 29-year-olds. INTERPRETATION: This is the most comprehensive study to report the survival of 12 cancers in AYAs in 29 European countries. We showed variability in survival among countries most likely due to differences in stage at diagnosis, access to treatment, and lack of referral to expert centres. Survival has improved especially for haematological cancers. Further efforts are needed to improve survival for other cancers as well, especially in adolescents.

International study of childhood leukemia in residences near electrical transformer rooms.

OBJECTIVES: New epidemiologic approaches are needed to reduce the scientific uncertainty surrounding the association between extremely low frequency magnetic fields (ELF-MF) and childhood leukemia. While most previous studies focused on power lines, the Transformer Exposure study sought to assess this association using a multi-country study of children who had lived in buildings with built-in electrical transformers. ELF-MF in apartments above built-in transformers can be 5 times higher than in other apartments in the same building. This novel study design aimed to maximize the inclusion of highly exposed children while minimising the potential for selection bias. METHODS: We assessed associations between residential proximity to transformers and risk of childhood leukemia using registry based matched case-control data collected in five countries. Exposure was based on the location of the subject's apartment relative to the transformer, coded as high (above or adjacent to transformer), intermediate (same floor as apartments in high category), or unexposed (other apartments). Relative risk (RR) for childhood leukemia was estimated using conditional logistic and mixed logistic regression with a random effect for case-control set. RESULTS: Data pooling across countries yielded 16 intermediate and 3 highly exposed cases. RRs were 1.0 (95% CI: 0.5, 1.9) for intermediate and 1.1 (95% CI: 0.3, 3.8) for high exposure in the conditional logistic model. In the mixed logistic model, RRs were 1.4 (95% CI: 0.8, 2.5) for intermediate and 1.3 (95% CI: 0.4, 4.4) for high. Data of the most influential country showed RRs of 1.1 (95% CI: 0.5, 2.4) and 1.7 (95% CI: 0.4, 7.2) for intermediate (8 cases) and high (2 cases) exposure. DISCUSSION: Overall, evidence for an elevated risk was weak. However, small numbers and wide confidence intervals preclude strong conclusions and a risk of the magnitude observed in power line studies cannot be excluded.

Phenotypes of cough in children: A latent class analysis.

INTRODUCTION: Distinguishing phenotypes among children with cough helps understand underlying causes. Using a statistical data-driven approach, we aimed to identify and validate cough phenotypes based on measurable traits, physician diagnoses, and prognosis. METHODS: We used data from the Swiss Paediatric Airway Cohort and included 531 children aged 5-16 years seen in outpatient clinics since 2017. We included children with any parent-reported cough (i.e. cough without a cold, cough at night, cough more than other children, or cough longer than 4 weeks) without current wheeze. We applied latent class analysis to identify phenotypes using nine symptoms and characteristics and selected the best model using the Akaike information criterion. We assigned children to the most likely phenotype and compared the resulting groups for parental atopy history, comorbidities, spirometry, fractional exhaled nitric oxide (FeNO), skin prick tests and specific IgE, physician diagnoses, and 1-year prognosis. RESULTS: We identified four cough phenotypes: non-specific cough (26%); non-allergic infectious and night cough with snoring and otitis (4%); chronic allergic dry night cough with snoring (9%); and allergic non-infectious cough with rhino-conjunctivitis (61%). Children with the allergic phenotype often had family or personal history of atopy and asthma diagnosis. FeNO was highest for the allergic phenotype [median 17.9 parts per billion (ppb)] and lowest for the non-allergic infectious phenotype [median 7.0 parts per billion (ppb)]. Positive allergy test results differed across phenotypes (p < .001) and were most common among the allergic (70%) and least common among the non-specific cough (31%) phenotypes. Subsequent wheeze was more common among the allergic than the non-specific phenotype. CONCLUSION: We identified four clinically relevant cough phenotypes with different prognoses. Although we excluded children with current wheeze, most children with cough belonged to allergy-related phenotypes.

Risk factors for overweight and obesity after childhood acute lymphoblastic leukemia in North America and Switzerland: A comparison of two cohort studies.

BACKGROUND: After childhood acute lymphoblastic leukemia (ALL), sequelae include overweight and obesity, yet with conflicting evidence. We compared the prevalence of overweight and obesity between ≥5-year ALL survivors from the North American Childhood Cancer Survivor Study (CCSS) and the Swiss Childhood Cancer Survivor Study (SCCSS) and described risk factors. METHODS: We included adult childhood ALL survivors diagnosed between 1976 and 1999. We matched CCSS participants (3:1) to SCCSS participants by sex and attained age. We calculated body mass index (BMI) from self-reported height and weight for 1287 CCSS and 429 SCCSS participants; we then compared those with siblings (2034) in North America and Switzerland (678) siblings. We assessed risk factors for overweight (BMI 25-29.9 kg/m2 ) and obesity (≥30 kg/m2 ) using multinomial regression. RESULTS: We found overweight and obesity significantly more common among survivors in North America when compared with survivors in Switzerland [overweight: 30%, 95% confidence interval (CI): 27-32 vs. 24%, 21-29; obesity: 29%, 27-32 vs. 7%, 5-10] and siblings (overweight: 30%, 27-32 vs. 25%, 22-29; obesity: 24%, 22-26 vs. 6%, 4-8). Survivors in North America [odds ratio (OR) = 1.24, 1.01-1.53] and Switzerland (1.27, 0.74-2.21) were slightly more often obese than siblings. Among survivors, risk factors for obesity included residency in North America (5.8, 3.7-9.0); male (1.7, 1.3-2.3); attained age (≥45 years: 5.1, 2.4-10.8); Non-Hispanic Black (3.4, 1.6-7.0); low household income (2.3, 1.4-3.5); young age at diagnosis (1.6, 1.1-2.2). Cranial radiotherapy ≥18 Gray was only a risk factor for overweight (1.4, 1.0-1.8); steroids were not associated with overweight or obesity. Interaction tests found no evidence of difference in risk factors between cohorts. CONCLUSIONS: Although treatment-related risk for overweight and obesity were similar between regions, higher prevalence among survivors in North America identifies important sociodemographic drivers for informing health policy and targeted intervention trials.

Variability of clinically measured lung clearance index in children with cystic fibrosis.

RATIONALE: The lung clearance index (LCI) is increasingly being used in the clinical surveillance of patients with cystic fibrosis (CF). However, there are limited data on long-term variability and physiologically relevant changes in LCI during routine clinical surveillance. OBJECTIVES: To evaluate the long-term variability of LCI and propose a threshold for a physiologically relevant change. METHODS: In children aged 4-18 years with CF, LCI was measured every 3 months as part of routine clinical surveillance during 2011-2020 in two centers. The variability of LCI during periods of clinical stability was assessed using mixed-effects models and was used to identify thresholds for physiologically relevant changes. RESULTS: Repeated LCI measurements of acceptable quality (N = 858) were available in 100 patients with CF; for 74 patients, 399 visits at clinical stability were available. The variability of repeated LCI measurements over time expressed as the coefficient of variation (CV%) was 7.4%. The upper limit of normal (ULN) for relative changes in LCI between visits was 19%. CONCLUSION: We report the variability of LCI in children and adolescents with CF during routine clinical surveillance. According to our data, a change in LCI beyond 19% may be considered physiologically relevant. These findings will help guide clinical decisions according to LCI changes.

External validation of the Predicting Asthma Risk in Children tool in a clinical cohort.

INTRODUCTION: The Predicting Asthma Risk in Children (PARC) tool uses questionnaire-based respiratory symptoms collected from preschool children to predict asthma risk 5 years later. The tool was developed and validated in population cohorts but not validated using a clinical cohort. We aimed to externally validate the PARC tool in a pediatric pulmonology clinic setting. METHODS: The Swiss Paediatric Airway Cohort (SPAC) is a prospective cohort of children seen in pediatric pulmonology clinics across Switzerland. We included children aged 1-6 years with cough or wheeze at baseline who completed the 2-year follow-up questionnaire. The outcome was defined as current wheeze plus use of asthma medication. We assessed performance using: sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV), area under the curve (AUC), scaled Brier's score, and Nagelkerke's R2 scores. We compared performance in SPAC to that in the original population, the Leicester Respiratory Cohort (LRC). RESULTS: Among 346 children included, 125 (36%) reported the outcome after 2 years. At a PARC score of 4: sensitivity was higher (95% vs. 79%), specificity lower (14% vs. 57%), and NPV and PPV comparable (0.84 vs. 0.87 and 0.37 vs. 0.42) in SPAC versus LRC. AUC (0.71 vs. 0.78), R2 (0.18 vs. 0.28) and Brier's scores (0.13 vs. 0.22) were lower in SPAC. CONCLUSIONS: The PARC tool shows some clinical utility, particularly for ruling out the development of asthma in young children, but performance limitations highlight the need for new prediction tools to be developed specifically for the clinical setting.

Childhood cancer and traffic-related air pollution in Switzerland: A nationwide census-based cohort study.

Motor vehicle exhaust is a major contributor to air pollution, and exposure to benzene or other carcinogenic components may increase cancer risks. We aimed to investigate the association between traffic-related air pollution and risk of childhood cancer in a nationwide cohort study in Switzerland. We identified incident cases from the Swiss Childhood Cancer Registry diagnosed < 16 years of age between 1990 and 2015 and linked them probabilistically with the census-based Swiss National Cohort study. We developed land use regression models to estimate annual mean ambient levels of nitrogen dioxide (NO2) and benzene outside 1.4 million children's homes. We used risk-set sampling to facilitate the analysis of time-varying exposure and fitted conditional logistic regression models adjusting for neighborhood socio-economic position, level of urbanization, and background ionizing radiation. We included 2,960 cancer cases in the analyses. The adjusted hazard ratios (HR) and 95% confidence intervals for exposure to NO2 per 10 µg/m3 were 1.00 (95%-CI 0.88-1.13) for acute lymphoblastic leukemia (ALL) and 1.31 (95%-CI 1.00-1.71) for acute myeloid leukemia (AML). Using exposure lagged by 1 to 5 years instead of current exposure attenuated the effect for AML. The adjusted HR for exposure to benzene per 1 µg/m3 was 1.03 (95%-CI 0.86-1.23) for ALL and 1.29 (95%-CI 0.86-1.95) for AML. We also observed increased HRs for other diagnostic groups, notably non-Hodgkin lymphoma. Our study adds to the existing evidence that exposure to traffic-related air pollution is associated with an increased risk of childhood leukemia, particularly AML.

Measurements and determinants of children's exposure to background gamma radiation in Switzerland.

Epidemiological studies of children's cancer risks associated with background gamma radiation exposure have used geographic exposure models to estimate exposure at their locations of residence. We measured personal exposure to background gamma radiation, and we investigated the extent to which it was associated with children's whereabouts. We collected data on whereabouts and exposure to background gamma radiation over a 5-day period among children aged 4-15 years in Switzerland. We used D-Shuttle dosimeters to measure children's exposure, and we asked parents to write their children's activities in diaries. We used Poisson mixed-effects and linear regression models to investigate the association of hourly and overall doses, respectively, with children's reported whereabouts. During the observed time, 149 participating children spent 66% indoors at home; 19% indoors away from home; and 15% outdoors. The mean personal exposure was 85.7 nSv/h (range 52.3 nSv/h-145 nSv/h). Exposure was 1.077 (95% CI 1.067, 1.087) times higher indoors than outdoors and varied by building material and (predicted) outdoor dose rates. Our study provides detailed information about children's patterns of exposure to background gamma radiation in Switzerland. Dwelling building materials and outdoor dose rates are important determinants of children's exposure. Future epidemiological studies may benefit from including information about building materials.

Lung function from school age to adulthood in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV1, FVC and FEV1/FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis.

Childhood cancer and residential proximity to petrol stations: a nationwide registry-based case-control study in Switzerland and an updated meta-analysis.

PURPOSE: Benzene is a known carcinogen for adult leukemia. Exposure to benzene through parental occupation and the use of household products has been associated with childhood leukemia (CL). Ambient benzene has also been associated with CL and central nervous system (CNS) tumors. We aimed to investigate whether the higher ambient levels of benzene in proximity of petrol stations are associated with a greater risk of childhood cancers, leukemia, and CNS tumors. METHODS: We identified children diagnosed with cancer at age 0-15 years during 1985-2015 from the Swiss Childhood Cancer Registry and selected 10 age and sex-matched controls per case from national censuses. We calculated the distance from children's home to the nearest petrol station using precise geocodes. We estimated odds ratios using conditional logistic regression adjusting for ambient levels of NO2, distance to highways, level of urbanization, and presence of a cantonal cancer registry. In addition, we ran a meta-analysis pooling current results for CL with those of previous studies. RESULTS: We identified 6129 cases, of which 1880 were leukemias and 1290 CNS tumors. 24 cases lived within 50 m from a petrol station. The adjusted odds ratio of a cancer diagnosis for children thus exposed compared to unexposed children (> 500 m) was 1.29 (0.84-1.98) for all cancers combined, 1.08 (0.46-2.51) for leukemia, and 1.30 (0.51-3.35) for CNS tumors. During 2000-2015, when exposure assessment was more precise, the adjusted odds ratio for any cancer diagnosis was 1.77 (1.05-2.98). The summary relative risk estimate for CL in the meta-analysis including four studies was 2.01 (1.25-3.22). CONCLUSIONS: Our study provides weak support for an increased risk of childhood cancers among children living close to petrol stations. A meta-analysis including our study suggests an increased risk for CL.

Association of lung clearance index with survival in individuals with cystic fibrosis.

BACKGROUND: The lung clearance index (LCI) assesses global ventilation inhomogeneity and is a sensitive biomarker of airway function in cystic fibrosis (CF) lung disease. We examined the association of LCI with the risk of death or lung transplantation (LTx) in individuals with CF. METHODS: We performed a retrospective analysis in a cohort of individuals with CF aged ≥5 years with LCI and forced expired volume in 1 s (FEV1) measurements performed between 1980 and 2006. The outcome was time until death or LTx. We used the earliest available LCI and FEV1 values in a Cox proportional hazards regression adjusted for demographic and clinical variables. For sensitivity analyses, we used the mean of the first three LCI and FEV1 measurements, stratified the cohort based on age, and investigated individuals with normal FEV1. RESULTS: In total, 237 individuals with CF with a mean (range) age of 13.9 (5.6-41.0) years were included. The time-to-event analysis accrued 3813 person-years and 94 (40%) individuals died or received LTx. Crude hazard ratios were 1.04 (95% CI 1.01-1.06) per 1.0 z-score increase in LCI and 1.25 (95% CI 1.11-1.41) per 1.0 z-score decrease in FEV1. After adjusting LCI and FEV1 mutually in addition to sex, age, body mass index and number of hospitalisations, hazard ratios were 1.04 (95% CI 1.01-1.07) for LCI and 1.12 (95% CI 0.95-1.33) for FEV1. Sensitivity analyses yielded similar results and using the mean LCI strengthened the associations. CONCLUSIONS: Increased ventilation inhomogeneity is associated with greater risk of death or LTx. Our data support LCI as novel surrogate of survival in individuals with CF.

Longitudinal lung function in childhood cancer survivors after hematopoietic stem cell transplantation.

Longitudinal data on pulmonary function after pediatric allogeneic or autologous hematopoietic stem cell transplantation (HSCT) are rare. We examined pulmonary function and associated risk factors in 5-year childhood cancer survivors (CCSs) longitudinally. We included 74 CCSs diagnosed between 1976 and 2010, treated with HSCT, and with at least two pulmonary function tests performed during follow-up. Median follow-up was 9 years (range 6-13). We described pulmonary function as z-scores for lung volumes (forced vital capacity [FVC], residual volume [RV], total lung capacity [TLC]), flows (forced expiratory volume in 1 s [FEV1], maximal mid-expiratory flow [MMEF]), and diffusion capacity for carbon monoxide (DLCO) and assessed associations with potential risk factors using multivariable regression analysis. The median z-scores for FEV1, FVC, and TLC were below the expected throughout the follow-up period. This was not the case for RV, MMEF and DLCO. Female gender, radiotherapy to the chest, and relapse were associated with lower z-scores of FEV1, FVC, MMEF, RV or DLCO. Childhood cancer survivors after HSCT are at risk of pulmonary dysfunction. The complex and multifactorial etiology of pulmonary dysfunction emphasizes the need for longitudinal prospective studies to better characterize the course and causes of pulmonary function impairment in CCSs.

SwissPedData: Standardising hospital records for the benefit of paediatric research.

BACKGROUND: Improvement of paediatric healthcare is hampered by inefficient processes for generating new evidence. Clinical research often requires extra encounters with patients, is costly, takes place in an artificial situation with a biased selection of patients, and entails long delays until new evidence is implemented into health care. Electronic health records (EHR) contain detailed information on real patients and cover the entirety of patients. However, the use of EHR for research is limited because they are not standardised between hospitals. This leads to disproportionate amounts of work for extracting data of interest and frequently data are incomplete and of poor quality. AIMS: SwissPedData aims to lay the foundation for a paediatric learning health system in Switzerland by facilitating EHR-based research. In this project, we aimed to assess the way routine clinical data are currently recorded in large paediatric clinics in Switzerland and to develop a national EHR-based set of common data elements (CDEs) that covers all processes of routine paediatric care in hospitals. METHODS: A taskforce of paediatricians from large Swiss children's hospitals reviewed the current status of routine data documentation in paediatric clinical care and the extent of digitalisation. We then used a modified Delphi method to reach a broad consensus on a national EHR-based set of CDEs. RESULTS: All Swiss children's hospitals use EHR to document some or all aspects of care. One hundred and nineteen paediatricians, representing eight hospitals and all paediatric subspecialties, participated in an extended Delphi process to create SwissPedData. The group agreed on a national set of CDEs that comprises a main module with general paediatric data and sub-modules relevant to paediatric subspecialties. The data dictionary includes 336 CDEs: 76 in the main module on general paediatrics and between 11 and 59 CDEs per subspecialty module. Among these, 266 were classified as mandatory, 52 as recommended and 18 as optional. CONCLUSION: SwissPedData is a set of CDEs for information to be collected in EHR of Swiss children's hospitals. It covers all care processes including clinical and paraclinical assessment, diagnosis, treatment, disposition and care site. All participating hospitals agreed to implement SwissPedData in their clinical routine and clinic information systems. This will pave the way for a national paediatric learning health system in Switzerland that enables fast and efficient answers to urgent clinical questions by facilitating high-quality nationwide retrospective and prospective observational studies and recruitment of patients for nested prospective studies and clinical trials.

Clinical data for paediatric research: the Swiss approach : Proceedings of the National Symposium in Bern, Switzerland, Dec 5-6, 2019.

BACKGROUND AND PURPOSE: Continuous improvement of health and healthcare system is hampered by inefficient processes of generating new evidence, particularly in the case of rare diseases and paediatrics. Currently, most evidence is generated through specific research projects, which typically require extra encounters with patients, are costly and entail long delays between the recognition of specific needs in healthcare and the generation of necessary evidence to address those needs. The Swiss Personalised Health Network (SPHN) aims to improve the use of data obtained during routine healthcare encounters by harmonizing data across Switzerland and facilitating accessibility for research. The project "Harmonising the collection of health-related data and biospecimens in paediatric hospitals throughout Switzerland (SwissPedData)" was an infrastructure development project funded by the SPHN, which aimed to identify and describe available data on child health in Switzerland and to agree on a standardised core dataset for electronic health records across all paediatric teaching hospitals. Here, we describe the results of a two-day symposium that aimed to summarise what had been achieved in the SwissPedData project, to put it in an international context, and to discuss the next steps for a sustainable future. The target audience included clinicians and researchers who produce and use health-related data on children in Switzerland. KEY HIGHLIGHTS: The symposium consisted of state-of-the-art lectures from national and international keynote speakers, workshops and plenary discussions. This manuscript summarises the talks and discussions in four sections: (I) a description of the Swiss Personalized Health Network and the results of the SwissPedData project; (II) examples of similar initiatives from other countries; (III) an overview of existing health-related datasets and projects in Switzerland; and (IV) a summary of the lessons learned and future prospective from workshops and plenary discussions. IMPLICATIONS: Streamlined processes linking initial collection of information during routine healthcare encounters, standardised recording of this information in electronic health records and fast accessibility for research are essential to accelerate research in child health and make it affordable. Ongoing projects prove that this is feasible in Switzerland and elsewhere. International collaboration is vital to success. The next steps include the implementation of the SwissPedData core dataset in the clinical information systems of Swiss hospitals, the use of this data to address priority research questions, and the acquisition of sustainable funding to support a slim central infrastructure and local support in each hospital. This will lay the foundation for a national paediatric learning health system in Switzerland.

External background ionizing radiation and childhood cancer: Update of a nationwide cohort analysis.

BACKGROUND: Exposure to high doses of ionizing radiation is known to cause cancer. Exposure during childhood is associated with a greater excess relative risk for leukemia and tumors of the central nervous system (CNS) than exposure in later life. Cancer risks associated with low-dose exposure (<100 mSv) are uncertain. We previously investigated the association between the incidence of childhood cancer and levels of exposure to external background radiation from terrestrial gamma and cosmic rays in Switzerland using data from a nationwide census-based cohort study. Here, we provide an update of that study using an extended follow-up period and an improved exposure model. METHODS: We included all children 0-15 years of age registered in the Swiss national censuses 1990, 2000, and 2010-2015. We identified incident cancer cases during 1990-2016 using probabilistic record linkage with the Swiss Childhood Cancer Registry. Exposure to terrestrial and cosmic radiation at children's place of residence was estimated using geographic exposure models based on aerial spectrometric gamma-ray measurements. We estimated and included the contribution from 137Cs deposition after the Chernobyl accident. We created a nested case-control sample and fitted conditional logistic regression models adjusting for sex, year of birth, neighborhood socioeconomic position, and modelled outdoor NO2 concentration. We also estimated the population attributable fraction for childhood cancer due to external background radiation. RESULTS: We included 3,401,113 children and identified 3,137 incident cases of cancer, including 951 leukemia, 495 lymphoma, and 701 CNS tumor cases. Median follow-up in the cohort was 6.0 years (interquartile range: 4.3-10.1) and median cumulative exposure since birth was 8.2 mSv (range: 0-31.2). Hazard ratios per 1 mSv increase in cumulative dose of external background radiation were 1.04 (95% CI: 1.01-1.06) for all cancers combined, 1.06 (1.01-1.10) for leukemia, 1.03 (0.98-1.08) for lymphoma, and 1.06 (1.01-1.11) for CNS tumors. Adjustment for potential confounders had little effect on the results. Based on these results, the estimated population attributable fraction for leukemia and CNS tumors due to external background radiation was 32% (7-49%) and 34% (5-51%), respectively. CONCLUSIONS: Our results suggest that background ionizing radiation contributes to the risk of leukemia and CNS tumors in children.

Respiratory symptoms do not reflect functional impairment in early CF lung disease.

BACKGROUND: Lung disease can develop within the first year of life in infants with cystic fibrosis (CF). However, the frequency and severity of respiratory symptoms in infancy are not known. METHODS: We assessed respiratory symptoms in 50 infants with CF and 50 healthy matched controls from two prospective birth cohort studies. Respiratory symptoms and respiratory rate were documented by standardized weekly interviews throughout the first year. Infants performed multiple breath washout in the first weeks of life. RESULTS: We analyzed 4552 data points (2217 in CF). Respiratory symptoms (either mild or severe) were not more frequent in infants with CF (OR:1.1;95% CI:[0.76, 1.59]; p=0.6). Higher lung clearance index and higher respiratory rate in infants with CF were not associated with respiratory symptoms. CONCLUSIONS: We found no difference in respiratory symptoms between healthy and CF infants. These data indicate that early CF lung disease may not be captured by clinical presentation alone.

Birth characteristics and childhood leukemia in Switzerland: a register-based case-control study.

PURPOSE: Initial genetic alterations in the development of childhood leukemia occur in utero or before conception; both genetic and environmental factors are suspected to play a role. We aimed to investigate the associations between childhood leukemia and perinatal characteristics including birth order, birth interval to older siblings, parental age, birth weight, and multiple birth. METHODS: We identified cases diagnosed between 1981 and 2015 and born in Switzerland between 1969 and 2015 from the Swiss Childhood Cancer Registry and randomly sampled five controls per case from national birth records matched on date of birth, sex, and municipality of residence at birth. We used conditional logistic regression to investigate associations between perinatal characteristics and leukemia at ages 0-15 and 0-4 years, and the subtypes acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). RESULTS: The study included 1,403 cases of leukemia. We observed increased risks associated with high birth weight (adjusted OR 1.37, 95% CI 1.12-1.69) and multiple birth (1.89, 1.24-2.86). These associations were similar for ALL and stronger for leukemia at ages 0-4 years. For AML, we observed an increased risk for higher birth order (3.08, 0.43-22.03 for fourth or later born children). We found no associations with other perinatal characteristics. CONCLUSION: This register-based case-control study adds to the existing evidence of a positive association between high birth weight and risk of childhood leukemia. Furthermore, it suggests children from multiple births are at an increased risk of leukemia.

Bayesian spatial modelling of terrestrial radiation in Switzerland.

The geographic variation of terrestrial radiation can be exploited in epidemiological studies of the health effects of protracted low-dose exposure. Various methods have been applied to derive maps of this variation. We aimed to construct a map of terrestrial radiation for Switzerland. We used airborne γ-spectrometry measurements to model the ambient dose rates from terrestrial radiation through a Bayesian mixed-effects model and conducted inference using Integrated Nested Laplace Approximation (INLA). We predicted higher levels of ambient dose rates in the alpine regions and Ticino compared with the western and northern parts of Switzerland. We provide a map that can be used for exposure assessment in epidemiological studies and as a baseline map for assessing potential contamination.

Cancer predisposition syndromes as a risk factor for early second primary neoplasms after childhood cancer - A national cohort study.

BACKGROUND: Childhood cancer patients are at increased risk of second primary neoplasms (SPNs). We assessed incidence and risk factors for early SPNs with a focus on cancer predisposition syndromes (CPSs). PATIENTS AND METHODS: This cohort study used data from the Swiss Childhood Cancer Registry. We included patients with first primary neoplasms (FPNs) diagnosed before age 21 years from 1986 to 2015 and identified SPNs occurring before age 21. We calculated standardised incidence ratios (SIRs) and absolute excess risks (AERs) using Swiss population cancer incidence data, and cumulative incidence of SPNs. We calculated hazard ratios (HRs) of risk factors for SPNs using Fine and Gray competing risk regression. RESULTS: Among 8074 childhood cancer patients, 304 (4%) were diagnosed with a CPS and 94 (1%) developed early SPNs. The incidence of SPNs was more than 10-fold higher in childhood cancer patients than the incidence of neoplasms in the general population (SIR = 10.6, 95% confidence interval [CI]: 8.7-13.1) and the AER was 179/100,000 person-years (CI: 139-219). Cumulative incidence of SPNs 20 years after FPN diagnosis was 23% in patients with CPSs (CI: 12-41%) and 2.7% in those without (CI: 2.0-3.6%). Risk factors for SPNs were CPSs (HR = 7.8, CI: 4.8-12.7), chemotherapy (HR = 2.2, CI: 1.1-4.6), radiotherapy (HR = 1.9, CI = 1.2-2.9), haematopoietic stem cell transplantation (HR = 1.8, CI: 1-3.3), and older age (15-20 years) at FPN diagnosis (HR = 1.9, CI: 1.1-3.2). CONCLUSION: CPSs are associated with a high risk of SPNs before age 21 years. Identification of CPSs is important for appropriate cancer surveillance and targeted screening.

Longitudinal course of clinical lung clearance index in children with cystic fibrosis.

BACKGROUND: Although the lung clearance index (LCI) is a sensitive marker of small airway disease in individuals with cystic fibrosis (CF), less is known about longitudinal changes in LCI during routine clinical surveillance. Here, our objectives were to describe the longitudinal course of LCI in children with CF during routine clinical surveillance and assess influencing factors. METHODS: Children with CF aged 3-18 years performed LCI measurements every 3 months as part of routine clinical care between 2011 and 2018. We recorded clinical data at every visit. We used a multilevel mixed effect model to determine changes in LCI over time and identify clinical factors that influence LCI course. RESULTS: We collected LCI measurements from 1204 visits (3603 trials) in 78 participants, of which 907 visits had acceptable LCI data. The average unadjusted increase in LCI for the entire population was 0.29 (95% CI 0.20-0.38) LCI units·year-1. The increase in LCI was more pronounced in adolescence (0.41 (95% CI 0.27-0.54) LCI units·year-1). Colonisation with either Pseudomonas aeruginosa or Aspergillus fumigatus, pulmonary exacerbations, CF-related diabetes and bronchopulmonary aspergillosis were associated with a higher increase in LCI over time. Adjusting for clinical risk factors reduced the increase in LCI over time to 0.24 (95% CI 0.16-0.33) LCI units·year-1. CONCLUSIONS: LCI measured during routine clinical surveillance is associated with underlying disease progression in children with CF. An increased change in LCI over time should prompt further diagnostic intervention.