Incidence and prevalence of musculoskeletal health conditions in survivors of childhood and adolescent cancers: A report from the Swiss childhood cancer survivor study.

PURPOSE: Childhood cancer and its treatment can cause damage to the musculoskeletal system. We aimed to determine the incidence and prevalence of musculoskeletal health conditions (MSHC) in survivors, and to investigate differences by cancer-related characteristics. METHODS: We used data from the Childhood Cancer Registry and the Swiss Childhood Cancer Survivor Study, including survivors (≥5 years since diagnosis; diagnosed 1976-2015 at <20 years of age) aged ≥15 years at study. Cumulative incidence and prevalence of MSHCs (osteoporosis, limb length discrepancy, limited joint mobility, bone/joint pain, scoliosis, changes to chest/ribs and amputation) were calculated from self-reported data. RESULTS: We included 2645 survivors (53% men; median age 24 years, range 15-59 years). Prevalence and cumulative incidence of any MSHC was 21% and 26%, respectively. Incidence rate for any MSHC was 15.6/1000 person-years. Scoliosis (8%), bone/joint pain (7%) and limited joint mobility (7%) were the most prevalent MSHC. MSHC co-occurred with other health conditions in 87% of survivors. We found increased rates of MSHC in women (RR = 1.4, 95%CI: 1.2-1.7), bone tumour survivors (RR = 6.0, 95%CI: 4.5-7.9), survivors older at diagnosis (11-15 years: RR = 1.8, 95%CI: 1.5-2.3), after a relapse (RR = 1.5, 95%CI: 1.3-1.9), treatment with surgery (RR = 1.2, 95%CI: 1.0-1.5), chemotherapy (RR = 1.4, 95%CI: 1.1-1.8) or stem cell transplantation (RR = 1.6, 95%CI: 1.0-2.5), and more recent year of diagnosis (2011-2015: RR = 4.3, 95%CI: 2.8-6.8). CONCLUSION: MSHCs are prevalent in survivors, the risk is increasing in younger survivor cohorts, and MSHCs usually occur in multimorbid survivors. Strengthening of rehabilitation services and appropriate referrals are needed to mitigate the effects of the cancer and cancer treatment.

Characterization of 35 novel NR5A1/SF-1 variants identified in individuals with atypical sexual development: The SF1next study.

CONTEXT: Steroidogenic factor 1 (NR5A1/SF-1) is a nuclear receptor that regulates sex development, steroidogenesis and reproduction. Genetic variants in NR5A1/SF-1 are common among differences of sex development (DSD) and associate with a wide range of phenotypes, but their pathogenic mechanisms remain unclear. OBJECTIVE: Novel, likely disease-causing NR5A1/SF-1 variants from the SF1next cohort of individuals with DSD were characterized to elucidate their pathogenic effect. METHODS: Different in silico tools were used to predict the impact of novel NR5A1/SF-1 variants on protein function. An extensive literature review was conducted to compare and select the best functional studies for testing the pathogenic effect of the variants in a classic cell culture model. The missense NR5A1/SF-1 variants were tested on the promoter luciferase reporter vector -152CYP11A1_pGL3 in HEK293T cells and assessed for their cytoplasmic/nuclear localization by Western blot. RESULTS: Thirty-five novel NR5A1/SF-1 variants were identified in the SF1next cohort. Seventeen missense NR5A1/SF-1 variants were functionally tested. Transactivation assays showed reduced activity for 40% of the variants located in the DNA binding domain and variable activity for variants located elsewhere. Translocation assessment revealed three variants (3/17) with affected nuclear translocation. No clear genotype-phenotype, structure-function correlation was found. CONCLUSIONS: Genetic analyses and functional assays do not explain the observed wide phenotype of individuals with these novel NR5A1/SF-1 variants. In nine individuals, additional likely disease-causing variants in other genes were found, strengthening the hypothesis that the broad phenotype of DSD associated with NR5A1/SF-1 variants may be caused by an oligogenic mechanism.

Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors.

Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development.

BACKGROUND: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. METHODS: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. FINDINGS: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. INTERPRETATION: The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors. FUNDING: Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland.

Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study.

PURPOSE: Childhood cancer survivors are at the risk of developing subsequent colorectal cancers (CRCs), but the absolute risks by treatment modality are uncertain. We quantified the absolute risks by radiotherapy treatment characteristics using clinically accessible data from a Pan-European wide case-control study nested within a large cohort of childhood cancer survivors: the PanCareSurFup Study. METHODS: Odds ratios (ORs) from a case-control study comprising 143 CRC cases and 143 controls nested within a cohort of 69,460 survivors were calculated. These, together with standardized incidence ratios for CRC for this cohort and European general population CRC incidence rates and survivors' mortality rates, were used to estimate cumulative absolute risks (CARs) by attained age for different categories of radiation to the abdominopelvic area. RESULTS: Overall, survivors treated with abdominopelvic radiotherapy treatment (ART) were three times more likely to develop a subsequent CRC than those who did not receive ART (OR, 3.1 [95% CI, 1.4 to 6.6]). For male survivors treated with ART, the CAR was 0.27% (95% CI, 0.17 to 0.59) by age 40 years, 1.08% (95% CI, 0.69 to 2.34) by age 50 years (0.27% expected in the general population), and 3.7% (95% CI, 2.36 to 7.80) by age 60 years (0.95% expected). For female survivors treated with ART, the CAR was 0.29% (95% CI, 0.18 to 0.62) by age 40 years, 1.03% (95% CI, 0.65 to 2.22) by age 50 years (0.27% expected), and 3.0% (95% CI, 1.91 to 6.37) by age 60 years (0.82% expected). CONCLUSION: We demonstrated that by age 40 years survivors of childhood cancer treated with ART already have a similar risk of CRC as those age 50 years in the general population for whom population-based CRC screening begins in many countries. This information should be used in the development of survivorship guidelines for the risk stratification of survivors concerning CRC risk.

Auditory complications among childhood cancer survivors and health-related quality of life: a PanCareLIFE study.

PURPOSE: Auditory complications are potential side effects from childhood cancer treatment. Yet, limited evidence exists about the impact of auditory complications-particularly tinnitus-on health-related quality of life (HRQoL) among childhood cancer survivors (CCS). We determined the prevalence of hearing loss and tinnitus in the European PanCareLIFE cohort of CCS and examined its effect on HRQoL. METHODS: We included CCS from four European countries who were diagnosed at age ≤ 18 years; survived ≥ 5 years; and aged 25-44 years at study. We assessed HRQoL (Short Form 36), hearing loss, and tinnitus using questionnaires. We used multivariable linear regression to examine associations between these two auditory complications and HRQoL adjusting for socio-demographic and clinical factors. RESULTS: Our study population consisted of 6,318 CCS (53% female; median age at cancer diagnosis 9 years interquartile range [IQR] 5-13 years) with median age at survey of 31 years (IQR 28-35 years). Prevalence was 7.5% (476/6,318; confidence interval [CI]: 6.9-8.2) for hearing loss and 7.6% (127/1,668; CI: 6.4-9.0) for tinnitus. CCS with hearing loss had impaired physical (coefficient [coef.] -4.3, CI: -7.0 to -1.6) and mental (coef. -3.2, CI: -5.5 to -0.8) HRQoL when compared with CCS with normal hearing. Tinnitus was associated with impaired physical (coef. -8.2, CI: -11.8 to -4.7) and mental (coef. -5.9, CI: -8.8 to -3.1) HRQoL. CONCLUSION: We observed reduced HRQoL among CCS with hearing loss and tinnitus. Our findings indicate timely treatment of hearing loss and tinnitus may contribute to quality of life of survivors. IMPLICATIONS FOR CANCER SURVIVORS: CCS who experience auditory complications should be counseled about possible therapeutic and supportive measures during follow-up care.

Impaired health-related quality of life in long-COVID syndrome after mild to moderate COVID-19.

A growing number of patients with SARS-CoV-2 infections experience long-lasting symptoms. Even patients who suffered from a mild acute infection show a variety of persisting and debilitating neurocognitive, respiratory, or cardiac symptoms (Long-Covid syndrome), consequently leading to limitations in everyday life. Because data on health-related quality of life (HRQoL) is scarce, we aimed to characterize the impact of Long-Covid symptoms after a mild or moderate acute infection on HRQoL. In this observational study, outpatients seeking counseling in the interdisciplinary Post-Covid consultation of the University Hospital Zurich with symptoms persisting for more than 4 weeks were included. Patients who received an alternative diagnosis or suffered from a severe acute Covid-19 infection were excluded. St. George's Respiratory Questionnaire (SGRQ), Euroquol-5D-5L (EQ-5D-5L), and the Short form 36 (SF-36) were distributed to assess HRQoL. 112 patients were included, 86 (76.8%) were female, median (IQR) age was 43 (32.0, 52.5) years with 126 (91, 180) days of symptoms. Patients suffered frequently from fatigue (81%), concentration difficulties (60%), and dyspnea (60%). Patients mostly stated impairment in performing usual activities and having pain/discomfort or anxiety out of the EQ-5D-5L. EQ index value and SGRQ activity score component were significantly lower in females. SF-36 scores showed remarkably lower scores in the physical health domain compared to the Swiss general population before and during the COVID-19 pandemic. Long-Covid syndrome has a substantial impact on HRQoL. Long-term surveillance of patients must provide clarity on the duration of impairments in physical and mental health.Trial registration: The study is registered on www.ClinicalTrials.gov , NCT04793269.

Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.

PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

Health-related quality of life before and during the COVID-19 pandemic in Switzerland: a cross-sectional study.

INTRODUCTION: The COVID-19 pandemic forced people to give up their daily routines and adjust to new circumstances. This might have affected health-related quality of life (HRQOL). We aimed to compare HRQOL during the first COVID-19 wave in 2020 to HRQOL before the pandemic and to identify determinants of HRQOL during the pandemic in Switzerland. METHODS: We conducted a cross-sectional online survey during the pandemic (between May and July 2020; CoWELL sample; convenience sample). Before the pandemic (2015-2016), we had conducted a cross-sectional paper-based survey among a representative random sample of the Swiss general population (SGP sample). In both samples, we assessed physical and mental HRQOL (Short Form-36) and socio-demographic characteristics. In the CoWELL sample, we additionally assessed health- and COVID-19-related characteristics. Data were analysed using linear regressions. RESULTS: The CoWELL sample included 1581 participants (76% women; mean age = 43 years, SD = 14 years) and the SGP sample 1209 participants (58% women, mean age = 49 years, SD = 15 years). Adjusted for sex, age, and education, the CoWELL sample reported higher physical HRQOL (PCS, +5.8 (95% CI: 5.1, 6.6), p < 0.001) and lower mental HRQOL (MCS, -6.9 (-7.8, -6.0), p < 0.001) than the SGP sample. In the CoWELL sample, especially persons with lower health literacy, who had no support network or who have had COVID-19, reported lower HRQOL. DISCUSSION: Aspects unique to the COVID-19 pandemic affected HRQOL. Vulnerable persons such as those having had COVID-19, less support opportunities, and with lower health literacy are especially prone to impaired HRQOL during the COVID-19 pandemic.

Oligogenic Causes of Human Differences of Sex Development: Facing the Challenge of Genetic Complexity.

BACKGROUND: Deviations of intrauterine sex determination and differentiation and postnatal sex development can result in a very heterogeneous group of differences of sex development (DSD) with a broad spectrum of phenotypes. Variants in genes involved in sexual development cause different types of DSD, but predicting the phenotype from an individual's genotype and vice versa remains challenging. SUMMARY: Next Generation Sequencing (NGS) studies suggested that oligogenic inheritance contributes to the broad manifestation of DSD phenotypes. This review will focus on possible oligogenic inheritance in DSD identified by NGS studies with a special emphasis on NR5A1variants as an example of oligogenic origin associated with a broad range of DSD phenotypes. We thoroughly searched the literature for evidence regarding oligogenic inheritance in DSD diagnosis with NGS technology and describe the challenges to interpret contribution of these genes to DSD phenotypic variability and pathogenicity. KEY MESSAGES: Variants in common DSD genes like androgen receptor (AR), mitogen-activated protein kinase kinase kinase 1 (MAP3K1), Hydroxy-Delta-5-Steroid Dehydrogenase 3 Beta- And Steroid Delta-Isomerase 2 (HSD3B2), GATA Binding Protein 4 (GATA4), zinc finger protein friend of GATA family member 2 (ZFPM2), 17b-hydroxysteroid dehydrogenase type 3 (HSD17B3), mastermind-like domain-containing protein 1 (MAMLD1), and nuclear receptor subfamily 5 group A member 1 (NR5A1) have been detected in combination with additional variants in related genes in DSD patients with a broad range of phenotypes, implying a role of oligogenic inheritance in DSD, while still awaiting proof. Use of NGS approach for genetic diagnosis of DSD patients can reveal more complex genetic traits supporting the concept of oligogenic cause of DSD. However, assessing the pathomechanistic contribution of multiple gene variants on a DSD phenotype remains an unsolved conundrum.

Leukocyte Telomere Length in Children With Congenital Adrenal Hyperplasia.

CONTEXT: Exposure to chronic stress and hypercortisolism is associated with decreased leukocyte telomere length (LTL), a marker for biological aging and cardiovascular disease. Children with congenital adrenal hyperplasia (CAH) are treated with glucocorticoids. OBJECTIVE: To investigate LTL in children with CAH. METHODS: In this prospective observational cohort study, conducted at 4 academic pediatric endocrinology outpatient clinics, children with genetically confirmed CAH were assessed at 2 follow-up visits (mean 4.1 ± 0.7 months apart). At each visit, LTL was determined by quantitative real-time PCR. All subjects underwent detailed clinical and endocrinologic evaluation and were classified as undertreated, optimally treated, or overtreated, accordingly. The influence of clinical factors on LTL was investigated using linear mixed models adjusted for age, sex, and BMI-z. RESULTS: We studied 76 patients, of whom 31 (41%) were girls, 63 (83%) had classic CAH, 67 (88%) received hydrocortisone, and 8 (11%) prednisolone. Median age at first visit was 12.0 years (IQR, 6.3-15.1), and median BMI-z was 0.51 (IQR, -0.12 to 1.43). LTL was shorter in patients with classic vs nonclassic CAH (-0.29, P = 0.012), in overtreated than in optimally treated patients (-0.07, P = 0.002), and patients receiving prednisolone compared with hydrocortisone (-0.34, P < 0.001). LTL was not associated with undertreatment or daily hydrocortisone-equivalent dose (P > 0.05). CONCLUSION: LTL is shorter in patients with classic than nonclassic CAH, and in those who are overtreated with hydrocortisone or treated with long-acting glucocorticoids. These findings may be attributed to chronic exposure to supraphysiologic glucocorticoid concentrations and indicate that LTL may be used as a biomarker for monitoring glucocorticoid treatment.

COVID-19 Information-Seeking, Health Literacy, and Worry and Anxiety During the Early Stage of the Pandemic in Switzerland: A Cross-Sectional Study.

Objectives: To describe COVID-19 information-seeking behavior (CISB) during the first stage of the pandemic in Switzerland and identify its determinants. Methods: We conducted an online cross-sectional survey (4 May to 6 July 2020). Participants self-reported their CISB (information sources and frequency), personal COVID-19 situation (e.g., perception about having had COVID-19), sociodemographic information, and completed validated measures of health literacy, and worry and anxiety. Data were analyzed using descriptive statistics and logistic regressions. Results: We included 1,505 participants (24.7% male; mean age = 43.0 years, SD = 13.9). Most participants reported searching for information daily (n = 1,023, 68.0%) and referring to multiple information sources (mean 3.7, SD = 1.5). Commonly used sources were official websites (n = 1,129, 75.0%) and newspapers (n = 997, 66.2%). Participants with higher health literacy were more likely to seek information daily and use online resources, but less likely to use personal networks than those with lower health literacy. We did not find any association between CISB and worry and anxiety. Conclusion: More opportunities for personal dialogue and education about reliable online information resources should be encouraged to optimize the CISB of groups with lower health literacy.

Stable Metabolic Control but Increased Demand for Professional Support in Children with Type 1 Diabetes in the Past Ten Years in Bern/Switzerland: A Quality Control Study.

Introduction: Lower HbA1c targets and increasingly complex diabetes management with substantially increasing costs dominate today's type 1 diabetes therapy in children and adolescents. Objective: To evaluate metabolic control in children and adolescents with type 1 diabetes and assess associated factors, evaluate determinants for frequency of healthcare contacts, and compare actual with historical data. Method: This cross-sectional observational study collected data on 178 children and adolescents with type 1 diabetes treated at the University Children's Hospital in Bern. Results: Mean HbA1c was 7.9% (63 mmol/mol), 33.1% (59/178) of children reached the target of HbA1c < 7.5% (<59 mmol/mol), and 18.0% (32/178) had an HbA1c value < 7.0% (<53 mmol/mol). Compared to historical data, stable HbA1c levels appeared with a doubled proportion of individuals using insulin pumps. Metabolic control was worse with a longer duration of diabetes and younger age at diagnosis but better when parents came from a Western European country. Age at the consultation, use of diabetes technology and native language influenced the number of healthcare contacts. Younger patients, patients using CSII, and patients without an official Swiss language as mother tongue had more consultations with a healthcare professional than older and native language individuals. Conclusion: The metabolic targets in childhood and adolescent type 1 diabetes are still unmet despite a shift towards more technology. Our study documents a higher demand for support and supervision in specific patient groups. An investment to increase healthcare contacts could help combat the increase in total diabetes cost and significantly improve metabolic control.

Short-Term Fasting Attenuates Overall Steroid Hormone Biosynthesis in Healthy Young Women.

Context: Fasting is stressful for the human body. It is managed by metabolic adaptations maintaining energy homeostasis and involves steroid hormone biosynthesis, but the exact interplay between energy and steroid metabolism remains elusive. Women with polycystic ovary syndrome (PCOS) suffer from disturbed metabolism and androgen excess, while in women with anorexia nervosa, cortisol and androgen production are decreased. By contrast, starvation of steroidogenic cells shifts adrenal steroid biosynthesis toward enhanced androgen production. Aim: This study investigated the effect of fasting on steroid production in healthy women. Methods: Twenty healthy young women fasted for 48 hours; steroid profiles from plasma and urine samples were assessed at baseline, after 24 hours, and 48 hours by liquid and gas chromatography-mass spectrometry. Results: Fasting did not change overall steroidogenesis, although it increased progestogen production and lowered relative mineralocorticoid, glucocorticoid, and androgen production. The largest decrease in urine metabolites was seen for ß-cortol, dehydroepiandrosterone, and androstenediol; higher levels were found for pregnanediol in urine and progesterone and aldosterone in serum. Activity of 17α-hydroxylase/17,20-lyase (CYP17A1), essential for androgen biosynthesis, was decreased after fasting in healthy women as were 21-hydroxylase (CYP21A2) and 5α-reductase activities. By contrast, hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) activity for cortisol inactivation seemed to increase with fasting. Conclusion: Significant changes in steroid metabolism occurred after 48 hours of fasting in healthy women. In contrast to metabolic changes seen at baseline in PCOS women compared to healthy women, and after starving of steroidogenic cells, no androgen excess was observed after short-term fasting in healthy young women.

Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Characteristics of Growth in Children With Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency During Adrenarche and Beyond.

CONTEXT: Patients with classic congenital adrenal hyperplasia (CAH) often do not achieve their full growth potential. Adrenarche may accelerate bone maturation and thereby result in decreased growth in CAH. OBJECTIVE: The study aimed to analyze the impact of growth during adrenarche on final height of adequately treated classic CAH patients. METHODS: This retrospective, multicenter study (4 academic pediatric endocrinology centers) included 41 patients with classical CAH, born 1990-2012. We assessed skeletal maturation (bone age), growth velocity, and (projected) adult height outcomes, and analyzed potential influencing factors, such as sex, genotype, and glucocorticoid therapy. RESULTS: Patients with classic CAH were shorter than peers (-0.4 SDS ±â€…0.8 SD) and their parents (corrected final height -0.6 SDS ±â€…1.0 SD). Analysis of growth during adrenarche revealed 2 different growth patterns: patients with accelerating bone age (49%), and patients with nonaccelerating bone age relative to chronological age (BA-CA). Patients with accelerating BA-CA were taller than the normal population during adrenarche years (P = 0.001) and were predicted to achieve lower adult height SDS (-0.9 SDS [95% CI, -1.3; -0.5]) than nonaccelerating patients when assessed during adrenarche (0.2 SDS [95% CI, -0.3; 0.8]). Final adult height was similarly reduced in both accelerating and nonaccelerating BA-CA groups (-0.4 SDS [95% CI, -0.9; 0.1] vs -0.3 SDS [95% CI, [-0.8; 0.1]). CONCLUSION: Patients with and without significant bone age advancement, and thus differing height prediction during adrenarche, showed similar (predicted) final height when reassessed during pubertal years. Bone age alone should not be used during adrenarche as clinical marker for metabolic control in CAH treatment.

Health behaviour of women with Turner Syndrome.

AIM: This study assessed lifestyle-related risk factors for cardiovascular disease in young women with Turner syndrome. METHODS: In 2012, we sent a questionnaire to women with Turner syndrome aged ≥18 years and living in Switzerland with questions on socio-demographic and medical data as well as health behaviour. We compared the reported lifestyle with that of women from the Swiss Health Survey 2012, a representative survey of the general population. RESULTS: Fifty-seven per cent (45/79) of women with Turner syndrome answered the questionnaire (mean age: 24 years). Eighty per cent (36/45) had never smoked compared with 58% (1156/1972) of the general population (p < 0.01). Women with Turner syndrome engaged less often in binge drinking (34% vs. 71%) (p < 0.001), but consumed alcohol equally often as the general population (p = 0.327). They performed sports as often as the general population (p = 0.34), but only one quarter (11/45) of women with Turner syndrome adhered to official physical activity recommendations. CONCLUSION: Although most women with Turner syndrome had a healthy lifestyle, only a minority had sufficient physical activity. Paediatricians should promote structured physical activity in girls with Turner syndrome from early childhood onwards to reduce their cardiovascular risk in adulthood and to increase long-term health-related quality of life.

Health-Related Quality of Life in European Childhood Cancer Survivors: Protocol for a Study Within PanCareLIFE.

BACKGROUND: Survival after childhood cancer has improved to more than 80% during the last few years, leading to an increased number of childhood cancer survivors. Cancer itself, or its treatment, may cause chronic health conditions, including somatic and mental sequelae, which may affect survivors' health-related quality of life (HRQoL). OBJECTIVE: The project PanCareLIFE aims to establish a large database with comprehensive data on childhood cancer survivors from different European countries, including data on HRQoL. Within PanCareLIFE, this study aims to describe HRQoL in survivors, investigate predictors of HRQoL, and describe the association of HRQoL with hearing and female fertility impairment. This paper describes the design of the HRQoL study, the origin of data, strategies for data collection, and sampling characteristics of survivors from each contributing country. METHODS: A total of 6 institutions from 5 European countries (the Czech Republic, France, Germany, the Netherlands, and Switzerland) provided data on HRQoL assessed with the Short Form 36 and on relevant predictors. The central PanCareLIFE data center aggregated the data and harmonized the variables between the institutions. Survivors were eligible if they received a diagnosis of cancer according to the 12 main groups of the International Classification of Childhood Cancer, 3rd edition, or Langerhans cell histiocytosis; were aged ≤18 years at the time of diagnosis; were residents of the respective country at the time of diagnosis; had survived ≥5 years after cancer diagnosis; were aged ≥18 years at the time of the questionnaire survey; and did not refuse to registration in the national or local childhood cancer cohort. RESULTS: We identified 24,993 eligible survivors. Of those, 19,268 survivors received a questionnaire and 9871 survivors participated, resulting in response rates of 9871/24,993 (39.50%) of eligible survivors and of 9871/19,268 (51.23%) invited survivors. Most participants were diagnosed with cancer between the ages of 10 and 14 years (3448/9871, 34.93%) or <5 years (3201/9871, 32.43%). The median age was 8 years. Of the 9871 participants, 3157 (31.97%) were survivors of leukemia, 2075 (21.02%) lymphoma, and 1356 (13.7%) central nervous system (CNS) tumors. Most participants (9225/9871, 93.46%) had no history of a subsequent tumor; 77.45% (7645/9871) received chemotherapy with or without other treatments. More than half (5460/9871, 55.31%) were aged 25 to 34 years at the time of the HRQoL study. Participating survivors differed from nonparticipants; participants were more often women, survivors of leukemia or lymphoma, and less frequently, survivors of CNS tumors than nonparticipants. CONCLUSIONS: PanCareLIFE successfully assessed HRQoL and its predictors in 9871 European survivors of childhood cancer. This large population will permit detailed investigations of HRQoL after childhood cancer, particularly the impact of hearing and female fertility impairment on HRQoL. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/21851.

Differential Responses of Urinary Epinephrine and Norepinephrine to 24-h Shift-Work Stressor in Physicians.

Multiple stressors, including 24-h-shifts characterise the working environment of physicians, influencing well-being, health and performance. We aimed to evaluate the effect of the stressor 24-h-shift on the adrenal medullary and sympathoneural system in physicians with the hypothesis that shift work might have different impacts on both systems. Twenty-two physicians collected two 12-h-urine samples ("daytime" and "nighttime") during a 24-h shift ("on-duty") and on a free weekend ("off-duty"), respectively. Urinary excretion rates per m2 body surface area were assessed for the catecholamines epinephrine, norepinephrine and their respective free O-methylated metabolites metanephrine and normetanephrine by LC-MS/MS-analysis. The stressor provoked differential responses of epinephrine and norepinephrine. Epinephrine excretion rates showed significant increases from off to on duty. The largest proportional change (off-duty to on-duty) for epinephrine was observed for nighttime (205%), the increase for daytime was 84%. An increase in norepinephrine from off to on duty was only visible for nighttime collections. For the catecholamine metabolites, normetanephrine paralleled norepinephrine and exhibited an increase in excretion from off to on duty during nighttime collections of 53% whereas there was no change during daytime collections (3%). In conclusion: Whilst the 24-h-shift-work stressor in physicians activates the sympatho-adrenomedullary system, represented by epinephrine, the sympathoneural response through norepinephrine reflects mainly an ambulatory position during working hours.

Quality of Life in Autosomal Dominant Polycystic Kidney Disease Patients Treated With Tolvaptan.

RATIONALE & OBJECTIVE: The impact of tolvaptan on health-related quality-of-life (HRQoL) in patients with autosomal dominant polycystic kidney disease (ADPKD) is unknown. To address this knowledge gap, we studied patient-reported HRQoL in patients enrolled in the Bern ADPKD registry. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: Inclusion criteria were age 18 years or older, clinical diagnosis of ADPKD, and informed consent. The main exclusion criterion was need for kidney replacement therapy. OUTCOME: HRQoL was assessed using the standardized Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire at start of the study (baseline) and after 1 year (follow-up). The KDQOL-SF has 2 parts: a generic 36-Item Health Survey instrument with 8 subscores and 2 summary scores and a kidney disease-specific instrument to assess health concerns. Higher scores indicate better HRQoL. The influence of tolvaptan treatment on HRQoL and kidney-specific health concerns was analyzed using analysis of covariance, adjusting for HRQoL and health concerns before the start of the study, sex, and age. RESULTS: In 38 of 121 registry patients, tolvaptan treatment was initiated. Within the first 3 months, treatment had to be discontinued in 6 (16%) patients due to aquaretic side effects (n = 4; 11%) or elevated liver enzyme levels (n = 2; 5%), and a dose reduction was necessary in 8 (21%) patients. We included 98 patients (30 with and 68 without tolvaptan treatment) in the analysis for which baseline and 1-year follow-up data were available. At follow-up, and after adjusting for baseline scores, sex, and age, HRQoL and kidney-specific health concerns were not influenced by tolvaptan treatment, except for patient satisfaction, which was increased. LIMITATIONS: Observational study design, monocentric study at tertiary referral hospital, almost exclusively white study population, grant support by Otsuka Pharmaceuticals. CONCLUSIONS: Our results indicate that tolvaptan does not significantly affect HRQoL in patients with ADPKD who tolerate treatment beyond the first 3 months of therapy.