Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function.

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk-contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Prospective Longitudinal Assessment of Linear Growth and Adult Height in Female Adolescents With Anorexia Nervosa.

CONTEXT: Growth retardation is an established complication of anorexia nervosa (AN); however, findings concerning the adult height of AN patients are inconsistent. OBJECTIVE: The objective of this work was to assess linear growth and adult height in female adolescents with AN. DESIGN AND SETTING: A prospective observational study was conducted in a tertiary university hospital. PARTICIPANTS: Participants included all 255 female adolescent AN patients hospitalized in the pediatric psychosomatic department between January 1, 2000 and May 31, 2015. INTERVENTIONS: Height and weight were assessed at admission and during hospitalization. Patients were subsequently invited for measurement of adult height. Additional data collected included premorbid height data, menstrual history, skeletal age, pertinent laboratory studies, and parental heights. MAIN OUTCOME MEASURE: The main outcome measure of this study was adult height. RESULTS: Mean age at admission was 15.4 ±â€…1.75 years, mean body mass index (BMI) was 15.7 ±â€…1.8 kg/m2 (BMI SDS = -2.3 ±â€…1.45 kg/m2). Premorbid height SD scores (SDS) were not significantly different from those expected in normal adolescents (0.005 ±â€…0.96). However, height SDS at admission (-0.36 ±â€…0.99), discharge (-0.34 ±â€…0.96), and at adult height (-0.29 ±â€…0.95), were significantly (P < .001) lower than expected. Furthermore, adult height was significantly (P = .006) shorter compared to the midparental target height. Stepwise forward linear regression analysis identified age (r = 0.32, P = .002) and bone age (r = -0.29, P = .006) on admission, linear growth during hospitalization (r = 0.47, P < .001), and change in luteinizing hormone during hospitalization (r = -0.265, P = .021) as independent predictors of improvement in height SDS from the time of admission to adult height. CONCLUSIONS: Whereas the premorbid height of female adolescent AN patients is normal, linear growth retardation is a prominent feature of their illness. Weight restoration is associated with catch-up growth, but complete catch-up is often not achieved.

Resting energy expenditure in acutely ill and stabilized patients with anorexia nervosa and bulimia nervosa.

OBJECTIVE: Determining resting energy expenditure (REE) may be important in the nutritional assessment of adolescents with eating disorders (EDs). Calculated equations assessing REE, developed according to data from healthy people, may under- or overestimate REE in EDs. We have sought to compare the REE measured in clinical settings to that calculated using equations in actively ill adolescents with anorexia nervosa (AN) and bulimia nervosa (BN), and following stabilization of weight and disordered eating. METHODS: Thirty-five female adolescents with AN and 25 with BN were assessed at admission to inpatient treatment and at discharge. REE was measured using indirect calorimetry (DELTATRAC Metabolic Monitor). Expected REE was calculated using the Harris-Benedict equation. RESULTS: An overestimation of expected versus measured REE was found for both patients with AN and BN, both at admission and discharge. Second, the differences between expected and measured REE were significantly less robust in BN versus AN. Third, REE before renourishing was lower in inpatients with AN versus BN. Fourth, the REE of patients with AN (both measured and expected) increased from admission to discharge, to a greater extent than expected solely from the increase in weight. The difference between admission and discharge expected and measured REE was significant also in patients with BN. DISCUSSION: Our findings suggest that predicted and measured REE are different in both AN and BN, and that both expected and measured REE are not useful in the planning of renourishing programs in patients with AN.