Screening, assessment and management of type 2 diabetes mellitus in children and adolescents: Australasian Paediatric Endocrine Group guidelines.

INTRODUCTION: The incidence of type 2 diabetes mellitus has increased in children and adolescents due largely to the obesity epidemic, particularly in high risk ethnic groups. ß-Cell function declines faster and diabetes complications develop earlier in paediatric type 2 diabetes compared with adult-onset type 2 diabetes. There are no consensus guidelines in Australasia for assessment and management of type 2 diabetes in paediatric populations and health professionals have had to refer to adult guidelines. Recent international paediatric guidelines did not address adaptations to care for patients from Indigenous backgrounds. MAIN RECOMMENDATIONS: This guideline provides advice on paediatric type 2 diabetes in relation to screening, diagnosis, diabetes education, monitoring including targets, multicomponent healthy lifestyle, pharmacotherapy, assessment and management of complications and comorbidities, and transition. There is also a dedicated section on considerations of care for children and adolescents from Indigenous background in Australia and New Zealand. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINES: Published international guidelines currently exist, but the challenges and specifics to care for children and adolescents with type 2 diabetes which should apply to Australasia have not been addressed to date. These include: recommendations regarding care of children and adolescents from Indigenous backgrounds in Australia and New Zealand including screening and management; tighter diabetes targets (glycated haemoglobin, ≤ 48 mmol/mol [≤ 6.5%]) for all children and adolescents; considering the use of newer medications approved for adults with type 2 diabetes under the guidance of a paediatric endocrinologist; and the need to transition adolescents with type 2 diabetes to a diabetes multidisciplinary care team including an adult endocrinologist for their ongoing care.

How physically active do Australian and New Zealander childhood cancer survivors perceive themselves? A report from the ANZCHOG survivorship study.

PURPOSE: Childhood cancer survivors are at risk of treatment late-effects. Physical activity represents a necessary complementary therapy and modifiable risk-factor across all ages for many cardio-metabolic late-effects. This study assessed perceived physical activity in Australian and New Zealander childhood cancer survivors. METHODS: We recruited parents of survivors aged <16 years, and adult survivors of childhood cancer aged ≥16 years, ≥5 years since diagnosis, with age-matched controls for comparison. We compared perceived moderate-vigorous physical activity between survivors and controls, using regression to identify associations with physical activity. RESULTS: We recruited 914 participants (570 childhood cancer survivors and 344 age-matched controls). Parents of survivors perceived more moderate-vigorous physical activity than child controls (248 ± 218, 95% Confidence Interval (CI) = 218-280 vs 185 ± 214 min/week, 95% CI = 144-225, p = 0.036), with no perceived difference between adult survivors and controls (125 ± 152, 95% CI = 108-140 vs 160 ± 201 min/week, 95% CI = 132-187, p = 0.477). Twenty-seven percent of child survivors (vs. 14.5% controls) and 30% of adult survivors (vs. 39.4% controls) met recommendations. Adult survivors who received radiotherapy (OR = 0.585, 95% CI = 0.343-0.995, p = 0.048) or not completed university (OR = 1.808, 95% CI = 1.071-3.053, p = 0.027) were less likely to meet recommendations. CONCLUSIONS: Over two-thirds of Australian and New Zealander childhood cancer survivors across all ages are perceived to not meet physical activity recommendations. Adult survivors who had radiotherapy or did not complete university appeared at-risk for low physical activity. PRACTICAL IMPLICATIONS: Physical activity is important for everyone, but critical among childhood cancer survivors due to increased late cardio-metabolic risks. Monitoring survivors' perceived but also objectively measured physical activity as complementary to routine care is warranted, to provide education and motivate survivors to take control of their health.

Salivary cortisol reveals overt and hidden anxiety in survivors of childhood cancer attending clinic.

BACKGROUND: Symptoms of anxiety may arise from fear of cancer recurrence and memories of traumatic experiences during treatment. This study aimed to identify changes in mental health and cortisol, a biological marker of stress, associated with oncology surveillance clinic attendance. METHODS: Adolescent and young adult (AYA) survivors of childhood cancer (aged 12-30 years, N = 46) attending a survivorship clinic were recruited. The State-Trait Anxiety Inventory, an anxiety self-rating and open answer question, and salivary cortisol collections were completed two weeks before and one day before clinic, on clinic day and two weeks after. RESULTS: Trait anxiety scores were consistent with the normal population. State anxiety scores two weeks after clinic were significantly lower than baseline (p = 0.02). Cortisol diurnal slopes were flatter than baseline after clinic (p = 0.02). Evening cortisol levels were significantly higher than baseline two weeks post clinic (p = 0.02). LIMITATIONS: Combined results from biological and psychometric assessments can be difficult to interpret. Larger cohorts will further delineate cortisol pathway activity and distress in AYA cancer survivors. CONCLUSIONS: Psychometric evidence indicates that AYA survivors of childhood cancer perceive themselves to be less anxious after a survivorship clinic visit. Biological evidence, however, indicates a dysregulation of the hypothalamic-pituitary-adrenal axis which may be linked to clinic attendance. Weak correlations suggest that cortisol may not be a reliable indicator of self-perceived anxiety. This may be due to confounding lifestyle factors influencing the stress response or potential 'coping strategies' developed during past treatment experience which may, hypothetically, have masked self-perceived anxiety.

Attitudes and experiences of childhood cancer survivors transitioning from pediatric care to adult care.

PURPOSE: Survivors of pediatric cancer are prone to late effects which require ongoing medical care. Young adult survivors often transition from specialist pediatric care to adult-oriented or community-based healthcare. This study aims to describe the attitudes and experiences of survivors and their parents towards transition barriers and enablers. METHODS: Long-term survivors and parents (of survivors < 16 years) were recruited from 11 hospitals in Australia and New Zealand to participate in a semi-structured telephone interview regarding their transition experiences. Transcribed interviews were coded and content analysis was used to number participants within themes. RESULTS: Thirty-three participants were interviewed, of which 18 were survivors (mean age 26 years, SD = 6.3; mean time since treatment completion 13.3 years, SD = 6.1) and 15 were parents (mean survivor age 15 years, SD = 1.9; mean time since treatment completion 8.4 years, SD = 2.8). Participants described their transition attitudes as positive (55%), neutral (15%), or negative (30%). Key barriers to transition included dependence on pediatric healthcare providers, less confidence in primary care physicians (PCPs), inadequate communication, and cognitive difficulty. Enablers included confidence in and proximity to physicians, good communication, information, independence, and age. CONCLUSIONS: Many survivors face barriers to their transition out of pediatric care. Early introduction to transition, greater collaboration between healthcare professionals, and better information provision to survivors may improve the transition process. Future research of survivors' experience of barriers/enablers to transition is needed. Development of interventions, such as those that address self-management skills, is required to facilitate transition and encourage long-term engagement.

Primary Gonadal Insufficiency in Male and Female Childhood Cancer Survivors in a Long-Term Follow-Up Clinic.

PURPOSE: Childhood cancer survivors (CCS) are at increased risk of primary gonadal insufficiency (PGI). This study evaluated the prevalence and clinical characteristics of PGI in CCS. METHODS: In this single-center, retrospective, observational, longitudinal study, we characterized CCS with PGI attending the oncology Long-Term Follow-Up (LTFU) Clinic at an Australian university hospital (January 2012-August 2014). From a cohort of 276 CCS, 54 (32 males) met criteria for PGI: elevated gonadotropins plus low estradiol/amenorrhoea (females) or low testosterone/small testicles for age (males). RESULTS: Median age at primary diagnosis was 4.8 years (inter-quartile range [IQR] 3.0-9.7 years) and at LTFU, it was 22.3 years (IQR 18.2-25.7 years). Fifty-three participants (98.1%) were treated with known highly gonadotoxic therapies: alkylating chemotherapy (96.3%), radiotherapy (70.3%), total body irradiation (29.6%), bone marrow transplantation (51.9%), or multimodal protocols (68.5%). At primary diagnosis, 86.7% participants were Tanner stage I and at LTFU, 89.1% participants were Tanner stage V. More females (95.5%; n = 21) than males (40.6%; n = 13) were treated with hormone development therapy (HDT) (p < 0.01). Of these, more than half (n = 18; 7 males) required pubertal induction. There was no significant difference in serum luteinizing hormone/follicle stimulating hormone (LH/FSH), testosterone/estradiol between those untreated and those treated with HDT. Among those on HDT, 60.7% had persistently elevated FSH±LH and 33.3% had low testosterone or estradiol. Six males had semen analysis (five azoospermic, one oligospermic). Psychological assessment was documented in 61.1% of participants, and two-thirds reported fertility concerns. CONCLUSION: PGI is an evolving phenotype that is common in CCS. Suboptimal treatment and non-adherence occur frequently. Ongoing assessment is essential to ensure prompt diagnosis, adequate intervention and to promote HDT adherence.

Metabolic Health in Childhood Cancer Survivors: A Longitudinal Study in a Long-Term Follow-Up Clinic.

PURPOSE: Childhood cancer survivors (CCS) are at increased risk of metabolic dysfunction as a late effect of cancer treatment. However, pediatric metabolic syndrome (MetS) lacks a unified definition, limiting the diagnosis of MetS in CCS. This study evaluated individual metabolic health risk factors and potential areas for intervention in this at-risk population. METHODS: This single center, retrospective observational longitudinal study evaluated the metabolic health of all CCS attending an oncology long-term follow-up clinic at a university hospital in Sydney, Australia (January 2012-August 2014). Participants were 276 CCS (52.2% male; mean age 18.0 years; range 6.8-37.9 years), at least 5 years disease free with a broad spectrum of oncological diagnoses. Primary metabolic health risk factors included raised body mass index, hypertension, and hypertransaminasemia. Participants treated with cranial radiotherapy (n = 47; 17.0% of cohort) had additional biochemical variables analyzed: fasting glucose/insulin, HDL/LDL cholesterol, and triglycerides. RESULTS: Hypertension was common (19.0%), with male sex (p < 0.01) and being aged 18 years or above (p < 0.01) identified as risk factors. Cranial irradiation was a risk factor for overweight/obesity (47.8% in cranial radiotherapy-treated participants vs. 30.4%; p = 0.02). Hypertransaminasemia was more prevalent among participants treated with radiotherapy (15.6% vs. 7.3%; p = 0.03), and overweight/obese participants (17.6% vs. 8.2%; p = 0.04). CONCLUSION: Metabolic health risk factors comprising MetS are common in CCS, placing this population at risk of premature adverse cardiovascular consequences. Proactive surveillance and targeted interventions are required to minimize these metabolic complications, and a unified definition for pediatric MetS would improve identification and monitoring.

Desmopressin administration in children with central diabetes insipidus: a retrospective review.

BACKGROUND: Central diabetes insipidus (DI) is a rare disorder in children caused by a deficiency of antidiuretic hormone arginine (vasopressin). Desmopressin is the first line agent in management of central DI. However, one of the side effects of desmopressin is water intoxication and hyponatraemia. This study reviews the patterns of desmopressin use and side effects in our institution. METHODS: Retrospective chart review of all patients with central DI followed up in one tertiary centre between 1 January 2008 and 31 December 2010. RESULTS: Forty-one patients (22 males and 19 females) were included. Twelve patients (29.3%) had congenital and 29 patients (70.7%) had acquired DI, mostly as a result of intracranial tumours. Thirty-six (87.8%) patients were on oral desmopressin and the remaining on nasal formulation. The median oral dose was 9.5 (4.2-17.0) µg/kg/day with median frequency of 2.5 (2-3). The median nasal dose was 0.7 (0.4-1.4) µg/kg/day with median frequency of 2.0 (2-3.5). Fourteen patients (34.1%) were switched from nasal to oral desmopressin with the median dose conversion factor of 20.1 (10.7-31.8). Forty percent of patients on nasal desmopressin experienced hypo/hypernatraemia compared to 18.1% on oral, however, there were no significance difference between standardized hypo/hypernatraemia episodes per treatment year. CONCLUSIONS: Oral desmopressin is used in the majority of our patients including infants and toddlers. There is wide inter-individual variation in dose requirement and dosing intervals. Management of central diabetes insipidus remains a challenge in adipsic patients and in young children during intercurrent illness regardless of the desmopressin formulation.

Cortisol response to general anaesthesia for medical imaging in children.

OBJECTIVE: The cortisol response to surgical stress has been frequently studied, and recommendations developed for steroid replacement in adrenally insufficient patients. There are currently no guidelines, however, for adrenal hormone replacement during anaesthesia alone. The objective of this study was to characterize the normal cortisol response to general anaesthesia in the absence of a surgical procedure in children. DESIGN: Prospective observational study. PATIENTS: Thirty-seven children (aged 0.5-7 years) without known endocrine disease or cranial neoplasms undergoing outpatient magnetic resonance imaging, under general anaesthesia for investigation of nonacute problems in a tertiary referral paediatric hospital. MEASUREMENTS: Serum cortisol and salivary cortisol were measured before and after anaesthesia and during recovery. RESULTS: The mean cortisol level was 303 (± 117) nmol/l at induction, 396 (± 241) nmol/l at emergence from anaesthesia and 584 (± 218) nmol/l during recovery. A stress response (increase in serum cortisol >550 nmol/l) occurred in 23% of children at emergence and in 52% of children at recovery. Eight children (31%) actually demonstrated a decrease in cortisol levels during anaesthesia, without an increase in complications. Mean salivary cortisol levels were 6.5 ± 4.8 nmol/l before induction, 23.5 ± 13.8 nmol/l at emergence from anaesthesia and 26.9 ± 21.6 nmol/l during recovery. A stress response (an increase in salivary cortisol greater than seven-fold) occurred in 26% of children during the study. CONCLUSIONS: While some children demonstrated a rise in their cortisol levels in response to anaesthesia without surgery, the response was variable and often more pronounced during recovery. There was consistently no classic stress response.

Prolonged hypocortisolemia in hydrocortisone replacement regimens in adrenocorticotrophic hormone deficiency.

OBJECTIVES: Studies of adults have shown that thrice-daily hydrocortisone dosing results in more physiologic cortisol profiles than twice-daily dosing. There are no data on thrice-daily dosing and only limited data on twice-daily dosing in children despite the possible adverse effects of glucocorticoid underreplacement or overreplacement. METHODS: Using 24-hour cortisol and glucose profiles, along with computerized cognitive testing, our aim was to assess prescribed hydrocortisone regimens in children and adolescents with hypopituitarism. RESULTS: Twenty patients with adrenocorticotrophic hormone deficiency participated. The hydrocortisone dosing regimen was thrice daily in 9 patients and twice daily in 11 patients (mean total daily dose: 8.3 +/- 2.6 and 7.6 +/- 2.1 mg/m2 per day, respectively). Those on twice-daily dosing had more waking hours (between 8:00 am and 8:00 pm) below the reference range than those on thrice-daily dosing (5.5 vs 2.1) and more daytime prolonged hypocortisolemia, defined as plasma cortisol level of < 50 nmol/L for > or = 4 hours (64% vs 0%). Morning doses > 4 mg/m2 caused larger postdose peaks than < 4 mg/m2 (151 vs 47 nmol/L, above the 97.5th percentile). However, there was no difference in the length of time taken to reach nadir below the 2.5th percentile (5.2 vs 4.8 hours). This was true for evening doses of > 2.5 mg/m2 and < 2.5 mg/m2. No hypoglycemia or hyperglycemia was detected in association with low or high cortisol levels. On predose and postdose cognitive testing (34 paired tests), no significant change in reaction speed was detected (453.3 vs 438.8 milliseconds) or in subgroup analysis of those who had symptoms of lethargy, predose cortisol levels of < 50 nmol/L, or prolonged hypocortisolemia. CONCLUSIONS: Thrice-daily dosing resulted in less frequent and prolonged hypocortisolemia than twice-daily regimens, but we were unable to relate either regimen to acute clinical end points of glycemia, lethargy, or cognitive function.

The clinical utility of alternative, less invasive sampling techniques in the assessment of oral hydrocortisone therapy in children and adolescents with hypopituitarism.

OBJECTIVE: The aim of glucocorticoid replacement therapy in ACTH-deficient patients is to mimic the normal diurnal variation of cortisol. However, current hydrocortisone (HC) replacement results in prolonged episodes of hypocortisolaemia and supraphysiological peaks. Plasma cortisol profiles are an accurate yet labour-intensive method of assessing HC replacement. Salivary and bloodspot cortisol sampling methods are less invasive and may be useful tools for assessing glucocorticoid replacement, particularly in children. Therefore, we aimed to define normal salivary and bloodspot cortisol levels in children and their correlations with the gold standard (plasma cortisol). DESIGN: Cross-sectional study in a paediatric teaching hospital. METHODS: Plasma, saliva and bloodspot cortisol profiles were performed on 30 ACTH-deficient children and 22 healthy siblings. RESULTS: In ACTH-deficient patients taking oral HC, the bloodspot-plasma correlation (p=0.90) was stronger than the salivary-plasma correlation (p=0.49). Using target ranges for salivary and bloodspot cortisol levels based on normal data from control subjects, the less invasive sampling methods had low rates of agreement with plasma cortisol target ranges (saliva 65% and bloodspot 75%). Using the plasma-bloodspot correlation regression equation to convert bloodspot to calculated plasma cortisol, there was a high concordance between calculated and actual measured plasma cortisol (88%). CONCLUSION: Bloodspot cortisol sampling is a feasible and accurate method for monitoring oral HC replacement in paediatric patients without necessitating hospital admission, but salivary sampling is not useful.