Elevated IGF-1 concentrations in children with low grade glioma: A descriptive analysis in a retrospective national cohort.

Children with low grade glioma (LGG) may present with, or develop, elevated concentrations of insulin-like growth factor 1 (IGF-1). The prevalence, pathophysiology, or its possible clinical effects are poorly understood. Our aim was to evaluate the prevalence of such elevated IGF-1 concentrations and to describe its association with linear growth, body mass index (BMI), pituitary outcome, and tumor behavior in a large retrospective national cohort. From a nationwide retrospective cohort of pediatric brain tumor survivors diagnosed between 2002 and 2012, tumor, treatment, endocrine, and auxological data of children with LGG were collected (n = 358). Prevalence and risk factors for elevated IGF-1 concentrations, as well as the association between having elevated IGF-1 concentrations and receiving tumor treatment, were explored. IGF-1 concentrations had only been measured in 45.5% of cases (n = 163/358). In 18.4% of 163 children with available IGF-1 measurements, IGF-1 concentrations were found elevated. No association was described between having an elevated IGF-1 concentration and tumor behavior or height SDS at last moment of follow-up. Multivariate logistic regression identified posterior pituitary disorder (OR 6.14 95% CI: 2.21-17.09) and BMI SDS at follow-up (OR 1.56 95% CI: 1.09-2.20) to be significantly associated with elevated IGF-1 concentrations. In this retrospective cohort of children with LGG, IGF-1 was found elevated in 18.4% of children with available IGF-1 measurements. Elevated IGF-1 seems to be related to hypothalamic dysfunction worsening over time. Larger prospective cohort studies are needed.

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.

High Prevalence of Weight Gain in Childhood Brain Tumor Survivors and Its Association With Hypothalamic-Pituitary Dysfunction.

PURPOSE: Childhood brain tumor survivors (CBTS) are at risk for developing obesity, which negatively influences cardiometabolic health. The prevalence of obesity in CBTS may have been overestimated in previous cohorts because of inclusion of children with craniopharyngioma. On the contrary, the degree of weight gain may have been underestimated because of exclusion of CBTS who experienced weight gain, but were neither overweight nor obese. Weight gain may be an indicator of underlying hypothalamic-pituitary (HP) dysfunction. We aimed to study prevalence of and risk factors for significant weight gain, overweight, or obesity, and its association with HP dysfunction in a national cohort of noncraniopharyngioma and nonpituitary CBTS. METHODS: Prevalence of and risk factors for significant weight gain (body mass index [BMI] change ≥ +2.0 standard deviation score [SDS]), overweight, or obesity at follow-up, and its association with HP dysfunction were studied in a nationwide cohort of CBTS, diagnosed in a 10-year period (2002-2012), excluding all craniopharyngioma and pituitary tumors. RESULTS: Of 661 CBTS, with a median age at follow-up of 7.3 years, 33.1% had significant weight gain, overweight, or obesity. Of the CBTS between 4 and 20 years of age, 28.7% were overweight or obese, compared with 13.2% of the general population between 4 and 20 years of age. BMI SDS at diagnosis, diagnosis of low-grade glioma, diabetes insipidus, and central precocious puberty were associated with weight gain, overweight, or obesity. The prevalence of HP dysfunction was higher in overweight and obese CTBS compared with normal-weight CBTS. CONCLUSION: Overweight, obesity, and significant weight gain are prevalent in CBTS. An increase in BMI during follow-up may be a reflection of HP dysfunction, necessitating more intense endocrine surveillance.

Hypothalamic-Pituitary Dysfunctions Other Than Growth Hormone Deficiency in Cancer Survivors.

Hypothalamic-pituitary (HP) dysfunctions are commonly reported complications in survivors of childhood cancer. These include growth hormone deficiency, luteinizing hormone/follicle-stimulating hormone deficiency, thyroid-stimulating hormone deficiency, adrenocorticotropic hormone deficiency, central precocious puberty, hyperprolactinemia, and central diabetes insipidus. Local tumor invasion and surgical or radiation-induced injury represent the highest risk factors. New treatment modalities, such as immunotherapy and molecular targeted therapy have the potential to cause autoimmune hypophysitis. Untreated HP dysfunctions are associated with adverse physical and psychosocial consequences and reduced quality of life. Systematic and periodic endocrine assessments optimize early diagnosis and timely treatment and may improve long-term health outcomes.

Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma.

BACKGROUND: To determine the impact of hypothalamic-pituitary (HP) disorders on health outcomes in children and adolescents who received conformal radiation therapy (RT) for central nervous system tumors. PROCEDURE: Cohort study including 355 patients (age ≤25 years at diagnosis) treated with high-dose (50.4-59.4 Gy) RT using photons for low-grade glioma or ependymoma. Patients (median age, 6.4 years at RT) received systematic endocrine follow-up (median duration, 10.1 years; range, 0.1-19.6). Associations between HP disorders and adverse health outcomes were determined by multivariable analysis. RESULTS: Prevalence was 37.2% for growth hormone deficiency (GHD), 17.7% for gonadotropin deficiency (LH/FSHD), 14.9% for thyroid-stimulating hormone deficiency (TSHD), 10.3% for adrenocorticotropic hormone deficiency (ACTHD), and 12.6% for central precocious puberty (CPP). Hypothalamus mean dose ≥ 36 Gy was associated with higher odds of any deficiency. GHD was associated with short stature (OR 2.77; 95% CI 1.34-5.70), low bone mineral density (OR 3.47; 95% CI 1.16-10.40), and TSHD with dyslipidemia (OR 5.54; 95% CI 1.66-18.52). Patients with ACTHD and CPP had lower intelligence quotient scores, and memory scores were impaired in patients with GHD (P = 0.02). Treatment of GHD was not associated with increased risk for tumor recurrence, secondary tumors, or mortality. CONCLUSIONS: HP disorders occur frequently in patients receiving high-dose RT and are related to physical and neurocognitive well-being. Future studies are needed to assess whether further optimization of endocrine management yields better health outcomes.

Experiences with Glucagon-Like Peptide-1 Receptor Agonist in Children with Acquired Hypothalamic Obesity.

OBJECTIVE: Hypothalamic obesity (HO) in children after treatment for a tumor in the suprasellar region has severe implications. Previous studies have shown various effects of glucagon-like peptide-1 (GLP-1) receptor agonist in acquired HO, but in adults only. We present our experience of GLP-1 receptor agonist (exenatide) treatment during a 1-year period on body mass index (BMI) in children with acquired HO. PATIENTS AND METHODS: Children with severe weight gain after treatment for suprasellar tumor were given 2 mg exenatide weekly for a 12-month period. All had undergone previous dietary intervention. BMI standard deviation score (SDS), weight change, and adverse effects were assessed. RESULTS: Five children with a mean age of 15.4 years (range 13-18) and a mean follow-up time of 8.4 years (mean age of 7.0 years at the time of brain tumor diagnosis) were treated with GLP-1 receptor agonist. After 1 year, BMI SDS or absolute weight had not changed significantly compared to the period without treatment (BMI SDS change +0.005, 95% CI -0.07 to 0.08, p = 0.89, and absolute weight change +1.5 kg, 95% CI -0.08 to 3.1, p = 0.061). Only 1 patient experienced weight loss after 1 year (-5.4 kg, BMI SDS -0.33). All patients experienced mild side effects, such as injection pain or nausea, and 2 patients stopped treatment upon their own request after 8 and 11 months, respectively. CONCLUSIONS: In this small cohort, we found little effect of GLP-1 receptor agonist in the treatment for acquired HO. Future research should focus on the prevention of HO or, if prevention is not possible, on alternative, individualized interventions.

Leydig Cell Function in Male Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study.

PURPOSE: Direct assessment of Leydig cell function in childhood cancer survivors has been limited. The objectives of this study were to describe the prevalence of and risk factors for Leydig cell failure (LCF), Leydig cell dysfunction (LCD), and associated adverse health outcomes. PATIENTS AND METHODS: In this retrospective study with cross-sectional health outcomes analysis, we evaluated 1,516 participants (median age, 30.8 years) at a median of 22.0 years after cancer diagnosis. LCF was defined as serum total testosterone less than 250 ng/dL (or 8.67 nmol/L) and luteinizing hormone greater than 9.85 IU/L, and LCD by testosterone as 250 ng/dL or greater and luteinizing hormone greater than 9.85 IU/L. Polytomous logistic regression evaluated associations with demographic and treatment-related risk factors. Log-binomial regression evaluated associations with adverse physical and psychosocial outcomes. Piecewise exponential models assessed the association with all-cause mortality. RESULTS: The prevalence of LCF and LCD was 6.9% and 14.7%, respectively. Independent risk factors for LCF included an age of 26 years or older at assessment, testicular radiotherapy at any dose, and alkylating agents at cyclophosphamide equivalent doses of 4,000 mg/m2 or greater. The risk increased with older age, higher doses of testicular radiotherapy, and cyclophosphamide equivalent doses. LCF was significantly associated with abdominal obesity, diabetes mellitus, erectile dysfunction, muscle weakness, and all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF; no significant associations were found with adverse physical or psychosocial outcomes. CONCLUSION: Older age, testicular radiotherapy, and exposure to alkylating agents were associated with LCF, which was associated with adverse physical and psychosexual outcomes. LCD, although having similar risk factors, was not associated with adverse health outcomes. Additional studies are needed to investigate the role of sex hormone replacement in mitigating the burden from adverse outcomes in survivors.

Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes.

CONTEXT: Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited. OBJECTIVE: To describe prevalence, risk factors, and associated adverse health outcomes of deficiencies in GH deficiency (GHD), TSH deficiency (TSHD), LH/FSH deficiency (LH/FSHD), and ACTH deficiency (ACTHD), and central precocious puberty (CPP). DESIGN: Retrospective with cross-sectional health outcomes analysis. SETTING: Established cohort; tertiary care center. PATIENTS: Participants (N = 3141; median age, 31.7 years) were followed for a median 24.1 years. MAIN OUTCOME MEASURE: Multivariable logistic regression was used to calculate ORs and 95% CIs for associations among HP disorders, tumor- and treatment-related risk factors, and health outcomes. RESULTS: The estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n = 1089), and 6.2% for GHD, and <1% for other HP disorders without HP radiotherapy. Clinical factors independently associated with HP disorders included HP radiotherapy (at any dose for GHD, TSHD, LH/FSHD, >30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD), and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory, and processing speed (GHD, TSHD). CONCLUSION: HP radiotherapy, central nervous system injury, and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes.

Clinical Importance of Free Thyroxine Concentration Decline After Radiotherapy for Pediatric and Adolescent Brain Tumors.

CONTEXT: Clinical significance of a decline in free T4 (FT4) concentrations across the reference range in children with brain tumors treated with radiation therapy (RT) is uncertain. OBJECTIVES: To study trends in FT4 in children after RT and risk factors and health outcomes associated with plasma FT4 concentrations. DESIGN AND SETTING: Longitudinal, single-center retrospective cohort study. PATIENTS: Low-grade glioma or ependymoma patients (n = 267; age ≤25 years) who received RT (50.4 to 59.4 Gy) at a single institution (1996 to 2016) and followed with serial FT4 measurements. MAIN OUTCOME MEASURE: A linear mixed-effects model with a random intercept was used to investigate risk factors for longitudinal changes in FT4 concentrations. A two-stage mixed-effects model examined associations between clinical outcomes and plasma FT4 concentrations. RESULTS: FT4 concentrations declined over time after RT (P < 0.001). Females (P < 0.001) and younger patients (P < 0.001) demonstrated greater declines in FT4 concentrations over time. The rate of weight gain, but not of height loss, increased with a higher FT4 decline rate (P < 0.001). At last follow-up, patients with lower baseline FT4 concentrations had increased risk of glucose disorder (OR, 19.73; P = 0.002) or dyslipidemia (OR, 19.40; P = 0.003) but not high fat mass (P = 0.18). Lower baseline FT4 concentrations were not associated with impaired scores for intelligence, attention, memory, or psychosocial functioning. CONCLUSIONS: FT4 concentrations significantly decline in children with brain tumor after RT. Variation and trends in FT4 concentration are associated with physical health outcomes. Future studies should assess whether continuous FT4 concentrations and trends, rather than population-based cut-off values, can distinguish between euthyroid and hypothyroid states.

Pathophysiology and Individualized Treatment of Hypothalamic Obesity Following Craniopharyngioma and Other Suprasellar Tumors: A Systematic Review.

The development of hypothalamic obesity (HO) following craniopharyngioma (CP) and other suprasellar tumors leads to reduced patient quality of life. No treatment algorithms are currently available for management of HO. Depending on which hypothalamic nuclei are destroyed, the pathophysiologic mechanisms and clinical symptoms that contribute to HO differ among patients. Herein, we review the contribution of the hypothalamus to the pathophysiologic mechanisms and symptoms underlying CP-associated HO. Additionally, we performed a systematic search of MEDLINE and Embase to identify all intervention studies for weight management in patients with CP or other suprasellar tumors published until September 2017. The search yielded 1866 publications, of which 40 were included. Of these 40 studies, we identified four modalities for intervention (i.e., lifestyle, dietary, pharmacotherapeutic, or surgical) within six clinical domains (i.e., psychosocial disorders, hyperphagia, sleep disturbances, decreased energy expenditure, hyperinsulinemia, and hypopituitarism). We used the findings from our systematic review, in addition to current knowledge on the pathophysiology of HO, to develop an evidence-based treatment algorithm for patients with HO caused by CP or other suprasellar tumors. Although the individual effects of the HO interventions were modest, beneficial individual effects may be achieved when the pathophysiologic background and correct clinical domain are considered. These two aspects can be combined in an individualized treatment algorithm with a stepwise approach for each clinical domain. Recently elucidated targets for HO intervention were also explored to improve future management of HO for patients with CP and other suprasellar tumors.

Declining free thyroxine levels over time in irradiated childhood brain tumor survivors.

OBJECTIVE: The incidence of cranial radiotherapy (cRT)-induced central hypothyroidism (TSHD) in childhood brain tumor survivors (CBTS) is reported to be low. However, TSHD may be more frequent than currently suspected, as its diagnosis is challenging due to broad reference ranges for free thyroxine (FT4) concentrations. TSHD is more likely to be present when FT4 levels progressively decline over time. Therefore, we determined the incidence and latency time of TSHD and changes of FT4 levels over time in irradiated CBTS. DESIGN: Nationwide, 10-year retrospective study of irradiated CBTS. METHODS: TSHD was defined as 'diagnosed' when FT4 concentrations were below the reference range with low, normal or mildly elevated thyrotropin levels, and as 'presumed' when FT4 declined ≥ 20% within the reference range. Longitudinal FT4 concentrations over time were determined in growth hormone deficient (GHD) CBTS with and without diagnosed TSHD from cRT to last follow-up (paired t-test). RESULTS: Of 207 included CBTS, the 5-year cumulative incidence of diagnosed TSHD was 20.3%, which occurred in 50% (25/50) of CBTS with GHD by 3.4 years (range, 0.9-9.7) after cRT. Presumed TSHD was present in 20 additional CBTS. The median FT4 decline in GH-deficient CBTS was 41.3% (P < 0.01) to diagnosis of TSHD and 12.4% (P = 0.02) in GH-deficient CBTS without diagnosed TSHD. CONCLUSIONS: FT4 concentrations in CBTS significantly decline over time after cRT, also in those not diagnosed with TSHD, suggesting that TSHD occurs more frequently and earlier than currently reported. The clinical relevance of cRT-induced FT4 decline over time should be investigated in future studies.

Low FT4 Concentrations around the Start of Recombinant Human Growth Hormone Treatment: Predictor of Congenital Structural Hypothalamic-Pituitary Abnormalities?

BACKGROUND: Growth hormone (GH) treatment may unmask central hypothyroidism (CeH). This was first observed in children with GH deficiency (GHD), later also in adults with GHD due to acquired "organic" pituitary disease. We hypothesized that newly diagnosed CeH in children after starting GH treatment for nonacquired, apparent isolated GHD points to congenital "organic" pituitary disease. METHODS: Nationwide, retrospective cohort study including all children with nonacquired GHD between 2001 and 2011 in The Netherlands. The prevalence of CeH, hypothalamic-pituitary (HP) abnormalities, and neonatal congenital hypothyroidism screening results were evaluated. RESULTS: Twenty-three (6.3%) of 367 children with apparent isolated GHD were prescribed LT4 for presumed CeH within 2 years after starting GH treatment. Similarly to children already diagnosed with multiple pituitary hormone deficiency, 75% of these 23 had structural HP abnormalities. In children not prescribed LT4, low pre- or post-GH treatment FT4 concentrations were also associated with structural HP abnormalities. Neonatal screening results of only 4 of the 23 children could be retrieved. CONCLUSION: In children with nonacquired, apparent isolated GHD, a diagnosis of CeH after, or a low FT4 concentration around the start of GH treatment, is associated with congenital structural HP abnormalities, i.e., "organic" pituitary disease. Neonatal values could not be judged reliably.

The development of hypothalamic obesity in craniopharyngioma patients: A risk factor analysis in a well-defined cohort.

BACKGROUND: Hypothalamic obesity (HO) is a major concern in patients treated for craniopharyngioma (CP). The influence of degree of resection on development of HO, event-free survival (EFS), and neuroendocrine sequelae is an issue of debate. PROCEDURE: A retrospective cohort consisting of all CP patients treated between 2002 and 2012 in two university hospitals was identified. Multivariable logistic regression was used to study the associations between preoperative BMI, age at diagnosis, tumor volume, performed surgical resection, and presence of HO at follow-up. RESULTS: Thirty-five patients (21 children and 14 adults) were included. Median follow-up time was 35.6 months (4.1-114.7). Four patients were obese at diagnosis. HO was present in 19 (54.3%) patients at last follow-up of whom eight were morbidly obese. Thirteen (37.1%) patients underwent partial resection (PR) and 22 (62.9%) gross total resection (GTR). GTR was related to HO (OR 9.19, 95% CI 1.43-59.01), but for morbid HO, obesity at diagnosis was the only risk factor (OR 12.92, 95% CI 1.05-158.73). EFS in patients after GTR was 86%, compared to 42% after PR (log-rank 9.2, P = 0.003). Adjuvant radiotherapy after PR improved EFS (log-rank 8.2, P = 0.004). Panhypopituitarism, present in 15 patients, was mainly seen after GTR. CONCLUSIONS: HO is less frequent after PR than after GTR, but PR cannot always prevent the development of morbid obesity in patients with obesity at diagnosis. PR reduces the occurrence of panhypopituitarism. When developing a treatment algorithm, all these factors should be considered.