Transition From Diencephalic Syndrome to Hypothalamic Obesity in Children With Suprasellar Low Grade Glioma: A Case Series

Background: Children with suprasellar low grade glioma (LGG) frequently develop problems to maintain their body weight within the normal range, due to hypothalamic dysfunction. Hypothalamic damage may result in the diencephalic syndrome (DS), characterized by underweight or failure to thrive, but also in hypothalamic obesity (HO). Children with LGG presenting with DS at young age often develop HO later in life. The underlying pathophysiology for this change in body mass index (BMI) is not understood. Previous hypotheses have focused on the tumor or its treatment as the underlying cause. To better understand its etiology, we aimed to relate changes in BMI over time in children with suprasellar LGG presenting with DS to age, tumor progression, treatment, and endocrine function. We hypothesize that the development of HO in children with LGG presenting with DS is related to maturation status of the hypothalamus at time of injury and thus age. Methods: In this retrospective case series, all cases diagnosed in the Netherlands with suprasellar located LGG, currently treated or followed, with a history of DS developing into HO were included. Results: In total, 10 children were included. Median age at LGG diagnosis was 1.5 years (range 0.4–5.5), median BMI SDS was −2.64. The children developed overweight at a median age of 4.5 years (2.2–9.8). The median total difference in BMI SDS between underweight and obesity was +5.75 SDS (4.5–8.7). No association could be found between transition of DS to HO and onset of a pituitary disorder (present in 70.0%), surgery, chemotherapy, or tumor behavior. Two had developed central precocious puberty (CPP), both while having underweight or normal weight. Conclusion: The shift from DS to HO in children with hypothalamic LGG may be associated with age and not to tumor behavior, treatment characteristics or pituitary function. The development of CPP in these children seems not to be related to obesity. Our findings may indicate that the clinical picture of hypothalamic dysfunction reflects the maturation state of the hypothalamus at time of lesioning. Future prospective studies are needed to better understand underlying causative mechanisms of the morbid changes in body weight

Development of the Dutch Structure for Integrated Children's Palliative Care

Children’s palliative care (CPC) is gaining attention worldwide, facilitated by the exchange of knowledge during regular specialised congresses. This article describes the developments in the Netherlands over the past 15 years. The Foundation for Children’s Palliative Expertise (PAL) was established as a nationwide initiative committed to improving palliative care for children countrywide. This led to the development of the first hospital-based CPC team in 2012, which expanded to a total of seven teams adjacent to children’s university hospitals. Regional networks for CPC were developed in parallel to these teams from 2014 onwards. The networks are a collaboration of professionals from different disciplines and organisations, from hospital to homecare, and have covered the aspects of CPC nationally from 2019 onwards. They are connected through the Dutch Knowledge Centre for CPC. This centre was established in 2018 by the PAL Foundation in collaboration with the Dutch Association for Pediatrics. In 2013, the first evidence-based guideline, ‘palliative care for children’, provided access to knowledge for parents and healthcare providers, and in 2017, a format for an individual palliative care plan was established. Within the Knowledge Centre for CPC, a physician’s support centre for dilemma’s regarding the end of life of children was set up. The efforts to have children’s palliative care embedded in the regular Dutch health care insurance are ongoing

The diagnostic accuracy and prognostic value of OCT for the evaluation of the visual function in children with a brain tumour: A systematic review

PURPOSE: To systematically review the evidence on the diagnostic accuracy and prognostic value of retinal optical coherence tomography (OCT) to detect visual acuity (VA) or visual field (VF) loss in children with a brain tumour. METHODS: PubMed, Embase and Cochrane Library databases were searched from inception to February 2021. We included studies evaluating retinal OCT and standard visual function parameters (VA and or VF) in children with a brain tumour. Two authors independently extracted data from each included study. They also assessed the methodological quality of the studies using the QUADAS-2 or QUIPS tool. The diagnostic accuracy of OCT was evaluated with receiver operating characteristic analysis, sensitivity, specificity, positive predictive value and negative predictive value. The prognostic value of OCT was evaluated with predictive measures (odds ratio). RESULTS: We included five diagnostic studies, with a total of 186 patients, all diagnosed with optic pathway glioma. No prognostic studies were eligible for inclusion. Included studies evaluated either retinal nerve fiber layer (RNFL) thickness or ganglion cell layer-inner plexiform layer (GCL-IPL) thickness. There was considerable heterogeneity between OCT devices, OCT protocols, visual function parameters and threshold values. Sensitivity and specificity for RNFL thickness measurement ranged from 60.0% to 100.0% and 76.6% to 100%, respectively. For GCL-IPL thickness measurement, area under the curve ranged from 0.91 to 0.98 for different diameters. CONCLUSION: The literature regarding the diagnostic accuracy and prognostic value of OCT parameters in children with a brain tumour is scarce. Due to heterogeneity and a considerable risk of bias of included studies, we cannot draw solid conclusions regarding the accuracy of retinal OCT. Future research should investigate the potential of OCT as diagnostic and prognostic tool for the evaluation of the visual function and detection of visual impairment in children with any type of brain tumour

The development of fatigue after treatment for pediatric brain tumors does not differ between tumor locations

Background: Children and adolescents treated for a brain tumor suffer from more fatigue than survivors of other types of childhood cancer. As tumor location might be predictive of fatigue, our aim was to investigate the longitudinal development of fatigue in children with brain tumors and risk factors for fatigue separately for different tumor locations. Methods: Fatigue was assessed 1235 times for 425 participants. Self-report versions of PedsQL Multidimensional Fatigue Scale were used to repeatedly assess fatigue from the end of treatment up to 8 years later. Mixed models were used to analyze fatigue over time and determinants separately for infratentorial (N = 205), supratentorial hemispheric (N = 91), and supratentorial midline tumors (N = 129). Results: Cognitive fatigue worsened with time, while sleep-rest and general fatigue first decreased and then increased. There was no difference in fatigue between the tumor locations, but the risk factors differed when stratified by location. Radiotherapy was associated with more fatigue for infratentorial tumors, and centralization of care was associated with less fatigue for the supratentorial midline tumors. For supratentorial hemispheric tumors, female sex was associated with more fatigue. Higher parental education was associated with less fatigue regardless of tumor location. Conclusions: The development of fatigue seems to be more related to sociodemographic and treatment variables than to tumor location. Healthcare providers need to be aware that fatigue may develop in the years following end of treatment, and that patients with a low/middle educational family background might be more vulnerable and in need of targeted support

Diagnostic accuracy of retinal optical coherence tomography in children with a newly diagnosed brain tumour

Purpose: To estimate the diagnostic accuracy of circumpapillary retinal nerve fibre layer (RNFL) thickness and macular ganglion cell layer–inner plexiform layer (GCL-IPL) thickness measurements to discriminate an abnormal visual function (i.e. abnormal age-based visual acuity and/or visual field defect) in children with a newly diagnosed brain tumour. Methods: This cross-sectional analysis of a prospective longitudinal nationwide cohort study was conducted at four hospitals in the Netherlands, including the national referral centre for paediatric oncology. Patients aged 0–18 years with a newly diagnosed brain tumour and reliable visual acuity and/or visual field examination and optical coherence tomography were included. Diagnostic accuracy was evaluated with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Results: Of 115 patients included in the study (67 [58.3%] male; median age 10.6 years [range, 0.2–17.8 years]), reliable RNFL thickness and GCL-IPL thickness measurements were available in 92 patients (80.0%) and 84 patients (73.0%), respectively. The sensitivity for detecting an abnormal visual function was 74.5% for average RNFL thickness and 41.7% for average GCL-IPL thickness at a specificity of 44.5% and 82.9%, respectively. The PPV and NPV were 33.0% and 82.6% for the average RNFL thickness and 57.1% and 82.2% for the average GCL-IPL thickness. Conclusion: An abnormal visual function was discriminated correctly by using the average RNFL thickness in seven out of ten patients and by using the average GCL-IPL thickness in four out of ten patients. The relatively high NPVs signified that patients with normal average RNFL thickness and average GCL-IPL thickness measurements had a relative high certainty of a normal visual function

Dextroamphetamine Treatment in Children With Hypothalamic Obesity

INTRODUCTION: Hypothalamic obesity (HO) in children has severe health consequences. Lifestyle interventions are mostly insufficient and currently no drug treatment is approved for children with HO. Amphetamines are known for their stimulant side-effect on resting energy expenditure (REE) and suppressing of appetite. Earlier case series have shown positive effects of amphetamines on weight in children with acquired HO. We present our experiences with dextroamphetamine treatment in the, up to now, largest cohort of children with HO. METHODS: A retrospective cohort evaluation was performed of children with HO treated with dextroamphetamine at two academic endocrine pediatric clinics. Off-label use of dextroamphetamine was initiated in patients with progressive, therapy-resistant acquired or congenital HO. Anthropometrics, REE, self-reported (hyperphagic) behavior and energy level, and side effects were assessed at start and during treatment. RESULTS: Nineteen patients with a mean age of 12.3 ± 4.0 years had been treated with dextroamphetamine. In two patients, ΔBMI SDS could not be evaluated due to short treatment duration or the simultaneous start of extensive lifestyle treatment. Mean treatment duration of the 17 evaluated patients was 23.7 ± 12.7 months. Fourteen patients (n = 10 with acquired HO, n = 4 with congenital HO) responded by BMI decline or BMI stabilization (mean ΔBMI SDS of -0.6 ± 0.8, after a mean period of 22.4 ± 10.5 months). In three patients, BMI SDS increased (mean ΔBMI SDS of +0.5 ± 0.1, after a mean period of 29.7 ± 22.6 months). In 11 responders, measured REE divided by predicted REE increased with +8.9%. Thirteen patients (68.4%) reported decreased hyperphagia, improvement of energy level and/or behavior during treatment. Two patients developed hypertension during treatment, which resulted in dosage adjustment or discontinuation of treatment. Twelve children continued treatment at last moment of follow-up. CONCLUSION: In addition to supportive lifestyle interventions, dextroamphetamine treatment may improve BMI in children with HO. Furthermore, dextroamphetamines have the potential to decrease hyperphagia and improve resting energy expenditure, behavior, and energy level. In patients with acquired HO, these effects seem to be more pronounced when compared to patients with congenital HO. Future studies are needed to support these results

Tocilizumab for the fifth progression of cystic childhood craniopharyngioma-a case report

We present the case of a 15-year-old girl, with a fifth cystic progression of an adamantinomatous craniopharyngioma after multiple surgeries and previous local radiotherapy. She had severe visual impairment, panhypopituitarism including diabetes insipidus, and several components of hypothalamic damage, including morbid obesity and severe fatigue. To prevent further late effects hampering her quality of survival, she was treated biweekly with intravenous tocilizumab, an anti-interleukin-6 agent, which stabilized the cyst for a prolonged time. Based on the biology of adamantinomatous craniopharyngioma, this immune-modulating treatment seems promising for the treatment of this cystic tumor in order to reduce surgery and delay or omit radiotherapy

Ophthalmological Evaluation in Children Presenting with a Primary Brain Tumor

Background:Children with a brain tumor are prone to develop visual impairment, which to date is often underestimated and unrecognized. Our aim was to assess the prevalence of ophthalmological evaluation and abnormal ophthalmological findings, and investigate whether demographic and tumor-related characteristics are associated with abnormal ophthalmological findings in children presenting with a primary brain tumor.Methods:Medical records of all 90 children diagnosed with a primary brain tumor between June 2018 and May 2019 and treated at the Princess Máxima Center for Pediatric Oncology, a tertiary referral center in the Netherlands, were retrospectively reviewed. Univariate regression analysis was used to investigate associations between demographic, tumor-related and clinical characteristics, and abnormal ophthalmological findings.Results:Sixty children (34 male [56.7%]; median [range] age, 9.3 [0-16.9] years) underwent ophthalmological evaluation within 6 weeks before or after diagnosis, 11 children (5 male [45.5%]; median [range] age, 5.7 [0.1-17.2] years) were seen more than 6 weeks before or after diagnosis, and 19 children (7 male [36.8%]; median [range] age, 7.2 [1.9-16.6] years) did not receive ophthalmological evaluation within at least 6 months from diagnosis. A total of 19 children (21.1%) presented with visual symptoms as first sign leading to the diagnosis of a brain tumor. Children who presented with visual symptoms (odds ratio [OR], 22.52; 95% confidence interval [CI], 4.90-103.60) and/or hydrocephalus (OR, 3.60; 95% CI, 1.38-9.36) at diagnosis were more often seen for ophthalmological evaluation. The most common abnormal ophthalmological findings were eye movement disorders (66.0%), papilledema (44.1%), and visual field defects (58.1%). Eye movement disorders occurred more frequently in patients with an infratentorial tumor (OR, 4.71; 95% CI, 1.03-21.65). The risk of papilledema was associated with older age (OR, 1.19; 95% CI, 1.05-1.34), hydrocephalus (OR, 9.63; 95% CI, 2.68-34.61), and infratentorial (OR, 9.11; 95% CI, 1.77-46.78) and supratentorial (OR, 13.13; 95% CI, 1.92-89.52) tumors.Conclusions:In this study, most children with a primary brain tumor underwent ophthalmological evaluation around diagnosis, 21% of the children were not evaluated. The high prevalence of abnormal ophthalmological findings stresses the importance of early standardized ophthalmological evaluation to detect visual impairment and provide timely treatment to potentially prevent permanent visual loss

Safety of growth hormone replacement therapy in childhood-onset craniopharyngioma: a systematic review and cohort study

Introduction: Survival of childhood-onset craniopharyngioma (cCP) is excellent; however, many survivors suffer from hypothalamic-pituitary dysfunction. Growth hormone replacement therapy (GHRT) is of high importance for linear growth and metabolic outcome. Optimal timing for initiation of GHRT in cCP is on debate because of concerns regarding tumor progression or recurrence. Methods: A systematic review and cohort studys were performed for the effect and timing of GHRT on overall mortality, tumor progression/recurrence, and secondary tumors in cCP. Within the cohort, cCP receiving GHRT ≤1 year after diagnosis were compared to those receiving GHRT >1 year after diagnosis. Results: Evidence of 18 included studies, reporting on 6,603 cCP with GHRT, suggests that GHRT does not increase the risk for overall mortality, progression, or recurrent disease. One study evaluated timing of GHRT and progression/recurrence-free survival and found no increased risk with earlier initiation. One study reported a higher than expected prevalence of secondary intracranial tumors compared to a healthy population, possibly confounded by radiotherapy. In our cohort, 75 of 87 cCP (86.2%) received GHRT for median of 4.9 years [0.0-17.1]. No effect of timing of GHRT was found on mortality, progression/recurrence-free survival, or secondary tumors. Conclusion: Although the quality of the evidence is low, the available evidence suggests no effect of GHRT or its timing on mortality, tumor progression/recurrence, or secondary neoplasms in cCP. These results support early initiation of GHRT in cCP aiming to optimize linear growth and metabolic outcome. Prospective studies are needed to increase the level of evidence upon the optimal timing to start GHRT in cCP patients

LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration

BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022