Management of severe pulmonary Langerhans cell histiocytosis in children.

Patients with pulmonary Langerhans cell histiocytosis (LCH) typically have a benign course but may have extensive cystic lung disease with rare life-threatening complications including multiple and recurrent pneumothoraces and respiratory failure. We report seven severely affected pediatric patients treated with chemotherapy, aggressive chest tube management, and pleurodesis of whom five survived. Patients with extraordinary amounts of pulmonary cystic disease and multiple pneumothoraces due to LCH can have remarkable, curative outcomes with early recognition, optimal LCH-directed therapy, and supportive care.

Therapeutic Targeting of Histone Modifications in Adult and Pediatric High-Grade Glioma.

Recent exciting work partly through The Cancer Genome Atlas has implicated epigenetic mechanisms including histone modifications in the development of both pediatric and adult high-grade glioma (HGG). Histone lysine methylation has emerged as an important player in regulating gene expression and chromatin function. Lysine (K) 27 (K27) is a critical residue in all seven histone 3 variants and the subject of posttranslational histone modifications, as it can be both methylated and acetylated. In pediatric HGG, two critical single-point mutations occur in the H3F3A gene encoding the regulatory histone variant H3.3. These mutations occur at lysine (K) 27 (K27M) and glycine (G) 34 (G34R/V), both of which are involved with key regulatory posttranscriptional modifications. Therefore, these mutations effect gene expression, cell differentiation, and telomere maintenance. In recent years, alterations in histone acetylation have provided novel opportunities to explore new pharmacological targeting, with histone deacetylase (HDAC) overexpression reported in high-grade, late-stage proliferative tumors. HDAC inhibitors have shown promising therapeutic potential in many malignancies. This review focuses on the epigenetic mechanisms propagating pediatric and adult HGGs, as well as summarizing the current advances in clinical trials using HDAC inhibitors.

Current Understanding of BRAF Alterations in Diagnosis, Prognosis, and Therapeutic Targeting in Pediatric Low-Grade Gliomas.

The mitogen-activated protein kinase (MAPK) pathway is known to play a key role in the initiation and maintenance of many tumors as well as normal development. This often occurs through mutation of the genes encoding RAS and RAF proteins which are involved in signal transduction in this pathway. BRAF is one of three RAF kinases which act as downstream effectors of growth factor signaling leading to cell cycle progression, proliferation, and survival. Initially reported as a point mutation (V600E) in the majority of metastatic melanomas, other alterations in the BRAF gene have now been reported in a variety of human cancers including papillary thyroid cancer, colon carcinomas, hairy cell leukemia, and more recently in gliomas. The identification of oncogenic mutations in the BRAF gene have led to a revolution in the treatment of metastatic melanoma using targeted molecular therapies that affect the MAPK pathway either directly through BRAF inhibition or downstream through inhibition of MEK. This review describes the molecular biology of BRAF in the context of pediatric low-grade gliomas, the role of BRAF as a diagnostic marker, the prognostic implications of BRAF, and evidence for therapeutic targeting of BRAF.

Pediatric medulloblastoma - update on molecular classification driving targeted therapies.

As advances in the molecular and genetic profiling of pediatric medulloblastoma evolve, associations with prognosis and treatment are found (prognostic and predictive biomarkers) and research is directed at molecular therapies. Medulloblastoma typically affects young patients, where the implications of any treatment on the developing brain must be carefully considered. The aim of this article is to provide a clear comprehensible update on the role molecular profiling and subgroups in pediatric medulloblastoma as it is likely to contribute significantly toward prognostication. Knowledge of this classification is of particular interest because there are new molecular therapies targeting the Shh subgroup of medulloblastomas.

Cognitive function in children with brain tumors in the first year after diagnosis compared to healthy matched controls.

BACKGROUND: Improved survival of children with brain tumors (BTs) has increased focus on ameliorating morbidity. To reduce the risk of progressive cognitive decline, remedial strategies need to be instituted early, based upon accurate appraisal of need, yet few studies have investigated cognition in BT children early post-diagnosis. The study aims were to investigate cognition in children with primary BTs 1, 6, and 12 months post-diagnosis compared with healthy children, exploring the impact of disease and treatment variables. METHODS: Forty-eight children aged 2-16 years with primary BTs, referred to a Regional Neurosurgical Unit over the 2-year study period were eligible for enrollment. The "best friends" model was used to recruit matched controls. Cognition was assessed using age-appropriate Wechsler Intelligence scales; Children's Memory Scale; Test of Everyday Attention for Children, and Wechsler Quicktest. RESULTS: Patients with BTs had significantly reduced performance compared to controls early post-diagnosis in tests of Performance IQ, processing speed, verbal and visual memory, and selective attention. Improved performance over 12 months was seen in patients with BTs although also, for some measures, in controls. Significant deficits in cognitive performance were seen one year post-diagnosis for Verbal IQ; processing speed, visual and verbal immediate memory, and selective attention. Infratentorial site, high tumor grade, hydrocephalus, radiotherapy, and chemotherapy were associated with poorer functioning. CONCLUSION: Early cognitive impairment is present in BT children, sometimes prior to radiotherapy/chemotherapy treatment, and is associated with hydrocephalus, high tumor grade and infratentorial site. Future studies should investigate the role of early rehabilitation in improving cognition.

A detailed prospective longitudinal assessment of health status in children with brain tumors in the first year after diagnosis.

PURPOSE: To compare health status (HS) in children with brain tumors at 1 (t1), 6 (t6), and 12 (t12) months after diagnosis with "normal" controls. To assess the relationship between parent-report and self-report HS for patients at t12. METHODS: HS was assessed using the Health Utilities Index Mark III parent-report at all time points and self-report at t12. Twenty-nine patients and 32 controls were included in analysis of parent-report, and 21 patients and 22 controls in self-report HS at t12. Nonparametric analyses were used. RESULTS: Patients scored significantly lower than controls for global overall HS at all time points for parent-report and at t12 for self-report (Pmax=0.009). For parent-report, patients scored significantly lower than controls in the attributes of emotion, cognition, and pain at t1 and t6, in ambulation at t1 and in dexterity at t6. At t12, the difference was statistically significant for parent-report cognition only (all P<0.01). No attributes reached significance for self-report at t12. For patients, correlations between parent-report and self-report were good (rs>0.73) for all Health Utilities Index Mark 3 scores with the exception of emotion and pain. CONCLUSION: HS is significantly compromised in children with brain tumors over the first year after diagnosis, but improves with time. Parent-report and self-report differ, and both should be considered in assessing outcomes or defining interventions.

Child-related determinants of health-related quality of life in children with brain tumours 1 year after diagnosis.

OBJECTIVES: Infratentorial tumour site and health-related quality of life (HRQL) 1 month after diagnosis have been shown to predict HRQL 1 year after diagnosis in children with brain tumours. This study aimed to identify additional early child-related determinants of parent- and child-report HRQL. METHODS: Longitudinal prospective study. Semi-structured interviews took place approximately 1 and 12 months after diagnosis. HRQL was measured using the self- and parent-report Pediatric Quality of Life Scales (PedsQL 4.0) Total Scale Score and Health Utilities Index Mark 3 (HUI3) multi-attribute utility function. Child variables included performance and verbal IQ, general memory, selective attention executive function, behaviour problems, adaptive behaviour, symptoms of depression and anxiety and event related anxiety. Univariate analyses were used to identify potential early predictors of HRQL. Regression analysis was then used to identify the most important determinants of HRQL at 1 year. RESULTS: Thirty-five patients completed the 12-month interviews. Multivariate analysis showed infratentorial tumour site remained an important determinant of HRQL 1 year after diagnosis. Infratentorial tumour site and selective attention at 1 month generally best predicted poor self- and parent-report HRQL at 12 months. Adaptive behaviour and performance IQ may be important. CONCLUSION: Selective attention and infratentorial tumour site are most important in predicting both parent- and self-report HRQL at 1 year after diagnosis. Larger prospective studies are needed to confirm these findings. Cognitive remediation or/and pharmacological intervention, particularly aimed at children with infratentorial tumours may improve attention and subsequently HRQL and both merit further investigation.

Family, demographic and illness-related determinants of HRQL in children with brain tumours in the first year after diagnosis.

AIMS: To evaluate the relationship between parent- and child-report Health-Related Quality of Life (HRQL) and demographic, tumour and family variables in children with a brain tumour in the first year after diagnosis and to identify determinants of HRQL at 12 months. PROCEDURE: Longitudinal prospective study: Semi-structured interviews took place approximately 1, 6 and 12 months after diagnosis. HRQL was measured using the self- and parent-report PedsQL 4.0 Total Scale Score. Tumour and treatment variables considered included tumour site and grade, hydrocephalus at diagnosis, chemotherapy and radiotherapy. Family variables included measures of family function, family support and family stress, the primary carer's coping strategies and symptoms of depression and anxiety. Univariate analyses were used at all three time points, and to identify potential early predictors of HRQL at 1 year. Regression analysis was then used to identify the most important determinants of HRQL at 1 year. RESULTS: Thirty-five patients completed the 12-month interviews. There were consistent significant negative correlations between concurrent family impact of illness and parent and self-report HRQL, and positive correlations between concurrent family support and parent-report HRQL. Treatment with radio- or chemotherapy correlated with child-report HRQL only at some time points. Multivariate analysis showed infratentorial tumour site, and poor HRQL at 1 month best predicted poor self- and parent-report HRQL at 12 months. CONCLUSION: Children with infratentorial tumours and poor HRQL early after diagnosis tend to have poor HRQL at 1 year. While family factors are important modulators of concurrent HRQL, they do not appear important in predicting HRQL.

Health related quality of life in the first year after diagnosis in children with brain tumours compared with matched healthy controls; a prospective longitudinal study.

This paper compares parent- and self-report health-related quality of life (HRQL) in children aged 2-16 years with brain tumours, one, six and twelve months after diagnosis with matched normal controls. HRQL was assessed using the PedsQL generic core scales. 37 tumour patients and 42 controls were included in analysis of parent-report, and 27 patients and 31 controls in self-report HRQL. Parent-report scores were significantly lower in patients than controls for all PedsQL scores at all time points (max p=0.002). Differences in self-report PedsQL between patients and controls were variable. The relationship between self- and parent-report in patients and controls was inconsistent; varied over time; and did not consistently correlate with parental depressive symptoms, suggesting parents and their children do not regard HRQL in a similar way. Prospective, longitudinal assessment of HRQL is important, but should be supplemented with other outcome measures such as health status and behaviour in this population.

Atypical external hydrocephalus with visual failure due to occult leptomeningeal dissemination of a pontine glioma. Case report.

The authors report on the case of a diffuse pontine glioma in a 5-year-old boy in whom radiologically and cytologically occult leptomeningeal metastases led to the development of an atypical "external" hydrocephalus, associated with grossly elevated intracranial pressure (ICP). Initial neuroimaging demonstrated only mild communicating ventricular dilation associated with a noticeable enlargement of the subarachnoid space, particularly over the surface of the frontal lobes; these features are not usually associated with significantly elevated ICP. Possible pathophysiological mechanisms resulting in this unusual clinical presentation are discussed. Early recognition of the severity of the raised ICP despite the paucity of clinical and radiological signs may have averted the development of blindness due to optic atrophy.