Stephen P. Lowis

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.

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

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.

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

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.

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

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.

Highlights from the Third International Central Nervous System Germ Cell Tumour symposium: laying the foundations for future consensus.

The Third International Central Nervous System (CNS) Germ Cell Tumour (GCT) Symposium brought together over 100 delegates from all over the world to learn about the latest developments in these tumours and discuss future strategies for their management. Some areas of consensus were agreed upon, and controversies were discussed. Among these, the classification of GCTs and the surgical approach to their management were among the greatest areas of difference between different parts of the world. The need for radiotherapy (RT) as a part of standard first-line management for all malignant CNS GCTs was agreed, as well as the need for additional chemotherapy to maximise the cure in nongerminomatous malignant GCTs; the benefit of the addition of chemotherapy in localised germinoma to reduce the RT burden was also accepted as a good practice. The potential of biological parameters to assist the future diagnosis, treatment stratification, and disease monitoring for CNS GCTs was discussed. Such biological parameters may also represent targets for the development of novel therapies. The need for further collaboration between groups engaged in biological studies was agreed. The merits of proton beam RT were debated, and the importance of mitigating the long-term side effects of the treatment was underlined by a session on late effects.

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.

BRAF Fusion Analysis in Pilocytic Astrocytomas: KIAA1549-BRAF 15-9 Fusions Are More Frequent in the Midline Than Within the Cerebellum.

Abstract Pilocytic astrocytomas (PAs) are increasingly tested for KIAA1549-BRAF fusions. We used reverse transcription polymerase chain reaction for the 3 most common KIAA1549-BRAF fusions, together with BRAF V600E and histone H3.3 K27M analyses to identify relationships of these molecular characteristics with clinical features in a cohort of 32 PA patients. In this group, the overall BRAF fusion detection rate was 24 (75%). Ten (42%) of the 24 had the 16-9 fusion, 8 (33%) had only the 15-9 fusion, and 1 (4%) of the patients had only the 16-11 fusion. In the PAs with only the 15-9 fusion, 1 PA was in the cerebellum and 7 were centered in the midline outside of the cerebellum, that is, in the hypothalamus (n = 4), optic pathways (n = 2), and brainstem (n = 1). Tumors within the cerebellum were negatively associated with fusion 15-9. Seven (22%) of the 32 patients had tumor-related deaths and 25 of the patients (78%) were alive between 2 and 14 years after initial biopsy. Age, sex, tumor location, 16-9 fusion, and 15-9 fusion were not associated with overall survival. Thus, in this small cohort, 15-9 KIAA1549-BRAF fusion was associated with midline PAs located outside of the cerebellum; these tumors, which are generally difficult to resect, are prone to recurrence.

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.

Proton beam therapy for medulloblastoma

It is heartening to read a report of good functional outcomes following proton beam therapy in young patients with medulloblastoma, including the absence of many unpleasant side eff ects that can occur after conventional photon therapy. The authors quote UK research, which criticises the current proton therapy treatment policy of dividing the x-ray (photon) equivalent dose by 1·1. This is done in order to compensate for the enhanced eff ectiveness of proton therapy caused by the greater proximity of ionisation in proton beam therapy compared with photons. Radiobiological modelling studies, based on the high radiosensitivity of medulloblastoma cells, suggest a lower necessary dose reduction of 1·03–1·08 in order to maintain the same tumour control eff ect. A dose division by 1·1, compared with, for example, 1·05 (if correct), would incur a 4% overall change in eff ective dose, which could translate into a 4–8% reduction in tumour control. The number of patients required to detect such a change would be much larger than the 59 patients included in the study by Yock and colleagues, however: a minimum of several hundred and perhaps over a thousand patients might be necessary. This statistical power requirement indicates the need for national and international cooperation in the conduct and analysis of such rare treatments. The reported maintenance of cognitive function is important. With a predicted dose reduction for neural tissues of 1·2 or more, rather than the 1·1 used in practice, this outcome implies a suffi cient reserve of cortical neural radiation tolerance compared with the dose required for tumour control. The brainstem necrosis in one child is likely to be caused by a combination of the lower radiation tolerance of brainstem than cortical brain, enhanced ionisation density eff ects, previous surgery, and the chemotherapy regimen used. Another important factor is that the meticulous treatments in Boston are given to children who may not only be fi tter to travel, but are also from wealthier backgrounds, with better outcomes than those of less privileged children without such access to excellent care.

Early morning headache with vomiting in a 5 year old boy

A 5½ year old boy presented with a 10 day history of progressively worsening early morning headache, with vomiting and subsequent development of slurred speech. Before this presentation his development had been normal, with no delay in developmental milestones or abnormality in vision. He was referred to the emergency department for an urgent magnetic resonance imaging (MRI) scan, which showed a tumour arising from the fourth ventricle with a maximum dimension of 3 cm. There was slight dilation of the fourth ventricle, but no hydrocephalus or obvious disease in the spine or leptomeninges. He underwent craniotomy and gross total excision of the mass. Cytological examination of the cerebrospinal fluid showed no malignant cells. Histological examination of the tumour showed that it was a medulloblastoma, with large pale nuclei (high nuclear to cytoplasmic ratio), cell-cell wrapping, and a high mitotic rate. There were several foci of apoptosis but no sheets of necrosis. Molecular analysis of the tumour showed that the c-Myc and N-Myc genes were amplified. Chemotherapy was started in accordance with Children Cancer and Leukaemia Group guidelines. This involves high dose intensity chemotherapy followed by craniospinal hyperfractionated accelerated radiotherapy. ### 1 What is the differential diagnosis for his initial presenting symptoms of early morning headache with vomiting? #### Short answer Although relatively short, the history of early morning vomiting and slurred speech suggests a neurological cause. Differential diagnoses include raised intracranial pressure, migraine, and viral meningitis. Lack of meningism or signs of sepsis suggest that raised intracranial pressure is the most likely cause. #### Long answer A 10 day history of early morning …