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Tumours of the central nervous system (CNS) represent the most common group of solid tumours in children and adolescents up to the age of 18 years. They comprise several biological entities, subgroups, and subtypes. These subtypes and additional factors, including age at diagnosis, location, stage, or genetic characteristics of the tumours result in a very heterogeneous spectrum of treatment-relevant strata for risk-adapted multimodal treatment recommendations, clinical courses, and long-term outcomes. Multidisciplinary teams with highly experienced members are needed to treat these children and adolescents to achieve the best possible outcome in the short and long-term. This is particularly important for the new CNS tumour entities with no established standard of care. On behalf of the Brain Tumour Group of the European Society for Paediatric Oncology, we summarize the key statements of the involved disciplines that need to cooperate in the diagnosis and risk-adapted treatment of children with CNS tumours: neuroradiology, neurosurgery, neuropathology, radiotherapy, endocrinology, neuro-ophthalmology, and quality of survival professionals, covering what should be considered standard clinical practice for diagnostic assessments, treatment modalities, and follow-up of children with CNS-tumours.

Central nervous system germ cell tumours (CNS GCT) form a diverse group of tumour entities, including germinoma, yolk sac tumour, embryonal carcinoma, choriocarcinoma, teratoma, and mixed tumours. Incidence peaks in the second decade, predominantly in males. Incidence rates vary globally, higher in Asia, suggesting genetic factors are important. CNS GCTs split into pure germinomas and non-germinomatous GCTs (NGGCT), influencing prognosis/treatment. Serum and CSF markers (alpha-fetoprotein, human chorionic gonadotropin) aid diagnosis, potentially avoiding neurosurgical biopsy. Histological features are distinguished by immunohistochemical staining. Studies have identified specific microRNAs in serum/CSF at diagnosis as promising biomarkers. Mutated pathways have been identified, but targeted therapies have shown limited success to date. Diagnosis involves recognising symptoms like raised intracranial pressure, endocrinological, and ophthalmological disturbances. MRI imaging is crucial for diagnosis and guiding treatment decisions. Treatment strategies vary, as pure germinomas respond well to chemotherapy and radiotherapy, or craniospinal radiotherapy alone, with excellent outcomes; in contrast NGGCTs demand aggressive combined chemo-radiotherapy, yielding generally inferior outcomes. Teratomas are typically chemo-/radio-resistant, requiring surgical intervention. Relapses need re-staging and (re-)biopsy consideration. Relapsed germinomas, though rare, may be cured with standard-dose chemotherapy and re-irradiation, or high-dose chemotherapy with stem-cell-transplantation, with/without further radiation. The more commonly observed NGGCT relapses have poor prognosis, even with thiotepa-based high-dose chemotherapy and stem-cell-transplantation delivered with curative intent. In summary, CNS GCT management integrates clinical, radiological, and histological findings, along with serum and CSF markers, for tailored treatment. Ongoing research aims to incorporate microRNA markers and molecular pathology for improved diagnosis, prognostication, and therapeutic intervention.

Summary: Background: The malignant childhood brain tumour, medulloblastoma, is classified clinically into molecular groups which guide therapy. DNA-methylation profiling is the current classification ‘gold-standard’, typically delivered 3–4 weeks post-surgery. Pre-surgery non-invasive diagnostics thus offer significant potential to improve early diagnosis and clinical management. Here, we determine tumour metabolite profiles of the four medulloblastoma groups, assess their diagnostic utility using tumour tissue and potential for non-invasive diagnosis using in vivo magnetic resonance spectroscopy (MRS). Methods: Metabolite profiles were acquired by high-resolution magic-angle spinning NMR spectroscopy (MAS) from 86 medulloblastomas (from 59 male and 27 female patients), previously classified by DNA-methylation array (WNT (n = 9), SHH (n = 22), Group3 (n = 21), Group4 (n = 34)); RNA-seq data was available for sixty. Unsupervised class-discovery was performed and a support vector machine (SVM) constructed to assess diagnostic performance. The SVM classifier was adapted to use only metabolites (n = 10) routinely quantified from in vivo MRS data, and re-tested. Glutamate was assessed as a predictor of overall survival. Findings: Group-specific metabolite profiles were identified; tumours clustered with good concordance to their reference molecular group (93%). GABA was only detected in WNT, taurine was low in SHH and lipids were high in Group3. The tissue-based metabolite SVM classifier had a cross-validated accuracy of 89% (100% for WNT) and, adapted to use metabolites routinely quantified in vivo, gave a combined classification accuracy of 90% for SHH, Group3 and Group4. Glutamate predicted survival after incorporating known risk-factors (HR = 3.39, 95% CI 1.4–8.1, p = 0.025). Interpretation: Tissue metabolite profiles characterise medulloblastoma molecular groups. Their combination with machine learning can aid rapid diagnosis from tissue and potentially in vivo. Specific metabolites provide important information; GABA identifying WNT and glutamate conferring poor prognosis. Funding: Children with Cancer UK, Cancer Research UK, Children’s Cancer North and a Newcastle University PhD studentship.

Introduction: Chemotherapy-induced nausea and vomiting (CINV) are common adverse drug reactions (ADR) experienced by children undergoing treatment for cancer. New paediatric ADR Assessment Causality and Avoidability tools (LCAT and LAAT) of Liverpool are suitable for categorizing factors related to ADR prevention and improving patient care. Still, no studies to date have compared the utility and results of its application for CINV in countries with different levels of development. Objective: To investigate the utility of the Liverpool Adverse Drug Reaction Causality and Avoidability Assessment Tools (LCAT and LAAT) in assessing CINV in children. Method: Prospective observational study of CINV assessment in children aged 4 to 16 years from Alder Hey Children’s Hospital (Liverpool, UK) and “Instituto de Puericultura e Pediatria Martagão Gesteira” (Rio de Janeiro, Brazil). Children (helped by the parents) completed a symptom diary during chemotherapy and for 24 hours after treatment. Information regarding underlying diagnosis, past medical history, and medications administered was collected from the patient record. Case reports were prepared, and the temporal relationship between nausea and vomiting and exposure to chemotherapy, including any strategy to prevent CINV, was recorded. The causality and avoidability were assessed with LCAT and LAAT, respectively. Results: There were 26 reports of CINV in 36 chemotherapy cycles. The causality assessment was ‘definite’ for 24 cases. Twenty ADRs were deemed ‘definitely avoidable’ and four ‘not avoidable’. Selection of inappropriate therapeutic options and non-administration of antiemetic were the most common factors observed in the hospitals studied. Conclusion: The LCAT and LAAT were helpful for assessing CINV in children in two different hospitals.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value

Abstract Brain tumors represent the highest cause of mortality in the pediatric oncological population. Diagnosis is commonly performed with magnetic resonance imaging. Survival biomarkers are challenging to identify due to the relatively low numbers of individual tumor types. 69 children with biopsy-confirmed brain tumors were recruited into this study. All participants had perfusion and diffusion weighted imaging performed at diagnosis. Imaging data were processed using conventional methods, and a Bayesian survival analysis performed. Unsupervised and supervised machine learning were performed with the survival features, to determine novel sub-groups related to survival. Sub-group analysis was undertaken to understand differences in imaging features. Survival analysis showed that a combination of diffusion and perfusion imaging were able to determine two novel sub-groups of brain tumors with different survival characteristics (p

Post-operative cerebellar mutism syndrome (CMS), also known as posterior fossa syndrome (PFS), is a well-recognized and frequent complication of surgery for posterior fossa tumours in children and young people. Its incidence varies between 8 and 31%, and the pathophysiological mechanisms of delayed onset and resolution of cerebellar mutism are not clear, but axonal damage, oedema, and perfusion defects may be involved. Magnetic resonance imaging has failed to reveal a universal anatomical substrate or a single definite mechanism of injury. We present a case of 16-year-old boy who developed CMS three days after resection of a medulloblastoma, a primary fourth ventricular tumour. Early post-operative imaging showed bleeding in the posterior fossa which required evacuation. CT angiography seven days after surgery demonstrated basilar artery vasospasm. Magnetic resonance brain angiography confirmed persistent narrowing of a segment of the basilar artery closely related to a left cerebellopontine (CP) angle peri-operative haematoma. The patient was treated with nimodipine and hypervolemia. The patient started vocalisation without speech five days later with reversal of radiological lesions. Further recovery of post-operative neurological deficits occurred over a protracted period of several months. This case represents a rare cause of post-operative CMS, with rapid initial recovery that occurred after specific treatment directed at the cause. To our knowledge, this is the first reported case showing mutism associated with basilar artery vasospasm with imaging evidence. This case may suggest the need to undertake urgent vascular imaging in selected cases of post-operative CMS.

Glioblastoma, a grade IV astrocytoma, has a poor survival rate in part due to ineffective treatment options available. These tumours are heterogeneous with areas of low oxygen levels, termed hypoxic regions. Many intra-cellular signalling pathways, including DNA repair, can be altered by hypoxia. Since DNA damage induction and subsequent activation of DNA repair mechanisms is the cornerstone of glioblastoma treatment, alterations to DNA repair mechanisms could have a direct influence on treatment success. Our aim was to elucidate the impact of chronic hypoxia on DNA repair gene expression in a range of glioblastoma cell lines. We adopted a NanoString transcriptomic approach to examine the expression of 180 DNA repair-related genes in four classical glioblastoma cell lines (U87-MG, U251-MG, D566-MG, T98G) exposed to 5 days of normoxia (21% O2), moderate (1% O2) or severe (0.1% O2) hypoxia. We observed altered gene expression in several DNA repair pathways including homologous recombination repair, non-homologous end-joining and mismatch repair, with hypoxia primarily resulting in downregulation of gene expression. The extent of gene expression changes was dependent on hypoxic severity. Some, but not all, of these downregulations were directly under the control of HIF activity. For example, the downregulation of LIG4, a key component of non-homologous end-joining, was reversed upon inhibition of the hypoxia-inducible factor (HIF). In contrast, the downregulation of the mismatch repair gene, PMS2, was not affected by HIF inhibition. This suggests that numerous molecular mechanisms lead to hypoxia-induced reprogramming of the transcriptional landscape of DNA repair. Whilst the global impact of hypoxia on DNA repair gene expression is likely to lead to genomic instability, tumorigenesis and reduced sensitivity to anti-cancer treatment, treatment re-sensitising might require additional approaches to a simple HIF inhibition.

Abstract Background Solid tumours are less oxygenated than normal tissues. This is called tumour hypoxia and leads to resistance to radiotherapy and chemotherapy. The molecular mechanisms underlying such resistance have been investigated in a range of tumour types, including the adult brain tumours glioblastoma, yet little is known for paediatric brain tumours. Medulloblastoma (MB) is the most common malignant brain tumour in children. We aimed to elucidate the impact of hypoxia on the sensitivity of MB cells to chemo- and radiotherapy. Methods We used two MB cell line (D283-MED and MEB-Med8A) and a widely used glioblastoma cell line (U87MG) for comparison. We applied a range of molecular and cellular techniques to measure cell survival, cell cycle progression, protein expression and DNA damage combined with a transcriptomic micro-array approach in D283-MED cells, for global gene expression analysis in acute and chronic hypoxic conditions. Results In D283-MED and U87MG, chronic hypoxia (5 days), but not acute hypoxia (24 h) induced resistance to chemotherapy and X-ray irradiation. This acquired resistance upon chronic hypoxia was present but less pronounced in MEB-Med8A cells. Using transcriptomic analysis in D283-MED cells, we found a large transcriptional remodelling upon long term hypoxia, in particular the expression of a number of genes involved in detection and repair of double strand breaks (DSB) was altered. The levels of Nibrin (NBN) and MRE11, members of the MRN complex (MRE11/Rad50/NBN) responsible for DSB recognition, were significantly down-regulated. This was associated with a reduction of Ataxia Telangiectasia Mutated (ATM) activation by etoposide, indicating a profound dampening of the DNA damage signalling in hypoxic conditions. As a consequence, p53 activation by etoposide was reduced, and cell survival enhanced. Whilst U87MG shared the same dampened p53 activity, upon chemotherapeutic drug treatment in chronic hypoxic conditions, these cells used a different mechanism, independent of the DNA damage pathway. Conclusion Together our results demonstrate a new mechanism explaining hypoxia-induced resistance involving the alteration of the response to DSB in D283-MED cells, but also highlight the cell type to cell type diversity and the necessity to take into account the differing tumour genetic make-up when considering re-sensitisation therapeutic protocols.

The imaging and subsequent accurate diagnosis of paediatric brain tumours presents a radiological challenge, with magnetic resonance imaging playing a key role in providing tumour specific imaging information. Diffusion weighted and perfusion imaging are commonly used to aid the non-invasive diagnosis of children's brain tumours, but are usually evaluated by expert qualitative review. Quantitative studies are mainly single centre and single modality.The aim of this work was to combine multi-centre diffusion and perfusion imaging, with machine learning, to develop machine learning based classifiers to discriminate between three common paediatric tumour types.The results show that diffusion and perfusion weighted imaging of both the tumour and whole brain provide significant features which differ between tumour types, and that combining these features gives the optimal machine learning classifier with >80% predictive precision. This work represents a step forward to aid in the non-invasive diagnosis of paediatric brain tumours, using advanced clinical imaging. Keywords: Perfusion, Diffusion, Machine learning

Chemotherapeutic drug resistance and relapse remains a major challenge for paediatric (medulloblastoma) and adult (glioblastoma) brain tumour treatment. Medulloblastoma tumours and cell lines with mutations in the p53 signalling pathway have been shown to be specifically insensitive to DNA damaging agents. The aim of this study was to investigate the potential of triggering cell death in p53 mutated medulloblastoma cells by a direct activation of pro-death signalling downstream of p53 activation. Since non-coding microRNAs (miRNAs) have the ability to fine tune the expression of a variety of target genes, orchestrating multiple downstream effects, we hypothesised that triggering the expression of a p53 target miRNA could induce cell death in chemo-resistant cells. Treatment with etoposide, increased miR-34a levels in a p53-dependent fashion and the level of miR-34a transcription was correlated with the cell sensitivity to etoposide. miR-34a activity was validated by measuring the expression levels of one of its well described target: the NADH dependent sirtuin1 (SIRT1). Whilst drugs directly targeting SIRT1, were potent to trigger cell death at high concentrations only, introduction of synthetic miR-34a mimics was able to induce cell death in p53 mutated medulloblastoma and glioblastoma cell lines. Our results show that the need of a functional p53 signaling pathway can be bypassed by direct activation of miR-34a in brain tumour cells.

Purpose. To correlate the radiological aspects of metastases, the response to chemotherapy, and patient outcome in disseminated childhood medulloblastoma. Patients and Methods. This population-based study concerned 117 newly diagnosed children with disseminated medulloblastoma treated at the Institute Gustave Roussy between 1988 and 2008. Metastatic disease was assessed using the Chang staging system, their form (positive cerebrospinal fluid (CSF), nodular or laminar), and their extension (positive cerebrospinal fluid, local, extensive). All patients received preirradiation chemotherapy. Results. The overall survival did not differ according to Chang M-stage. The 5-year overall survival was 59% in patients with nodular metastases compared to 35% in those with laminar metastases. The 5-year overall survival was 76% in patients without disease at the end of pre-irradiation chemotherapy compared to 34% in those without a complete response (P=0.0008). Conclusions. Radiological characteristics of metastases correlated with survival in patients with medulloblastoma. Complete response to sandwich chemotherapy was a strong predictor of survival.

Screening for coeliac disease is recommended for children from certain risk groups, with implications for diagnostic procedures and dietetic management. The risk of a malignant complication in untreated coeliac disease is not considered high in children. We present the case of a girl with type I diabetes who developed weight loss, fatigue, and inguinal lymphadenopathy. Four years before, when she was asymptomatic, a screening coeliac tTG test was positive, but gluten was not eliminated from her diet. Based on clinical examination, a duodenal biopsy, and an inguinal lymph node biopsy were performed, which confirmed both coeliac disease and an anaplastic large-cell lymphoma. HLA-typing demonstrated that she was homozygous for HLA-DQ8, which is associated with higher risk for celiac disease, more severe gluten sensitivity, and diabetes susceptibility. She responded well to chemotherapy and has been in remission for over 4 years. She remains on a gluten-free diet. This is the first case reporting the association of coeliac disease, type I diabetes, and anaplastic large-cell lymphoma in childhood. The case highlights the malignancy risk in a genetically predisposed individual, and the possible role of a perpetuated immunologic response by prolonged gluten exposure.

Cancer in children is one of the emerging noncommunicable diseases in Nepal with significant morbidity and mortality. Significant efforts are being made at the government and nongovernment level to provide awareness, early diagnosis, and effective treatment to improve the cure rate of children with cancer. The major challenges include: lack of education, late diagnosis, advanced disease at presentation, financial problems, geographical and transportation difficulties, and inconsistent supply of chemotherapy medicines.

Abstract Introduction  A rare case of a large jugular foramen tumour presenting as a posterior fossa mass is described. Materials and methods  The patient, a 13-year-old boy presented with symptoms of raised intracranial pressure and on MRI imaging demonstrated the tumour origin within the jugular foramen, with appearances suggestive of schwannoma. He underwent a complete excision as a single-stage procedure thorough a lateral suboccipital craniotomy with minimal morbidity. Histology confirmed the diagnosis of schwannoma (WHO I). Jugular foramen schwannoma is virtually unheard of in the paediatric population. Conclusion  The differential diagnosis of a jugular foramen tumour includes tumours of the glomus jugulare, meningiomas, schwannomas, myxomas and chondrosarcomas. The imaging characteristics are important when considering this differential diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Background  Herpes simplex virus (HSV) encephalitis is a rare association with pediatric neurosurgical pathologies. Case report  A 13-year-old boy was diagnosed with an inoperable, biopsy-proven pontine grade II astrocytoma. During radiotherapy, he developed status epilepticus controlled by thiopentone with intubation and ventilation. Empiric cefotaxime and aciclovir were given. Lumbar cerebrospinal fluid (CSF) showed a normal white cell count, normal glucose, and a slightly elevated protein level. However, the CSF showed a positive polymerase chain reaction (PCR) for HSV type 1 DNA. Intravenous aciclovir was given for 21 days and foscarnet for 7 days. He was extubated after 4 weeks at which time he was aphasic with spastic diplegia. After 8 weeks, MRI brain scan showed the typical bitemporal pattern of HSV encephalitis. He made slow improvement but died 8 months after diagnosis from tumor progression. Conclusion  HSV encephalitis is a rare but life threatening complication in neurosurgical patients. A low threshold for both investigation with CSF PCR and empirical treatment with intravenous aciclovir is warranted. As in this case, initial microscopic examination of the CSF may be normal. The literature on HSV encephalitis in neurosurgical patients is discussed. [ABSTRACT FROM AUTHOR]

Abstract