Incidence of childhood CNS tumours in Britain and variation in rates by definition of malignant behaviour: population-based study.

BACKGROUND: Intracranial and intraspinal tumours are the most numerous solid tumours in children. Some recently defined subtypes are relatively frequent in childhood. Many cancer registries routinely ascertain CNS tumours of all behaviours, while others only cover malignant neoplasms. Some behaviour codes have changed between revisions of the International Classification of Diseases for Oncology, including pilocytic astrocytoma, downgraded to uncertain behaviour in ICD-O-3. METHODS: We used data from the population-based National Registry of Childhood Tumours, which routinely included non-malignant CNS tumours, to document the occurrence of CNS tumours among children aged < 15 years in Great Britain during 2001-2010 and to document the descriptive epidemiology of childhood CNS tumours over the 40-year period 1971-2010, during which several new entities were accommodated in successive editions of the WHO Classification and revisions of ICD-O. Eligible cases were all those with a diagnosis included in Groups III (CNS tumours) and Xa (CNS germ-cell tumours) of the International Classification of Childhood Cancer, Third Edition. The population at risk was derived from annual mid-year estimates by sex and single year of age compiled by the Office for National Statistics and its predecessors. Incidence rates were calculated for age groups 0, 1-4, 5-9 and 10-14 years, and age-standardised rates were calculated using the weights of the world standard population. RESULTS: Age-standardised incidence in 2001-10 was 40.1 per million. Astrocytomas accounted for 41%, embryonal tumours for 17%, other gliomas for 10%, ependymomas for 7%, rarer subtypes for 20% and unspecified tumours for 5%. Incidence of tumours classified as malignant and non-malignant by ICD-O-3 increased by 30 and 137% respectively between 1971-75 and 2006-10. CONCLUSIONS: Total incidence was similar to that in other large western countries. Deficits of some, predominantly low-grade, tumours or differences in their age distribution compared with the United States and Nordic countries are compatible with delayed diagnosis. Complete registration regardless of tumour behaviour is essential for assessing burden of disease and changes over time. This is particularly important for pilocytic astrocytoma, because of its recent downgrading to non-malignant and time trends in the proportion of astrocytomas with specified subtype

Motor seizures confer overall survival benefit in who grade 2 glioma

Objective: The prevalence of epilepsy in World Health Organization (WHO) grade 2 glioma is high, with seizures being the presenting symptom in 60%–90%. We explore the epidemiology of seizures in this patient population in a regional neurosurgical center. Methods: Electronic health records of patients with histologically-proven WHO grade 2 glioma (n = 228) were reviewed between 1997 and 2021, with data collected including patient demographics, epilepsy prevalence, and seizure semiology. The influence of seizure type on overall survival was calculated using a Cox proportional hazards model. Results: Overall, 197 of 228 patients (86.4%) were diagnosed with epilepsy—either at presentation or during the course of their disease. Male patients were more likely than female patients to be diagnosed with epilepsy (91.1% vs 77.1%, p =.003) and, in those with epilepsy, more likely to experience at least one focal to bilateral tonic–clonic seizure (69.4% vs 54.1%, p =.05). Patients with left-sided tumors were twice as likely to have experienced a focal to bilateral tonic–clonic seizure (p =.02, odds ratio [OR] =.47). Predominantly experiencing seizures with motor activity appeared to confer better overall survival, with a 65% decrease in the risk of death 10 years post diagnosis (hazard ratio [HR] =.35, p =.02). This is despite accounting for previously described prognostic markers including tumor histology/genetics, time from diagnosis to surgery, and the extent of tumor resection. Significance: Motor seizure activity is a frequent feature in WHO grade 2 glioma and appears to confer a survival benefit regardless of histology or surgical factors. Seizures due to dominant hemisphere tumors may be more likely to propagate and cause bilateral tonic–clonic activity

Neuropsychological outcomes following paediatric temporal lobe surgery for epilepsies: Evidence from a systematic review

Objective: The systematic review aimed to assess the neuropsychological outcomes of temporal lobe resections for epilepsy in children. Additional objectives included determining whether earlier age at surgery leads to better neuropsychological outcomes; the relationships between and predictors of these outcomes. Methods: Using advanced search terms, a systematic review of electronic databases was conducted, comprising MEDLINE, Embase, PsycINFO, Global Health, Web of Science and CINAHL. Included studies reported on outcome following neurosurgical treatment for epilepsy. Specifically, studies were included if they reported neuropsychological outcomes and were concerned only with temporal lobe resection. Results: 73 studies met inclusion criteria. For reported neuropsychological outcomes, the majority of participants remained stable after surgery; some declined and some improved. There was some evidence for increased material-specific memory deficits after temporal lobe surgery based on resection side, and more positive cognitive outcome for those with lower pre-surgical ability level. Significance: Retrieved evidence highlights the need for improvements to quality of methodology and reporting. Appropriately designed prospective multicentre trials should be conducted with adequate follow-up for long-term outcomes to be measured. Core outcome measures should be agreed between centres. This would permit higher quality evidence so that clinicians, young people and their families may make better informed decisions about whether or not to proceed with surgery and likely post-operative profile

Demographics, presentation and clinical outcomes after traumatic bifrontal contusions: a systematic review

Traumatic bifrontal contusions (TBC) form a recognised clinical entity among patients with traumatic brain injury (TBI). This study aims to systematically review current literature on demographics, management, and predictors of outcomes of patients with TBC. A multi-database literature search (PubMed, Cochrane, OVID Medline/Embase) was performed using PRISMA as a search strategy. Studies were selected by predefined selection criteria (PROSPERO: CRD42018055390), and risk of bias was assessed using an adapted form of ROBINS-I tool. Of the 275 studies yielded by the literature search, seven articles met the criteria for inclusion, all of which were level III evidence. Total cohort consisted of 468 patients; predominantly male (n = 5; 303/417 patients) with average age 44.3 years (range, 7–81). Falls (44.9%) and road traffic accidents (46.6%) were the commonest mechanisms of injury with an average presentation GCS of 9.2 (n = 3, 119 patients). GCS on admission of ≤ 13.1 and contusion volume at day 2 post-injury of ≥ 62.9cm3 were associated with increased risk of deterioration needing surgical interventions (n = 1, 7 patients). The majority of patients underwent surgery; the average GOS was 4, at an average follow-up duration of 11.7 months (n = 6, 356 patients). The currently available evidence on the management of TBC is scarce. Larger multicentre well-designed studies are needed to further delineate the factors behind acute deterioration, the effectiveness of management options. Once in place, this can be used to develop and test an algorithmic approach to management of TBC resulting in consistently improved outcomes

Do animal models of brain tumors replicate human peritumoral edema? a systematic literature search

Introduction Brain tumors cause morbidity and mortality in part through peritumoral brain edema. The current main treatment for peritumoral brain edema are corticosteroids. Due to the increased recognition of their side-effect profile, there is growing interest in finding alternatives to steroids but there is little formal study of animal models of peritumoral brain edema. This study aims to summarize the available literature. Methods A systematic search was undertaken of 5 literature databases (Medline, Embase, CINAHL, PubMed and the Cochrane Library). The generic strategy was to search for various terms associated with “brain tumors”, “brain edema” and “animal models”. Results We identified 603 reports, of which 112 were identified as relevant for full text analysis that studied 114 peritumoral brain edema animal models. We found significant heterogeneity in the species and strain of tumor-bearing animals, tumor implantation method and edema assessment. Most models did not produce appreciable brain edema and did not test for observable manifestations thereof. Conclusion No animal model currently exists that enable the investigation of novel candidates for the treatment of peritumoral brain edema. With current interest in alternative treatments for peritumoral brain edema, there is an unmet need for clinically relevant animal models

Investigations on a clinically and functionally unusual and novel germline p53 mutation

This report describes an individual with a rare choroid plexus papilloma in adulthood (age 29) after earlier having an osteosarcoma (age 22). The results from this study, and others, suggest that it may be advisable to consider the possibility of a germline p53 mutation in adults presenting with choroid plexus tumours. In the current study automated DNA sequencing of genomic DNA detected a novel germline 7 base pair insertion in exon 5 of the p53 gene in this patient. The alteration in frame would produce amino acid substitutions beginning with alanine to glycine at position 161 and a stop codon at position 182 in the mutated protein. Surprisingly two assays of p53 function gave apparently wild-type results on peripheral blood lymphocytes from this individual. These results led us to carry out more detailed functional tests on the mutant protein. The mutant allele was expressed either at very low levels or not at all in phytohaemagglutinin stimulated lymphocytes. Further, the mutant protein was completely non-functional in terms of its ability to transactivate a series of p53-responsive genes (p21WAF1, bax, PIG3), to transrepress a target gene and to inhibit colony growth in transfected Saos-2 cells. However, surprisingly, data from irradiated peripheral blood lymphocytes and transfected Saos-2 cells, suggested that this truncated, mutant protein retains significant ability to induce apoptosis

Mechanisms of cerebellar tonsil herniation in patients with Chiari malformations as guide to clinical management

Background The pathogenesis of Chiari malformations is incompletely understood. We tested the hypothesis that different etiologies have different mechanisms of cerebellar tonsil herniation (CTH), as revealed by posterior cranial fossa (PCF) morphology. Methods In 741 patients with Chiari malformation type I (CM-I) and 11 patients with Chiari malformation type II (CM-II), the size of the occipital enchondrium and volume of the PCF (PCFV) were measured on reconstructed 2D-CT and MR images of the skull. Measurements were compared with those in 80 age- and sex-matched healthy control individuals, and the results were correlated with clinical findings. Results Significant reductions of PCF size and volume were present in 388 patients with classical CM-I, 11 patients with CM-II, and five patients with CM-I and craniosynostosis. Occipital bone size and PCFV were normal in 225 patients with CM-I and occipitoatlantoaxial joint instability, 55 patients with CM-I and tethered cord syndrome (TCS), 30 patients with CM-I and intracranial mass lesions, and 28 patients with CM-I and lumboperitoneal shunts. Ten patients had miscellaneous etiologies. The size and area of the foramen magnum were significantly smaller in patients with classical CM-I and CM-I occurring with craniosynostosis and significantly larger in patients with CM-II and CM-I occurring with TCS. Conclusions Important clues concerning the pathogenesis of CTH were provided by morphometric measurements of the PCF. When these assessments were correlated with etiological factors, the following causal mechanisms were suggested: (1) cranial constriction; (2) cranial settling; (3) spinal cord tethering; (4) intracranial hypertension; and (5) intraspinal hypotension

Pre-surgical mapping of eloquent cortex for paediatric epilepsy surgery candidates: Evidence from a review of advanced functional neuroimaging

Purpose: A review of all published evidence for mapping eloquent (motor, language and memory) cortex using advanced functional neuroimaging (functional magnetic resonance imaging [fMRI] and magnetoencephalography [MEG]) for paediatric epilepsy surgery candidates has not been conducted previously. Research in this area has predominantly been in adult populations and applicability of these techniques to paediatric populations is less established. Methods: A review was performed using an advanced systematic search and retrieval of all published papers examining the use of functional neuroimaging for paediatric epilepsy surgery candidates. Results: Of the 2,724 papers retrieved, 34 met the inclusion criteria. Total paediatric participants identified were 353 with an age range of 5 months-19 years. Sample sizes and comparisons with alternative investigations to validate techniques are small and variable paradigms are used. Sensitivity 0.72 (95% CI 0.52-0.86) and specificity 0.60 (95% CI 0.35-0.92) values with a Positive Predictive Value of 74% (95% CI 61-87) and a Negative Predictive Value of 65% (95% CI 52-78) for fMRI language lateralisation with validation, were obtained. Retrieved studies indicate evidence that both fMRI and MEG are able to provide information lateralising and localising motor and language functions. Conclusions: A striking finding of the review is the paucity of studies (n = 34) focusing on the paediatric epilepsy surgery population. For children, it remains unclear which language and memory paradigms produce optimal activation and how these should be quantified in a statistically robust manner. Consensus needs to be achieved for statistical analyses and the uniformity and yield of language, motor and memory paradigms. Larger scale studies are required to produce patient series data which clinicians may refer to interpret results objectively. If functional imaging techniques are to be the viable alternative for pre-surgical mapping of eloquent cortex for children, paradigms and analyses demonstrating concordance with independent measures must be developed

KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice

Pharmacological inhibition of uncontrolled cell growth with small-molecule inhibitors is a potential strategy for treating glioblastoma multiforme (GBM), the most malignant primary brain cancer. We showed that the synthetic small-molecule KHS101 promoted tumor cell death in diverse GBM cell models, independent of their tumor subtype, and without affecting the viability of noncancerous brain cell lines. KHS101 exerted cytotoxic effects by disrupting the mitochondrial chaperone heat shock protein family D member 1 (HSPD1). In GBM cells, KHS101 promoted aggregation of proteins regulating mitochondrial integrity and energy metabolism. Mitochondrial bioenergetic capacity and glycolytic activity were selectively impaired in KHS101-treated GBM cells. In two intracranial patient-derived xenograft tumor models in mice, systemic administration of KHS101 reduced tumor growth and increased survival without discernible side effects. These findings suggest that targeting of HSPD1-dependent metabolic pathways might be an effective strategy for treating GBM

Benign external hydrocephalus: a review, with emphasis on management

Benign external hydrocephalus in infants, characterized by macrocephaly and typical neuroimaging findings, is considered as a self-limiting condition and is therefore rarely treated. This review concerns all aspects of this condition: etiology, neuroimaging, symptoms and clinical findings, treatment, and outcome, with emphasis on management. The review is based on a systematic search in the Pubmed and Web of Science databases. The search covered various forms of hydrocephalus, extracerebral fluid, and macrocephaly. Studies reporting small children with idiopathic external hydrocephalus were included, mostly focusing on the studies reporting a long-term outcome. A total of 147 studies are included, the majority however with a limited methodological quality. Several theories regarding pathophysiology and various symptoms, signs, and clinical findings underscore the heterogeneity of the condition. Neuroimaging is important in the differentiation between external hydrocephalus and similar conditions. A transient delay of psychomotor development is commonly seen during childhood. A long-term outcome is scarcely reported, and the results are varying. Although most children with external hydrocephalus seem to do well both initially and in the long term, a substantial number of patients show temporary or permanent psychomotor delay. To verify that this truly is a benign condition, we suggest that future research on external hydrocephalus should focus on the long-term effects of surgical treatment as opposed to conservative management