Prospective registration of symptoms and times to diagnosis in children and adolescents with central nervous system tumors: A study of the Swedish Childhood Cancer Registry

Background: The elapsed time taken to diagnose tumors of the central nervous system in children and adolescents varies widely. The aim of the present study was to investigate such diagnostic time intervals at a national level in Sweden as they correlate with clinical features. Methods: Data prospectively accumulated over a 4-year period in the Swedish Childhood Cancer Registry from patients aged 0-18 years were pooled, and diagnostic time intervals were analyzed considering tumor location, tumor type, patient age and sex, initial symptoms, and clinical timelines. All six pediatric oncology centers in Sweden contributed to collection of data. Time points for calculating the total diagnostic interval (TDI) defined as the time from symptom onset to diagnosis were reported in 257 of 319 patients (81%). Results: The time from symptom onset to the first healthcare consultation, median 2.6 weeks, did not vary significantly between patients categorized according to tumor type or location. The median TDI was 8.3 weeks for the 4-year study period. Patients with optic pathway glioma (TDI 26.6 weeks), those with tumors of the spinal cord (TDI 25.9 weeks), and those with midline tumors (TDI 24.6 weeks) had the longest lead times. Additionally, older age, too few initial symptoms, and seeking initial redress outside an emergency ward were factors associated with a longer time to diagnosis. Conclusion: This study identified several factors associated with delayed diagnosis of central nervous system tumors among Swedish children and adolescents. These novel data ought to help direct future efforts toward clinical improvement.</p

Cerebellar mutism syndrome in children with brain tumours of the posterior fossa

Background: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. Methods: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre- operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. Discussion: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition.Peer reviewe

Afferent input to midbrain dopamine neurones and its modulation : an electrophysiological study i vitro

Dopamine (DA) neurones of the ventral mesencephalon are involved in the control of reward related behaviour, cognitive functions and motor performances, and provide a critical site of action for major categories of neuropsychiatric drugs, such as antipsychotic agents, dependence producing drugs and anti-Parkinson medication. The midbrain DA neurones are mainly located in the substantia nigra pars compacta (SNPC) and the ventral tegmental area (VTA). Their activity is regulated by the intrinsic properties of the DA neurones as well as by the activity of the afferent inputs. The aim of the present work was to study the function and modulatory role of the glutamatergic and cholinergic afferent inputs in regulating the midbrain DAergic neuronal activity. The slice preparation of the rat ventral mesencephalon in vitro was used and intracellular or whole-cell patch clamp recordings were performed from the DA neurones. Repetitive stimulation of the afferents in the slice preparation was shown to elicit a slow excitatory postsynaptic event that was blocked by application of the NMDA antagonist AP5. Moreover, the amplitude of the slow postsynaptic event was markedly reduced by L-type Ca2+ channel blockers such as nifedipine. Specific agonists to group I, II and III metabotropic glutamate receptors (mGluRs) were all shown to reduce the amplitude of both glutamatergic and GABAergic synaptic inputs to the DA neurones. A presynaptic site of action was indicated by a paired-pulse protocol. Also muscarine depressed both glutamatergic and GABAergic synaptic transmission to the DA neurones. These effects were completely blocked by the M3/M1 receptor antagonist 4-DAMP, but not significantly affected by the M, receptor antagonist pirenzepine. Moreover, the postsynaptic responses to glutamate or GABA were not changed by muscarine. The nicotine-induced excitation of DA neurones was reduced in the presence of AP5 or the AMPA/kainate receptor antagonist CNQX. However, neither glutamate- nor GABA-mediated spontaneous synaptic transmission was affected by nicotine application. The results demonstrate that NMDA-mediated glutamatergic synaptic transmission to midbrain DA neurones involves activation of presynaptic L-type Ca2+ channels. Moreover, mGluRs and muscarinic receptors mediate presynaptic inhibition of both glutamatergic and GABAergic synaptic inputs to the midbrain DA neurones. Finally, the nicotine-induced excitation of the DA neurones in the slice preparation seems essentially to be mediated through postsynaptically located nicotinic receptors

Whole Exome- and mRNA-Sequencing of an AT/RT Case Reveals Few Somatic Mutations and Several Deregulated Signalling Pathways in the Context of SMARCB1 Deficiency

Background. AT/RTs are rare aggressive brain tumours, mainly affecting young children. Most cases present with genetic inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodeling complex. We have performed whole exome- and mRNA-sequencing on an early onset AT/RT case for detection of genetic events potentially contributing to the disease. Results. A de novo germline variant in SMARCB1, c.601C>T p.Arg201∗, in combination with somatic deletion of the healthy allele is likely the major tumour causing event. Only seven somatic small scale mutations were discovered (hitting SEPT03, H2BFM, ZIC4, HIST2H2AB, ZIK1, KRTAP6-3, and IFNA8). All were found with subclonal allele frequencies (range 5.7–17%) and none were expressed. However, besides SMARCB1, candidate genes affected by predicted damaging germline variants that were expressed were detected (KDM5C, NUMA1, and PCM1). Analysis of differently expressed genes revealed many dysregulated pathways in the tumour, such as cell cycle, CXCR4 pathway, GPCR-signalling, and neuronal system. FGFR1, CXCR4, and MDK were upregulated and may represent possible drug targets. Conclusion. The loss of SMARCB1 function leads to AT/RT development and deregulated genes and pathways. Additional predisposing events may however contribute. Studies utilizing NGS technologies in larger cohorts will probably identify recurrent genetic and epigenetic alterations and molecular subgroups with implications for clinical practice and development of targeted therapies

Prospective registration of symptoms and times to diagnosis in children and adolescents with central nervous system tumors : A study of the Swedish Childhood Cancer Registry

BACKGROUND: The elapsed time taken to diagnose tumors of the central nervous system in children and adolescents varies widely. The aim of the present study was to investigate such diagnostic time intervals at a national level in Sweden as they correlate with clinical features.METHODS: Data prospectively accumulated over a 4-year period in the Swedish Childhood Cancer Registry from patients aged 0-18 years were pooled, and diagnostic time intervals were analyzed considering tumor location, tumor type, patient age and sex, initial symptoms, and clinical timelines. All six pediatric oncology centers in Sweden contributed to collection of data. Time points for calculating the total diagnostic interval (TDI) defined as the time from symptom onset to diagnosis were reported in 257 of 319 patients (81%).RESULTS: The time from symptom onset to the first healthcare consultation, median 2.6 weeks, did not vary significantly between patients categorized according to tumor type or location. The median TDI was 8.3 weeks for the 4-year study period. Patients with optic pathway glioma (TDI 26.6 weeks), those with tumors of the spinal cord (TDI 25.9 weeks), and those with midline tumors (TDI 24.6 weeks) had the longest lead times. Additionally, older age, too few initial symptoms, and seeking initial redress outside an emergency ward were factors associated with a longer time to diagnosis.CONCLUSION: This study identified several factors associated with delayed diagnosis of central nervous system tumors among Swedish children and adolescents. These novel data ought to help direct future efforts toward clinical improvement