Background
Posterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors’ knowledge, the long‐term outcomes of ...PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years.
Methods
Demographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome‐wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3).
Results
A total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10‐year progression‐free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%‐53.1%). Analysis of consecutive 10‐year epochs revealed significant improvements in progression‐free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full‐scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (‐1.33 ± 0.42 points/year; P = .0042).
Conclusions
Data from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors’ knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time.
In a subgroup‐specific manner, the results of the current study demonstrate that survival among patients with posterior fossa ependymoma has improved over time, and this improvement clearly is related to a change in practice with regard to pursuing aggressive surgical resections with upfront postoperative radiotherapy in all patients. This significant improvement highlights an urgent need for the implementation of early intervention and neuroprotective strategies.
Choroid plexus carcinomas (CPC) are rare aggressive tumours that primarily affect very young children. Treatment for CPC typically involves a combination of surgery, chemotherapy, and radiation ...therapy. Whilst considered necessary for a cure, these therapies have significant neurocognitive consequences for patients, negatively impacting cognitive function including memory, attention, executive functioning, and full-scale intelligence quotients (FSIQ). These challenges significantly impact the quality of life and ultimately socioeconomic parameters such as the level of educational attainment, marital status, and socioeconomic status. This review looks at the tumour- and treatment-related causes of neurocognitive damage in CPC patients and the progress made in finding strategies to reduce these. Opportunities to mitigate the neurodevelopmental consequences of surgery, chemotherapy, and radiation therapy are explored in the context of CPC treatment. Evaluation of the pathological and biological mechanisms of injury has identified innovative approaches to neurocognitive protection and neurorehabilitation, which aim to limit the neurocognitive damage. This review aims to highlight multiple approaches physicians can use when treating young children with CPC, to focus on neurocognitive outcomes as a measure of success.
Abstract
Background
When children and young people (CYP) are diagnosed with a brain tumour, Magnetic Resonance Imaging (MRI) is key to the clinical management of this condition. This can produce ...hundreds, and often thousands, of Magnetic Resonance Images (MRIs).
Methods
Semi-structured interviews were undertaken with 14 families (15 parents and 8 patients), and analysed using Grounded Theory. Analysis was supported by the Framework Method.
Results
Although the focus of the research was whether paediatric patients and their families find viewing MRIs beneficial, all patients and parents discussed difficult times during the illness and using various strategies to cope. This article explores the identified coping strategies that involved MRIs, and the role that MRIs can play in coping. Coping strategies were classified under the aim of the strategy when used: ‘Normalising’; ‘Maintaining hope and a sense of the future’; ‘Dealing with an uncertain future’; and ‘Seeking Support’.
Conclusions
Coping and finding ways to cope are clearly used by patients and their families and are something that they wish to discuss, as they were raised in conversations that were not necessarily about coping. This suggests clinicians should always allow time and space (in appointments, consultations, or impromptu conversations on the ward) for patient families to discuss ways of coping.
MRIs were found to be used in various ways: to maintain or adapt normal; maintain hope and a sense of the future; deal with an uncertain future; and seek support from others. Clinicians should recognise the potential for MRIs to aid coping and if appropriate, suggest that families take copies of scans (MRIs) home. Professional coaches or counsellors may also find MRIs beneficial as a way to remind families that the child is in a more stable or ‘better’ place than they have been previously.
Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI ...monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.
Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.
The survival for many children with relapsed/refractory cancers remains poor despite advances in therapies. Arginine metabolism plays a key role in the pathophysiology of a number of pediatric ...cancers. We report the first in child study of a recombinant human arginase, BCT-100, in children with relapsed/refractory hematological, solid or CNS cancers.
PARC was a single arm, Phase I/II, international, open label study. BCT-100 was given intravenously over one hour at weekly intervals. The Phase I section utilized a modified 3 + 3 design where escalation/de-escalation was based on both the safety profile and the complete depletion of arginine (defined as adequate arginine depletion; AAD <8μM arginine in the blood after 4 doses of BCT-100). The Phase II section was designed to further evaluate the clinical activity of BCT-100 at the pediatric RP2D determined in the Phase I section, by recruitment of patients with pediatric cancers into 4 individual groups. A primary evaluation of response was conducted at eight weeks with patients continuing to receive treatment until disease progression or unacceptable toxicity.
49 children were recruited globally. The Phase I cohort of the trial established the Recommended Phase II Dose of 1600U/kg iv weekly in children, matching that of adults. BCT-100 was very well tolerated. No responses defined as a CR, CRi or PR were seen in any cohort within the defined 8 week primary evaluation period. However a number of these relapsed/refractory patients experienced prolonged radiological SD.
Arginine depletion is a clinically safe and achievable strategy in children with cancer. The RP2D of BCT-100 in children with relapsed/refractory cancers is established at 1600U/kg intravenously weekly and can lead to sustained disease stability in this hard to treat population.
EudraCT, 2017-002762-44; ISRCTN, 21727048; and ClinicalTrials.gov, NCT03455140.
This article aims to explore and record the role of shadowing in preparation for a qualitative study involving children and families with sensitive health issues. The researcher was engaged for a ...study involving qualitative research involving paediatric patients (those under 18 years old) and their families, but was unfamiliar with a hospital environment and interviewing children and young people (CYP) with a serious health condition. The researcher ‘shadowed’ healthcare professionals (HCPs) at a children’s hospital during their day-to-day work in order to prepare for the research interviewing. From shadowing, the researcher gained: familiarity with a hospital environment, organisational processes, and medical terminology; an understanding of the appropriate ways to refer to patients; confidence and competence in talking to children with serious health conditions; and resilience to becoming upset during interviews while hearing patients’ distressing stories—they became ‘desensitised’. Shadowing can therefore be highly beneficial for researchers undertaking research in unfamiliar contexts, environments, and populations prior to interviewing.
Abstract
The last five years has shown advances in the molecular classification of brain tumour, molecular profiling techniques and an increased use of targeted therapies. We reviewed the molecular ...analysis pathways and use of targeted agents at Birmingham Children’s Hospital (BCH), a large (~55 new cases/year) neuro-oncology centre, between 2016-2021. Having previously been analysed locally by limited directed immuno-histochemical stains and referral for specific genetic tests, tissue is now referred for a range of second histopathological opinions and in depth molecular classification, via methylation array, panel sequencing, RNA fusion analysis, and whole genome sequencing. These are accessed through different evolving pathways and consent processes, including referral to other centres, national reference laboratories, clinical studies, and local genetics laboratories with links to national sequencing infrastructures. Different routes result in different reporting structures, timescales and with varying levels of interpretation, often without adequate access to clinical information and context. 21 patients were treated on five targeted agent clinical trials (Afatanib (n=6), Biomede (n=3), eSmart(n=1), PARC (n=7), Vinilo (n=5)), with one patient on both Afatanib and PARC trials. A further two patients visited other centres for trials. Eight patients received MAPK pathway inhibitors through compassionate access pathways, with benefit, including radiological response, in four. Cardiac toxicity was observed in three and retinal oedema in one. Two patients received immune checkpoint inhibition, with rapid fatal enlargement, either progression or pseudo-progression, in one case. These rapid changes in diagnostic and management options offer new opportunities for patients, but bring challenges to the delivery of neuro-oncology services, including the logistics of sample, report, clinical trial, compassionate access management and the increased multi-specialist support required for monitoring and management of toxicities. Integration of targeted agents into the appropriate part of a patient’s treatment strategy requires skilled interpretation of the benefits compared to conventional therapies.
Abstract BACKGROUND The West Midlands Regional Children’s Tumour Registry is a specialist paediatric cancer registry in the West Midlands region of England, representing 9% of the national ...population. Our aim was to produce an historical, regional overview of central nervous system (CNS) tumour incidence and survival from 1957 onwards. METHODS Paediatric CNS tumour records included in the Registry from 01/01/57 to 31/12/16 were reviewed. There were 1945 cases: 1066 males and 879 females (M:F ratio 1.2:1) aged 0-14 years, resident in the West Midlands and diagnosed with a malignant, uncertain, or benign tumour. Patients were categorised according to the International Classification of Childhood Cancer, Third Edition (ICCC-3). Age and sex-specific incidence rates per million and directly age standardised incidence rates were calculated. Survival by decade of diagnosis was calculated using Kaplan-Meier survival analysis. RESULTS Incidence rates were broadly comparable to national data. Five-year survival for all CNS tumours combined increased from 38.0% CI 32.2-43.8% during 1957-1966 to 79.8% CI 75.4-83.5 for diagnoses 2007-2016. Five-year survival for patients with ependymoma, astrocytoma and medulloblastoma diagnosed 2007-2016 was 95.7% CI 72.9-99.4, 86.9% CI 80.3-91.3 and 68.0% CI 52.0-79.7 respectively: substantially above equivalent national figures. Five-year survival for groups including ‘Other Gliomas’ and Atypical teratoid/rhabdoid tumour (ATRT) had lower than nationally reported survival rates at 53.3% CI 37.6-66.8 and 9.1% 0.5-33.3 however, small numbers and wide confidence intervals must be considered. CONCLUSIONS Huge improvements in survival, nationally and in the West Midlands, over the past 60 years are attributable to a greater understanding of tumour biology, intensification of multi-agent chemotherapy and new treatments. Despite these gains, certain diagnoses - most prominently ATRT - remain resistant to cure with five-year survival below 10%. Certain diagnoses showed a notable rise in late mortality, demonstrating the importance of long-term follow-up for detecting late effects and subsequent malignancies.
Abstract
Adamantinomatous craniopharyngiomas are challenging intracranial tumours associated with significant morbidity. Management includes surgery and radiotherapy, with a shift towards more ...conservative surgery in recent years, aimed at preserving hypothalamic function. The West Midlands Regional Children’s Tumour Registry collects detailed clinical, pathological and follow up information on patients treated within the region from 1957. 52 cases (26 male, 26 female) of craniopharyngioma treated at Birmingham Children’s Hospital 1957-2018, were identified, with further clinical details obtained from patient records, where available. Visual symptoms were the commonest presenting feature (63%), followed by headache (48%), vomiting (31%), neurological symptoms (31%) and features of endocrine disorders (21%) with a median symptom duration of 6 months (range <1-24). Initial management was with gross total resection (GTR) in 14 patients, subtotal resection in 22 patients and subtotal resection with adjuvant radiotherapy in seven patients. Two patients received radiotherapy without resection, and five patients underwent cystic drainage procedures alone. Two patients initially underwent shunt insertion alone, but received radiotherapy at progression. 30 (58%) patients underwent relapse/progression, with a median time to progression of 1.2 years (range 0.2-6.3). 15 had further surgery. Radiotherapy was used in 14/15 patients who had not previously received radiotherapy, with the other undergoing a GTR. To date 10 patients have died, nine from tumour related reasons and one from pulmonary embolism. Where data was available at follow up, all patients had at least one endocrinopathy, with 38/45 patients having diabetes insipidus. Hypothalamic obesity was identified in 14/36 (39%) patients with sufficient records, with this more common in those undergoing GTR (7/9 (78%)) compared to other surgical procedures (7/27)(26%)(p<0.05). Three patients have developed neurovascular complications and three fatty liver disease. This experience is consistent with the literature and supports the increasing usage of hypothalamic sparing surgical management.
MRI is essential to the clinical management of children and young people with brain tumours. Advances in technology have made images more complicated to interpret, yet more easily available ...digitally. It is common practice to show these to patients and families, but how they emotionally respond to, understand and value, seeing brain tumour MRIs has not been formally studied.
Qualitative semi-structured interviews were undertaken with 14 families (8 patients, 15 parents) purposively sampled from paediatric patients (0 to 18 years) attending a large UK children's hospital for treatment or monitoring of a brain tumour. Transcripts were analysed thematically using the Framework Method.
Four themes were identified: Receiving results (waiting for results, getting results back, preferences to see images), Emotional responses to MRIs, Understanding of images (what they can show, what they cannot show, confusion) and Value of MRIs (aesthetics, aiding understanding, contextualised knowledge/emotional benefits, enhanced control, enhanced working relationships, no value). All families found value in seeing MRIs, including reassurance, hope, improved understanding and enhanced feeling of control over the condition. However emotional responses varied enormously.
Clinical teams should always explain MRIs after 'framing' the information. This should minimise participant confusion around meaning, periodically evident even after many years. Patient and parent preferences for being shown MRIs varied, and often changed over time, therefore clinicians should identify, record and update these preferences. Time between scanning and receiving the result was stressful causing 'scanxiety', but most prioritised accuracy over speed of receiving results.
PDF
