Summary Background International consensus recognises four medulloblastoma molecular subgroups: WNT (MBWNT ), SHH (MBSHH ), group 3 (MBGrp3 ), and group 4 (MBGrp4 ), each defined by their ...characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. Methods In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0–16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3–16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. Findings Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MBWNT remained unchanged and each remaining consensus subgroup was split in two. MBSHH was split into age-dependent subgroups corresponding to infant (<4·3 years; MBSHH-Infant ; n=65) and childhood patients (≥4·3 years; MBSHH-Child ; n=38). MBGrp3 and MBGrp4 were each split into high-risk (MBGrp3-HR n=65 and MBGrp4-HR n=85) and low-risk (MBGrp3-LR n=50 and MBGrp4-LR n=73) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroup-dependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 25% of 215 patients; 91% survival 95% CI 82–100); standard risk (50 23% patients; 81% survival 70–94); high-risk (82 38% patients; 42% survival 31–56); and very high-risk (29 13% patients; 28% survival 14–56). Interpretation The discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations. Funding Cancer Research UK, The Tom Grahame Trust, Star for Harris, Action Medical Research, SPARKS, The JGW Patterson Foundation, The INSTINCT network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK).
Introduction
Intensive postsurgical therapies have improved survival in children with primitive neuroectodermal tumour, but there is concern that the combination of chemotherapy and radiotherapy may ...result in a compound injury to normal brain. The purposes of this analysis were to characterise what types of imaging abnormalities occur, identify risk factors and explore how treatment‐related changes may be distinguished from tumour.
Method
One hundred fifty‐three MRI studies in 14 children treated with sequential chemotherapy, hyperfractionated accelerated radiotherapy and high‐dose thiotepa were retrospectively analysed at a paediatric national referral centre.
Results
We observed 11 episodes of new focal enhancing lesions, 5 of which were transient and judged to be treatment related. In addition, 7/14 (50%) of children demonstrated moderate to severe brain volume loss featuring a leukodystrophy pattern.
Conclusion
Treatment‐related brain MRI abnormalities occurred frequently in this series with a risk of misdiagnosis as tumour. A proportion of patients suffer generalised white matter injury, which has not been appreciated as a side effect of this particular therapy.
The National Confidential Enquiry into Patient Outcome and Death reviewed the quality of care provided to adults who presented to hospital following an epileptic seizure. Clinical and organisational ...changes are highlighted that aim to improve patient care and outcomes.
The National Confidential Enquiry into Patient Outcome and Death reviewed the barriers and facilitators in the process of the transition of children and young people with chronic health conditions ...into adult health services. The report focuses on five issues - developmentally appropriate healthcare, the involvement of children and young people and their parents or carers in transition planning, communication and coordination of care, the organisation of transition services and leadership - and makes recommendations for practice.
Abstract
INTRODUCTION: The number of children and young people (CYP) surviving brain tumours is increasing annually with a doubling of 5-year survival over the last 40 years. More than two-thirds of ...these survivors suffer multiple long-term co-morbidities (“late effects”) from their tumour and/ or treatment(s) necessitating lifelong multiprofessional follow-up. This results in multiple appointments and increases the burden of care on patients. Method/Project description To establish a collaborative multidisciplinary “one stop shop” long-term follow-up clinic for CYP >5 years from the end of neuro-oncological treatment to the reduce the need for multiple hospital appointments and to provide holistic assessment and care.The first clinic began in January 2020 as a collaboration between the departments of neuro-oncology, endocrinology, neuropsychology, psychology, physiotherapy and occupational therapy. RESULTS: We have audited the last 60 patients seen in clinic in 2 years and the services they required both in and out of clinic are noted below: Endocrinology – 58 patients Educational help and formal neuropsychology (44 and 39 respectively) There are significant emotional problems in the group and 32 saw clinical psychology and 13 were referred to CAMHS. Physical function issues – 31 saw both physiotherapy and occupational therapy. 10 required referral to orthopaedics Neurology and neurosurgery (13 and 11 respectively) Visual impairment – 33 saw ophthalmology Hearing problems – 17 saw audiology Other organ dysfunction – 4 saw cardiology and 3 urology. We have some feedback data on patient and parent satisfaction with the clinic which shows 92% (13 of 14) families preferred to be seen in the MDT setting rather than by separate clinicians. DISCUSSION: Few models of similar multidisciplinary neuro-oncology long-term follow-up clinics exist in the UK with a lack of streamlined funding, despite recognition from families and professionals about their utility.
Abstract
Background
Less than 5% of medulloblastoma (MB) patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse ...(rMB) will be essential to improve outcomes. Initial genome-wide investigations have suggested significant genetic divergence of the relapsed disease.
Methods
We undertook large-scale integrated characterization of the molecular features of rMB—molecular subgroup, novel subtypes, copy number variation (CNV), and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n = 107), alongside an independent reference cohort sampled at diagnosis (n = 282). rMB events were investigated for association with outcome post-relapse in clinically annotated patients (n = 54).
Results
Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. Non-infant MBSHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (eg, CDK amplifications) and novel (eg, USH2A mutations) events. Importantly, many hallmark features of MB were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (eg, SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (eg, DNA damage signaling) and specific events (eg, 3p loss) predicted survival post-relapse.
Conclusions
rMB is characterised by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.
Aims
Application of advanced molecular pathology in rare tumours is hindered by low sample numbers, access to specialised expertise/technologies and tissue/assay QC and rapid reporting requirements. ...We assessed the feasibility of co‐ordinated real‐time centralised pathology review (CPR), encompassing molecular diagnostics and contemporary genomics (RNA‐seq/DNA methylation‐array).
Methods
This nationwide trial in medulloblastoma (<80 UK diagnoses/year) introduced a national reference centre (NRC) and assessed its performance and reporting to World Health Organisation standards. Paired frozen/formalin‐fixed, paraffin‐embedded tumour material were co‐submitted from 135 patients (16 referral centres).
Results
Complete CPR diagnostics were successful for 88% (120/135). Inadequate sampling was the most common cause of failure; biomaterials were typically suitable for methylation‐array (129/135, 94%), but frozen tissues commonly fell below RNA‐seq QC requirements (53/135, 39%). Late reporting was most often due to delayed submission. CPR assigned or altered histological variant (vs local diagnosis) for 40/135 tumours (30%). Benchmarking/QC of specific biomarker assays impacted test results; fluorescent in‐situ hybridisation most accurately identified high‐risk MYC/MYCN amplification (20/135, 15%), while combined methods (CTNNB1/chr6 status, methylation‐array subgrouping) best defined favourable‐risk WNT tumours (14/135; 10%). Engagement of a specialist pathologist panel was essential for consensus assessment of histological variants and immunohistochemistry. Overall, CPR altered clinical risk‐status for 29% of patients.
Conclusion
National real‐time CPR is feasible, delivering robust diagnostics to WHO criteria and assignment of clinical risk‐status, significantly altering clinical management. Recommendations and experience from our study are applicable to advanced molecular diagnostics systems, both local and centralised, across rare tumour types, enabling their application in biomarker‐driven routine diagnostics and clinical/research studies.
Application of advanced molecular pathology in rare tumours is hindered by low sample numbers, access to specialised expertise/technologies, and tissue/assay QC and rapid reporting requirements. We undertook a UK‐wide trial in medulloblastoma (<80 UK diagnoses/year) to establish, and objectively assess, the performance of real‐time centralised pathology review (CPR), incorporating delivery of molecular diagnostics and assessment of genome‐wide technologies (RNA‐seq/DNA methylation array). We demonstrate establishment of national CPR is feasible and enables robust diagnosis to World Health Organisation standards and subsequent risk‐stratification, and highlight essential elements in the implementation of centralised pathology and diagnostics pathways, which are critical to their establishment.
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