Prevention of radiotherapy-induced neurocognitive dysfunction in survivors of paediatric brain tumours: the potential role of modern imaging and radiotherapy techniques.

Neurocognitive dysfunction is the leading cause of reduced quality of life in long-term survivors of paediatric brain tumours. Radiotherapy is one of the main contributors to neurocognitive sequelae. Current approaches for prevention and reduction of neurocognitive dysfunction include avoidance of radiotherapy in young children and reduction of the radiotherapy dose and volume of brain irradiated. Substantial advances have been made in brain imaging, especially with functional imaging and fibre tracking with the use of diffusion tensor imaging. Radiotherapy techniques for photon therapy have also evolved, with widespread use of techniques such as image-guided radiotherapy, volumetric modulated arc therapy, helical tomotherapy, and adaptive radiotherapy. The number of proton beam and heavy ion therapy facilities is increasing worldwide and there is great enthusiasm for clinical use of advanced MRI-guided radiotherapy systems. Here, we review the potential role of modern imaging and innovative radiotherapy techniques in minimisation of neurocognitive sequelae in children with brain tumours, and discuss various strategies to integrate these advances to drive further research

Non-Hodgkin lymphoma.

The term non-Hodgkin lymphoma (NHL) covers a spectrum of malignant disorders arising from cells of the immune system and manifesting predominantly as lymphadenopathy or solid tumour. The classification of NHL is complex and ever-evolving, with more than 50 different subtypes listed in the latest WHO classification of lymphoma (1). In this clinical update, we address the distinction between low-grade (indolent) and high-grade lymphoma, and discuss the principles of diagnosis and management that are of particular relevance to the non-specialist physician who may encounter patients with NHL during their initial presentation, during therapy and during periods of follow-up

Anticancer chemotherapy in teenagers and young adults: managing long term side effects.

SSA is supported by the Cambridge Cancer Centre.This is the final version of the article. It first appeared from BMJ Group at http://dx.doi.org/10.1136/bmj.i4567

GCT-03. MonoGerm, a novel proof-of-principle Bayesian phase II trial design of carboplatin or vinblastine monotherapy induction prior to radiotherapy for intracranial germinoma [Abstract]

BACKGROUND Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely. METHODS Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440). RESULTS MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (<30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design. CONCLUSION MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial

Overview of European standard clinical practice recommendations for multidiscplinary teams involved in the treatment of central nervous system tumours in children and adolescents – SIOPE Brain Tumour Group

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

Benefits for children with suspected cancer from routine whole-genome sequencing

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care.</p

Neurocognitive Dysfunction After Treatment for Pediatric Brain Tumors: Subtype-Specific Findings and Proposal for Brain Network-Informed Evaluations.

Acknowledgements: During the literature review phase, C.S. was funded by the Fonds voor Wetenschappelijk Onderzoek for a senior post-doctoral fellowship. PCF is supported by funding from the Bernard Wolfe Health Neuroscience Fund (206368/Z/17/Z). His research is also supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).The increasing number of long-term survivors of pediatric brain tumors requires us to incorporate the most recent knowledge derived from cognitive neuroscience into their oncological treatment. As the lesion itself, as well as each treatment, can cause specific neural damage, the long-term neurocognitive outcomes are highly complex and challenging to assess. The number of neurocognitive studies in this population grows exponentially worldwide, motivating modern neuroscience to provide guidance in follow-up before, during and after treatment. In this review, we provide an overview of structural and functional brain connectomes and their role in the neuropsychological outcomes of specific brain tumor types. Based on this information, we propose a theoretical neuroscientific framework to apply appropriate neuropsychological and imaging follow-up for future clinical care and rehabilitation trials