Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis:A potential model for rare diseases

Background Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments.Methods Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts.Results The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF.Conclusions These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials

Mapping of long-term cognitive and motor deficits in pediatric cerebellar brain tumor survivors into a cerebellar white matter atlas

Purpose!#!Diaschisis of cerebrocerebellar loops contributes to cognitive and motor deficits in pediatric cerebellar brain tumor survivors. We used a cerebellar white matter atlas and hypothesized that lesion symptom mapping may reveal the critical lesions of cerebellar tracts.!##!Methods!#!We examined 31 long-term survivors of pediatric posterior fossa tumors (13 pilocytic astrocytoma, 18 medulloblastoma). Patients underwent neuronal imaging, examination for ataxia, fine motor and cognitive function, planning abilities, and executive function. Individual consolidated cerebellar lesions were drawn manually onto patients' individual MRI and normalized into Montreal Neurologic Institute (MNI) space for further analysis with voxel-based lesion symptom mapping.!##!Results!#!Lesion symptom mapping linked deficits of motor function to the superior cerebellar peduncle (SCP), deep cerebellar nuclei (interposed nucleus (IN), fastigial nucleus (FN), ventromedial dentate nucleus (DN)), and inferior vermis (VIIIa, VIIIb, IX, X). Statistical maps of deficits of intelligence and executive function mapped with minor variations to the same cerebellar structures.!##!Conclusion!#!We identified lesions to the SCP next to deep cerebellar nuclei as critical for limiting both motor and cognitive function in pediatric cerebellar tumor survivors. Future strategies safeguarding motor and cognitive function will have to identify patients preoperatively at risk for damage to these critical structures and adapt multimodal therapeutic options accordingly

Multidisciplinary Network ActiveOncoKids guidelines for providing movement and exercise in pediatric oncology: Consensus-based recommendations

Background Pediatric cancer leads to reduced participation in exercise and only few patients comply with national physical activity recommendations. Physically inactive behavior hinders motor development and increases physical and psychological adverse effects of therapy and incidence of sequelae. Currently, there is neither nationwide coverage nor uniform level of knowledge regarding exercise promotion. The objective of the guideline is to facilitate qualified exercise interventions through standardized procedures in addition to regular physiotherapy and overall avoid physical inactivity in pediatric cancer patients. Methods This guideline addresses the multidisciplinary treatment team and informs physiotherapists and decision-makers in tertiary care hospitals and health insurance companies. The requirements of the Association of the Scientific Medical Societies in Germany were followed. Contents were based on best practice experience of experts, patient advocates, as well as on scientific evidence. Results The guideline includes 11 recommendations. Recommendations 1-4 declare the relevance of implementing exercise interventions and address general framework conditions. Recommendations 5-11 focus on the design of exercise programs, prevention and safety issues, relative contraindications for specific training loads, and options to overcome barriers to exercise. Conclusion This guideline summarizes existing and established structures and evidence in the context of movement and exercise in pediatric oncology. It takes into consideration the rights, varying needs, and characteristics of children and adolescents as well as national and international experience in this field. In the future, relevant research gaps need to be addressed by high-quality intervention studies to provide the scientific background for a stronger evidence-based guideline

Impact of chemotherapy for childhood leukemia on brain morphology and function.

OBJECTIVE: Using multidisciplinary treatment modalities the majority of children with cancer can be cured but we are increasingly faced with therapy-related toxicities. We studied brain morphology and neurocognitive functions in adolescent and young adult survivors of childhood acute, low and standard risk lymphoblastic leukemia (ALL), which was successfully treated with chemotherapy. We expected that intravenous and intrathecal chemotherapy administered in childhood will affect grey matter structures, including hippocampus and olfactory bulbs, areas where postnatal neurogenesis is ongoing. METHODS: We examined 27 ALL-survivors and 27 age-matched healthy controls, ages 15-22 years. ALL-survivors developed disease prior to their 11th birthday without central nervous system involvement, were treated with intrathecal and systemic chemotherapy and received no radiation. Volumes of grey, white matter and olfactory bulbs were measured on T1 and T2 magnetic resonance images manually, using FIRST (FMRIB's integrated Registration and Segmentation Tool) and voxel-based morphometry (VBM). Memory, executive functions, attention, intelligence and olfaction were assessed. RESULTS: Mean volumes of left hippocampus, amygdala, thalamus and nucleus accumbens were smaller in the ALL group. VBM analysis revealed significantly smaller volumes of the left calcarine gyrus, both lingual gyri and the left precuneus. DTI data analysis provided no evidence for white matter pathology. Lower scores in hippocampus-dependent memory were measured in ALL-subjects, while lower figural memory correlated with smaller hippocampal volumes. INTERPRETATION: Findings demonstrate that childhood ALL, treated with chemotherapy, is associated with smaller grey matter volumes of neocortical and subcortical grey matter and lower hippocampal memory performance in adolescence and adulthood

Olfactory bulb volumes.

*<p>two-tailed = 0.179.</p