QOL-04. Histology, treatment, and extent of pretreatment hydrocephalus are major determents of neurocognitive outcome for survivors of pediatric posterior fossa tumors - report from the German HIT-studies [Abstract]

BACKGROUND: Cognitive impairments following pediatric brain tumors are generally attributed to tumor site, surgical intervention, complications as well as to nonsurgical treatment. We investigated impairments for patients with medulloblastoma (MB), ependymoma (EP) and low-grade glioma (LGG) of the cerebellum treated within the German pediatric brain tumor network to compare and rank major determents. PATIENTS+METHODS: Following protocol treatment, 245 patients with MB (n=106), EP (n=32), and cerebellar LGG (n=107, surgery only) were examined 2 + 5 years after diagnosis using the German “Neuropsychological-Basic-Diagnostic” (NBD) tool based on the Cattell-Horn-Carroll model for intelligence. Within this retrospective study, multiple linear regression models were applied. RESULTS: The MB+EP vs. LGG-cohort differed slightly in median age at diagnosis (8.7/6.1 years) and location (cerebellar hemispheres: 8%MB+EP/49.5%LGG), while sex-ratio, grade of resection, extent of pre-operative hydrocephalus were comparable. With smaller median tumor-volume in the MB+EP vs. LGG-cohort (34.1/44.1cm3), ranges broadly overlapped. Median scores of age-appropriate tests were in the lower normal range for all patients for fluid and crystallized intelligence, selective attention, visual-spatial processing (VSP) and verbal short-term memory (median=93-103), but distinctly below for processing speed (PS), and psychomotor speed abilities (PMS) (median=65-84). Higher doses of craniospinal irradiation (>23.4Gy/23.4Gy) resulted in lower scores for most domains for MB-patients compared to LGG-patients (e.g., PS-estimate: >23.4Gy:-27.71, p=0.026/23.4Gy:-9.93, p=0.286). EP-patients (surgery+54Gy local radiation) scored better than LGG-patients except for PS (estimate:-15.65, p=0.111). Impairments were accentuated with higher degrees of hydrocephalus (estimate:-7.64, p=0.103) in patients with incomplete resection (estimate:12.23, p=0.006) for PMS both hands. CONCLUSION: Following age-adapted comprehensive treatment, survivors of a cerebellar tumor show significant impairments of PMS abilities in our trials. Our data suggest that slow growing LGG impair neurocognitive development more than local radiotherapy for ependymoma, while craniospinal irradiation compromises VSP and PS in MB. Initial symptomatic intracranial pressure remains a strong predictor for general neuropsychological impairment

Neurological manifestations in children and adolescents with neurofibromatosis type-1-implications for management and surveillance [Abstract]

INTRODUCTION: We aimed to (1) characterize the spectrum of clinical phenotypes of NF1 in a random pediatric population, (2) correlate genotype with phenotypic expression for those with a genetic diagnosis, and (3) explore radiological features of NF1 in the central nervous system (CNS) by radiomics analyses to predict clinical course. METHODS: We performed a database search in the hospital information system of the University Children′s Hospital between January 2017 and December 2020 for patients with NF1 and evaluated the clinical phenotype by retrospective chart review. RESULTS: 75 children/adolescents were identified with suspicion/clinical diagnosis of NF1 (median age 10.0 years (range, 1.1-22.6); 35 female), confirmatory revised “diagnostic criteria” were met in 57 patients at the last follow-up. Per number of documented items, major signs were detected as 73/75 café-au-lait macules, 31/63 freckling, 38/71 neurofibromas (thereof 21 plexiform neurofibromas), 18/43 optic pathway glioma, 5/66 Lisch nodules, and two patients with sphenoid dysplasia. Genetic analysis (31/75) identified pathogenic NF1 variants in 27 patients. In 20/66 cases a parent met diagnostic criteria. Cognitive symptoms included developmental delay (28/68), learning deficits (12/48), attention-deficit hyperactivity disorder (3/53), and behavior anomalies (7/63). Classical unidentified bright objects were seen in 29/43, other intracranial tumors in 7/43, and cerebrovascular abnormalities in 5/43. Analysis of imaging features of the CNS in these patients will involve lesion segmentation and radiomics features. Symptomatic/progressive low-grade glioma necessitated neurosurgical resection (4/25) and/or chemotherapy (12/25). In 10/25 neuropsychological functions were assessed by the German neuropsychological basic diagnostic instrument. Until June 30th, 2021, one patient died of progressive plexiform neurofibroma. CONCLUSIONS: A wide range of neurological manifestations, including neuropsychological deficits, should raise the suspicion of NF1 in an unselected pediatric population. We expect imaging features of the CNS to better predict the clinical course and enhance decision-making

ATRT-02. Neuropsychological function in infant atypical teratoid/rhabdoid tumor versus low-grade glioma survivors reflects tumor malignancy and multimodal treatment [Abstract]

BACKGROUND: Therapy of infants with brain tumors predisposes these patients to increased risks for cognitive sequelae, especially following radiotherapy. Neuropsychological outcome gains importance for those 40-60% of patients with an atypical teratoid/rhabdoid tumor (ATRT) who survive beyond 2 years. Still, reports on cognitive late-effects in children with ATRT are scarce compared to other pediatric brain tumor groups. We analyzed neuropsychological outcome for long-term ATRT-survivors registered in EU-RHAB and infant low-grade glioma (LGG) survivors from the SIOP-LGG 2004-study and LGG-registry. PATIENTS+METHODS: Age at diagnosis of both cohorts was 0-36 months. ATRT-patients (n=13) treated with up to 54Gy radiotherapy (median age 22 months (±7.1)) were evaluated with the “ATRT-Neuropsychology” tool based on SIOPE-BTG QoS-Group recommendations at median 6.8 years (±2.8) after diagnosis. LGG-patients (n=15) treated without radiotherapy (4/15 with chemotherapy) were analyzed with the German “Neuropsychological-Basic-Diagnostic” tool 5.2 years (±0.6) post-diagnosis. RESULTS: The ATRT- vs. LGG-cohorts were comparable for median age at diagnosis, sex-ratio and tumor-localization, though they differed slightly in median age at assessment (9.5/7.2 years (±2.5/1.1)). Results of age-appropriate tests showed increased impairments for ATRT-patients in fluid intelligence (FI) (p=.006, d=1.214) and in visual-spatial processing (VSP) (p<.001, d=2.233) compared to LGG-patients. The median for neuropsychological test results of ATRT-patients spanned from considerably below the normal to the lower normal range (median=65-90), while results of LGG-patients were mostly in the lower normal range (median=83-103). Results for psychomotor speed abilities (PMS) were distinctly below the norm for both patient groups (p=.002-.007). CONCLUSION: Infant ATRT- and LGG-patients develop significant impairments in PMS abilities following multimodal treatment. Long-term survivors of ATRT suffer from additional FI and VSP deficits. Our data suggest that high malignancy requiring multimodal treatment determines the inferior cognitive outcome for the ATRT-cohort. Long-term neuropsychological monitoring (and treatment options) should be implemented as standard of care in ATRT- and LGG-trials

Comparison of fitness scores of genes important during phosphorus-limited growth and phosphate starvation and seventeen other previously tested stresses or growth conditions.

<p>Genes with the potential to inform about responses specific to phosphate-limited conditions are listed along the y-axis on the right. Experimental conditions are labeled on top, along the x-axis. The color bar in the top right corner shows colors assigned to the numerical values of fitness scores: negative scores representing fitness defects are blue, positive scores representing fitness benefits are yellow, and fitness-neutral scores are black. The first seven columns starting from the left show scores measured and reported in the current study, the adjacent seventeen columns show scores measured by previous studies and stored in the <a href="http://microbesonline.org" target="_blank">microbesonline.org</a> database. The names of genes with predicted direct roles in phosphorus homeostasis are labeled by light blue-colored boxes. The names of genes with predicted or confirmed direct roles in the biosynthesis of the cell envelope are labeled by rose-colored boxes. The names of genes with predicted roles in transport are labeled by yellow-colored boxes, those encoding the Hmc complex are labeled by green-colored boxes.</p

Quality of survival assessment in European childhood brain tumour trials, for children below the age of 5 years

The highest incidence rate of childhood brain tumours is in children below the age of five years, who are particularly vulnerable to the effects of treatments. The assessment of quality of survival (QoS) in multiple domains is essential to compare the outcomes for different tumour types and treatment regimens. The aim of this position statement is to present the domains of health and functioning to be assessed in children from birth to five years, to advance the collection of a common QoS data set in European brain tumour trials. The QoS group of the European Society of Paediatric Oncology (SIOP-E) Brain Tumour group conducted consensus discussions over a period of six years to establish domains of QoS that should be prioritised in clinical trials involving children under 5 years. The domains of health and functioning that were agreed to affect QoS included: medical outcomes (e.g. vision, hearing, mobility, endocrine), emotion, behaviour, adaptive behaviour, and cognitive functioning. As for children aged five years and older, a ‘core plus’ approach is suggested in which core assessments are recommended for all clinical trials. The core component for children from birth to three years includes indirect assessment which, in this age-group, requires proxy assessment by a parent, of cognitive, emotional and behaviour variables and both direct and indirect endocrine measures. For children from four years of age direct cognitive assessment is also recommended as ‘core’. The ‘plus’ components enable the addition of assessments which can be selected by individual countries and/or by, age-, treatment-, tumour type- and tumour location- specific trials.<br/

Comprehensive neurological evaluation of a cohort of patients with neurofibromatosis type 1 from a single institution

Neurofibromatosis type 1 (NF1) is a phenotypically heterogenous multisystem cancer predisposition syndrome manifesting in childhood and adolescents. Central nervous system (CNS) manifestations include structural, neurodevelopmental, and neoplastic disease. We aimed to (1) characterize the spectrum of CNS manifestations of NF1 in a paediatric population, (2) explore radiological features in the CNS by image analyses, and (3) correlate genotype with phenotypic expression for those with a genetic diagnosis. We performed a database search in the hospital information system covering the period between January 2017 and December 2020. We evaluated the phenotype by retrospective chart review and imaging analysis. 59 patients were diagnosed with NF1 [median age 10.6 years (range, 1.1–22.6); 31 female] at last follow-up, pathogenic NF1 variants were identified in 26/29. 49/59 patients presented with neurological manifestations including 28 with structural and neurodevelopmental findings, 16 with neurodevelopmental, and 5 with structural findings only. Focal areas of signal intensity (FASI) were identified in 29/39, cerebrovascular anomalies in 4/39. Neurodevelopmental delay was reported in 27/59 patients, learning difficulties in 19/59. Optic pathway gliomas (OPG) were diagnosed in 18/59 patients, 13/59 had low-grade gliomas outside the visual pathways. 12 patients received chemotherapy. Beside the established NF1 microdeletion, neither genotype nor FASI were associated with the neurological phenotype. NF1 was associated with a spectrum of CNS manifestations in at least 83.0% of patients. Regular neuropsychological assessment complementing frequent clinical and ophthalmologic testing for OPG is necessary in the care of each child with NF1