Purpose
The challenges of treating central nervous system (CNS) tumors in young children are many. These include age-specific tumor characteristics, limited treatment options, and susceptibility of ...the developing CNS to cytotoxic therapy. The aim of this study was to analyze the long-term survival, health-related, and educational/occupational outcomes of this vulnerable patient population.
Methods
Retrospective study of 128 children diagnosed with a CNS tumor under 5 years of age at a single center in Switzerland between 1990 and 2019.
Results
Median age at diagnosis was 1.81 years IQR, 0.98–3.17. Median follow-up time of surviving patients was 8.39 years range, 0.74–23.65. The main tumor subtypes were pediatric low-grade glioma (36%), pediatric high-grade glioma (11%), ependymoma (16%), medulloblastoma (11%), other embryonal tumors (7%), germ cell tumors (3%), choroid plexus tumors (6%), and others (9%). The 5-year overall survival (OS) was 78.8% (95% CI, 71.8–86.4%) for the whole cohort. Eighty-seven percent of survivors > 5 years had any tumor- or treatment-related sequelae with 61% neurological complications, 30% endocrine sequelae, 17% hearing impairment, and 56% visual impairment at last follow-up. Most patients (72%) attended regular school or worked in a skilled job at last follow-up.
Conclusion
Young children diagnosed with a CNS tumor experience a range of complications after treatment, many of which are long-lasting and potentially debilitating. Our findings highlight the vulnerabilities of this population, the need for long-term support and strategies for rehabilitation, specifically tailored for young children.
Gliomas are the most common primary central nervous system (CNS) tumors and a major cause of cancer-related mortality in children (age <15 years), adolescents and young adults (AYA, ages 15–39 ...years), and adults (age >39 years). Molecular pathology has helped enhance the characterization of these tumors, revealing a heterogeneous and ever more complex group of malignancies. Recent molecular analyses have led to an increased appreciation of common genomic alterations prevalent across all ages. The 2021 World Health Organization (WHO) CNS tumor classification, 5th edition (WHO CNS5) brings forward a nomenclature distinguishing “pediatric-type” and “adult-type” gliomas. The spectrum of gliomas in AYA comprises both “pediatric-like” and “adult-like” tumor entities but remains ill-defined. With fragmentation of clinical management between pediatric and adult centers, AYAs face challenges related to gaps in medical care, lower rates of enrollment in clinical trials and additional psychosocial and economic challenges. This calls for a rethinking of diagnostic and therapeutic approaches, to improve access to appropriate testing and potentially beneficial treatments to patients of all ages.
The microenvironment shapes cell behavior and determines metastatic outcomes of tumors. We addressed how microenvironmental cues control tumor cell invasion in pediatric medulloblastoma (MB). We show ...that bFGF promotes MB tumor cell invasion through FGF receptor (FGFR) in vitro and that blockade of FGFR represses brain tissue infiltration in vivo. TGF-β regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-β pathway causes ROCK activation and cortical translocation of ERK1/2, which antagonizes FGFR signaling by inactivating FGFR substrate 2 (FRS2), and promotes a contractile, non-motile phenotype. Under high bFGF, negative-feedback regulation of FRS2 by bFGF-induced ERK1/2 causes repression of the FGFR pathway. Under these conditions, TGF-β counters inactivation of FRS2 and restores pro-migratory signaling. These findings pinpoint coincidence detection of bFGF and TGF-β signaling by FRS2 as a mechanism that controls tumor cell invasion. Thus, targeting FRS2 represents an emerging strategy to abrogate aberrant FGFR signaling.
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•FGFR-FRS2 activation promotes brain tissue infiltration and tumor dissemination•FRS2 integrates bFGF and TGF-β signaling to enable pro-invasive cell functions•Non-canonical TGF-β signaling represses pro-invasive FGFR-FRS2 function•TGF-β represses ERK-mediated negativefeedback regulation of FRS2
Santhana Kumar et al. describe how growth factors in the microenvironment of medulloblastoma, the most common malignant brain tumor in children, are sensed by the tumor cells and how they respond to these factors. They identify the adaptor protein FRS2 as a key molecule controlling growth factor-induced tissue infiltration.
Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children. Though histologically benign and associated with excellent outcome, patients with unresectable lesions--mostly young ...children with midline tumors--experience multiple progressions and are at increased risk for long-term neurological sequelae. PLGGs in children with underlying genetic predisposition syndromes--especially neurofibromatosis type 1 and tuberous sclerosis--have a distinct natural history and biology with important treatment implications. Given the complexity of medical issues, optimal management requires a large network of health care providers; treatment decisions must address both tumor control and potential side effects of the therapy. Current treatment strategies often fail to induce sustained tumor regression and many children require several lines of therapy, highlighting the need for novel therapies. Here, we review the current management of PLGG and discuss how new molecular targets--in particular alterations of the Ras/MAPK pathway--are rapidly changing our approach to PLGG.
Children diagnosed with diffuse midline gliomas (DMG) have an extremely poor overall survival: 9–12 months from diagnosis with currently no curative treatment options. Given DMG molecular ...heterogeneity, surgical biopsies are needed for molecular profiling and as part of enrolment into molecular-based and precision medicine type clinical interventions. In this study, we describe the results of real time profiling and drug testing at the diffuse intrinsic pontine glioma/DMG Research Centre at University Children's Hospital Zurich.
Biopsies were taken using a frame based stereotactic robot system (NeuroMate®, Renishaw) at University Children's Hospital Zurich. Tissue samples were evaluated to confirm diagnosis by H3K27M and H3K27 trimethylation loss. Genomic analyses were done using a variety of platforms (INFORM, Oncomine, UCSF500 gene panel).
Cell lines were developed by mechanical tissue dissociation and verified by either sequencing or immunofluorescence staining confirming H3K27M mutation and used afterwards for drug testing.
Twenty-five robot-assisted primary biopsies were successfully performed. Median hospital stay was 2 days (range 1–4 days). Nine low-passage patient-derived cells were developed, whereas 8 cell lines were used to inform response to clinically relevant drugs. Genome and RNA expression were used to further guide treatment strategies with targeted agents such as dual PI3K/mTOR inhibitor paxalisib.
We established a systematic workflow for safe, robot-assisted brainstem biopsies and in-house tissue processing, followed by real-time drug testing. This provides valuable insights into tumour prognostic and individual treatment strategies targeting relevant vulnerabilities in these tumours in a clinically meaningful time frame.
•Robot-assisted brainstem biopsy for pontine diffuse midline gliomas (DMG) is feasible and safe.•Real-time drug testing on patient-derived DMG cells define individualised treatments.•Targeted agents as paxalisib can be successfully integrated into the care of DMG.
The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of post-pubertal and adult patients ...with medulloblastoma. The guideline is based on the 2016 WHO classification of tumours of the CNS and on scientific developments published since 1980. It aims to provide direction for diagnostic and management decisions, and for limiting unnecessary treatments and cost. In view of the scarcity of data in adults with medulloblastoma, we base our recommendations on adult data when possible, but also include recommendations derived from paediatric data if justified. Our recommendations are a resource for professionals involved in the management of post-pubertal and adult patients with medulloblastoma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
Diencephalic syndrome is usually associated with tumors in the hypothalamic region, rarely occurring in patients with neurofibromatosis type 1 (NF1)-associated gliomas. We describe the clinical ...presentation and response to treatment in 3 patients with NF1 presenting with diencephalic syndrome as first symptom of optic pathway/hypothalamic glioma (OPHG). Because of the rarity of this constellation, knowledge about the clinical course and best treatment options for patients with NF1-associated OPHG and diencephalic syndrome is still limited. All 3 patients showed good response to treatment with normalization of body mass index and decrease in tumor volume within 6 months.
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