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Neuro-oncology Jan 2021The aim of the project was to identify risk factors associated with visual progression and treatment indications in pediatric patients with neurofibromatosis type 1...
BACKGROUND
The aim of the project was to identify risk factors associated with visual progression and treatment indications in pediatric patients with neurofibromatosis type 1 associated optic pathway glioma (NF1-OPG).
METHODS
A multidisciplinary expert group consisting of ophthalmologists, pediatric neuro-oncologists, neurofibromatosis specialists, and neuro-radiologists involved in therapy trials assembled a cohort of children with NF1-OPG from 6 European countries with complete clinical, imaging, and visual outcome datasets. Using methods developed during a consensus workshop, visual and imaging data were reviewed by the expert team and analyzed to identify associations between factors at diagnosis with visual and imaging outcomes.
RESULTS
Eighty-three patients (37 males, 46 females, mean age 5.1 ± 2.6 y; 1-13.1 y) registered in the European treatment trial SIOP LGG-2004 (recruited 2004-2012) were included. They were either observed or treated (at diagnosis/after follow-up).In multivariable analysis, factors present at diagnosis associated with adverse visual outcomes included: multiple visual signs and symptoms (adjusted odds ratio [adjOR]: 8.33; 95% CI: 1.9-36.45), abnormal visual behavior (adjOR: 4.15; 95% CI: 1.20-14.34), new onset of visual symptoms (adjOR: 4.04; 95% CI: 1.26-12.95), and optic atrophy (adjOR: 3.73; 95% CI: 1.13-12.53). Squint, posterior visual pathway tumor involvement, and bilateral pathway tumor involvement showed borderline significance. Treatment appeared to reduce tumor size but improved vision in only 10/45 treated patients. Children with visual deterioration after primary observation are more likely to improve with treatment than children treated at diagnosis.
CONCLUSIONS
The analysis identified the importance of symptomatology, optic atrophy, and history of vision loss as predictive factors for poor visual outcomes in children with NF1-OPG.
Topics: Child; Child, Preschool; Cohort Studies; Europe; Female; Humans; Magnetic Resonance Imaging; Male; Neurofibromatosis 1; Optic Nerve Glioma; Risk Factors
PubMed: 32628746
DOI: 10.1093/neuonc/noaa153 -
Journal of Medical Genetics Jun 2003
Topics: Alternative Splicing; Amino Acid Substitution; Cafe-au-Lait Spots; Child; Child, Preschool; DNA; Genes, Neurofibromatosis 1; Genetic Variation; Genotype; Humans; Infant; Infant, Newborn; Intellectual Disability; Learning Disabilities; Mutation; Neurofibroma; Neurofibroma, Plexiform; Neurofibromatosis 1; Neurofibromin 1; Optic Nerve Glioma; Phenotype; RNA Processing, Post-Transcriptional; Recurrence; Scoliosis; Skin Neoplasms
PubMed: 12807981
DOI: 10.1136/jmg.40.6.e82 -
Orphanet Journal of Rare Diseases Feb 2017Non-optic gliomas occur in 5% of children with NF1, but little is known about these tumours in adults. We aimed to investigate progression, spontaneous regression and...
BACKGROUND
Non-optic gliomas occur in 5% of children with NF1, but little is known about these tumours in adults. We aimed to investigate progression, spontaneous regression and the natural history of non-optic gliomas in adults and compare these findings to the results found in children.
RESULTS
One thousand seven hundred twenty-two brain MRI scans of 562 unselected individuals with NF1 were collected at the NF outpatient department of the University Hospital Hamburg-Eppendorf between 2003 and 2015. The number of scans per patient ranged from one to 12; patients were followed for a median of 3.7 years. We identified 24 patients (4.3%) with non-optic gliomas. Median age at first scan with glioma was 21.2 years, much higher than in previous publications. Only seven of the 24 non-optic glioma patients were symptomatic. Five of 24 patients had multiple non-optic gliomas. Four individuals developed a new tumour, and 4 cases showed progression. The risk of new tumour development was 0.19% (95% confidence interval 0.06% to 0.52%) per patient year of follow-up for patients over 10 years. The rate of progressing non-optic gliomas per patient year of follow-up in the first 5 years after tumour diagnosis was 4.7% (95% confidence interval 1.5% to 12%).
CONCLUSIONS
Non-optic gliomas are twice as common in an unselected cohort of NF1 patients as previously reported. This is likely due to increased frequency of diagnosis of asymptomatic tumours when routine MRIs are performed and a higher prevalence in older individuals.
Topics: Adolescent; Adult; Central Nervous System Neoplasms; Child; Female; Glioma; Humans; Male; Middle Aged; Neurofibromatoses; Young Adult
PubMed: 28202035
DOI: 10.1186/s13023-017-0588-2 -
Neuro-oncology Advances 2019As a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One... (Review)
Review
As a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One of the most common locations for these cancers is the central nervous system, where low-grade gliomas predominate in children. During early childhood, gliomas affecting the optic pathway are most frequently encountered, whereas gliomas of the brainstem and other locations are observed in slightly older children. In contrast, the majority of gliomas arising in adults with NF1 are malignant cancers, typically glioblastoma, involving the cerebral hemispheres. Our understanding of the pathogenesis of NF1-associated gliomas has been significantly advanced through the use of genetically engineered mice, yielding new targets for therapeutic drug design and evaluation. In addition, murine glioma models have served as instructive platforms for defining the cell of origin of these tumors, elucidating the critical role of the tumor microenvironment in determining tumor growth and vision loss, and determining how cancer risk factors (sex, germline mutation) impact on glioma formation and progression. Moreover, these preclinical models have permitted early phase analysis of promising drugs that reduce tumor growth and attenuate vision loss, as an initial step prior to translation to human clinical trials.
PubMed: 32642668
DOI: 10.1093/noajnl/vdz040 -
Journal of Child Neurology Jan 2018Neurofibromatosis type 1 (NF1) is one of the most common brain tumor predisposition syndromes, in which affected children are prone to the development of low-grade... (Review)
Review
Neurofibromatosis type 1 (NF1) is one of the most common brain tumor predisposition syndromes, in which affected children are prone to the development of low-grade gliomas. While NF1-associated gliomas can be found in several brain regions, the majority arise in the optic nerves, chiasm, tracts, and radiations (optic pathway gliomas; OPGs). Owing to their location, 35-50% of affected children present with reduced visual acuity. Unfortunately, despite tumor stabilization following chemotherapy, vision does not improve in most children. For this reasons, more effective therapies are being sought that reflect a deeper understanding of the NF1 gene and the use of authenticated Nf1 genetically-engineered mouse strains. The implementation of these models for drug discovery and validation has galvanized molecularly-targeted clinical trials in children with NF1-OPG. Future research focused on defining the cellular and molecular factors that underlie optic glioma development and progression also has the potential to provide personalized risk assessment strategies for this pediatric population.
Topics: Animals; Humans; Neurofibromatosis 1; Optic Nerve Glioma
PubMed: 29246098
DOI: 10.1177/0883073817739509 -
Frontiers in Oncology 2023Diencephalic tumors tend to be low grade tumors located near several critical structures, including the optic nerves, optic chiasm, pituitary, hypothalamus, Circle of... (Review)
Review
Diencephalic tumors tend to be low grade tumors located near several critical structures, including the optic nerves, optic chiasm, pituitary, hypothalamus, Circle of Willis, and hippocampi. In children, damage to these structures can impact physical and cognitive development over time. Thus, the goal of radiotherapy is to maximize long term survival while minimizing late effects, including endocrine disruption leading to precocious puberty, height loss, hypogonadotropic hypogonadism, and primary amenorrhea; visual disruption including blindness; and vascular damage resulting in cerebral vasculopathy. Compared to photon therapy, proton therapy offers the potential to decrease unnecessary dose to these critical structures while maintaining adequate dose to the tumor. In this article, we review the acute and chronic toxicities associated with radiation for pediatric diencephalic tumors, focusing on the use of proton therapy to minimize treatment-related morbidity. Emerging strategies to further reduce radiation dose to critical structures will also be considered.
PubMed: 37213290
DOI: 10.3389/fonc.2023.1123082 -
Brain Tumor Research and Treatment Apr 2022Optic pathway glioma (OPG) is a rare tumor located in optic nerve, optic tract, or optic chiasm. Treatment options for OPG include surgery, radiation therapy (RT), and... (Review)
Review
Optic pathway glioma (OPG) is a rare tumor located in optic nerve, optic tract, or optic chiasm. Treatment options for OPG include surgery, radiation therapy (RT), and chemotherapy. Although RT may provide favorable long-term outcomes in manner of either adjuvant or salvage aim, chemotherapy-first approach is increasingly performed due to possible late effects of RT. Proton beam RT may allow normal tissue sparing of radiation exposure compared to conventional X-ray treatment. Therefore, proton beam RT is expected to reduce complications from RT. This review discusses the recent updates on oncologic outcomes of OPG, late toxicities following RT, and compares the outcomes between X-ray treatment and proton beam RT.
PubMed: 35545828
DOI: 10.14791/btrt.2022.0003 -
Cancer Management and Research 2023Optic pathway glioma (OPG) occurs in as many as one-fifth of individuals with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Generally considered... (Review)
Review
Optic pathway glioma (OPG) occurs in as many as one-fifth of individuals with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Generally considered low-grade and slow growing, many children with NF1-OPGs remain asymptomatic. However, due to their location within the optic pathway, ~20-30% of those harboring NF1-OPGs will experience symptoms, including progressive vision loss, proptosis, diplopia, and precocious puberty. While treatment with conventional chemotherapy is largely effective at attenuating tumor growth, it is not clear whether there is much long-term recovery of visual function. Additionally, because these tumors predominantly affect young children, there are unique challenges to NF1-OPG diagnosis, monitoring, and longitudinal management. Over the past two decades, the employment of authenticated genetically engineered -OPG mouse models have provided key insights into the function of the protein, neurofibromin, as well as the molecular and cellular pathways that contribute to optic gliomagenesis. Findings from these studies have resulted in the identification of new molecular targets whose inhibition blocks murine -OPG growth in preclinical studies. Some of these promising compounds have now entered into early clinical trials. Future research focused on defining the determinants that underlie optic glioma initiation, expansion, and tumor-induced optic nerve injury will pave the way to personalized risk assessment strategies, improved tumor monitoring, and optimized treatment plans for children with NF1-OPG.
PubMed: 37465080
DOI: 10.2147/CMAR.S362678 -
Journal of Neuroscience Research Jan 2019Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 gene. The NF1-encoded protein (neurofibromin) is an inhibitor of... (Review)
Review
Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 gene. The NF1-encoded protein (neurofibromin) is an inhibitor of the oncoprotein RAS and controls cell growth and survival. Individuals with NF1 are prone to developing low-grade tumors of the optic nerves, chiasm, tracts, and radiations, termed optic pathway gliomas (OPGs), which can cause vision loss. A paucity of surgical tumor specimens and of patient-derived xenografts for investigative studies has limited our understanding of human NF1-associated OPG (NF1-OPG). However, mice genetically engineered to harbor Nf1 gene mutations develop optic gliomas that share many features of their human counterparts. These genetically engineered mouse (GEM) strains have provided important insights into the cellular and molecular determinants that underlie mouse Nf1 optic glioma development, maintenance, and associated vision loss, with relevance by extension to human NF1-OPG disease. Herein, we review our current understanding of NF1-OPG pathobiology and describe the mechanisms responsible for tumor initiation, growth, and associated vision loss in Nf1 GEM models. We also discuss how Nf1 GEM and other preclinical models can be deployed to identify and evaluate molecularly targeted therapies for OPG, particularly as they pertain to future strategies aimed at preventing or improving tumor-associated vision loss in children with NF1.
Topics: Animals; Disease Models, Animal; Genes, Neurofibromatosis 1; Humans; Mice; Neurofibromatosis 1; Optic Nerve Glioma
PubMed: 29704429
DOI: 10.1002/jnr.24250 -
Neuro-oncology Aug 2022Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk...
BACKGROUND
Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk factors for treatment failure.
METHODS
We performed a retrospective multi-institutional cohort study to identify baseline risk factors for treatment-refractory/relapsed disease and poor visual outcome in children with NF1-OPG. Refractory/relapsed NF1-OPG was defined as a requirement of two or more treatment regimens due to progression or relapse.
RESULTS
Of 111 subjects eligible for inclusion, adequate clinical and visual data were available for 103 subjects from 7 institutions. Median follow-up from the initiation of first chemotherapy regimen was 95 months (range 13-185). Eighty-four (82%) subjects received carboplatin-based frontline chemotherapy. Forty-five subjects (44%) experienced refractory/relapsed disease, with a median time of 21.5 months (range 2-149) from the initiation of first treatment to the start of second treatment. The proportion of patients without refractory/relapsed disease at 2 and 5 years was 78% and 60%. In multivariable analyses, age less than 24 months at initial treatment, posterior tumor location, and familial inheritance were associated with refractory/relapsed NF1-OPG by 2 years. Both age less than 24 months and posterior tumor location were associated with refractory/relapsed NF1-OPG by 5 years. Subjects with moderate to severe vision loss at last follow-up were more likely to have posterior tumor location, optic disc abnormalities, or abnormal visual acuity at initial treatment.
CONCLUSION
Young age, posterior tumor location, and optic disc abnormalities may identify patients with the greatest likelihood of refractory/relapsed NF1-OPG and poor visual outcomes, and who may benefit from newer treatment strategies.
Topics: Child; Cohort Studies; Humans; Infant; Neurofibromatosis 1; Optic Nerve Glioma; Retrospective Studies; Risk Factors
PubMed: 35018469
DOI: 10.1093/neuonc/noac013