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Neuro-oncology Jun 2015Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the...
BACKGROUND
Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth.
METHODS
Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma-bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction.
RESULTS
Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1-deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1-deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK-mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma-associated retinal ganglion cell loss and nerve fiber layer thinning.
CONCLUSION
These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1-optic pathway glioma clinical trials.
Topics: Animals; Astrocytes; Brain Neoplasms; Cell Proliferation; Humans; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Neurofibromatosis 1; Neurofibromin 1; Optic Nerve Glioma; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases
PubMed: 25534823
DOI: 10.1093/neuonc/nou329 -
Operative Neurosurgery (Hagerstown, Md.) Feb 2022There is no consensus on the optimal surgical approach for managing optic nerve gliomas. For solely intraorbital tumors, a single-stage lateral orbitotomy approach for...
BACKGROUND AND IMPORTANCE
There is no consensus on the optimal surgical approach for managing optic nerve gliomas. For solely intraorbital tumors, a single-stage lateral orbitotomy approach for resection may be performed, but when the nerve within the optic canal is affected, two-stage cranial and orbital approaches are often used. The authors describe their technique to safely achieve aggressive nerve resection to minimize the probability of recurrence that might affect the optic tracts, optic chiasm, and contralateral optic nerve.
CLINICAL PRESENTATION
A 28-yr-old woman presented with painless progressive vision loss, resulting in blindness. The second of 2 transorbital biopsies was diagnostic and consistent with low-grade glioma. The lesion continued to grow on serial imaging. The patient was offered a globe-sparing operative approach, with aggressive resection of the lesion to minimize the probability of tumor recurrence, which could possibly affect vision in her contralateral eye. The patient did well postoperatively, with clean tumor margins on pathological analysis and no evidence of residual on imaging. On postoperative examination, she had a mild ptosis, which was nearly resolved at her 6-wk outpatient follow-up.
CONCLUSION
This aggressive single-stage en bloc resection of an optic nerve glioma can achieve excellent tumor margins and preservation of extraocular muscle function.
Topics: Female; Humans; Margins of Excision; Optic Chiasm; Optic Nerve; Optic Nerve Glioma; Orbit
PubMed: 35007223
DOI: 10.1227/ONS.0000000000000027 -
Journal Francais D'ophtalmologie May 2020
Topics: Child; Female; Humans; Magnetic Resonance Imaging; Neurofibromatosis 1; Optic Nerve Glioma
PubMed: 32241588
DOI: 10.1016/j.jfo.2019.09.016 -
AJR. American Journal of Roentgenology Apr 2019Neurofibromatosis type 1 (NF1) is a multisystemic genetic disease in which patients develop benign tumors including optic nerve gliomas (ONG). Optic nerve thickening and...
OBJECTIVE
Neurofibromatosis type 1 (NF1) is a multisystemic genetic disease in which patients develop benign tumors including optic nerve gliomas (ONG). Optic nerve thickening and tortuosity are radiologic markers of tumors but can also be present in children with NF1 who do not have gliomas, thus complicating screening and diagnosis. We undertook this study to retrospectively determine quantitative and qualitative diagnostic criteria using MRI of the orbits for ONG in children with NF1.
MATERIALS AND METHODS
MR images of the orbits obtained from 2003 to 2016 for children with and without NF1 were reviewed. Optic nerves were divided into three groups: NF1 with glioma (n = 71 nerves), NF1 without glioma (n = 151 nerves), and healthy control subjects (n = 66 nerves). The diameter of each nerve was measured at multiple locations. Two radiologists assessed tortuosity using validated criteria, and subarachnoid dilatation was quantified. Last, a composite score using both optic nerve diameter and tortuosity was proposed.
RESULTS
The mean diameter of the optic nerve was significantly larger in patients with NF1 with glioma compared with those with NF1 without glioma and with control subjects at all locations. Maximal nerve diameter greater than 2 SD above the mean maximal diameter for control nerves was considered abnormally enlarged. The tortuosity parameters were all significantly associated with ONG compared with absence of ONG in NF1. A scoring system derived from these data were highly reliable in differentiating ONG from absence of ONG in NF1.
CONCLUSION
The radiologic diagnosis of ONG in patients with NF1 is challenging. The scoring systems we describe provide a framework for simple radiologic criteria for ONG in these patients.
Topics: Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Magnetic Resonance Imaging; Male; Neurofibromatosis 1; Optic Nerve Glioma; Retrospective Studies
PubMed: 30741560
DOI: 10.2214/AJR.18.20044 -
Current Opinion in Neurology Dec 2003Optic tract low-grade gliomas are one of the commonest category of neoplasm presenting in childhood and early adolescence. Recent reports covering their aetiology,... (Review)
Review
PURPOSE OF REVIEW
Optic tract low-grade gliomas are one of the commonest category of neoplasm presenting in childhood and early adolescence. Recent reports covering their aetiology, imaging techniques, the application of novel radiotherapy techniques and chemotherapy are reported.
RECENT FINDINGS
These tumours are increasingly being seen as markers of enhanced risk in patients and their families for the subsequent development of central nervous system tumours. Modern imaging techniques are being explored for their diagnostic sensitivity and specificity as well as their ability to describe, with greater precision, anatomical boundaries in order to minimize, through conformal techniques, radiation doses to organs at risk within the brain. Increasing numbers of trials of chemotherapy agents are demonstrating efficacy in this tumour category.
SUMMARY
Visual pathway low-grade astrocytomas of childhood are the subject of diverse research into diagnostic aetiological and treatment aspects aimed at tailoring diagnostic and treatment procedures more precisely to the needs of the young patient for this tumour type.
Topics: Child; Drug Therapy; Genetic Predisposition to Disease; Humans; Neoplasm Invasiveness; Neurofibromatosis 1; Optic Nerve; Optic Nerve Glioma; Pedigree; Predictive Value of Tests; Radiography; Radiotherapy
PubMed: 14624073
DOI: 10.1097/01.wco.0000102628.38669.14 -
Journal of Neuropathology and... May 2009Individuals with neurofibromatosis type 1 (NF1) are prone to develop optic pathway gliomas that can result in significant visual impairment. To explore the cellular...
Individuals with neurofibromatosis type 1 (NF1) are prone to develop optic pathway gliomas that can result in significant visual impairment. To explore the cellular basis for the reduced visual function resulting from optic glioma formation, we used a genetically engineered mouse model of Nf1 optic glioma (Nf1+/-(GFAP)CKO mice). We performed multimodal functional and structural analyses both before and after the appearance of macroscopic tumors. At 6 weeks of age, before obvious glioma formation, Nf1+/-(GFAP)CKO mice had decreased visual-evoked potential amplitudes and increased optic nerve axon calibers. By 3 months of age, Nf1+/-(GFAP)CKO mice exhibited pronounced optic nerve axonopathy and apoptosis of neurons in the retinal ganglion cell layer. Magnetic resonance diffusion tensor imaging showed a progressive increase in radial diffusivity between 6 weeks and 6 months of age in the optic nerve proximal to the tumor indicating ongoing deterioration of axons. These data suggest that optic glioma formation results in early axonal disorganization and damage, which culminates in retinal ganglion cell death. Collectively, this study shows that Nf1+/-(GFAP)CKO mice can provide a useful model for defining mechanisms of visual abnormalities in children with NF1 and lay the foundations for future interventional studies aimed at reducing visual loss.
Topics: Age Factors; Animals; Anisotropy; Axons; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Electroretinography; Evoked Potentials, Visual; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Neurofibromatosis 1; Optic Nerve; Optic Nerve Glioma; Phosphopyruvate Hydratase
PubMed: 19525901
DOI: 10.1097/NEN.0b013e3181a3240b -
European Journal of Cancer (Oxford,... Aug 2006A systematic literature review was carried out to evaluate best existing evidence on prognostic factors for progression of childhood optic pathway glioma. Databases were... (Review)
Review
A systematic literature review was carried out to evaluate best existing evidence on prognostic factors for progression of childhood optic pathway glioma. Databases were searched for relevant articles and articles selected independently by two authors. Information about study design, population, treatment, outcome and prognostic analysis were abstracted and the quality of each article was assessed. A total of 23 articles met the inclusion criteria. Many studies had important methodological limitations, regarding external and internal validity. Eleven studies evaluated possible prognostic factors in a multivariate analysis. Three high-quality studies indicated age<1 year as an independent prognostic factor for a worse progression-free survival. Three studies with multivariate analysis, including one high-quality study, found that children with neurofibromatosis type 1 (NF-1) have a better progression-free survival than those without NF-1. Two studies with multivariate analysis found tumour site to be a prognostic factor, both with some methodological limitations. In conclusion, this systematic review demonstrates that only a few of the prognostic factors proposed have been proven to be clinically relevant. Age<1 year is a clear and independent prognostic factor for progression-free survival. Other prognostic factors, such as NF-1, tumour site and others, are suggested, but are still without solid evidence and need further high-quality studies to be clearly proven.
Topics: Disease Progression; Epidemiologic Methods; Humans; Optic Nerve Glioma; Prognosis
PubMed: 16809032
DOI: 10.1016/j.ejca.2006.02.022 -
Journal of Neuro-ophthalmology : the... Dec 2022To determine whether patients with biopsy-confirmed optic nerve glioma differ in clinical features and outcomes from those diagnosed by neuroradiologic imaging alone.
BACKGROUND
To determine whether patients with biopsy-confirmed optic nerve glioma differ in clinical features and outcomes from those diagnosed by neuroradiologic imaging alone.
METHODS
Retrospective comparative analysis. Pilocytic astrocytomas (PAs) and gliomas of the optic nerve were identified through ICD-O codes in the Surveillance, Epidemiology, and End Results (SEER) cancer registry from 1975 through 2017. Demographics, clinical features, and outcomes were compared according to the method of diagnosis (biopsy-confirmed and radiologic only) and by age (birth through 19 years and 20 years of age and older). Differences in proportions were tested with the chi-square test. Associations with tumor-related death were evaluated with logistic regression. Statistical significance: α < 0.01.
RESULTS
Over 42 years, 313 PAs and 720 gliomas of the optic nerve were identified. The young age distributions were similar between the 2 groups. PAs were biopsied more often than gliomas (54% vs 13.2% [ P < 0.001]). Tumor-attributable death occurred more often among PAs and gliomas that were biopsied than those that were not (7.1% vs 0.7% [ P < 0.01]; 7.4% vs 1.1% [ P < 0.01], respectively). Roughly 15% of both PAs and gliomas were diagnosed in persons 20 years and older.
CONCLUSIONS
Biopsy-confirmed cases of PA and glioma of the optic nerve were associated with more therapeutic interventions and worse outcomes compared with patients who were diagnosed radiologically. Clinical variables relevant to clinical decision-making not captured by SEER likely explain the inability to meaningfully interpret outcome from the registry database. Cancer registries should avoid coding specific histopathologic diagnoses when tissue is not obtained.
Topics: Humans; Young Adult; Adult; Retrospective Studies; Astrocytoma; Optic Nerve Glioma; Optic Nerve; Biopsy
PubMed: 36166806
DOI: 10.1097/WNO.0000000000001630 -
Child's Nervous System : ChNS :... Jun 2021Optic pathway gliomas (OPGs), also known as visual pathway gliomas, are debilitating tumors that account for 3-5% of all pediatric brain tumors. They are most commonly... (Review)
Review
BACKGROUND
Optic pathway gliomas (OPGs), also known as visual pathway gliomas, are debilitating tumors that account for 3-5% of all pediatric brain tumors. They are most commonly WHO grade 1 pilocytic astrocytomas and frequently occur in patients with neurofibromatosis type 1. The location of these tumors results in visual loss and blindness, endocrine and hypothalamic dysfunction, hydrocephalus, and premature death. Their involvement of the visual pathways and proximity to other eloquent brain structures typically precludes complete resection or optimal radiation dosing without incurring significant neurological injury. There are various surgical interventions that can be performed in relation to these lesions including biopsy, cerebrospinal fluid diversion, and partial or radical resection, but their role is a source of debate. This study catalogues our surgical experience and patient outcomes in order to support decision-making in this challenging pathology.
METHODS
A retrospective review of all cases of OPGs treated in a single center from July 1990 to July 2020. Data was collected on patient demographics, radiographic findings, pathology, and management including surgical interventions. Outcome data included survival, visual function, endocrine, and hypothalamic dysfunction.
RESULTS
One hundred twenty-one patients with OPG were identified, and 50 of these patients underwent a total of 104 surgical procedures. These included biopsy (31), subtotal or gross total resection (20 operations in 17 patients), cyst drainage (17), Ommaya reservoir insertion (9), or cerebrospinal fluid diversion (27). During the study period, there was 6% overall mortality, 18% hypothalamic dysfunction, 20% endocrine dysfunction, and 42% had some cognitive dysfunction. At diagnosis 75% of patients had good or moderate visual function in at least one eye, and overall, this improved to 83% at the end of the study period. In comparison the worst eye had good or moderate visual function in 56%, and this reduced to 53%. Baseline and final visual function were poorer in patients who had a surgical resection, but improvements in vision were still found-particularly in the best eye.
DISCUSSION/CONCLUSION
OPG are debilitating childhood tumor that have lifelong consequences in terms of visual function and endocrinopathies/hypothalamic dysfunction; this can result in substantial patient morbidity. Decisions regarding management and the role of surgery in this condition are challenging and include cerebrospinal fluid diversion, biopsy, and in highly select cases cystic decompression or surgical resection. In this paper, we review our own experience, outcomes, and surgical philosophy.
Topics: Astrocytoma; Brain Neoplasms; Child; Humans; Neurofibromatosis 1; Neurosurgical Procedures; Optic Nerve Glioma; Retrospective Studies; Treatment Outcome
PubMed: 33532921
DOI: 10.1007/s00381-021-05060-8 -
Handbook of Clinical Neurology 2012
Review
Topics: Humans; Hypothalamic Neoplasms; Optic Nerve Glioma; Thalamus
PubMed: 22230521
DOI: 10.1016/B978-0-444-53502-3.00011-2