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Nature Jun 2021Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse...
Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours. Although the role of neurons in tumour progression has previously been demonstrated, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood, raising the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1) to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.
Topics: Animals; Astrocytoma; Cell Adhesion Molecules, Neuronal; Cell Transformation, Neoplastic; Female; Genes, Neurofibromatosis 1; Germ-Line Mutation; Humans; Male; Membrane Proteins; Mice; Mutation; Nerve Tissue Proteins; Neurofibromin 1; Neurons; Optic Nerve; Optic Nerve Glioma; Photic Stimulation; Retina
PubMed: 34040258
DOI: 10.1038/s41586-021-03580-6 -
Cells Sep 2023Optic pathway gliomas (OPGs) encompass two distinct categories: benign pediatric gliomas, which are characterized by favorable prognosis, and malignant adult gliomas,... (Review)
Review
Optic pathway gliomas (OPGs) encompass two distinct categories: benign pediatric gliomas, which are characterized by favorable prognosis, and malignant adult gliomas, which are aggressive cancers associated with a poor outcome. Our review aims to explore the established standards of care for both types of tumors, highlight the emerging therapeutic strategies for OPG treatment, and propose potential alternative therapies that, while originally studied in a broader glioma context, may hold promise for OPGs pending further investigation. These potential therapies encompass immunotherapy approaches, molecular-targeted therapy, modulation of the tumor microenvironment, nanotechnologies, magnetic hyperthermia therapy, cyberKnife, cannabinoids, and the ketogenic diet. Restoring visual function is a significant challenge in cases where optic nerve damage has occurred due to the tumor or its therapeutic interventions. Numerous approaches, particularly those involving stem cells, are currently being investigated as potential facilitators of visual recovery in these patients.
Topics: Adult; Humans; Child; Neurofibromatosis 1; Optic Nerve Glioma; Brain Neoplasms; Hyperthermia, Induced; Immunotherapy; Tumor Microenvironment
PubMed: 37830595
DOI: 10.3390/cells12192380 -
Current Opinion in Ophthalmology May 2017Optic pathway gliomas (OPG) are the most common tumor of the anterior visual pathway and can involve the optic nerve, chiasm, tract, and optic radiations. They are... (Review)
Review
PURPOSE OF REVIEW
Optic pathway gliomas (OPG) are the most common tumor of the anterior visual pathway and can involve the optic nerve, chiasm, tract, and optic radiations. They are typically benign lesions, often pilocytic astrocytomas, which are diagnosed in childhood. We review the epidemiology, clinical presentation, diagnosis, and management of these lesions in patients with and without neurofibromatosis type 1 (NF-1).
RECENT FINDINGS
Most commonly, patients diagnosed with OPG have NF-1 especially if the lesions are bilateral. Such lesions tend to have a relatively indolent course and at least 50% of patients have no evidence of visual loss. Rarely, children without NF-1 may sporadically develop OPG with such lesions often having a more aggressive nature and greater propensity for visual dysfunction. The gold standard for diagnosis and follow-up are thorough neuro-ophthalmic examinations with specific attention to visual acuity. Management must be individualized and may comprise conservative follow-up, chemotherapy, radiation and/or surgical intervention.
SUMMARY
OPG may range in their behavior based upon the nature of the tumor (NF-1 or sporadic). Current guidelines recommend following patients with regular clinical examinations. Management of these lesions is highly individualized based upon the nature and extent of the lesion, visual function and side-effect profile of the treatment. Clinicians should be aware of the available options to determine which may be best suited for their patient.
Topics: Child; Child, Preschool; Humans; Magnetic Resonance Imaging; Neurofibromatosis 1; Optic Nerve Glioma; Optic Nerve Neoplasms; Visual Acuity; Visual Pathways
PubMed: 28257299
DOI: 10.1097/ICU.0000000000000370 -
International Ophthalmology Aug 2014Optic nerve glioma is the most common optic nerve tumour. However, it has an unpredictable natural history. The treatment of optic nerve gliomas has changed considerably... (Review)
Review
Optic nerve glioma is the most common optic nerve tumour. However, it has an unpredictable natural history. The treatment of optic nerve gliomas has changed considerably over the past few years. Chemotherapy and radiation therapy can now stabilize and in some cases improve the vision of patients with optic nerve gliomas. The treatment of optic nerve glioma requires a multi-disciplinary approach where all treatment options may have to be implemented in a highly individualized manner. The aim of this review article is to present current diagnostic and treatment protocols for optic nerve glioma.
Topics: Antineoplastic Agents; Combined Modality Therapy; Humans; Magnetic Resonance Imaging; Optic Nerve Glioma; Radiotherapy, Adjuvant; Tomography, Optical Coherence
PubMed: 24736941
DOI: 10.1007/s10792-014-9942-8 -
Current Opinion in Ophthalmology Sep 2019Optic pathway gliomas are low-grade neoplasms that affect the precortical visual pathway of children and adolescents. They can affect the optic nerve, optic chiasm,... (Review)
Review
PURPOSE OF REVIEW
Optic pathway gliomas are low-grade neoplasms that affect the precortical visual pathway of children and adolescents. They can affect the optic nerve, optic chiasm, optic tracts and radiations and can either be sporadic or associated with neurofibromatosis type one. Gliomas isolated to the optic nerve (ONG) represent a subgroup of optic pathway gliomas, and their treatment remains controversial. New developments in ONG treatment have emerged in recent years, and it is necessary for clinicians to have a current understanding of available therapies.
RECENT FINDINGS
The current review of the literature covers the background of and recent developments in ONG treatment, with a focus on standard chemotherapy, new molecularly targeted therapies, radiation therapy and surgical resection and debulking.
SUMMARY
Although standard chemotherapy remains the mainstay of ONG treatment, newer molecularly targeted therapies such as mitogen-activated protein kinase kinase inhibitors and bevacizumab represent a promising new treatment modality, and clinical studies are ongoing.
Topics: Adolescent; Antineoplastic Agents; Child; Female; Humans; Male; Molecular Targeted Therapy; Ophthalmologic Surgical Procedures; Optic Chiasm; Optic Nerve Glioma; Optic Nerve Neoplasms; Optic Tract; Radiotherapy
PubMed: 31246635
DOI: 10.1097/ICU.0000000000000587 -
Neuro-oncology Oct 2021Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need...
BACKGROUND
Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes.
METHODS
We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses.
RESULTS
Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash.
CONCLUSIONS
Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.
Topics: Benzimidazoles; Brain Neoplasms; Child; Humans; Neurofibromatosis 1; Optic Nerve Glioma
PubMed: 33631016
DOI: 10.1093/neuonc/noab047 -
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 -
Journal of Neurosurgery Dec 2018OBJECTIVEHemorrhage (also known as apoplexy) in optic pathway gliomas (OPGs) is rare. Because of the variable presentations and low incidence of OPG hemorrhages, little... (Review)
Review
OBJECTIVEHemorrhage (also known as apoplexy) in optic pathway gliomas (OPGs) is rare. Because of the variable presentations and low incidence of OPG hemorrhages, little is known about their clinical course and the best treatment options. The aim of this work was to review risk factors, clinical course, and treatment strategies of optic glioma hemorrhages in the largest possible number of cases.METHODSA total of 34 patients were analyzed. Nine new cases were collected, and 25 were identified in the literature. Data regarding demographics, radiological and histological features, treatment, and outcome were retrospectively reviewed.RESULTSThe majority of patients were younger than 20 years. Only 3 patients were known to have neurofibromatosis. The histopathological diagnosis was pilocytic astrocytoma in the majority of cases. Five patients had intraorbital hemorrhages, whereas 29 patients had intracranial hemorrhage; the majority of intracranial bleeds were treated surgically. Six patients, all with intracranial hemorrhage, died due to recurrent bleeding, hydrocephalus, or surgical complications. No clear risk factors could be identified.CONCLUSIONSIntracerebral OPG hemorrhages have a fatal outcome in 20% of cases. Age, hormonal status, neurofibromatosis involvement, and histopathological diagnosis have been suggested as risk factors for hemorrhage, but this cannot be reliably established from the present series. The goals of surgery should be patient survival and prevention of further neurological and ophthalmological deterioration.
Topics: Astrocytoma; Brain Neoplasms; Child; Child, Preschool; Ganglioglioma; Humans; Intracranial Hemorrhages; Magnetic Resonance Imaging; Male; Optic Nerve Glioma
PubMed: 29424646
DOI: 10.3171/2017.8.JNS163085 -
Zhurnal Voprosy Neirokhirurgii Imeni N.... 2022Optic nerve glioma is a rather rare tumor. It predominantly arises in pediatric patients, including those with type I neurofibromatosis. This neoplasm is accompanied by...
UNLABELLED
Optic nerve glioma is a rather rare tumor. It predominantly arises in pediatric patients, including those with type I neurofibromatosis. This neoplasm is accompanied by decreased visual function and exophthalmos. Treatment strategy is individualized depending on age, volume and spread of tumor, as well as severity of clinical manifestations. Possible treatment options are surgical resection, chemotherapy, radiotherapy and their combination. Radiotherapy can be recommended for patients with intact visual functions, no severe proptosis and trophic lesions. Classic fractionation mode is used as a standard. Currently, the possibility of hypofractionated irradiation is being considered.
OBJECTIVE
To evaluate safety and efficacy of hypofractionated radiotherapy in patients with optic nerve glioma.
MATERIAL AND METHODS
Sixteen patients with optic nerve gliomas underwent hypofractionated stereotactic irradiation (CyberKnife) between May 2014 and October 2019. Single focal dose was 5.5 Gy. There were 5 fractions up to total focal dose of 27.5 Gy. The sample enrolled 14 children with a median age of 4 years (range 23 months - 13 years) and 2 adults aged 47 and 66 years, respectively. Median of tumor volume was 2.77 cm (range 1.69-10.01 cm).
RESULTS
Tumor growth control was achieved in all patients, partial remission was observed in 5 (32%) patients. None patient had deterioration of visual function. Improvement of visual acuity was noted in 3 (19%) cases. Visual field enlargement occurred in 4 (67%) out of 6 patients who were preoperatively examined. After irradiation, proptosis decreased by ≥ 1 mm in 9 (60%) out of 15 patients.
Topics: Adult; Child; Child, Preschool; Exophthalmos; Humans; Infant; Neoplasms; Optic Nerve Glioma; Radiation Dose Hypofractionation; Radiosurgery; Treatment Outcome
PubMed: 36252196
DOI: 10.17116/neiro20228605174 -
[Zhonghua Yan Ke Za Zhi] Chinese... May 2023Optic nerve glioma (ONG) is a relatively rare central nervous system tumor that mainly affects children and adolescents. It can be classified into sporadic and... (Review)
Review
Optic nerve glioma (ONG) is a relatively rare central nervous system tumor that mainly affects children and adolescents. It can be classified into sporadic and neurofibromatosis type 1 (NF1)-associated types. The histological type is mainly a low-grade pilocytic astrocytoma. The typical clinical manifestations are visual impairment and painless eye protrusion, and the imaging features mainly present as fusiform swelling or irregular masses. Chemotherapy is still the first-line treatment for ONG, and other treatment options include radiotherapy, surgical resection, and molecular targeted therapy. Screening and monitoring of NF1 patients are also crucial. The prognosis of ONG is difficult to predict, and close monitoring and timely effective intervention are necessary.
Topics: Child; Adolescent; Humans; Optic Nerve Glioma; Neurofibromatosis 1; Prognosis; Vision, Low
PubMed: 37151013
DOI: 10.3760/cma.j.cn112142-20221230-00664