optic glioma
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Author(s):  
Amanda de Andrade Costa ◽  
Jit Chatterjee ◽  
Olivia Cobb ◽  
Elizabeth Cordell ◽  
Astoria Chao ◽  
...  

Abstract Background Brain tumor formation and progression are dictated by cooperative interactions between neoplastic and non-neoplastic cells. This stromal dependence is nicely illustrated by tumors arising in the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where children develop low-grade optic pathway gliomas (OPGs). Using several authenticated Nf1-OPG murine models, we previously demonstrated that murine Nf1-OPG growth is regulated by T cell function and microglia Ccl5 production, such that their inhibition reduces tumor proliferation in vivo. While these interactions are critical for established Nf1-OPG tumor growth, their importance in tumor formation has not been explored. Methods A combination of bulk and single cell RNA mouse optic nerve sequencing, immunohistochemistry, T cell assays, and pharmacologic and antibody-mediated inhibition methods were used in these experiments. Results We show that T cells and microglia are the main non-neoplastic immune cell populations in both murine and human LGGs. Moreover, we demonstrate that CD8 + T cells, the predominant LGG-infiltrating lymphocyte population, are selectively recruited through increased Ccl2 receptor (Ccr4) expression in CD8 +, but not CD4 +, T cells, in a NF1/RAS-dependent manner. Finally, we identify the times during gliomagenesis when microglia Ccl5 production (3-6 weeks of age) and Ccl2-mediated T cell infiltration (7-10 weeks of age) occur, such that temporally-restricted Ccl2 or Ccl5 inhibition abrogates tumor formation >3.5 months following the cessation of treatment. Conclusions Collectively, these findings provide proof-of-concept demonstrations that targeting stromal support during early gliomagenesis durably blocks murine LGG formation.


2021 ◽  
Vol 12 ◽  
pp. 630
Author(s):  
Christopher Newell ◽  
Alan Chalil ◽  
Kristopher D. Langdon ◽  
Vahagn Karapetyan ◽  
Matthew O. Hebb ◽  
...  

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon but aggressive neoplasms associated with radiation exposure and neurofibromatosis Type I (NF1). Their incidence is low compared to other nervous system cancers, and intramedullary spinal lesions are exceedingly rare. Only a few case reports have described intramedullary spinal cord MPNST. Case Description: We describe the clinical findings, management, and outcome of a young patient with NF1 who developed aggressive cranial nerve and spinal MPNST tumors. This 35-year-old patient had familial NF1 and a history of optic glioma treated with radiation therapy (RT). She developed a trigeminal MPNST that was resected and treated with RT. Four years later, she developed bilateral lower extremity deficits related to an intramedullary cervical spine tumor, treated surgically, and found to be a second MPNST. Conclusion: To the best of our knowledge, this is the first report of cranial nerve and intramedullary spinal MPNSTs manifesting in a single patient, and only the third report of a confined intramedullary spinal MPNST. This unusual case is discussed in the context of a contemporary literature review.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jit Chatterjee ◽  
Shilpa Sanapala ◽  
Olivia Cobb ◽  
Alice Bewley ◽  
Andrea K. Goldstein ◽  
...  

AbstractTo elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4–6 weeks of age (WOA), Nf1OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1OPG mice at 4–6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi212-vi212
Author(s):  
Yuan Pan ◽  
Jared Hysinger ◽  
Tara Barron ◽  
Nicki Schindler ◽  
Olivia Cobb ◽  
...  

Abstract Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis-1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic pathway gliomas [OPGs]), during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1-OPG to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing visual experience via light deprivation prevents tumor formation and maintenance. We show that Nf1-OPG initiation depends on visual experience during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.


Phacomatosis is the general name for a group of diseases (Neurofibromatosis 1 (NF-1), Neurofibromatosis 2 (NF-2), Von Hippel Lindau, tuberous sclerosis, ataxia-telangiectasia, and Sturge Weber syndrome) that include different clinical syndromes characterized by eye, skin, neurological and oncological symptoms. They are formed as a result of tumor suppressor protein loss, which controls the abnormal growth of cells. Most of these diseases are autosomal dominant. Neurofibromatosis -1 is the most common type of phacomatosis. autosomal dominant passes. Skin (cafe au-lait = milk coffee stain, armpit, and inguinal freckles), ocular involvement, and nerve involvement (neurofibromas) are seen. In NF-2, in addition to NF-1, 8th cranial nerve involvement is present. In ocular involvement of neurofibromatosis, proptosis, strabismus, pulsatile exophthalmos, ptosis may occur due to neurofibromas. Hamartomas in iris (lisch nodules), posterior subcapsular cataract (more often in NF-2), retinal astrocytic hamartomas, and optic glioma can be seen. Von Hippel Lindau passes autosomal dominant. Brain (cerebellum) spinal cord, renal cell carcinoma, pheochromocytoma, pancreatic neuroendocrine tumors, and renal or pancreatic cysts may occur as systemic involvement. Retinal hemangioblastomas can be seen in ocular involvement. Tuberous sclerosis passes autosomal dominantly. It is a disease in the group of phacomatosis, characterized by hamartomas affecting more than one organ, including the skin, central nervous system, lung, heart, and kidney. Multiple astrocytic hamartomas can be seen in ocular involvement. In conclusion, when these lesions are seen in the eyes, it is necessary to treat them with a multidisciplinary approach considering that systemic involvement may occur.


2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i31-i31
Author(s):  
Yuan Pan ◽  
Jared Hysinger ◽  
Nicki Schindler ◽  
Olivia Cobb ◽  
Xiaofan Guo ◽  
...  

Abstract Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic gliomas) during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1 optic glioma to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing optic nerve activity via light deprivation prevents tumor formation and maintenance. By manipulating environmental light to modulate optic pathway (retinal) neuron activity, we show that Nf1 optic glioma initiation depends on neuronal activity during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacologic inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce optic glioma incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.


Nature ◽  
2021 ◽  
Author(s):  
Yuan Pan ◽  
Jared D. Hysinger ◽  
Tara Barron ◽  
Nicki F. Schindler ◽  
Olivia Cobb ◽  
...  

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14042-e14042
Author(s):  
Inci Yaman Bajin ◽  
David Nathan Korones ◽  
Burca Aydin ◽  
Kader Karli Oguz ◽  
Nilgun Kurucu ◽  
...  

e14042 Background: Optic gliomas are the most common tumors of the optic pathway, comprising about 1% of all intracranial tumours. Here we present the clinical characteristics and the outcome of patients with optic glioma at our institution. Methods: Seventy two patients diagnosed and followed up at a pediatric cancer center in Ankara, Turkey between January 1, 2008 and December 31, 2020 were included in this analysis. The clinical features and outcome of patients were recorded from patient files and hospital information system retrospectively. Results: The median age at the time of diagnosis was 3.5 years (4-157 months), the female/male ratio was 1.3. Fourteen children (19%) were asymptomatic and tumors were detected with routine surveillance, and 58 (81%) had symptoms (the most common being proptosis in 16 patients (22%)). The most common site of optic glioma was the intraorbital region (31%). Fourty patients (55%) had neurofibromatosis type 1 (NF-1). Five patients had histopathological diagnoses; 3 pilomyxoid astrocytoma, 2 pilocytic astrocytoma. Children were treated if they had tumor progression on MRI and/or worsening visual acuity. Twenty seven (38%) children were observed without any therapy, 6 patients (8%) received radiation and chemotherapy, 4 patients (5%) received radiation only, and 35 patients (49%) received chemotherapy only. Treatment regimens for the 41 children who received chemotherapy included carboplatin/etoposide (17), cisplatin/etoposide (18), carboplatin/vincristine (5), and temozolomide (1). The 5-year progression-free survival (PFS) and overall survival (OS) were 64% and 90%, respectively with a 31 month median follow-up. The 5 year PFS was significantly lower in patients with optic tract-hypothalamic-chiasmatic involvement (34%) than orbital involvement (83%) (p=0.013). Five year PFS was significantly higher in patients with NF-1 (80%) than patients without NF-1(46%) (p=0.027) and significantly lower in patients diagnosed at <3 years old (37%) (p=0.05). Five patients died of disease, and one died of infection after chemotherapy. Two patients treated with platin (1 carboplatin, 1 cisplatin) developed ototoxicity. One patient with NF-1 developed Moya-Moya disease. Two patients developed multiple pituitary hormone deficiencies and one patient developed precocious puberty during follow-up. No secondary malignancy was observed. Conclusions: The management of optic glioma remains challenging. Although the overall survival for children with this disease is excellent, progression of disease is frequent, particularly in those children without NF-1, younger children and non-orbital tumors. This study from Turkey showed comparable results with high-income countries. Further studies with longer follow-up periods are needed to find appropriate treatment strategies.


2020 ◽  
Author(s):  
Nicole M Brossier ◽  
Sharanya Thondapu ◽  
Olivia M Cobb ◽  
Sonika Dahiya ◽  
David H Gutmann

Abstract Background Brain tumors are the most common solid tumors of childhood, but little is understood about the factors that influence their development. Pediatric low-grade gliomas in particular display unique temporal and spatial localization associated with different genetic mutations (eg, BRAF genomic alterations, mutations in the neurofibromatosis type 1 [NF1] gene) for reasons that remain unclear. NF1 low-grade gliomas typically arise in the optic pathway of young children as optic pathway gliomas (OPGs), likely from a cell of origin that resides within the third ventricular zone (TVZ). However, the factors that contribute to their distinct temporal patterning and penetrance have not been adequately explored. Methods TVZ neuroglial progenitor cells (NPCs) were analyzed over the course of mouse brain development. Progenitors isolated by fluorescence-activated cell sorting (FACS) were assessed for functional and molecular differences. The impact of different germline Nf1 mutations on TVZ NPC properties was analyzed using genetically engineered mice. Results We identify 3 individual factors that could each contribute to Nf1 optic glioma temporal patterning and penetrance. First, there are 3 functionally and molecularly distinct populations of mouse TVZ NPCs, one of which (“M” cells) exhibits the highest clonogenic incidence, proliferation, and abundance during embryogenesis. Second, TVZ NPC proliferation dramatically decreases after birth. Third, germline Nf1 mutations differentially increase TVZ NPC proliferation during embryogenesis. Conclusions The unique temporal patterning and penetrance of Nf1 optic glioma reflects the combined effects of TVZ NPC population composition, time-dependent changes in progenitor proliferation, and the differential impact of the germline Nf1 mutation on TVZ NPC expansion.


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