Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

Ahead of print publication  

Pediatric low-grade glioma and neurofibromatosis type 1: A single-institution experience

1 Pediatric Oncology Unit, Department of Women and Child Health, Fondazione Policlinico Universitario A. Gemelli Hospital Foundation IRCCS, Universita' Cattolica del Sacro Cuore, Rome, Italy
2 Pediatric Neurosurgery Unit, Department of Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universita' Cattolica del Sacro Cuore, Rome, Italy
3 Radiology and Neuroradiology Unit, Department of Radiological Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universita' Cattolica del Sacro Cuore, Rome, Italy

Date of Submission22-Sep-2021
Date of Acceptance22-Jan-2022
Date of Web Publication02-Nov-2022

Correspondence Address:
Antonio Ruggiero,
Paediatric Oncology Unit,. Gemelli Hospital Foundation IRCCS, Catholic University of Sacred Hearth, Largo A. Gemelli 8, 00168 Rome
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_1677_21

 > Abstract 

Background: Neurofibromatosis type 1 (NF1)-related gliomas appear to have a clinical behavior different from that of sporadic cases. The purpose of the study was to investigate the role of different factors in influencing the tumor response rate of children receiving chemotherapy for their symptomatic glioma.
Methods: Between 1995 and 2015, 60 patients with low-grade glioma (42 sporadic cases and 18 cases with NF1) were treated. Patients with brainstem gliomas were excluded. Thirty-nine patients underwent exclusive or postsurgical chemotherapy (vincristine/carboplatin-based regimen).
Results: Disease reduction was achieved in 12 of the 28 patients (42.8%) with sporadic low-grade glioma and in 9 of the 11 patients (81.8%) with NF1, with a significant difference between the 2 groups (P < 0.05). The response to chemotherapy in both the patient groups was not significantly influenced by sex, age, tumor site, and histopathology, although disease reduction occurred more frequently in children aged under 3 years.
Conclusions: Our study showed that pediatric patients with low-grade glioma and NF1 are more likely to respond to chemotherapy than those with non-NF1.

Keywords: carboplatin, chemotherapy, children, glioma, neurofibromatosis type 1, outcome

How to cite this URL:
Ruggiero A, Attinà G, Campanelli A, Maurizi P, Triarico S, Romano A, Massimi L, Tamburrini G, Verdolotti T, Mastrangelo S. Pediatric low-grade glioma and neurofibromatosis type 1: A single-institution experience. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=360435

 > Introduction Top

Low-grade gliomas represent 35% of central nervous system tumors in the pediatric age group. Children with neurofibromatosis type 1 (NF1) are at a risk of developing tumors. Up to 20% of children with NF1 can develop a low-grade glioma, with optic pathway gliomas being a hallmark lesion.[1],[2] High-grade gliomas can also be found in NF1 but are almost only observed during adulthood.[3]

NF1 is a genetic neurocutaneous disease caused by a mutation in the NF1 gene at chromosome 17 that encodes neurofibromin, which is a cytoplasmic protein that acts as a negative regulator of cell proliferation.[4],[5]

Conversely, sporadic glioma development is caused by the activation of the BRAF oncogene, resulting from the fusion of its kinase domain coding region with the KIAA1549 gene.[6]

Surgical resection, when possible, is generally the preferred treatment, although the application of surgery can be limited in certain anatomical sites as in optic pathway gliomas. Radiotherapy is generally restricted to older children, but it is usually not performed in children with NF1 owing to the risk of vasculopathy and second malignancies.[7],[8],[9] Incompletely resected gliomas can have a different behavior, especially in patients with NF1: They may remain stable for a long time, progress, or even present spontaneous regression.[10],[11] Although the natural history of Optic pathway gliomas (OPGs) is not yet fully understood, it is known that they are often indolent in NF1 with prolonged stable disease (SD) and even spontaneous regressions. In addition, in NF1-associated gliomas, tumor enhancement can fluctuate over time. At present, no risk factors are reported to be predictive of tumor progression, with the rates of progression quite variable.

The primary approach for children with nonprogressive or nonsurgical tumors is close clinical observation both in children with NF1-associated and sporadic glioma. The therapeutic course in pediatric glioma is performed when tumor progression with documented clinical deterioration (impairment of visual or neurological function, diencephalic syndrome, or raised intracranial pressure) is detected and, less commonly, when further progression is identified by imaging investigations.[12]

The main therapeutic approach in children is based on chemotherapy with carboplatin/vincristine combination therapy;[13] in addition to these two drugs, vinblastine, temozolomide, and nerve growth factors have also been used in patients unresponsive to first-line chemotherapy.[14],[15],[16]

NF1-related gliomas seem to have a clinical behavior different from that of sporadic cases. They are more often symptom free, tend to have a very slow progression, and may undergo spontaneous regression; conversely, sporadic cases tend to have earlier and more severe clinical presentation.[17],[18]

Recent data have shown the potential different role of peri-tumoral microenvironment; in NF1-related gliomas, neoplastic cells stimulate microglial activation, which consequently increases tumor growth. However, the role of microglia in the growth of sporadic gliomas is not known.[19]

Therefore, a different action of this microenvironment could play a role in determining a different clinical behavior and response to chemotherapy.

The purpose of our study was to investigate the role of different factors in determining the tumor response rate of children receiving chemotherapy for symptomatic glioma.

The identification of predictive factors regarding the tumor response to chemotherapy might be of interest in future clinical trials for tailoring treatment in children affected by NF1 or sporadic low-grade gliomas.


Our study assessed 74 consecutive children with low-grade gliomas treated in the Paediatric Oncology Unit of A. Gemelli Hospital between 1995 and 2015.

The patients had newly diagnosed gliomas with symptomatic residual tumors and/or progressive tumors after surgery. If surgery was not feasible, further nonsurgical treatment was determined by neuroimaging evidence of progression and/or by the appearance of visual, endocrinological, and neurologic symptoms.

The additional inclusion criteria were as follows: diagnosis of NF1 or non-NF1-related low-grade glioma; no previous treatment, except for surgery; age < 18 years; and follow-up duration of at least 2 years since the end of treatment or, for those undergoing clinical and neuroradiological checkups only, diagnosis.

In addition, children with a chiasmatic–hypothalamic tumor intrinsic to the optic pathway (mostly patients with NF1 and classical optic pathway glioma) but without radiological criteria of high-grade malignancy were considered eligible without histopathological assessment.

The children with sporadic and NF1 gliomas presented a variety of symptoms at the time of diagnosis, including visual impairment, endocrine alterations (diabetes insipidus and/or precocious puberty), developmental delay, raised intracranial pressure, and epilepsy. However, the presence of visual and endocrine disturbances was more frequent in the children with NF1.

Patients with diffuse intrinsic pontine glioma were excluded.[20]

Fourteen children (n = 3 with NF1) were considered ineligible because they discontinued the treatment (presence of toxicity, n = 9; withdrawal by parents, n = 2; and loss to follow-up, n = 3).

For each patient, the following characteristics were analyzed: age at the time of diagnosis, NF1 status, lesion location, onset symptoms, treatment, and lesion progression and evolution over time. All children with newly diagnosed incompletely resected gliomas who were symptomatic were treated within 6 weeks of surgery.

By assessing the subgroup of patients undergoing chemotherapy (exclusive or postsurgery), the response to treatment in terms of progression, stability, or lesion reduction was evaluated. Twenty-seven children were treated after 2004 and underwent treatment with the International Society for Paediatric Oncology (SIOP) low-grade glioma (LGG) 2004 carboplatin and vincristine-based protocol.[21] Ten patients were treated according to the previous SIOP LGG protocols (2001 and 1997) using carboplatin/vincristine/cisplatin and two patients were treated according to different protocols, where lomustine and procarbazine were added to vincristine and carboplatin. However, regardless of the scheme used, all patients undergoing chemotherapy were administered carboplatin and vincristine.

To evaluate the response to therapy, the low-grade glioma Response Assessment in Neuro-Oncology criteria were used to divide the response into five types based on magnetic resonance imaging (MRI) findings: complete response (disappearance of all lesions), partial response (reduction of ≥ 50%), minor response (MR, disease reduction of 25%–50%), (SD, lesion stability or lesion increase or decrease of < 25%), and progressive disease (PD, increase of ≥ 25%).[22] T2- and T2-fluid-attenuated inversion recovery sequences were considered for assessing tumor changes.

Specific cerebral lesions or changes of signal intensity identified on MRI of NF-1-associated glioma, formerly known as “unidentified bright objects” but now preferentially termed “focal areas of (high) signal intensity” or alternatively “focal abnormal signal intensities,” as well as hamartomatous lesions were not considered for the present analysis.

The findings of the MRIs performed at the end of the induction and consolidation phases of the treatment protocol were examined. The sixty patients were subdivided into subgroups to highlight any parameters that correlated with a better response to chemotherapy.

The data obtained were assessed using the SPSS version 24 software (IBM SPSS Statistics for Windows, Version 24. Armonk, NY: IBM Corp). The descriptive data were expressed as percentages for categorical variables and as means/medians and standard deviations for continuous variables.

The variables were compared using Fisher's exact test, with the significance level set at α = 0.05.

Prior to their participation, the caregivers provided signed consent forms after being informed about the aim of the project as foreseen by the Italian law on privacy and the safeguarding of sensitive data (D. Lgs n196, 2003). The project was performed in accordance with the principles of the Declaration of Helsinki. Approval by the ethics committee was not necessary for a retrospective observational study on clinical practice data.

 > Results Top

The follow-up duration for the 60 patients starting from the end of treatment or from the time of diagnosis (for those who underwent only clinical and neuroradiological checkups) ranged from 2 to 20 years, with a mean of 7 years and 5 months and a median of 5 years and 5 months. Forty-two patients (70%) had sporadic gliomas, and 18 (30%) had NF1-related gliomas.

The sample consisted of 34 boys (56.7%) and 26 girls (43.3%). The age at diagnosis ranged from 4 months to 16 years, with a mean of 5 years and 5 months and a median of 4 years.

The 60 children were divided into 4 age groups: <3 years, 21 patients (35%); 3–8 years, 24 (40.3%); 8–14 years, 12 (20%); and 14–18 years, 3 (5%).

Regarding the location, the tumors were predominantly located at the optic pathways in 35 patients (58.3%), posterior fossa in 9 (15%), hemispheres in 10 (16.7%), thalamus in 2 (3.3%), and median line in 2 (3.3%); 2 patients (3.3%) had a multifocal tumor distribution. Fifty-five patients had pilocytic astrocytoma, and 5 had pilomyxoid astrocytoma.

The 60 patients received the following treatments: chemotherapy using vincristine and carboplatin exclusively (n = 14) or postsurgery (n = 25), exclusive surgery (biopsy or partial removal, n = 19), and local radiotherapy (n = 2). Of the 39 patients receiving chemotherapy, 11 had NF1, and 28 had sporadic gliomas. The 21 children who received only surgery or radiotherapy did not need adjunctive treatments because, during their regular clinical and radiological follow-up for the residual tumor, no signs and/or symptoms of PD were detected.

Treatment outcomes

Taking into account the findings of the brain MRIs performed at the end of induction and the end of consolidation, 21 of the 39 patients receiving chemotherapy had MR and 18 patients had SD.

Comparison between patients with NF1-associated gliomas and those with sporadic gliomas.

Overall, disease reduction was achieved in 21 patients: 9 with NF1 and 12 with sporadic gliomas.

Hence, further chemotherapy glioma reduction was achieved in 9 out of the 11 patients with NF1 (81.8%) and 12 out of the 28 patients with sporadic gliomas (42.8%) (P < 0.05).

There were no significant differences between NF1-related and sporadic gliomas with respect to age, sex, tumor site, tumor size, and histopathology [Table 1].
Table 1: Clinical features of children with sporadic and neurofibromatosis type 1-gliomas receiving chemotherapy

Click here to view


The 39 children undergoing chemotherapy were divided according to their age at the time of low-grade glioma treatment.

Sixteen children were < 3 years old at the time of treatment; 9 of them (56.3%) showed disease reduction (MR), and 7 had SD. The age of 17 children ranged from 3 to 8 years: 10 (58.8%) showed disease reduction (MR), and 7 had SD. The age of 5 patients ranged from 8 to 14 years; 1 (20%) showed disease reduction (MR), and the other 4 had SD. Finally, only 1 patient was in the age group of 14–18 years and achieved disease reduction (MR).

Therefore, after further chemotherapy, a better response was observed among patients with an earlier onset age; however, this correlation did not reach the level of statistical significance (P = 0.38).

In addition, our sample was analyzed to assess the potential correlation between early-onset age and the worst response to therapy in patients with optic pathway gliomas.[15]

There were 28 patients with optic pathway gliomas undergoing chemotherapy; they were divided into subgroups based on the age at the time of treatment, similarly to what has been performed previously. Fourteen patients were < 3 years old at the time of diagnosis; 8 (57.1%) showed disease reduction (MR), and 6 had SD. The age of 11 patients ranged from 3 to 8 years; among these, disease reduction (MR) occurred in 7 patients (63.6%) and SD in the other 4. The age of the last 3 patients ranged from 8 to 14 years; of these, 1 patient showed disease reduction (MR), and 2 showed SD. No patient with optic pathway glioma undergoing chemotherapy was aged above 14 years at the time of diagnosis.


Of the 39 patients receiving chemotherapy, 23 were boys, and 16 were girls. Among the 23 boys treated, 12 (52.2%) showed disease reduction (MR), and 11 showed SD. Among the 16 girls, 9 (56.3%) showed disease reduction (MR), and 7 showed SD.

Tumor site

Among the 39 patients receiving chemotherapy for their symptomatic tumor, 28 had gliomas involving the optic pathway; 1, thalamus; 1, midline; 5, posterior fossa/brainstem; and 3, cerebral hemisphere; 1 had multifocal localization. The 5 children with posterior fossa/brainstem tumors were not eligible for further surgery owing to brainstem involvement.

In the subgroup of patients with optic pathway gliomas, 16 children (57.1%) with disease reduction (MR) and 12 with SD were registered. Of the patients with posterior fossa/brainstem gliomas, 3 (60%) showed disease reduction (MR), and 2 showed SD.

Of the patients with cerebral hemisphere gliomas and those with multifocal gliomas, none showed disease reduction. Conversely, both patients with thalamic gliomas and the single patient with midline glioma showed disease reduction (MR).

Tumor size

Thirteen children had a residual tumor size of < 1.5 cm2, 17 children had a residual tumor size between 1.5 and 3 cm2, and 9 children had a residual tumor size of > 3 cm2; the response rate (MR + SD) was 65%, 62%, and 55%, respectively (P > 0.5).


Among the 39 patients receiving chemotherapy, 34 had pilocytic astrocytoma, and 5 had pilomyxoid astrocytoma. Of the patients with pilocytic astrocytoma, 16 (47%) had disease reduction (MR), and 18 had SD. Of the patients with pilomyxoid astrocytoma, 4 (80%) showed disease reduction (MR), and 1 showed SD.


The 5-year overall survival (OS) was 94.4% for patients with NF1 and 95.2% for those with sporadic gliomas (among the 39 patients treated with chemotherapy).

The event-free survival (EFS) for patients with NF1 was 53 ± 31.3 months (confidence interval [CI]: 0.000–114.3) and that for patients with non-NF1-related low-grade gliomas was 41.6 ± 7.6 months (CI: 26.7–56.6) [Figure 1]. However, the EFS difference between the two groups was not statistically significant (P = 0.580).
Figure 1: EFS in the patient groups (Kaplan–Meier survival curves) (EFS = event-free survival)

Click here to view

 > Discussion Top

Some studies seem to demonstrate that NF1-related low-grade gliomas have a better clinical behavior and prognosis than sporadic gliomas, i.e., higher OS and fewer associated complications.[4],[23]

The primary aims of our study were to compare the tumor response between patients with NF1 and non-NF1 low-grade gliomas receiving chemotherapy and to identify potential prognostic factors that can help stratification in future clinical trials among children.

In our analysis, no significant differences between NF1-related and sporadic gliomas has been registered with respect to age, sex, tumor site, size, and histopathology. However, disease reduction was achieved with a significant difference more frequently in children with NF1-glioma.

The peculiarities of the gliomas associated with this genetic pathology are not limited to the clinical presentation, location, and prognosis; they also affect the response to chemotherapy.

There are only a few published series systematically comparing the role of chemotherapy in children with NF1 and non-NF1 low-grade gliomas.

Ater et al. showed that the combination of carboplatin and vincristine is associated with a 5-year EFS of 39% for non-NF1-related gliomas and 69% for gliomas related to NF1 status.[24] However, up to 47% of responsive patients receiving carboplatin-based chemotherapy can develop hypersensitivity to carboplatin, a significant complication that can cause sometimes life-threatening events, requiring discontinuation of treatment.[25],[26],[27]

Packer et al. have reported a response rate of 56% in their 31 patients receiving carboplatin/vincristine, with no significant difference in the 2-year progression-free survival between children with NF1 and non-NF1 (79% and 75%, respectively).[13]

In their series of 44 patients (16 with NF1), Deliganis et al. compared the 5- and 10-year survival rates between NF1- and non-NF1-associated optic pathway gliomas. The 5- and 10-year survival rates for patients with optic pathway gliomas and NF1 were 93% and 81%, respectively; conversely, those for children without NF1 were 83% and 76%, respectively. However, the OS, as evaluated using the log-rank test for the respective Kaplan–Meier survival curves, was not statistically significant between the two groups.[28]

Similar and favorable survival rates were reported by Singhal et al. in their series of sporadic and NF1-associated optic pathway gliomas. The 5- and 10-year survival rates for NF1 gliomas were 77% and 67% compared with 80% and 57% for sporadic optic pathway gliomas, respectively.[29]

Studies adopting carboplatin as monotherapy have reported a limited response rate but no significant differences between patients with NF1 and sporadic gliomas.[30],[31]

The results of our retrospective study confirm that pediatric patients with NF1-related low-grade gliomas have a significantly higher response to chemotherapy than patients with sporadic gliomas although the OS and EFS are not significantly different in both the groups. Therefore, chemotherapy could be helpful in symptom control rather than long survival.

Younger age at diagnosis, subtotal surgical resection, and chiasmatic–hypothalamic tumor location have been considered significant predictors for tumor progression and as potential factors impacting OS. However, previous studies have reported no definitive data on the role of these prognostic factors in terms of response to chemotherapy.[24],[29],[32]

In our series, the response to chemotherapy in both the groups was not significantly influenced by sex, age, anatomical site, tumor size, and histopathology, although disease reductions occurred more frequently in children aged < 3 years. Such a difference could be useful for planning future clinical studies for children with low-grade gliomas considering risk stratification, thus avoiding comparisons between the patient groups (NF1 versus non-NF1) with different clinical outcomes and prognoses. In addition, considering this difference, treatment could be reduced for children's groups with better prognosis to permit a more tailored treatment, avoiding the risk of long-term toxicity, such as ototoxicity, cognitive deficits, or second malignant neoplasms.

A significant role in determining a different clinical behavior of sporadic NF1-related low-grade gliomas might involve the tumor microenvironment.

Microglia are among the most important stromal cells in the tumor microenvironment; they belong to the mononuclear phagocytic system and play a role in the maintenance of cerebral homoeostasis by promoting neuronal survival, potentiating synaptic transmission, and synthesizing neurotrophic factors; however, they can also produce chemokines, growth factors, and inflammatory mediators.[33],[34]

To induce NF1-associated gliomagenesis in mice, both copies of the NF1 gene must be inactivated in the GFAP-positive neuroglial progenitors; however, this is not sufficient for the development of gliomas. This implies that additional factors are necessary for carcinogenesis.[19] It was suggested that neoplastic glial cells release soluble factors (”stromagens”) that recruit or activate the microglia, which consequently produce molecules that promote tumor proliferation (”gliomagens”).[19],[35] The CX3CR1 chemokine receptor is highly expressed in NF1+/− microglia, and a reduction in its expression is associated with a delayed development of optic pathway gliomas in heterozygous NF1 mice.[4] Furthermore, Simmons et al. showed that the inactivation of microglia in genetically engineered mice using minocycline or a JNK inhibitor resulted in a reduction in glioma proliferation in vivo.[36],[37]

The role of the microenvironment in the formation of non-NF1-related gliomas is different and less clear. KIAA1549:BRAF regulates neuroglial growth through the activation of mTOR; however, the role of microglia in glioma growth is not known.[38],[39]

Therefore, a different action of the microenvironment on sporadic and NF1-related gliomas could play a role in determining a different clinical behavior and a different response to chemotherapy; furthermore, as it might represent an important therapeutic target, its role must be further explored.

The use of measuring contrast enhancement on MRI to define response to treatment in children with LGG can be negatively affected due to the evidence that these tumors might not enhance at all or might enhance heterogeneously. Diffusion-weighted imaging can be utilized in addition to conventional MRI to provide further information on tumor response to treatment. The apparent diffusion coefficient (ADC), a measure of the magnitude of tissutal water molecules diffusion, is generally higher in LGG than in high-grade gliomas. Following antineoplastic treatment and consequent cellular lysis, changes in ADC values are expected as response to therapy.

Anyway, potential misinterpretations when measuring ADC values can be present. ADC values can be reduced in the presence of cytotoxic edema and increased when tumoral tissue undergoes lysis. In addition, intratumoral hemorrhages and calcifications can influence the diffusion imaging and relative ADC values. Therefore, these data should be always integrated with other MRI sequences in order to detect correctly the tumoral changes.[39],[40]

Targeted therapies have been recently adopted for the treatment of LGGs. Bevacizumab, a monoclonal anti-vascular endothelial growth factor antibody, has been used for the treatment of NF1-related OPGs obtaining visual improvement in some children. More recently, investigational clinical trials with MEK inhibitors, such as trametinib and selumetinib, have been completed suggesting activity in relapsed or progressive LGGs.[41],[42],[43]

The large-scale use of sophisticated technologies and effective preclinical models allowed the conception of personalized treatments for NF1-related tumors.[33] However, precision medicine requires the identification of subgroups of patients with a higher probability of response to specific treatments, and this stratification assumes an extensive understanding of the factors that determine disease heterogeneity. In this context, our study emphasizes the possible role of the microenvironment in determining different responses to chemotherapy in the two subgroups.

However, our study's limitations include the retrospective analysis, the lack of sample homogeneity, both for age and location, the fact that the IDH status of the assessed patients and their molecular biology were not known.[39]

 > Conclusions Top

The response to chemotherapy in both the groups of patients was not significantly influenced by sex, age, tumor location, tumor size, and histopathology, although disease reductions occurred more frequently in children affected by NF1.

In conclusion, our study confirms that children with low-grade gliomas and NF1 have significantly higher response rates to chemotherapy than patients with low-grade gliomas not associated with this genetic disorder.

 > Acknowledgments Top

The authors thank the “Carriero Family” for their support to the pediatric research in remembrance of Carriero Lino.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

de Blank PM, Fisher MJ, Liu GT, Gutmann DH, Listernick R, Ferner RE, et al. Optic pathway gliomas in neurofibromatosis type 1: An update: Surveillance, treatment indications, and biomarkers of vision. J Neuroophthalmol 2017;37 Suppl 1:S23-32.  Back to cited text no. 1
Szudek J, Birch P, Riccardi VM, Evans DG, Friedman JM. Associations of clinical features in neurofibromatosis 1 (NF1). Genet Epidemiol 2000;19:429-39.  Back to cited text no. 2
D'Angelo F, Ceccarelli M, Tala, Garofano L, Zhang J, Frattini V, et al. The molecular landscape of glioma in patients with Neurofibromatosis 1. Nat Med 2019;25:176-87.  Back to cited text no. 3
Helfferich J, Nijmeijer R, Brouwer OF, Boon M, Fock A, Hoving EW, et al. Neurofibromatosis type 1 associated low grade gliomas: A comparison with sporadic low grade gliomas. Crit Rev Oncol Hematol 2016;104:30-41.  Back to cited text no. 4
Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis type 1 revisited. Pediatrics 2009;123:124-33.  Back to cited text no. 5
Jones DT, Kocialkowski S, Liu L, Pearson DM, Bäcklund LM, Ichimura K, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008;68:8673-7.  Back to cited text no. 6
Guillamo JS, Créange A, Kalifa C, Grill J, Rodriguez D, Doz F, et al. Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1): A retrospective study of 104 patients. Brain 2003;126:152-60.  Back to cited text no. 7
Sharif S, Ferner R, Birch JM, Gillespie JE, Gattamaneni HR, Baser ME, et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: Substantial risks after radiotherapy. J Clin Oncol 2006;24:2570-5.  Back to cited text no. 8
Grill J, Couanet D, Cappelli C, Habrand JL, Rodriguez D, Sainte-Rose C, et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 1999;45:393-6.  Back to cited text no. 9
Perilongo G, Moras P, Carollo C, Battistella A, Clementi M, Laverda A, et al. Spontaneous partial regression of low-grade glioma in children with neurofibromatosis-1: A real possibility. J Child Neurol 1999;14:352-6.  Back to cited text no. 10
Rozen WM, Joseph S, Lo PA. Spontaneous regression of low-grade gliomas in pediatric patients without neurofibromatosis. Pediatr Neurosurg 2008;44:324-8.  Back to cited text no. 11
Rasool N, Odel JG, Kazim M. Optic pathway glioma of childhood. Curr Opin Ophthalmol 2017;28:289-95.  Back to cited text no. 12
Packer RJ, Ater J, Allen J, Phillips P, Geyer R, Nicholson HS, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 1997;86:747-54.  Back to cited text no. 13
Falsini B, Ziccardi L, Lazzareschi I, Ruggiero A, Placentino L, Dickmann A, et al. Longitudinal assessment of childhood optic gliomas: Relationship between flicker visual evoked potentials and magnetic resonance imaging findings. J Neurooncol 2008;88:87-96.  Back to cited text no. 14
Falsini B, Chiaretti A, Rizzo D, Piccardi M, Ruggiero A, Manni L, et al. Nerve growth factor improves visual loss in childhood optic gliomas: A randomized, double-blind, phase II clinical trial. Brain 2016;139:404-14.  Back to cited text no. 15
Ruggiero A, Rizzo D, Attinà G, Lazzareschi I, Mastrangelo S, Maurizi P, et al. Phase I study of temozolomide combined with oral etoposide in children with recurrent or progressive medulloblastoma. Eur J Cancer 2010;46:2943-9.  Back to cited text no. 16
Robert-Boire V, Rosca L, Samson Y, Ospina LH, Perreault S. Clinical presentation and outcome of patients with optic pathway glioma. Pediatr Neurol 2017;75:55-60.  Back to cited text no. 17
Czyzyk E, Jóźwiak S, Roszkowski M, Schwartz RA. Optic pathway gliomas in children with and without neurofibromatosis 1. J Child Neurol 2003;18:471-8.  Back to cited text no. 18
Chen YH, Gutmann DH. The molecular and cell biology of pediatric low-grade gliomas. Oncogene 2014;33:2019-26.  Back to cited text no. 19
Louis N, Liu S, He X, Drummond DC, Noble CO, Goldman S, et al. New therapeutic approaches for brainstem tumors: A comparison of delivery routes using nanoliposomal irinotecan in an animal model. J Neurooncol 2018;136:475-84.  Back to cited text no. 20
Cooperative Multicenter Study for Children and Adolescents with Low Grade Glioma – SIOP LGG 2004. International Consortium on Low Grade Glioma – ICLGG of the International Society of Pediatric Oncology –SIOP; 2004.  Back to cited text no. 21
Wen PY, Chang SM, Van den Bent MJ, Vogelbaum MA, Macdonald DR, Lee EQ. Response assessment in neuro-oncology clinical trials. J Clin Oncol 2017;35:2439-49.  Back to cited text no. 22
Krishnatry R, Zhukova N, Guerreiro Stucklin AS, Pole JD, Mistry M, Fried I, et al. Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study. Cancer 2016;122:1261-9.  Back to cited text no. 23
Ater JL, Xia C, Mazewski CM, Booth TN, Freyer DR, Packer RJ, et al. Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: A report from the Children's Oncology Group. Cancer 2016;122:1928-36.  Back to cited text no. 24
Ruggiero A, Triarico S, Trombatore G, Battista A, Dell'acqua F, Rizzari C, et al. Incidence, clinical features and management of hypersensitivity reactions to chemotherapeutic drugs in children with cancer. Eur J Clin Pharmacol 2013;69:1739-46.  Back to cited text no. 25
Timeus F, Crescenzio N, Longoni D, Doria A, Foglia L, Pagliano S, et al. Paroxysmal nocturnal hemoglobinuria clones in children with acquired aplastic anemia: A multicentre study. PLoS One 2014;9:e101948.  Back to cited text no. 26
Ruggiero A, Rizzo D, Catalano M, Maurizi P, Mastrangelo S, Attinà G, et al. Rechallenge to carboplatin in children with low grade glioma and carboplatin hypersensitivity reactions. Front Pharmacol 2017;8:179.  Back to cited text no. 27
Deliganis AV, Geyer JR, Berger MS. Prognostic significance of type 1 neurofibromatosis (von Recklinghausen Disease) in childhood optic glioma. Neurosurgery 1996;38:1114-8.  Back to cited text no. 28
Singhal S, Birch JM, Kerr B, Lashford L, Evans DG. Neurofibromatosis type 1 and sporadic optic gliomas. Arch Dis Child 2002;87:65-70.  Back to cited text no. 29
Mahoney DH Jr., Cohen ME, Friedman HS, Kepner JL, Gemer L, Langston JW, et al. Carboplatin is effective therapy for young children with progressive optic pathway tumors: A Pediatric Oncology Group phase II study. Neuro Oncol 2000;2:213-20.  Back to cited text no. 30
Listernick R, Charrow J, Tomita T, Goldman S. Carboplatin therapy for optic pathway tumors in children with neurofibromatosis type-1. J Neurooncol 1999;45:185-90.  Back to cited text no. 31
Stokland T, Liu JF, Ironside JW, Ellison DW, Taylor R, Robinson KJ, et al. A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: A population-based cohort study (CCLG CNS9702). Neuro Oncol 2010;12:1257-68.  Back to cited text no. 32
Chiaretti A, Aloe L, Antonelli A, Ruggiero A, Piastra M, Riccardi R, et al. Neurotrophic factor expression in childhood low-grade astrocytomas and ependymomas. Childs Nerv Syst 2004;20:412-9.  Back to cited text no. 33
Hanisch UK. Microglia as a source and target of cytokines. Glia 2002;40:140-55.  Back to cited text no. 34
Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garbow JR, et al. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res 2003;63:8573-7.  Back to cited text no. 35
Warrington NM, Woerner BM, Daginakatte GC, Dasgupta B, Perry A, Gutmann DH, et al. Spatiotemporal differences in CXCL12 expression and cyclic AMP underlie the unique pattern of optic glioma growth in neurofibromatosis type 1. Cancer Res 2007;67:8588-95.  Back to cited text no. 36
Simmons GW, Pong WW, Emnett RJ, White CR, Gianino SM, Rodriguez FJ, et al. Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth. J Neuropathol Exp Neurol 2011;70:51-62.  Back to cited text no. 37
Kaul A, Chen YH, Emnett RJ, Dahiya S, Gutmann DH. Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev 2012;26:2561-6.  Back to cited text no. 38
D'Arco F, Culleton S, De Cocker LJ, Mankad K, Davila J, Tamrazi B. Current concepts in radiologic assessment of pediatric brain tumors during treatment, part 1. Pediatr Radiol 2018;48:1833-43.  Back to cited text no. 39
Boonzaier NR, Hales PW, D'Arco F, Walters BC, Kaur R, Mankad K, et al. Quantitative MRI demonstrates abnormalities of the third ventricle subventricular zone in neurofibromatosis type-1 and sporadic paediatric optic pathway glioma. Neuroimage Clin 2020;28:102447.  Back to cited text no. 40
Nellan A, Wright E, Campbell K, Davies KD, Donson AM, Amani V, et al. Retrospective analysis of combination carboplatin and vinblastine for pediatric low-grade glioma. J Neurooncol 2020;148:569-75.  Back to cited text no. 41
Fangusaro J, Onar-Thomas A, Poussaint TY, Wu S, Ligon AH, Lindeman N, et al. A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: A Pediatric Brain Tumor Consortium study. Neuro Oncol 2021;23:1777-88.  Back to cited text no. 42
Selt F, van Tilburg CM, Bison B, Sievers P, Harting I, Ecker J, et al. Response to trametinib treatment in progressive pediatric low-grade glioma patients. J Neurooncol 2020;149:499-510.  Back to cited text no. 43


  [Figure 1]

  [Table 1]


     Search Pubmed for
    -  Ruggiero A
    -  Attinà G
    -  Campanelli A
    -  Maurizi P
    -  Triarico S
    -  Romano A
    -  Massimi L
    -  Tamburrini G
    -  Verdolotti T
    -  Mastrangelo S
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  >Abstract>Introduction>Results>Discussion>Conclusions>Acknowledgments>Article Figures>Article Tables
  In this article

 Article Access Statistics
    PDF Downloaded1    

Recommend this journal