Guss ZD, Moningi S, Jallo GI, et al.
Management of pediatric spinal cord astrocytomas: outcomes with adjuvant radiation.
Int J Radiat Oncol Biol Phys. 2013; 85(5):1307-11 [PubMed]

PURPOSE: Pediatric intramedullary spinal cord tumors are exceedingly rare; in the United States, 100 to 200 cases are recognized annually, of these, most are astrocytomas. The purpose of this study is to report the outcomes in pediatric patients with spinal cord astrocytomas treated at a tertiary care center.
METHODS AND MATERIALS: An institutional review board-approved retrospective single-institution study was performed for pediatric patients with spinal cord astrocytomas treated at our hospital from 1990 to 2010. The patients were evaluated on the extent of resection, progression-free survival (PFS), and development of radiation-related toxicities. Kaplan-Meier curves and multivariate regression model methods were used for analysis.
RESULTS: Twenty-nine patients were included in the study, 24 with grade 1 or 2 (low-grade) tumors and 5 with grade 3 or 4 (high-grade) tumors. The median follow-up time was 55 months (range, 1-215 months) for patients with low-grade tumors and 17 months (range, 10-52 months) for those with high-grade tumors. Thirteen patients in the cohort received chemotherapy. All patients underwent at least 1 surgical resection. Twelve patients received radiation therapy to a median radiation dose of 47.5 Gy (range, 28.6-54.0 Gy). Fifteen patients with low-grade tumors and 1 patient with a high-grade tumor exhibited stable disease at the last follow-up visit. Acute toxicities of radiation therapy were low grade, whereas long-term sequelae were infrequent and manageable when they arose. All patients with low-grade tumors were alive at the last follow-up visit, compared with 1 patient with a high-grade tumor.
CONCLUSION: Primary pediatric spinal cord astrocytomas vary widely in presentation and clinical course. Histopathologic grade remains a major prognostic factor. Patients with low-grade tumors tend to have excellent disease control and long-term survival compared to those with high-grade tumors. This experience suggests that radiation therapy may enhance tumor control with an acceptably low risk of long-term sequelae in this sensitive patient population.

Gielen GH, Gessi M, Hammes J, et al.
H3F3A K27M mutation in pediatric CNS tumors: a marker for diffuse high-grade astrocytomas.
Am J Clin Pathol. 2013; 139(3):345-9 [PubMed]

Brain tumors are one of the most common childhood malignancies. Diffuse high-grade gliomas represent approximately 10% of pediatric brain tumors. Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors. We performed a pyrosequencing-based analysis for the identification of H3F3A codon 27 and codon 34 mutations in 338 pediatric brain tumors. The K27M mutation occurred in 35 of 129 glioblastomas (27.1%) and in 5 of 28 (17.9%) anaplastic astrocytomas. None of the other tumor entities showed H3F3A K27M mutation. Because H3F3A K27M mutations occur exclusively in pediatric diffuse high-grade astrocytomas, analysis of codon 27 mutational status could be useful in the differential diagnosis of these neoplasms.

Friedman GK, Spiller SE, Harrison DK, et al.
Treatment of children with glioblastoma with conformal radiation, temozolomide, and bevacizumab as adjuncts to surgical resection.
J Pediatr Hematol Oncol. 2013; 35(3):e123-6 [PubMed]

Prognosis for children with glioblastoma is unacceptably poor. Modest improvements in progression-free survival were seen in adults with glioblastoma by combining temozolomide and bevacizumab with conformal radiation. We retrospectively reviewed 3 cases of glioblastoma in children treated using upfront bevacizumab and temozolomide during radiation, followed by 12 cycles of maintenance therapy. All patients completed therapy with minimal toxicity and no delays in treatment. Two patients remain disease free at 38 and 49 months from diagnosis. One patient recurred 14 months off therapy and currently receives salvage therapy 48 months from diagnosis. These results support further investigation of this regimen.

Avery RA, Bouffet E, Packer RJ, Reginald A
Feasibility and comparison of visual acuity testing methods in children with neurofibromatosis type 1 and/or optic pathway gliomas.
Invest Ophthalmol Vis Sci. 2013; 54(2):1034-8 [PubMed]

PURPOSE: Longitudinal ophthalmologic clinical trials in young children require multiple visual acuity (VA) testing methods-especially when the subjects have cognitive and developmental delay. This study evaluated the success rate and comparability of two different VA testing methods in children with neurofibromatosis type 1 (NF1) and/or optic pathway gliomas (OPGs).
METHODS: Two institutions prospectively enrolled children 10 years or younger with NF1 and/or an OPG. Both Teller grating acuity (TAC) and recognition acuity using the computerized version of the Amblyopia Treatment Study VA testing protocol that limits responses to four letters (H, O, T, or V) were attempted in all subjects. The association of age and diagnosis of NF1 on success rate was analyzed. Differences in grating and recognition acuity were compared.
RESULTS: One hundred twenty-seven children met inclusion criteria (median age = 5.58 years). Of 127 subjects, 11 (8.7%) could not complete monocular TAC testing in either eye; 39 (30.7%) could not complete HOTV testing and were younger than those able to complete HOTV testing (mean = 2.9 vs. 7.0 years, respectively; Z = -8.3, P < 0.01). Older age was associated with successful HOTV testing and remained significant in all regression analyses (P < 0.01). The within-subject logMAR values for TAC and HOTV testing results were significantly correlated (r = 0.69, P < 0.01).
CONCLUSIONS: Young children with NF1 and/or OPGs were frequently unable to complete recognition acuity testing. These factors are important to consider when designing a clinical trial for children with NF1 and/or OPGs.

Due-Tønnessen BJ, Lundar T, Egge A, Scheie D
Neurosurgical treatment of low-grade cerebellar astrocytoma in children and adolescents: a single consecutive institutional series of 100 patients.
J Neurosurg Pediatr. 2013; 11(3):245-9 [PubMed]

OBJECT: The objective of this study was to delineate the long-term results of surgical treatment of pediatric low-grade cerebellar astrocytoma.
METHODS: One hundred consecutive children and adolescents (0-19 years old) who underwent primary tumor resection for a low-grade cerebellar astrocytoma during the years 1980-2011 were included in this retrospective study on surgical morbidity, mortality rate, academic achievement, and/or work participation. Gross motor function and activities of daily living were scored according to the Barthel Index.
RESULTS: Of the 100 patients, 61 children were in the 1st decade, and 39 were 10-19 years old. The male/female ratio was 1.13:1 (53 males, 47 females). No patients were lost to follow-up. There were no deaths in this series and all 100 patients are currently alive. In 29 patients, the follow-up duration was less than 10 years, in 37 it was between 10 and 19 years, and in 34 it was between 20 and 31 years. The Barthel Index was 100 (normal) in 97 patients, 90 in 2 patients, and 40 in the last patient. A total of 113 tumor resections were performed. Two patients underwent further tumor resection due to MRI-confirmed residual tumor demonstrated on the immediate postoperative MR image (obtained the day after the initial procedure). Furthermore, 9 children underwent repeat tumor resection after MRI-confirmed progressive tumor recurrence up to 10 years after the initial operation. Two of these patients also underwent a third resection, without subsequent radiation therapy, and have experienced 8 and 12 years of tumor-free follow-up thereafter, respectively. A total of 15% of the patients required treatment for persistent hydrocephalus.
CONCLUSIONS: Low-grade cerebellar astrocytoma is a surgical disease, in need of long-term follow-up, but with excellent long-term results. Nine percent of the children in this study underwent repeated surgery due to progressive tumor recurrence, and 15% were treated for persistent hydrocephalus.

Rodriguez FJ, Lim KS, Bowers D, Eberhart CG
Pathological and molecular advances in pediatric low-grade astrocytoma.
Annu Rev Pathol. 2013; 8:361-79 [PubMed] Article available free on PMC after 24/01/2014

Pediatric low-grade astrocytomas are the most common brain tumors in children. They can have similar microscopic and clinical features, making accurate diagnosis difficult. For patients whose tumors are in locations that do not permit full resection, or those with an intrinsically aggressive biology, more effective therapies are required. Until recently, little was known about the molecular changes that drive the initiation and growth of pilocytic and other low-grade astrocytomas beyond the association of a minority of cases, primarily in the optic nerve, with neurofibromatosis type 1. Over the past several years, a wide range of studies have implicated the BRAF oncogene and other members of this signaling cascade in the pathobiology of pediatric low-grade astrocytoma. In this review, we attempt to summarize this rapidly developing field and discuss the potential for translating our growing molecular knowledge into improved diagnostic and prognostic biomarkers and new targeted therapies.

Combs SE, Kessel KA, Herfarth K, et al.
Treatment of pediatric patients and young adults with particle therapy at the Heidelberg Ion Therapy Center (HIT): establishment of workflow and initial clinical data.
Radiat Oncol. 2012; 7:170 [PubMed] Article available free on PMC after 24/01/2014

BACKGROUND: To report on establishment of workflow and clinical results of particle therapy at the Heidelberg Ion Therapy Center.
MATERIALS AND METHODS: We treated 36 pediatric patients (aged 21 or younger) with particle therapy at HIT. Median age was 12 years (range 2-21 years), five patients (14%) were younger than 5 years of age. Indications included pilocytic astrocytoma, parameningeal and orbital rhabdomyosarcoma, skull base and cervical chordoma, osteosarcoma and adenoid-cystic carcinoma (ACC), as well as one patient with an angiofibroma of the nasopharynx. For the treatment of small children, an anesthesia unit at HIT was established in cooperation with the Department of Anesthesiology.
RESULTS: Treatment concepts depended on tumor type, staging, age of the patient, as well as availability of specific study protocols. In all patients, particle radiotherapy was well tolerated and no interruptions due to toxicity had to be undertaken. During follow-up, only mild toxicites were observed. Only one patient died of tumor progression: Carbon ion radiotherapy was performed as an individual treatment approach in a child with a skull base recurrence of the previously irradiated rhabdomyosarcoma. Besides this patient, tumor recurrence was observed in two additional patients.
CONCLUSION: Clinical protocols have been generated to evaluate the real potential of particle therapy, also with respect to carbon ions in distinct pediatric patient populations. The strong cooperation between the pediatric department and the department of radiation oncology enable an interdisciplinary treatment and stream-lined workflow and acceptance of the treatment for the patients and their parents.

Singh G, Wei XC, Hader W, et al.
Sustained response to weekly vinblastine in 2 children with pilomyxoid astrocytoma associated with diencephalic syndrome.
J Pediatr Hematol Oncol. 2013; 35(2):e53-6 [PubMed]

Diencephalic syndrome (DS) related to hypothalamic/chiasmatic region tumor has mainly been reported with low-grade glioma. We described 2 young children with DS related to pilomyxoid astrocytoma. Despite the recognized more agressive clinical behavior of this histologic subtype, we report successful resolution of DS and sustained tumor response with prolonged use of single-agent vinblastine.

Engler JR, Robinson AE, Smirnov I, et al.
Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas.
PLoS One. 2012; 7(8):e43339 [PubMed] Article available free on PMC after 24/01/2014

Glioblastoma (GBM) is a highly malignant brain tumor with a dismal prognosis. Gene expression profiling of GBM has revealed clinically relevant tumor subtypes, and this provides exciting opportunities to better understand disease pathogenesis. Results from an increasing number of studies demonstrate a role for the immune response in cancer progression, yet it is unclear how the immune response differs across tumor subtypes and how it affects outcome. Utilizing gene expression data from The Cancer Genome Atlas Project and the Gene Expression Omnibus database, we demonstrate an enrichment of immune response-related gene expression in the mesenchymal subtype of adult GBM (n = 173) and pediatric high-grade gliomas (n = 53). In an independent cohort of pediatric astrocytomas (n = 24) from UCSF, we stratified tumors into subtypes and confirmed these findings. Using novel immune cell-specific gene signatures we demonstrate selective enrichment of microglia/macrophage-related genes in adult and pediatric GBM tumors of the mesenchymal subtype. Furthermore, immunostaining of adult GBM tumors showed significantly higher cell numbers of microglia/macrophages in mesenchymal versus non-mesenchymal tumors (p = 0.04). Interestingly, adult GBM tumors with the shortest survival had significant enrichment of microglia/macrophage-related genes but this was not true for pediatric GBMs. Consistent with an association with poor outcome, immune response-related genes were highly represented in an adult poor prognosis gene signature, with the expression of genes related to macrophage recruitment and activation being most strongly associated with survival (p<0.05) using CoxBoost multivariate modeling. Using a microglia/macrophage high gene signature derived from quantification of tumor-infiltrating cells in adult GBM, we identified enrichment of genes characteristic of CD4 T cells, granulocytes, and microglia/macrophages (n = 573). These studies support a role for the immune response, particularly the microglia/macrophage response, in the biology of an important subset of GBM. Identification of this subset may be important for future therapeutic stratification.

Das KK, Mehrotra A, Nair AP, et al.
Pediatric glioblastoma: clinico-radiological profile and factors affecting the outcome.
Childs Nerv Syst. 2012; 28(12):2055-62 [PubMed]

BACKGROUND AND PURPOSE: Glioblastoma in the pediatric age group is relatively rare. As a result, it has been difficult to deduce any consistent clinico-radiological and pathological profiles on these patients. Also, the prognostic factors affecting the survival in pediatric glioblastoma are not as well defined as in adults.
PATIENTS AND METHODS: In this retrospective series, 65 pediatric patients (age ≤ 18 years) from January 1995 to December 2011 with histopathologically proven diagnosis of intracranial glioblastoma were studied. Clinico-radiological, pathological, treatment, and follow-up data were collected. Progression-free and overall survivals were assessed using the Kaplan-Meier method.
RESULTS: The male-to-female ratio was 2.6:1 with a mean age of 13.29 ± 4.53 years (range 2-18 years). Headache with or without vomiting (n = 51, 78 %), followed by seizures (n = 42, 65 %), and focal deficits (n = 31, 47 %) were the leading symptoms. Forty-nine (75 %) patients had tumors located superficially, whereas there were 16 patients with deeply located glioblastomas (25 %). Gross total tumor excision was achieved in 43 (66 %) patients, while the remaining patients had incomplete excision (n = 22, 34 %). Mean follow-up was 17.7 months (range 1.5-119 months). The median progression-free and overall survivals were 10 and 20 months, respectively. Extent of resection was found to be the independent predictor of survival (p value = 0.002).
CONCLUSION: Pediatric glioblastomas are associated with longer progression-free as well as overall survivals. Extent of tumor resection is the strongest predictor of survival in pediatric glioblastoma. Hence, an aggressive surgical resection may fetch a better outcome in children with glioblastoma.

Lober RM, Guzman R, Cheshier SH, et al.
Application of diffusion tensor tractography in pediatric optic pathway glioma.
J Neurosurg Pediatr. 2012; 10(4):273-80 [PubMed]

OBJECT: Magnetic resonance imaging is commonly used in diagnosis and surveillance for optic pathway glioma (OPG). The authors investigated the role of diffusion tensor (DT) tractography in assessing the location of visual pathway fibers in the presence of tumor.
METHODS: Data in 10 children with OPG were acquired using a 3T MRI generalized autocalibrating parallel acquisitions DT-echo planar imaging sequence (25 isotropic directions with a b value of 1000 seconds/mm(2), slice thickness 3 mm). Fiber tractography was performed, with seed regions placed within the optic chiasm and bilateral nerves on the coronal plane, including the tumor and surrounding normal-appearing tissue. Tracking was performed with a curvature threshold of 30°.
RESULTS: For prechiasmatic lesions, fibers either stopped abruptly at the tumor or traversed abnormally dilated nerve segments. Similar findings were seen with chiasmatic lesions, with an additional arrangement in which fibers diverged around the tumor. For each patient, DT tractography provided additional information about visual fiber arrangement in relation to the tumor that was not evident by using conventional MRI methods. Retrospective reconstruction of visual fibers in 1 patient with new postoperative hemianopia revealed an unexpected superior displacement of the optic tract that might have been helpful information had it been applied to preoperative planning or surgical navigation.
CONCLUSIONS: Optic pathway DT tractography is feasible in patients with OPG and provides new information about the arrangement of visual fibers in relation to tumors that could be incorporated into surgical navigation for tumor biopsy or debulking procedures.

Avery RA, Ferner RE, Listernick R, et al.
Visual acuity in children with low grade gliomas of the visual pathway: implications for patient care and clinical research.
J Neurooncol. 2012; 110(1):1-7 [PubMed]

Low grade gliomas affecting the visual pathway, commonly referred to as optic pathway gliomas (OPGs), have a relatively high survival rate but can cause significant vision loss. While previous treatment outcomes for tumors of the central nervous system have focused primarily on changes in tumor size or patient survival, more recently preservation of vision has also become a primary objective when treating these tumors. Visual acuity (VA) is the most testable and reliable visual parameter in young children with OPGs. Unfortunately, standardized VA assessments have neither been employed to make treatment decisions nor used as primary outcomes in clinical trials. The lack of a standardized VA assessment has also hindered the ability to interpret and compare results between studies. It is essential that all members of the multidisciplinary care team (i.e., pediatric neuro-oncologist, neurologist, neurosurgeon, and ophthalmologist) can accurately interpret VA results and properly use them to guide management decisions. Specifically, determining what constitutes a significant change in VA and the factors that may influence these results should be incorporated into collective team recommendations. This review describes the VA assessment in children with OPGs and proposes a standardized VA testing protocol for future pediatric OPG clinical treatment trials.

Mascelli S, Raso A, Biassoni R, et al.
Analysis of NADP+-dependent isocitrate dehydrogenase-1/2 gene mutations in pediatric brain tumors: report of a secondary anaplastic astrocytoma carrying the IDH1 mutation.
J Neurooncol. 2012; 109(3):477-84 [PubMed]

Somatic mutations of the isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (p.R132H), have been reported for WHO grade II and III diffuse gliomas and secondary glioblastomas. We investigated IDH1/2 mutations in a retrospective series of 165 pediatric brain tumors, including atypical teratoid/rhabdoid tumors (AT/RT) and choroid plexus tumors, which had not previously been investigated. Mutation analysis was performed by use of pyrosequencing and, additionally, data were validated for a cohort of 70 gliomas from among the series by use of the arrayed primer extension technique. We identified one tumor which harbored mutation of IDH1 at codon 132 and no alteration was identified in the matched-germline DNA. No IDH2 mutations were detected. Most noteworthy, the IDH1 mutant tumor was an anaplastic astrocytoma involving the cortex in the left frontal lobe which appeared seven years after radiation treatment for an extensive sellar/suprasellar craniopharyngioma. This anaplastic astrocytoma was regarded as secondary to radiation treatment because it seemed to originate within the irradiation field that received a dose varying from a maximum of 30.6 Gy of 4 MV X-rays down to very few Gy of lower-energy scattered radiation. In this work our observations agree with those in previous reports showing the rarity of IDH1/2 mutations in childhood tumors. The interesting identification of an IDH1 mutation in a radiation-induced secondary malignant glioma raises the likelihood that these types of tumor may develop IDH1/2 mutations. Thus, caution is needed when dealing with these tumors, and further genetic analysis is warranted.

Winograd E, Pencovich N, Yalon M, et al.
Malignant transformation in pediatric spinal intramedullary tumors: case-based update.
Childs Nerv Syst. 2012; 28(10):1679-86 [PubMed]

BACKGROUND: In children, intramedullary spinal cord neoplasms are rare. These are typically low-grade neuroepithelial tumors, most commonly astrocytomas, ependymomas, and gangliogliomas. Malignant transformation, while common in recurrent adult low-grade gliomas, is an unusual event in pediatric low-grade neoplasms, specifically in intramedullary spinal cord tumors. ILLUSTRATIVE CASES: We report two cases of malignant transformation in low-grade neuroepithelial tumors of the pediatric intramedullary spinal cord. Two children with intramedullary tumors, one with a WHO grade I ganglioglioma and one with a low-grade astrocytoma, were treated surgically, diagnosed histologically, and followed through the course of their disease. Both patients' tumors transformed to higher grades without prior irradiation or chemotherapy, and without a genetic predisposition to tumorigenesis.
DISCUSSION: Malignant transformation can occur in low-grade intramedullary neoplasms in children. This is a novel documented event for pediatric intramedullary spinal cord tumors and a rare event for all pediatric low-grade neuroepithelial tumors without induction by irradiation. A survey of the relevant literature reveals an underwhelming number of studies focusing on malignant transformation in children's CNS tumors relative to adults. Further investigation into molecular mechanisms of pediatric low-grade neoplasms may reveal more aggressive tumor sub-variants predisposed to malignant degeneration.

El-Gaidi MA
Descriptive epidemiology of pediatric intracranial neoplasms in Egypt.
Pediatr Neurosurg. 2011; 47(6):385-95 [PubMed]

OBJECTIVE: The characteristics of 451 Egyptian children (aged 0-14 years) with primary intracranial neoplasms were investigated for demographic, clinical, topographical and pathological features using the most recent 2007 Classification of Central Nervous System Tumors.
PATIENTS AND METHODS: This was a retrospective study performed in the Departments of Pediatric Neurosurgery of the Cairo University Hospitals from 2005 to 2008.
RESULTS: There was a slight male predominance (51.4%) observed in our study, and the most affected age group was 5-9 years old (43.2%). Most of the tumors were confined to a single compartment (infratentorial in 49.7%, supratentorial in 46.6%), while 3.8% of the tumors involved multiple compartments. The most common intracranial tumors were astrocytomas (35%), medulloblastomas (18.8%), craniopharyngiomas (11.3%) and ependymomas (10%). Pilocytic astrocytomas constituted 55% of all astrocytomas and 19.3% of all brain tumors, only slightly ahead of medulloblastomas. Less common types were primitive neuroectodermal tumors (2.7%), followed by meningiomas, germ cell tumors and choroid plexus tumors (2.4% each). According to the International Classification of Diseases for Oncology Coding (ICD-O-4), benign, borderline and malignant tumors constituted 7.54, 36.14 and 56.32%, respectively.
CONCLUSION: The characteristics of pediatric intracranial tumors in Egypt are generally similar to those reported in the literature, with only minor differences.

Cage TA, Mueller S, Haas-Kogan D, Gupta N
High-grade gliomas in children.
Neurosurg Clin N Am. 2012; 23(3):515-23 [PubMed]

High-grade gliomas (HGGs) are malignant tumors and typically include glioblastoma multiforme and anaplastic astrocytoma subtypes. Brainstem gliomas and ependymomas are separate entities with respect to clinical presentation, treatment, prognosis, and outcome in comparison with supratentorial HGGs. In children, these tumors account for 3% to 7% of newly diagnosed brain tumors and 20% of all diagnoses of pediatric supratentorial brain tumors. These neoplasms are highly proliferative and mitotically active and of glial origin. This article reviews clinical, diagnostic, and pathologic features of HGG and current treatments and potential future therapies specific to pediatric patients with HGGs.

Rasalkar DD, Paunipagar BK, Ng A
Primary spinal cord desmoplastic astrocytoma in an adolescent: a rare tumour at rare site and rare age.
Hong Kong Med J. 2012; 18(3):253-5 [PubMed]

We report a case of a non-infantile primary intramedullary spinal cord desmoplastic astrocytoma in an 18-year-old girl who presented with spastic paraparesis. The patient had been unable to run for 1 year. Magnetic resonance imaging of her spine showed an intramedullary solid and cystic heterogeneously enhancing lesion located at T7-T8 level. Partial excision was performed. Histology revealed a desmoplastic astrocytoma. To the best of our knowledge, there is no report on primary desmoplastic astrocytoma of the spinal cord in literature. Nor has such a symptomatic tumour manifesting at the age of 18 years been documented.

Gilheeney SW, Kieran MW
Differences in molecular genetics between pediatric and adult malignant astrocytomas: age matters.
Future Oncol. 2012; 8(5):549-58 [PubMed]

The microscope - the classical tool for the investigation of cells and tissues - remains the basis for the classification of tumors throughout the body. Nowhere has this been more true than in the grading of astrocytomas. In spite of the fact that our parents warned us not to judge a book by its cover, we have continued to assume that adult and pediatric malignant gliomas that look the same, will have the same mutations, and thus respond to the same therapy. Rapid advances in molecular biology have permitted us the opportunity to go inside the cell and characterize the genetic events that underlie the true molecular heterogeneity of adult and pediatric brain tumors. In this paper, we will discuss some of the important clinical differences between pediatric and adult gliomas, with a focus on the molecular analysis of these different age groups.

Awdeh RM, Kiehna EN, Drewry RD, et al.
Visual outcomes in pediatric optic pathway glioma after conformal radiation therapy.
Int J Radiat Oncol Biol Phys. 2012; 84(1):46-51 [PubMed] Article available free on PMC after 01/09/2013

PURPOSE: To assess visual outcome prospectively after conformal radiation therapy (CRT) in children with optic pathway glioma.
METHODS AND MATERIALS: We used CRT to treat optic pathway glioma in 20 children (median age 9.3 years) between July 1997 and January 2002. We assessed changes in visual acuity using the logarithm of the minimal angle of resolution after CRT (54 Gy) with a median follow-up of 24 months. We included in the study children who underwent chemotherapy (8 patients) or resection (9 patients) before CRT.
RESULTS: Surgery played a major role in determining baseline (pre-CRT) visual acuity (better eye: P=.0431; worse eye: P=.0032). The visual acuity in the worse eye was diminished at baseline (borderline significant) with administration of chemotherapy before CRT (P=.0726) and progression of disease prior to receiving CRT (P=.0220). In the worse eye, improvement in visual acuity was observed in patients who did not receive chemotherapy before CRT (P=.0289).
CONCLUSIONS: Children with optic pathway glioma initially treated with chemotherapy prior to receiving radiation therapy have decreased visual acuity compared with those who receive primary radiation therapy. Limited surgery before radiation therapy may have a role in preserving visual acuity.

Huillard E, Hashizume R, Phillips JJ, et al.
Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy.
Proc Natl Acad Sci U S A. 2012; 109(22):8710-5 [PubMed] Article available free on PMC after 01/09/2013

Although malignant astrocytomas are a leading cause of cancer-related death in children, rational therapeutic strategies are lacking. We previously identified activating mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) (BRAF(T1799A) encoding BRAF(V600E)) in association with homozygous cyclin-dependent kinase inhibitor 2A (CDKN2A, encoding p14ARF and p16Ink4a) deletions in pediatric infiltrative astrocytomas. Here we report that BRAF(V600E) expression in neural progenitors (NPs) is insufficient for tumorigenesis and increases NP cellular differentiation as well as apoptosis. In contrast, astrocytomas are readily generated from NPs with additional Ink4a-Arf deletion. The BRAF(V600E) inhibitor PLX4720 significantly increased survival of mice after intracranial transplant of genetically relevant murine or human astrocytoma cells. Moreover, combination therapy using PLX4720 plus the Cyclin-dependent kinase (CDK) 4/6-specific inhibitor PD0332991 further extended survival relative to either monotherapy. Our findings indicate a rational therapeutic strategy for treating a subset of pediatric astrocytomas with BRAF(V600E) mutation and CDKN2A deficiency.

Byeon SJ, Myung JK, Kim SH, et al.
Distinct genetic alterations in pediatric glioblastomas.
Childs Nerv Syst. 2012; 28(7):1025-32 [PubMed]

BACKGROUND: Pediatric high-grade tumors, especially glioblastomas (GBs), can be clinically devastating but are under-studied in comparison with adult GBs (aGBs). Molecular features of pediatric GBs (pGBs) are poorly understood and novel-targeted therapies have not been routinely used in pediatric patients with GBs.
METHODS: Twenty-four non-brainstem pGBs were studied. To compare pGBs with aGBs, immunohistochemical staining and fluorescent in situ hybridization were performed in paraffin-embedded tissues. Microarray gene expression analyses were performed in snap-frozen tissues of four primary pGBs, six primary aGBs, and one non-neoplastic brain.
RESULTS: Immunohistochemial p16 loss was more frequent in pGBs, whereas p53, epidermal growth factor receptor, and phosphatase and tensin homolog loss were similar to that of aGBs. No case was isocitrate dehydrogenase (IDH)1 immunopositive or showed the IDH1 R132/IDH2 R172 mutation, suggesting primary GB. Microarray analysis revealed two pGB subtypes (A and B). Type B pGBs and aGBs had similar gene expression profiles; however, the profiles of type A pGBs differed from those of aGBs. In type A pGBs, we identified 90 up- and 63 down-regulated genes; platelet-derived growth factor receptor α polypeptide and CCND2 expression were significantly reduced, whereas they were up-regulated in aGBs.
CONCLUSIONS: Our study found two distinct pGB gene expression profiles: one similar to that of aGBs and the other different. We identified significantly up- and down-regulated genes in pGBs that may provide better targets for diagnostic, prognostic, and therapeutic uses; however, more studies are required to determine the classification and optimal treatment of pediatric patients with GBs.

Ferguson AE, Cohn RJ, Ashton LJ
Use of formalin-fixed paraffin-embedded tumor tissue as a DNA source in molecular epidemiological studies of pediatric CNS tumors.
Diagn Mol Pathol. 2012; 21(2):105-13 [PubMed]

Formalin-fixed paraffin-embedded tissue (FFPET) samples are a potential source of DNA for molecular epidemiological studies. However, the use of FFPET samples can be restricted by the yield and quality of DNA isolated. The aim of this study was to examine whether FFPET biopsies from pediatric central nervous system tumors were a feasible alternative to archival frozen tissue when characterizing common gene polymorphisms. DNA was isolated from 50 frozen pediatric central nervous system tumor biopsies and matched FFPET samples. Real-time polymerase chain reaction (PCR) was used to quantify DNA and characterize GSTT1, GSTM1, GSTP1, and MTHFR gene polymorphisms. The use of whole-genome amplification (WGA) to increase DNA yields was also investigated. The results showed that DNA isolated from FFPET samples was more fragmented and provided smaller yields than DNA isolated from frozen samples. Attempts to increase the DNA yield from FFPET using WGA were unsuccessful. DNA from FFPET samples was successfully genotyped for the GSTP1 Ile105Val and MTHFR 677 C>T polymorphisms in 98% of samples and was 100% concordant with the results from frozen tissue. However, DNA from FFPET performed poorly in real-time PCR assays for GSTM1 and GSTT1 deletion polymorphisms. Our investigations show that DNA extracted from FFPET is substantially fragmented and not readily amplified using WGA. In addition, careful validation of PCR assays should be carried out due to the variable amplification of fragmented FFPET DNA.

Gimi B, Cederberg K, Derinkuyu B, et al.
Utility of apparent diffusion coefficient ratios in distinguishing common pediatric cerebellar tumors.
Acad Radiol. 2012; 19(7):794-800 [PubMed]

RATIONALE AND OBJECTIVES: The aim of this study was to identify clinically useful tumor/normal brain apparent diffusion coefficient (ADC) ratios for distinguishing common pediatric cerebellar tumors.
MATERIALS AND METHODS: Review of medical records revealed 79 patients with cerebellar tumors who underwent preoperative magnetic resonance imaging, including diffusion-weighted imaging sequences, and surgery. There were 31 pilocytic astrocytomas, 27 medulloblastomas, 14 ependymomas, and seven atypical teratoid/rhabdoid tumors. ADC values were measured by placing regions of interest on the solid tumor and normal brain parenchyma by two reviewers. Tumor/normal brain ADC ratios were calculated.
RESULTS: Mean ADC values of the pilocytic astrocytomas were greater than those of ependymomas, whose mean ADC values were greater than those of medulloblastomas and atypical teratoid/rhabdoid tumors. Using a tumor/normal brain ADC ratio threshold of 1.70 to distinguish pilocytic astrocytomas from ependymomas, sensitivity of 92% and specificity of 79% were achieved. A tumor/normal brain ADC ratio threshold of 1.20 enabled the sorting of ependymomas from medulloblastomas with sensitivity of 93% and specificity of 88%.
CONCLUSIONS: Tumor/normal brain ADC ratios allow the distinguishing of common pediatric cerebellar tumors.

Fisher MJ, Loguidice M, Gutmann DH, et al.
Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis.
Neuro Oncol. 2012; 14(6):790-7 [PubMed] Article available free on PMC after 01/06/2013

Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1); up to half become symptomatic. There is little information regarding ophthalmologic outcomes after chemotherapy. A retrospective multicenter study was undertaken to evaluate visual outcomes following chemotherapy for NF1-associated OPG, to identify risks for visual loss, and to ascertain indications for treatment. Subjects included children undergoing initial treatment for OPGs with chemotherapy between January 1997 and December 2007. Of 115 subjects, visual acuity (VA) decline and tumor progression were the primary reasons to initiate treatment, although there were significant differences in the pattern of indications cited among the institutions. Eighty-eight subjects and 168 eyes were evaluable for VA outcome. At completion of chemotherapy, VA improved (32% of subjects), remained stable (40%), or declined (28%). Tumor location was the most consistent prognostic factor for poor VA outcome. There was poor correlation between radiographic and VA outcomes. Although visual outcomes for NF1-associated OPG are not optimal, approximately one-third of children regain some vision with treatment. Since radiographic outcomes do not predict visual outcomes, their use as the primary measure of treatment success is in question. The lack of consensus regarding the indications for treatment underlines the need for better standardization of care. Future clinical trials for OPG require standardized visual assessment methods and clear definitions of visual outcomes.

Buccoliero AM, Castiglione F, Degl'Innocenti DR, et al.
IDH1 mutation in pediatric gliomas: has it a diagnostic and prognostic value?
Fetal Pediatr Pathol. 2012; 31(5):278-82 [PubMed]

Mutations in IDH1 gene are observed in gliomas with significant differences according to histotype, grade, prognosis, and age. We analyzed the IDH1 gene mutations frequency in 42 gliomas from 40 children (14 pilocytic astrocytomas; 3 pilomyxoid astrocytomas; 3 diffuse astrocytomas; 1 gliomatosi cerebri; 8 subependymal giant cell astrocytomas; 2 anaplastic astrocytomas; 9 glioblastomas). No IDH1 mutation was detected. Our results indicate that there is no IDH1 gene involvement in the onset and progression of pediatric astrocytomas. We argue that it is not useful in children to assess the status of IDH1 gene nor for diagnostic nor prognostic purposes.

Lehrer S
Cytomegalovirus infection in early childhood may be protective against glioblastoma multiforme, while later infection is a risk factor.
Med Hypotheses. 2012; 78(5):657-8 [PubMed]

Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors. Recently, evidence for a viral cause has been postulated, possibly cytomegalovirus (CMV). In one report, 80% of patients with newly diagnosed glioblastoma multiforme had detectable cytomegalovirus DNA in their peripheral blood, while sero-positive normal donors and other surgical patients did not exhibit detectable virus. However, another study reported that five glioblastoma patients showed no circulating CMV detected either with RT-PCR or blood culture. But CMV could still be a factor in the genesis of glioblastoma multiforme, if age at infection is taken into account, since the incidence of both glioblastoma multiforme and CMV infection are inversely related to socioeconomic status. CMV infection in early childhood, more common in lower socioeconomic groups, may be protective against glioblastoma multiforme, whereas CMV infection in later childhood or adulthood may be a risk factor for glioblastoma. If so, glioblastoma multiforme occurrence would resemble paralytic polio, where low socioeconomic status, poor hygiene and early infection are protective.

Ononiwu C, Mehta V, Bettegowda C, Jallo G
Pediatric spinal glioblastoma multiforme: current treatment strategies and possible predictors of survival.
Childs Nerv Syst. 2012; 28(5):715-20 [PubMed]

PURPOSE: Pediatric spinal glioblastoma multiforme (GBM) is rare. Evidence-directed management relies on studies in which such cases are only a subset of a larger group. We reviewed cases of pediatric spinal GBM to assess outcomes and identify prognostic factors related to treatment.
METHODS: Clinical presentations, radiologic findings, surgical variables, radio- and chemotherapeutic management, and outcomes of eight pathologically proven cases of pediatric spinal GBM were reviewed.
RESULTS: Median age was 10 years. All patients presented with motor deficits. Four had sensory symptoms. Average McCormick score at presentation was II. There were three cervical, one cervicothoracic, and four thoracic tumors. Five had cysts. Patients underwent gross total resection (GTR) (n = 4), subtotal resection (STR) (n = 3), or biopsy (n = 1). Four patients improved neurologically after surgery. One patient was lost to follow-up. Seven received both chemo- and radiotherapy. Average overall survival was 15 months. Average survival after STR and GTR were 12.6 and 19.2 months, respectively. In the GTR subset, the 18-month-old patient survived 30 months, while the other two (>10 years) survived an average of 13.75 months. This difference based on age was not seen in the STR subset. Patients survived an average of 17.5 and 10.5 months, respectively, with and without tumoral cysts. Patients with cervical tumors survived an average of 12.5 months, 18.7 months with thoracic tumors, and 11.5 months with a cervicothoracic tumor.
CONCLUSIONS: Tumor location, presence of a cyst, gross total resection, and younger age are possible predictors of prolonged survival. Radiotherapy and chemotherapy remain widely used.

Wu G, Broniscer A, McEachron TA, et al.
Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas.
Nat Genet. 2012; 44(3):251-3 [PubMed] Article available free on PMC after 01/06/2013

To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration.

Gaudino S, Quaglio F, Schiarelli C, et al.
Spontaneous modifications of contrast enhancement in childhood non-cerebellar pilocytic astrocytomas.
Neuroradiology. 2012; 54(9):989-95 [PubMed]

INTRODUCTION: Pilocytic astrocytoma (PA) is classified by the World Health Organization as a grade I tumor. Magnetic resonance imaging (MRI) is the gold standard in the diagnosis and follow-up of this neoplasm, and assessment of contrast enhancement (CE) pattern is essential. The purpose of this study was to investigate CE changes of non-cerebellar PA (n-C PA) stable in size with serial MRI.
METHODS: Nine hundred and twelve MRI exams of 140 children with histologically proven PA were retrospectively reviewed. Patients were chosen for study inclusion if they were off therapy, without neurofibromatosis type 1, and without dimensional changes of tumor/residual tumor. In patients with CE changes, tumor size and CE size were calculated with a cross product. Descriptive statistics were calculated for continuous variables; effects of possible factors influencing changes of contrast-enhanced areas were tested.
RESULTS: Of 39 n-C PA satisfying the inclusion criteria, 12 showed CE changes in terms of appearance/increase or disappearance/decrease of CE areas. Three of these 12 PA were infratentorial and nine supratentorial. There were no significant correlations between age, gender, tumor localization, tumor size, and modification of CE areas.
CONCLUSION: In our experience, n-C PA may show variable CE over time in the absence of tumor/residual tumor dimension change. We recommend that CE fluctuations alone cannot be considered an indicator of tumor progression/regression.

De Smet HJ, Catsman-Berrevoets C, Aarsen F, et al.
Auditory-perceptual speech analysis in children with cerebellar tumours: a long-term follow-up study.
Eur J Paediatr Neurol. 2012; 16(5):434-42 [PubMed]

Mutism and Subsequent Dysarthria (MSD) and the Posterior Fossa Syndrome (PFS) have become well-recognized clinical entities which may develop after resection of cerebellar tumours. However, speech characteristics following a period of mutism have not been documented in much detail. This study carried out a perceptual speech analysis in 24 children and adolescents (of whom 12 became mute in the immediate postoperative phase) 1-12.2 years after cerebellar tumour resection. The most prominent speech deficits in this study were distorted vowels, slow rate, voice tremor, and monopitch. Factors influencing long-term speech disturbances are presence or absence of postoperative PFS, the localisation of the surgical lesion and the type of adjuvant treatment. Long-term speech deficits may be present up to 12 years post-surgery. The speech deficits found in children and adolescents with cerebellar lesions following cerebellar tumour surgery do not necessarily resemble adult speech characteristics of ataxic dysarthria.