Childhood Brain Tumours
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Brain tumours are the most common solid tumour of childhood. Some are benign others are malignant. There are a number of different types of brain tumour; how they are classified depends on the histology and location within the brain. This page contains links to information specifically related to Childhood Brain Tumours, other relevant resources are availible via the Main Menu of Children's Cancer Web.

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Latest Research Publications
Childhood Astrocytoma
Childhood Brain Stem Glioma
Childhood Craniopharyngioma
Childhood Ependymoma

Information Patients and Family (13 links)

Information for Health Professionals / Researchers (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Arslan A, Guney Y, Cihan YB, Cetindag MF
Characteristics of childhood glial tumors, management approaches and life expectancy of the patients.
J BUON. 2014 Jul-Sep; 19(3):724-32 [PubMed] Related Publications
PURPOSE: To evaluate the clinical characteristics, management approaches and life expectancy in pediatric patients with neuroepithelial glial tumors except ependymal tumors.
METHODS: Between January 2003 and August 2008, 48 patients (30 boys, 18 girls; mean age: 10.9 ± 4.6 years) who were diagnosed with neuroepithelial glial tumors except ependymal tumors and underwent curative radiotherapy (RT) for inoperable, postoperative adjuvant or palliative for residual/recurrent disease at Dr. Abdurahman Yurtsalan Ankara Oncology Education and Research Hospital, Radiation Oncology Clinic, were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were evaluated in relation to sex, previous surgical procedure, pathological diagnosis, low/high grade and the histopathological grade of disease.
RESULTS: The mean follow-up was 28.8 ± 4.8 months. The mean and median PFS were 36.2 months and 20 months, respectively, while mean and median OS were 40.3 months and 23 months, respectively. One-year PFS and OS were 65.8% and 71%, respectively, whereas 3-year PFS and OS were 36.3% and 42.3%, respectively. Univariate Cox regression model and Log-Rank test revealed no statistical significance. Prolonged PFS and OS were observed in boys compared to girls, those who underwent total/gross total resection compared to subtotal resection, those with low grade tumors compared to high-grade tumors, and those with histopathological grade I disease compared to grade IV disease (p>0.05). The PFS and OS times were shortened in patients who developed side effects at any time following surgery and RT, compared to those without any side effects (p>0.05).
CONCLUSION: Low-grade disease and total/gross total resection prolong PFS and OS in patients with childhood glial tumors.

Related: Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood

Kitahara CM, Gamborg M, Rajaraman P, et al.
A prospective study of height and body mass index in childhood, birth weight, and risk of adult glioma over 40 years of follow-up.
Am J Epidemiol. 2014; 180(8):821-9 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
Greater attained height and greater body mass index (BMI; weight (kg)/height (m)(2)) in young adulthood have been associated with glioma risk, but few studies have investigated the association with body size at birth or during childhood, when the brain undergoes rapid cell growth and differentiation. The Copenhagen School Health Records Register includes data on 320,425 Danish schoolchildren born between 1930 and 1989, with height and weight measurements from ages 7-13 years and parentally recorded birth weights. We prospectively evaluated associations between childhood height and BMI, birth weight, and adult glioma risk. During follow-up (1968-2010), 355 men and 253 women aged ≥18 years were diagnosed with glioma. In boys, height at each age between 7 and 13 years was positively associated with glioma risk; hazard ratios per standard-deviation score at ages 7 (approximately 5.1 cm) and 13 (approximately 7.6 cm) years were 1.17 (95% confidence interval (CI): 1.05, 1.30) and 1.21 (95% CI: 1.09, 1.35), respectively. No associations were observed for childhood height in girls or for BMI. Birth weight was positively associated with risk (per 0.5 kg: hazard ratio = 1.13, 95% CI: 1.04, 1.24). These results suggest that exposures associated with higher birth weight and, in boys, greater height during childhood may contribute to the etiology of adult glioma.

Related: Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood

Peretz B, Sarnat H, Kharouba J
Chemotherapy induced dental changes in a child with medulloblastoma: a case report.
J Clin Pediatr Dent. 2014; 38(3):251-4 [PubMed] Related Publications
We describe the dental findings and therapeutic management of a child aged three years and eight months with medulloblastoma treated by surgical resection at age eight months followed by 20 months of chemotherapy. Thin and short roots of the primary molars were observed, as were microdontia and anodontia of the premolars. The boy suffered from severe early childhood caries (ECC). Dental treatment was carried out under general anesthesia. Follow-up examinations at three, six and twelve months after the initial dental treatment revealed healthy gingival tissue and no new caries. The boy passed away before the next scheduled follow-up dental examination.

Related: Childhood Medulloblastoma / PNET

Zukotynski K, Fahey F, Kocak M, et al.
18F-FDG PET and MR imaging associations across a spectrum of pediatric brain tumors: a report from the pediatric brain tumor consortium.
J Nucl Med. 2014; 55(9):1473-80 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
UNLABELLED: The purpose of this study was to describe (18)F-FDG uptake across a spectrum of pediatric brain tumors and correlate (18)F-FDG PET with MR imaging variables, progression-free survival (PFS), and overall survival (OS).
METHODS: A retrospective analysis was conducted of children enrolled in phase I/II clinical trials through the Pediatric Brain Tumor Consortium from August 2000 to June 2010. PET variables were summarized within diagnostic categories using descriptive statistics. Associations of PET with MR imaging variables and PFS and OS by tumor types were evaluated.
RESULTS: Baseline (18)F-FDG PET was available in 203 children; 66 had newly diagnosed brain tumors, and 137 had recurrent/refractory brain tumors before enrolling in a Pediatric Brain Tumor Consortium trial. MR imaging was performed within 2 wk of PET and before therapy in all cases. The (18)F-FDG uptake pattern and MR imaging contrast enhancement (CE) varied by tumor type. On average, glioblastoma multiforme and medulloblastoma had uniform, intense uptake throughout the tumor, whereas brain stem gliomas (BSGs) had low uptake in less than 50% of the tumor and ependymoma had low uptake throughout the tumor. For newly diagnosed BSG, correlation of (18)F-FDG uptake with CE portended reduced OS (P = 0.032); in refractory/recurrent BSG, lack of correlation between (18)F-FDG uptake and CE suggested decreased PFS (P = 0.023). In newly diagnosed BSG for which more than 50% of the tumor had (18)F-FDG uptake, there was a suggestion of lower apparent diffusion coefficient (P = 0.061) and decreased PFS (P = 0.065).
CONCLUSION: (18)F-FDG PET and MR imaging showed a spectrum of patterns depending on tumor type. In newly diagnosed BSG, the correlation of (18)F-FDG uptake and CE suggested decreased OS, likely related to more aggressive disease. When more than 50% of the tumor had (18)F-FDG uptake, the apparent diffusion coefficient was lower, consistent with increased cellularity. In refractory/recurrent BSG, poor correlation between (18)F-FDG uptake and CE was associated with decreased PFS, which may reflect concurrent tissue breakdown at sites of treated disease and development of new sites of (18)F-FDG-avid malignancy.

Related: Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood

Bishop AJ, Greenfield B, Mahajan A, et al.
Proton beam therapy versus conformal photon radiation therapy for childhood craniopharyngioma: multi-institutional analysis of outcomes, cyst dynamics, and toxicity.
Int J Radiat Oncol Biol Phys. 2014; 90(2):354-61 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
PURPOSE: We compared proton beam therapy (PBT) with intensity modulated radiation therapy (IMRT) for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxicity.
METHODS AND MATERIALS: We reviewed records from 52 children treated with PBT (n=21) or IMRT (n=31) at 2 institutions from 1996-2012. Endpoints were overall survival (OS), disease control, cyst dynamics, and toxicity.
RESULTS: At 59.6 months' median follow-up (PBT 33 mo vs IMRT 106 mo; P<.001), the 3-year outcomes were 96% for OS, 95% for nodular failure-free survival and 76% for cystic failure-free survival. Neither OS nor disease control differed between treatment groups (OS P=.742; nodular failure-free survival P=.546; cystic failure-free survival P=.994). During therapy, 40% of patients had cyst growth (20% requiring intervention); immediately after therapy, 17 patients (33%) had cyst growth (transient in 14), more commonly in the IMRT group (42% vs 19% PBT; P=.082); and 27% experienced late cyst growth (32% IMRT, 19% PBT; P=.353), with intervention required in 40%. Toxicity did not differ between groups. On multivariate analysis, cyst growth was related to visual and hypothalamic toxicity (P=.009 and .04, respectively). Patients given radiation as salvage therapy (for recurrence) rather than adjuvant therapy had higher rates of visual and endocrine (P=.017 and .024, respectively) dysfunction.
CONCLUSIONS: Survival and disease-control outcomes were equivalent for PBT and IMRT. Cyst growth is common, unpredictable, and should be followed during and after therapy, because it contributes to late toxicity. Delaying radiation therapy until recurrence may result in worse visual and endocrine function.

Related: Childhood Craniopharyngioma Pituitary Tumors

Greenberger BA, Pulsifer MB, Ebb DH, et al.
Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas.
Int J Radiat Oncol Biol Phys. 2014; 89(5):1060-8 [PubMed] Related Publications
PURPOSE/OBJECTIVE(S): Primary low-grade gliomas are common brain tumors of childhood, many of which require radiation therapy (RT) as definitive treatment. Increased conformality of RT could decrease the incidence and severity of late effects. We report our experience with 32 pediatric patients treated with proton RT.
METHODS AND MATERIALS: Thirty-two pediatric patients with low-grade gliomas of the brain or spinal cord were treated with proton RT from 1995 to 2007. Sixteen patients received at least 1 regimen of chemotherapy before definitive RT. The median radiation dose was 52.2 GyRBE (48.6-54 GyRBE).
RESULTS: The median age at treatment was 11.0 years (range, 2.7-21.5 years), with a median follow-up time of 7.6 years (range, 3.2-18.2 years). The 6-year and 8-year rates of progression-free survival were 89.7% and 82.8%, respectively, with an 8-year overall survival of 100%. For the subset of patients who received serial neurocognitive testing, there were no significant declines in Full-Scale Intelligence Quotient (P=.80), with a median neurocognitive testing interval of 4.5 years (range, 1.2-8.1 years) from baseline to follow-up, but subgroup analysis indicated some significant decline in neurocognitive outcomes for young children (<7 years) and those with significant dose to the left temporal lobe/hippocampus. The incidence of endocrinopathy correlated with a mean dose of ≥40 GyRBE to the hypothalamus, pituitary, or optic chiasm. Stabilization or improvement of visual acuity was achieved in 83.3% of patients at risk for radiation-induced injury to the optic pathways.
CONCLUSIONS: This report of late effects in children with low-grade gliomas after proton RT is encouraging. Proton RT appears to be associated with good clinical outcome, especially when the tumor location allows for increased sparing of the left temporal lobe, hippocampus, and hypothalamic-pituitary axis.

Related: Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood

Furuya K, Takanashi S, Ogawa A, et al.
High-dose methotrexate monotherapy followed by radiation for CD30-positive, anaplastic lymphoma kinase-1-positive anaplastic large-cell lymphoma in the brain of a child.
J Neurosurg Pediatr. 2014; 14(3):311-5 [PubMed] Related Publications
The authors report the case of an 11-year-old immunocompetent boy with primary CNS CD30-positive anaplastic large-cell lymphoma (ALCL) that was also positive for anaplastic lymphoma kinase-1. His initial clinical manifestation was acute meningitis of unknown etiology. Findings on CT scanning were normal. Although he received empirical treatment against infection, his systemic and neurological status deteriorated. Subsequent MRI revealed newly emerged enhanced lesions and concomitant edema in the left parietal lobe. Diagnosis was confirmed following a brain biopsy and immunohistochemical staining. Three courses of systemic high-dose methotrexate (HD-MTX) treatment with 2-week intervals was started, followed by whole-brain radiation. His clinical course improved, and he has remained disease-free for more than 8 years without any additional treatment. Because ALCL originating in the brain is extremely rare and difficult to diagnose, no standard treatment has been established. This report suggests that systemic HD-MTX monotherapy can be an effective and worthwhile tailored therapeutic option for pediatric primary CNS ALCL.

Related: Childhood Brain Tumours Childhood Brain Tumors Methotrexate ALK

Gerber NU, von Hoff K, Resch A, et al.
Treatment of children with central nervous system primitive neuroectodermal tumors/pinealoblastomas in the prospective multicentric trial HIT 2000 using hyperfractionated radiation therapy followed by maintenance chemotherapy.
Int J Radiat Oncol Biol Phys. 2014; 89(4):863-71 [PubMed] Related Publications
PURPOSE: The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4.
METHODS AND MATERIALS: After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine).
RESULTS: Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (± standard error [SE]) were each 58% (± 10%) for the entire cohort: CNS-PNET was 53% (± 13); pinealoblastoma was 64% (± 15%; P=.524 and P=.627, respectively).
CONCLUSIONS: Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.

Related: Childhood Brain Tumours Childhood Brain Tumors

Chojnacka M, Pędziwiatr K, Skowrońska-Gardas A, et al.
Second brain tumors following central nervous system radiotherapy in childhood.
Br J Radiol. 2014; 87(1041):20140211 [PubMed] Related Publications
OBJECTIVE: The second tumour (ST) occurrence is a relatively uncommon late complication of radiotherapy but represents one of the most significant issues, especially in childhood oncology. We describe our experience with patients who developed second brain neoplasm following cranial irradiation in childhood.
METHODS: We identified nine patients who received radiotherapy owing to central nervous system tumour in childhood and subsequently developed the second brain tumour. The full clinical and radiological documentation and histopathological reports were reviewed. Risk factors such as age at irradiation, latency period to ST diagnosis, radiotherapy doses and volumes and other therapy methods were evaluated. We correlated the ST location with the three levels of irradiation dose (high, >40 Gy; medium, 25-40 Gy; and low <25 Gy).
RESULTS: Five meningiomas and four gliomas occurred as the ST after the mean time of 11.7 years after radiotherapy. The average age of children during irradiation was 4.6 years. The shorter latency time to the ST induction was found in children treated with chemotherapy (9 years vs 17.2 years). Seven STs developed in the area of high and moderate dose (>25 Gy), only two low-grade gliomas appeared in the low-dose region.
CONCLUSION: Our data suggest that the STs usually develop in the brain tissues that received doses >25 Gy in patients irradiated at a young age.
ADVANCES IN KNOWLEDGE: The low-dose volume seems not to be so significant for second brain neoplasm induction. Therefore, the modern intensity-modulated radiotherapy technique could be safely applied in paediatric patients.

Related: Childhood Brain Tumours Childhood Brain Tumors Brain and Spinal Cord Tumours Brain Stem Glioma - Childhood

Dockstader C, Wang F, Bouffet E, Mabbott DJ
Gamma deficits as a neural signature of cognitive impairment in children treated for brain tumors.
J Neurosci. 2014; 34(26):8813-24 [PubMed] Related Publications
Cognitive impairment is consistently reported in children treated for brain tumors, particularly in the categories of processing speed, memory, and attention. Although tumor site, hydrocephalus, chemotherapy, and cranial radiation therapy (CRT) are all associated with poorer function, CRT predicts the greatest deficits. There is a particularly high correlation between CRT and slowed information-processing speed. Cortical gamma-band oscillations have been associated with processing behaviorally relevant information; however, their role in the maintenance of cognition in individuals with processing deficits is unclear. We examined gamma oscillations using magnetoencephalography (MEG) in children undergoing CRT to test whether gamma characteristics can be a signature of cognitive impairment in this population. We collected resting-state data as well as data from baseline and active periods during two visual-motor reaction time tasks of varying cognitive loads from 18 healthy children and 20 patients. We found that only high-gamma oscillations (60-100 Hz), and not low-gamma oscillations (30-59 Hz), showed significant group differences in absolute power levels. Overall, compared with healthy children, patients showed the following: (1) lower total high-gamma (60-100 Hz) power during the resting state, as well as during task-related baseline and performance measures; (2) no change in gamma reactivity to increases in cognitive load; and (3) slower processing speeds both inside and outside MEG. Our findings show that high-gamma oscillations are disrupted in children after treatment for a brain tumor. The temporal dynamic of the high-gamma response during information processing may index cognitive impairment in humans with neurological injury.

Related: Childhood Brain Tumours Childhood Brain Tumors

Peters S, Glass DC, Greenop KR, et al.
Childhood brain tumours: associations with parental occupational exposure to solvents.
Br J Cancer. 2014; 111(5):998-1003 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: Parental occupational exposures have been associated with childhood brain tumours (CBT), but results are inconsistent. Few studies have studied CBT risk and parental solvent exposure, suggesting a possible association. We examined the association between CBT and parental occupational exposure to solvents in a case-control study.
METHODS: Parents of 306 cases and 950 controls completed detailed occupational histories. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for both maternal and paternal exposure to benzene, other aromatics, aliphatics and chlorinated solvents in key time periods relative to the birth of their child. Adjustments were made for matching variables (child's age, sex and state of residence), best parental education and occupational exposure to diesel exhaust.
RESULTS: An increased risk of CBT was observed with maternal occupational exposures to chlorinated solvents (OR=8.59, 95% CI 0.94-78.9) any time before birth. Paternal exposure to solvents in the year before conception was associated with an increased CBT risk: OR=1.55 (95% CI 0.99-2.43). This increased risk appeared to be mainly attributable to exposure to aromatic solvents: OR=2.72 (95% CI 0.94-7.86) for benzene and OR=1.76 (95% CI 1.10-2.82) for other aromatics.
CONCLUSIONS: Our results indicate that parental occupational exposures to solvents may be related to an increased risk of CBT.

Related: Childhood Brain Tumours Childhood Brain Tumors

Hoang DH, Pagnier A, Guichardet K, et al.
Cognitive disorders in pediatric medulloblastoma: what neuroimaging has to offer.
J Neurosurg Pediatr. 2014; 14(2):136-44 [PubMed] Related Publications
Medulloblastomas are the most common malignant childhood brain tumors arising in the posterior fossa. Treatment improvements for these tumors have meant that there are a greater number of survivors, but this long-term patient survival has increased the awareness of resulting neurocognitive deficits. Impairments in attention, memory, executive functions, and intelligence quotient demonstrate that the cerebellum likely plays a significant role in numerous higher cognitive functions such as language, cognitive, and emotional functions. In addition, children with medulloblastoma not only have cerebellar lesions but also brain white matter damages due to radiation and chemotherapy. Functional neuroimaging, a noninvasive method with many advantages, has become the standard tool in clinical and cognitive neuroscience research. By reviewing functional neuroimaging studies, this review aims to clarify the role of the cerebellum in cognitive function and explain more clearly cognitive sequelae due to polytherapy in children with medulloblastoma. This review suggests that the posterior cerebellar lobes are crucial to maintaining cognitive performance. Clinical investigations could help to better assess the involvement of these lobes in cognitive functions.

Related: Childhood Medulloblastoma / PNET

Pollack IF, Jakacki RI, Butterfield LH, et al.
Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas.
J Clin Oncol. 2014; 32(19):2050-8 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
PURPOSE: Diffuse brainstem gliomas (BSGs) and other high-grade gliomas (HGGs) of childhood carry a dismal prognosis despite current treatments, and new therapies are needed. Having identified a series of glioma-associated antigens (GAAs) commonly overexpressed in pediatric gliomas, we initiated a pilot study of subcutaneous vaccinations with GAA epitope peptides in HLA-A2-positive children with newly diagnosed BSG and HGG.
PATIENTS AND METHODS: GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks. Primary end points were safety and T-cell responses against vaccine-targeted GAA epitopes. Treatment response was evaluated clinically and by magnetic resonance imaging.
RESULTS: Twenty-six children were enrolled, 14 with newly diagnosed BSG treated with irradiation and 12 with newly diagnosed BSG or HGG treated with irradiation and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to dexamethasone and was associated with prolonged survival. Only two patients had progressive disease during the first two vaccine courses; 19 had stable disease, two had partial responses, one had a minor response, and two had prolonged disease-free status after surgery. Enzyme-linked immunosorbent spot analysis in 21 children showed positive anti-GAA immune responses in 13: to IL-13Rα2 in 10, EphA2 in 11, and survivin in three.
CONCLUSION: GAA peptide vaccination in children with gliomas is generally well tolerated and has preliminary evidence of immunologic and clinical responses. Careful monitoring and management of pseudoprogression is essential.

Related: Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood BIRC5

Pfitzer C, Chen CM, Wessel T, et al.
Dynamics of fertility impairment in childhood brain tumour survivors.
J Cancer Res Clin Oncol. 2014; 140(10):1759-67 [PubMed] Related Publications
PURPOSE: Fertility impairment and recovery after chemo- and radiotherapy have been reported in both male and female childhood cancer survivors, but little is known about the dynamics. Our aim, therefore, was to describe the development of fertility impairment and possible recovery in childhood brain tumour survivors.
METHODS: In this longitudinal study, we included 144 survivors, who were treated in two German paediatric oncology centres between 2000 and 2005. Fertility parameters were retrieved from medical records up to 12 years after diagnosis.
RESULTS: Participants with age ≥13 years and formerly cranial irradiation ≥30 Gray (n = 23), including 83 % (n = 19) with craniospinal irradiation ≥30 Gray, had a higher median FSH concentration compared to 29 patients without chemoradiotherapy: 8.3 IU/l (IQR 6.5-11.2) versus 4.1 IU/l (IQR 3.2-5.1) 2 years after initial treatment; 8.9 IU/l (IQR 8.5-10.8) versus 4.2 IU/l (IQR 2.4-6.7) after 8 years; and 7.1 IU/l (IQR 6.7-7.7) versus 3.5 IU/l (IQR 2.8-4.2) after 10 years. Altogether, 11/65 women reported the occurrence of amenorrhoea 6.0 years (range 1-10) after diagnosis. Five of these women later developed a regular menstrual cycle without hormone replacement therapy. Patients' chance of recovery from fertility impairment was increased with time since diagnosis (p = 0.074).
CONCLUSION: Signs of fertility impairment such as amenorrhoea and elevated FSH levels were observed at variable time points between 1 and 12 years after chemoradiotherapy. Decreasing FSH levels were observed 1-7 years after elevation and were interpreted either as an atrophy of the pituitary gland or as recovery from fertility impairment.

Related: Childhood Brain Tumours Childhood Brain Tumors

Moteabbed M, Yock TI, Paganetti H
The risk of radiation-induced second cancers in the high to medium dose region: a comparison between passive and scanned proton therapy, IMRT and VMAT for pediatric patients with brain tumors.
Phys Med Biol. 2014; 59(12):2883-99 [PubMed] Related Publications
The incidence of second malignant tumors is a clinically observed adverse late effect of radiation therapy, especially in organs close to the treatment site, receiving medium to high doses (>2.5 Gy). For pediatric patients, choosing the least toxic radiation modality is of utmost importance, due to their high radiosensitivity and small size. This study aims to evaluate the risk of second cancer incidence in the vicinity of the primary radiation field, for pediatric patients with brain/head and neck tumors and compare four treatment modalities: passive scattering and pencil beam scanning proton therapy (PPT and PBS), intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). For a cohort of six pediatric patients originally treated with PPT, additional PBS, IMRT and VMAT plans were created. Dose distributions from these plans were used to calculate the excess absolute risk (EAR) and lifetime attributable risk (LAR) for developing a second tumor in soft tissue and skull. A widely used risk assessment formalism was employed and compared with a linear model based on recent clinical findings. In general, LAR was found to range between 0.01%-2.8% for PPT/PBS and 0.04%-4.9% for IMRT/VMAT. PBS was associated with the lowest risk for most patients using carcinoma and sarcoma models, whereas IMRT and VMAT risks were comparable and the highest among all modalities. The LAR for IMRT/VMAT relative to PPT ranged from 1.3-4.6 for soft tissue and from 3.5-9.5 for skull. Larger absolute LAR was observed for younger patients and using linear risk models. The number of fields used in proton therapy and IMRT had minimal effect on the risk. When planning treatments and deciding on the treatment modality, the probability of second cancer incidence should be carefully examined and weighed against the possibility of developing acute side effects for each patient individually.

Related: Childhood Brain Tumours Childhood Brain Tumors Head and Neck Cancers Head and Neck Cancers - Molecular Biology

Lee YY, Yang YP, Huang MC, et al.
MicroRNA142-3p promotes tumor-initiating and radioresistant properties in malignant pediatric brain tumors.
Cell Transplant. 2014; 23(4-5):669-90 [PubMed] Related Publications
Primary central nervous system (CNS) atypical teratoid/rhabdoid tumor (ATRT) is an extremely malignant pediatric brain tumor observed in infancy and childhood. It has been reported that a subpopulation of CD133(+) cells isolated from ATRT tumors present with cancer stem-like and radioresistant properties. However, the exact biomolecular mechanisms of ATRT or CD133-positive ATRT (ATRT-CD133(+)) cells are still unclear. We have previously shown that ATRT-CD133(+) cells have pluripotent differentiation ability and the capability of malignant cells to be highly resistant to ionizing radiation (IR). By using microRNA array and quantitative RT-PCR in this study, we showed that expression of miR142-3p was lower in ATRT-CD133(+) cells than in ATRT-CD133(-) cells. miR142-3p overexpression significantly inhibited the self-renewal and tumorigenicity of ATRT-CD133(+) cells. On the contrary, silencing of endogenous miR142-3p dramatically increased the tumor-initiating and stem-like cell capacities in ATRT cells or ATRT-CD133(-) cells and further promoted the mesenchymal transitional and radioresistant properties of ATRT cells. Most importantly, therapeutic delivery of miR142-3p in ATRT cells effectively reduced its lethality by blocking tumor growth, repressing invasiveness, increasing radiosensitivity, and prolonging survival time in orthotropic-transplanted immunocompromised mice. These results demonstrate the prospect of developing novel miRNA-based strategies to block the stem-like and radioresistant properties of malignant pediatric brain cancer stem cells.

Related: Childhood Brain Tumours Childhood Brain Tumors Childhood Medulloblastoma / PNET MicroRNAs

Ferraz ST, Valera ET, Brassesco MS, et al.
Intracranial teratoma in children: the role of chromosome 21 trisomy.
Neuropathology. 2014; 34(2):197-200 [PubMed] Related Publications
Teratomas are very rare intracranial tumors and cytogenetic information on this group remains rare. We report a case of a mature teratoma with abnormal +21 trisomy in tumor karyotype ocurring in a non-Down syndrome(DS) infant. Additionally, the evidence for the contribution of chromosome 21 trisomy in this neoplasia are briefly reviewed. The 6-month-old male baby presented with a posterior fossa tumor. Histological evaluation of tumor specimen showed a mature teratoma composed of fully differentiated ectodermal, mesodermal and endodermal components. Although somatic karyotyping of the index case was normal, composite tumor karyotype depicted 47,XY,+21[6]/46,XY[6]. Besides previous reports of children with DS and intracranial teratomas, this is the first report to describe the occurrence of an isolated chromosome 21 trisomy within the tumor of a non-DS child. The participation of chromosome 21 in this rare pediatric tumor, either somatic or restricted to tumor specimen,may deserve special interest and further investigation.

Related: Chromosome 21 Down Syndrome and Cancer

Rodriguez FJ, Tihan T, Lin D, et al.
Clinicopathologic features of pediatric oligodendrogliomas: a series of 50 patients.
Am J Surg Pathol. 2014; 38(8):1058-70 [PubMed] Related Publications
Oligodendrogliomas are an important adult form of diffuse gliomas with a distinctive clinical and genetic profile. Histologically similar tumors occurring rarely in children are incompletely characterized. We studied 50 patients with oligodendrogliomas (median age at diagnosis 8 y, range 7 mo to 20 y). Tumors resembling dysembryoplastic neuroepithelial tumors or pilocytic astrocytomas or those having a "mixed" histology were excluded. Tumors at first diagnosis were low grade (n=38) or anaplastic (n=12). Histologic features included uniform round cells with perinuclear halos (100%), secondary structures (predominantly perineuronal satellitosis) (90%), calcifications (46%), and microcysts (44%). Sequential surgical specimens were obtained in 8 low-grade oligodendroglioma patients, with only 1 progressing to anaplasia. Studies for 1p19q performed in 40 cases demonstrated intact 1p19q loci in 29 (73%), 1p19q codeletion in 10 (25%), and 1p deletion with intact 19q in 1 (2%). Except for 2 young patients (3 and 11 y of age), patients with 1p19q codeletion were older than 16 years at diagnosis. Mutant IDH1 (R132H) protein immunohistochemistry was positive in 4 (of 22) (18%) cases, 3 of which also had 1p19q codeletion, whereas 1p19q status was not available on the fourth case. There was a nonsignificant trend for worse overall survival in grade III tumors, but no significant association with age, extent of resection, or 1p19q status. In summary, oligodendrogliomas with classic histology occur in the pediatric population but lack 1p19q codeletion and IDH1 (R132H) mutations in most instances. They are predominantly low grade, recur/clinically progress in a subset, but demonstrate a relatively low frequency of histologic progression.

Related: Childhood Brain Tumours Childhood Brain Tumors Chromosome 1 FISH

Roth JJ, Santi M, Rorke-Adams LB, et al.
Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors.
Cancer Genet. 2014; 207(4):111-23 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Single nucleotide polymorphism (SNP) array analysis is currently used as a first tier test for pediatric brain tumors at The Children's Hospital of Philadelphia. The results from 100 consecutive patients are summarized in the present report. Eighty-seven percent of the tumors had at least one pathogenic copy number alteration. Nineteen of 56 low grade gliomas (LGGs) demonstrated a duplication in 7q34, which resulted in a KIAA1549-BRAF fusion. Chromosome band 7q34 deletions, which resulted in a FAM131B-BRAF fusion, were identified in one pilocytic astrocytoma (PA) and one dysembryoplastic neuroepithelial tumor (DNT). One ganglioglioma (GG) demonstrated a 6q23.3q26 deletion that was predicted to result in a MYB-QKI fusion. Gains of chromosomes 5, 6, 7, 11, and 20 were seen in a subset of LGGs. Monosomy 6, deletion of 9q and 10q, and an i(17)(q10) were each detected in the medulloblastomas (MBs). Deletions and regions of loss of heterozygosity that encompassed TP53, RB1, CDKN2A/B, CHEK2, NF1, and NF2 were identified in a variety of tumors, which led to a recommendation for germline testing. A BRAF p.Thr599dup or p.V600E mutation was identified by Sanger sequencing in one and five gliomas, respectively, and a somatic TP53 mutation was identified in a fibrillary astrocytoma. No TP53 hot-spot mutations were detected in the MBs. SNP array analysis of pediatric brain tumors can be combined with pathologic examination and molecular analyses to further refine diagnoses, offer more accurate prognostic assessments, and identify patients who should be referred for cancer risk assessment.

Related: Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood FISH Childhood Medulloblastoma / PNET BRAF gene

Pierce T, Kranz PG, Roth C, et al.
Use of apparent diffusion coefficient values for diagnosis of pediatric posterior fossa tumors.
Neuroradiol J. 2014; 27(2):233-44 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
We prospectively compared the ability of neuroradiologists to diagnose medulloblastoma with novice raters using only apparent diffusion coefficient (ADC) values measured on ADC maps. One hundred and three pediatric patients with pre-operative magnetic resonance imaging scans showing a posterior fossa tumor with histological verification were retrospectively identified from a ten-year period at a tertiary care medical center. A single observer measured the lowest ADC values in all tumors to determine the mean minimum ADC (ADCmin) value that provided greatest accuracy in distinguishing medulloblastomas from other tumors, which was determined to be 0.66×10(-3) mm(2)/s. Imaging studies, including ADC maps, from 90 patients were provided to two neuroradiologists, who provided a diagnosis, which was later dichotomized as medulloblastoma or other. Two medical students measured ADCmin within tumors and those with ADCmin < 0.66×10(-3) mm(2)/s were recorded as medulloblastoma; any other value was recorded as other. Diagnostic accuracy was measured. ADCmin values allowed a correct identification of lesions as either medulloblastoma or other in 91% of cases. After diagnoses by the two neuroradiologists were categorized as either medulloblastoma or other, their diagnoses were correct in 90% and 84% of cases, respectively. In 19 cases, at least one neuroradiologist was incorrect; the addition of ADC values to clinical interpretation would have allowed a correct diagnosis in 63% of such cases. Diagnostic accuracy based on ADC values by medical students was comparable to that of subspecialty-trained neuroradiologists. Our findings suggest that the addition of ADC values to standard film interpretation may improve the diagnostic rate for these tumors.

Related: Childhood Astrocytoma Childhood Brain Tumours Childhood Brain Tumors Childhood Ependymoma Childhood Medulloblastoma / PNET

Meulepas JM, Ronckers CM, Smets AM, et al.
Leukemia and brain tumors among children after radiation exposure from CT scans: design and methodological opportunities of the Dutch Pediatric CT Study.
Eur J Epidemiol. 2014; 29(4):293-301 [PubMed] Related Publications
Computed tomography (CT) scans are indispensable in modern medicine; however, the spectacular rise in global use coupled with relatively high doses of ionizing radiation per examination have raised radiation protection concerns. Children are of particular concern because they are more sensitive to radiation-induced cancer compared with adults and have a long lifespan to express harmful effects which may offset clinical benefits of performing a scan. This paper describes the design and methodology of a nationwide study, the Dutch Pediatric CT Study, regarding risk of leukemia and brain tumors in children after radiation exposure from CT scans. It is a retrospective record-linkage cohort study with an expected number of 100,000 children who received at least one electronically archived CT scan covering the calendar period since the introduction of digital archiving until 2012. Information on all archived CT scans of these children will be obtained, including date of examination, scanned body part and radiologist's report, as well as the machine settings required for organ dose estimation. We will obtain cancer incidence by record linkage with external databases. In this article, we describe several approaches to the collection of data on archived CT scans, the estimation of radiation doses and the assessment of confounding. The proposed approaches provide useful strategies for data collection and confounder assessment for general retrospective record-linkage studies, particular those using hospital databases on radiological procedures for the assessment of exposure to ionizing or non-ionizing radiation.

Related: Childhood Brain Tumours Childhood Brain Tumors Leukemia Childhood Leukaemia Leukemia - Molecular Biology

Alaqeel AM, Sabbagh AJ
Pediatric brainstem tumors. Classifications, investigations, and growth patterns.
Neurosciences (Riyadh). 2014; 19(2):93-9 [PubMed] Related Publications
Brainstem gliomas occur in 10-20% of brain tumors in pediatrics. Over the past 3 decades, the treatment of brainstem gliomas has significantly progressed as a result of the gradual advancements in microsurgical techniques, sophisticated imaging technology and, most importantly, the availability of MRI. In this article, we review the current literature on brainstem gliomas and cover diagnosis, imaging, classification, and management. Surgical approaches and intraoperative modalities to tackle operable cases of brainstem gliomas will be discussed in a follow up article.

Wang C, Roberts KB, Bindra RS, et al.
Delayed cerebral vasculopathy following cranial radiation therapy for pediatric tumors.
Pediatr Neurol. 2014; 50(6):549-56 [PubMed] Related Publications
BACKGROUND: Radiation-induced cerebrovascular injury is a well-known phenomenon. We analyze reported cases of delayed radiation-induced cerebrovasculopathy that present as moyamoya syndrome and/or intracerebral hemorrhage and to statistically analyze the relationship between radiation dose and the interval period between radiation and the presentation of cerebrovasculopathy.
METHODS: Patients ages <21 years at the time of radiation were included in analysis. A review of previous publications yielded 77 cases of delayed radiation-induced cerebrovasculopathy consisting of 45 cases of moyamoya syndrome, 30 cases of intracerebral hemorrhage, and two cases of both.
RESULTS: The median age at radiation was 4.8 years, with a range of 0.5-20 years. Approximately, 75% of these patients received radiation at the age of <9 years. The median interval period for moyamoya cases was 3.3 years (range: 0.3-20; P < 0.001), whereas the median interval period from radiation to presentation for intracerebral hemorrhage cases was 7.5 years (range: 0.8-27). There was significant association between radiation dose and interval from radiation to moyamoya syndrome (P < 0.001), whereas for patients with intracerebral hemorrhage, the association was insignificant (P = 0.31).
CONCLUSIONS: Pediatric patients who presented with moyamoya generally presented earlier than those who presented with intracerebral hemorrhage, suggesting that moyamoya may be a factor that predisposes the patient to intracerebral hemorrhage. In patients who presented with moyamoya, there was a statistically significant correlation between increasing doses of radiation and shorter time from radiation to disease presentation.

Related: Childhood Brain Tumours Childhood Brain Tumors

Wang ZJ, Altonok D, Sood S, et al.
Inadvertent high-dose therapy with temozolomide in a child with recurrent pontine glioma followed by a rapid clinical response but deteriorated after substitution with low-dose therapy.
J Pediatr Hematol Oncol. 2014; 36(8):e549-52 [PubMed] Related Publications
We present a case of inadvertent high-dose therapy with temozolomide in a child with recurrent diffuse intrinsic pontine glioma followed by a rapid clinical response. The patient was a 7-year-old boy who initially presented with a history of left facial palsy, double vision, headache, and ataxia. His symptoms were completely resolved following radiotherapy but recurred 3 months after. Following recurrence, he received temozolomide in a dose >3 times higher than prescribed inadvertently but tolerated well with a rapid clinical response. He eventually deteriorated after he was substituted with a lower dose of temozolomide and died.

Related: Dacarbazine Brain Stem Glioma - Childhood Temozolomide

Hiniker SM, Agarwal R, Modlin LA, et al.
Survival and neurocognitive outcomes after cranial or craniospinal irradiation plus total-body irradiation before stem cell transplantation in pediatric leukemia patients with central nervous system involvement.
Int J Radiat Oncol Biol Phys. 2014; 89(1):67-74 [PubMed] Related Publications
PURPOSE: To evaluate survival and neurocognitive outcomes in pediatric acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement treated according to an institutional protocol with stem cell transplantation (SCT) and a component of craniospinal irradiation (CSI) in addition to total-body irradiation (TBI) as preparative regimen.
METHODS AND MATERIALS: Forty-one pediatric ALL patients underwent SCT with TBI and received additional cranial irradiation or CSI because of CNS leukemic involvement. Prospective neurocognitive testing was performed before and after SCT in a subset of patients. Cox regression models were used to determine associations of patient and disease characteristics and treatment methods with outcomes.
RESULTS: All patients received a cranial radiation boost; median total cranial dose was 24 Gy. Eighteen patients (44%) received a spinal boost; median total spinal dose for these patients was 18 Gy. Five-year disease-free survival (DFS) for all patients was 67%. Those receiving CSI had a trend toward superior DFS compared with those receiving a cranial boost alone (hazard ratio 3.23, P=.14). Patients with isolated CNS disease before SCT had a trend toward superior DFS (hazard ratio 3.64, P=.11, 5-year DFS 74%) compared with those with combined CNS and bone marrow disease (5-year DFS 59%). Neurocognitive testing revealed a mean post-SCT overall intelligence quotient of 103.7 at 4.4 years. Relative deficiencies in processing speed and/or working memory were noted in 6 of 16 tested patients (38%). Pre- and post-SCT neurocognitive testing revealed no significant change in intelligence quotient (mean increase +4.7 points). At a mean of 12.5 years after transplant, 11 of 13 long-term survivors (85%) had completed at least some coursework at a 2- or 4-year college.
CONCLUSION: The addition of CSI to TBI before SCT in pediatric ALL with CNS involvement is effective and well-tolerated. Craniospinal irradiation plus TBI is worthy of further protocol investigation in children with CNS leukemia.

Related: Childhood Brain Tumours Childhood Brain Tumors Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology Stem Cell and Bone Marrow Transplants

Ding D, Zhao A, Qiu B, et al.
Ependymoblastoma with cystic change in a child.
J Neurosurg Pediatr. 2014; 13(6):658-65 [PubMed] Related Publications
Ependymoblastoma is a rare and devastating primitive neuroectodermal tumor with ependymal differentiation. This tumor occurs very early in life and shows rapid growth and a diffuse infiltration through the leptomeningeal space. This neoplasm is characterized by uniform neuroepithelial cells, multilayered ependymal rosettes, perivascular pseudorosettes, and numerous mitotic figures. In this article, the authors report on a 4-year-old girl who was diagnosed as having an ependymoblastoma with cystic change. After a series of laboratory and imaging examinations, the left frontal solid-cystic lesion was surgically excised. Histological examinations confirmed the diagnosis of ependymoblastoma. The patient's intracranial hypertension symptoms were alleviated, and postoperative chemotherapy was performed. At the 6-month follow-up visit, MRI demonstrated evidence of relapse, and the girl died of tumor recurrence 14 months after surgery. Databases (PubMed, MEDLINE, Embase, and Web of Science) were searched for relevant articles published from 1970 to 2012; 71 eligible cases of ependymoblastoma were obtained, and 42 provided complete clinical details. Prognosis of children with ependymoblastoma is poor, and data on clinical behavior and optimal treatment strategies are lacking, but sustained remissions have been achieved after multimodal treatment according to existing literature. In this report, the clinical and histopathological features and therapeutic options of this tumor are discussed in the light of the published data. Further studies, especially those examining multimodality therapy, are needed to improve survival of children with this rare malignant CNS tumor.

Raikar SS, Halloran DR, Elliot M, et al.
Outcomes of pediatric low-grade gliomas treated with radiation therapy: a single-institution study.
J Pediatr Hematol Oncol. 2014; 36(6):e366-70 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Radiation therapy is often considered the treatment of choice for low-grade gliomas. However, given the long-term effects of radiation on the developing brain, the appropriate use of radiation therapy in pediatric patients remains controversial. The purpose of this study was to evaluate progression-free survival (PFS) of pediatric low-grade glioma patients treated with radiation therapy. Data were obtained through a retrospective chart review of patients treated between 1991 and 2008 from a single tertiary care center in the midwest. The study population consisted of 17 patients, of whom 8 (47%) had tumor recurrence after radiation therapy. The median follow-up time was 8.2 years, with a range of 2.3 to 17.2 years. The median age at diagnosis was 5.4 years, and the median age at radiation therapy was 9.4 years. The 3- and the 10-year PFS were 69%± 11.7% and 46%± 13.3%, respectively. A significant difference in PFS was seen when comparing brainstem tumors with hypothalamic/optic pathway tumors (P=0.019). Differences in PFS based on the age at diagnosis, the extent of initial surgery, and indication for radiation therapy were not significant. A larger multicenter study is needed to better assess PFS in these patients.

Related: Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood

Navid F, Sondel PM, Barfield R, et al.
Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma.
J Clin Oncol. 2014; 32(14):1445-52 [PubMed] Article available free on PMC after 10/05/2015 Related Publications
PURPOSE: The addition of immunotherapy, including a combination of anti-GD2 monoclonal antibody (mAb), ch14.18, and cytokines, improves outcome for patients with high-risk neuroblastoma. However, this therapy is limited by ch14.18-related toxicities that may be partially mediated by complement activation. We report the results of a phase I trial to determine the maximum-tolerated dose (MTD), safety profile, and pharmacokinetics of hu14.18K322A, a humanized anti-GD2 mAb with a single point mutation (K322A) that reduces complement-dependent lysis.
PATIENTS AND METHODS: Eligible patients with refractory or recurrent neuroblastoma received escalating doses of hu14.18K322A ranging from 2 to 70 mg/m(2) per day for 4 consecutive days every 28 days (one course).
RESULTS: Thirty-eight patients (23 males; median age, 7.2 years) received a median of two courses (range, one to 15). Dose-limiting grade 3 or 4 toxicities occurred in four of 36 evaluable patients and were characterized by cough, asthenia, sensory neuropathy, anorexia, serum sickness, and hypertensive encephalopathy. The most common non-dose-limiting grade 3 or 4 toxicities during course one were pain (68%) and fever (21%). Six of 31 patients evaluable for response by iodine-123 metaiodobenzylguanidine score had objective responses (four complete responses; two partial responses). The first-course pharmacokinetics of hu14.18K322A were best described by a two-compartment linear model. Median hu14.18K322A α (initial phase) and β (terminal phase) half-lives were 1.74 and 21.1 days, respectively.
CONCLUSION: The MTD, and recommended phase II dose, of hu14.18K322A is 60 mg/m(2) per day for 4 days. Adverse effects, predominately pain, were manageable and improved with subsequent courses.

Related: Monoclonal Antibodies Childhood Brain Tumours Childhood Brain Tumors Neuroblastoma

Fiaschetti G, Schroeder C, Castelletti D, et al.
NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma.
Acta Neuropathol Commun. 2014; 2:39 [PubMed] Article available free on PMC after 10/05/2015 Related Publications
Medulloblastoma (MB), the most common pediatric malignant brain cancer, typically arises as pathological result of deregulated developmental pathways, including the NOTCH signaling cascade. Unlike the evidence supporting a role for NOTCH receptors in MB development, the pathological functions of NOTCH ligands remain largely unexplored. By examining the expression in large cohorts of MB primary tumors, and in established in vitro MB models, this research study demonstrates that MB cells bear abnormal levels of distinct NOTCH ligands. We explored the potential association between NOTCH ligands and the clinical outcome of MB patients, and investigated the rational of inhibiting NOTCH signaling by targeting specific ligands to ultimately provide therapeutic benefits in MB. The research revealed a significant over-expression of ligand JAG1 in the vast majority of MBs, and proved that JAG1 mediates pro-proliferative signals via activation of NOTCH2 receptor and induction of HES1 expression, thus representing an attractive therapeutic target. Furthermore, we could identify a clinically relevant association between ligand JAG2 and the oncogene MYC, specific for MYC-driven Group 3 MB cases. We describe for the first time a mechanistic link between the oncogene MYC and NOTCH pathway in MB, by identifying JAG2 as MYC target, and by showing that MB cells acquire induced expression of JAG2 through MYC-induced transcriptional activation. Finally, the positive correlation of MYC and JAG2 also with aggressive anaplastic tumors and highly metastatic MB stages suggested that high JAG2 expression may be useful as additional marker to identify aggressive MBs.

Related: Apoptosis Childhood Medulloblastoma / PNET MYC gene

Wu G, Diaz AK, Paugh BS, et al.
The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.
Nat Genet. 2014; 46(5):444-50 [PubMed] Article available free on PMC after 10/05/2015 Related Publications
Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.

Related: Brain Stem Glioma - Childhood NTRK1 gene NTRK2 NTRK3 gene Signal Transduction

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