Brassesco MS, Valera ET, Neder L, et al.
Cytogenetic findings in pediatric radiation-induced atypical meningioma after treatment of medulloblastoma: case report and review of the literature.
J Neurooncol. 2012; 110(3):397-402 [PubMed]

Ionizing radiation is the most recognized risk factor for meningioma in pediatric long-term cancer survivors. Information in this rare setting is exceptional. We report the clinical and cytogenetic findings in a radiation-induced atypical meningioma following treatment for desmoplastic medulloblastoma in a child. This is the second study to describe the cytogenetic aspects on radiation-induced meningiomas in children. Chromosome banding analysis revealed a 46, XX, t(1;3)(p22;q12), del(1)(p?)[8]/46, XX[12]. Loss of chromosome 1p as a consequence of irradiation has been proposed to be more important in the development of secondary meningiomas in adults. Deletions in the short arm of chromosome 1 also appear to be a shared feature in both pediatric cases so far analyzed.

Rednam S, Scheurer ME, Adesina A, et al.
Glutathione S-transferase P1 single nucleotide polymorphism predicts permanent ototoxicity in children with medulloblastoma.
Pediatr Blood Cancer. 2013; 60(4):593-8 [PubMed] Article available free on PMC after 01/04/2014

BACKGROUND: Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy and clearing reactive oxygen species formed by radiation. We explored the relationship between the host GSTP1 105 A > G polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1 105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events.
PROCEDURE: The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children's Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and logistic regression for toxicity comparisons.
RESULTS: Patients with a GSTP1 105 AG/GG genotype (vs. AA) or who had received high dose craniospinal radiation (≥34 Gy vs. <26 Gy) had a greater risk of requiring hearing aids than their counterparts (OR 4.0, 95% CI 1.2-13.6, and OR 3.1, 95% CI 1.1-8.8, respectively, n = 69). Additionally, there was a statistically significant interaction between these variables. Compared with the lowest risk group (GSTP1 105 AA-low dose radiation), patients with a GSTP1 105 AG/GG genotype who received high dose radiation were 8.4 times more likely to require hearing aids (95% CI 1.4-49.9, p-trend = 0.005, n = 69). When adjusted for age, cumulative cisplatin dose, and amifostine use, the association remained.
CONCLUSIONS: The GSTP1 105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. Patients with this allele should be considered for clinical trials employing radiation dose modifications and cytoprotectant strategies.

Lafay-Cousin L, Purdy E, Huang A, et al.
Early cisplatin induced ototoxicity profile may predict the need for hearing support in children with medulloblastoma.
Pediatr Blood Cancer. 2013; 60(2):287-92 [PubMed]

BACKGROUND: Cisplatin (CDDP) ototoxicity is a significant side effect of the current treatment of medulloblastoma (MB). Cumulative dose of CDDP and age are recognized risk factors for hearing loss, but inter-individual susceptibility limits our ability to identify patients at risk for hearing loss. We describe the kinetics of early audiometric changes during therapy and identify profiles associated with a higher risk of needing hearing aids.
PROCEDURE: Serial audiometric evaluations were performed during and after completion of therapy in children with average risk (AR) and high-risk (HR) MB. Each audiogram was scored according to five grading systems. Variations of pure tone thresholds were analyzed at each frequency for each consecutive audiogram. CDDP dose modifications and hearing outcome were recorded.
RESULTS: A total of 258 audiograms from 35 patients (22 AR, 13 HR) were analyzed. Eighteen AR patients (81.3%) required dose reduction and the median cumulative dose of CDDP administered was 412.5 mg/m(2) (150-600), corresponding to 68% of the intended dose. Three HR patients (23.0%) required dose reduction. At a median follow-up of 67 months (11-117), nine patients (25.7%) required hearing support: After two cycles of CDDP (150 mg/m(2) ), the average hearing loss at 8,000 Hz was twice higher in the group that eventually required hearing support.
CONCLUSION: Early alteration of high-frequency thresholds may help identify individuals who will require hearing support. In the MB population, alternative strategies should be developed to limit the cumulative dose of CDDP to prevent significant ototoxicity.

Lupo PJ, Nousome D, Okcu MF, et al.
Maternal variation in EPHX1, a xenobiotic metabolism gene, is associated with childhood medulloblastoma: an exploratory case-parent triad study.
Pediatr Hematol Oncol. 2012; 29(8):679-85 [PubMed]

Common epidemiologic study designs used for evaluating germline genetic determinants of childhood medulloblastoma are often subject to population stratification bias and do not account for maternal genetic effects, a proxy for the intrauterine environment, which may be important in determining etiologic factors for this outcome. The case-parent triad design overcomes these limitations. Therefore, we conducted an exploratory study among 27 childhood medulloblastoma case-parent triads recruited from the Childhood Cancer Epidemiology and Prevention Center at Texas Children's Hospital (Houston, USA) between 2003 and 2010. We assessed 13 single nucleotide polymorphisms (SNPs) in nine xenobiotic detoxification genes, as deficiencies in this pathway may induce brain tumorigenesis. Log-linear modeling was used to assess the association between medulloblastoma and both the offspring (i.e., case) and maternal genotypes of each SNP. In our population, there were no offspring genotypes that were significantly associated with disease risk. However, the maternal EPHX1 rs1051740 genotype (RR = 3.26, P = .01) was associated with medulloblastoma risk. This exploratory study highlights the utility of the case-parent triad design, but these results should be interpreted cautiously due to the limited sample size.

Smith RL, Shi X, Estlin EJ
Chemotherapy dose-intensity and survival for childhood medulloblastoma.
Anticancer Res. 2012; 32(9):3885-92 [PubMed]

AIM: To determine the relationship between prescribed dose-intensity of chemotherapy and survival in childhood medulloblastoma.
MATERIALS AND METHODS: A total of 55 trials from 1970-2009 were identified, 30 were eligible for analysis, with individual treatment regimes with 5-year (or more) outcome figures. Relationships of outcome to dose-intensity were analysed using weighted regression.
RESULTS: Overall, 2,434 patients were identified, 1,010 were classified as 'standard'- and 671 as 'high'-risk patients, with 5-year overall survivals (OS) of 67.2% (95% Confidence Interval=60.5%-73.6%) and 47.6% (95% Confidence Interval=39.5%-55.7%), respectively. A protective effect for chemotherapy versus craniospinal radiotherapy alone (5-year OS of 58.2% versus 51.6%) was found. Individually, vincristine, cisplatin, lomustine (CCNU) and cyclophosphamide appear to confer the most beneficial effect, particularly for high-risk patients. Positive relationships between OS and dose-intensity were found, except for lomustine, with cyclophosphamide offering the greatest protection.
CONCLUSION: Consideration of chemotherapy dose-intensity may further optimise treatment, particularly in the context of risk stratification.

Smoll NR, Drummond KJ
The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children.
J Clin Neurosci. 2012; 19(11):1541-4 [PubMed]

Medulloblastomas (MB) and primitive neurectodermal tumours (PNET) are known to affect children more than adults. To estimate the magnitude of the differences between the incidence of adults and children, the incidence rates, ratios and time trends of MB and PNET in children and adults are measured using data from the Surveillance, Epidemiology and End-Results (SEER) database. Between 1973 and 2007 in the SEER 9 registries, 1372 people were diagnosed with a MB and 530 with a PNET. The overall incidence rate of MB and PNET is approximately 1.5 and 0.62 per million population in the USA. Children (1-9 years of age) with MB had an incidence rate of 6.0, compared to 0.6 in adults, and therefore children are 10 times more likely to be affected by an MB than adults. Children are 4.6 times as likely to be afflicted by a PNET than adults. The difference in incidence rates based on sex existed only in children. Our study confirmed that the incidence rates of MB has not changed over time.

Zhang R, Yuan Y, Zuo J, Liu W
Prognostic and clinical implication of a disintegrin and metalloprotease 8 expression in pediatric medulloblastoma.
J Neurol Sci. 2012; 323(1-2):46-51 [PubMed]

AIM: To investigate the expression patterns and clinical value of a disintegrin and metalloprotease 8 (ADAM8) in pediatric medulloblastoma.
METHODS: We evaluated the expression of ADAM8 mRNA and protein in pediatric medulloblastoma tissues by Quantitative RT-PCR, Western blot analysis and Immunohistochemical staining, respectively. The correlation of ADAM8 immunostaining with clinical-pathological features of medulloblastoma patients and its prognostic relevance were further determined.
RESULTS: ADAM8 mRNA and protein were both most highly expressed in medulloblastoma tissues when compared with normal cerebellum tissues (both P<0.001). According to the immunohistochemisty analysis, we found statistically significant correlations of high ADAM8 protein expression with advanced metastatic stage (P=0.01), aggressive histopathological type (P=0.006), as well as with undifferentiated tumor (P=0.02). We further determined a statistically significant association between ADAM8 protein expression and clinical outcome of medulloblastoma patients, with higher expression levels of ADAM8 associating with a worse overall survival (P=0.02).
CONCLUSION: Our results provide the first evidence that the up-regulation of ADAM8 in medulloblastoma tissues might be correlated with the advanced tumor progression and poor prognosis of patients with this disease. Detection of ADAM8 expression might facilitate the prognostic assessment and improve the therapeutic strategy for medulloblastoma patients.

Thomas M, Enciso V, Stratton R, et al.
Metastatic medulloblastoma in an adolescent with Simpson-Golabi-Behmel syndrome.
Am J Med Genet A. 2012; 158A(10):2534-6 [PubMed]

We describe the case of a 12-year-old Hispanic male with a clinical and molecular diagnosis of Simpson-Golabi-Behmel Syndrome (SGBS) who subsequently developed metastatic medulloblastoma. While individuals with SGBS have been documented to have increased risk for intra-abdominal tumors such as Wilms tumor and neuroblastoma, medulloblastomas, or CNS tumors in general, have not been reported in patients with this syndrome. Our patient was clinically diagnosed with SGBS as an infant. He presented with many of the common features of the syndrome, such as cleft palate, macroglossia, post-axial polydactyly, "coarse" facial features, and ventricular septal defects (VSDs). Molecular testing performed in April 2009 confirmed the SGBS diagnosis. This testing detected a large intragenic deletion in the GPC3 gene (more than 500 kb, 8 exons) extending from intron 2, 37 kb downstream of exon 2, to the 5' end of the gene, deleting exons 1 and 2. However, subsequent testing by gene-centric high-density array comparative genomic hybridization (aCGH) detected a deletion encompassing only exon 2. Therefore, the exact 5' boundary of the deletion cannot currently be determined, due to an apparent complex rearrangement upstream of exon 1. We present this case of metastatic medulloblastoma as a unique malignancy in a patient with SGBS.

Ashley DM, Merchant TE, Strother D, et al.
Induction chemotherapy and conformal radiation therapy for very young children with nonmetastatic medulloblastoma: Children's Oncology Group study P9934.
J Clin Oncol. 2012; 30(26):3181-6 [PubMed] Article available free on PMC after 10/09/2013

PURPOSE: P9934 was a prospective trial of systemic chemotherapy, second surgery, and conformal radiation therapy (CRT) limited to the posterior fossa and primary site for children between 8 months and 3 years old with nonmetastatic medulloblastoma. The study was open from June 2000 until June 2006.
PATIENTS AND METHODS: After initial surgery, children received four cycles of induction chemotherapy, followed by age- and response-adjusted CRT to the posterior fossa (18 or 23.4 Gy) and tumor bed (cumulative 50.4 or 54 Gy) and maintenance chemotherapy. Neurodevelopmental outcomes were evaluated and event-free survival (EFS) results were directly compared with a previous study of multiagent chemotherapy without irradiation (Pediatric Oncology Group [POG] trial 9233).
RESULTS: Seventy-four patients met eligibility requirements. The 4-year EFS and overall survival probabilities were 50% ± 6% and 69% ± 5.5%, respectively, which compared favorably to the results from POG 9233. Analysis showed that the desmoplastic/nodular subtype was a favorable factor in predicting survival. Our 4-year EFS rate was 58% ± 8% for patients with desmoplasia. Whereas seven of 10 patients who had disease progression before CRT had primary-site failure, 15 of 19 patients who progressed after CRT had distant-site failure. Neurodevelopmental assessments did not show a decline in cognitive or motor function after protocol-directed chemotherapy and CRT.
CONCLUSION: The addition of CRT to postoperative chemotherapy in young children with nonmetastatic medulloblastoma increased event-free survival compared with the use of postoperative chemotherapy alone. Future studies will use histopathologic typing (desmoplastic/nodular versus nondesmoplastic/nodular) to stratify patients for therapy by risk of relapse.

Coco S, De Mariano M, Valdora F, et al.
Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma.
J Hum Genet. 2012; 57(10):682-4 [PubMed]

The anaplastic lymphoma kinase (ALK) gene has been found either rearranged or mutated in several neoplasms such as anaplastic large-cell lymphoma, non-small-cell lung cancer, neuroblastoma and anaplastic thyroid cancer. Medulloblastoma (MB) is an embryonic pediatric cancer arising from nervous system, a tissue in which ALK is expressed during embryonic development. We performed an ALK mutation screening in 52 MBs and we found a novel heterozygous germline deletion of a single base in exon 23 (3605delG) in a case with marked anaplasia. This G deletion results in a frameshift mutation producing a premature stop codon in exon 25 of ALK tyrosine kinase domain. We also screened three human MB cell lines without finding any mutation of ALK gene. Quantitative expression analysis of 16 out of 52 samples showed overexpression of ALK mRNA in three MBs. In the present study, we report the first mutation of ALK found in MB. Moreover, a deletion of ALK gene producing a stop codon has not been detected in human tumors up to now. Further investigations are now required to elucidate whether the truncated form of ALK may have a role in signal transduction.

Costa B, Kean MJ, Ast V, et al.
STK25 protein mediates TrkA and CCM2 protein-dependent death in pediatric tumor cells of neural origin.
J Biol Chem. 2012; 287(35):29285-9 [PubMed] Article available free on PMC after 24/08/2013

The TrkA receptor tyrosine kinase induces death in medulloblastoma cells via an interaction with the cerebral cavernous malformation 2 (CCM2) protein. We used affinity proteomics to identify the germinal center kinase class III (GCKIII) kinases STK24 and STK25 as novel CCM2 interactors. Down-modulation of STK25, but not STK24, rescued medulloblastoma cells from NGF-induced TrkA-dependent cell death, suggesting that STK25 is part of the death-signaling pathway initiated by TrkA and CCM2. CCM2 can be phosphorylated by STK25, and the kinase activity of STK25 is required for death signaling. Finally, STK25 expression in tumors is correlated with positive prognosis in neuroblastoma patients. These findings delineate a death-signaling pathway downstream of neurotrophic receptor tyrosine kinases that may provide targets for therapeutic intervention in pediatric tumors of neural origin.

Murphy ES, Merchant TE, Wu S, et al.
Necrosis after craniospinal irradiation: results from a prospective series of children with central nervous system embryonal tumors.
Int J Radiat Oncol Biol Phys. 2012; 83(5):e655-60 [PubMed] Article available free on PMC after 01/08/2013

PURPOSE: Necrosis of the central nervous system (CNS) is a known complication of craniospinal irradiation (CSI) in children with medulloblastoma and similar tumors. We reviewed the incidence of necrosis in our prospective treatment series.
PATIENTS AND METHODS: Between 1996 and 2009, 236 children with medulloblastoma (n = 185) or other CNS embryonal tumors (n = 51) received postoperative CSI followed by dose-intense cyclophosphamide, vincristine, and cisplatin. Average risk cases (n = 148) received 23.4 Gy CSI, 36 Gy to the posterior fossa, and 55.8 Gy to the primary; after 2003, the treatment was 23.4 Gy CSI and 55.8 Gy to the primary. All high-risk cases (n = 88) received 36-39.6 Gy CSI and 55.8 Gy primary. The primary site clinical target volume margin was 2 cm (pre-2003) or 1 cm (post-2003). With competing risk of death by any cause, we determined the cumulative incidence of necrosis.
RESULTS: With a median follow-up of 52 months (range, 4-163 months), eight cases of necrosis were documented. One death was attributed. The median time to the imaging evidence was 4.8 months and to symptoms 6.0 months. The cumulative incidence at 5 years was 3.7% ± 1.3% (n = 236) for the entire cohort and 4.4% ± 1.5% (n = 196) for infratentorial tumor location. The mean relative volume of infratentorial brain receiving high-dose irradiation was significantly greater for patients with necrosis than for those without: ≥ 50 Gy (92.12% ± 4.58% vs 72.89% ± 1.96%; P=.0337), ≥ 52 Gy (88.95% ± 5.50% vs 69.16% ± 1.97%; P=.0275), and ≥ 54 Gy (82.28% ± 7.06% vs 63.37% ± 1.96%; P=.0488), respectively.
CONCLUSIONS: Necrosis in patients with CNS embryonal tumors is uncommon. When competing risks are considered, the incidence is 3.7% at 5 years. The volume of infratentorial brain receiving greater than 50, 52, and 54 Gy, respectively, is predictive for necrosis.

Sikkema AH, den Dunnen WF, Hulleman E, et al.
EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion.
Neuro Oncol. 2012; 14(9):1125-35 [PubMed] Article available free on PMC after 01/09/2013

Eph/ephrin signaling has been implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinase-activity profiling data published recently, we hypothesized a key role for the Eph/ephrin signaling system in medulloblastoma invasion. In primary medulloblastoma samples, a significantly higher expression of EphB2 and the ligand ephrin-B1 was observed compared with normal cerebellum. Furthermore, medulloblastoma cell lines showed high expression of EphA2, EphB2, and EphB4. Stimulation of medulloblastoma cells with ephrin-B1 resulted in a marked decrease in in vitro cell adhesion and an increase in the invasion capacity of cells expressing high levels of EphB2. The cell lines that showed an ephrin-B1-induced phenotype possessed increased levels of phosphorylated EphB2 and, to a lesser extent, EphB4 after stimulation. Knockdown of EphB2 expression by short hairpin RNA completely abolished ephrin ligand-induced effects on adhesion and migration. Analysis of signal transduction identified p38, Erk, and mTOR as downstream signaling mediators potentially inducing the ephrin-B1 phenotype. In conclusion, the observed deregulation of Eph/ephrin expression in medulloblastoma enhances the invasive phenotype, suggesting a potential role in local tumor cell invasion and the formation of metastases.

van den Akker M, Northcott P, Taylor MD, et al.
Anaplastic medulloblastoma in a child with Duchenne muscular dystrophy.
J Neurosurg Pediatr. 2012; 10(1):21-4 [PubMed]

A 9-year-old boy with known Duchenne type muscular dystrophy (DMD) presented with signs of increased intracranial pressure. Radiological investigations revealed a lesion in the midline of the posterior fossa. Subtotal resection was performed. Pathology findings were consistent with the diagnosis of anaplastic medulloblastoma. The postoperative lumbar CSF was positive for malignant cells. Postoperatively, the patient showed severe neurological deterioration and lost his capacity to walk. He was treated with craniospinal radiation followed by nonintensive chemotherapy. At 30 months postsurgery, he was still in complete remission but had not recovered his walking ability. This is the second report of a malignant brain tumor in a boy with DMD. The possible link between the 2 conditions is discussed, as are ethical considerations regarding the management of medulloblastoma in children with DMD.

Jakacki RI, Burger PC, Zhou T, et al.
Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study.
J Clin Oncol. 2012; 30(21):2648-53 [PubMed]

PURPOSE: We evaluated the feasibility of administering carboplatin as a radiosensitizer during craniospinal radiation therapy (CSRT) to patients with high-risk medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumors, and we report the outcome in the subset with metastatic (M+) MB.
PATIENTS AND METHODS: After surgery, patients received 36 Gy CSRT with boosts to sites of disease. During radiation, patients received 15 to 30 doses of carboplatin (30-45 mg/m(2)/dose), along with vincristine (VCR) once per week for 6 weeks. Patients on regimen A received 6 months of maintenance chemotherapy (MC) with cyclophosphamide and VCR. Once the recommended phase II dose (RP2D) of carboplatin was determined, cisplatin was added to the MC (regimen B).
RESULTS: In all, 161 eligible patients (median age, 8.7 years; range, 3.1 to 21.6 years) were enrolled. Myelosuppression was dose limiting and 35 mg/m(2)/dose × 30 was determined to be the RP2D of carboplatin. Twenty-nine (36%) of 81 patients with M+ MB had diffuse anaplasia. Four patients were taken off study within 11 months of completing radiotherapy for presumed metastatic progression and are long-term survivors following palliative chemotherapy. Excluding these four patients, 5-year overall survival ± SE and progression-free survival ± SE for M+ patients treated at the RP2D on regimen A was 82% ± 9% and 71% ± 11% versus 68% ± 10% and 59% ± 10% on regimen B (P = .36). There was no difference in survival by M stage. Anaplasia was a negative predictor of outcome.
CONCLUSION: The use of carboplatin as a radiosensitizer is a promising strategy for patients with M+ MB. Early progression should be confirmed by biopsy.

Brackett J, Krull KR, Scheurer ME, et al.
Antioxidant enzyme polymorphisms and neuropsychological outcomes in medulloblastoma survivors: a report from the Childhood Cancer Survivor Study.
Neuro Oncol. 2012; 14(8):1018-25 [PubMed] Article available free on PMC after 01/08/2013

Psychological or neurocognitive impairment is often seen in medulloblastoma survivors after craniospinal radiation; however, significant variability in outcomes exists. This study investigated the role of antioxidant enzyme polymorphisms in moderating this outcome and hypothesized that patients who had polymorphisms associated with lower antioxidant enzyme function would have a higher occurrence of impairment. From the Childhood Cancer Survivor Study (CCSS) cohort, 109 medulloblastoma survivors and 143 siblings were identified who completed the CCSS Neurocognitive Questionnaire (NCQ) and the Brief Symptom Inventory-18 (BSI-18) and who provided buccal DNA samples. Real-time polymerase chain reaction (PCR) allelic discrimination was used for SOD2 (rs4880), GPX1 (rs1050450), and GSTP1 (rs1695 and rs1138272) genotyping and PCR for GSTM1 and GSTT1 gene deletions. Outcomes on NCQ and BSI-18 subscale scores were examined in association with genotypes and clinical factors, including age at diagnosis, sex, and radiation dose, using univariate and multivariate analysis of variance. Patients <7 years of age at diagnosis displayed more problems with task efficiency (P < .001) and fewer problems with somatic complaints (P = .004) than did patients ≥7 years of age. Female patients reported more organization problems than did male patients (P = .02). Patients with homozygous GSTM1 gene deletion reported higher anxiety (mean null genotype = 47.3 ± 9.2, non-null = 43.9 ± 7.8; P = .04), more depression (null = 51.0 ± 9.8, non-null = 47.0 ± 9.4; P = .03), and more global distress (null = 50.2 ± 9.7, non-null = 45.2 ± 9.9; P = .01). All associations for the GSTM1 polymorphism remained statistically significant in a multivariate model controlling for age, sex, and radiation dose. Homozygous GSTM1 gene deletion was consistently associated with greater psychological distress in medulloblastoma survivors across multiple domains, suggesting that this genotype may predispose patients for increased emotional late effects.

Agnihotri S, Gray J, Colantonio A, et al.
Two case study evaluations of an arts-based social skills intervention for adolescents with childhood brain disorder.
Dev Neurorehabil. 2012; 15(4):284-97 [PubMed]

OBJECTIVE: Arts-based programmes have been shown to be useful for individuals with disturbances in cognitive and behavioural functioning. The current case studies examined the feasibility and effectiveness of a theatre skills training programme to facilitate social skills and participation for adolescents with childhood brain disorder.
METHODS: A case study approach was used with two adolescent participants. Focus groups were conducted immediately post-intervention, while a battery of quantitative measures were administered pre- and post-treatment, as well as 8 months post-treatment.
RESULTS: Perceived and documented improvements in social skills and participation were observed from pre- to post-intervention and at follow-up.
CONCLUSION: Results support the use of an arts-based intervention for youth with brain injuries to facilitate social skills and participation. Findings also highlight the need for more sensitive measures of these skills for youth with childhood brain disorder, who may have impaired awareness of their abilities and/or impairments in memory and language comprehension.

Blomstrand M, Brodin NP, Munck Af Rosenschöld P, et al.
Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma.
Neuro Oncol. 2012; 14(7):882-9 [PubMed] Article available free on PMC after 01/07/2013

We sought to assess the feasibility and estimate the benefit of sparing the neurogenic niches when irradiating the brain of pediatric patients with medulloblastoma (MB) based on clinical outcome data. Pediatric MB survivors experience a high risk of neurocognitive adverse effects, often attributed to the whole-brain irradiation that is part of standard management. Neurogenesis is very sensitive to radiation, and limiting the radiation dose to the hippocampus and the subventricular zone (SVZ) may preserve neurocognitive function. Radiotherapy plans were created using 4 techniques: standard opposing fields, intensity-modulated radiotherapy (IMRT), intensity-modulated arc therapy (IMAT), and intensity-modulated proton therapy (IMPT). Mean dose to the hippocampus and SVZ (mean for both sites) could be limited to 88.3% (range, 83.6%-91.0%), 77.1% (range, 71.5%-81.3%), and 42.3% (range, 26.6%-51.2%) with IMAT, IMRT, and IMPT, respectively, while maintaining at least 95% of the prescribed dose in 95% of the whole-brain target volume. Estimated risks for developing memory impairment after a prescribed dose of 23.4 Gy were 47% (95% confidence interval [CI], 21%-69%), 44% (95% CI, 21%-65%), 41% (95% CI, 22%-60%), and 33% (95% CI, 23%-44%) with opposing fields, IMAT, IMRT, and IMPT, respectively. Neurogenic niche sparing during cranial irradiation of pediatric patients with MB is feasible and is estimated to lower the risks of long-term neurocognitive sequelae. Greatest sparing is achieved with intensity-modulated proton therapy, thus making this an attractive option to be tested in a prospective clinical trial.

Alexiou GA, Siozos G, Stefanaki K, et al.
Medulloblastoma in a child with fragile X syndrome.
Neuropediatrics. 2012; 43(3):155-8 [PubMed]

Fragile X syndrome is the most common cause of inherited intellectual impairment and has been associated with decreased incidence of cancer. We present the case of an 11-year-old boy with a diagnosis of fragile X syndrome who presented with gait imbalance, headache, and episodes of vomiting. Radiological investigation revealed the presence of a posterior fossa tumor. The patient was operated upon and the tumor proved to be a medulloblastoma (MB). To the best of our knowledge this is the first reported case of MB in a child with fragile X syndrome.

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.

Brodin NP, Vogelius IR, Maraldo MV, et al.
Life years lost--comparing potentially fatal late complications after radiotherapy for pediatric medulloblastoma on a common scale.
Cancer. 2012; 118(21):5432-40 [PubMed] Article available free on PMC after 01/11/2013

BACKGROUND: The authors developed a framework for estimating and comparing the risks of various long-term complications on a common scale and applied it to 3 different techniques for craniospinal irradiation in patients with pediatric medulloblastoma.
METHODS: Radiation dose-response parameters related to excess hazard ratios for secondary breast, lung, stomach, and thyroid cancer; heart failure, and myocardial infarction were derived from large published clinical series. Combined with age-specific and sex-specific hazards in the US general population, the dose-response analysis yielded excess hazards of complications for a cancer survivor as a function of attained age. After adjusting for competing risks of death, life years lost (LYL) were estimated based on excess hazard and prognosis of a complication for 3-dimensional conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), and intensity-modulated proton therapy (IMPT).
RESULTS: Lung cancer contributed most to the estimated LYL, followed by myocardial infarction, and stomach cancer. The estimates of breast or thyroid cancer incidence were higher than those for lung and stomach cancer incidence, but LYL were lower because of the relatively good prognosis. Estimated LYL ranged between 1.90 years for 3D CRT to 0.28 years for IMPT. In a paired comparison, IMPT was associated with significantly fewer LYL than both photon techniques.
CONCLUSIONS: Estimating the risk of late complications is associated with considerable uncertainty, but including prognosis and attained age at an event to obtain the more informative LYL estimate added relatively little to this uncertainty.

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.

Brugières L, Remenieras A, Pierron G, et al.
High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age.
J Clin Oncol. 2012; 30(17):2087-93 [PubMed]

PURPOSE: Germline mutations of the SUFU gene have been shown to be associated with genetic predisposition to medulloblastoma, mainly in families with multiple cases of medulloblastoma and/or in patients with symptoms similar to those of Gorlin syndrome. To evaluate the contribution of these mutations to the genesis of sporadic medulloblastomas, we screened a series of unselected patients with medulloblastoma for germline SUFU mutations.
PATIENTS AND METHODS: A complete mutational analysis of the SUFU gene was performed on genomic DNA in all 131 consecutive patients treated for medulloblastoma in the pediatrics department of the Institut Gustave Roussy between 1972 and 2009 and for whom a blood sample was available.
RESULTS: We identified eight germline mutations of the SUFU gene: one large genomic duplication and seven point mutations. Mutations were identified in three of three individuals with medulloblastoma with extensive nodularity, four of 20 with desmoplastic/nodular medulloblastomas, and one of 108 with other subtypes. All eight patients were younger than 3 years of age at diagnosis. The mutations were inherited from the healthy father in four of six patient cases in which the parents accepted genetic testing; de novo mutations accounted for the other two patient cases. Associated events were macrocrania in six patients, hypertelorism in three patients, and multiple basal cell carcinomas in the radiation field after age 18 years in one patient.
CONCLUSION: These data indicate that germline SUFU mutations were responsible for a high proportion of desmoplastic medulloblastoma in children younger than 3 years of age. Genetic testing should be offered to all children diagnosed with sonic hedgehog-driven medulloblastoma at a young age.

Brasme JF, Grill J, Doz F, et al.
Long time to diagnosis of medulloblastoma in children is not associated with decreased survival or with worse neurological outcome.
PLoS One. 2012; 7(4):e33415 [PubMed] Article available free on PMC after 01/11/2013

BACKGROUND: The long time to diagnosis of medulloblastoma, one of the most frequent brain tumors in children, is the source of painful remorse and sometimes lawsuits. We analyzed its consequences for tumor stage, survival, and sequelae.
PATIENTS AND METHODS: This retrospective population-based cohort study included all cases of pediatric medulloblastoma from a region of France between 1990 and 2005. We collected the demographic, clinical, and tumor data and analyzed the relations between the interval from symptom onset until diagnosis, initial disease stage, survival, and neuropsychological and neurological outcome.
RESULTS: The median interval from symptom onset until diagnosis for the 166 cases was 65 days (interquartile range 31-121, range 3-457). A long interval (defined as longer than the median) was associated with a lower frequency of metastasis in the univariate and multivariate analyses and with a larger tumor volume, desmoplastic histology, and longer survival in the univariate analysis, but not after adjustment for confounding factors. The time to diagnosis was significantly associated with IQ score among survivors. No significant relation was found between the time to diagnosis and neurological disability. In the 62 patients with metastases, a long prediagnosis interval was associated with a higher T stage, infiltration of the fourth ventricle floor, and incomplete surgical resection; it nonetheless did not influence survival significantly in this subgroup.
CONCLUSIONS: We found complex and often inverse relations between time to diagnosis of medulloblastoma in children and initial severity factors, survival, and neuropsychological and neurological outcome. This interval appears due more to the nature of the tumor and its progression than to parental or medical factors. These conclusions should be taken into account in the information provided to parents and in expert assessments produced for malpractice claims.

Onvani S, Terakawa Y, Smith C, et al.
Molecular genetic analysis of the hepatocyte growth factor/MET signaling pathway in pediatric medulloblastoma.
Genes Chromosomes Cancer. 2012; 51(7):675-88 [PubMed]

The hepatocyte growth factor (HGF)/MET pathway plays a critical role in the development of the nervous system and has been implicated in medulloblastoma pathogenesis. Recent studies have shown a role for gene amplification of activators of this pathway, as well as silencing of its inhibitors in medulloblastoma pathogenesis. We analyzed exon array data from a cohort of 103 primary medulloblastomas to show that HGF/MET pathway elements are dysregulated in tumors compared to normal cerebellum. To determine if mutation of HGF/MET pathway genes is a mechanism for pathway dysregulation, we conducted a mutational analysis by exon resequencing of three key components of this pathway, including serine protease inhibitor Kunitz-type 1 (SPINT1), serine protease inhibitor Kunitz-type 2 (SPINT2), and MET, in 32 primary human medulloblastoma specimens. From this analysis, we identified multiple coding synonymous and nonsynonymous single nucleotide polymorphisms in these genes among the 32 tumor samples. Interestingly, we also discovered two unreported sequence variants in SPINT1 and SPINT2 in two tumors that resulted in Arginine to Histidine amino acid substitutions at codons 418 and 233, respectively. However, conservation assessment and functional assays of these two variants indicate that they involve nonconserved residues and that they do not affect the function of SPINT1 and SPINT2 as tumor suppressor genes. In conclusion, our data suggest that mutation alone plays a minor role in causing aberrancies of the HGF/MET pathway in medulloblastoma in comparison with other malignancies such as breast, hepatocellular, renal, and lung carcinomas.

Lupo PJ, Lee LJ, Okcu MF, et al.
An exploratory case-only analysis of gene-hazardous air pollutant interactions and the risk of childhood medulloblastoma.
Pediatr Blood Cancer. 2012; 59(4):605-10 [PubMed] Article available free on PMC after 01/10/2013

BACKGROUND: There is evidence that exposure to chlorinated solvents may be associated with childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET) risk. Animal models suggest genes related to detoxification and DNA repair are important in the carcinogenicity of these pollutants; however, there have been no human studies assessing the modifying effects of these genotypes on the association between chlorinated solvents and childhood M/PNET risk.
PROCEDURE: We conducted a case-only study to evaluate census tract-level exposure to chlorinated solvents and the risk of childhood M/PNET in the context of detoxification and DNA repair genotypes. Cases (n = 98) were obtained from Texas Children's Hospital and MD Anderson Cancer Center. Key genotypes (n = 22) were selected from the Illumina Human 1M Quad SNP Chip. Exposure to chlorinated solvents (methylene chloride, perchloroethylene, trichloroethylene, and vinyl chloride) was estimated from the US EPA's 1999 Assessment System for Population Exposure Nationwide (ASPEN). Logistic regression was used to estimate the case-only odds ratios and 95% confidence intervals (CIs).
RESULTS: There were 11 significant gene-environment interactions associated with childhood M/PNET risk. However, after correcting for multiple comparisons, only the interaction between high trichloroethylene levels and OGG1 rs293795 significantly increased the risk of childhood M/PNET risk (OR = 9.24, 95% CI: 2.24, 38.24, Q = 0.04).
CONCLUSIONS: This study provides an initial assessment of the interaction between ambient levels of chlorinated solvents and potentially relevant genotypes on childhood M/PNET risk. Our results are exploratory and must be validated in animal models, as well as additional human studies.

Massimino M, Cefalo G, Riva D, et al.
Long-term results of combined preradiation chemotherapy and age-tailored radiotherapy doses for childhood medulloblastoma.
J Neurooncol. 2012; 108(1):163-71 [PubMed]

To reduce the sequelae of craniospinal irradiation (CSI) in children under 10 (≥3) years old and to improve the prognosis for high-risk medulloblastoma in adolescents, we adjusted postoperative chemotherapy and CSI doses to patients' stage and age. From 1986 to 1995, 73 patients entered the study. Children under 10 and adolescents with metastases, residual disease (RD) or stage >T3 received postoperative IV vincristine and high-dose (HD) ± intrathecal (IT) methotrexate, while standard-risk adolescents were given IV vincristine and IT methotrexate. Chemotherapy was followed by CSI (19.8 Gy for children <10; 36 Gy for adolescents), with a 54-Gy posterior fossa boost. Maintenance chemotherapy with lomustine and vincristine was administered for a year afterwards. A total of 39 children were under 10 of whom 20 had metastases. Response to chemotherapy was recorded in 70%, but 5-year EFS and OS were only 48 and 56%, respectively. Results were significantly worse for metastatic cases, patients under 10, those with RD, and those staged without MRI (unavailable early in the study). Efforts to preserve survivors' quality of life did not pay off, and most patients over 30 still depended on their parents' income and had severe cognitive/endocrine disabilities. In conclusion, despite a very high response rate with this preradiation HD methotrexate schedule, the outcome for high-risk medulloblastoma patients did not improve (especially when lower CSI doses were used) and patients still developed severe morbidities.

Gupta T, Jalali R, Goswami S, et al.
Early clinical outcomes demonstrate preserved cognitive function in children with average-risk medulloblastoma when treated with hyperfractionated radiation therapy.
Int J Radiat Oncol Biol Phys. 2012; 83(5):1534-40 [PubMed]

PURPOSE: To report on acute toxicity, longitudinal cognitive function, and early clinical outcomes in children with average-risk medulloblastoma.
METHODS AND MATERIALS: Twenty children ≥ 5 years of age classified as having average-risk medulloblastoma were accrued on a prospective protocol of hyperfractionated radiation therapy (HFRT) alone. Radiotherapy was delivered with two daily fractions (1 Gy/fraction, 6 to 8 hours apart, 5 days/week), initially to the neuraxis (36 Gy/36 fractions), followed by conformal tumor bed boost (32 Gy/32 fractions) for a total tumor bed dose of 68 Gy/68 fractions over 6 to 7 weeks. Cognitive function was prospectively assessed longitudinally (pretreatment and at specified posttreatment follow-up visits) with the Wechsler Intelligence Scale for Children to give verbal quotient, performance quotient, and full-scale intelligence quotient (FSIQ).
RESULTS: The median age of the study cohort was 8 years (range, 5-14 years), representing a slightly older cohort. Acute hematologic toxicity was mild and self-limiting. Eight (40%) children had subnormal intelligence (FSIQ <85), including 3 (15%) with mild mental retardation (FSIQ 56-70) even before radiotherapy. Cognitive functioning for all tested domains was preserved in children evaluable at 3 months, 1 year, and 2 years after completion of HFRT, with no significant decline over time. Age at diagnosis or baseline FSIQ did not have a significant impact on longitudinal cognitive function. At a median follow-up time of 33 months (range, 16-58 months), 3 patients had died (2 of relapse and 1 of accidental burns), resulting in 3-year relapse-free survival and overall survival of 83.5% and 83.2%, respectively.
CONCLUSION: HFRT without upfront chemotherapy has an acceptable acute toxicity profile, without an unduly increased risk of relapse, with preserved cognitive functioning in children with average-risk medulloblastoma.

Khatua S, Sadighi ZS, Pearlman ML, et al.
Brain tumors in children--current therapies and newer directions.
Indian J Pediatr. 2012; 79(7):922-7 [PubMed]

Brain tumors are the second most common malignancy and the major cause of cancer related mortality in children. Though significant advances in neuroimaging, neurosurgery, radiation therapy and chemotherapy have evolved over the years, overall survival rate remains less than 75%. Malignant gliomas, high risk medulloblastoma with recurrence and infant brain tumors continue to be a major cause of therapeutic frustration. Even today diffuse pontine gliomas are universally fatal. Though tumors like low grade glioma have an overall excellent survival, recurrences and progression in eloquent areas pose therapeutic challenges. As research continues to unravel the biology including key molecules and signaling pathways responsible for the oncogenesis of different childhood brain tumors, novel targeted therapies are profiled. Identification of major targets like the Epidermal Growth factor Receptor (EGFR), Platelet Derived Growth Factor Receptor (PDGFR), Vascular Endothelial Growth factor (VEGF) and key signaling pathways like the MAPK and PI3K/Akt/mTOR has enabled us over the recent years to better understand tumor behavior and design tailored therapy. These efforts have improved overall survival of children with brain tumors. This review article discusses the current status of common brain tumors in children and the newer therapeutic approaches.

Rausch T, Jones DT, Zapatka M, et al.
Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.
Cell. 2012; 148(1-2):59-71 [PubMed] Article available free on PMC after 01/10/2013

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.