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Klinger PH, Andrade AF, Delsin LE, et al.
Inhibition of SHH pathway mechanisms by arsenic trioxide in pediatric medulloblastomas: a comprehensive literature review.
Genet Mol Res. 2017; 16(1) [PubMed] Related Publications

Recent innovations in the genomic understanding of medulloblastomas have provided new ways to explore this highly invasive malignant brain cancer arising from the cerebellum. Among the four different medulloblastoma subgroups described to date, the sonic hedgehog (SHH) genetic pathway is the pathway activated in the tumorigenesis of medulloblastoma. SHH-related medulloblastomas are usually of nodular/desmoplastic histology and frequently occur in children under the age of three, an age group highly susceptible to the acute and long-term effects of treatment. Several new drugs aimed at SHH modulation are currently under development. This review focuses on the role of arsenic trioxide, a drug well established in clinical practice and probably an under-explored agent in medulloblastoma management, in the SHH pathway.

Related: Signal Transduction

Yu J, Li H
The expression of FAT1 is associated with overall survival in children with medulloblastoma.
Tumori. 2017; 103(1):44-52 [PubMed] Related Publications

PURPOSE: The FAT1 gene is involved in some cancers; however, its role in medulloblastoma is less clear. This study investigated the effects of FAT1 expression on the prognosis of medulloblastoma patients.
METHODS: Whole exome sequencing was undertaken in 40 medulloblastoma patient samples. FAT1 mRNA and protein expression levels in normal and brain tumor tissues were determined by fluorescence quantitative PCR and immunohistochemistry, respectively. The association of FAT1 expression with overall survival (OS) was examined by Kaplan-Meier curve analysis with a log-rank test. Following lentiviral-mediated FAT1 knockdown using shRNA in Daoy cells, proliferation, Wnt signaling, and β-catenin protein expression were determined.
RESULTS: Eight FAT1 missense mutations were detected in 7 patients. FAT1 mRNA expression in tumors was significantly lower than in adjacent normal tissue (p = 0.043). The OS of patients with high FAT1 protein expression was significantly longer than that of patients with low FAT1 protein expression (median survival time: 24.3 vs 4.8 months, respectively; p = 0.002). shFAT1 cells had significantly higher proliferation rates than shControl cells (p≤0.028). Furthermore, the mRNA expression of LEF1, β-catenin, and cyclin D1 was significantly upregulated in shFAT1-Daoy cells (p≤0.018).
CONCLUSIONS: Low FAT1 expression was associated with poor prognosis in children with medulloblastoma. Furthermore, FAT1 may act on Wnt signaling pathway to exert its antitumor effect.

Related: Signal Transduction CTNNB1 FAT1

Kann BH, Park HS, Lester-Coll NH, et al.
Postoperative Radiotherapy Patterns of Care and Survival Implications for Medulloblastoma in Young Children.
JAMA Oncol. 2016; 2(12):1574-1581 [PubMed] Related Publications

Importance: Postoperative radiotherapy to the craniospinal axis is standard-of-care for pediatric medulloblastoma but is associated with long-term morbidity, particularly in young children. With the advent of modern adjuvant chemotherapy strategies, postoperative radiotherapy deferral has gained acceptance in children younger than 3 years, although it remains controversial in older children.
Objective: To analyze recent postoperative radiotherapy national treatment patterns and implications for overall survival in patients with medulloblastoma ages 3 to 8 years.
Design, Setting, and Exposures: Using the National Cancer Data Base, patients ages 3 to 8 years diagnosed as having histologically confirmed medulloblastoma in 2004 to 2012, without distant metastases, who underwent surgery and adjuvant chemotherapy with or without postoperative radiotherapy at facilities nationwide accredited by the Commission on Cancer were identified. Patients were designated as having "postoperative radiotherapy upfront" if they received radiotherapy within 90 days of surgery or "postoperative radiotherapy deferred" otherwise. Factors associated with postoperative radiotherapy deferral were identified using multivariable logistic regression. Overall survival (OS) was compared using Kaplan-Meier analysis with log-rank tests and multivariable Cox regression. Statistical tests were 2-sided.
Main Outcomes and Measures: Postoperative radiotherapy utilization and overall survival.
Results: Among 816 patients, 123 (15.1%) had postoperative radiotherapy deferred, and 693 (84.9%) had postoperative radiotherapy upfront; 36.8% of 3-year-olds and 4.1% of 8-year-olds had postoperative radiotherapy deferred (P < .001). On multivariable logistic regression, variables associated with postoperative radiotherapy deferral were age (odds ratio [OR], 0.57 per year; 95% CI, 0.49-0.67 per year) and year of diagnosis (OR, 1.18 per year; 95% CI, 1.08-1.29 per year). On survival analysis, with median follow-up of 4.8 years, OS was improved for those receiving postoperative radiotherapy upfront vs postoperative radiotherapy deferred (5-year OS: 82.0% vs 63.4%; P < .001). On multivariable analysis, variables associated with poorer OS were postoperative radiotherapy deferral (hazards ratio [HR], 1.95; 95% CI, 1.15-3.31); stage M1-3 disease (HR, 1.86; 95% CI, 1.10-3.16), and low facility volume (HR, 1.75; 95% CI, 1.04-2.94).
Conclusions and Relevance: Our national database analysis reveals a higher-than-expected and increasing rate of postoperative radiotherapy deferral in children with medulloblastoma ages 3 to 8 years. The analysis suggests that postoperative radiotherapy deferral is associated with worse survival in this age group, even in the modern era of chemotherapy.

Massimino M, Biassoni V, Gandola L, et al.
Childhood medulloblastoma.
Crit Rev Oncol Hematol. 2016; 105:35-51 [PubMed] Related Publications

Medulloblastoma accounts for 15-20% of childhood nervous system tumours. The risk of dying was reduced by 30% in the last twenty years. Patients are divided in risk strata according to post-surgical disease, dissemination, histology and some molecular features such as WNT subgroup and MYC status. Sixty to 70% of patients older than 3 years are assigned to the average-risk group. High-risk patients include those with disseminated and/or residual disease, large cell and/or anaplastic histotypes, MYC genes amplification. Current and currently planned clinical trials will: (1) evaluate the feasibility of reducing both the dose of craniospinal irradiation and the volume of the posterior fossa radiotherapy (RT) for those patients at low biologic risk, commonly identified as those having a medulloblastoma of the WNT subgroup; (2) determine whether intensification of chemotherapy (CT) or irradiation can improve outcome in patients with high-risk disease; (3) find target therapies allowing tailored therapies especially for relapsing patients and those with higher biological risk.

Ehrstedt C, Kristiansen I, Ahlsten G, et al.
Clinical characteristics and late effects in CNS tumours of childhood: Do not forget long term follow-up of the low grade tumours.
Eur J Paediatr Neurol. 2016; 20(4):580-7 [PubMed] Related Publications

AIM: To investigate clinical characteristics and late effects of CNS tumours in childhood with a special focus on low-grade tumours, especially low-grade astrocytoma and glioneuronal tumours.
METHODS: A retrospective population based study was performed at Uppsala University Children's Hospital, a tertiary referral centre for children with CNS tumours. Patients were identified from the National Brain Tumour Registry and the National Epilepsy Surgery Registry. Hospital medical records were analysed for patients with a follow up of ≥5 years after diagnosis. A re-evaluation of the neuro-pathological diagnosis was performed.
RESULTS: A total of 193 patients (age 0-17.99 years) during a twelve-year period (1995-2006) were included; 149 survived ≥5 years. Three larger subgroups could be identified: astrocytic, embryonal and glioneuronal tumours. A supratentorial location was found in 52%. Medical late effects were mainly neurological and endocrinological, affecting 81% and 26% of surviving patients. Cognitive late effects were a frequent finding in the whole group but also in low-grade astrocytoma and glioneuronal tumours (53% and 67%). Thirty per cent had some kind of pedagogic support in school.
CONCLUSION: Late effects are common in long-term survivors of CNS tumours in childhood. Low-grade astrocytoma and glioneuronal tumours are no exception, and the findings support the need for long-term follow up.

Related: Childhood Astrocytoma Brain and Spinal Cord Tumours Brain Stem Glioma - Childhood Germ Cell Tumors Germ Cell Tumours in Children and Young Adults Germ Cell Tumors (Pediatric)

Moxon-Emre I, Bouffet E, Taylor MD, et al.
Vulnerability of white matter to insult during childhood: evidence from patients treated for medulloblastoma.
J Neurosurg Pediatr. 2016; 18(1):29-40 [PubMed] Related Publications

OBJECTIVE Craniospinal irradiation damages the white matter in children treated for medulloblastoma, but the treatment-intensity effects are unclear. In a cross-sectional retrospective study, the effects of treatment with the least intensive radiation protocol versus protocols that delivered more radiation to the brain, in addition to the effects of continuous radiation dose, on white matter architecture were evaluated. METHODS Diffusion tensor imaging was used to assess fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. First, regional white matter analyses and tract-based spatial statistics were conducted in 34 medulloblastoma patients and 38 healthy controls. Patients were stratified according to those treated with 1) the least intensive radiation protocol, specifically reduced-dose craniospinal irradiation plus a boost to the tumor bed only (n = 17), or 2) any other dose and boost combination that delivered more radiation to the brain, which was also termed the "all-other-treatments" group (n = 17), and comprised patients treated with standard-dose craniospinal irradiation plus a posterior fossa boost, standard-dose craniospinal irradiation plus a tumor bed boost, or reduced-dose craniospinal irradiation plus a posterior fossa boost. Second, voxel-wise dose-distribution analyses were conducted on a separate cohort of medulloblastoma patients (n = 15). RESULTS The all-other-treatments group, but not the reduced-dose craniospinal irradiation plus tumor bed group, had lower fractional anisotropy and higher radial diffusivity than controls in all brain regions (all p < 0.05). The reduced-dose craniospinal irradiation plus tumor bed boost group had higher fractional anisotropy (p = 0.05) and lower radial diffusivity (p = 0.04) in the temporal region, and higher fractional anisotropy in the frontal region (p = 0.04), than the all-other-treatments group. Linear mixed-effects modeling revealed that the dose and age at diagnosis together 1) better predicted fractional anisotropy in the temporal region than models with either alone (p < 0.005), but 2) did not better predict fractional anisotropy in comparison with dose alone in the occipital region (p > 0.05). CONCLUSIONS Together, the results show that white matter damage has a clear association with increasing radiation dose, and that treatment with reduced-dose craniospinal irradiation plus tumor bed boost appears to preserve white matter in some brain regions.

Damiani D, Suciu V, Andreiuolo F, et al.
Young investigator challenge: Cytomorphologic analysis of cerebrospinal fluid in 70 pediatric patients with medulloblastoma and review of the literature focusing on novel diagnostic and prognostic tests.
Cancer Cytopathol. 2015; 123(11):644-9 [PubMed] Related Publications

BACKGROUND: Medulloblastoma (MB) is the most common malignant pediatric brain tumor and is currently treated with combined therapies. Recent advances in genetics and protein expression in this entity have led to the elaboration of a new molecular classification, and novel targeted therapies are currently under trial. This objective of this study was to describe the cytomorphologic features of MB in cerebrospinal fluid (CSF).
METHODS: The authors conducted a retrospective study of 194 CSF samples from 70 pediatric patients who had a history of primary MB. The samples consisted of CSF cytospins that were stained according to the May-Grunwald Giemsa and/or Papanicolaou methods.
RESULTS: In 32 patients, it was possible to establish a confident diagnosis of metastatic MB. Common morphologic features included cell clustering, nuclear irregularity, molding and enlargement, and prominent nucleoli. Multinucleation as well as mitotic and apoptotic figures were less frequently observed. Fifteen samples that presented neither cell clustering nor nuclear molding were classified as suspicious.
CONCLUSIONS: Cell clustering with nuclear molding is a key feature for the diagnosis of leptomeningeal metastasis of MB.

Eaton BR, Esiashvili N, Kim S, et al.
Clinical Outcomes Among Children With Standard-Risk Medulloblastoma Treated With Proton and Photon Radiation Therapy: A Comparison of Disease Control and Overall Survival.
Int J Radiat Oncol Biol Phys. 2016; 94(1):133-8 [PubMed] Free Access to Full Article Related Publications

PURPOSE: The purpose of this study was to compare long-term disease control and overall survival between children treated with proton and photon radiation therapy (RT) for standard-risk medulloblastoma.
METHODS AND MATERIALS: This multi-institution cohort study includes 88 children treated with chemotherapy and proton (n=45) or photon (n=43) RT between 2000 and 2009. Overall survival (OS), recurrence-free survival (RFS), and patterns of failure were compared between the 2 cohorts.
RESULTS: Median (range) age was 6 years old at diagnosis (3-21 years) for proton patients versus 8 years (3-19 years) for photon patients (P=.011). Cohorts were similar with respect to sex, histology, extent of surgical resection, craniospinal irradiation (CSI) RT dose, total RT dose, whether the RT boost was delivered to the posterior fossa (PF) or tumor bed (TB), time from surgery to RT start, or total duration of RT. RT consisted of a median (range) CSI dose of 23.4 Gy (18-27 Gy) and a boost of 30.6 Gy (27-37.8 Gy). Median follow-up time is 6.2 years (95% confidence interval [CI]: 5.1-6.6 years) for proton patients versus 7.0 years (95% CI: 5.8-8.9 years) for photon patients. There was no significant difference in RFS or OS between patients treated with proton versus photon RT; 6-year RFS was 78.8% versus 76.5% (P=.948) and 6-year OS was 82.0% versus 87.6%, respectively (P=.285). On multivariate analysis, there was a trend for longer RFS with females (P=.058) and higher CSI dose (P=.096) and for longer OS with females (P=.093). Patterns of failure were similar between the 2 cohorts (P=.908).
CONCLUSIONS: Disease control with proton and photon radiation therapy appears equivalent for standard risk medulloblastoma.

Khatua S
Evolving molecular era of childhood medulloblastoma: time to revisit therapy.
Future Oncol. 2016; 12(1):107-17 [PubMed] Related Publications

Currently medulloblastoma is treated with a uniform therapeutic approach based on histopathology and clinico-radiological risk stratification, resulting in unpredictable treatment failure and relapses. Improved understanding of the biological, molecular and genetic make-up of these tumors now clearly identifies it as a compendium of four distinct subtypes (WNT, SHH, group 3 and 4). Advances in utilization of the genomic and epigenomic machinery have now delineated genetic aberrations and epigenetic perturbations in each subgroup as potential druggable targets. This has resulted in endeavors to profile targeted therapy. The challenge and future of medulloblastoma therapeutics will be to keep pace with the evolving novel biological insights and translating them into optimal targeted treatment regimens.

Cox MC, Kusters JM, Gidding CE, et al.
Acute toxicity profile of craniospinal irradiation with intensity-modulated radiation therapy in children with medulloblastoma: A prospective analysis.
Radiat Oncol. 2015; 10:241 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: To report on the acute toxicity in children with medulloblastoma undergoing intensity-modulated radiation therapy (IMRT) with daily intrafractionally modulated junctions.
METHODS: Newly diagnosed patients, aged 3-21, with standard-risk (SR) or high-risk (HR) medulloblastoma were eligible. A dose of 23.4 or 36.0 Gy in daily fractions of 1.8 Gy was prescribed to the craniospinal axis, followed by a boost to the primary tumor bed (54 or 55.8 Gy) and metastases (39.6-55.8 Gy), when indicated. Weekly, an intravenous bolus of vincristine was combined for patients with SR medulloblastoma and patients participating in the COG-ACNS-0332 study. Common toxicity criteria (CTC, version 2.0) focusing on skin, alopecia, voice changes, conjunctivitis, anorexia, dysphagia, gastro-intestinal symptoms, headache, fatigue and hematological changes were scored weekly during radiotherapy.
RESULTS: From 2010 to 2014, data from 15 consecutive patients (SR, n = 7; HR, n = 8) were collected. Within 72 h from onset of treatment, vomiting (66 %) and headache (46 %) occurred. During week 3 of treatment, a peak incidence in constipation (33 %) and abdominal pain/cramping (40 %) was observed, but only in the subgroup of patients (n = 9) receiving vincristine (constipation: 56 vs 0 %, P = .04; pain/cramping: 67 vs 0 %, P = .03). At week 6, 73 % of the patients developed faint erythema of the cranial skin with dry desquamation (40 %) or moist desquamation confined to the skin folds of the auricle (33 %). No reaction of the skin overlying the spinal target volume was observed.
CONCLUSIONS: Headache at onset and gastro-intestinal toxicity, especially in patients receiving weekly vincristine, were the major complaints of patients with medulloblastoma undergoing craniospinal irradiation with IMRT.

Related: Vincristine

Pezuk JA, Valera ET, Delsin LE, et al.
The Antiproliferative and Pro-apoptotic Effects of Methoxyamine on Pediatric Medulloblastoma Cell Lines Exposed to Ionizing Radiation and Chemotherapy.
Cent Nerv Syst Agents Med Chem. 2015; 16(1):67-72 [PubMed] Related Publications

Medulloblastoma (MB) treatment is continuously evolving. Better treatment approaches, focused on particular molecular pathways involved in MB development and progression support new treatment strategies. This article explores the antiproliferative, proapoptotic and radiosensitizing effects of Methoxyamine (MX), a base excision repair (BER) inhibitor that has shown anticancer potential by sensitizing tumor cells to ionizing radiation and chemotherapy. The DAOY (a desmoplastic cerebellar-derived MB) and ONS-76 (classical MB) cell lines were treated with MX at different concentrations, either alone or combined with various chemotherapeutic compounds: cisplatin (CDDP), temozolomide (TMZ) and thiotepa (THIO). Additionally, cell lines were exposed to MX and treated at different ionizing radiation fractions. Measurement of cell growth by XTT assay, clonogenic assay and detection of apoptotic cell death through caspase activity was obtained. Exposure to MX significantly decreased cell proliferation (p<0.05) while increasing cell apoptosis (p<0.05). Growth reduction was concentration-dependent for both DAOY and ONS-76 cells lines. Conversely, MX failed to enhance the cytotoxicity of CDDP, TMZ, and THIO. Moreover, MX treatment radiosensitized both cell lines, with ONS-76 cells being more prone to radiation effects at higher doses of exposure. These data support the role of MX as a direct cytotoxic compound for pediatric MB cells by inhibiting the BER pathway. Nevertheless, an antagonism, rather than a synergic or additive effect of MX with different concentrations of CDDP, TMZ and THIO was observed. Likewise, the radiosensitizing effect on MB cell lines seems to depend on radiation doses and MB subtype. This information may be relevant for clinical study designs employing BER inhibitors for MB.

Related: Apoptosis Cisplatin Dacarbazine Thiotepa Temozolomide

Atas E, Korkmazer N, Artik HA, et al.
Raynaud's phenomenon in a child with medulloblastoma as a late effect of chemotherapy.
J Cancer Res Ther. 2015 Jul-Sep; 11(3):666 [PubMed] Related Publications

There are a lot of early or late side effects of chemotherapies. One of them is Raynaud's phenomenon (RP). Vascular toxicity associated with antineoplastic agents is notified in bleomycin alone therapy or in combination with cisplatin, vinblastine, and vincristine. The mechanism of RP associated with antineoplastic agents is unknown. All children receiving vinblastine, vincristine, bleomycin and cisplatin therapy, are followed and questioned about their complaint on RP. Long-term follow-up of surviving patients is recommended. Oncologists should be aware of the potential late toxic effects of antineoplastic drugs.

Related: Cisplatin Lomustine Vincristine

Wang C, Yuan XJ, Jiang MW, Wang LF
Clinical characteristics and abandonment and outcome of treatment in 67 Chinese children with medulloblastoma.
J Neurosurg Pediatr. 2016; 17(1):49-56 [PubMed] Related Publications

OBJECT The purpose of this study was to explore the clinical features and outcome of medulloblastoma in Chinese children. The authors analyze the reasons that treatment is abandoned and attempt to provide evidence-based recommendations for improving the prognosis of medulloblastoma in this population. METHODS A total of 67 pediatric cases of newly diagnosed medulloblastoma were included in this study. All of the children were treated at Xinhua Hospital between January 2007 and June 2013. The authors retrospectively analyzed the clinical data, treatment modalities, and outcome. The male-to-female ratio was 2:1, and the patients' median age at diagnosis was 51.96 months (range 3.96-168.24 months). The median duration of follow-up was 32 months (range 3-70 months). RESULTS At the most recent follow-up date, 31 patients (46%) were alive, 30 (45%) had died, and 6 (9%) had been lost to follow-up. The estimated 3-year overall survival and progression-free survival, based on Kaplan-Meier analysis, were 55.1% ± 6.4% and 45.6% ± 6.7%, respectively. Univariate analysis showed that standard-risk group (p = 0.009), postoperative radiotherapy (RT) combined with chemotherapy (p < 0.001), older age (≥ 3 years) at diagnosis (p = 0.010), gross-total resection (p = 0.012), annual family income higher than $3000 (p = 0.033), and living in urban areas (p = 0.008) were favorable prognostic factors. Multivariate analysis revealed that postoperative RT combined with chemotherapy was an independent prognostic factor (p < 0.001). The treatment abandonment rate in this cohort was 31% (21 of 67 cases). CONCLUSIONS There was a large gap between the outcome of medulloblastoma in Chinese children and the outcome in Western children. Based on our data, treatment abandonment was the major cause of therapeutic failure. Parents' misunderstanding of medulloblastoma played a major role in abandonment, followed by financial and transportation difficulties. Establishment of multidisciplinary treatment teams could improve the prognosis of medulloblastoma in Chinese children.

Brown AL, Lupo PJ, Okcu MF, et al.
SOD2 genetic variant associated with treatment-related ototoxicity in cisplatin-treated pediatric medulloblastoma.
Cancer Med. 2015; 4(11):1679-86 [PubMed] Free Access to Full Article Related Publications

Manganese superoxide dismutase (MnSOD), encoded by the SOD2 gene, is involved in the detoxification of superoxide anion. Superoxide is likely a source of oxidative stress in the cochlea following treatment with platinum agents and radiation. Therefore, we examined SOD2 variants in association with ototoxicity among cisplatin-treated childhood medulloblastoma patients. Blood samples were obtained from 71 eligible patients treated for pediatric medulloblastoma at Texas Children's Cancer Center (1987-2010). Ototoxicity was defined as requiring the use of a hearing aid sometime after the initiation of therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip. A linkage disequilibrium (LD)-based single-nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative variants. Associations between SNPs and ototoxicity were assessed using logistic regression. Of the 71 eligible patients, 26 (37%) suffered from cisplatin-related ototoxicity. Study participants were primarily male (73%) and non-Hispanic white (42%). Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, and rs4880) identified by the LD-based selection strategy were genotyped. After correcting for multiple comparisons, the C-allele of the rs4880 variant was significantly associated with ototoxicity (odds ratio = 3.06, 95% confidence interval: 1.30-7.20) in adjusted models. The rs4880 T > C substitution results in a Val > Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. The Ala variant, which has been associated with increased MnSOD activity, was associated with hearing damage in this study. Platinum-based therapies increase the expression of MnSOD, which may result in an abundance of hydrogen peroxide, a reactive oxygen species. Therefore, oxidative stress may be an important mechanism in therapy-related cochlear damage.

Related: Cisplatin

Wong TT, Liu YL, Ho DM, et al.
Factors affecting survival of medulloblastoma in children: the changing concept of management.
Childs Nerv Syst. 2015; 31(10):1687-98 [PubMed] Related Publications

Medulloblastoma (MB) is a type of malignant tumor arising only in the cerebellum that was first defined by Cushing and Bailey in 1920s. In this review paper, we trace the evolution of risk stratification and the correlated changing concept of management in the past years. Outcome analysis of the hospital series of the Taipei Veterans General Hospital, Cheng Hsin General Hospital, and Taipei Medical University Hospital was performed to correlate prognostic indicators with reported studies. The purpose is to provide clues for age-specific and risk-adjusted optimal, effective, but beneficial and protective treatment strategies of these tumors in children.

Pompe RS, von Bueren AO, Mynarek M, et al.
Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy.
Eur J Cancer. 2015; 51(17):2634-42 [PubMed] Related Publications

BACKGROUND: To assess feasibility, acute toxicity, and efficacy of intraventricular methotrexate administered as part of the primary therapy in medulloblastoma.
METHODS: From 2001 to 2007, 240 patients < 22 years from 61 treatment centres were registered. Patients received 2-3 cycles of intraventricular methotrexate with systemic chemotherapy in three different treatment arms of the prospective multicentre trial HIT2000 (150 children > 4 years with metastatic, 59 < 4 years with non-metastatic, 31 < 4 years with metastatic medulloblastoma).
RESULTS: 211 patients received an intraventricular access device with a subcutaneous reservoir for the application of chemotherapy. Reservoir-associated complications were documented in 57 (27%) patients, mostly due to infection (n = 32) and reservoir malfunction (n = 19), requiring removal in 39 (18%) patients. Acute neurotoxicity likely associated with intraventricular MTX was observed in 9/202 documented patients. Toxicity was usually mild, apart from one therapy-associated death due to toxic oedema followed by seizures. Of 519 treatment cycles including intraventricular methotrexate, 226 (43%) were reduced or omitted, most frequently due to the absence of an intraventricular device. Survival rates were higher in patients receiving ⩾ 75% of the scheduled intraventricular methotrexate dose compared to those receiving < 75% in both univariate and multivariate models (event-free survival (EFS), 61.5 versus 46.2%, p = 0.004; OS, 75.5% versus 60.4%, p = 0.015; hazard ratio: EFS 1.723, p = 0.016; OS 1.648, p = 0.051).
CONCLUSION: Intraventricular methotrexate therapy was feasible and mostly well tolerated. Infections were the most frequent complication. A higher cumulative dose of intraventricular methotrexate was associated with better survival. Further evaluation of efficacy and late effects is warranted.

Related: Methotrexate

Patay Z, DeSain LA, Hwang SN, et al.
MR Imaging Characteristics of Wingless-Type-Subgroup Pediatric Medulloblastoma.
AJNR Am J Neuroradiol. 2015; 36(12):2386-93 [PubMed] Free Access to Full Article Related Publications

BACKGROUND AND PURPOSE: "Transcriptionally different" medulloblastoma groups are associated with specific signaling pathway abnormalities; hence, they may present with distinct imaging manifestations. In this study, we sought to describe the MR imaging features of wingless-type-subgroup medulloblastomas with embryologic correlations.
MATERIALS AND METHODS: Pre- and postoperative imaging studies of 16 patients with wingless-type-subgroup medulloblastoma were evaluated for tumor location, involvement of surrounding CSF spaces or parenchymal structures, conventional and DWI signal properties, and postsurgical damage patterns. Laterality scores were assigned to tumors at each step in the evaluation process. Continuous variables were summarized by using descriptive statistics. The Wilcoxon signed rank test was performed to compare laterality scores. To determine the interobserver variability, we computed the intraclass correlation and Cohen κ coefficients.
RESULTS: Wingless-type-subgroup medulloblastomas in our series were histopathologically "classic." Wingless-type-subgroup medulloblastomas occur in specific sites, with involvement of the foramen of Luschka (75%), the fourth ventricle (68.75%), the cisterna magna (31.25%), and the cerebellopontine angle cistern (18.75%). Laterality scores were low (<2) when preoperative primary and secondary anatomic features were evaluated separately, but they increased (>2) when all pre- and postoperative anatomic features were considered. Results were statistically shown to be reproducible (interclass correlation coefficient, 0.71-0.94; Cohen κ, 0.63-1.00). On the basis of anatomic lesion patterns, 4 location-based subtypes may be distinguished: 1) midline-intraventricular, 2) midline-extraventricular, 3) off-midline-intraventricular, and 4) off-midline-extraventricular, which represent a continuum.
CONCLUSIONS: Wingless-type-subgroup medulloblastomas are lateralized tumors arising from the brain stem and cerebellum around the foramen of Luschka. Our current understanding of their embryologic origins is in concordance with the spatial distribution of these tumors.

Al-Wassia RK, Ghassal NM, Naga A, et al.
Optimization of Craniospinal Irradiation for Pediatric Medulloblastoma Using VMAT and IMRT.
J Pediatr Hematol Oncol. 2015; 37(7):e405-11 [PubMed] Related Publications

PURPOSE: Intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) provide highly conformal target radiation doses, but also expose large volumes of healthy tissue to low-dose radiation. With improving survival, more children with medulloblastoma (MB) are at risk of late adverse effects of radiotherapy, including secondary cancers. We evaluated the characteristics of IMRT and VMAT craniospinal irradiation treatment plans in children with standard-risk MB to compare radiation dose delivery to target organs and organs at risk (OAR).
PATIENTS AND METHODS: Each of 10 children with standard-risk MB underwent both IMRT and VMAT treatment planning. Dose calculations used inverse planning optimization with a craniospinal dose of 23.4 Gy followed by a posterior fossa boost to 55.8 Gy. Clinical and planning target volumes were demarcated on axial computed tomography images. Dose distributions to target organs and OAR for each planning technique were measured and compared with published dose-volume toxicity data for pediatric patients.
RESULTS: All patients completed treatment planning for both techniques. Analyses and comparisons of dose distributions and dose-volume histograms for the planned target volumes, and dose delivery to the OAR for each technique demonstrated the following: (1) VMAT had a modest, but significantly better, planning target volume-dose coverage and homogeneity compared with IMRT; (2) there were different OAR dose-sparing profiles for IMRT versus VMAT; and (3) neither IMRT nor VMAT demonstrated dose reductions to the published pediatric dose limits for the eyes, the lens, the cochlea, the pituitary, and the brain.
CONCLUSIONS: The use of both IMRT and VMAT provides good target tissue coverage and sparing of the adjacent tissue for MB. Both techniques resulted in OAR dose delivery within published pediatric dose guidelines, except those mentioned above. Pediatric patients with standard-risk MB remain at risk for late endocrinologic, sensory (auditory and visual), and brain functional impairments.

Zhao R, Shi W, Yu J, et al.
Complete Intestinal Obstruction and Necrosis as a Complication of a Ventriculoperitoneal Shunt in Children: A Report of 2 Cases and Systematic Literature Review.
Medicine (Baltimore). 2015; 94(34):e1375 [PubMed] Free Access to Full Article Related Publications

Ventriculoperitoneal (VP) shunt complications are common, but abdominal complications are rare. The objective of this report is to present 2 cases of intestinal obstruction due to a VP shunt and review the literature for data on this rare occurrence.A 4-month-old boy received surgical resection of a medulloblastoma and a VP shunt was inserted to manage progressive hydrocephalus. Two months later, he was admitted with intermittent vomiting, and plain abdominal radiography showed complete intestinal obstruction. Emergency laparotomy revealed an adhesive intestinal obstruction around the catheter, and approximately 5 cm of necrotic ileum was resected. His recovery was uneventful. In the second case, a 6-year-old boy was diagnosed with a primary nongerminomatous malignant germ cell tumor and a VP shunt was place to treat hydrocephalus. Two weeks after the first course of chemotherapy, he went into a coma; computed tomography demonstrated enlargement of the tumor and gross total resection was performed. Two weeks later, he developed abdominal distention; plain radiography showed intestinal obstruction and laparotomy revealed adhesive intestinal obstruction around the catheter with 15 cm of necrotic ileum. The necrotic bowel was resected. Unfortunately, the patient developed sepsis and despite treatment remained in a vegetative state.Medline, Central, Embase, and Google Scholar databases were searched up to May 9, 2014, using the terms VP shunt, shunting, and/or intestinal obstruction. Only cases involving children or adolescents were included. Eleven reports involving patients with abdominal complications resulting from a VP shunt for hydrocephalus were identified. The dates of the reports spanned from 1971 to 2014. Volvulus was the most common cause of VP shunt-related obstruction, and mechanical obstruction due to twisting of the catheter the second most common. Only 1 case in the literature review was related to intestinal adhesions. Treatment in most cases was laparotomy.Although intestinal obstruction is a rare complication of a VP shunt, it should be considered in the presence of abdominal symptoms and prompt treatment provided to have a good outcome.

Related: Germ Cell Tumors Germ Cell Tumours in Children and Young Adults Germ Cell Tumors (Pediatric) Testicular Cancer

Nair SK, Driscoll T, Boczkowski D, et al.
Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma.
J Neurooncol. 2015; 125(1):65-74 [PubMed] Free Access to Full Article Related Publications

Generation of patient-derived, autologous dendritic cells (DCs) is a critical component of cancer immunotherapy with ex vivo-generated, tumor antigen-loaded DCs. An important factor in the ability to generate DCs is the potential impact of prior therapies on DC phenotype and function. We investigated the ability to generate DCs using cells harvested from pediatric patients with medulloblastoma for potential evaluation of DC-RNA based vaccination approach in this patient population. Cells harvested from medulloblastoma patient leukapheresis following induction chemotherapy and granulocyte colony stimulating factor mobilization were cryopreserved prior to use in DC generation. DCs were generated from the adherent CD14+ monocytes using standard procedures and analyzed for cell recovery, phenotype and function. To summarize, 4 out of 5 patients (80%) had sufficient monocyte recovery to permit DC generation, and we were able to generate DCs from 3 out of these 4 patient samples (75%). Overall, we successfully generated DCs that met phenotypic requisites for DC-based cancer therapy from 3 out of 5 (60%) patient samples and met both phenotypic and functional requisites from 2 out of 5 (40%) patient samples. This study highlights the potential to generate functional DCs for further clinical treatments from refractory patients that have been heavily pretreated with myelosuppressive chemotherapy. Here we demonstrate the utility of evaluating the effect of the currently employed standard-of-care therapies on the ex vivo generation of DCs for DC-based clinical studies in cancer patients.

Related: Childhood Brain Tumours Childhood Brain Tumors BIRC5

Amayiri N, Al-Hussaini M, Swaidan M, et al.
Synchronous glioblastoma and medulloblastoma in a child with mismatch repair mutation.
Childs Nerv Syst. 2016; 32(3):553-7 [PubMed] Related Publications

Synchronous primary malignant brain tumors are rare. We present a 5-year-old boy with synchronous glioblastoma and medulloblastoma. Both tumor samples had positive p53 stain and loss of PMS2 and MLH1 stains. The child had multiple café au lait spots and a significant family history of cancer. After subtotal resection of both tumors, he received craniospinal radiation with concomitant temozolomide followed by chemotherapy, alternating cycles of cisplatin/lomustine/vincristine with temozolomide. Then, he started maintenance treatment with cis-retinoic acid (100 mg/m(2)/day for 21 days). He remained asymptomatic for 34 months despite a follow-up brain MRI consistent with glioblastoma relapse 9 months before his death. Cis-retinoic acid may have contributed to prolong survival in this child with a probable biallelic mismatch repair syndrome.

Related: Colorectal (Bowel) Cancer TP53 MLH1

Dahlin AM, Hollegaard MV, Wibom C, et al.
CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma.
J Neurooncol. 2015; 125(1):75-8 [PubMed] Free Access to Full Article Related Publications

Recent studies have described a number of genes that are frequently altered in medulloblastoma tumors and that have putative key roles in the development of the disease. We hypothesized that common germline genetic variations in these genes may be associated with medulloblastoma development. Based on recent publications, we selected 10 genes that were frequently altered in medulloblastoma: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 (now renamed as KMT2D). Common genetic variants (single nucleotide polymorphisms) annotating these genes (n = 221) were genotyped in germline DNA (neonatal dried blood spot samples) from 243 childhood medulloblastoma cases and 247 control subjects from Sweden and Denmark. Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P(combined) < 0.05). The findings were however not statistically significant following correction for multiple testing by the very stringent Bonferroni method. The results do not support our hypothesis that common germline genetic variants in the ten studied genes are associated with the risk of developing medulloblastoma.

Related: Childhood Brain Tumours Childhood Brain Tumors CCND2

Alexiou GA, Vartholomatos G, Stefanaki K, et al.
The Role of Fast Cell Cycle Analysis in Pediatric Brain Tumors.
Pediatr Neurosurg. 2015; 50(5):257-63 [PubMed] Related Publications

Cell cycle analysis by flow cytometry has not been adequately studied in pediatric brain tumors. We investigated the value of a modified rapid (within 6 min) cell cycle analysis protocol for the characterization of malignancy of pediatric brain tumors and for the differentiation of neoplastic from nonneoplastic tissue for possible intraoperative application. We retrospectively studied brain tumor specimens from patients treated at our institute over a 5-year period. All tumor samples were histopathologically verified before flow-cytometric analysis. The histopathological examination of permanent tissue sections was the gold standard. There were 68 brain tumor cases. All tumors had significantly lower G0/G1 and significantly higher S phase and mitosis fractions than normal brain tissue. Furthermore low-grade tumors could be differentiated from high-grade tumors. DNA aneuploidy was detected in 35 tumors. A correlation between S phase fraction and Ki-67 index was found in medulloblastomas and anaplastic ependymomas. Rapid cell cycle analysis by flow cytometry is a promising method for the identification of neoplastic tissue intraoperatively. Low-grade tumors could be differentiated from high-grade tumors. Thus, cell cycle analysis can be a valuable adjunct to the histopathological evaluation of pediatric brain tumors, whereas its intraoperative application warrants further investigation.

Related: Childhood Brain Tumours Childhood Brain Tumors Childhood Ependymoma MKI67

Vivekanandan S, Breene R, Ramanujachar R, et al.
The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy and Response Directed High Dose Myeloablative Chemotherapy or Maintenance Chemotherapy (Milan Strategy).
Pediatr Blood Cancer. 2015; 62(12):2132-9 [PubMed] Related Publications

BACKGROUND: Historically, the 5-year overall survival (OS) for metastatic medulloblastoma (MMB) was less than 40%. The strategy of post-operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed high dose chemotherapy (HDC) was reported in a single center study to improve 5-year OS to 73%. We report outcomes of this strategy in UK.
METHODS: Questionnaires were sent to all 20 UK pediatric oncology primary treatment centers to collect retrospective data on delivered treatment, toxicity and survival with this strategy in children aged 3-19 years with MMB.
RESULTS: Between February 2009 and October 2011, 34 patients fulfilled the entry criteria of the original study. The median age was 7 years (range 3-15). Median interval from surgery to HART was 109 versus 85 days in the original series. The incidence of grade 3 or 4 hematological toxicities with IC and HDC was 83-100%. All 16 patients who achieved complete response by the end of the regimen remain in remission but only three of 18 patients with lesser responses are still alive (P < 0.0001). With a median follow-up of 45 months for survivors, the estimated 3-year OS is 56% (95% CI 38, 71). This result is outside the 95% CI of the original study results and encompasses the historical survival result of 40%.
CONCLUSION: Within the limits of statistical significance, we did not replicate the improved survival results reported in the original series. The reasons include differences in patient sub-groups and protocol administration. International randomized phase III studies are needed.

Sandberg DI, Rytting M, Zaky W, et al.
Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial.
J Neurooncol. 2015; 125(1):133-41 [PubMed] Free Access to Full Article Related Publications

We hypothesize that chemotherapy can be safely administered directly into the fourth ventricle to treat recurrent malignant brain tumors in children. For the first time in humans, methotrexate was infused into the fourth ventricle in children with recurrent, malignant brain tumors. A catheter was surgically placed into the fourth ventricle and attached to a ventricular access device. Cerebrospinal fluid (CSF) flow was confirmed by CINE MRI postoperatively. Each cycle consisted of 4 consecutive daily methotrexate infusions (2 milligrams). Disease response was monitored with serial MRI scans and CSF cytologic analysis. Trough CSF methotrexate levels were sampled. Five patients (3 with medulloblastoma and 2 with ependymoma) received 18, 18, 12, 9, and 3 cycles, respectively. There were no serious adverse events or new neurological deficits attributed to methotrexate. Two additional enrolled patients were withdrawn prior to planned infusions due to rapid disease progression. Median serum methotrexate level 4 h after infusion was 0.04 µmol/L. Range was 0.02-0.13 µmol/L. Median trough CSF methotrexate level 24 h after infusion was 3.18 µmol/L (range 0.53-212.36 µmol/L). All three patients with medulloblastoma had partial response or stable disease until one patient had progressive disease after cycle 18. Both patients with ependymoma had progressive disease after 9 and 3 cycles, respectively. Low-dose methotrexate can be infused into the fourth ventricle without causing neurological toxicity. Some patients with recurrent medulloblastoma experience a beneficial anti-tumor effect both within the fourth ventricle and at distant sites.

Related: Childhood Ependymoma Methotrexate Malignant Rhabdoid Tumour

Batista A, Riedemann L, Vardam T, Jain RK
Targeting the Tumor Microenvironment to Enhance Pediatric Brain Cancer Treatment.
Cancer J. 2015 Jul-Aug; 21(4):307-13 [PubMed] Related Publications

Strategies targeting the microenvironment of pediatric brain cancers have the potential to improve the efficacy of standard and genome-based molecular therapeutics. These strategies also have the potential of helping resolve many of the challenges associated with developing new drugs and running clinical trials for relatively small pediatric brain tumor population. Disrupting vital paracrine and physical interactions between cancer cells and surrounding stroma, targeting and normalizing the abnormal tumor vasculature, and/or inducing antitumor immunity represent some of the most promising approaches. A comprehensive characterization of the pediatric brain tumor microenvironment's composition and function and its modulation by chemoradiation and molecularly targeted therapies is warranted to develop and effectively implement these approaches.

Related: Angiogenesis Inhibitors Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood Angiogenesis and Cancer

Bull KS, Liossi C, Peacock JL, et al.
Screening for cognitive deficits in 8 to 14-year old children with cerebellar tumors using self-report measures of executive and behavioral functioning and health-related quality of life.
Neuro Oncol. 2015; 17(12):1628-36 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: We aimed to identify a brief screening measure for detection of cognitive deficit in children treated for cerebellar tumors that would be useful in clinical practice.
METHODS: A sample of 72 children, aged 8-14 years, and within 3 years post diagnosis for standard-risk medulloblastoma (n = 37) or low-grade cerebellar astrocytoma (n = 35) and 38 children in a nontumor group were assessed using teacher-, parent-, and child-report of the Behavior Rating Inventory of Executive Function (BRIEF), Strengths and Difficulties Questionnaire (SDQ), and Pediatric Quality of Life Inventory (PedsQL). The accuracy of these scores as a screen for a full-scale Intelligence Quotient (FSIQ) < 80 on the Wechsler Intelligence Scale for Children (WISC-IV UK) was assessed using their receiver operating characteristic (ROC) curves.
RESULTS: The questionnaires with the highest areas under the ROC curves were the child- and parent-report PedsQL, the teacher-report BRIEF, and the SDQ. At optimal cutoff scores, their sensitivities (95% CIs) to cases of FSIQ < 80 were 84 (60-96)%, 65 (41-84)%, 79 (54-93)%, and 84 (60-96)%, and their specificities (95% CIs) were 79 (68-86)%, 87 (77-93)%, 77 (66-86)%, and 71 (64-84)% respectively. All cases of FSIQ < 80 screened positive on either teacher-report SDQ or self-report PedsQL.
CONCLUSIONS: The PedsQL child- and parent-report and the teacher-report BRIEF and SDQ have moderately good accuracy for discriminating between children with and without a FSIQ < 80. The PedsQL could be used in a clinical setting, and the BRIEF and SDQ in an educational setting, to screen for cases with FSIQ < 80 in children treated for brain tumors.

Related: Childhood Astrocytoma

Chai YH, Jung TY, Lee KH, Kim SK
Progressive Multiple Cavernous Angiomas after Radiotherapy in a Pediatric Patient with Medulloblastoma: A Case Report.
Pediatr Neurosurg. 2015; 50(5):270-4 [PubMed] Related Publications

BACKGROUND: We report a case of progressive multiple cavernous angiomas.
PATIENT AND METHOD: A 16-year-old boy presented with a 2-month history of headache and dizziness. Six years earlier, he underwent surgery for cerebellar medulloblastoma and subsequent chemoradiotherapy according to the M-051 protocol of the Korean Society of Pediatric Neuro-Oncology. Follow-up brain magnetic resonance imaging (MRI) revealed a tiny hemorrhage on the cerebellum 3 months after 23.4-Gy craniospinal and 32.4-Gy boost radiotherapy.
RESULT: The multiple hemorrhagic lesions had progressively developed on the whole brain without any symptoms for 6 years. On admission, MRI revealed a 1.5-cm enlarged mass with subacute hemorrhage on the right frontal area. The mass was totally removed and diagnosed as cavernous angioma. However, 5 months later, the patient complained of a headache. MRI revealed 1.4- and 0.7-cm enlarged masses on the left frontal and right temporal areas with internal hemorrhage, respectively. The left frontal mass was totally removed, and the histopathological finding was suggestive of cavernous angioma.
CONCLUSION: This case showed early-developed multiple hemorrhagic lesions after radiotherapy, which had been progressive and were associated with some symptomatic cavernous angiomas. Pediatric patients with brain radiotherapy should undergo radiological check-up to identify vascular lesions, especially symptomatic patients.

Câmara-Costa H, Resch A, Kieffer V, et al.
Neuropsychological Outcome of Children Treated for Standard Risk Medulloblastoma in the PNET4 European Randomized Controlled Trial of Hyperfractionated Versus Standard Radiation Therapy and Maintenance Chemotherapy.
Int J Radiat Oncol Biol Phys. 2015; 92(5):978-85 [PubMed] Related Publications

PURPOSE: In the European HIT-SIOP PNET4 randomized controlled trial, children with standard risk medulloblastoma were allocated to hyperfractionated radiation therapy (HFRT arm, including a partially focused boost) or standard radiation therapy (STRT arm), followed, in both arms, by maintenance chemotherapy. Event-free survival was similar in both arms. Previous work showed that the HFRT arm was associated with worse growth and better questionnaire-based executive function, especially in children <8 years of age at diagnosis. Therefore, the aim of this study was to compare performance-based cognitive outcomes between treatment arms.
METHODS AND MATERIALS: Neuropsychological data were collected prospectively in 137 patients. Using the Wechsler Intelligence Scales, Kaufman Assessment Battery for Children, and Raven's Progressive Matrices, we estimated full-scale intelligence quotient (FSIQ) and, when available, verbal IQ (VIQ), performance IQ (PIQ), working memory index (WMI), and processing speed index (PSI).
RESULTS: Among the 137 participants (HFRT arm n=71, STRT arm n=66, 63.5% males), mean (±SD) ages at diagnosis and assessment respectively were 9.3 (±3.2) years of age (40.8% < 8 years of age at diagnosis) and 14.6 (±4.3) years of age. Mean (±SD) FSIQ was 88 (±19), and mean intergroup difference was 3.88 (95% confidence interval: -2.66 to 10.42, P=.24). No significant differences were found in children >8 years of age at diagnosis. In children <8 years of age at diagnosis, a marginally significant trend toward higher VIQ was found in those treated in the HFRT arm; a similar trend was found for PSI but not for PIQ, WMI, or FSIQ (mean intergroup differences were: 12.02 for VIQ [95% CI: 2.37-21.67; P=.02]; 3.77 for PIQ [95% CI: -5.19 to 12.74; P>.10]; 5.20 for WMI [95% CI: -2.07 to 12.47; P>.10]; 10.90 for PSI [95% CI: -1.54 to 23.36; P=.08]; and 5.28 for FSIQ [95% CI: -4.23 to 14.79; P>.10]).
CONCLUSIONS: HFRT was associated with marginally higher VIQ in children <8 years of age at diagnosis, consistent with a previous report using questionnaire-based data. However, overall cognitive ability was not significantly different.

Related: Cisplatin Lomustine Vincristine

Friedman GK, Moore BP, Nan L, et al.
Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses.
Neuro Oncol. 2016; 18(2):227-35 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Childhood medulloblastoma is associated with significant morbidity and mortality that is compounded by neurotoxicity for the developing brain caused by current therapies, including surgery, craniospinal radiation, and chemotherapy. Innate therapeutic resistance of some aggressive pediatric medulloblastoma has been attributed to a subpopulation of cells, termed cancer-initiating cells or cancer stemlike cells (CSCs), marked by the surface protein CD133 or CD15. Brain tumors characteristically contain areas of pathophysiologic hypoxia, which has been shown to drive the CSC phenotype leading to heightened invasiveness, angiogenesis, and metastasis. Novel therapies that target medulloblastoma CSCs are needed to improve outcomes and decrease toxicity. We hypothesized that oncolytic engineered herpes simplex virus (oHSV) therapy could effectively infect and kill pediatric medulloblastoma cells, including CSCs marked by CD133 or CD15.
METHODS: Using 4 human pediatric medulloblastoma xenografts, including 3 molecular subgroup 3 tumors, which portend worse patient outcomes, we determined the expression of CD133, CD15, and the primary HSV-1 entry molecule nectin-1 (CD111) by fluorescence activated cell sorting (FACS) analysis. Infectability and cytotoxicity of clinically relevant oHSVs (G207 and M002) were determined in vitro and in vivo by FACS, immunofluorescent staining, cytotoxicity assays, and murine survival studies.
RESULTS: We demonstrate that hypoxia increased the CD133+ cell fraction, while having the opposite effect on CD15 expression. We established that all 4 xenografts, including the CSCs, expressed CD111 and were highly sensitive to killing by G207 or M002.
CONCLUSIONS: Pediatric medulloblastoma, including Group 3 tumors, may be an excellent target for oHSV virotherapy, and a clinical trial in medulloblastoma is warranted.

Related: Apoptosis

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