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Case-based review: pediatric medulloblastoma.

ABSTRACT: Medulloblastoma is the most common malignant brain tumor affecting children. These tumors are high grade with propensity to metastasize within the central nervous system and, less frequently, outside the neuraxis. Recent advancements in molecular subgrouping of medulloblastoma refine diagnosis and improve counseling in regards to overall prognosis. Both are predicated on the molecular drivers of each subgroup-WNT-activated, SHH-activated, group 3, and group 4. The traditional therapeutic mainstay for medulloblastoma includes a multimodal approach with surgery, radiation, and multiagent chemotherapy. As we discover more about the molecular basis of medulloblastoma, efforts to adjust treatment approaches based on molecular risk stratification are under active investigation. Certainly, the known neurological, developmental, endocrine, and psychosocial injury related to medulloblastoma and its associated therapies motivate ongoing research towards improving treatment for this life-threatening tumor while at the same time minimizing long-term side effects.

SUBMITTER: Kline CN

PROVIDER: S-EPMC5909805 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Case-based review: pediatric medulloblastoma.

Kline Cassie N CN Packer Roger J RJ Hwang Eugene I EI Raleigh David R DR Braunstein Steve S Raffel Corey C Bandopadhayay Pratiti P Solomon David A DA Aboian Mariam M Cha Soonmee S Mueller Sabine S

Neuro-oncology practice 20170811 3

Medulloblastoma is the most common malignant brain tumor affecting children. These tumors are high grade with propensity to metastasize within the central nervous system and, less frequently, outside the neuraxis. Recent advancements in molecular subgrouping of medulloblastoma refine diagnosis and improve counseling in regards to overall prognosis. Both are predicated on the molecular drivers of each subgroup-WNT-activated, SHH-activated, group 3, and group 4. The traditional therapeutic mainsta ...[more]

PMID: 29692919

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Project description:Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor. The aim of our study was to understand which mechanisms are involved in aberrant activation of Wnt pathway and its association with MB tumor development. We studied the expression profiles of 19 MBs tumors using a genome-wide approach, furthermore we have included the data obtained from four independent public Datasets of gene expression (see README file below) to increase the statistical power of the study. The expression profiles identified the Wnt inhibitor gene, DKK3, significant down-regulated. DKK3 down-regulation was confirmed by qPCR in 80% of samples (27/33 MB tumors and in 3/5 MB human cell lines). Since DKK3 was found methylated in several cancers we also investigated the status of methylated CpG sites within the three promoters by a combination of two approaches: the MSP and pyrosequencing. MSP showed no methylation in all promoters while the pyrosequencing, a quantitative technique, indicated a very low level of methylation. To verify the epigenetic involvement on DKK3 silencing, we also studied the effect of Trichostatin A (TSA) in 4 MB cell lines (DAOY; D283; D425; D458). After TSA treatment we observed a significant DKK3 mRNA expression increase in 3/4 cell lines compared to the no treated cells. DAOY cells, that have a normal DKK3 expression value, did not change significantly the DKK3 expression after TSA treatment. To further validate the role of histone tail modifications as an epigenetic silencing mechanism for DKK3 in MB, we performed Chromatin Immunoprecipitation (ChIP) experiment using antibodies against acetylated histones. According to our earlier results, TSA treatment increased the signal of the histone modification meH3K4 which is related to a transcriptionally active gene respect to the untreated controls. Finally, we evaluated the DKK3 protein in three MB cell lines (DAOY; D283; D425) after 24h of TSA treatment, by immunofluorescence. We analysed 19 Medulloblastoma tumor from pediatric patients, a commercial pool (Clontech) of 24 normal cerebellum from female and male Caucasians (ages: 16-70 years; cause of death: sudden death) and a pool of 10 normal cerebellum from children (6 Caucasians and 4 African Americans; ages: 0-16 years; cause of death: sudden death) using 44K whole genome oligonucleotids microarray

Project description:BackgroundCentral nervous system tumors remain the leading cause of cancer-related mortality amongst children with solid tumors, with medulloblastoma (MB) representing the most common pediatric brain malignancy. Despite best current therapies, patients with recurrent MB experience have an alarmingly high mortality rate and often have limited therapeutic options beyond inadequate chemotherapy or experimental clinical trials. Therefore, a systematic review of the literature regarding treatment strategies employed in recurrent pediatric MB will evaluate previous salvage therapies in order to guide future clinical trials. The aim of this systematic review will be to investigate the efficacy and safety of salvage therapies for the management of children with progressive, treatment-refractory, or recurrent MB.MethodsWe will conduct literature searches (from 1995 onwards) in MEDLINE, EMBASE, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and Cochrane Central Register of Controlled Trials. Studies examining the survival and toxicity of therapies administered to treatment-refractory pediatric MB patients will be included. Two reviewers will independently assess the search results based on predefined selection criteria, complete data abstraction, and quality assessment. The primary outcomes of this review will be overall and progression-free survival. Secondary outcomes will include safety and toxicity of each therapy administered. The study methodological quality (or bias) will be appraised using an appropriate tool. Due to the nature of the research question and published literature, we expect large inter-study heterogeneity and therefore will use random effects regression analysis to extract the combined effect. In additional analyses, we will investigate the role of re-irradiation and mono- vs. poly-therapy in recurrent disease, and whether molecular subgrouping of MB influences salvage therapy.DiscussionThis systematic review will provide an overview of the current literature regarding salvage therapies for relapsed MB patients. Investigation of clinically tested therapies for children with recurrent MB has significant implications for clinical practice. By reviewing the efficacy and toxicity of MB salvage therapies, this study will identify effective therapeutic strategies administered to recurrent MB patients and can inform future clinical trials aimed to improve patient survivorship and quality of life.Systematic review registrationPROSPERO CRD42020167421.

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Case-based review: pediatric medulloblastoma.

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Case-based review: pediatric medulloblastoma.

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