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Medulloblastoma
Kinds of Medulloblastoma Selected AbstractsBoth CD133+ and CD133, medulloblastoma cell lines express ligands for triggering NK receptors and are susceptible to NK-mediated cytotoxicityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2007Roberta Castriconi Abstract Adoptive cellular immunotherapy has been proposed as an additional treatment of medulloblastoma, an intracranial tumor characterized by a particularly poor prognosis. However, little is known on the ability of the immune system to effectively attack this tumor. In this study, we show that activated human NK cells efficiently kill medulloblastoma cell lines in vitro. NK-mediated killing involved different activating receptors (including NKp46, NKp30, DNAM-1 and NKG2D) and correlated with the presence of their specific ligands on tumor cells. In contrast, the absence of major adhesion interactions, such as LFA-1/ICAM did not impair the NK-mediated cytotoxicity. Medulloblastoma expressed a number of tumor-associated molecules including CD146 and CD133, considered a marker for cancer stem cells. Remarkably, both CD133-positive and CD133-negative cell lines were susceptible to lysis. Tumor cells also expressed molecules that are currently used as diagnostic tools for neuroblastoma cell identification. In particular, B7 homolog 3 (B7-H3) was expressed by all the medulloblastoma cell lines analyzed, while the presence of GD2 and NB84 was restricted to given cell lines and/or marked a defined tumor cell subset. [source] Pathogenesis of medulloblastoma and current treatment outlookMEDICINAL RESEARCH REVIEWS, Issue 6 2007Jaroslaw Jozwiak Abstract Medulloblastoma is the most common malignant tumor of the cerebellum in children, with a tendency to metastasize via CSF pathway. Survival rate varies depending on several factors, but is rather favorable, with radiotherapy as the treatment of choice. Irradiation of the craniospinal axis results, however, in severe neuropsychological and psychosocial impairments pertaining to memory, attention, motor functioning, language, and visuospatial abilities. Precise mechanisms underlying the formation of medulloblastoma are still unclear, but implication of at least three signaling molecules is postulated: insulin-like growth factor-I, WNT, and Sonic hedgehog. Thanks to increasing knowledge on the cellular mechanisms contributing to tumor formation, it is possible to propose new therapies that could replace radiotherapy or allow decreasing irradiation doses. The current review presents recent developments in medulloblastoma pathophysiology research and proposed inhibitors that could constitute good candidates for further pharmacological research. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 6, 869,890, 2007 [source] In vitro, high-resolution 1H and 31P NMR based analysis of the lipid components in the tissue, serum, and CSF of the patients with primary brain tumors: one possible diagnostic viewNMR IN BIOMEDICINE, Issue 2 2010Niraj Kumar Srivastava Abstract In vitro, high-resolution 1H and 31P NMR based qualitative and quantitative analyses of the lipid components of the tissue, serum, and CSF of patients with primary brain tumors were performed. Proton NMR spectra of the lipid extract of serum (blood specimen collected before the surgical procedure) and surgically discarded tissue showed that the total cholesterol (T.CHOL) and choline containing phospholipids (PL) were significantly higher in quantity in medulloblastoma and glioblastoma multiforme as compared to normal subjects. Serum lipid extracts of grade II/ III gliomas showed a higher quantity of PL than normal subjects. Cholestrol esters (CHOLest) were detectable in the tissue lipid extract of the patients with tumors and absent in normal tissue. There was a reduction in the quantity of CHOLest in the serum lipid extract of the tumor patients as compared to normal subjects. Ratio of PL to T.CHOL in serum lipid extract showed a significant difference between different grades of tumors versus normal subjects, while, a significant difference was observed only in medulloblastoma versus normal subjects in tissue lipid extract. Ratio of CHOL to CHOLest distinguishes the different grades of tumors versus normal subjects as well as between different grades of tumors (except medulloblastoma versus glioblastoma). The ratio of the Ph (total phospholipids except phosphatidylcholine) to PC (phosphatidylcholine) in 31P NMR based study showed a significant difference in all grades of tumors (except medulloblastoma) in normal subjects in tissue lipid extract as well as between different grades of tumors. Medulloblastoma could be differentiated from glioblastoma as well as from normal subjects in serum lipid extract by the ratio of the Ph to PC. Proton NMR spectra of the lipid extract of CSF showed that the CHOL, CHOLest, and PL were present in the patients with tumors, although these were absent in the patients with meningitis, motor neuron disease, and mitochondrial myopathies as well as in normal subjects. PL and T.CHOL provided discrimination between different grades of tumors (except glioblastoma versus medulloblastoma) in the lipid extract of the CSF. This study suggests the role of lipid estimation in CSF and serum as a complementary diagnostic tool for the evaluation of brain tumors preoperatively. NMR-based lipid estimation of post-surgical tumor tissue may also contribute to differentiating the tumor types. Copyright © 2009 John Wiley & Sons, Ltd. [source] Inhibition of Aurora Kinase A enhances chemosensitivity of medulloblastoma cell lines,PEDIATRIC BLOOD & CANCER, Issue 1 2010Ayman El-Sheikh MD Abstract Background Medulloblastoma comprises approximately 20% of all primary pediatric brain tumors. Despite recent advances, the survival rate for high-risk patients and the morbidity associated with these treatments remains suboptimal. To improve outcomes and decrease morbidity, more targeted therapy is required. One possible target is the Aurora Kinase family. The objective of this study was to evaluate the impact of Aurora Kinase A inhibition in medulloblastoma cell lines. Procedure Cell proliferation was measured using an MTS assay after adding an Aurora Kinase inhibitor (C1368) at different concentrations. Cell cycle analysis was carried out by Flow Cytometry using propidium iodide (PI). RNAi experiments were performed using siRNA oligonucleotides. Luciferase experiments were carried out using the Cignal Finder 10 Pathway Reporter Arrays. Results Inhibition of Aurora Kinase A induces cell death in medulloblastoma cells and lowers the IC50 of other chemotherapeutic agents (etoposide and cisplatin) used in medulloblastoma treatment. Cell arrest at G2/M phase was significantly increased in medulloblastoma cell lines treated with C1368 Sigma at IC30 or transfected siRNA. Inhibition of Aurora Kinase A resulted in decreased activity of pro-proliferative signaling pathways including Wnt, Myc, and RB as measured by luciferase reporter assays. Conclusions These data indicate that inhibition of Aurora Kinase A inhibits cell growth in medulloblastoma through inhibition of pro-proliferative signaling pathways Wnt, Myc, and RB. Additionally, combining Aurora Kinase A inhibition with other chemotherapeutic agents significantly lowers their IC50, which make it a promising small molecule target for medulloblastoma therapy. Pediatr Blood Cancer 2010;55:35,41. © 2010 Wiley-Liss, Inc. [source] Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics,THE JOURNAL OF PATHOLOGY, Issue 1 2009Sarah Fattet Abstract Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/,-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for ,-catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of ,-catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all ,-catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/,-catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear ,-catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/,-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5,121.2 months) from diagnosis. All three patients with focal nuclear staining of ,-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1 -mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de-escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Cochlear Implantation following Treatment for MedulloblastomaTHE LARYNGOSCOPE, Issue S1 2009John Thomas Roland Jr. MD No abstract is available for this article. [source] Control of ,-catenin/Tcf-directed transcription in medulloblastomaACTA PAEDIATRICA, Issue 2004C Raffel The ,-catenin, glycogen synthase kinase 3, (GSK-3,), and adenomatous polyposis coli (APC) gene products interact to form a network that influences the rate of cell proliferation. Medulloblastoma occurs as part of Turcot's syndrome and patients with Turcot's syndrome, who develop medulloblastomas, have been shown to harbor germline APC mutations. While APC mutations have been investigated and not identified in sporadic medulloblastomas, the status of the ,-catenin and GSK-3, genes has not been evaluated in this tumor. This study shows that 3 of 67 medulloblastomas harbor ,-catenin mutations, each of which converts a GSK-3, phosphorylation site from serine to cysteine. The ,-catenin mutation seen in the tumors was not present in matched constitutional DNA in the 2 cases where matched normal DNA was available. A loss of heterozygosity (LOH) analysis of 32 medulloblastomas with paired normal DNA samples was performed with 4 microsatellite markers flanking the GSK-3, locus; LOH with at least one marker was identified in 7 tumors. Sequencing of the remaining GSK-3, allele in these cases failed to identify any mutations. Taken together, these data suggest that activating mutations in the ,-catenin gene may be involved in the development of a subset of medulloblastomas. The GSK-3, gene does not appear to be a target for inactivation in this tumor. [source] Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF-dependent transcription in medulloblastomasINTERNATIONAL JOURNAL OF CANCER, Issue 2 2007Arend Koch Abstract Medulloblastomas (MBs) represent the most common malignant brain tumors in children. Most MBs develop sporadically in the cerebellum, but their incidence is highly elevated in patients with familial adenomatous polyposis coli. These patients carry germline mutations in the APC tumor suppressor gene. APC is part of a multiprotein complex involved in the Wnt signaling pathway that controls the stability of ,-catenin, the central effector in this cascade. Previous genetic studies in MBs have identified mutations in genes coding for ,-catenin and its partners, APC and AXIN1, which cause activation of Wnt signaling. The pathway is negatively controlled by the tumor suppressor AXIN2 (Conductin), a scaffold protein of this signaling complex. To investigate whether alterations in AXIN2 may also be involved in the pathogenesis of sporadic MBs, we performed a mutational screening of the AXIN2 gene in 116 MB biopsy samples and 11 MB cell lines using single-strand conformation polymorphism and sequencing analysis. One MB displayed a somatic, tumor-specific 2 bp insertion in exon 5, leading to carboxy-terminal truncation of the AXIN2 protein. This tumor biopsy showed nuclear accumulation of ,-catenin protein, indicating an activation of Wnt signaling. In 2 further MB biopsies, mutations were identified in exon 5 (Glu408Lys) and exon 8 (Ser738Phe) of the AXIN2 gene, which are due to predicted germline mutations and rare polymorphisms. mRNA expression analysis in 22 MBs revealed reduced expression of AXIN2 mRNA compared to 8 fetal cerebellar tissues. Promoter hypermethylation could be ruled out as a major cause for transcriptional silencing by bisulfite sequencing. To study the functional role of AXIN2 in MBs, wild-type AXIN2 was overexpressed in MB cell lines in which the Wnt signaling pathway was activated by Wnt-3a. In this assay, AXIN2 inhibited Wnt signaling demonstrated in luciferase reporter assays. In contrast, overexpression of mutated AXIN2 with a deleted C-terminal DIX-domain resulted in an activation of the Wnt signaling pathway. These findings indicate that mutations of AXIN2 can lead to an oncogenic activation of the Wnt pathway in MBs. © 2007 Wiley-Liss, Inc. [source] TrkA expression is associated with an elevated level of apoptosis in classic medulloblastomasNEUROPATHOLOGY, Issue 3 2006Takashi Ohta Medulloblastomas represent the most common central nervous system malignancies in children. Despite intensive modality treatment with craniospinal irradiation and multiple drug chemotherapy, their prognosis remains dismal. In the present study, we examined the potential roles of cellular differentiation, proliferation and apoptosis in 21 pediatric patients with newly diagnosed classic medulloblastomas treated by conventional radiation therapy and adjuvant chemotherapy. The expression of glial fibrillary acidic protein, S-100, synaptophysin, TrkA and TrkC, and the proliferation index of MIB-1 were evaluated by immunohistochemistry and the apoptotic index was determined using terminal deoxytransferase-mediated deoxyuridine-5,-triphosphate nick-end labeling assay. The prognostic value of these biological markers was also assessed. Immunoreactive glial fibrillary acidic protein, S-100, synaptophysin, TrkA and TrkC were observed in seven (33%), four (19%), 12 (57%), 14 (67%) and 11 (52%) of the 21 cases, respectively. TrkA expression was positively correlated with the MIB-1 staining index (P = 0.0228) and the apoptotic index (P = 0.0058). None of the immunohistochemical markers was found to be of value in predicting the prognosis. Although the present small sample size does not provide sufficient power to discount biological variables as prognostic markers, it was the well-established clinical prognostic factors, i.e. tumor stage and extent of surgery, that stood out as the most important predictors of survival. The close association between apoptosis and TrkA expression is consistent with in vitro data demonstrating the capacity of the NGF/TrkA signaling pathway to increase medulloblastoma apoptotic cell death, suggesting that this pathway may yield alternative therapeutic targets for novel therapies. [source] Immunohistochemical analysis for histopathological subtypes in pediatric medulloblastomasPATHOLOGY INTERNATIONAL, Issue 2 2003Eun-Ik Son Medulloblastomas occurring in children represent a histological spectrum of varying anaplasia and nodularity. In order to determine whether immunohistochemical markers might be useful parameters in subclassifying these tumors, 17 pediatric medulloblastomas, including nine diffuse/non-anaplastic, four diffuse/anaplastic, three nodular/non-anaplastic and one nodular/anaplastic subtypes, were studied. In the present report, we investigate the expression of neural cell adhesion molecule (NCAM), nerve growth factor receptor (NGFR), neurofilament (NF), synaptophysin (SYN), glial fibrillary acidic protein (GFAP), S100, Bcl-2, and Ki-67 by using the immunohistochemistry against specific antibodies. This study showed that NGFR, NF, GFAP and S100 were not detected in anaplastic subtypes of medulloblastomas (0/5), while non-anaplastic subtypes were mainly expressed within the nodules. All 17 tumors were reactive for NCAM, SYN and Bcl-2. In addition, Ki-67 labeling indices for anaplastic subtypes (39.0 ± 7.42%) were significantly higher than that of non-anaplastic medulloblastomas (11.4 ± 8.04%; P < 0.0001). These results suggest that immunohistochemical markers are a useful adjunct in characterizing subtypes of pediatric medulloblastomas. [source] Anaplasia and Grading in MedulloblastomasBRAIN PATHOLOGY, Issue 3 2003Charles G. Eberhart; The variable clinical outcomes of medulloblastoma patients have prompted a search for markers with which to tailor therapies to individuals. In this review, we discuss clinical, histological and molecular features that can be used in such treatment customization, focusing on how histopathological grading can impact both patient care and research on the molecular basis of CNS embryonal tumors. Medulloblastomas span a histological spectrum ending in overtly malignant large cell/anaplastic lesions characterized by increased nuclear size, marked cytological anaplasia, and increased mitotic and apoptotic rates. These "high-grade" lesions make up approximately one quarter of medulloblastomas, and recur and metastasize more frequently than tumors lacking anaplasia. We believe anaplastic change represents a type of malignant progression common to many medulloblastoma subtypes and to other CNS embryonal lesions as well. Correlation of these histological changes with the accumulation of genetic events suggests a model for the histological and molecular progression of medulloblastoma. [source] Histopathologic grading of medulloblastomasCANCER, Issue 2 2002A Pediatric Oncology Group Study Abstract BACKGROUND Medulloblastomas are small cell embryonal tumors of the cerebellum found predominantly in children, only slightly more than half of whom survive. Predicting favorable outcome has been difficult, and improved stratification clearly is required to avoid both undertreatment and overtreatment. Patients currently are staged clinically, but no pathologic staging system is in use. Two rare subtypes at extreme ends of the histologic spectrum, i.e., medulloblastomas with extensive nodularity and large cell/anaplastic medulloblastomas, are associated with better and worse clinical outcomes, respectively. However, there is little data about correlations between histologic features and clinical outcome for most patients with medulloblastomas that fall between these histologic extremes of nodularity and anaplasia. Therefore, the authors evaluated the clinical effects of increasing anaplasia and nodularity in a large group of children with medulloblastomas, hypothesizing that increasing nodularity would predict better clinical outcomes and that increasing anaplasia would presage less favorable results. METHODS Medulloblastomas from 330 Pediatric Oncology Group patients were evaluated histologically with respect to extent of nodularity, presence of desmoplasia, grade of anaplasia, and extent of anaplasia. Pathologic and clinical data were then compared using Kaplan,Meier and log-rank analyses. RESULTS Increasing grade of anaplasia and extent of anaplasia were associated strongly with progressively worse clinical outcomes (P < 0.0001 for both). Significant anaplasia (moderate or severe) was identified in 24% of medulloblastoma specimens. Neither increasing degrees of nodularity nor desmoplasia were associated significantly with longer survival. CONCLUSIONS Moderate anaplasia and severe anaplasia were associated with aggressive clinical behavior in patients with medulloblastomas and were detected in a significant number of specimens (24%). Pathologic grading of medulloblastomas with respect to anaplasia may be of clinical utility. Cancer 2002;94:552,60. © 2002 American Cancer Society. [source] Neurodevelopmental impact on children treated for medulloblastoma: A review and proposed conceptual modelDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 3 2008Shawna L. Palmer Abstract The population of survivors following diagnosis and treatment for medulloblastoma is thankfully on the rise. An increased focus on the quality of that survivorship has expanded the concept of cure to include efforts aimed at improving long-term cognitive outcome. It is well established in the literature that decline in overall intellect and academic performance is experienced by a majority of those undergoing treatment for pediatric medulloblastoma. This decline is believed to be secondary to decline in core cognitive abilities, which in turn are related to underlying damage to neuroanatomical substrates. A review of research on neurodevelopmental impacts following diagnosis and treatment for pediatric medulloblastoma is presented. Particular consideration is given to studies recently published that also reflect critical collaboration among those within the fields of neuropsychology and neuro-imaging. Results from the review are combined within a conceptual model upon which to guide future research and clinical efforts. © 2008 Wiley-Liss, Inc. Dev Disabil Res Rev 2008;14:203,210. [source] Fine-needle aspiration diagnosis of medulloblastoma metastatic to the pelvisDIAGNOSTIC CYTOPATHOLOGY, Issue 5 2001Kent C. New M.D., Ph.D. Abstract A 25-yr-old male presented with a cerebellar mass, underwent a suboccipital craniotomy, and was diagnosed with medulloblastoma. Six months later he developed a large mass in the right iliac crest. Fine-needle aspiration biopsy (FNAB) confirmed the diagnosis of metastatic medulloblastoma. The diagnosis of metastatic medulloblastoma is usually suspected clinically or radiographically, and is uncommonly confirmed by cytologic evaluation. Here we report on a rare case of FNAB used to diagnose metastatic medulloblastoma. Diagn. Cytopathol. 24:361,363, 2001. © 2001 Wiley-Liss, Inc. [source] Both CD133+ and CD133, medulloblastoma cell lines express ligands for triggering NK receptors and are susceptible to NK-mediated cytotoxicityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2007Roberta Castriconi Abstract Adoptive cellular immunotherapy has been proposed as an additional treatment of medulloblastoma, an intracranial tumor characterized by a particularly poor prognosis. However, little is known on the ability of the immune system to effectively attack this tumor. In this study, we show that activated human NK cells efficiently kill medulloblastoma cell lines in vitro. NK-mediated killing involved different activating receptors (including NKp46, NKp30, DNAM-1 and NKG2D) and correlated with the presence of their specific ligands on tumor cells. In contrast, the absence of major adhesion interactions, such as LFA-1/ICAM did not impair the NK-mediated cytotoxicity. Medulloblastoma expressed a number of tumor-associated molecules including CD146 and CD133, considered a marker for cancer stem cells. Remarkably, both CD133-positive and CD133-negative cell lines were susceptible to lysis. Tumor cells also expressed molecules that are currently used as diagnostic tools for neuroblastoma cell identification. In particular, B7 homolog 3 (B7-H3) was expressed by all the medulloblastoma cell lines analyzed, while the presence of GD2 and NB84 was restricted to given cell lines and/or marked a defined tumor cell subset. [source] Defining a role for Sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genesINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Joon Won Yoon Abstract A subgroup of medulloblastomas shows constitutive activation of the Sonic hedgehog pathway with expression of GLI1. We identified the subset of GLI1 transforming target genes specifically expressed in medulloblastomas by comparing GLI1 targets in RK3E cells transformed by GLI1 with the gene expression profile of Sonic hedgehog signature medulloblastomas. We identified 1,823 genes whose expression was altered more than 2-fold in 2 independent RK3E + GLI1 cell lines. We identified 25 whose expression was altered similarly in medulloblastomas expressing GLI1. We identified potential GLI binding elements in the regulatory regions of 10 of these genes, confirmed that GLI1 binds the regulatory regions and activates transcription of select genes, and showed that GLI1 directly represses transcription of Krox-20. We identified upregulation of CXCR4, a chemokine receptor that plays roles in the proliferation and migration of granule cell neuron precursors during development, supporting the concept that reinitiation of developmental programs may contribute to medulloblastoma tumorigenesis. In addition, the targets suggest a pathway through which GLI1 may ultimately affect medulloblastoma cell proliferation, survival and genomic stability by converging on p53, SGK1, MGMT and NTRK2. We identify a p53 mutation in RK3E + GLI1 cells, suggesting that p53 mutations may sometimes shift the balance toward dysregulated tumor cell survival. © 2008 Wiley-Liss, Inc. [source] Various components of the insulin-like growth factor system in tumor tissue, cerebrospinal fluid and peripheral blood of pediatric medulloblastoma and ependymoma patientsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2008Judith M. de Bont Abstract The insulin-like growth factor (IGF) system plays an important role in neuronal development and may contribute to the development of brain tumors. In this study, we studied mRNA expression levels of IGFs, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor receptors (IGFRs) in 27 pediatric medulloblastomas, 13 pediatric ependymomas and 5 control cerebella. Compared to normal cerebellum, mRNA levels of IGFBP-2 and IGFBP-3 were significantly increased in medulloblastomas and ependymomas. IGFBP-2 expression was indicative of poor prognosis in medulloblastomas, whereas IGFBP-3 mRNA levels were especially high in anaplastic ependymomas. IGFBP-5 and IGF-II mRNA levels were significantly increased in ependymomas compared to control cerebellum. Protein expression levels of IGFs and IGFBPs were analyzed in the cerebrospinal fluid (CSF) of 16 medulloblastoma, 4 ependymoma and 23 control patients by radioimmuno assay to determine whether they could be used as markers for residual disease after surgery. No aberrant CSF protein expression levels were found for ependymoma patients. In medulloblastoma patients, the IGFBP-3 protein levels were significantly higher than in ependymoma patients and controls. Moreover, enhanced levels of proteolytic fragments of IGFBP-3 were found in the CSF of medulloblastoma patients, being in concordance with a significantly increased IGFBP-3 proteolytic activity in the CSF of these patients. In conclusion, our data suggest that the IGF system is of importance in pediatric medulloblastomas and ependymomas. Larger studies should be conducted to validate the predictive values of the levels of intact IGFBP-3 and proteolytic fragments in CSF in the follow-up of medulloblastomas. © 2008 Wiley-Liss, Inc. [source] Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomasINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008Suely K.N. Marie Abstract We have performed cDNA microarray analyses to identify gene expression differences between highly invasive glioblastoma multiforme (GBM) and typically benign pilocytic astrocytomas (PA). Despite the significant clinical and pathological differences between the 2 tumor types, only 63 genes were found to exhibit 2-fold or greater overexpression in GBM as compared to PA. Forty percent of these genes are related to the regulation of the cell cycle and mitosis. QT-PCR validation of 6 overexpressed genes: MELK, AUKB, ASPM, PRC1, IL13RA2 and KIAA0101 confirmed at least a 5-fold increase in the average expression levels in GBM. Maternal embryonic leucine zipper kinase (MELK) exhibited the most statistically significant difference. A more detailed investigation of MELK expression was undertaken to study its oncogenic relevance. In the examination of more than 100 tumors of the central nervous system, we found progressively higher expression of MELK with astrocytoma grade and a noteworthy uniformity of high level expression in GBM. Similar level of overexpression was also observed in medulloblastoma. We found neither gene promoter hypomethylation nor amplification to be a factor in MELK expression, but were able to demonstrate that MELK knockdown in malignant astrocytoma cell lines caused a reduction in proliferation and anchorage-independent growth in in vitro assays. Our results indicate that GBM and PA differ by the expression of surprisingly few genes. Among them, MELK correlated with malignancy grade in astrocytomas and represents a therapeutic target for the management of the most frequent brain tumors in adult and children. © 2007 Wiley-Liss, Inc. [source] KEYNOTE ADDRESS Ku80-deletion causes early ageing and suppresses cancerJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 2 2009P. Hasty Ageing is widespread cellular decline resulting in a loss of fitness that is both pleiotropic and stochastic and influenced by both genetics and environment. As a result the fundamental underling causes of ageing are diverse and controversial. One potential ageing target is nuclear DNA, as it is a permanent blueprint that controls cellular processes. Thus, DNA replication and genome maintenance are highly regulated events that ensure faithful reproduction and maintenance of the blueprint and these pathways assure sufficient longevity for reproduction and survival of the species. As a consequence, imperfections or defects in maintaining the genome may contribute to ageing. Therefore, genome maintenance pathways are longevity-assurance mechanisms that sustain an organism long enough to reproduce and propagate. Chief among these mechanisms are those that respond to damaged DNA. There are two basics responses to genomic damage: DNA repair and cell cycle checkpoints. Both are considered to be tumour suppressors and are categorized as either caretakers or gatekeepers, respectively. Interestingly, observations of human and mouse pre-mature ageing models suggest these anti-tumour pathways impact the ageing process. Caretakers suppress cancer by repairing DNA damage caused by defects in replication or by a variety of agents including endogenously produced reactive by-products of oxygen metabolism and exogenous agents naturally encountered in our environment. As a consequence DNA is subject to a variety of insults that cause a diverse range of lesions and phenotypic outcomes. There are many forms of DNA damage including base lesions and double-strand breaks (DSBs) with the latter being more toxic. Cancer-causing chromosomal rearrangements may result if DSBs are not repaired properly. Additionally, an accumulation of these rearrangements may contribute to ageing since they increase in some cell types as humans and mice age. Furthermore, early ageing models suggest that defects in repairing DSBs lead to early ageing in humans and mice. Non-homologous end joining (NHEJ) is an important pathway for repairing DNA DSBs and is considered a caretaker. The Ku heterodimer (composed of Ku70 and Ku80) binds to DNA ends to initiate NHEJ, and defects in either Ku70 or Ku80 lead to increased levels of DNA DSBs and chromosomal rearrangements, leading many to believe Ku is a caretaker. Ku-mutant mice display increased GCRs, but without increased cancer. Instead, these mice show early ageing and shortened life span. Thus, Ku's role as a caretaker is uncertain as the low cancer levels may be due to Ku80-deletion or, instead, the low cancer levels may simply be a consequence of the shortened life span that prohibits sufficient time for tumours to develop. Gatekeepers respond to DNA damage by halting the cell cycle long enough for the DNA to be repaired. If the damage is irreparable, gatekeepers induce either apoptosis or senescence. These responses are deleterious to the cell but protect the organism from cancer as one potential outcome of genetic mutations is uncontrolled proliferation. p53 is critical for checkpoints and is the best-known gatekeeper because it is mutated in over half of all cancers. In addition, p53 activity influences many aspects of the Ku-mutant phenotype suggesting that Ku-deletion leads to persistent p53-mediated responses and presenting the possibility that low cancer levels and early ageing are caused by elevated gatekeeper responses. Our hypothesis is that Ku-mutant mice exhibit low cancer levels and, perhaps, ageing due to persistent p53-mediated responses to inefficiently repaired DNA. To test this hypothesis, Ku80-mutant mice were crossed to cancer-prone mice with either non-functional or functional gatekeeper responses. Ku80-mutant mice were crossed to p53-mutant mice to determine if Ku80-deletion exacerbates oncogenesis when gatekeeper responses are diminished. Ku80-mutant mice deleted for p53 exhibit early onset and high levels of two forms of cancer: pro-B cell lymphoma and medulloblastoma, thus supporting the hypothesis. Ku80-mutant mice were also crossed to APCMIN mice to determine if Ku80-deletion ameliorates oncogenesis gatekeeper responses are intact. APCMIN mice exhibit high levels of intestinal adenomas and adenocarcinomas but have normal p53-mediated responses to DNA damage. APCMIN mice, deleted for Ku80, exhibit about 67% fewer tumours than APCMIN mice with Ku80. Thus, deletion of Ku80 suppresses tumour formation, again supporting the hypothesis. Ku80-mutant cells and tissues were tested for p53-mediated DNA damage responses, levels of DNA damage, and mutations. Ku80-mutant fibroblasts exhibit elevated levels of p53-mediated DNA damage responses that increase p21-mediated cellular senescence. In addition, there are elevated levels DNA damage as seen by increased 53BP1 foci and elevated levels of chromosomal rearrangements. Thus, these data support the hypothesis that Ku80-deletion reduces tumors by elevating DNA damage gatekeeper responses to inefficiently repaired DNA. These data also support the possibility that the Ku80-mutant ageing phenotype is also due to elevated gatekeeper responses. [source] Pathogenesis of medulloblastoma and current treatment outlookMEDICINAL RESEARCH REVIEWS, Issue 6 2007Jaroslaw Jozwiak Abstract Medulloblastoma is the most common malignant tumor of the cerebellum in children, with a tendency to metastasize via CSF pathway. Survival rate varies depending on several factors, but is rather favorable, with radiotherapy as the treatment of choice. Irradiation of the craniospinal axis results, however, in severe neuropsychological and psychosocial impairments pertaining to memory, attention, motor functioning, language, and visuospatial abilities. Precise mechanisms underlying the formation of medulloblastoma are still unclear, but implication of at least three signaling molecules is postulated: insulin-like growth factor-I, WNT, and Sonic hedgehog. Thanks to increasing knowledge on the cellular mechanisms contributing to tumor formation, it is possible to propose new therapies that could replace radiotherapy or allow decreasing irradiation doses. The current review presents recent developments in medulloblastoma pathophysiology research and proposed inhibitors that could constitute good candidates for further pharmacological research. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 6, 869,890, 2007 [source] Tumor suppressor gene Co-operativity in compound Patched1 and suppressor of fused heterozygous mutant miceMOLECULAR CARCINOGENESIS, Issue 5 2009Jessica Svärd Abstract Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1+/, mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu+/, mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tumor development in Sufu+/,Ptch1+/, mice to determine the effect of compound heterozygosity on the onset, incidence, and spectrum of tumors. We found significantly more (2.3-fold) basaloid proliferations in Sufu+/,Ptch1+/, compared to Sufu+/, female, but not male, mice. For medulloblastoma, the cumulative 1-yr incidence was 1.5-fold higher in Sufu+/,Ptch1+/, compared to Ptch1+/, female mice but this strong trend was not statistically significant. Together this suggests a weak genetic interaction of the two tumor suppressor genes. We noted a few rhabdomyosarcomas and pancreatic cysts in the Sufu+/,Ptch1+/, mice, but the numbers were not significantly different from the single heterozygous mice. Hydrocephalus developed in ,20% of the Ptch1+/, and Sufu+/,Ptch1+/, but not in Sufu+/, mice. Interestingly, most of the medulloblastomas from the Sufu+/,Ptch1+/, mice had lost expression of the remaining Ptch1 wild-type allele but not the Sufu wild-type allele. On the contrary, Sufu as well as Gli1 and Gli2 expression was upregulated in the medulloblastomas compared to adult cerebellum in Ptch1+/, and Sufu+/,Ptch1+/, mice. This suggests that Sufu expression may be regulated by Hedgehog pathway activity and could constitute another negative feedback loop in the pathway. © 2008 Wiley-Liss, Inc. [source] Melanocytic medulloblastoma with ganglioneurocytomatous differentiation: A case reportNEUROPATHOLOGY, Issue 1 2009Kanako C. Kubota Melanotic or melanocytic medulloblastoma is a rare variant of medulloblastoma, especially when the tumor shows advanced neuronal differentiation. We report a case of this tumor, which developed in the cerebellar vermis in an 8-year-old girl. Initial biopsy specimens were identified as classical medulloblastoma with a high MIB1 index. Surgical removal of the tumor was performed after chemo-radiotherapy, and black pigments were noticed on the tumor surface. Histologically, the tumor was composed of classical medulloblastoma with the presence of pigmented epithelial cells forming tubules and clusters. Immunohistochemically, the pigmented tumor cells were positive for S100 protein, HMB45, and MART1, indicating that the pigments were derived from melanosomes, and these features were compatible with melanocytic medulloblastoma. Interestingly, some of the non-pigmented or amelanotic tumor cells were also positive for HMB45 and S100 protein. Although the tumor showed an unusual cell combination, it was distinguished from atypical teratoid/rhabdoid tumor (AT/RT) by nuclear expression of INI1/BAF45 protein. The tumor also possessed ganglion-like cells within the neuropil matrix, which resembled small mature ganglion cells, and was consequently designated as ganglioneurocytoma. The melanotic medulloblastoma and part of the ganglioneurocytomatous area were fused with each other. Hence, the present case provides new information indicating that melanocytic medulloblastoma differs from AT/RT, and that it can exhibit advanced neuronal differentiation. In addition, reduction of the tumor MIB1 index was observed after chemo-radiotherapy. [source] Classifying the medulloblastoma: insights from morphology and molecular geneticsNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2002D. Ellison Significant advances in the treatment of the medulloblastoma (MB) have been made in the last 30 years, reducing mortality by 2-fold. Further improvements in the cure rate require an increased understanding of the biology of MBs, and this will translate into refinements in their classification. Scrutiny of the cytological variation found among MBs has recently led to the concept of the anaplastic MB, which overlaps the large-cell variant and appears to share its poor prognosis. In contrast, the MB with extensive nodularity, a distinctive nodular/desmoplastic variant occurring in infants, has a better outcome than most MBs in these young patients. Building on cytogenetic studies that have drawn attention to abnormalities on chromosome 17 in over a third of MBs, research shows non-random losses on chromosomes 8, 9, 10, 11 and 16, and gains on chromosomes 1, 7 and 9. Overexpression of ErbB2 receptors and losses on chromosome 17p have been proposed as independent indicators of aggressive behaviour, while high TrkC receptor expression indicates a favourable outcome. There is a strong association between anaplastic/large-cell tumours and MYC amplification, which has previously been linked with aggressive disease, but associations between abnormalities on chromosome 17 and anaplastic/large-cell MBs and between abnormalities in the shh/PTCH pathway and the desmoplastic variant are more controversial. Classification of the MB histopathologically and according to profiles of molecular abnormalities will help both to rationalize approaches to therapy, increasing the cure rate and reducing long-term side-effects, and to suggest novel treatments. [source] In vitro, high-resolution 1H and 31P NMR based analysis of the lipid components in the tissue, serum, and CSF of the patients with primary brain tumors: one possible diagnostic viewNMR IN BIOMEDICINE, Issue 2 2010Niraj Kumar Srivastava Abstract In vitro, high-resolution 1H and 31P NMR based qualitative and quantitative analyses of the lipid components of the tissue, serum, and CSF of patients with primary brain tumors were performed. Proton NMR spectra of the lipid extract of serum (blood specimen collected before the surgical procedure) and surgically discarded tissue showed that the total cholesterol (T.CHOL) and choline containing phospholipids (PL) were significantly higher in quantity in medulloblastoma and glioblastoma multiforme as compared to normal subjects. Serum lipid extracts of grade II/ III gliomas showed a higher quantity of PL than normal subjects. Cholestrol esters (CHOLest) were detectable in the tissue lipid extract of the patients with tumors and absent in normal tissue. There was a reduction in the quantity of CHOLest in the serum lipid extract of the tumor patients as compared to normal subjects. Ratio of PL to T.CHOL in serum lipid extract showed a significant difference between different grades of tumors versus normal subjects, while, a significant difference was observed only in medulloblastoma versus normal subjects in tissue lipid extract. Ratio of CHOL to CHOLest distinguishes the different grades of tumors versus normal subjects as well as between different grades of tumors (except medulloblastoma versus glioblastoma). The ratio of the Ph (total phospholipids except phosphatidylcholine) to PC (phosphatidylcholine) in 31P NMR based study showed a significant difference in all grades of tumors (except medulloblastoma) in normal subjects in tissue lipid extract as well as between different grades of tumors. Medulloblastoma could be differentiated from glioblastoma as well as from normal subjects in serum lipid extract by the ratio of the Ph to PC. Proton NMR spectra of the lipid extract of CSF showed that the CHOL, CHOLest, and PL were present in the patients with tumors, although these were absent in the patients with meningitis, motor neuron disease, and mitochondrial myopathies as well as in normal subjects. PL and T.CHOL provided discrimination between different grades of tumors (except glioblastoma versus medulloblastoma) in the lipid extract of the CSF. This study suggests the role of lipid estimation in CSF and serum as a complementary diagnostic tool for the evaluation of brain tumors preoperatively. NMR-based lipid estimation of post-surgical tumor tissue may also contribute to differentiating the tumor types. Copyright © 2009 John Wiley & Sons, Ltd. [source] Near total effacement of bone marrow by medulloblastoma,AMERICAN JOURNAL OF HEMATOLOGY, Issue 2 2010Parameswaran Anoop No abstract is available for this article. [source] Anaesthetic management of a child with a positive family history of malignant hyperthermia for posterior fossa surgery in the sitting positionPEDIATRIC ANESTHESIA, Issue 4 2001M.A. Wootton FRCA A 6-year-old boy with a positive family history of malignant hyperthermia presented for posterior fossa craniectomy and excision of medulloblastoma. A nontriggering anaesthetic was therefore planned using infusions of propofol and remifentanil and a vapour free anaesthetic system delivering an oxygen/air mixture. The surgery was carried out with the child in the sitting position. [source] Initial testing of the aurora kinase a inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP),PEDIATRIC BLOOD & CANCER, Issue 1 2010John M. Maris MD Abstract Background MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA) that is currently in early phase clinical testing. AURKA plays a pivotal role in centrosome maturation and spindle formation during mitosis. Procedures MLN8237 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0,nM to 10,µM and was tested against the PPTP in vivo panels at a dose of 20,mg/kg administered orally twice daily,×,5 days. Treatment duration was 6 weeks for solid tumor xenografts and 3 weeks for ALL xenografts. Results MLN8237 had a median IC50 of 61,nM against the PPTP in vitro panel. The ALL cell lines were more sensitive and the rhabdomyosarcoma cell lines less sensitive than the remaining PPTP cell lines. In vivo, MLN8237 induced significant differences in event-free survival (EFS) distributions compared to controls in 32/40 (80%) solid tumor models and all (6/6) ALL models. Maintained complete responses (CRs) were observed in 3 of 7 neuroblastoma xenografts, and all 6 evaluable ALL xenografts achieved CR (n,=,4) or maintained CR (n,=,2) status. Maintained CRs were observed among single xenografts in other panels, including the Wilms tumor, rhabdoid tumor, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, and medulloblastoma. Conclusions The in vivo activity observed against the neuroblastoma panel far exceeds that observed for standard agents evaluated against the panel by the PPTP. High levels of in vivo activity were also observed against the ALL xenograft panel. These data support expedited clinical development of MLN8237 in childhood cancer. Pediatr Blood Cancer 2010;55:26,34. © 2010 Wiley-Liss, Inc. [source] Inhibition of Aurora Kinase A enhances chemosensitivity of medulloblastoma cell lines,PEDIATRIC BLOOD & CANCER, Issue 1 2010Ayman El-Sheikh MD Abstract Background Medulloblastoma comprises approximately 20% of all primary pediatric brain tumors. Despite recent advances, the survival rate for high-risk patients and the morbidity associated with these treatments remains suboptimal. To improve outcomes and decrease morbidity, more targeted therapy is required. One possible target is the Aurora Kinase family. The objective of this study was to evaluate the impact of Aurora Kinase A inhibition in medulloblastoma cell lines. Procedure Cell proliferation was measured using an MTS assay after adding an Aurora Kinase inhibitor (C1368) at different concentrations. Cell cycle analysis was carried out by Flow Cytometry using propidium iodide (PI). RNAi experiments were performed using siRNA oligonucleotides. Luciferase experiments were carried out using the Cignal Finder 10 Pathway Reporter Arrays. Results Inhibition of Aurora Kinase A induces cell death in medulloblastoma cells and lowers the IC50 of other chemotherapeutic agents (etoposide and cisplatin) used in medulloblastoma treatment. Cell arrest at G2/M phase was significantly increased in medulloblastoma cell lines treated with C1368 Sigma at IC30 or transfected siRNA. Inhibition of Aurora Kinase A resulted in decreased activity of pro-proliferative signaling pathways including Wnt, Myc, and RB as measured by luciferase reporter assays. Conclusions These data indicate that inhibition of Aurora Kinase A inhibits cell growth in medulloblastoma through inhibition of pro-proliferative signaling pathways Wnt, Myc, and RB. Additionally, combining Aurora Kinase A inhibition with other chemotherapeutic agents significantly lowers their IC50, which make it a promising small molecule target for medulloblastoma therapy. Pediatr Blood Cancer 2010;55:35,41. © 2010 Wiley-Liss, Inc. [source] PARP1 expression in pediatric central nervous system tumors,PEDIATRIC BLOOD & CANCER, Issue 7 2009Valerie N. Barton BA Abstract Background Despite advances in therapy, outcome in many high-grade pediatric central nervous system (CNS) tumors remains poor. The focus of neuro-oncology research has thus turned towards identifying novel therapeutic targets. Poly(ADP-ribose) polymerase-1 (PARP1) is a DNA repair protein that has been studied in a variety of malignancies and may interfere with therapy-induced DNA damage, however expression in pediatric CNS tumors is unknown. Procedure We evaluated PARP1 mRNA expression in 81 pediatric CNS tumors using microarray technology. Protein expression was examined by Western blot. Results PARP1 mRNA is highly expressed in high-grade tumors (P,<,0.0001). PARP1 mRNA expression was greater in high-grade glioma than pilocytic astrocytoma (P,=,3.5,×,10,5) and in large cell medulloblastoma over classic medulloblastoma (P,=,0.0053). PARP1 protein was also prominent in high-grade tumors (P,=,0.022). Conclusion These findings indicate that PARP1 is expressed in high-grade pediatric CNS tumors, implicating PARP1 inhibition as a potential therapeutic target. Pediatr Blood Cancer 2009; 53:1227,1230. © 2009 Wiley-Liss, Inc. [source] Nutritional problems in children treated for medulloblastoma: Implications for enteral nutrition supportPEDIATRIC BLOOD & CANCER, Issue 4 2009Evelyn Ward BSc Abstract Background The aim of this study was to identify the nature and severity of nutritional problems associated with the current treatment of medulloblastoma and to identify any risk factors for nutritional morbidity during treatment. Procedure A multicentre retrospective audit of medical and dietetic notes of 41 children treated for medulloblastoma in three UK paediatric oncology centres was undertaken. Data on nutritional status, nutritional support, mutism, swallowing and common toxicity criteria (CTC) scores for vomiting, constipation and mobility were collected at defined points in treatment from diagnosis until 12 months post-treatment. Results Significant problems including weight loss, vomiting and constipation were highlighted early on in treatment. The majority of patients were well nourished at diagnosis with a mean percentage weight: height of 99.8%, however nutritional status started to decline early in treatment during radiotherapy, coinciding with 49% of patients having grade 1 or above CTC score for vomiting and constipation. The decline in nutritional status continued, peaking by course 2 of chemotherapy with a mean weight loss of 8.2% since diagnosis. Proactive supplementary feeding early in treatment by one of the three centres demonstrated a superior nutritional outcome when compared statistically to the two centres that fed only as a response to nutritional decline. Conclusion The study highlighted significant morbidity associated with the current treatment of medulloblastoma. Findings suggest the need to consider earlier proactive nutritional intervention to prevent nutritional decline during treatment. These early nutritional problems may be related to toxicities of radiotherapy and concomitant vincristine. Pediatr Blood Cancer 2009;53:570,575. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||