Anesthesia Exposure during Therapy Predicts Neurocognitive Outcomes in Survivors of Childhood Medulloblastoma.

OBJECTIVE: To examine the contribution of anesthesia exposure during treatment for childhood medulloblastoma to neurocognitive outcomes 3 years after tumor diagnosis. STUDY DESIGN: In this retrospective study, anesthesia data were abstracted from medical records for 111 patients treated with risk-adapted protocol therapy at St Jude Children's Research Hospital. Neurocognitive testing data were obtained for 90.9% of patients. RESULTS: For the 101 patients (62.4% male) who completed testing, mean age at diagnosis was 10.1 years, and 74.3% were staged to have average-risk disease. Anesthesia exposure during treatment ranged from 1 to 52 events (mean = 19.9); mean cumulative duration per patient was 21.1 hours (range 0.7-59.7). Compared with normative expectations (16%), the group had a significantly greater frequency of at-risk scores (<1 SD) on measures of intelligence (28.7%), attention (35.2%), working memory (26.6%), processing speed (46.7%), and reading (25.8%). Including anesthesia exposure duration to linear regression models accounting for age at diagnosis, treatment intensity, and baseline IQ significantly increased the predicted variance for intelligence (r2 = 0.59), attention (r2 = 0.29), working memory (r2 = 0.31), processing speed (r2 = 0.44), and reading (r2 = 0.25; all P values <.001). CONCLUSIONS: In survivors of childhood medulloblastoma, a neurodevelopmentally vulnerable population, greater exposure to anesthesia significantly and independently predicts deficits in neurocognitive and academic functioning. When feasible, anesthesia exposure during treatment should be reduced.

Medulloblastoma in a calf of the flemish breed / Meduloblastoma em bezerro da raça Flamenga

Medulloblastomas are neuroectodermal tumors of embryonic origin developing in cerebellum and spinal cord and have an unusual occurrence. When occurs in cattle, it is observed in neonatal cases, leading to multiple neurological clinical signs. Flemish cattle are considered at risk of extinction and the rare specimens of Brazil are in Lages, Santa Catarina. The case of a two-month-old calf with difficulty to remain in a standing position, imbalance, opisthotonus, strabismus, and broad-based gait is described in this study. The animal was euthanized and the necropsy showed an irregular, whitish pink, and friable mass in the cerebellar vermis region, measuring 5×6×3.8 cm associated with the dilation of the lateral ventricles, which extended through the interventricular foramen, midbrain aqueduct, and fourth ventricle. Histologically, it presented elongated triangular neuronal cells arranged in a dense sheet that sometimes encircled small areas of neuropil to form Homer-Wright pseudorosettes. These tumor characteristics were compatible with a medulloblastoma. The immunohistochemical (IHC) evaluation of the tumor demonstrated a positive staining for vimentin in neoplastic cells and glial fibrillary acidic protein in neoplastic stromal cells, non-reactive for synaptophysin, and negative for S100 protein and pan-cytokeratin. The histological and topographical characteristics were paramount for determining the medulloblastoma diagnosis and the IHC panl is similar to that observed in other studies. Tumor growth is limited by skull bony structures, allowing determining that the clinical signs expressed by the animal were directly related to the compression of important functional structures due to tumor expansion. Medulloblastoma is an unusual tumor in all animal species, not previously reported in Flemish cattle, and necropsy followed by histopathological examination is essential for diagnosis.(AU)

Meduloblastomas são tumores da neuroectoderme com origem embrionária, que se desenvolvem no cerebelo e na medula espinhal com ocorrência incomum. Quando ocorre em bovinos é observado em casos neonatal, levando a múltiplos sinais clínicos neurológicos. Os bovinos da raça Flamenga estão considerados em risco de extinção e os raros exemplares do Brasil estão localizados em Lages, Santa Catarina. Descreve-se o caso de um bezerro com dois meses de idade, apresentando dificuldade para manter-se em estação, desequilíbrio, opistótono, estrabismo e caminhar em base ampla. O animal foi submetido a eutanásia e na necropsia observou-se na região do vérmis do cerebelo uma massa irregular, rosa esbranquiçada e friável, medindo 5x6x3,8cm associado a dilatação dos ventrículos laterais, que prolongava pelo forame interventricular, aqueduto do mesencéfalo e IV ventrículo. Histologicamente, observava células neuronais triangulares alongadas organizadas em um lençol denso, que às vezes circundavam pequenas áreas de neurópilo para formar pseudorosetas de Homer-Wright, estas características do tumor eram compatíveis com um meduloblastoma. A avaliação imuno-histoquímica (IHQ) do tumor demonstrou marcação positiva para vimentina em células neoplásicas e para proteína glial fibrilar ácida em células do estroma neoplásico, não reagente para sinaptofisina e negativo para proteína S100 e pan-citoqueratina. As características histológicas e topográficas foram primordiais para a determinação do diagnóstico de meduloblastoma e o painel IHQ é semelhante à observada em outros trabalhos. O crescimento do tumor é limitado pelas estruturas ósseas do crânio, permitindo determinar que os sinais clínicos expressos pelo animal estavam diretamente relacionados com a compressão de estruturas funcionais importantes em decorrência da expansão tumoral.(AU)

Medulloblastoma in a calf of the flemish breed / Meduloblastoma em bezerro da raça Flamenga

Medulloblastomas are neuroectodermal tumors of embryonic origin developing in cerebellum and spinal cord and have an unusual occurrence. When occurs in cattle, it is observed in neonatal cases, leading to multiple neurological clinical signs. Flemish cattle are considered at risk of extinction and the rare specimens of Brazil are in Lages, Santa Catarina. The case of a two-month-old calf with difficulty to remain in a standing position, imbalance, opisthotonus, strabismus, and broad-based gait is described in this study. The animal was euthanized and the necropsy showed an irregular, whitish pink, and friable mass in the cerebellar vermis region, measuring 5×6×3.8 cm associated with the dilation of the lateral ventricles, which extended through the interventricular foramen, midbrain aqueduct, and fourth ventricle. Histologically, it presented elongated triangular neuronal cells arranged in a dense sheet that sometimes encircled small areas of neuropil to form Homer-Wright pseudorosettes. These tumor characteristics were compatible with a medulloblastoma. The immunohistochemical (IHC) evaluation of the tumor demonstrated a positive staining for vimentin in neoplastic cells and glial fibrillary acidic protein in neoplastic stromal cells, non-reactive for synaptophysin, and negative for S100 protein and pan-cytokeratin. The histological and topographical characteristics were paramount for determining the medulloblastoma diagnosis and the IHC panl is similar to that observed in other studies. Tumor growth is limited by skull bony structures, allowing determining that the clinical signs expressed by the animal were directly related to the compression of important functional structures due to tumor expansion. Medulloblastoma is an unusual tumor in all animal species, not previously reported in Flemish cattle, and necropsy followed by histopathological examination is essential for diagnosis.

Meduloblastomas são tumores da neuroectoderme com origem embrionária, que se desenvolvem no cerebelo e na medula espinhal com ocorrência incomum. Quando ocorre em bovinos é observado em casos neonatal, levando a múltiplos sinais clínicos neurológicos. Os bovinos da raça Flamenga estão considerados em risco de extinção e os raros exemplares do Brasil estão localizados em Lages, Santa Catarina. Descreve-se o caso de um bezerro com dois meses de idade, apresentando dificuldade para manter-se em estação, desequilíbrio, opistótono, estrabismo e caminhar em base ampla. O animal foi submetido a eutanásia e na necropsia observou-se na região do vérmis do cerebelo uma massa irregular, rosa esbranquiçada e friável, medindo 5x6x3,8cm associado a dilatação dos ventrículos laterais, que prolongava pelo forame interventricular, aqueduto do mesencéfalo e IV ventrículo. Histologicamente, observava células neuronais triangulares alongadas organizadas em um lençol denso, que às vezes circundavam pequenas áreas de neurópilo para formar pseudorosetas de Homer-Wright, estas características do tumor eram compatíveis com um meduloblastoma. A avaliação imuno-histoquímica (IHQ) do tumor demonstrou marcação positiva para vimentina em células neoplásicas e para proteína glial fibrilar ácida em células do estroma neoplásico, não reagente para sinaptofisina e negativo para proteína S100 e pan-citoqueratina. As características histológicas e topográficas foram primordiais para a determinação do diagnóstico de meduloblastoma e o painel IHQ é semelhante à observada em outros trabalhos. O crescimento do tumor é limitado pelas estruturas ósseas do crânio, permitindo determinar que os sinais clínicos expressos pelo animal estavam diretamente relacionados com a compressão de estruturas funcionais importantes em decorrência da expansão tumoral.

Brain Perfusion and Diffusion Abnormalities in Children Treated for Posterior Fossa Brain Tumors.

OBJECTIVE: To compare cerebral perfusion and diffusion in survivors of childhood posterior fossa brain tumor with neurologically normal controls and correlate differences with cognitive dysfunction. STUDY DESIGN: We analyzed retrospectively arterial spin-labeled cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) in 21 patients with medulloblastoma (MB), 18 patients with pilocytic astrocytoma (PA), and 64 neurologically normal children. We generated ANCOVA models to evaluate treatment effects on the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, and cerebral white matter at time points an average of 5.7 years after original diagnosis. A retrospective review of patient charts identified 12 patients with neurocognitive data and in whom the relationship between IQ and magnetic resonance imaging variables was assessed for each brain structure. RESULTS: Patients with MB (all treated with surgery, chemotherapy, and radiation) had significantly lower global CBF relative to controls (10%-23% lower, varying by anatomic region, all adjusted P?

Metastasis-associated gene 1 expression in human medulloblastoma and its association with invasion and metastasis in medulloblastoma Daoy cell lines.

This study aims to investigate the expression of metastasis-associated gene 1 (MTA1) in human medulloblastoma, and its significance in the invasion and metastasis in a medulloblastoma cell line. Positive expression rate of MTA1 protein in medulloblastoma and adjacent normal tissues collected from 29 medulloblastoma patients was detected by immunohistochemistry assay in vivo. In in vitro experiments, Daoy cells were transfected with MTA1-targeted small interfering RNA (siRNA, MTA1-siRNA group), niRNA (MTA1-niRNA group), and plasmid vectors (control group). Transfection efficiency was evaluated by PT-PCR and western blot; cell adhesion, migration, and invasion capacity was assessed by adhesion assays, scratch assays, and transwell chamber invasion assays, respectively. Results indicated that the positive expression rate of MTA1 protein in the medulloblastoma tissues was higher as compared with that of the adjacent normal tissues (P < 0.05). In addition, mRNA and protein expression of MTA1 in the MTA1-siRNA group was lower than that in the control and MTA1- niRNA groups (P < 0.05). Adhesion, migration, and invasion capacity of Daoy cells in the MTA1-siRNA group was inhibited as compared with the control and MTA1-niRNA groups (P < 0.05). In conclusion, MTA1 expression was increased in medulloblastoma cells, while MTA1 knockdown in medulloblastoma cells inhibited MTA1 expression. In addition, MTA1 knockdown inhibited the adhesion, migration, and invasive capabilities of medulloblastoma cells. It is possible that MTA1 can serve as a biomarker and a potential therapeutic target for medulloblastoma.

Cancer stem cells and the biology of brain tumors.

There is now compelling evidence that brain tumors harbor a small population of cells characterized by their ability to undergo self-renewal and initiate tumors, termed cancer stem cells (CSCs). The development of therapeutic strategies targeted towards CSC signaling may improve the treatment of brain tumors such as malignant gliomas and medulloblastomas. Here we review the role of cancer stem cells in glioma and medulloblastoma and some of the signaling mechanisms involved in brain tumor stem cell (BTSC) biology, and discuss how these signaling pathways may represent new stem cell targets for the treatment of brain tumors. In addition, we provide illustrative immunohistochemical data on the presence of BTSCs in human gliomas and medulloblastomas, and show preliminary findings suggesting the involvement of a GPCR, the gastrin-releasing peptide receptor (GRPR), in the expansion of BTSCs in vitro.

MRI of medulloblastoma in adults.

Medulloblastoma has variable appearances on MRI in both children and adults. Adults are more likely to have heterogeneous cerebellar hemisphere tumours, and this is thought to be related to the greater prevalence of desmoplastic tumours in adulthood. Few studies have addressed the MRI features of adult medulloblastoma and the specific characteristics of desmoplastic and classic tumours have not been analysed. Our aim was to analyse the imaging characteristics of desmoplastic (DM) and classic (CM) medulloblastomas in adult. We retrospectively studied preoperative MRI of six men and three women, median age 33 years, range 23-53 years, with pathologically proved medulloblastomas. There were six (67%) with DM. The tumour was in the cerebellar hemisphere in eight patients (89%), including the three with CM, one of which was bilateral. All tumours were heterogeneous, giving predominantly low or isointense signal on T1- and isointense signal on T2-weighted images. Cystic or necrotic areas in all patients were particularly visible on T2-weighted images. Contrast enhancement was absent in one DM and varied from slight to intense in eight (three CM), homogeneous in one DM and patchy in seven. All tumours extended to the surface of the cerebellum and two had well-defined margins. MRI does not allow a clear distinction between DM and CM in adults.

Primary gonadal damage following treatment of brain tumors in childhood.

Gonadal function was studied in two groups of children previously treated for medulloblastoma with surgery followed by postoperative craniospinal irradiation. In group 1 but not in group 2, the children also received adjuvant chemotherapy for one to two years. All children in group 1 received a nitrosourea (BCNU or CCNU), plus vincristine in four and procarbazine in three patients. The nine children in group 1 showed clinical and biochemical evidence of gonadal damage with elevated serum FSH concentrations and, in the boys, small testes for their stage of pubertal development. In group 2 (n = 8), each child had completed pubertal development normally, the boys had adult sized testes and the girls regular menses. Gonadotropin values were normal in all eight children. We conclude that nitrosoureas were responsible for the gonadal damage in the children in group 1, with procarbazine also contributing to the damage in the three children who received this drug. In view of the limited proved value of adjuvant chemotherapy with nitrosoureas in the treatment of medulloblastoma, recognition of this serious complication of cytotoxic drug therapy may necessitate reassessing in which subgroups of children with medulloblastoma the benefits of adjuvant chemotherapy outweight the complications.