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Sample records for medulloblastoma

  1. Medulloblastoma.

    Science.gov (United States)

    Millard, Nathan E; De Braganca, Kevin C

    2016-10-01

    Medulloblastoma accounts for nearly 10% of all childhood brain tumors. These tumors occur exclusively in the posterior fossa and have the potential for leptomeningeal spread. Treatment includes a combination of surgery, radiation therapy (in patients >3 years old). Patients >3 years old are stratified based on the volume of postoperative residual tumor and the presence or absence of metastases into "standard risk" and "high risk" categories with long-term survival rates of approximately 85% and 70%, respectively. Outcomes are inferior in infants and children younger than 3 years with exception of those patients with the medulloblastoma with extensive nodularity histologic subtype. Treatment for medulloblastoma is associated with significant morbidity, especially in the youngest patients. Recent molecular subclassification of medulloblastoma has potential prognostic and therapeutic implications. Future incorporation of molecular subgroups into treatment protocols will hopefully improve both survival outcomes and posttreatment quality of life. © The Author(s) 2016.

  2. Medulloblastoma

    OpenAIRE

    Millard, Nathan E.; De Braganca, Kevin C.

    2015-01-01

    Medulloblastoma accounts for nearly 10% of all childhood brain tumors. These tumors occur exclusively in the posterior fossa and have the potential for leptomeningeal spread. Treatment includes a combination of surgery, radiation therapy (in patients > 3 years old). Patients > 3 years old are stratified based on the volume of postoperative residual tumor and the presence or absence of metastases into “standard risk” and “high risk” categories with long term survival rates of approximately 85%...

  3. Adult medulloblastoma

    OpenAIRE

    Rege S.V.; Patil Harshad; Narayan Sharadendu

    2016-01-01

    Medulloblastoma is a highly malignant central nervous system (CNS) tumor that arises from the cerebellum. It is the most common primary malignant intracranial childhood neoplasm. In adults, medulloblastoma are much less common, accounting for < 1% of all adult brain tumors. Herein, author has described a rare case of cerebellar medulloblastoma in adult.

  4. Cystic medulloblastoma

    International Nuclear Information System (INIS)

    Mahapatra, A.K.; Paul, H.K.; Sarkar, C.

    1989-01-01

    In children medulloblastoma is a commonly encountered posterior fossa midline tumour in which cystic degeneration is not uncommon. A cystic medulloblastoma without solid component has, however, not been described. We report a 12-year-old boy with a posterior fossa midline cystic lesion on CT with surgical and histological confirmation of the diagnosis. (orig.)

  5. [Medulloblastoma. Pathology].

    Science.gov (United States)

    Siegfried, A; Delisle, M-B

    2018-04-24

    Medulloblastomas, embryonal neuroepithelial tumors developed in the cerebellum or brain stem, are mainly observed in childhood. The treatment of WHO-Grade IV tumors depends on stratifications that are usually based on postoperative data, histopathological subtype, tumor extension and presence of MYC or NMYC amplifications. Recently, molecular biology studies, based on new technologies (i.e. sequencing, transcriptomic, methylomic) have introduced genetic subtypes integrated into the latest WHO-2016 neuropathological classification. According to this classification, the three genetic groups WNT, SHH, with or without mutated TP53 gene, and non-WNT/non-SHH, comprising subgroups 3 and 4, are recalled in this review. The contribution of immunohistochemistry to define these groups is specified. The four histopathological groups are detailed in comparison to the WHO-2007 classification and the molecular data: classic medulloblastoma, desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, and large cell/anaplastic medulloblastoma. The groups defined on genetic and histopathological grounds are not strictly concordant. Depending on the age of the patients, their correlations are different, as well as their role in the management and prognosis of these tumors. Other embryonal tumors, for which new classifications are in progress and gliomas may be confused with a medulloblastoma and the elements of the differential diagnosis of these entities are discussed. This evolution in classification fully justifies ongoing structuring procedures such as histopathological review (RENOCLIP) and the organization of molecular biology platforms. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  6. Adult patient with medulloblastoma

    International Nuclear Information System (INIS)

    Mejia, Luis Fernando; Fabian, Neira

    2005-01-01

    The medulloblastoma is the most frequent tumor in the pediatric population but is infrequent in adults. If we find a hyper dense lesion that compromises the cerebellum in an adult, first we have to think in metastasis, hemangioblastoma, astrocytoma and less frequently in the medulloblastoma. The desmoplasic subtype is the most prevalent variety in adult populations. Simple computed tomography regularly shows a medulloblastoma as a hyperattenuated lesion located in the cerebellar hemispheres

  7. CT findings of medulloblastoma

    International Nuclear Information System (INIS)

    Tsuchida, Tadashi; Fukuda, Mitsunori; Takeda, Norio; Tanaka, Ryuichi; Ito, Jusuke.

    1982-01-01

    Computed tomography (CT) of ten patients with medulloblastomas was evaluated. Six of them showed solid, nearly homogeneous lesions and a definite enhancement after the infusion of the contrast medium. However, 4 cases showed heterogenous mass lesions composed of areas of a low density and an iso- or slightly high density which was attenuated by contrast enhancement. Histological examinations revealed differentiated medulloblastomas in two of them, but the other two cases were typical medulloblastomas. It should be remembered that medulloblastomas can reveal heterogenous cerebellar midline mass lesions in CT scans. (author)

  8. Molecular subgroups of medulloblastoma

    OpenAIRE

    Northcott, Paul A; Dubuc, Adrian M; Pfister, Stefan; Taylor, Michael D

    2012-01-01

    Recent efforts at stratifying medulloblastomas based on their molecular features have revolutionized our understanding of this morbidity. Collective efforts by multiple independent groups have subdivided medulloblastoma from a single disease into four distinct molecular subgroups characterized by disparate transcriptional signatures, mutational spectra, copy number profiles and, most importantly, clinical features. We present a summary of recent studies that have contributed to our understand...

  9. Extraneural metastases in medulloblastoma

    Directory of Open Access Journals (Sweden)

    V M F Muoio

    2011-01-01

    Full Text Available Medulloblastoma is the most common childhood malignant tumor of central nervous system, but it may also occur in adults. It presents high invasive growth with spreading of tumor cells into the leptomeningeal space along the neuroaxis early in the course of the disease. Extraneural metastases are rare but frequently lethal, occurring only in 1 to 5% of patients, and are related, in the most of cases, to the presence of ventriculoperitoneal shunt. Here we characterize the clinical profile of five cases of medulloblastoma with systemic spreading of tumor cells, also comparing them to cases already described in the literature.

  10. Molecular Biology of Medulloblastoma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2007-12-01

    Full Text Available Current methods of diagnosis and treatment of medulloblastoma, and the influence of new biological advances in the development of more effective and less toxic therapies are reviewed by researchers at Children’s National Medical Center, The George Washington University, Washington, DC.

  11. Postoperative Chemotherapy for Medulloblastoma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-03-01

    Full Text Available The survival rate and cognitive function of 43 children, age <3 years, with medulloblastoma treated with intensive postoperative chemotherapy alone, without radiotherapy, were determined at the University of Wurzburg and other centers in Germany Chemotherapy consisted of three two-month cycles of cyclophosphamide, methotrexate, vincristine, carboplatin, and etoposide.

  12. Intertumoral Heterogeneity within Medulloblastoma Subgroups.

    Science.gov (United States)

    Cavalli, Florence M G; Remke, Marc; Rampasek, Ladislav; Peacock, John; Shih, David J H; Luu, Betty; Garzia, Livia; Torchia, Jonathon; Nor, Carolina; Morrissy, A Sorana; Agnihotri, Sameer; Thompson, Yuan Yao; Kuzan-Fischer, Claudia M; Farooq, Hamza; Isaev, Keren; Daniels, Craig; Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang; Lee, Ji Yeoun; Grajkowska, Wieslawa A; Perek-Polnik, Marta; Vasiljevic, Alexandre; Faure-Conter, Cecile; Jouvet, Anne; Giannini, Caterina; Nageswara Rao, Amulya A; Li, Kay Ka Wai; Ng, Ho-Keung; Eberhart, Charles G; Pollack, Ian F; Hamilton, Ronald L; Gillespie, G Yancey; Olson, James M; Leary, Sarah; Weiss, William A; Lach, Boleslaw; Chambless, Lola B; Thompson, Reid C; Cooper, Michael K; Vibhakar, Rajeev; Hauser, Peter; van Veelen, Marie-Lise C; Kros, Johan M; French, Pim J; Ra, Young Shin; Kumabe, Toshihiro; López-Aguilar, Enrique; Zitterbart, Karel; Sterba, Jaroslav; Finocchiaro, Gaetano; Massimino, Maura; Van Meir, Erwin G; Osuka, Satoru; Shofuda, Tomoko; Klekner, Almos; Zollo, Massimo; Leonard, Jeffrey R; Rubin, Joshua B; Jabado, Nada; Albrecht, Steffen; Mora, Jaume; Van Meter, Timothy E; Jung, Shin; Moore, Andrew S; Hallahan, Andrew R; Chan, Jennifer A; Tirapelli, Daniela P C; Carlotti, Carlos G; Fouladi, Maryam; Pimentel, José; Faria, Claudia C; Saad, Ali G; Massimi, Luca; Liau, Linda M; Wheeler, Helen; Nakamura, Hideo; Elbabaa, Samer K; Perezpeña-Diazconti, Mario; Chico Ponce de León, Fernando; Robinson, Shenandoah; Zapotocky, Michal; Lassaletta, Alvaro; Huang, Annie; Hawkins, Cynthia E; Tabori, Uri; Bouffet, Eric; Bartels, Ute; Dirks, Peter B; Rutka, James T; Bader, Gary D; Reimand, Jüri; Goldenberg, Anna; Ramaswamy, Vijay; Taylor, Michael D

    2017-06-12

    While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Metastases to bone in medulloblastoma

    International Nuclear Information System (INIS)

    Vieco, P.T.; Azouz, E.M.; Hoeffel, J.C.

    1989-01-01

    Medulloblastoma is a relatively common intracranial neoplasm in childhood. Its extraneural spread was, until recently, thought to be a rare occurrence. Metastases are most commonly to bone. Five patients with medulloblastoma metastatic to bone are presented, and findings are compared to those of previous reports. Two of the five cases showed patchy extensive osteosclerosis of the pelvis and/or proximal femora. One case had concurrent lymph node involvement. In patients with past or present medulloblastoma and bone pain, metastases to bone should be excluded. Medulloblastoma metastatic to bone is a rare cause of extensive osteosclerosis. (orig.)

  14. SnapShot: Medulloblastoma

    OpenAIRE

    Rusert, Jessica M.; Wu, Xiaochong; Eberhart, Charles G.; Taylor, Michael D.; Wechsler-Reya, Robert J.

    2014-01-01

    Medulloblastoma (MB) is the most common malignant brain tumor in children. Current treatment includes surgery, craniospinal radiation, and high-dose cytotoxic chemotherapy. Despite these aggressive therapies, one-third of patients still succumb to their disease, and survivors suffer devastating side effects, including cognitive deficits, endocrine disorders, and increased incidence of secondary cancers later in life. More effective and less toxic therapies are desperately needed for MB.

  15. Molecular Classification of Medulloblastoma

    OpenAIRE

    KIJIMA, Noriyuki; KANEMURA, Yonehiro

    2015-01-01

    Medulloblastoma (MB) is one of the most frequent malignant brain tumors in children. The current standard treatment regimen consists of surgical resection, craniospinal irradiation, and adjuvant chemotherapy. Although these treatments have the potential to increase the survival of 70–80% of patients with MB, they are also associated with serious treatment-induced morbidity. The current risk stratification of MB is based on clinical factors, including age at presentation, metastatic status, an...

  16. Multimodality therapy for medulloblastoma

    International Nuclear Information System (INIS)

    Thomas, P.R.M.; Duffner, P.K.; Cohen, M.E.; Sinks, L.F.; Tebbi, C.; Freeman, A.I.

    1980-01-01

    Eight patients with recurrent medulloblastoma were treated with a chemotherapy regimen consisting of vincristine, BCNU, dexamethasone and intrathecal and intermediate dose intravenous methotrexate (500 mg/m 2 ). Five also received local low dose radiotherapy (RT). All 8 patients responded to treatment; 6 completely and 2 partially. These latter 2 were in their second and third recurrences. Three remain in remission. The median duration of response was 18.8 months, and median time from start of chemotherapy to death was 32 months using the Kaplan-Meier technique. In addition, 9 other patients with newly diagnosed medulloblastoma were treated with craniospinal radiation and the same adjuvant chemotherapy as above. The first 5 patients also received intraventricular methotrexate and/or intravenous BCNU during radiotherapy. The toxicity in the 5 patients was very severe. There were three toxic deaths, one death from cancer; one patient survives disease-free, but he is demented. With the discontinuance of intraventricular methotrexate and the postponement of myelosuppressive chemotherapy until after the completion of radiotherapy, the regimen has been well tolerated. All 4 patients treated this way remain alive, well, and disease-free at intervals up to 36 months. We conclude that recurrent medulloblastomas are sensitive to multiagent chemotherapy and that prolonged remissions may occur. With primary adjuvant chemotherapy, extreme caution with myelosuppressive drugs must be exercised during the period of craniospinal radiotherapy. We also do not recommend the use of intraventricular methotrexate. When these two criteria were followed, the preliminary results with adjuvant chemotherapy appear encouraging

  17. Anaplasia and grading in medulloblastomas.

    Science.gov (United States)

    Eberhart, Charles G; Burger, Peter C

    2003-07-01

    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.

  18. Radiotherapy for the medulloblastoma

    International Nuclear Information System (INIS)

    Gose, Kyuhei; Imajo, Yoshinari; Imanaka, Kazufumi

    1983-01-01

    Eighteen patients with medulloblastoma, treated between 1972 and 1981, at Kobe University School of Medicine, were retrospectively studied. Of those completing post operative irradiation, 50% have survived for 2 years, 15% for 5 years and mean survival periods was 22.2 months. 13 out of 18 patients developed local recurrence and spinal dissemination. The mean time from the initial radiotherapy to recurrence was 8.5 months. It was suggested that posterior fossa should recieve 5,000 rad, the spine should 2,000 rad and recurrences should be treated by the combination of radiotherapy and chemotherapy. (author)

  19. Prognostic factors for medulloblastoma

    International Nuclear Information System (INIS)

    Jenkin, Derek; Al Shabanah, Mohamed; Al Shail, Essam; Gray, Alan; Hassounah, Maher; Khafaga, Yasser; Kofide, Amani; Mustafa, Mahmoud; Schultz, Henrik

    2000-01-01

    Purpose: To evaluate prognostic factors for medulloblastoma. Methods and Materials: One hundred and seventy-three consecutive patients with medulloblastoma, treated at King Faisal Specialist Hospital (KFSH) from 1988-1997, were reviewed. Eighty-four percent were children less than 15 years old. From 1988-1994, treatment was at the discretion of the investigator. From 1994-1998, patients entered a single-arm best practice protocol in which, in staged patients, the surgical intent was total resection, standard radiation treatment was defined, and adjuvant chemotherapy was given to a 'high-risk' subset. Results: For 150 patients who completed surgical and radiation treatment, the 5-year survival rate was 58%, compared with 0% for 16 patients who were unable to start or complete radiation treatment. For staged patients, the 5-year survival was M0 + M1, 78% and M2 + M3, 21% (p 14 years and gross cystic/necrotic features in the primary tumor. The size of the primary tumor, the degree of hydrocephalus at diagnosis, the presence of residual tumor in the post-operative CT/MRI, and the functional status of the patient prior to radiation treatment were not significant factors. Conclusions: Stage M0 + M1 was the most powerful favorable prognostic factor. In Saudi Arabia more patients present with advanced disseminated disease, 41% M2 + M3, than in the West, and this impacts adversely on overall survival. Total resection and standard radiation treatment were not sensitive prognostic factors in a treatment environment in which 78% of patients underwent at least 90% tumor resection and 60% received standard radiation treatment. In order to improve the proportion of patients able to complete radiation treatment, consideration should be given to limiting resection when the attainment of total resection is likely to be morbid, and to delaying rather than omitting radiation treatment in the patient severely compromised postoperatively

  20. Cerebellar medulloblastoma presenting with skeletal metastasis

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    Barai Sukanta

    2004-04-01

    Full Text Available Medulloblastomas are highly malignant brain tumours, but only rarely produce skeletal metastases. No case of medulloblastoma has been documented to have produced skeletal metastases prior to craniotomy or shunt surgery. A 21-year-old male presented with pain in the hip and lower back with difficulty in walking of 3 months′ duration. Signs of cerebellar dysfunction were present hence a diagnosis of cerebellar neoplasm or skeletal tuberculosis with cerebellar abscess formation was considered. MRI of brain revealed a lesion in the cerebellum suggestive of medulloblastoma. Bone scan revealed multiple sites of skeletal metastases excluding the lumbar vertebrae. MRI of lumbar spine and hip revealed metastases to all lumbar vertebrae and both hips. Computed tomography-guided biopsy was obtained from the L3 vertebra, which revealed metastatic deposits from medulloblastoma. Cerebrospinal fluid cytology showed the presence of medulloblastoma cells. A final diagnosis of cerebellar medulloblastoma with skeletal metastases was made. He underwent craniotomy and histopathology confirmed medulloblastoma.

  1. Cytogenetic prognostication within medulloblastoma subgroups.

    Science.gov (United States)

    Shih, David J H; Northcott, Paul A; Remke, Marc; Korshunov, Andrey; Ramaswamy, Vijay; Kool, Marcel; Luu, Betty; Yao, Yuan; Wang, Xin; Dubuc, Adrian M; Garzia, Livia; Peacock, John; Mack, Stephen C; Wu, Xiaochong; Rolider, Adi; Morrissy, A Sorana; Cavalli, Florence M G; Jones, David T W; Zitterbart, Karel; Faria, Claudia C; Schüller, Ulrich; Kren, Leos; Kumabe, Toshihiro; Tominaga, Teiji; Shin Ra, Young; Garami, Miklós; Hauser, Peter; Chan, Jennifer A; Robinson, Shenandoah; Bognár, László; Klekner, Almos; Saad, Ali G; Liau, Linda M; Albrecht, Steffen; Fontebasso, Adam; Cinalli, Giuseppe; De Antonellis, Pasqualino; Zollo, Massimo; Cooper, Michael K; Thompson, Reid C; Bailey, Simon; Lindsey, Janet C; Di Rocco, Concezio; Massimi, Luca; Michiels, Erna M C; Scherer, Stephen W; Phillips, Joanna J; Gupta, Nalin; Fan, Xing; Muraszko, Karin M; Vibhakar, Rajeev; Eberhart, Charles G; Fouladi, Maryam; Lach, Boleslaw; Jung, Shin; Wechsler-Reya, Robert J; Fèvre-Montange, Michelle; Jouvet, Anne; Jabado, Nada; Pollack, Ian F; Weiss, William A; Lee, Ji-Yeoun; Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang; Leonard, Jeffrey R; Rubin, Joshua B; de Torres, Carmen; Lavarino, Cinzia; Mora, Jaume; Cho, Yoon-Jae; Tabori, Uri; Olson, James M; Gajjar, Amar; Packer, Roger J; Rutkowski, Stefan; Pomeroy, Scott L; French, Pim J; Kloosterhof, Nanne K; Kros, Johan M; Van Meir, Erwin G; Clifford, Steven C; Bourdeaut, Franck; Delattre, Olivier; Doz, François F; Hawkins, Cynthia E; Malkin, David; Grajkowska, Wieslawa A; Perek-Polnik, Marta; Bouffet, Eric; Rutka, James T; Pfister, Stefan M; Taylor, Michael D

    2014-03-20

    Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

  2. Medulloblastoma in childhood

    International Nuclear Information System (INIS)

    Hirsch, J.F.; Renier, D.; Czernichow, P.; Benveniste, L.; Pierre-Kahn, A.

    1979-01-01

    The authors report on a series of 57 medulloblastomas in children operated upon between 1964 and 1976. Among these children, 44 completed the treatment with radiotherapy to the whole central nervous system. The postoperative mortality rate is 10.5%. Postoperative deaths occurred mainly in infants or when a tumour involved the brain stem. The five-year survival rate is 54% in the whole series. It rose to 71% in the patients who completed the treatment with radiotherapy. The study shows that the life of survivals is frequently impaired by mental or behavioural disturbances. IQ varies from 70 to 90 in 58% of the children; it is below 70 in 31%. Behavioural disturbances are found in 93% of cases. 82% have defective spatial orientation, dysphasia, or dysgraphia. In order to evaluate the responsibility of X-ray therapy for the development of these sequelae, the results have been compared to those of a series of cerebellar astrocytomas surgically removed, but not irradiated. The comparison shows that radiotherapy is at least partially responsible for the mental and behavioural disturbances. No relation was found between these disturbances and a persistent ventricular dilatation or an endocrine dysfunction. However the endocrine assessment showed growth hormone deficiency in 65% of the children, short stature in 55%, and compensated hypothyroidism in 58%. (author)

  3. Imaging Biomarkers for Adult Medulloblastomas

    DEFF Research Database (Denmark)

    Keil, V C; Warmuth-Metz, M; Reh, C

    2017-01-01

    BACKGROUND AND PURPOSE: The occurrence of medulloblastomas in adults is rare; nevertheless, these tumors can be subdivided into genetic and histologic entities each having distinct prognoses. This study aimed to identify MR imaging biomarkers to classify these entities and to uncover differences ...

  4. The child medulloblastoma in Tunisia

    International Nuclear Information System (INIS)

    Kochbati, L.; Bouaouina, N.; Besbes, M.; Frikha, H.; Benna, F.; Daoud, J.; Gargouri, W.; Damak, H.; Ben Abdallah, M.; Maalej, M.

    2000-01-01

    The medulloblastoma is the first pediatric cerebral tumor in Tunisia. Its treatment relies on the surgery and radiotherapy of cerebro-spinal axis. The chemotherapy is in progress for evaluation to try a de-escalation of irradiation dose. (N.C.)

  5. MRI findings of vermian medulloblastoma

    International Nuclear Information System (INIS)

    Jung, Seung Eun; Choi, Kyu Ho; Chung, Myung Hee; Yang, Il Kwon; Shinn, Kyung Sub; Park, Young Sub

    1996-01-01

    To find characteristic MRI features of vermian medulloblastoma. Materials and methods; MRI studies and medical records were retrospectively reviewed for 12 patients with surgically proven midline medulloblastoma. The assessment concerned appearance of the mass in relation to surrounding structures: MR signal intensity; the enhancement pattern; the mass's location and size: presence of a cystic/necrotic area, calcification, or vascular void: extension through the foramen Luschka: degree of hydrocephalus: and presence of tonsillar herniation. The midline medulloblastoma commonly showed roundish moon-surface appearance, especially on the axial T2-weighted images. All tumors showed heterogeneous signal intensities mainly due to intratumoral cystic/necrotic or hemorrhagic changes. The tumors were commonly located at mid-and/or inferior vermis. Occasionally the tumors extended through the foramen Luschka, and caused obstructive hydrocephalus of moderate to severe degree. Post-contrast study showed heterogeneous, dense contrast enhancement in the majority of patients. The MR finding of the moon-surface appearance formed by both the mass and the intratumoral cystic/necrotic change as seen on axial T2-weighted images could be helpful in the diagnosis of vermian medulloblastoma

  6. MRI of medulloblastoma in adults

    International Nuclear Information System (INIS)

    Malheiros, S.M.F.; Santos, A.J.; Borges, L.R.R.; Guimaraes, I.F.; Franco, C.M.R.; Gabbai, A.A.; Carrete, H.; Stavale, J.N.; Pelaez, M.P.

    2003-01-01

    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. (orig.)

  7. Medulloblastoma: progress over time

    International Nuclear Information System (INIS)

    Smee, Robert I.; Williams, Janet R.; De-loyde, Katie J.; Meagher, Nicola S.; Cohn, Richard

    2012-01-01

    Medulloblastoma is the most common central nervous system tumour in children aged 0–4 years, with 75% of cases occurring in patients <16 years, and rare in adults. The intent of this audit is to review a single centre's experience and to compare outcomes with other centres' outcomes. This Ethics approved retrospective audit evaluates the paediatric population aged <16 years who received radiotherapy as their initial or salvage treatment at the Prince of Wales Hospital Cancer Centre between 1972 and 2007. The primary and secondary end-points were progression-free survival (PFS) and cancer-specific survival (CSS), with comparisons made between patients treated before and after 1990, and the impact of high- and low-risk disease. There were 80 eligible patients, 78 who had radiotherapy at initial presentation, and 2 at the time of recurrence. Median age was 6.5 years, 52 were boys and 28 were girls. Seventy-eight patients had a surgical procedure and ultimately received craniospinal radiotherapy. Of these 78 patients, 32 (40%) had a macroscopically complete resection. The 5-year PFS was 69.7%. The 5-year PFS for patients treated pre and post 1990 was 66.1% and 71.8%, respectively. The 5-year CSS for high- and low-risk patients was 61.1% and 78.4%, respectively. Ultimately, 33% of patients were dead due to disease. This audit demonstrates those children referred to this facility for treatment have comparable survival to that of other major centres.

  8. Medulloblastoma stem cells: Promising targets in medulloblastoma therapy

    OpenAIRE

    Huang, Guo?Hao; Xu, Qing?Fu; Cui, You?Hong; Li, Ningning; Bian, Xiu?Wu; Lv, Sheng?Qing

    2016-01-01

    Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination still pose great challenges to the long?term survival of MB patients. Developing more effective strategies has become extremely urgent. In recent years, a number of malignancies, including MB, have been found to contain a subpopulation of cancer cells known as cancer stem cells (CSCs), or tumor initiating/propagating cells. Th...

  9. Medulloblastoma: toward biologically based management.

    Science.gov (United States)

    Samkari, Ayman; White, Jason C; Packer, Roger J

    2015-03-01

    Medulloblastoma is the most common malignant brain tumor in children and, as such, has been the focus of tremendous efforts to genomically characterize it. What was once thought to be a single disease has been divided into multiple, molecularly unique subgroups through gene expression profiling. Each subgroup is not only unique in its origin and pathogenesis but also in the prognosis and potential therapeutic options. Targeted therapy of malignancies has long been the goal of clinical oncology. The progress made in the classification of medulloblastoma should be used as a model for future studies. With the evolution of epigenetic and genomic sequencing, especially when used in tandem with high-throughput pharmacologic screening protocols, the potential for subgroup-specific targeting is closer than ever. This review focuses on the development of the molecular classification system and its potential use in developing prognostic models as well as for the advancement of targeted therapeutic interventions. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. The cellular and molecular biology of medulloblastoma

    NARCIS (Netherlands)

    Peringa, A; Fung, KM; Muragaki, Y; Trojanowski, JQ

    1995-01-01

    Medulloblastomas are prototypical of primitive neuroectodermal tumors which are some of the most frequent malignant brain tumors of childhood. The cell biology of medulloblastomas is still poorly understood, but recent studies of the expression of trophic factors and their receptors in

  11. Adult medulloblastoma with myogenic differentiation

    Directory of Open Access Journals (Sweden)

    Xia-ling ZHANG

    2015-09-01

    Full Text Available Objective To explore the clinicopathological features of adult medulloblastoma with myogenic differentiation and to discuss clinicopathological differentiations from relevant tumors, so as to improve the ability of diagnosing and differentiating this kind of tumor. Methods The clinical manifestations, imaging, pathological features and immunohistochemical features of one case of adult medulloblastoma with myogenic differentiation were analyzed, and related literatures were reviewed. Results A 32-year-old female patient presented with repeated distortion of mouth and facial numbness for over 6 years. T1WI showed a mixed-signal lesion in the cerebellar vermis and dorsal part of brainstem, and protruded toward the fourth ventricle. Enhanced T1WI showed a round strengthened nodule in the lesion. During operation, it was seen that the tumor arised in cerebellar vermis, projected into the fourth ventricle and invaded brainstem. On microscopy examination, it was found that oval nuclei tumor cells were distributed in sheet or scattered patterns, and neuroblastic rosettes were observed. Abundant and eosinophilic cytoplasm, eccentrically placed and atypical nuclei containing hyperchromatic chromatin or prominent nucleoli in the tumor could be displayed. Mitoses were frequently seen. The tumor also presented with fresh and old hemorrhage in some place. Immunohistochemical staining showed that tumor cells were diffusely positive for integrase interactor 1 (INI1, synaptophysin (Syn, chromogranin A (CgA, human internexin neuronal intermediate filament protein α (INα, neurofilament protein (NF, Nestin (Nes, β-catenin and P53, and partly positive for desmin (Des, neuronal nuclei (NeuN and S-100 protein (S-100, but negative for glial fibrillary acidic protein (GFAP, oligodendrocyte transcription factor-2 (Olig-2, CD99, pan cytokeratin (PCK, epithelial membrane antigen (EMA, MyoD1, myogenin, muscle-specific actin (MSA and smooth muscle actin (SMA. Ki-67

  12. Twelve clinically significant points in medulloblastoma

    International Nuclear Information System (INIS)

    Sugiyama, Kazuhiko; Yamasaki, Fumiyuki; Kajiwara, Yoshinori; Watanabe, Yosuke; Takayasu, Takeshi; Kurisu, Kaoru

    2011-01-01

    Though medulloblastoma is the most common malignant brain tumor during childhood, only 80 newly-diagnosed tumors develos every year, as the annual incidence is extremely rare with an occurrence of 0.5 per 100,000 children younger than 15-year-old and of 0.7 per 100,000 for the entire population. Images obtained of medulloblastoma are characterized by a round heterogeously-enhanced mass in or adjacent to the VIth ventricle. Objectives of surgical treatment are the maximum resectioning of the main mass and the relief of the obstructive hydrocephalus. Cerebellar mutism occurs a few days after one fourth of medulloblastoma surgery, and lasts approximately for 50 days followed by subsequent dysarthria. Pathological subtypes include classic medulloblastoma, desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, large cell/anaplastic medulloblastoma, all corresponding to World Health Organization (WHO) grade IV. According to age, residual tumor size, and disseminated staging, patients are divided into average-risk group, high-risk group, or baby-medulloblastoma after surgery. Standard treatment in average-risk group includes 23.4-Gy cranio-spinal irradiation (CSI) with posterior boost followed by chemotherapy consisting of cisplatin (CDDP), alkylating agents, and vincristine. Patients in high-risk group receive over 36-Gy CSI with boost radiotherapy to nodular lesions before, concomitantly with, or followed by dose-intensity chemotherapy. In cases with gross total removal, or desmoplastic/nodular pathology radiotherapy for patients younger than 3-year-old are often delayed until they turn 3-year-old, and are able to survive for long time by appropriate chemotherapy alone. Adolescent survivors with childhood medulloblastoma have a number of late adverse effects regarding another neoplasm, neuro-cognitive function, endocrine activity, cardiovascular organs, and skeletal system. Comprehensive follow-up and support system are mandatory. (author)

  13. Radiation therapy for pinealoma, medulloblastoma and ependymoma

    International Nuclear Information System (INIS)

    Miyata, Samon; Saito, Yasuo; Takashima, Tsutomu; Kubota, Norihiko; Ito, Hideharu

    1984-01-01

    Eight cases with pinealoma, 4 cases with medulloblastoma and 3 cases with ependymoma those recieved radiotherapy with or without operative procedures were reported. All patients were childrens or young adults. The responses to irradiation evaluated on computed tomography were very good in most of these tumors. Cerebrospinal disseminations were observed in 3 cases with pinealoma, 3 cases with medulloblastoma and 2 cases with ependymoma. Therefore, it is considered that the whole brain irradiation is necessary in patients with pinealoma and whole brain and whole spinal irradiations should be done in patients with medulloblastoma and patients with ependymoblastoma. (author)

  14. Craniospinal radiotherapy in adult medulloblastoma

    International Nuclear Information System (INIS)

    Selek, U.; Zorlu, F.; Hurmuz, P.; Cengiz, M.; Gurkaynak, M.; Turker, A.; Soylemezoglu, F.

    2007-01-01

    Purpose: To evaluate the outcome and prognostic factors of adult patients with medulloblastoma. Patients and Methods: 26 adult medulloblastoma patients with a median age of 27 were subjected to craniospinal radiotherapy. A dose of 30.6 Gy with 1.8 Gy/fraction/day was prescribed to M0 patients, while 36 Gy were to be applied in patients with positive cerebrospinal liquor findings. The posterior fossa was boosted to 54 Gy. While 20 patients underwent external-beam radiotherapy alone, only six received sequential adjuvant chemotherapy. Results: Male/female ratio was 1.2. Preradiotherapy Karnofsky performance status was recorded as median 100%. 50% were classified as poor risk (n = 10, subtotal resection; n = 3, M+). The median follow-up time was 46.5 months. The 5-year actuarial survival rates for recurrence-free, distant metastasis-free, disease-free, and overall survival were 82.5%, 90.8%, 73.5%, and 89.7%, respectively. Patient characteristics, treatment factors and tumor characteristics failed to show any significance in univariate analysis. Grade 3 or 4 late morbidities were not observed. Conclusion: Yet, the current standard of care seems to remain craniospinal irradiation after maximal surgical resection of the primary neoplasm without clear indications for adjuvant chemotherapy. (orig.)

  15. Less common CT features of medulloblastoma

    International Nuclear Information System (INIS)

    Zee, C.S; Segall, H.D.; Miller, C.; Ahmad, J.; McComb, J.G.; Han, J.S.; Park, S.H.

    1982-01-01

    While many medulloblastomas have characteristic features on computed tomography (CT), a significant number have atypical features, including a cystic or necrotic component, calcification, hemorrhage, lack of contrast enhancement, and eccentric location, and/or direct supratentorial extension. Of 30 consecutive untreated cases reviewed by the authors, 14 (47%) had such findings. Failure to make the proper diagnosis will result in some cases if these features are not recognized as possible signs of medulloblastoma

  16. Insights into cerebellar development and medulloblastoma.

    Science.gov (United States)

    Bihannic, Laure; Ayrault, Olivier

    2016-01-01

    Cerebellar development is an extensive process that begins during early embryonic stages and persists more than one year after birth in human. Therefore, the cerebellum is susceptible to acquire various developmental abnormalities leading to numerous diseases such as medulloblastoma, the most common pediatric malignant brain tumor. One third of the patients with medulloblastoma are incurable and survivors have a poor quality of life due to the aggressiveness of the broad-spectrum treatments. Within the past few years, it has been highlighted that medulloblastoma is a heterogeneous disease that is divided in four molecular subgroups. This recent advance in the field, combined with the development of associated preclinical models for each subgroup, should enable, in the future, the discovery and use of targeted therapy in clinical treatments for each subtype of medulloblastoma. In this review, we first aim to show how deregulation of cerebellar development can lead to medulloblastoma formation and then to present the advances in the molecular subgrouping of medulloblastoma and the associated preclinical models. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  17. Magnetic resonance imaging spectrum of medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Fruehwald-Pallamar, Julia; Puchner, Stefan B.; Koelblinger, Claus [Medical University of Vienna, Department of Radiology, Vienna (Austria); Rossi, Andrea [G. Gaslini Children' s Hospital, Department of Pediatric Neuroradiology, Genova (Italy); Garre, Maria L. [G. Gaslini Children' s Research Hospital (IRCCS), Neurooncology Unit, Genova (Italy); Cama, Armando [G. Gaslini Children' s Hospital, Neurosurgery Department, Genova (Italy); Osborn, Anne G. [University of Utah, Department of Radiology, Salt Lake City, UT (United States); Thurnher, Majda M. [Medical University of Vienna, Department of Radiology, Vienna (Austria); Medical University of Vienna, Division of Neuro- and Musculoskeletal Radiology, Vienna (Austria)

    2011-06-15

    Two medulloblastoma variants were recently added to the WHO classification of CNS tumours. We retrospectively analysed the imaging findings of 37 classic and 27 cases of variant medulloblastomas to identify imaging characteristics that might suggest a particular MB subtype. Sixty-four patients from three institutions were included. Location, tumour margins, signal intensities on conventional MRI, enhancement pattern, the presence of haemorrhage, calcifications and hydrocephalus were recorded and analysed. Signal characteristics on diffusion-weighted MR images and MR spectra were evaluated when available. Thirty-seven classic type of MB (CMB), twelve cases of desmoplastic/nodular medulloblastoma (DMB), nine medulloblastomas with extensive nodularity (MB-EN), five cases of anaplastic and one of large-cell medulloblastoma were included. Fifty of 64 tumours were located in the 4th ventricle region. On T2WI, CMB were all hyperintense, whereas DMB and MB-EN showed isointensity in up to 66%. One third of the classic MB showed only subtle marginal or linear enhancement. All medulloblastoma variants showed marked enhancement. The results of our study suggest: (a) an age-dependent distribution of MB variants, with DMB and MB-EN more common in younger children; (b) a female predominance in DMB; (c) a more common off-midline location in DMB (50%) and MB-EN (33%) variants. (orig.)

  18. Magnetic resonance imaging spectrum of medulloblastoma

    International Nuclear Information System (INIS)

    Fruehwald-Pallamar, Julia; Puchner, Stefan B.; Koelblinger, Claus; Rossi, Andrea; Garre, Maria L.; Cama, Armando; Osborn, Anne G.; Thurnher, Majda M.

    2011-01-01

    Two medulloblastoma variants were recently added to the WHO classification of CNS tumours. We retrospectively analysed the imaging findings of 37 classic and 27 cases of variant medulloblastomas to identify imaging characteristics that might suggest a particular MB subtype. Sixty-four patients from three institutions were included. Location, tumour margins, signal intensities on conventional MRI, enhancement pattern, the presence of haemorrhage, calcifications and hydrocephalus were recorded and analysed. Signal characteristics on diffusion-weighted MR images and MR spectra were evaluated when available. Thirty-seven classic type of MB (CMB), twelve cases of desmoplastic/nodular medulloblastoma (DMB), nine medulloblastomas with extensive nodularity (MB-EN), five cases of anaplastic and one of large-cell medulloblastoma were included. Fifty of 64 tumours were located in the 4th ventricle region. On T2WI, CMB were all hyperintense, whereas DMB and MB-EN showed isointensity in up to 66%. One third of the classic MB showed only subtle marginal or linear enhancement. All medulloblastoma variants showed marked enhancement. The results of our study suggest: (a) an age-dependent distribution of MB variants, with DMB and MB-EN more common in younger children; (b) a female predominance in DMB; (c) a more common off-midline location in DMB (50%) and MB-EN (33%) variants. (orig.)

  19. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

    NARCIS (Netherlands)

    Northcott, Paul A.; Lee, Catherine; Zichner, Thomas; Stütz, Adrian M.; Erkek, Serap; Kawauchi, Daisuke; Shih, David J. H.; Hovestadt, Volker; Zapatka, Marc; Sturm, Dominik; Jones, David T. W.; Kool, Marcel; Remke, Marc; Cavalli, Florence M. G.; Zuyderduyn, Scott; Bader, Gary D.; VandenBerg, Scott; Esparza, Lourdes Adriana; Ryzhova, Marina; Wang, Wei; Wittmann, Andrea; Stark, Sebastian; Sieber, Laura; Seker-Cin, Huriye; Linke, Linda; Kratochwil, Fabian; Jäger, Natalie; Buchhalter, Ivo; Imbusch, Charles D.; Zipprich, Gideon; Raeder, Benjamin; Schmidt, Sabine; Diessl, Nicolle; Wolf, Stephan; Wiemann, Stefan; Brors, Benedikt; Lawerenz, Chris; Eils, Jürgen; Warnatz, Hans-Jörg; Risch, Thomas; Yaspo, Marie-Laure; Weber, Ursula D.; Bartholomae, Cynthia C.; von Kalle, Christof; Turányi, Eszter; Hauser, Peter; Sanden, Emma; Darabi, Anna; Siesjö, Peter; Sterba, Jaroslav; Zitterbart, Karel; Sumerauer, David; van Sluis, Peter; Versteeg, Rogier; Volckmann, Richard; Koster, Jan; Schuhmann, Martin U.; Ebinger, Martin; Grimes, H. Leighton; Robinson, Giles W.; Gajjar, Amar; Mynarek, Martin; von Hoff, Katja; Rutkowski, Stefan; Pietsch, Torsten; Scheurlen, Wolfram; Felsberg, Jörg; Reifenberger, Guido; Kulozik, Andreas E.; von Deimling, Andreas; Witt, Olaf; Eils, Roland; Gilbertson, Richard J.; Korshunov, Andrey; Taylor, Michael D.; Lichter, Peter; Korbel, Jan O.; Wechsler-Reya, Robert J.; Pfister, Stefan M.

    2014-01-01

    Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma,

  20. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

    NARCIS (Netherlands)

    M. Remke (Marc); E.A. Ramaswamy; M. Peacock (Munro); D.J.H. Shih (David J.); C. Koelsche (Christian); P.A. Northcott (Paul A.); N. Hill (Nadia); S. Cavalli (Silvia); M. Kool (Marcel); X. Wang (Xin); S. Mack (Stephen); M. Barszczyk (Mark); A.S. Morrissy (A. Sorana); X. Wu (Xiaochong); S. Agnihotri (Sameer); P. Luu (Phan); D. Jones (David); L. Garzia (Livia); A.M. Dubuc (Adrian); N. Zhukova (Nataliya); R. Vanner (Robert); J.M. Kros (Johan); P.J. French (Pim); E.G. van Meir (Erwin); R. Vibhakar (Rajeev); K. Zitterbart (Karel); J.A. Chan (Jennifer); L. Bognár (László); A. Klekner (Almos); B. Lach (Boleslaw); S. Jung (Shin); F. Saad (Fred); L.M. Liau (Linda); S. Albrecht (Steffen); M. Zollo (Maurizio); M.K. Cooper (Michael); R.C. Thompson (Reid); O. Delattre (Olivier); F. Bourdeaut (Franck); F.F. Doz (François); M. Garami (Miklós); P. Hauser (Peter); C.G. Carlotti (Carlos); T.E. Van Meter (Timothy); L. Massimi (Luca); D. Fults (Daniel); L.W. Pomeroy (Laura); T. Kumabe (Toshiro); Y.S. Ra (Young Shin); J.R. Leonard (Jeffrey); S.K. Elbabaa (Samer); J. Mora (Jaume); J.B. Rubin (Joshua); Y.-J. Cho (Yoon-Jae); R.E. McLendon (Roger); D.D. Bigner (Darell); C.G. Eberhart (Charles); M. Fouladi (Maryam); R.J. Wechsler-Reya (Robert); R. Faria (Rui); S.E. Croul (Sidney); A. Huang (Anding); E. Bouffet (Eric); C.E. Hawkins (Cynthia); M. Dirks (Maaike); W.A. Weiss (William); U. Schüller (Ulrich); A. Pollack (Aaron); P. Rutkowski (Piotr); D. Meyronet (David); A. Jouvet (Anne); M. Fèvre-Montange (Michelle); N. Jabado (Nada); M. Perek-Polnik (Marta); W.A. Grajkowska (Wieslawa); S.-K. Kim (Seung-Ki); J.T. Rutka (James); E. Malkin (Elissa); U. Tabori (Uri); S.M. Pfister (Stefan); A. Korshunov (Andrey); A. von Deimling (Andreas); M.D. Taylor (Michael)

    2013-01-01

    textabstractTelomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought

  1. Hand1 overexpression inhibits medulloblastoma metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Asuthkar, Swapna; Guda, Maheedhara R. [Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States); Martin, Sarah E. [Department of Pathology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States); Antony, Reuben; Fernandez, Karen [Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States); Lin, Julian [Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States); Tsung, Andrew J. [Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States); Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States); Illinois Neurological Institute, Peoria, IL 61656 (United States); Velpula, Kiran K., E-mail: velpula@uic.edu [Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States); Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL 61656 (United States)

    2016-08-19

    Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current treatment includes surgery, radiation and chemotherapy. However, ongoing treatment in patients is further classified according to the presence or absence of metastasis. Since metastatic medulloblastoma are refractory to current treatments, there is need to identify novel biomarkers that could be used to reduce metastatic potential, and more importantly be targeted therapeutically. Previously, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus. We further demonstrated that uPAR protein act as cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand1. Among the histological subtypes classical and desmoplastic subtypes account for the majority while large cell/anaplastic variant is most commonly associated with metastatic disease. In this present study using immunohistochemical approach and patient data mining for the first time, we demonstrated that Hand1 expression is observed to be downregulated in all the subtypes of medulloblastoma. Previously we showed that Hand1 overexpression regulated medulloblastoma angiogenesis and here we investigated the role of Hand1 in the context of Epithelial-Mesenchymal Transition (EMT). Moreover, UW228 and D283 cells overexpressing Hand1 demonstrated decreased-expression of mesenchymal markers (N-cadherin, β-catenin and SOX2); metastatic marker (SMA); and increased expression of epithelial marker (E-cadherin). Strikingly, human pluripotent stem cell antibody array showed that Hand1 overexpression resulted in substantial decrease in pluripotency markers (Nanog, Oct3/4, Otx2, Flk1) suggesting that Hand1 expression may be essential to attenuate the EMT and our findings underscore a novel role for Hand1 in medulloblastoma metastasis. - Highlights: • Hand1 expression is downregulated in Medulloblastoma. • Hand1 over expression reduce

  2. Hand1 overexpression inhibits medulloblastoma metastasis

    International Nuclear Information System (INIS)

    Asuthkar, Swapna; Guda, Maheedhara R.; Martin, Sarah E.; Antony, Reuben; Fernandez, Karen; Lin, Julian; Tsung, Andrew J.; Velpula, Kiran K.

    2016-01-01

    Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current treatment includes surgery, radiation and chemotherapy. However, ongoing treatment in patients is further classified according to the presence or absence of metastasis. Since metastatic medulloblastoma are refractory to current treatments, there is need to identify novel biomarkers that could be used to reduce metastatic potential, and more importantly be targeted therapeutically. Previously, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus. We further demonstrated that uPAR protein act as cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand1. Among the histological subtypes classical and desmoplastic subtypes account for the majority while large cell/anaplastic variant is most commonly associated with metastatic disease. In this present study using immunohistochemical approach and patient data mining for the first time, we demonstrated that Hand1 expression is observed to be downregulated in all the subtypes of medulloblastoma. Previously we showed that Hand1 overexpression regulated medulloblastoma angiogenesis and here we investigated the role of Hand1 in the context of Epithelial-Mesenchymal Transition (EMT). Moreover, UW228 and D283 cells overexpressing Hand1 demonstrated decreased-expression of mesenchymal markers (N-cadherin, β-catenin and SOX2); metastatic marker (SMA); and increased expression of epithelial marker (E-cadherin). Strikingly, human pluripotent stem cell antibody array showed that Hand1 overexpression resulted in substantial decrease in pluripotency markers (Nanog, Oct3/4, Otx2, Flk1) suggesting that Hand1 expression may be essential to attenuate the EMT and our findings underscore a novel role for Hand1 in medulloblastoma metastasis. - Highlights: • Hand1 expression is downregulated in Medulloblastoma. • Hand1 over expression reduce

  3. Overexpressed TP73 induces apoptosis in medulloblastoma

    International Nuclear Information System (INIS)

    Castellino, Robert C; De Bortoli, Massimiliano; Lin, Linda L; Skapura, Darlene G; Rajan, Jessen A; Adesina, Adekunle M; Perlaky, Laszlo; Irwin, Meredith S; Kim, John YH

    2007-01-01

    Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated ΔNp73 to assess their effects on growth. We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of TP73 RNA including the full-length transcript and the 5'-terminal variants that encode the ΔNp73 isoform, as well as TP53 RNA using quantitative real time-RTPCR. Protein expression of TAp73 and ΔNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on TP73 RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and ΔNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods. Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant TP73 RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated ΔNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or ΔNp73 induced apoptosis under basal growth conditions in vitro and sensitized them to cell death in response to

  4. Overexpressed TP73 induces apoptosis in medulloblastoma

    Directory of Open Access Journals (Sweden)

    Perlaky Laszlo

    2007-07-01

    Full Text Available Abstract Background Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated ΔNp73 to assess their effects on growth. Methods We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of TP73 RNA including the full-length transcript and the 5'-terminal variants that encode the ΔNp73 isoform, as well as TP53 RNA using quantitative real time-RTPCR. Protein expression of TAp73 and ΔNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on TP73 RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and ΔNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods. Results Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant TP73 RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated ΔNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or ΔNp73 induced apoptosis under basal growth conditions in vitro and

  5. Three-dimensional (3D) reconstruction and quantitative analysis of the microvasculature in medulloblastoma and ependymoma subtypes.

    NARCIS (Netherlands)

    Gilhuis, H.J.; Laak, J.A.W.M. van der; Pomp, J.; Kappelle, A.C.; Gijtenbeek, J.M.M.; Wesseling, P.

    2006-01-01

    In the World Health Organisation (WHO) classification of tumours of the nervous system, four main histopathological subtypes of medulloblastomas (classic medulloblastoma, desmoplastic medulloblastoma, medulloblastoma with extensive nodularity and advanced neuronal differentiation and large

  6. Divergent clonal selection dominates medulloblastoma at recurrence

    Science.gov (United States)

    Morrissy, A. Sorana; Garzia, Livia; Shih, David J. H.; Zuyderduyn, Scott; Huang, Xi; Skowron, Patryk; Remke, Marc; Cavalli, Florence M. G.; Ramaswamy, Vijay; Lindsay, Patricia E.; Jelveh, Salomeh; Donovan, Laura K.; Wang, Xin; Luu, Betty; Zayne, Kory; Li, Yisu; Mayoh, Chelsea; Thiessen, Nina; Mercier, Eloi; Mungall, Karen L.; Ma, Yusanne; Tse, Kane; Zeng, Thomas; Shumansky, Karey; Roth, Andrew J. L.; Shah, Sohrab; Farooq, Hamza; Kijima, Noriyuki; Holgado, Borja L.; Lee, John J. Y.; Matan-Lithwick, Stuart; Liu, Jessica; Mack, Stephen C.; Manno, Alex; Michealraj, K. A.; Nor, Carolina; Peacock, John; Qin, Lei; Reimand, Juri; Rolider, Adi; Thompson, Yuan Y.; Wu, Xiaochong; Pugh, Trevor; Ally, Adrian; Bilenky, Mikhail; Butterfield, Yaron S. N.; Carlsen, Rebecca; Cheng, Young; Chuah, Eric; Corbett, Richard D.; Dhalla, Noreen; He, An; Lee, Darlene; Li, Haiyan I.; Long, William; Mayo, Michael; Plettner, Patrick; Qian, Jenny Q.; Schein, Jacqueline E.; Tam, Angela; Wong, Tina; Birol, Inanc; Zhao, Yongjun; Faria, Claudia C.; Pimentel, José; Nunes, Sofia; Shalaby, Tarek; Grotzer, Michael; Pollack, Ian F.; Hamilton, Ronald L.; Li, Xiao-Nan; Bendel, Anne E.; Fults, Daniel W.; Walter, Andrew W.; Kumabe, Toshihiro; Tominaga, Teiji; Collins, V. Peter; Cho, Yoon-Jae; Hoffman, Caitlin; Lyden, David; Wisoff, Jeffrey H.; Garvin, James H.; Stearns, Duncan S.; Massimi, Luca; Schüller, Ulrich; Sterba, Jaroslav; Zitterbart, Karel; Puget, Stephanie; Ayrault, Olivier; Dunn, Sandra E.; Tirapelli, Daniela P. C.; Carlotti, Carlos G.; Wheeler, Helen; Hallahan, Andrew R.; Ingram, Wendy; MacDonald, Tobey J.; Olson, Jeffrey J.; Van Meir, Erwin G.; Lee, Ji-Yeoun; Wang, Kyu-Chang; Kim, Seung-Ki; Cho, Byung-Kyu; Pietsch, Torsten; Fleischhack, Gudrun; Tippelt, Stephan; Ra, Young Shin; Bailey, Simon; Lindsey, Janet C.; Clifford, Steven C.; Eberhart, Charles G.; Cooper, Michael K.; Packer, Roger J.; Massimino, Maura; Garre, Maria Luisa; Bartels, Ute; Tabori, Uri; Hawkins, Cynthia E.; Dirks, Peter; Bouffet, Eric; Rutka, James T.; Wechsler-Reya, Robert J.; Weiss, William A.; Collier, Lara S.; Dupuy, Adam J.; Korshunov, Andrey; Jones, David T. W.; Kool, Marcel; Northcott, Paul A.; Pfister, Stefan M.; Largaespada, David A.; Mungall, Andrew J.; Moore, Richard A.; Jabado, Nada; Bader, Gary D.; Jones, Steven J. M.; Malkin, David; Marra, Marco A.; Taylor, Michael D.

    2016-01-01

    The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy. PMID:26760213

  7. PRAME gene expression profile in medulloblastoma

    Directory of Open Access Journals (Sweden)

    Tânia Maria Vulcani-Freitas

    2011-02-01

    Full Text Available Medulloblastoma is the most common malignant tumors of central nervous system in the childhood. The treatment is severe, harmful and, thus, has a dismal prognosis. As PRAME is present in various cancers, including meduloblastoma, and has limited expression in normal tissues, this antigen can be an ideal vaccine target for tumor immunotherapy. In order to find a potential molecular target, we investigated PRAME expression in medulloblastoma fragments and we compare the results with the clinical features of each patient. Analysis of gene expression was performed by real-time quantitative PCR from 37 tumor samples. The Mann-Whitney test was used to analysis the relationship between gene expression and clinical characteristics. Kaplan-Meier curves were used to evaluate survival. PRAME was overexpressed in 84% samples. But no statistical association was found between clinical features and PRAME overexpression. Despite that PRAME gene could be a strong candidate for immunotherapy since it is highly expressed in medulloblastomas.

  8. Medulloblastoma: Molecular Genetics and Animal Models

    Directory of Open Access Journals (Sweden)

    Corey Raffel

    2004-07-01

    Full Text Available Medulloblastoma is a primary brain tumor found in the cerebellum of children. The tumor occurs in association with two inherited cancer syndromes: Turcot syndrome and Gorlin syndrome. Insights into the molecular biology of the tumor have come from looking at alterations in the genes altered in these syndromes, PTC and APC, respectively. Murine models of medulloblastoma have been constructed based on these alterations. Additional murine models that, while mimicking the appearance of the human tumor, seem unrelated to the human tumor's molecular alterations have been made. In this review, the clinical picture, origin, molecular biology, murine models of medulloblastoma are discussed. Although a great deal has been discovered about this tumor, the genetic alterations responsible for tumor development in a majority of patients have yet to be described.

  9. Sexual dimorphism in medulloblastoma features.

    Science.gov (United States)

    Zannoni, Gian Franco; Ciucci, Alessandra; Marucci, Gianluca; Travaglia, Daniele; Stigliano, Egidio; Foschini, Maria Pia; Scambia, Giovanni; Gallo, Daniela

    2016-03-01

    Male sex is a risk factor for medulloblastoma (MB), and is also a negative predictor for clinical outcome. The aim of this study was to assess sex differences in tumour biological features and hormone receptor profiles in a cohort of MB patients. Sixty-four MBs and five normal cerebella were included in the study. Cell proliferation (Ki67), apoptosis (cleaved caspase-3) and microvessel density (CD31) were evaluated in tumours by immunohistochemistry. Tissues were analysed for oestrogen receptor (ER)α, ERβ1, ERβ2, ERβ5 and androgen receptor (AR) expression. The results demonstrated sex-specific features in MBs, with tumours from females showing a higher apoptosis/proliferation ratio and less tumour vascularization than tumours from males. MBs were negative for ERα and AR, but expressed ERβ isoforms at similar levels between the sexes. Altogether, these findings indicate that signalling mechanisms that control cell turnover and angiogenesis operate more efficiently in females than in males. The lack of sex differences in the hormone receptor profiles suggests that circulating oestrogens could be the major determinants of the sexual dimorphism observed in MB features. Here, we provide molecular support for epidemiological data showing sex differences in MB incidence and outcome, completely defining the hormone receptor profile of the tumours. © 2015 John Wiley & Sons Ltd.

  10. Metastatic Medulloblastoma in Childhood: Chang's Classification Revisited

    Directory of Open Access Journals (Sweden)

    Christelle Dufour

    2012-01-01

    Patients and Methods. This population-based study concerned 117 newly diagnosed children with disseminated medulloblastoma treated at the Institute Gustave Roussy between 1988 and 2008. Metastatic disease was assessed using the Chang staging system, their form (positive cerebrospinal fluid (CSF, nodular or laminar, and their extension (positive cerebrospinal fluid, local, extensive. All patients received preirradiation chemotherapy. Results. The overall survival did not differ according to Chang M-stage. The 5-year overall survival was 59% in patients with nodular metastases compared to 35% in those with laminar metastases. The 5-year overall survival was 76% in patients without disease at the end of pre-irradiation chemotherapy compared to 34% in those without a complete response (P=0.0008. Conclusions. Radiological characteristics of metastases correlated with survival in patients with medulloblastoma. Complete response to sandwich chemotherapy was a strong predictor of survival.

  11. [Pediatric medulloblastoma: Retrospective series of 52 patients].

    Science.gov (United States)

    Vigneron, C; Antoni, D; Coca, A; Entz-Werlé, N; Lutz, P; Spiegel, A; Jannier, S; Niederst, C; Jarnet, D; Meyer, P; Kehrli, P; Noël, G

    2016-04-01

    Retrospective analysis of the results of 52 children irradiated for a medulloblastoma. Between 1974 and 2012, 52 children with an average age of 6 years and a half (11 months-17 years and a half) were treated with surgery then with radiotherapy at the Comprehensive Cancer Centre of Strasbourg (France). For 44 children, the treatment consisted of a chemotherapy. After a mean follow-up of 106.6 months (7-446 months), 13 relapses and 24 deaths were observed. Overall survival at 5 years and 10 years were 62% and 57%, respectively. Disease-free survival at 5 years and 10 years were 80% and 63%, respectively. Univariate analysis found the following adverse prognostic factors: the existence of a postoperative residue, the positivity of the cerebrospinal fluid, the metastatic status and medulloblastoma of high-risk. Positivity of the cerebrospinal fluid remains a negative factor in multivariate analysis. These results confirm the survival rate obtained by a conventional approach (surgery then irradiation). Insufficiency of results and rarity of medulloblastoma require the establishment of international protocols. Copyright © 2016. Published by Elsevier SAS.

  12. Neuropsychological sequelae of medulloblastoma in adults

    International Nuclear Information System (INIS)

    Kramer, Joel H.; Crowe, Amy Bassell; Larson, David A.; Sneed, Penny K.; Gutin, Philip H.; McDermott, Michael W.; Prados, Michael D.

    1997-01-01

    Purpose: To investigate the neuropsychological consequences of medulloblastoma in adults. Methods: Patients 18 years of age or older who had medulloblastoma and at least 3 years of disease-free survival were eligible. A battery of tests was conducted to assess global intellectual functioning, verbal ability, visuospatial ability, memory, reasoning, and academic proficiency. For the verbal memory performance, each patient was matched with two normal controls selected on the basis of age, sex, and level of education. Results: Review of the Neuro-Oncology database revealed 24 patients eligible for the study. Of these, 10 patients (6 good-risk and 4 poor-risk) agreed to participate; 7 patients were lost to follow-up; 5 lived too far away to come to the testing site, and 2 refused testing. There were four men and six women; their mean age was 36.5 years at testing and 29.9 years at surgical diagnosis. Mean dose of whole brain radiation was 34.5 Gy. Mean interval between diagnosis and testing was 79.1 months. Test results demonstrated below average intelligence quotients (mean intelligence quotient 90.2; range 67-103) and specific deficits in memory, reasoning, visuospatial ability, and arithmetic. Conclusion: Adults with medulloblastoma in a prolonged disease-free status may suffer significant cognitive deficits. We recommend further controlled, prospective studies to evaluate cognitive outcomes in this patient population in the hope that interventional strategies could be developed, or treatment modified to minimize such toxicities

  13. Genes differentially expressed in medulloblastoma and fetal brain

    NARCIS (Netherlands)

    Michiels, E. M.; Oussoren, E.; van Groenigen, M.; Pauws, E.; Bossuyt, P. M.; Voûte, P. A.; Baas, F.

    1999-01-01

    Serial analysis of gene expression (SAGE) was used to identify genes that might be involved in the development or growth of medulloblastoma, a childhood brain tumor. Sequence tags from medulloblastoma (10229) and fetal brain (10692) were determined. The distributions of sequence tags in each

  14. A Rare Case of Medulloblastoma with Excessive Nodularity: Imagistic Features

    Directory of Open Access Journals (Sweden)

    Tascu A.

    2014-10-01

    Full Text Available Medulloblastoma is the most common malignant tumor of childhood. Neuroimaging can play a role in the diagnosis of medulloblastoma, however atypical features do exist [2]. We report the case of a 1 year and 10- month-old infant diagnosed with a medulloblastoma with what we term “excessive” nodularity based on neuroimaging features and confirmed by neuropathology. CT-scan (CT and magnetic resonance imaging (MRI examination of the brain revealed a very large posterior fossa tumor attached to tentorium. On T2-weighted and post-gadolinium sequences, the tumor shows an extensive nodular grape-like appearance. Initial the patient was underwent a ventriculo-peritoneal shunt. The second operative procedure was tumour resection. Histology examen revealed a diagnosis of medulloblastoma desmoplastic with extensive nodularity. The neuroradiographic features of this medulloblastoma with what we describe as “excessive” nodularity are important to recognize as these children may be cured with chemotherapy alone.

  15. The Neuroradiological Spectra of Adult and Pediatric Medulloblastoma Differ

    DEFF Research Database (Denmark)

    Beier, Dagmar; Kocakaya, Selin; Hau, Peter

    2018-01-01

    PURPOSE: Current knowledge on the spectrum of the neuroradiological appearance of adult medulloblastoma is sparse. Due to the rarity of the disease, adult patients were generally diagnosed and treated similar to children; however, pediatric and adult medulloblastomas display substantial molecular...... differences that may influence the neuroradiological phenotype. This study therefore aimed at assessment of the neuroradiological spectrum of adult medulloblastoma in comparison to pediatric tumors. METHODS: All available publications on adult medulloblastoma published until June 2013 were screened...... for imaging data on single patients. A total of 109 patients were identified and compared to 118 pediatric patients described in 4 cohorts. RESULTS: The average age of the adult patients was 34.3 years. Most adult medulloblastomas (57.6 %) were localized laterally (vs. 14.4 % in pediatric patients). On T1...

  16. Clinical implications of medulloblastoma subgroups: incidence of CSF diversion surgery.

    Science.gov (United States)

    Schneider, Christian; Ramaswamy, Vijay; Kulkarni, Abhaya V; Rutka, James T; Remke, Marc; Tabori, Uri; Hawkins, Cynthia; Bouffet, Eric; Taylor, Michael D

    2015-03-01

    While medulloblastoma was initially thought to comprise a single homogeneous entity, it is now accepted that it in fact comprises 4 discrete subgroups, each with its own distinct demographics, clinical presentation, transcriptomics, genetics, and outcome. Hydrocephalus is a common complication of medulloblastoma and not infrequently requires CSF diversion. The authors report the incidence of CSF diversion surgery in each of the subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). The medical and imaging records for patients who underwent surgery for medulloblastoma at The Hospital for Sick Children were retrospectively reviewed. The primary outcome was the requirement for CSF diversion surgery either before or within 60 days of tumor resection. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) was compared among subgroups. Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower mCPPRH score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases. The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality

  17. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Ohshima-Hosoyama, Sachiko; Hosoyama, Tohru; Nelon, Laura D. [Greehey Children' s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Keller, Charles, E-mail: keller@ohsu.edu [Greehey Children' s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229 (United States)

    2010-09-03

    Research highlights: {yields} Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. {yields} Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. {yields} Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.

  18. Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma.

    Science.gov (United States)

    Faria, Claudia C; Golbourn, Brian J; Dubuc, Adrian M; Remke, Marc; Diaz, Roberto J; Agnihotri, Sameer; Luck, Amanda; Sabha, Nesrin; Olsen, Samantha; Wu, Xiaochong; Garzia, Livia; Ramaswamy, Vijay; Mack, Stephen C; Wang, Xin; Leadley, Michael; Reynaud, Denis; Ermini, Leonardo; Post, Martin; Northcott, Paul A; Pfister, Stefan M; Croul, Sidney E; Kool, Marcel; Korshunov, Andrey; Smith, Christian A; Taylor, Michael D; Rutka, James T

    2015-01-01

    Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)-driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood-brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma. ©2014 American Association for Cancer Research.

  19. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    International Nuclear Information System (INIS)

    Ohshima-Hosoyama, Sachiko; Hosoyama, Tohru; Nelon, Laura D.; Keller, Charles

    2010-01-01

    Research highlights: → Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. → Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. → Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.

  20. Adoptive immunotherapy using PRAME-specific T cells in medulloblastoma.

    Science.gov (United States)

    Orlando, Domenico; Miele, Evelina; De Angelis, Biagio; Guercio, Marika; Boffa, Iolanda; Sinibaldi, Matilde; Po, Agnese; Caruana, Ignazio; Abballe, Luana; Carai, Andrea; Caruso, Simona; Camera, Antonio; Moseley, Annemarie; Hagedoorn, Renate S; Heemskerk, Mirjam H M; Giangaspero, Felice; Mastronuzzi, Angela; Ferretti, Elisabetta; Locatelli, Franco; Quintarelli, Concetta

    2018-04-03

    Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 medulloblastoma patients. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T cell-related toxicity,an inducible caspase 9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically-modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating HLA-A*02+ medulloblastoma patients. Copyright ©2018, American Association for Cancer Research.

  1. Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study.

    Science.gov (United States)

    Eberhart, Charles G; Kepner, James L; Goldthwaite, Patricia T; Kun, Larry E; Duffner, Patricia K; Friedman, Henry S; Strother, Douglas R; Burger, Peter C

    2002-01-15

    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. 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. Increasing grade of anaplasia and extent of anaplasia were associated strongly with progressively worse clinical outcomes (P anaplasia (moderate or severe) was identified in 24% of medulloblastoma specimens. Neither increasing degrees of nodularity nor desmoplasia were associated significantly with longer survival. 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.

  2. Cerebellar Medulloblastoma in Middle-to-Late Adulthood

    Directory of Open Access Journals (Sweden)

    Majid Aljoghaiman

    2018-01-01

    Full Text Available Medulloblastoma is a malignant brain tumor that is typically seen in children. It is classified as an embryonal tumor, classically located within the posterior fossa. When it involves the fourth ventricle, the patient commonly presents with signs and symptoms of raised intracranial pressure secondary to obstructive hydrocephalus. It is exceedingly rare for Medulloblastoma to occur in middle and late adulthood. In this paper, we present a case of a 51-year-old man who presented with a posterior fossa mass that was diagnosed later as Medulloblastoma.

  3. Multiple bone metastasis of medulloblastoma; a case report

    International Nuclear Information System (INIS)

    Oh, Jae Cheon; Lee, Seoung Ro; Kim, Yong Soo; Park, Dong Woo; Joo, Kyung Bin; Hahm, Chang Kok

    1996-01-01

    Medulloblastoma is one of the most undifferentiated primitive neuroectodermal tumors and represents about 30% of all posterior fossa tumors in children. Disseminated medulloblastoma, mainly involving cerebral surfaces, ventricles and the subarachnoid space can, in 50% of patients, be identified on intial imaging studies. One third of these lesions metastasize to an extracranial sity, primarily to bone. Osseous metastases, which occur mainly after craniectomy are typically lytic, but osteoblastic lesions also may occur. We experienced the case of a 14 year-old female patient with multiple bone metastases of medulloblastoma after craniectomy. Bone metastatic lesions were present in the right femur and thoracic spine and were osteoblastic or osteolytic

  4. Medulloblastoma with Excessive Nodularity: Radiographic Features and Pathologic Correlate

    Directory of Open Access Journals (Sweden)

    L. A. Yeh-Nayre

    2012-01-01

    Full Text Available Medulloblastoma with extensive nodularity is a rare subtype of the most common malignant childhood brain tumor and has been associated with more favorable prognosis. The authors report the case of a 10-month-old girl with a posterior fossa tumor of excessive nodularity with decreased diffusivity on diffusion-weighted magnetic resonance imaging sequences and robust grape-like postgadolinium contrast enhancing features. The unique neuroradiographic features were confirmed by histopathology and a diagnosis of medulloblastoma with extensive nodularity was made. This case highlights the importance of recognizing this unique medulloblastoma subtype preoperatively, as the more favorable outcome may preclude less aggressive medical management.

  5. Evaluation of lens dose in medulloblastoma radiotherapy

    International Nuclear Information System (INIS)

    Oliveira, F.L.; Vilela, E.C.; Sousa, S.A; Lima, F.F. de

    2007-01-01

    The improvement of the applied radiotherapy techniques in the cranial-spinal therapy, which is used in the cases of medulloblastoma, aims the reduction of the risks of future damages in enclosed critical agencies in the irradiation fields. This work aims to evaluate the lens doses due two common techniques used in medulloblastoma radiotherapy. For this, thermoluminescent dosimeters, previously calibrated, were located in an anthropomorphic phantom (ALDERSON - RANDON Laboratory), in the tumor and lens positions. The employed techniques were as following: (1) angled fields technique and (2) half-beam block technique. The phantom was irradiated five times in each technique with two lateral opposed fields in the brain with a total prescribed dose of 1.5 Gy, followed of two posterior spinal fields with the same prescribed dose, using a 6MV accelerator. The results showed that the doses in the first technique were 0.10 +- 0,04 Gy and, in second one, 0.09 +- 0,02 Gy. It was observed that, independent of the employed technique, the lens doses practically are the same. (author)

  6. [Adult medulloblastoma: Retrospective series of 21 patients].

    Science.gov (United States)

    Vigneron, C; Antoni, D; Coca, A; Niederst, C; Jarnet, D; Meyer, P; Kehrli, P; Noël, G

    2016-02-01

    Retrospective analysis of the results of 21 adults treated for medulloblastoma. Between 1978 and 2011, 21 adults with an average age of 31 years (18.3-50) were treated with surgery then with radiotherapy (n=20) at the Comprehensive Cancer Center of Strasbourg. For some (n=12), treatment consisted of chemotherapy. After a mean follow-up of 122 months (19-423), six relapses and seven deaths were observed. Overall survival at 5 years and 10 years was 89.4 ± 7.1% for both. Disease-free survival at 5 years and 10 years was 79.6 ± 9.2% and 85.7 ± 7.6% and 60.6 ± 17.7%, respectively. The rarity of medulloblastoma, especially in adults and these results confirm the necessity of international protocols. Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  7. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

    NARCIS (Netherlands)

    Hovestadt, Volker; Jones, David T. W.; Picelli, Simone; Wang, Wei; Kool, Marcel; Northcott, Paul A.; Sultan, Marc; Stachurski, Katharina; Ryzhova, Marina; Warnatz, Hans-Jörg; Ralser, Meryem; Brun, Sonja; Bunt, Jens; Jäger, Natalie; Kleinheinz, Kortine; Erkek, Serap; Weber, Ursula D.; Bartholomae, Cynthia C.; von Kalle, Christof; Lawerenz, Chris; Eils, Jürgen; Koster, Jan; Versteeg, Rogier; Milde, Till; Witt, Olaf; Schmidt, Sabine; Wolf, Stephan; Pietsch, Torsten; Rutkowski, Stefan; Scheurlen, Wolfram; Taylor, Michael D.; Brors, Benedikt; Felsberg, Jörg; Reifenberger, Guido; Borkhardt, Arndt; Lehrach, Hans; Wechsler-Reya, Robert J.; Eils, Roland; Yaspo, Marie-Laure; Landgraf, Pablo; Korshunov, Andrey; Zapatka, Marc; Radlwimmer, Bernhard; Pfister, Stefan M.; Lichter, Peter

    2014-01-01

    Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies,

  8. Epidermal Nevus Syndrome Associated with Brain Malformations and Medulloblastoma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-01-01

    Full Text Available Researchers at Juntendo University and Tokyo Women’s Medical University, Japan; and University of California, San Francisco, Ca, report a male infant with epidermal nevus syndrome associated with brainstem and cerebellar malformations and neonatal medulloblastoma.

  9. Cell of Origin and Cancer Stem Cell Phenotype in Medulloblastomas

    Science.gov (United States)

    2015-07-01

    medulloblastoma by activating N1ICD and PIK3CA in cerebellar NSCs and NPCs in the developing mouse brain. N1ICD models : We previously published...Aims: 1. Validate general applicability and clinical potential of SP66 as a theragnostic agent by measuring tumor uptake in PDX GBM models and a...spontaneous mouse medulloblastoma model ; 2. Evaluate the therapeutic potential of SP66 in vitro and in vivo. Overlap: None Contracting/ Grants

  10. Cell of Origin and Cancer Stem Cell Phenotype in Medulloblastomas

    Science.gov (United States)

    2017-09-01

    AWARD NUMBER: W81XWH-14-1-0115 TITLE: Cell of Origin and Cancer Stem Cell Phenotype in Medulloblastomas PRINCIPAL INVESTIGATOR: Kyuson Yun...CA130273 - Cell of Origin and Cancer Stem Cell Phenotype in Medulloblastomas 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0115 5c. PROGRAM...hypothesis, we originally proposed to transform neural stem cells (NSCs) and neural progenitor cells (NPCs) in vivo by expressing an activated form

  11. Medulloblastoma in association with the Coffin-Siris syndrome.

    Science.gov (United States)

    Rogers, L; Pattisapu, J; Smith, R R; Parker, P

    1988-02-01

    An 8-year old patient with Coffin-Siris syndrome is presented, who was found to have a medulloblastoma during the evaluation of apnea and ventilator dependency. Although several cases of Dandy Walker cysts and one case of brain-stem heterotopia have been described in this rare syndrome, this is the first report of medulloblastoma in a patient with Coffin-Siris syndrome. Possible pathogenetic mechanisms are briefly discussed.

  12. BET bromodomain inhibition of MYC-amplified medulloblastoma.

    Science.gov (United States)

    Bandopadhayay, Pratiti; Bergthold, Guillaume; Nguyen, Brian; Schubert, Simone; Gholamin, Sharareh; Tang, Yujie; Bolin, Sara; Schumacher, Steven E; Zeid, Rhamy; Masoud, Sabran; Yu, Furong; Vue, Nujsaubnusi; Gibson, William J; Paolella, Brenton R; Mitra, Siddhartha S; Cheshier, Samuel H; Qi, Jun; Liu, Kun-Wei; Wechsler-Reya, Robert; Weiss, William A; Swartling, Fredrik J; Kieran, Mark W; Bradner, James E; Beroukhim, Rameen; Cho, Yoon-Jae

    2014-02-15

    MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma. ©2013 AACR

  13. Molecular subgroups of medulloblastoma identification using noninvasive magnetic resonance spectroscopy.

    Science.gov (United States)

    Blüml, Stefan; Margol, Ashley S; Sposto, Richard; Kennedy, Rebekah J; Robison, Nathan J; Vali, Marzieh; Hung, Long T; Muthugounder, Sakunthala; Finlay, Jonathan L; Erdreich-Epstein, Anat; Gilles, Floyd H; Judkins, Alexander R; Krieger, Mark D; Dhall, Girish; Nelson, Marvin D; Asgharzadeh, Shahab

    2016-01-01

    Medulloblastomas in children can be categorized into 4 molecular subgroups with differing clinical characteristics, such that subgroup determination aids in prognostication and risk-adaptive treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, noninvasive tool that is used to determine the metabolic characteristics of tumors and provide diagnostic information without the need for tumor tissue. In this study, we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma and allow accurate subgroup determination. MRS was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of 14 metabolites were analyzed to determine those that were the most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier for distinguishing between combined Group 3/4 and SHH tumors. Medulloblastomas across molecular subgroups revealed distinct spectral features. Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids, and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. A 5-metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate, and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated area under the curve [AUC] = 0.88). The data show that medulloblastomas of Group 3/4 differ metabolically as measured using MRS when compared with SHH molecular subgroups. MRS is a useful and accurate tool to determine medulloblastoma molecular subgroups. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. EG-15THE METHYLATION STATUS OF MGMT IN MEDULLOBLASTOMA

    Science.gov (United States)

    Shimizu, Yuzaburo; Kurimoto, Tomoko; Kondo, Akihide; Arai, Hajime

    2014-01-01

    BACKGROUND: Medulloblastoma is a highly malignant brain tumor in childhood. Some studies reported that alkylating chemotherapeutic drugs are effective agents in the treatment of patients with medulloblastoma. O6-methylguanine-DNA methyltransferase (MGMT) is one of the DNA repair enzymes and plays a significant role in tumor resistance to alkylating agents. Low MGMT expression or MGMT promoter methylation have been found to be associated with favorable outcomes in malignant glioma patients treated with alkylating agents such as temozolomide. However, impact of MGMT status on clinical outcomes in medulloblastoma patients is not fully evaluated. OBJECTIVE: The objective of this study is to investigate the association between MGMT status and the response for chemotherapy in pediatric patients with medulloblastoma. METHODS: Patients with medulloblastoma treated at our institution between 1995 and 2012 were reviewed retrospectively. Relevant clinical information including current disease status, tumor response to chemotherapy was obtained from the hospital charts. To evaluate the MGMT status, we performed bisulfite sequencing analysis to determine the methylation status of the MGMT promoter. RESULTS: Tumor material and detailed clinical information were available in 22 patients. Of them, 13 patients were alive (11 in CR), seven died of disease and two were lost to follow up. Five patients were with dissemination at diagnosis. We succeeded to evaluate both the MGMT status of tumors and the number of methylation sites in MGMT promoter. CONCLUSIONS: We studied the prognostic value of MGMT promoter methylation in medulloblastoma children.

  15. Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Tao Xu

    2017-03-01

    Full Text Available Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy have led to significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in ~30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the postphosphorylation fate of its targets. The GLI1/PIN1 interaction was validated by reciprocal pulldowns using epitope-tagged proteins in HEK293T cells as well as by co-immunoprecipiations of the endogenous proteins in a medulloblastoma cell line. Our results support a molecular model in which PIN1 promotes GLI1 protein abundance, thus contributing to the positive regulation of Hedgehog signals. Most importantly, in vivo functional analyses of Pin1 in the GFAP-tTA;TRE-SmoA1 mouse model of Hedgehog-driven medulloblastoma demonstrate that the loss of Pin1 impairs tumor development and dramatically increases survival. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in Hedgehog-driven medulloblastoma tumorigenesis.

  16. Expression of BARHL1 in medulloblastoma is associated with prolonged survival in mice and humans

    NARCIS (Netherlands)

    Pöschl, J.; Lorenz, A.; Hartmann, W.; von Bueren, A. O.; Kool, M.; Li, S.; Peraud, A.; Tonn, J.-C.; Herms, J.; Xiang, M.; Rutkowski, S.; Kretzschmar, H. A.; Schüller, U.

    2011-01-01

    Medulloblastoma is the most common malignant brain tumor in childhood, and development of targeted therapies is highly desired. Although the molecular mechanisms of malignant transformation are not fully understood, it is known that medulloblastomas may arise from cerebellar granule neuron

  17. Probable Opitz trigonocephaly C syndrome with medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Omran, H.; Hildebrandt, F.; Brandis, M. [Freiburg Univ. (Germany)] [and others

    1997-04-14

    We report on a patient with trigonocephaly, biparietal widening as a result of metopic synostosis, strabismus, upslanted palpebral fissures, apparently low-set ears with abnormal helices, deeply furrowed palate, postaxial polysyndactyly of the feet, ankle flexion deformities, cryptorchidism, loose skin, and severe mental retardation, findings compatible with a diagnosis of the Opitz trigonocephaly C syndrome (OTS). At the age of 12 years this patient presented with symptoms of raised intracranial pressure. A biopsy showed findings diagnostic of a medulloblastoma WHO Grade IV, an unprecedented finding in OTS. The possibility of coincidence should not prevent continued surveillance of OTS patients in the future for the occurrence of malignancy. 33 refs., 4 figs., 1 tab.

  18. Medulloblastoma in children: CT and MRI findings

    International Nuclear Information System (INIS)

    Tortori-Donati, P.; Fondelli, M.P.; Rossi, A.; Cama, A.; Caputo, L.; Andreussi, L.; Garre, M.L.

    1996-01-01

    Our purpose was to determine whether medulloblastoma (MB) shows specific neuroradiological features which may be employed in differential diagnosis from other common posterior cranial fossa tumours in childhood. Preoperative MRI was performed on 20 children with MB, and preoperative CT in 17 of them. All underwent surgery and histopathological diagnosis. There was a constant relationship between high density on CT and low signal on T1-weighted images. Signal behaviour on T2-weighted images and the degree of contrast enhancement were more variable. Most tumours arose in the midline, from the cerebellar vermis, involving the fourth ventricle, but hemisphere and extra-axial neoplasms were also seen. The combination of high density on CT and low signal on T1-weighted images is highly suggestive of MB and may assist preoperative differential diagnosis from other posterior cranial fossa tumours. (orig.). With 9 figs., 2 tabs

  19. Recent developments and current concepts in medulloblastoma.

    Science.gov (United States)

    Gerber, N U; Mynarek, M; von Hoff, K; Friedrich, C; Resch, A; Rutkowski, S

    2014-04-01

    Medulloblastoma is the most common malignant brain tumor of childhood. While prognosis has significantly improved in the last decades with multimodal therapy including surgery, radiotherapy, and chemotherapy, one third of patients still succumb to their disease. Further research is needed to find more efficient treatment strategies for prognostically unfavorable patient groups and to minimize long-term sequelae of tumor treatment. This review gives a summary of the current state of treatment concepts including an outlook on the near future. We describe recent advances in the understanding of molecular mechanisms, their potential impact on risk stratification in upcoming clinical trials, and perspectives for the clinical implementation of targeted therapies. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Contemporary issues in clinical trials for medulloblastoma

    International Nuclear Information System (INIS)

    Kun, Larry E.

    1996-01-01

    Medulloblastoma is the seminal pediatric brain tumor providing opportunities for clinical investigation to define improved treatment strategies for both disease control and ultimate functional integrity. Recent studies addressing neuraxis radiation dose provide a 'standard' for conventional therapy while establishing 5-year disease control rates for 'favorable' or 'low risk' presentations approximating 60% following surgery and irradiation. A highly visible recent report of combined post-operative irradiation and chemotherapy incorporating a platinum- and alkylator-based regimen indicates 5-year disease control approaching 90% in localized medulloblastoma. Despite unfavorable outcome with reduced-dose neuraxis irradiation in earlier trials, further data from recent studies suggest the addition of post-operative chemotherapy to similarly reduced-dose neuraxis irradiation (23.4 Gy) in 'favorable' presentations may result in progression-free survival rates at least equivalent to those achieved with full-dose neuraxis irradiation (36 Gy) absent chemotherapy. The panel will (1) provide updated information regarding the major clinical trials that form the basis for current and planned protocols and (2) debate the therapeutic modifications appropriate for contemporary clinical investigations. Critical in planning future studies in the analysis of risk factors that may identify 'favorable' patients versus 'high risk' patients. Risk-related studies appropriately address maintaining or improving current disease control rates in the context of diminishing late treatment sequelae for 'favorable' presentations. For those identified as 'high risk' (e.g., patients with disease beyond the primary site), studies are in development that increase the intensity of chemotherapy and explore modifications of radiation delivery. Study designs that permit assessment of innovations in surgical, radiotherapeutic, and chemotherapeutic approaches will be presented and debated by the panelists

  1. Intrathecal chemotherapy for refractory disseminated medulloblastoma.

    Science.gov (United States)

    Yoshimura, Junichi; Nishiyama, Kenichi; Mori, Hiroshi; Takahashi, Hideaki; Fujii, Yukihiko

    2008-05-01

    To analyze the effect of intrathecal (IT) chemotherapy for disseminated medulloblastoma. Twenty-one patients received IT chemotherapy using the chemotherapeutic agents of methotrexate (MTX) and nitrosoureas (ACNU, MCNU) including nine patients for residual leptomeningeal lesions after initial surgery and radiation, and 12 for a recurrence with leptomeningeal dissemination. Of these 21 patients, 12 received a lumbar and/or ventricular bolus injection of the chemotherapeutic agents, one received the ventriculolumbar perfusion of the agents, and eight received both the perfusion and bolus injection. The doses ranged from 6-7 mg/m(2) of ACNU for perfusion and 3-3.5 mg/m(2) of ACNU, MCNU, or MTX for the bolus injection, and the cycles were administered from 3 to 12 times for perfusion and from 5 to 54 times for the bolus injection. The effects of chemotherapy were assessed by both radiological and cytological examinations, and the clinical symptoms were also assessed. Radiological and/or cytological responses were observed in 10 of 21 patients (47.6%), including seven cases demonstrating a complete remission. The 5-year overall survival rate and 5-year survival rate after dissemination were 61.5 and 46.4%, respectively. Five patients who received a lumbar bolus injection of nitrosoureas experienced paraplegia and double incontinence. One patient who received a ventricular injection of nitrosoureas experienced truncal ataxia. IT chemotherapy was found to be effective in some cases with refractory disseminated medulloblastoma and it seems to be an appropriate treatment choice for leptomeningeal recurrence. However, the frequent bolus injections of nitrosoureas should be avoided to prevent the side effects.

  2. Targeting the Enhancer of Zeste Homologue 2 in Medulloblastoma

    Science.gov (United States)

    Alimova, Irina; Venkataraman, Sujatha; Harris, Peter; Marquez, Victor E.; Northcott, Paul A; Dubuc, Adrian; Taylor, Michael D; Foreman, Nicholas K; Vibhakar, Rajeev

    2012-01-01

    Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 that catalyzes the trimethylation of histone H3 on Lys 27, and represses gene transcription. EZH2 enhances cancer-cell proliferation and regulates stem cell maintenance and differentiation. Here, we demonstrate that EZH2 is highly expressed in medulloblastoma, a highly malignant brain tumor of childhood, and this altered expression is correlated with genomic gain of chromosome 7 in a subset of medulloblastoma. Inhibition of EZH2 by RNAi suppresses medulloblastoma tumor cell growth. We show that 3-deazaneplanocin A, a chemical inhibitor of EZH2, can suppress medulloblastoma cell growth partially by inducing apoptosis. Suppression of EZH2 expression diminishes the ability of tumor cells to form spheres in culture and strongly represses the ability of known oncogenes to transform neural stem cells. These findings establish a role of EZH2 in medulloblastoma and identify EZH2 as a potential therapeutic target especially in high-risk tumors. PMID:22287205

  3. c-myc overexpression causes anaplasia in medulloblastoma.

    Science.gov (United States)

    Stearns, Duncan; Chaudhry, Aneeka; Abel, Ty W; Burger, Peter C; Dang, Chi V; Eberhart, Charles G

    2006-01-15

    Both anaplasia and increased c-myc gene expression have been shown to be negative prognostic indicators for survival in medulloblastoma patients. myc gene amplification has been identified in many large cell/anaplastic medulloblastoma, but no causative link between c-myc and anaplastic changes has been established. To address this, we stably overexpressed c-myc in two medulloblastoma cell lines, DAOY and UW228, and examined the changes in growth characteristics. When analyzed in vitro, cell lines with increased levels of c-myc had higher rates of growth and apoptosis as well as significantly improved ability to form colonies in soft agar compared with control. When injected s.c. into nu/nu mice, flank xenograft tumors with high levels of c-myc in DAOY cell line background were 75% larger than those derived from control. Overexpression of c-myc was required for tumor formation by UW228 cells. Most remarkably, the histopathology of the Myc tumors was severely anaplastic, with large areas of necrosis/apoptosis, increased nuclear size, and macronucleoli. Indices of proliferation and apoptosis were also significantly higher in Myc xenografts. Thus, c-myc seems to play a causal role in inducing anaplasia in medulloblastoma. Because anaplastic changes are often observed in recurrent medulloblastoma, we propose that c-myc dysregulation is involved in the progression of these malignant embryonal neoplasms.

  4. Medulloblastoma with extensive nodularity: US, CT and MRI findings

    International Nuclear Information System (INIS)

    Bekiesinska-Figatowska, M.; Uliasz, M.; Roszkowski, M.

    2008-01-01

    Medulloblastoma accounts for up to 25% of all paediatric CNS tumours. According to WHO classification (2007) medulloblastoma with extensive nodularity (MBEN) is a separate rare entity associated with younger age and better prognosis. A 9-month-old girl was admitted and examined because of macrocephaly and disturbed psychomotor development. Transfontanel ultrasound revealed dilated ventricular system and hyperechoic mass in the posterior cranial fossa. Computed tomography showed hyperdense mass in the cerebellum. Magnetic resonance imaging revealed a mass with gyriform pattern and strong contrast enhancement after gadolinium administration. Differential diagnosis included dysplastic heterotopic cortex, Lhermitte-Duclos disease, atypical teratoid/rhabdoid tumour (AT/RT), and medulloblastoma (MB). The patient was operated on. Medulloblastoma with extensive nodularity (MBEN) was finally diagnosed. The authors present and discuss three other cases of this rare entity.Transfontanel sonografic examination is capable of detection of the posterior fossa tumour as a cause of hydrocephalus and macrocephaly. The mass in a child's posterior cranial fossa that is hyperdense on unenhanced CT and gyriform, nodular, and markedly enhancing on MRI may strongly suggest medulloblastoma with extensive nodularity (MBEN). (authors)

  5. Magnetic resonance imaging in the evaluation of medulloblastomas

    International Nuclear Information System (INIS)

    Tokimura, Hiroshi; Uetsuhara, Koichi; Komasaku, Ryuichiro; Kasamo, Shizuya; Asakura, Tetsuhiko

    1989-01-01

    Five patients with medulloblastomas were evaluated with Magnetic Resonance Imaging (MRI), and the results were compared with those of X-ray computed tomography (CT). On CT, medulloblastomas generally appeared as isodense or hyperdense masses and were enhanced uniformly with a contrast agent. On MRI, medulloblastomas appeared as low-intensity masses in T 1 -weighted images and as high-intensity masses in T 2 -weighted images. Moreover, the tumors were clearly differentiated from the surrounding tissue. In sagittal images, we could easily recognize the relation between the brainstem or the fourth ventiricle and the tumors. In spite of these merits, though, on MRI we could not detect the boundary between the tumors and the perifocal edema. In this point, we had to be dependent on CT. In one case, we could measure the T 1 value and the T 2 value both before and after irradiation. The T 2 value was markedly decreased after irradiation. Henceforth, the T 1 and T 2 values can be used to evaluate the effects of irradiation. Medulloblastomas are often disseminated through cerebrospinal fluid. We could detect this type of metastasis by means of the sagittal image on MRI. As has been mentioned above, MRI is very useful in diagnosing medulloblastomas and for the post-operative follow-up those tumors. (author)

  6. Adult cerebellar medulloblastoma: CT and MRI findings in eight cases

    Energy Technology Data Exchange (ETDEWEB)

    Carvalho Neto, Arnolfo de; Bertoldi, Guilherme A. [Parana Univ., Curitiba, PR (Brazil). Radiologia Diagnostica]. E-mail: arnolfo.carvalho@avalon.sul.com.br; Gasparetto, Emerson L. [Parana Univ., Curitiba, PR (Brazil). Hospital das Clinicas. Secao de Radiologia Diagnostica; Ono, Sergio E. [Parana Univ., Curitiba, PR (Brazil). Faculdade de Medicina; Gomes, Andre F. [Diagnostico Avancado Por Imagem (DAPI), Curitiba, PR (Brazil)

    2003-06-01

    Medulloblastoma is a brain tumor of neuro epithelial origin, which represents 15 to 30% of all pediatric brain tumors, and less than 1% of CNS adult neoplasms. We report the imaging findings of 8 adult patients with medulloblastoma. The mean age was 35 years, ranging from 20 to 65 years, and the male:female rate was 3:5. The tumors were predominantly lateral (63%), hyperdense on CT scans (83%), and on the MRI, hypointense on T1 (100%) and hyperintense on T2 (80%) weighted images. It was seen intratumoral necrosis and cysts in six cases and calcifications in three. Hydrocephalus was observed in 5 cases and brain stem invasion in four. The imaging findings of medulloblastomas in adults are different of those in child, and also nonspecific. Although these tumors are uncommon in adults, they must be considered in the differential diagnosis of cerebellar masses in the posterior fossa of this age group. (author)

  7. Is there a danger in delaying radiotherapy in childhood medulloblastoma?

    International Nuclear Information System (INIS)

    Attard-Montalto, S.; Plowman, N.; Saha, V.; Eden, O.B.; Breatnach, F.

    1993-01-01

    Approximately 45-50% of children with medulloblastoma are cured by conventional surgery and radiotherapy, but survivors may face severe late neuropsychological toxicity. Studies showing good partial responses to platinum-based chemotherapy in relapsed patients and the theoretical possibility of a therapeutic window immediately after surgery have prompted neoadjuvant treatment studies. However, the absolute benefit of chemotherapy for the treatment of medulloblastoma in childhood is, as yet, not proven. Chemotherapy may simply delay radiotherapy, and reduce the radiological impact of this known effective treatment. The authors report four children with medulloblastoma whose management was problematic because of either failure to respond to neoadjuvant chemotherapy or their young age. These cases are discussed in the light of the current literature and future treatment strategies. (author)

  8. Protein kinase A regulatory subunit distribution in medulloblastoma

    International Nuclear Information System (INIS)

    Mucignat-Caretta, Carla; Denaro, Luca; Redaelli, Marco; D'Avella, Domenico; Caretta, Antonio

    2010-01-01

    Previous studies showed a differential distribution of the four regulatory subunits of cAMP-dependent protein kinases inside the brain, that changed in rodent gliomas: therefore, the distribution of these proteins inside the brain can give information on the functional state of the cells. Our goal was to examine human brain tumors to provide evidence for a differential distribution of protein kinase A in different tumors. The distribution of detergent insoluble regulatory (R1 and R2) and catalytic subunits of cAMP dependent kinases was examined in pediatric brain tumors by immunohistochemistry and fluorescent cAMP analogues binding. R2 is organized in large single dots in medulloblastomas, while it has a different appearance in other tumors. Fluorescent cAMP labelling was observed only in medulloblastoma. A different distribution of cAMP dependent protein kinases has been observed in medulloblastoma

  9. Adult cerebellar medulloblastoma: CT and MRI findings in eight cases

    Directory of Open Access Journals (Sweden)

    Carvalho Neto Arnolfo de

    2003-01-01

    Full Text Available Medulloblastoma is a brain tumor of neuroepithelial origin, which represents 15 to 30% of all pediatric brain tumors, and less than 1% of CNS adult neoplasms. We report the imaging findings of 8 adult patients with medulloblastoma. The mean age was 35 years, ranging from 20 to 65 years, and the male:female rate was 3:5. The tumors were predominantly lateral (63%, hyperdense on CT scans (83%, and on the MRI, hypointense on T1 (100% and hyperintense on T2 (80% weighted images. It was seen intratumoral necrosis and cysts in six cases and calcifications in three. Hydrocephalus was observed in 5 cases and brain stem invasion in four. The imaging findings of medulloblastomas in adults are different of those in child, and also nonspecific. Although these tumors are uncommon in adults, they must be considered in the differential diagnosis of cerebellar masses in the posterior fossa of this age group.

  10. Evasion of Cell Senescence Leads to Medulloblastoma Progression

    Directory of Open Access Journals (Sweden)

    Lukas Tamayo-Orrego

    2016-03-01

    Full Text Available How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using Ptch1+/− mice to study medulloblastoma progression, we found that Ptch1 loss of heterozygosity (LOH is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence. Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic p53 mutations or Cdkn2a locus inactivation. Consistent with senescence evasion, these p53 mutations are always subsequent to Ptch1 LOH. Introduction of a p53 mutation prevents senescence, accelerates tumor formation, and increases medulloblastoma incidence. Altogether, our results show that evasion of senescence associated with Ptch1 LOH allows progression to advanced tumors.

  11. Adult cerebellar medulloblastoma: CT and MRI findings in eight cases

    International Nuclear Information System (INIS)

    Carvalho Neto, Arnolfo de; Bertoldi, Guilherme A.

    2003-01-01

    Medulloblastoma is a brain tumor of neuro epithelial origin, which represents 15 to 30% of all pediatric brain tumors, and less than 1% of CNS adult neoplasms. We report the imaging findings of 8 adult patients with medulloblastoma. The mean age was 35 years, ranging from 20 to 65 years, and the male:female rate was 3:5. The tumors were predominantly lateral (63%), hyperdense on CT scans (83%), and on the MRI, hypointense on T1 (100%) and hyperintense on T2 (80%) weighted images. It was seen intratumoral necrosis and cysts in six cases and calcifications in three. Hydrocephalus was observed in 5 cases and brain stem invasion in four. The imaging findings of medulloblastomas in adults are different of those in child, and also nonspecific. Although these tumors are uncommon in adults, they must be considered in the differential diagnosis of cerebellar masses in the posterior fossa of this age group. (author)

  12. ASC deficiency suppresses proliferation and prevents medulloblastoma incidence.

    Science.gov (United States)

    Knight, E R W; Patel, E Y; Flowers, C A; Crowther, A J; Ting, J P; Miller, C R; Gershon, T R; Deshmukh, M

    2015-01-15

    Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC's role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-β pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy.

  13. Extraneural metastases of medulloblastoma: desmoplastic variants may have prolonged survival.

    Science.gov (United States)

    Young, Robert J; Khakoo, Yasmin; Yhu, Stephen; Wolden, Suzanne; De Braganca, Kevin C; Gilheeney, Stephen W; Dunkel, Ira J

    2015-04-01

    Extraneural metastases from CNS medulloblastoma are rare and poorly described. The purpose of this study is to describe the clinical and radiological characteristics of a large single institution series of patients with medulloblastoma who developed extraneural metastases. We retrospectively reviewed a departmental database over a 20 year period for all patients with medulloblastoma who developed extraneural metastases. Chart and imaging reviews were performed, and overall survival (OS) estimated by the Kaplan-Meier method. We found 14 patients with medulloblastoma and extraneural metastases. The median age at initial diagnosis was 16.3 years (range, 3.2-44.2), and the most common subtype was desmoplastic (n = 6, 42.9%). After initial gross total resection, most patients received radiation therapy alone (n = 10, 71.4%). Metastases to bone were most common (n = 11, 78.6%) followed by metastases to bone marrow (n = 6, 42.9%), usually to the spine. The median time from initial diagnosis to first extraneural metastasis was 1.5 years (range, 0.2-17.4), and the median OS from extraneural metastasis to death was 3.3 years (range, 0-18). The Kaplan-Meier estimate of 5 year OS from extraneural metastasis diagnosis was 40.0% (95% CI, 20.2-79.2). Extraneural metastases from medulloblastoma may rarely develop after initial diagnosis to involve bone and bone marrow. We found that desmoplastic variant extraneural tumors had longer survival than nondesmoplastic variants, suggesting that histopathological and more recent molecular subtyping have important roles in determining the prognosis of medulloblastoma patients. © 2014 Wiley Periodicals, Inc.

  14. Epigenetic Silencing of DKK3 in Medulloblastoma

    Directory of Open Access Journals (Sweden)

    André Oberthuer

    2013-04-01

    Full Text Available Medulloblastoma (MB is a malignant pediatric brain tumor arising in the cerebellum consisting of four distinct subgroups: WNT, SHH, Group 3 and Group 4, which exhibit different molecular phenotypes. We studied the expression of Dickkopf (DKK 1–4 family genes, inhibitors of the Wnt signaling cascade, in MB by screening 355 expression profiles derived from four independent datasets. Upregulation of DKK1, DKK2 and DKK4 mRNA was observed in the WNT subgroup, whereas DKK3 was downregulated in 80% MBs across subgroups with respect to the normal cerebellum (p < 0.001. Since copy number aberrations targeting the DKK3 locus (11p15.3 are rare events, we hypothesized that epigenetic factors could play a role in DKK3 regulation. Accordingly, we studied 77 miRNAs predicting to repress DKK3; however, no significant inverse correlation between miRNA/mRNA expression was observed. Moreover, the low methylation levels in the DKK3 promoters (median: 3%, 5% and 5% for promoter 1, 2 and 3, respectively excluded the downregulation of gene expression by methylation. On the other hand, the treatment of MB cells with Trichostatin A (TSA, a potent inhibitor of histone deacetylases (HDAC, was able to restore both DKK3 mRNA and protein. In conclusion, DKK3 downregulation across all MB subgroups may be due to epigenetic mechanisms, in particular, through chromatin condensation.

  15. Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma

    Science.gov (United States)

    2018-06-18

    Constitutional Mismatch Repair Deficiency Syndrome; Lynch Syndrome; Malignant Glioma; Progressive Ependymoma; Progressive Medulloblastoma; Recurrent Brain Neoplasm; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Brain Neoplasm; Refractory Diffuse Intrinsic Pontine Glioma; Refractory Ependymoma; Refractory Medulloblastoma

  16. ID3 contributes to cerebrospinal fluid seeding and poor prognosis in medulloblastoma

    International Nuclear Information System (INIS)

    Phi, Ji Hoon; Choi, Seung Ah; Lim, Sang-Hee; Lee, Joongyub; Wang, Kyu-Chang; Park, Sung-Hye; Kim, Seung-Ki

    2013-01-01

    The inhibitor of differentiation (ID) genes have been implicated as promoters of tumor progression and metastasis in many human cancers. The current study investigated the expression and functional roles of ID genes in seeding and prognosis of medulloblastoma. ID gene expression was screened in human medulloblastoma tissues. Knockdown of ID3 gene was performed in medulloblastoma cells in vitro. The expression of metastasis-related genes after ID3 knockdown was assessed. The effect of ID3 knockdown on tumor seeding was observed in an animal model in vivo. The survival of medulloblastoma patients was plotted according to the ID3 expression levels. Significantly higher ID3 expression was observed in medulloblastoma with cerebrospinal fluid seeding than tumors without seeding. Knockdown of ID3 decreased proliferation, increased apoptosis, and suppressed the migration of D283 medulloblastoma cells in vitro. In a seeding model of medulloblastoma, ID3 knockdown in vivo with shRNA inhibited the growth of primary tumors, prevented the development of leptomeningeal seeding, and prolonged animal survival. High ID3 expression was associated with shorter survival of medulloblastoma patients, especially in Group 4 medulloblastomas. High ID3 expression is associated with medullolbastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors. ID3 may represent the metastatic/ aggressive phenotype of a subgroup of medulloblastoma

  17. Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Lee, Seung Joon; Krauthauser, Candice; Maduskuie, Victoria; Fawcett, Paul T; Olson, James M; Rajasekaran, Sigrid A

    2011-01-01

    Medulloblastoma is the most common brain tumor in children, and its prognosis is worse than for many other common pediatric cancers. Survivors undergoing treatment suffer from serious therapy-related side effects. Thus, it is imperative to identify safer, effective treatments for medulloblastoma. In this study we evaluated the anti-cancer potential of curcumin in medulloblastoma by testing its ability to induce apoptosis and inhibit tumor growth in vitro and in vivo using established medulloblastoma models. Using cultured medulloblastoma cells, tumor xenografts, and the Smo/Smo transgenic medulloblastoma mouse model, the antitumor effects of curcumin were tested in vitro and in vivo. Curcumin induced apoptosis and cell cycle arrest at the G2/M phase in medulloblastoma cells. These effects were accompanied by reduced histone deacetylase (HDAC) 4 expression and activity and increased tubulin acetylation, ultimately leading to mitotic catastrophe. In in vivo medulloblastoma xenografts, curcumin reduced tumor growth and significantly increased survival in the Smo/Smo transgenic medulloblastoma mouse model. The in vitro and in vivo data suggest that curcumin has the potential to be developed as a therapeutic agent for medulloblastoma

  18. Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Olson James M

    2011-04-01

    Full Text Available Abstract Background Medulloblastoma is the most common brain tumor in children, and its prognosis is worse than for many other common pediatric cancers. Survivors undergoing treatment suffer from serious therapy-related side effects. Thus, it is imperative to identify safer, effective treatments for medulloblastoma. In this study we evaluated the anti-cancer potential of curcumin in medulloblastoma by testing its ability to induce apoptosis and inhibit tumor growth in vitro and in vivo using established medulloblastoma models. Methods Using cultured medulloblastoma cells, tumor xenografts, and the Smo/Smo transgenic medulloblastoma mouse model, the antitumor effects of curcumin were tested in vitro and in vivo. Results Curcumin induced apoptosis and cell cycle arrest at the G2/M phase in medulloblastoma cells. These effects were accompanied by reduced histone deacetylase (HDAC 4 expression and activity and increased tubulin acetylation, ultimately leading to mitotic catastrophe. In in vivo medulloblastoma xenografts, curcumin reduced tumor growth and significantly increased survival in the Smo/Smo transgenic medulloblastoma mouse model. Conclusions The in vitro and in vivo data suggest that curcumin has the potential to be developed as a therapeutic agent for medulloblastoma.

  19. Stratification of medulloblastoma on the basis of histopathological grading.

    Science.gov (United States)

    Giangaspero, Felice; Wellek, Stefan; Masuoka, Jun; Gessi, Marco; Kleihues, Paul; Ohgaki, Hiroko

    2006-07-01

    Medulloblastoma (WHO grade IV) is an embryonal tumour of the cerebellum and the most common malignant central nervous system tumour in children. Despite significant advances in treatment, 5-year survival rates are still less than 70%, suggesting the presence of subgroups with different response to radio/chemotherapy. In the present study, we re-evaluated a series of 347 medulloblastomas from the SIOP II clinical trial of the International Society of Paediatric Oncology to identify features predictive of clinical outcome. Relapse free survival for medulloblastomas with severe anaplasia [5-year rate: S(60)=49.5%], was significantly shorter than for tumours with moderate or mild anaplasia S(60)=65.4%; P=0.001). The difference between both groups was even larger when the presence or absence of extensive apoptosis was included (46.5 vs. 66.7%; P=0.0216). Other histological features including nodularity, necrosis, vascular proliferation and the presence of beta-catenin mutations (7% of cases) were not predictive for relapse free survival. These findings indicate that degree of anaplasia is the most significant histologic feature predictive of the survival of medulloblastoma patients.

  20. Changes in Cerebral Cortex of Children Treated for Medulloblastoma

    International Nuclear Information System (INIS)

    Liu, Arthur K.; Marcus, Karen J.; Fischl, Bruce; Grant, P. Ellen; Young Poussaint, Tina; Rivkin, Michael J.; Davis, Peter; Tarbell, Nancy J.; Yock, Torunn I.

    2007-01-01

    Purpose: Children with medulloblastoma undergo surgery, radiotherapy, and chemotherapy. After treatment, these children have numerous structural abnormalities. Using high-resolution magnetic resonance imaging, we measured the thickness of the cerebral cortex in a group of medulloblastoma patients and a group of normally developing children. Methods and Materials: We obtained magnetic resonance imaging scans and measured the cortical thickness in 9 children after treatment of medulloblastoma. The measurements from these children were compared with the measurements from age- and gender-matched normally developing children previously scanned. For additional comparison, the pattern of thickness change was compared with the cortical thickness maps from a larger group of 65 normally developing children. Results: In the left hemisphere, relatively thinner cortex was found in the perirolandic region and the parieto-occipital lobe. In the right hemisphere, relatively thinner cortex was found in the parietal lobe, posterior superior temporal gyrus, and lateral temporal lobe. These regions of cortical thinning overlapped with the regions of cortex that undergo normal age-related thinning. Conclusion: The spatial distribution of cortical thinning suggested that the areas of cortex that are undergoing development are more sensitive to the effects of treatment of medulloblastoma. Such quantitative methods may improve our understanding of the biologic effects that treatment has on the cerebral development and their neuropsychological implications

  1. Bilateral Cerebellar Medulloblastoma in Adults: Report of Two Cases

    International Nuclear Information System (INIS)

    Cerquera Cabrera, Fredy Martin; Patino Mendez, Ricardo; Mantilla Mantilla, Maria Isabel

    2011-01-01

    Medulloblastoma is considered to be part of the group of primitive neuroectodermal tumors. It is well known that medulloblastoma is the most common malignancy of the central nervous system in the pediatric population, and the most common primary tumor of the posterior fossa in children. In contrast, it has a very low prevalence in adults. Imaging signs of medulloblastoma have been described in children, consisting of mid-line masses, usually well defined and typically hyperdense on non-contrast CT images, but that show intense homogeneous enhancement with contrast medium. in adults, these characteristics vary, usually with poorly defined cerebellar hemispheric masses showing cystic degeneration or necrosis, and minor enhancement with contrast medium, when compared to the pediatric population. Both children and adults share a variable appearance on MRI, as well as secondary leptomeningeal involvement and distant metastases. This paper describes two confirmed cases of bilateral hemispheric cerebellar medulloblastomas in adult patients with an unusual and interesting imaging presentation not yet reported in the literature.

  2. Primary ovarian leiomyosarcoma in an adolescent following radiation for medulloblastoma

    International Nuclear Information System (INIS)

    O'Sullivan, S.G.; Das Narla, L.; Ferraro, E.

    1998-01-01

    Primary ovarian leiomyosarcomas are rare neoplasms of the ovary, particularly in the pediatric population. Their occurrence following radiation therapy for previous malignancy has important implications. We present a case of primary ovarian leiomyosarcoma in an adolescent following therapy for medulloblastoma. (orig.)

  3. Cystic Medulloblastoma in a child | Agrawal | East and Central ...

    African Journals Online (AJOL)

    East and Central African Journal of Surgery. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 14, No 1 (2009) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Cystic Medulloblastoma in a child. A Agrawal ...

  4. Time Perception in Children Treated for a Cerebellar Medulloblastoma

    Science.gov (United States)

    Droit-Volet, Sylvie; Zelanti, Pierre S.; Dellatolas, Georges; Kieffer, Virginie; El Massioui, Nicole; Brown, Bruce L.; Doyere, Valerie; Provasi, Joelle; Grill, Jacques

    2013-01-01

    The aim of the present study was to investigate temporal abilities in children treated by surgery for a malignant tumor in the cerebellum. Children with a diagnosed medulloblastoma and age-paired control children were given a temporal discrimination task (bisection task) and a temporal reproduction task with two duration ranges, one shorter than 1…

  5. Even Cancers Want Commitment: Lineage Identity and Medulloblastoma Formation

    Science.gov (United States)

    Eberhart, Charles G.

    2015-01-01

    In this issue of Cancer Cell, Yang et al. (2008) and Schüller et al. (2008) show that Hedgehog activation in either multipotent neural stem cells or developmentally restricted progenitors causes only medulloblastomas to form. These data suggest that some stem cell-derived tumors must commit to a specific lineage in order to grow. PMID:18691544

  6. Radiation-induced motility alterations in medulloblastoma cells

    International Nuclear Information System (INIS)

    Rieken, Stefan; Rieber, Juliane; Brons, Stephan

    2015-01-01

    Photon irradiation has been repeatedly suspected of increasing tumor cell motility and promoting locoregional recurrence of disease. This study was set up to analyse possible mechanisms underlying the potentially radiation-altered motility in medulloblastoma cells. Medulloblastoma cell lines D425 and Med8A were analyzed in migration and adhesion experiments with and without photon and carbon ion irradiation. Expression of integrins was determined by quantitative FACS analysis. Matrix metalloproteinase concentrations within cell culture supernatants were investigated by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using Student's t-test. Both photon and carbon ion irradiation significantly reduced chemotactic medulloblastoma cell transmigration through 8-μm pore size membranes, while simultaneously increasing adherence to fibronectin- and collagen I- and IV-coated surfaces. Correspondingly, both photon and carbon ion irradiation downregulate soluble MMP9 concentrations, while upregulating cell surface expression of proadhesive extracellular matrix protein-binding integrin α 5 . The observed phenotype of radiation-altered motility is more pronounced following carbon ion than photon irradiation. Both photon and (even more so) carbon ion irradiation are effective in inhibiting medulloblastoma cell migration through downregulation of matrix metalloproteinase 9 and upregulation of proadhesive cell surface integrin α 5 , which lead to increased cell adherence to extracellular matrix proteins. (author)

  7. Management of Posterior Fossa Medulloblastoma in Adults | Fouad ...

    African Journals Online (AJOL)

    Background: Medulloblastoma is a malignant tumor of the cerebellum that occurs predominantly in children. It is rare in adults and accounts for less than 1 % of all adult primary brain tumors. Objective: This study was done ... treatment died: one from distant metastasis and one from recurrent disease. Ten patients remained ...

  8. The whole-genome landscape of medulloblastoma subtypes

    NARCIS (Netherlands)

    Northcott, Paul A.; Buchhalter, Ivo; Morrissy, A. Sorana; Hovestadt, Volker; Weischenfeldt, Joachim; Ehrenberger, Tobias; Gröbner, Susanne; Segura-Wang, Maia; Zichner, Thomas; Rudneva, Vasilisa A.; Warnatz, Hans-Jörg; Sidiropoulos, Nikos; Phillips, Aaron H.; Schumacher, Steven; Kleinheinz, Kortine; Waszak, Sebastian M.; Erkek, Serap; Jones, David T. W.; Worst, Barbara C.; Kool, Marcel; Zapatka, Marc; Jäger, Natalie; Chavez, Lukas; Hutter, Barbara; Bieg, Matthias; Paramasivam, Nagarajan; Heinold, Michael; Gu, Zuguang; Ishaque, Naveed; Jäger-Schmidt, Christina; Imbusch, Charles D.; Jugold, Alke; Hübschmann, Daniel; Risch, Thomas; Amstislavskiy, Vyacheslav; Gonzalez, Francisco German Rodriguez; Weber, Ursula D.; Wolf, Stephan; Robinson, Giles W.; Zhou, Xin; Wu, Gang; Finkelstein, David; Liu, Yanling; Cavalli, Florence M. G.; Luu, Betty; Ramaswamy, Vijay; Wu, Xiaochong; Koster, Jan; Ryzhova, Marina; Cho, Yoon-Jae; Pomeroy, Scott L.; Herold-Mende, Christel; Schuhmann, Martin; Ebinger, Martin; Liau, Linda M.; Mora, Jaume; McLendon, Roger E.; Jabado, Nada; Kumabe, Toshihiro; Chuah, Eric; Ma, Yussanne; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen L.; Thiessen, Nina; Tse, Kane; Wong, Tina; Jones, Steven J. M.; Witt, Olaf; Milde, Till; von Deimling, Andreas; Capper, David; Korshunov, Andrey; Yaspo, Marie-Laure; Kriwacki, Richard; Gajjar, Amar; Zhang, Jinghui; Beroukhim, Rameen; Fraenkel, Ernest; Korbel, Jan O.; Brors, Benedikt; Schlesner, Matthias; Eils, Roland; Marra, Marco A.; Pfister, Stefan M.; Taylor, Michael D.; Lichter, Peter

    2017-01-01

    Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and

  9. Medulloblastoma: histopathologic and molecular markers of anaplasia and biologic behavior.

    Science.gov (United States)

    Min, Hye Sook; Lee, You Jeong; Park, Kyeongmee; Cho, Byung-Kyu; Park, Sung-Hye

    2006-07-01

    Large cell/anaplastic (LC/A) medulloblastoma (MB) is a recently recognized variant of medulloblastoma known to be associated with an advanced stage and a poor prognosis. Although Eberhart et al. suggested histopathologic grading of medulloblastoma in 2002, no consensus has been reached in terms of determining the criteria of an LC/A variant, and its biological behavior continues to be the subject of debate. We retrospectively analyzed 74 cases (range 0.25-15 years) of MB clinicopathologically using the criteria established by Eberhart et al. The LC/A variant was identified in 16 cases (22% of MB cases), five of which showed a poor outcome. Most LC/A variant cases revealed synaptophysin immunoexpression (75%), but no epidermal growth factor receptor (EGFR) expression. Expression of synaptophysin, NeuN, GFAP, p53, c-erbB2, and EGFR did not differ in LC/A and non-LC/A variants. Seven of the 74 cases of medulloblastoma showed erbB2 amplification by FISH, four of which were LC/A variants. N-myc amplification was observed in only one LC/A variant, but no c-myc amplification was found. In patients younger than 10 years, the LC/A variant showed a significantly poorer outcome than the non-LC/A variant (P = 0.02), while no difference was found in older patients. Multivariate analysis revealed only metastasis on MRI and p53 expression, but not anaplasia as unfavorable prognostic factors. Our study suggests that prognostic implications of anaplasia in medulloblastoma are uncertain, and that the reproducibility of the histopathologic criteria of the LC/A variant should be reassessed before they can be applied in practical use.

  10. MRI features of primary, secondary and metastatic medulloblastoma

    International Nuclear Information System (INIS)

    Buehring, U.; Strayle-Batra, M.; Kueker, W.; Freudenstein, D.; Scheel-Walter, H.-G.

    2002-01-01

    Medulloblastoma is the most frequent paediatric malignant brain tumour. The purpose of this study was to define imaging characteristics and contrast uptake patterns of primary and recurrent medulloblastoma using MRI. The MRI examinations of 17 histologically proven cases of medulloblastoma diagnosed in our institution (13 males and 4 females; mean age 13 years, 7 months) were reviewed in retrospect. Only patients with pre-treatment and follow-up examinations including T2-weighted images (fluid-attenuated inversion recovery or turbo spin echo) and T1-weighted images after contrast injection (0.1 mmol/kg Gd-DTPA) were included in this study. Whereas 6 of 7 tumours (n=17) were hyperintense on T2-weighted images, contrast enhancement was detected in 13 patients. Fifteen tumours occurred in the cerebellar vermis, two were located in the cerebellar hemispheres. Mean size at the time of presentation was 30.1 mm. All patients presented with some extent of an occlusive hydrocephalus. Local recurrent tumour or metastases were seen in 6 patients (3 months to 7 years, mean age 2.5 years). Whereas the T2 signal intensity of recurrent tumour or subarachnoidal metastases resembled the primary neoplasms, the contrast uptake tended to be less pronounced (n=3) or was completely absent (n=2); thus, suggestive signs of primary medulloblastoma are location in the vermis, hyperintensity on T2-weighted images and hydrocephalus. The amount of contrast enhancement is variable and nonspecific. Secondary medulloblastoma manifestation is characterized by T2 hyperintensity but not by contrast uptake. (orig.)

  11. RITA displays anti-tumor activity in medulloblastomas independent of TP53 status.

    Science.gov (United States)

    Gottlieb, Aline; Althoff, Kristina; Grunewald, Laura; Thor, Theresa; Odersky, Andrea; Schulte, Marc; Deubzer, Hedwig E; Heukamp, Lukas; Eggert, Angelika; Schramm, Alexander; Schulte, Johannes H; Künkele, Annette

    2017-04-25

    Current therapy of medulloblastoma, the most common malignant brain tumor of childhood, achieves 40-70% survival. Secondary chemotherapy resistance contributes to treatment failure, where TP53 pathway dysfunction plays a key role. MDM2 interaction with TP53 leads to its degradation. Reactivating TP53 functionality using small-molecule inhibitors, such as RITA, to disrupt TP53-MDM2 binding may have therapeutic potential. We show here that RITA decreased viability of all 4 analyzed medulloblastoma cell lines, regardless of TP53 functional status. The decrease in cell viability was accompanied in 3 of the 4 medulloblastoma cell lines by accumulation of TP53 protein in the cells and increased CDKN1A expression. RITA treatment in mouse models inhibited medulloblastoma xenograft tumor growth. These data demonstrate that RITA treatment reduces medulloblastoma cell viability in both in vitro and in vivo models, and acts independently of cellular TP53 status, identifying RITA as a potential therapeutic agent to treat medulloblastoma.

  12. Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours

    NARCIS (Netherlands)

    von Bueren, A. O.; Bacolod, M. D.; Hagel, C.; Heinimann, K.; Fedier, A.; Kordes, U.; Pietsch, T.; Koster, J.; Grotzer, M. A.; Friedman, H. S.; Marra, G.; Kool, M.; Rutkowski, S.

    2012-01-01

    BACKGROUND: Tumours are responsive to temozolomide (TMZ) if they are deficient in O-6-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient. METHODS: The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA

  13. MR diffusion imaging and 1H spectroscopy in a child with medulloblastoma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Wilke, M. [Max-Planck-Institute of Psychiatry, Muenchen (Germany). NMR Study Group; Eidenschink, A.; Mueller-Weihrich, S. [Technical Univ. of Muenchen, (Germany). Childrens' Hospital; Auer, D.P. [Max-Planck-Institute of Psychiatry, Muenchen (Germany). NMR Study Group

    2000-01-01

    We report on a child with a metastasising medulloblastoma which was assessed by MR diffusion imaging and 1H MR spectroscopy (MRS). Reduced mean apparent diffusion coefficients and a high amount of taurine could be demonstrated. This is the first reported case of high taurine in medulloblastoma in vivo and confirms earlier in vitro findings. It is suggested that the changes on diffusion imaging, possibly reflecting the small-cell histology of the tumour and high taurine in MRS, are indicative of medulloblastoma.

  14. MR diffusion imaging and 1H spectroscopy in a child with medulloblastoma: A case report

    International Nuclear Information System (INIS)

    Wilke, M.; Eidenschink, A.; Mueller-Weihrich, S.; Auer, D.P.

    2000-01-01

    We report on a child with a metastasising medulloblastoma which was assessed by MR diffusion imaging and 1H MR spectroscopy (MRS). Reduced mean apparent diffusion coefficients and a high amount of taurine could be demonstrated. This is the first reported case of high taurine in medulloblastoma in vivo and confirms earlier in vitro findings. It is suggested that the changes on diffusion imaging, possibly reflecting the small-cell histology of the tumour and high taurine in MRS, are indicative of medulloblastoma

  15. The WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants.

    Science.gov (United States)

    Buss, M C; Remke, M; Lee, J; Gandhi, K; Schniederjan, M J; Kool, M; Northcott, P A; Pfister, S M; Taylor, M D; Castellino, R C

    2015-02-26

    Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified upregulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1α activated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knockdown inhibited medulloblastoma growth and invasion. WIP1 knockdown also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knockdown inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knockdown inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4 and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate crosstalk among WIP1, CXCR4 and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children.

  16. High expression of BAG3 predicts a poor prognosis in human medulloblastoma.

    Science.gov (United States)

    Yang, Dong; Zhou, Ji; Wang, Hao; Wang, Yutao; Yang, Ge; Zhang, Yundong

    2016-10-01

    Bcl2-associated athanogene 3 (BAG3), a co-chaperone of the heat shock protein (Hsp) 70, regulates various physiological and pathological processes. However, its role in human medulloblastoma has not been clarified. First of all, the expression of BAG3 was examined in formalin-fixed, paraffin-embedded specimens by immunohistochemical staining. And then, the prognostic role of BAG3 was analyzed in 51 medulloblastoma samples. Finally, the roles of BAG3 in the proliferation, migration, and invasion of Daoy medulloblastoma cell were investigated using a specific short hairpin RNA (shRNA). The expression of BAG3 in medulloblastoma tissues was higher than nontumorous samples. Furthermore, BAG3 overexpression significantly correlated with poor prognosis of patients with medulloblastoma. The overall survival and tumor-free survival in patients with BAG3 low expression were higher than high expression. Univariate and multivariate analysis showed that BAG3 overexpression was an independent prognostic marker for medulloblastoma. After the BAG3 knockdown, the Daoy cells exhibited decreased the ability to proliferate and form neurosphere. The preliminary mechanism study showed that overexpression of BAG3 might facilitate the cell cycle transition from G1 to S phase by modulating the cyclin-dependent kinase 2 (CDK2) and cyclin E expression. Additionally, we found that BAG3 might enhance the medulloblastoma cell migratory and invasive ability. In summary, BAG3 overexpression may regulate the survival and invasive properties of medulloblastoma and may serve as a potential therapy target for medulloblastoma.

  17. EZH2-Regulated DAB2IP Is a Medulloblastoma Tumor Suppressor and a Positive Marker for Survival

    NARCIS (Netherlands)

    Smits, Michiel; van Rijn, Sjoerd; Hulleman, Esther; Biesmans, Dennis; van Vuurden, Dannis G.; Kool, Marcel; Haberler, Christine; Aronica, Eleonora; Vandertop, W. Peter; Noske, David P.; Würdinger, Thomas

    2012-01-01

    Purpose: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements, the molecular mechanisms driving medulloblastoma are not fully understood and further elucidation could provide cues to improve outcome prediction and therapeutic approaches. Experimental

  18. MEDULLOBLASTOMA IN A GRIZZLY BEAR (URSUS ARCTOS HORRIBLIS).

    Science.gov (United States)

    Mitchell, Jeffrey W; Thomovsky, Stephanie A; Chen, Annie V; Layton, Arthur W; Haldorson, Gary; Tucker, Russell L; Roberts, Gregory

    2015-09-01

    A 3-yr-old female spayed grizzly bear (Ursus arctos horribilis) was evaluated for seizure activity along with lethargy, inappetence, dull mentation, and aggressive behavior. Magnetic resonance (MR) examination of the brain revealed a contrast-enhanced right cerebellar mass with multifocal smaller nodules located in the left cerebellum, thalamus, hippocampus, and cerebrum with resultant obstructive hydrocephalus. Cerebrospinal fluid analysis revealed mild mononuclear pleocytosis, with differentials including inflammatory versus neoplastic processes. Blood and cerebrospinal fluid were also submitted for polymerase chain reaction and agar gel immunodiffusion to rule out infectious causes of meningitis/encephalitis. While awaiting these results, the bear was placed on steroid and antibiotic therapy. Over the next week, the bear deteriorated; she died 1 wk after MR. A complete postmortem examination, including immunohistochemisty, revealed the cerebellar mass to be a medulloblastoma. This is the only case report, to the authors' knowledge, describing a medulloblastoma in a grizzly bear.

  19. Adult medulloblastoma: review of 13 cases with emphasis on MRI

    International Nuclear Information System (INIS)

    Becker, R.L.

    1995-01-01

    Medulloblastomas are generally associated with childhood, but 14-30% occur in adults, accounting for 1% of adult central nervous system tumors. While approximately one third of adult medulloblastomas present as vermian tumors similar to those seen in childhood, the majority differ substantially from the childhood variety. In this series of 13 patients, 5 had lateral, seemingly extra-axial masses in the cerebellopontine angle or at the tentorium, simulating meningiomas or acoustic neuromas, but angiographic hypovascularity in 2 of the latter suggested a diagnosis other than meningioma. Of 4 paramedian tumors, 3 diffusely infiltrated the cerebellar white matter, showed little or no gadolinium enhancement and were not associated with hydrocephalus. Hydrocephalus was present in less than half of our patients; in childhood the reported incidence is 85-100 %. A possible association with pregnancy was noted. (orig.)

  20. [Evolution of the management of pediatric and adult medulloblastoma].

    Science.gov (United States)

    Vigneron, C; Entz-Werlé, N; Lutz, P; Spiegel, A; Jannier, S; Helfre, S; Alapetite, C; Coca, A; Kehrli, P; Noël, G

    2015-08-01

    Medulloblastoma are cerebellar tumours belonging to the group of primitive neuroectodermal tumours (PNET) and are the most common malignant brain tumours of childhood. These tumours are rare and heterogeneous, requiring some multicentric prospective studies and multidisciplinary care. The classical therapeutic approaches are based on clinical, radiological and surgical data. They involve surgery, radiation therapy and chemotherapy. Some histological features were added to characterize risk. More recently, molecular knowledge has allowed to devise risk-adapted strategies and helped to define groups with good outcome and reduce long-term sequelae, improve the prognostic of high-risk medulloblastoma and develop new therapeutic tools. Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  1. Evolving molecular era of childhood medulloblastoma: time to revisit therapy.

    Science.gov (United States)

    Khatua, Soumen

    2016-01-01

    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.

  2. Spinal metastasis of medulloblastoma in adults: A case report

    Directory of Open Access Journals (Sweden)

    Živković Nenad

    2014-01-01

    Full Text Available Introduction. Medulloblastoma is a primitive neuro-ectodermal malignant tumor most commonly seen in childhood and rarely and uncommonly in adult age. Treatment consists of surgery followed by radiotherapy. In the case of a relapse there is no overall accepted treatment. Tumor metastasis can be seen along the neural axis, lymph nodes, soft tissues, bones and distant organs. Case Outline. In this paper we present a 45-year-old female patient with a thoraco-spinal extramedullary metastatic medulloblastoma and progressive neurological deterioration seen 11 months after the first operation and description of magnetic resonance and intraoperative finding. Conclusion. Although rare, the presence of metastasis is a poor prognostic factor. The treatment options for patients with metastases are limited and their prognosis continues to remain poor.

  3. [Medulloblastoma: improved survival in recent decades. Unicentric experience].

    Science.gov (United States)

    Igual Estellés, Lucía; Berlanga Charriel, Pablo; Cañete Nieto, Adela

    2017-01-01

    The aim of the study is to analyse variations in the treatment of medulloblastoma, the most common childhood brain tumour, and its impact on survival over the past two decades, as well as its clinical and pathological features. Survival analysis of all patients under 14 years old diagnosed with medulloblastoma between January 1990 and December 2013 in a Paediatric Oncology Unit. Sixty-three patients were diagnosed and treated for medulloblastoma, with a median follow-up of 5.1 years (range 0.65-21.7 years). The overall survival (OS) at 3 and 5 years was 66±13% and 55±14%, respectively. The OS at 5 years was 44%±25% in patients diagnosed in the 1990's, showing an increase to 70%±23% (p=0.032) since 2000. Clinical prognosis factors were included in the logistic regression model: age (p=0.008), presence of metastases and/or residual tumour (p=0.007), and receiving chemotherapy with radiotherapy after surgery (p=0.008). Statistically significant differences were observed for all of them. In our institution there has been a significant increase in medulloblastoma survival in the last decades. Multivariate analysis showed that this improvement was not related to the date of diagnosis, but with the introduction of chemotherapy in adjuvant treatment. This study confirmed that clinical factors significantly associated with worse outcome were age and presence of metastases at diagnosis. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Signaling pathway deregulation and molecular alterations across pediatric medulloblastomas.

    Science.gov (United States)

    Lhermitte, B; Blandin, A F; Coca, A; Guerin, E; Durand, A; Entz-Werlé, N

    2018-05-15

    Medulloblastomas (MBs) account for 15% of brain tumors in children under the age of 15. To date, the overall 5-year survival rate for all children is only around 60%. Recent advances in cancer genomics have led to a fundamental change in medulloblastoma classification and is evolving along with the genomic discoveries, allowing to regularly reclassify this disease. The previous molecular classification defined 4 groups (WNT-activated MB, SHH-activated MB and the groups 3 and 4 characterized partially by NMYC and MYC driven MBs). This stratification moved forward recently to better define these groups and their correlation to outcome. This new stratification into 7 novel subgroups was helpful to lay foundations and complementary data on the understanding regarding molecular pathways and gene mutations underlying medulloblastoma biology. This review was aimed at answering the recent key questions on MB genomics and go further in the relevance of those genes in MB development as well as in their targeted therapies. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  5. Aberrant signaling pathways in medulloblastomas: a stem cell connection

    Directory of Open Access Journals (Sweden)

    Carolina Oliveira Rodini

    2010-12-01

    Full Text Available Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFβ, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers.

  6. PTEN and DMBT1 homozygous deletion and expression in medulloblastomas and supratentorial primitive neuroectodermal tumors.

    Science.gov (United States)

    Inda, María Mar; Mercapide, Javier; Muñoz, Jorge; Coullin, Philippe; Danglot, Giséle; Tuñon, Teresa; Martínez-Peñuela, José María; Rivera, José María; Burgos, Juan J; Bernheim, Alain; Castresana, Javier S

    2004-12-01

    Medulloblastoma, which accounts for 20-25% of all childhood brain tumors, is defined as a primitive neuroectodermal tumor (PNET) located in the cerebellum. Supratentorial PNET are less frequent than medulloblastoma. But their clinical outcome is worse than in medulloblastomas. Chromosome 10q contains at least 2 tumor suppressor genes that might play a role in brain tumor development: PTEN and DMBT1. The aim of this study was to compare the status of homozygous deletion and expression of PTEN and DMBT1 genes in PNET primary tumor samples and cell lines. Homozygous deletions of PTEN and DMBT1 were studied in 32 paraffin-embedded PNET samples (23 medulloblastomas and 9 supratentorial PNET) and in 7 PNET cell lines, by differential PCR and by FISH. PTEN homozygous losses were demonstrated in 7 medulloblastomas (32%) and in no supratentorial PNET, while homozygous deletions of DMBT1 appeared in 1 supratentorial PNET (20%) and in 7 medulloblastomas (33%). No homozygous deletion of PTEN or DMBT1 was detected in any of the PNET cell lines either by differential PCR or by FISH. Expression study of the 2 genes was performed in the 7 PNET cell lines by RT-PCR. One PNET cell line lacked PTEN and DMBT1 expression, while 2 medulloblastoma cell lines did not express DMBT1. Our results add some positive data to the hypothesis that supratentorial PNETs and medulloblastomas might be genetically different.

  7. Bmi1 is required for hedgehog pathway-driven medulloblastoma expansion

    NARCIS (Netherlands)

    Michael, Lowell Evan; Westerman, Bart A.; Ermilov, Alexandre N.; Wang, Aiqin; Ferris, Jennifer; Liu, Jianhong; Blom, Marleen; Ellison, David W.; van Lohuizen, Maarten; Dlugosz, Andrzej A.

    2008-01-01

    Inappropriate Hedgehog (Hh) signaling underlies development of a subset of medulloblastomas, and tumors with elevated HH signaling activity express the stem cell self-renewal gene BMI1. To test whether Bmi1 is required for Hh-driven medulloblastoma development, we varied Bmi1 gene dosage in

  8. Abnormal diffusion-weighted MRI in medulloblastoma: does it reflect small cell histology?

    International Nuclear Information System (INIS)

    Kotsenas, A.L.; Roth, T.C.; Manness, W.K.; Faerber, E.N.

    1999-01-01

    A 12-year-old boy presented with the classic CT and MRI findings of medulloblastoma and the unusual finding of increased signal on diffusion MRI. The small-cell histology of medulloblastoma may account for the increased signal seen on diffusion MRI. Diffusion MRI with echoplanar technique may be useful in evaluation of these tumors and metastatic disease. (orig.)

  9. Genetic and Epigenetic Inactivation of Kruppel-like Factor 4 in Medulloblastoma

    Directory of Open Access Journals (Sweden)

    Yukiko Nakahara

    2010-01-01

    Full Text Available Although medulloblastoma is the most common pediatric malignant brain tumor, its molecular underpinnings are largely unknown. We have identified rare, recurrent homozygous deletions of Kruppel-like Factor 4 (KLF4 in medulloblastoma using high-resolution single nucleotide polymorphism arrays, digital karyotyping, and genomic real-time polymerase chain reaction (PCR. Furthermore, we show that there is loss of physiological KLF4 expression in more than 40% of primary medulloblastomas both at the RNA and protein levels. Medulloblastoma cell lines drastically increase the expression of KLF4 in response to the demethylating agent 5-azacytidine and demonstrate dense methylation of the promoter CpG island by bisulfite sequencing. Methylation-specific PCR targeting the KLF4 promoter demonstrates CpG methylation in approximately 16% of primary medulloblastomas. Reexpression of KLF4 in the D283 medulloblastoma cell line results in significant growth suppression both in vitro and in vivo. We conclude that KLF4 is inactivated by either genetic or epigenetic mechanisms in a large subset of medulloblastomas and that it likely functions as a tumor suppressor gene in the pathogenesis of medulloblastoma.

  10. Hippocampal sparing radiotherapy for pediatric medulloblastoma: impact of treatment margins and treatment technique

    DEFF Research Database (Denmark)

    Brodin, N. Patrik; af Rosenschold, Per Munck; Blomstrand, Malin

    2014-01-01

    BackgroundWe investigated how varying the treatment margin and applying hippocampal sparing and proton therapy impact the risk of neurocognitive impairment in pediatric medulloblastoma patients compared with current standard 3D conformal radiotherapy.MethodsWe included 17 pediatric medulloblastoma...

  11. Frontal recurrence of medulloblastoma five years after excision and craniospinal irradiation

    Directory of Open Access Journals (Sweden)

    Roka Y

    2009-07-01

    Full Text Available Medulloblastomas were originally classified under gliomas of the cerebellum until Bailey and Cushing in 1925 named these tumors as medulloblastoma. At present these tumors are classified under primitive neuroectodermal tumor. Surgical excision followed by craniospinal irradiation is the treatment of choice. A 13-year-old-girl operated for posterior fossa medulloblastoma 5 years ago presented with history of headache and vomiting on and off for 4 days in late August 2008. The MRI showed left frontal tumor which on excision was reported as medulloblastoma. Even after optimal treatment reports of recurrence abound in literature. The most common location is in the posterior fossa, followed by spinal, supratentorial, and uncommonly, systemic metastases. We conclude that medulloblastomas are highly aggressive tumor with high local recurrences if the initial excision is incomplete and that recurrence in the supratentorial area although uncommon is still a possibility. This mandates regular follow up of these children till adulthood to catch early recurrences and metastatic disease.

  12. Clinico-pathological studies of CSF dissemination of glioblastoma and medulloblastoma

    International Nuclear Information System (INIS)

    Kato, Kyozo; Yoshida, Jun; Kageyama, Naoki

    1986-01-01

    Clinico-pathological findings of CSF dissemination which was diagnosed on CT scan, were studied on 13 cases of glioblastoma and 9 cases of medulloblastoma. The type of CSF dissemination and the prognosis of patients were both different between glioblastoma and medulloblastoma. In the former, the dissemination was predominantly in ventricular walls and in the latter, in basal cisterns. The mean survival time after the diagnosis of dissemination is 6 months of glioblastoma as compared with 13 months of medulloblastoma. The Pathological studies show that subependymal and/or subpial infiltration of tumor cells, and thickness of arachnoid membrane by marked mesodermal reaction were demonstrated in cases of glioblastoma. On the contrary, tumor cells of medulloblastoma grow markedly in the subarachnoid space and/or on the ependymal layers. From these pathological findings of CSF dissemination, it will be resulted that the prognosis of glioblastoma is much more poor that of medulloblastoma. (author)

  13. A novel role of HLA class I in the pathology of medulloblastoma

    Directory of Open Access Journals (Sweden)

    Rood Brian R

    2009-07-01

    Full Text Available Abstract Background MHC class I expression by cancer cells enables specific antigen recognition by the immune system and protection of the host. However, in some cancer types MHC class I expression is associated with an unfavorable outcome. We explored the basis of MHC class I association with unfavorable prognostic marker expression in the case of medulloblastoma. Methods We investigated expression of four essential components of MHC class I (heavy chain, β2m, TAP1 and TAP2 in 10 medulloblastoma mRNA samples, a tissue microarray containing 139 medulloblastoma tissues and 3 medulloblastoma cell lines. Further, in medulloblastoma cell lines we evaluated the effects of HLA class I engagement on activation of ERK1/2 and migration in vitro. Results The majority of specimens displayed undetectable or low levels of the heavy chains. Medulloblastomas expressing high levels of HLA class I displayed significantly higher levels of anaplasia and c-myc expression, markers of poor prognosis. Binding of β2m or a specific antibody to open forms of HLA class I promoted phosphorylation of ERK1/2 in medulloblastoma cell line with high levels, but not in the cell line with low levels of HLA heavy chain. This treatment also promoted ERK1/2 activation dependent migration of medulloblastoma cells. Conclusion MHC class I expression in medulloblastoma is associated with anaplasia and c-myc expression, markers of poor prognosis. Peptide- and/or β2m-free forms of MHC class I may contribute to a more malignant phenotype of medulloblastoma by modulating activation of signaling molecules such as ERK1/2 that stimulates cell mobility.

  14. A novel role of HLA class I in the pathology of medulloblastoma.

    Science.gov (United States)

    Smith, Courtney; Santi, Mariarita; Rajan, Bhargavi; Rushing, Elisabeth J; Choi, Mi Rim; Rood, Brian R; Cornelison, Robert; MacDonald, Tobey J; Vukmanovic, Stanislav

    2009-07-12

    MHC class I expression by cancer cells enables specific antigen recognition by the immune system and protection of the host. However, in some cancer types MHC class I expression is associated with an unfavorable outcome. We explored the basis of MHC class I association with unfavorable prognostic marker expression in the case of medulloblastoma. We investigated expression of four essential components of MHC class I (heavy chain, beta2m, TAP1 and TAP2) in 10 medulloblastoma mRNA samples, a tissue microarray containing 139 medulloblastoma tissues and 3 medulloblastoma cell lines. Further, in medulloblastoma cell lines we evaluated the effects of HLA class I engagement on activation of ERK1/2 and migration in vitro. The majority of specimens displayed undetectable or low levels of the heavy chains. Medulloblastomas expressing high levels of HLA class I displayed significantly higher levels of anaplasia and c-myc expression, markers of poor prognosis. Binding of beta2m or a specific antibody to open forms of HLA class I promoted phosphorylation of ERK1/2 in medulloblastoma cell line with high levels, but not in the cell line with low levels of HLA heavy chain. This treatment also promoted ERK1/2 activation dependent migration of medulloblastoma cells. MHC class I expression in medulloblastoma is associated with anaplasia and c-myc expression, markers of poor prognosis. Peptide- and/or beta2m-free forms of MHC class I may contribute to a more malignant phenotype of medulloblastoma by modulating activation of signaling molecules such as ERK1/2 that stimulates cell mobility.

  15. Imaging Biomarkers for Adult Medulloblastomas: Genetic Entities May Be Identified by Their MR Imaging Radiophenotype.

    Science.gov (United States)

    Keil, V C; Warmuth-Metz, M; Reh, C; Enkirch, S J; Reinert, C; Beier, D; Jones, D T W; Pietsch, T; Schild, H H; Hattingen, E; Hau, P

    2017-10-01

    The occurrence of medulloblastomas in adults is rare; nevertheless, these tumors can be subdivided into genetic and histologic entities each having distinct prognoses. This study aimed to identify MR imaging biomarkers to classify these entities and to uncover differences in MR imaging biomarkers identified in pediatric medulloblastomas. Eligible preoperative MRIs from 28 patients (11 women; 22-53 years of age) of the Multicenter Pilot-study for the Therapy of Medulloblastoma of Adults (NOA-7) cohort were assessed by 3 experienced neuroradiologists. Lesions and perifocal edema were volumetrized and multiparametrically evaluated for classic morphologic characteristics, location, hydrocephalus, and Chang criteria. To identify MR imaging biomarkers, we correlated genetic entities sonic hedgehog ( SHH ) TP53 wild type, wingless ( WNT ), and non -WNT/ non -SHH medulloblastomas (in adults, Group 4), and histologic entities were correlated with the imaging criteria. These MR imaging biomarkers were compared with corresponding data from a pediatric study. There were 19 SHH TP53 wild type (69%), 4 WNT -activated (14%), and 5 Group 4 (17%) medulloblastomas. Six potential MR imaging biomarkers were identified, 3 of which, hydrocephalus ( P = .03), intraventricular macrometastases ( P = .02), and hemorrhage ( P = .04), when combined, could identify WNT medulloblastoma with 100% sensitivity and 88.3% specificity (95% CI, 39.8%-100.0% and 62.6%-95.3%). WNT -activated nuclear β-catenin accumulating medulloblastomas were smaller than the other entities (95% CI, 5.2-22.3 cm 3 versus 35.1-47.6 cm 3 ; P = .03). Hemorrhage was exclusively present in non -WNT/ non -SHH medulloblastomas ( P = .04; n = 2/5). MR imaging biomarkers were all discordant from those identified in the pediatric cohort. Desmoplastic/nodular medulloblastomas were more rarely in contact with the fourth ventricle (4/15 versus 7/13; P = .04). MR imaging biomarkers can help distinguish histologic and genetic

  16. Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group.

    Science.gov (United States)

    Gottardo, Nicholas G; Hansford, Jordan R; McGlade, Jacqueline P; Alvaro, Frank; Ashley, David M; Bailey, Simon; Baker, David L; Bourdeaut, Franck; Cho, Yoon-Jae; Clay, Moira; Clifford, Steven C; Cohn, Richard J; Cole, Catherine H; Dallas, Peter B; Downie, Peter; Doz, François; Ellison, David W; Endersby, Raelene; Fisher, Paul G; Hassall, Timothy; Heath, John A; Hii, Hilary L; Jones, David T W; Junckerstorff, Reimar; Kellie, Stewart; Kool, Marcel; Kotecha, Rishi S; Lichter, Peter; Laughton, Stephen J; Lee, Sharon; McCowage, Geoff; Northcott, Paul A; Olson, James M; Packer, Roger J; Pfister, Stefan M; Pietsch, Torsten; Pizer, Barry; Pomeroy, Scott L; Remke, Marc; Robinson, Giles W; Rutkowski, Stefan; Schoep, Tobias; Shelat, Anang A; Stewart, Clinton F; Sullivan, Michael; Taylor, Michael D; Wainwright, Brandon; Walwyn, Thomas; Weiss, William A; Williamson, Dan; Gajjar, Amar

    2014-02-01

    Medulloblastoma is curable in approximately 70% of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization's classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children's Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics

  17. Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

    Directory of Open Access Journals (Sweden)

    Cara J. Valvona

    2018-03-01

    Full Text Available Medulloblastoma is the most common malignant paediatric brain tumour and current therapies often leave patients with severe neurological disabilities. Four major molecular groups of medulloblastoma have been identified (Wnt, Shh, Group 3 and Group 4, which include additional, recently defined subgroups with different prognosis and genetic characteristics. Lactate dehydrogenase A (LDHA is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly observed in cancers, associated with tumour progression and metastasis. Studies indicate MBs have a glycolytic phenotype; however, LDHA has not yet been explored as a therapeutic target for medulloblastoma. LDHA expression was examined in medulloblastoma subgroups and cell lines. The effects of LDHA inhibition by oxamate or LDHA siRNA on medulloblastoma cell line metabolism, migration and proliferation were examined. LDHA was significantly overexpressed in Group 3 and Wnt MBs compared to non-neoplastic cerebellum. Furthermore, we found that oxamate significantly attenuated glycolysis, proliferation and motility in medulloblastoma cell lines, but LDHA siRNA did not. We established that aerobic glycolysis is a potential therapeutic target for medulloblastoma, but broader LDH inhibition (LDHA, B, and C may be more appropriate than LDHA inhibition alone.

  18. Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus

    International Nuclear Information System (INIS)

    Eberhart, Charles G; Chaudhry, Aneeka; Daniel, Richard W; Khaki, Leila; Shah, Keerti V; Gravitt, Patti E

    2005-01-01

    p53 mutations are relatively uncommon in medulloblastoma, but abnormalities in this cell cycle pathway have been associated with anaplasia and worse clinical outcomes. We correlated p53 protein expression with pathological subtype and clinical outcome in 75 embryonal brain tumors. The presence of JC virus, which results in p53 protein accumulation, was also examined. p53 protein levels were evaluated semi-quantitatively in 64 medulloblastomas, 3 atypical teratoid rhabdoid tumors (ATRT), and 8 supratentorial primitive neuroectodermal tumors (sPNET) using immunohistochemistry. JC viral sequences were analyzed in DNA extracted from 33 frozen medulloblastoma and PNET samples using quantitative polymerase chain reaction. p53 expression was detected in 18% of non-anaplastic medulloblastomas, 45% of anaplastic medulloblastomas, 67% of ATRT, and 88% of sPNET. The increased p53 immunoreactivity in anaplastic medulloblastoma, ATRT, and sPNET was statistically significant. Log rank analysis of clinical outcome revealed significantly shorter survival in patients with p53 immunopositive embryonal tumors. No JC virus was identified in the embryonal brain tumor samples, while an endogenous human retrovirus (ERV-3) was readily detected. Immunoreactivity for p53 protein is more common in anaplastic medulloblastomas, ATRT and sPNET than in non-anaplastic tumors, and is associated with worse clinical outcomes. However, JC virus infection is not responsible for increased levels of p53 protein

  19. Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus

    Directory of Open Access Journals (Sweden)

    Shah Keerti V

    2005-02-01

    Full Text Available Abstract Background p53 mutations are relatively uncommon in medulloblastoma, but abnormalities in this cell cycle pathway have been associated with anaplasia and worse clinical outcomes. We correlated p53 protein expression with pathological subtype and clinical outcome in 75 embryonal brain tumors. The presence of JC virus, which results in p53 protein accumulation, was also examined. Methods p53 protein levels were evaluated semi-quantitatively in 64 medulloblastomas, 3 atypical teratoid rhabdoid tumors (ATRT, and 8 supratentorial primitive neuroectodermal tumors (sPNET using immunohistochemistry. JC viral sequences were analyzed in DNA extracted from 33 frozen medulloblastoma and PNET samples using quantitative polymerase chain reaction. Results p53 expression was detected in 18% of non-anaplastic medulloblastomas, 45% of anaplastic medulloblastomas, 67% of ATRT, and 88% of sPNET. The increased p53 immunoreactivity in anaplastic medulloblastoma, ATRT, and sPNET was statistically significant. Log rank analysis of clinical outcome revealed significantly shorter survival in patients with p53 immunopositive embryonal tumors. No JC virus was identified in the embryonal brain tumor samples, while an endogenous human retrovirus (ERV-3 was readily detected. Conclusion Immunoreactivity for p53 protein is more common in anaplastic medulloblastomas, ATRT and sPNET than in non-anaplastic tumors, and is associated with worse clinical outcomes. However, JC virus infection is not responsible for increased levels of p53 protein.

  20. Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus

    Science.gov (United States)

    Eberhart, Charles G; Chaudhry, Aneeka; Daniel, Richard W; Khaki, Leila; Shah, Keerti V; Gravitt, Patti E

    2005-01-01

    Background p53 mutations are relatively uncommon in medulloblastoma, but abnormalities in this cell cycle pathway have been associated with anaplasia and worse clinical outcomes. We correlated p53 protein expression with pathological subtype and clinical outcome in 75 embryonal brain tumors. The presence of JC virus, which results in p53 protein accumulation, was also examined. Methods p53 protein levels were evaluated semi-quantitatively in 64 medulloblastomas, 3 atypical teratoid rhabdoid tumors (ATRT), and 8 supratentorial primitive neuroectodermal tumors (sPNET) using immunohistochemistry. JC viral sequences were analyzed in DNA extracted from 33 frozen medulloblastoma and PNET samples using quantitative polymerase chain reaction. Results p53 expression was detected in 18% of non-anaplastic medulloblastomas, 45% of anaplastic medulloblastomas, 67% of ATRT, and 88% of sPNET. The increased p53 immunoreactivity in anaplastic medulloblastoma, ATRT, and sPNET was statistically significant. Log rank analysis of clinical outcome revealed significantly shorter survival in patients with p53 immunopositive embryonal tumors. No JC virus was identified in the embryonal brain tumor samples, while an endogenous human retrovirus (ERV-3) was readily detected. Conclusion Immunoreactivity for p53 protein is more common in anaplastic medulloblastomas, ATRT and sPNET than in non-anaplastic tumors, and is associated with worse clinical outcomes. However, JC virus infection is not responsible for increased levels of p53 protein. PMID:15717928

  1. Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib.

    Science.gov (United States)

    Lou, Emil; Schomaker, Matthew; Wilson, Jon D; Ahrens, Mary; Dolan, Michelle; Nelson, Andrew C

    2016-08-12

    Medulloblastoma is an aggressive primitive neuroectodermal tumor of the cerebellum that is rare in adults. Medulloblastomas fall into 4 prognostically significant molecular subgroups that are best defined by experimental gene expression profiles: the WNT pathway, sonic hedgehog (SHH) pathway, and subgroups 3 and 4 (non-SHH/WNT). Medulloblastoma of adults belong primarily to the SHH category. Vismodegib, an SHH-pathway inhibitor FDA-approved in 2012 for treatment of basal cell carcinoma, has been used successfully in the setting of chemorefractory medulloblastoma, but not as a first-line therapy. In this report, we describe a sustained response of an unresectable multifocal form of adult medulloblastoma to vismodegib. Molecular analysis in this case revealed mutations in TP53 and a cytogenetic abnormality, i17q, that is prevalent and most often associated with subgroup 4 rather than the SHH-activated form of medulloblastoma. Our findings indicate that vismodegib may also block alternate, non-canonical forms of downstream SHH pathway activation. These findings provide strong impetus for further investigation of vismodegib in clinical trials in the first-line setting for pediatric and adult forms of medulloblastoma.

  2. Transitioning from genotypes to epigenotypes: why the time has come for medulloblastoma epigenomics.

    Science.gov (United States)

    Batora, N V; Sturm, D; Jones, D T W; Kool, M; Pfister, S M; Northcott, P A

    2014-04-04

    Recent advances in genomic technologies have allowed for tremendous progress in our understanding of the biology underlying medulloblastoma, a malignant childhood brain tumor. Consensus molecular subgroups have been put forth by the pediatric neuro-oncology community and next-generation genomic studies have led to an improved description of driver genes and pathways somatically altered in these subgroups. In contrast to the impressive pace at which advances have been made at the level of the medulloblastoma genome, comparable studies of the epigenome have lagged behind. Complementary data yielded from genomic sequencing and copy number profiling have verified frequent targeting of chromatin modifiers in medulloblastoma, highly suggestive of prominent epigenetic deregulation in the disease. Past studies of DNA methylation-dependent gene silencing and microRNA expression analyses further support the concept of medulloblastoma as an epigenetic disease. In this Review, we aim to summarize the key findings of past reports pertaining to medulloblastoma epigenetics as well as recent and ongoing genomic efforts linking somatic alterations of the genome with inferred deregulation of the epigenome. In addition, we predict what is on the horizon for medulloblastoma epigenetics and how aberrant changes in the medulloblastoma epigenome might serve as an attractive target for future therapies. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis.

    Science.gov (United States)

    Bai, Ren-Yuan; Staedtke, Verena; Rudin, Charles M; Bunz, Fred; Riggins, Gregory J

    2015-04-01

    Medulloblastoma is the most common malignant brain tumor in children. Current standard treatments cure 40%-60% of patients, while the majority of survivors suffer long-term neurological sequelae. The identification of 4 molecular groups of medulloblastoma improved the clinical management with the development of targeted therapies; however, the tumor acquires resistance quickly. Mebendazole (MBZ) has a long safety record as antiparasitic in children and has been recently implicated in inhibition of various tyrosine kinases in vitro. Here, we investigated the efficacy of MBZ in various medulloblastoma subtypes and MBZ's impact on vascular endothelial growth factor receptor 2 (VEGFR2) and tumor angiogenesis. The inhibition of MBZ on VEGFR2 kinase was investigated in an autophosphorylation assay and a cell-free kinase assay. Mice bearing orthotopic PTCH1-mutant medulloblastoma allografts, a group 3 medulloblastoma xenograft, and a PTCH1-mutant medulloblastoma with acquired resistance to the smoothened inhibitor vismodegib were treated with MBZ. The survival benefit and the impact on tumor angiogenesis and VEGFR2 kinase function were analyzed. We determined that MBZ interferes with VEGFR2 kinase by competing with ATP. MBZ selectively inhibited tumor angiogenesis but not the normal brain vasculatures in orthotopic medulloblastoma models and suppressed VEGFR2 kinase in vivo. MBZ significantly extended the survival of medulloblastoma models derived from different molecular backgrounds. Our findings support testing of MBZ as a possible low-toxicity therapy for medulloblastomas of various molecular subtypes, including tumors with acquired vismodegib resistance. Its antitumor mechanism may be partially explained by inhibition of tumor angiogenesis. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. CTNNB1, AXIN1 and APC expression analysis of different medulloblastoma variants

    Directory of Open Access Journals (Sweden)

    Roseli da Silva

    2013-01-01

    Full Text Available OBJECTIVES: We investigated four components of the Wnt signaling pathway in medulloblastomas. Medulloblastoma is the most common type of malignant pediatric brain tumor, and the Wnt signaling pathway has been shown to be activated in this type of tumor. METHODS: Sixty-one medulloblastoma cases were analyzed for β-catenin gene (CTNNB1 mutations, β-catenin protein expression via immunostaining and Wnt signaling pathway-related gene expression. All data were correlated with histological subtypes and patient clinical information. RESULTS: CTNNB1 sequencing analysis revealed that 11 out of 61 medulloblastomas harbored missense mutations in residues 32, 33, 34 and 37, which are located in exon 3. These mutations alter the glycogen synthase kinase-3β phosphorylation sites, which participate in β-catenin degradation. No significant differences were observed between mutation status and histological medulloblastoma type, patient age and overall or progression-free survival times. Nuclear β-catenin accumulation, which was observed in 27.9% of the cases, was not associated with the histological type, CTNNB1 mutation status or tumor cell dissemination. The relative expression levels of genes that code for proteins involved in the Wnt signaling pathway (CTNNB1, APC, AXIN1 and WNT1 were also analyzed, but no significant correlations were found. In addition, large-cell variant medulloblastomas presented lower relative CTNNB1 expression as compared to the other tumor variants. CONCLUSIONS: A small subset of medulloblastomas carry CTNNB1 mutations with consequent nuclear accumulation of β-catenin. The Wnt signaling pathway plays a role in classic, desmoplastic and extensive nodularity medulloblastoma variants but not in large-cell medulloblastomas.

  5. The whole-genome landscape of medulloblastoma subtypes

    DEFF Research Database (Denmark)

    Northcott, Paul A.; Buchhalter, Ivo; Morrissy, A. Sorana

    2017-01-01

    actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target...... KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive...

  6. Efficacy of the combined treatment of medulloblastoma depending on the irradiation techniques

    International Nuclear Information System (INIS)

    Ragajshene, V.N.; Tiknyavichus, K.P.

    1980-01-01

    The paper is concerned with the results of the combined treatment of medulloblastoma using the spatial radiation dose distribution technique. Biological tumor characteristics necessitates total prophylactic irradiation of the central nervous system (CNS) in medulloblastoma. Long-term results, i.e. the duration of life of patients treated by different methods, are used as a yardstick of therapeutic efficacy. To show statistical significance the authors used a simple and reliable mathematical method which demonstrates obvious advantages of prophylactic irradiation of the CNS in medulloblastoma

  7. Methods and results of radiotherapy in case of medulloblastoma

    International Nuclear Information System (INIS)

    Bamberg, M.; Sauerwein, W.; Scherer, E.

    1982-01-01

    The prognosis of the medulloblastoma with its marked tendency towards early formation of metastases by way of liquor circulation can be decisively improved by post-surgical homogenous irradiation. A successful radiotherapy is only possible by means of new irradiation methods which have been developed for high-voltage units during recent years and which require great experience and skill on the part of the radiotherapeutist. At the Radiological Centre of Essen, 26 patients with medulloblastoma have been submitted to such a specially developed post-surgical radiotherapy since 1974. After a follow-up period of at most seven years, 16 patients have survived (two of them with recurrences) and 10 patients died because of a local recurrence. In dependence on the patient's state of health after surgery and before irradiation, the neurologic state and physical condition of these patients seem favorable after unique post-operative radiotherapy. New therapeutic possibilities are provided by radiosensitizing substances. The actually most effective radiosensitizer Misonidazol, however, could not respond hitherto to clinical expectances. (orig.) [de

  8. Medulloblastomas - primitive neuroectodermal tumours in the adult population

    International Nuclear Information System (INIS)

    Smee, R.I.; Williams, J.R.

    2008-01-01

    Medulloblastomas - primitive neuroectodermal tumours are rare in adults. This review will evaluate a single centre's experience with this malignancy. The medulloblastoma - primitive neuroectodermal tumour database was evaluated for all patients aged more than 18 years who were referred for management. Relevant information from the database was abstracted to provide a descriptive record of this malignancy. Between 1977-2004 there were 11 patients referred, 1 with persistent disease and 10 were eligible, presenting with initial diagnosis. There was increased intracranial pressure in 50% of patients. Most patients had symptoms >3 months, with three having symptoms 1-3 months before diagnosis and one patient having thoracic dural metastases at presentation. Complete resection was recorded in four patients and six had 50-90% resection. All patients completed craniospinal radiotherapy (35-36 Gy at 1.8-2.0 Gy fractions) barring one patient, who died of surgical complications during his radiotherapy. Chemotherapy was given in five of the nine patients postradiotherapy. There were two posterior fossa recurrences, with associated supratentorial and extra central nervous system disease. Of the 10 primary patients 7 are alive with no evidence of diease, 2 died because of disease, with 1 intercurrent death. One patient developed a second malignancy. The outcome for adults matches that of the more common paediatric patients. Radiotherapy could control local disease even where complete resection was not achieved.

  9. Comparison of posterior fossa and tumor bed boost in medulloblastoma.

    Science.gov (United States)

    Paulino, A C; Saw, C B; Wen, B C

    2000-10-01

    To quantify the difference between the area of brain irradiated using the posterior fossa boost (PFB) and tumor bed boost (TBB) in medulloblastoma, we studied 15 simulation radiographs of patients treated in our institution from 1990 and 1999. The PFB was compared with the TBB, which was defined as the tumor bed plus 2-cm margin as demonstrated by postoperative magnetic resonance imaging. The PFB field treated a mean area of 9.43 cm2 more brain than the TBB. In 3 patients (20%), the area of the brain in the TBB was larger than the PFB. In 11 patients (73.3%), the PFB field had more than 10% more brain than the TBB. The cochlea was in the PFB and TBB field in all patients. In more than two thirds of patients, the area of brain irradiated with the PFB was at least 10% greater than the TBB. Future studies are needed to determine whether the TBB can replace the PFB in patients with medulloblastoma.

  10. Medulloblastoma in childhood: long-term results of treatment

    International Nuclear Information System (INIS)

    Broadbent, V.A.; Barnes, N.D.; Wheeler, T.K.

    1981-01-01

    Thirty-one children under the age of 15 years with verified medulloblastoma were treated at Addenbrookes Hospital from 1940 to 1976. In addition to surgical treatment, all received high dose irradiation to the whole neuraxis. Nine were still alive in 1979, of whom eight were examined. All these patients showed some residual problems, but five were leading active lives and had only minor physical disability. There was evidence of disturbance in growth, with shortening of the spine in relation to the limbs, in all the children. The height centile was lower than expected from parental height in four and one was severely dwarfed. Growth hormone secretion in response to exercise was, however, normal in five of six patients tested. Three children also showed failure of growth of the jaw sufficiently severe to be a cosmetic problem. Frank mental retardation was present in three children. A raised resting TSH level was found in two children, one of whom had a multinodular goiter. Of the three children with severe problems, two had been treated when under two years of age. Long-term follow-up of children who survive medulloblastoma is clearly necessary and consideration should perhaps be given to revision of current treatment regimes in very young children

  11. SIOP PODC adapted treatment recommendations for standard-risk medulloblastoma in low and middle income settings

    NARCIS (Netherlands)

    Parkes, Jeannette; Hendricks, Marc; Ssenyonga, Peter; Mugamba, John; Molyneux, Elizabeth; Schouten-van Meeteren, Antoinette; Qaddoumi, Ibrahim; Fieggen, Graham; Luna-Fineman, Sandra; Howard, Scott; Mitra, Dipayan; Bouffet, Eric; Davidson, Alan; Bailey, Simon

    2015-01-01

    Effective treatment of children with medulloblastoma requires a functioning multi-disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition the treating centre should have the capacity to effectively screen and

  12. Clinicopathological features of medulloblastoma: an overview with an emphasis on molecular biology

    NARCIS (Netherlands)

    de Haas, T. G. K. J.; Kool, M.

    2007-01-01

    Medulloblastoma is a malignant, invasive embryonal tumor of the cerebellum with preferential manifestation in children, predominantly neuronal differentiation and an inherent tendency to metastasize via CSF pathways. In this review we present an overview of the clinicopathological aspects of

  13. Treatment of medulloblastoma with oncolytic measles viruses expressing the angiogenesis inhibitors endostatin and angiostatin

    International Nuclear Information System (INIS)

    Hutzen, Brian; Bid, Hemant Kumar; Houghton, Peter J; Pierson, Christopher R; Powell, Kimerly; Bratasz, Anna; Raffel, Corey; Studebaker, Adam W

    2014-01-01

    Medulloblastoma is the most common type of pediatric brain tumor. Although numerous factors influence patient survival rates, more than 30% of all cases will ultimately be refractory to conventional therapies. Current standards of care are also associated with significant morbidities, giving impetus for the development of new treatments. We have previously shown that oncolytic measles virotherapy is effective against medulloblastoma, leading to significant prolongation of survival and even cures in mouse xenograft models of localized and metastatic disease. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Toward this end, we have engineered an oncolytic measles virus that express a fusion protein of endostatin and angiostatin, two endogenous and potent inhibitors of angiogenesis. Oncolytic measles viruses encoding human and mouse variants of a secretable endostatin/angiostatin fusion protein were designed and rescued according to established protocols. These viruses, known as MV-hE:A and MV-mE:A respectively, were then evaluated for their anti-angiogenic potential and efficacy against medulloblastoma cell lines and orthotopic mouse models of localized disease. Medulloblastoma cells infected by MV-E:A readily secrete endostatin and angiostatin prior to lysis. The inclusion of the endostatin/angiostatin gene did not negatively impact the measles virus’ cytotoxicity against medulloblastoma cells or alter its growth kinetics. Conditioned media obtained from these infected cells was capable of inhibiting multiple angiogenic factors in vitro, significantly reducing endothelial cell tube formation, viability and migration compared to conditioned media derived from cells infected by a control measles virus. Mice that were given a single intratumoral injection of MV-E:A likewise showed reduced numbers of tumor-associated blood

  14. α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth

    Science.gov (United States)

    Sengupta, Soma; Weeraratne, Shyamal Dilhan; Sun, Hongyu; Phallen, Jillian; Rallapalli, Sundari K.; Teider, Natalia; Kosaras, Bela; Amani, Vladimir; Pierre-Francois, Jessica; Tang, Yujie; Nguyen, Brian; Yu, Furong; Schubert, Simone; Balansay, Brianna; Mathios, Dimitris; Lechpammer, Mirna; Archer, Tenley C.; Tran, Phuoc; Reimer, Richard J.; Cook, James M.; Lim, Michael; Jensen, Frances E.; Pomeroy, Scott L.; Cho, Yoon-Jae

    2013-01-01

    Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors, and importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABR5, which encodes the α-subunit of the GABAA receptor complex, in aggressive MYC-driven, “Group 3” medulloblastomas. We hypothesized that modulation of α-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABR5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABR5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOX5 target gene expression. siRNA-mediated knockdown of HOX5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABR5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOX5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor. PMID:24196163

  15. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma.

    Science.gov (United States)

    Zhukova, Nataliya; Ramaswamy, Vijay; Remke, Marc; Martin, Dianna C; Castelo-Branco, Pedro; Zhang, Cindy H; Fraser, Michael; Tse, Ken; Poon, Raymond; Shih, David J H; Baskin, Berivan; Ray, Peter N; Bouffet, Eric; Dirks, Peter; von Bueren, Andre O; Pfaff, Elke; Korshunov, Andrey; Jones, David T W; Northcott, Paul A; Kool, Marcel; Pugh, Trevor J; Pomeroy, Scott L; Cho, Yoon-Jae; Pietsch, Torsten; Gessi, Marco; Rutkowski, Stefan; Bognár, Laszlo; Cho, Byung-Kyu; Eberhart, Charles G; Conter, Cecile Faure; Fouladi, Maryam; French, Pim J; Grajkowska, Wieslawa A; Gupta, Nalin; Hauser, Peter; Jabado, Nada; Vasiljevic, Alexandre; Jung, Shin; Kim, Seung-Ki; Klekner, Almos; Kumabe, Toshihiro; Lach, Boleslaw; Leonard, Jeffrey R; Liau, Linda M; Massimi, Luca; Pollack, Ian F; Ra, Young Shin; Rubin, Joshua B; Van Meir, Erwin G; Wang, Kyu-Chang; Weiss, William A; Zitterbart, Karel; Bristow, Robert G; Alman, Benjamin; Hawkins, Cynthia E; Malkin, David; Clifford, Steven C; Pfister, Stefan M; Taylor, Michael D; Tabori, Uri

    2014-12-24

    TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.

  16. α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth.

    Science.gov (United States)

    Sengupta, Soma; Weeraratne, Shyamal Dilhan; Sun, Hongyu; Phallen, Jillian; Rallapalli, Sundari K; Teider, Natalia; Kosaras, Bela; Amani, Vladimir; Pierre-Francois, Jessica; Tang, Yujie; Nguyen, Brian; Yu, Furong; Schubert, Simone; Balansay, Brianna; Mathios, Dimitris; Lechpammer, Mirna; Archer, Tenley C; Tran, Phuoc; Reimer, Richard J; Cook, James M; Lim, Michael; Jensen, Frances E; Pomeroy, Scott L; Cho, Yoon-Jae

    2014-04-01

    Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors and, importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABRA5, which encodes the α5-subunit of the GABAA receptor complex, in aggressive MYC-driven, "Group 3" medulloblastomas. We hypothesized that modulation of α5-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABRA5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABRA5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOXA5 target gene expression. siRNA-mediated knockdown of HOXA5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABRA5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOXA5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor.

  17. G-Protein Gαs controls medulloblastoma initiation by suppressing sonic hedgehog signaling.

    Science.gov (United States)

    He, Xuelian; Lu, Q Richard

    2015-01-01

    We identify Gαs as a novel tumor suppressor in medulloblastoma that functions principally by inhibition of sonic hedgehog signaling. Gαs not only stimulates cyclic adenosine monophosphate (cAMP)-dependent signaling but also inhibits ciliary trafficking of hedgehog components. Elevation of cAMP inhibits medulloblastoma growth and augments inhibition of smoothened to decrease tumor cell proliferation, thus highlighting Gαs as a potential therapeutic target.

  18. Social Behavior in Medulloblastoma: Functional Analysis of Tumor-Supporting Glial Cells

    Science.gov (United States)

    2015-10-01

    the manuscript with inputs from all authors. All authors reviewed the manuscript. Acknowledgements We thank Chris Doe, David Rowitch, and Praveen...201–208. Goodrich, L.V., Milenković, L., Higgins , K.M., and Scott, M.P. (1997). Altered Neural Cell Fates and Medulloblastoma in Mouse patched...Genes & Development 27, 98–115. Goodrich, L.V., Milenković, L., Higgins , K.M., and Scott, M.P. (1997). Altered Neural Cell Fates and Medulloblastoma in

  19. The contribution of radiotherapy in the adult patients with a medulloblastoma: a long mono-institutional experience

    International Nuclear Information System (INIS)

    Bari, B. de; Balducci, M.; Manfrida, S.; Chiesa, S.; Frascino, V.; Valentini, V.; Anile, C.

    2009-01-01

    The medulloblastoma is rare among adults (1% of primitive cerebral tumors). currently, the surgery constitutes the initial therapy approach, followed by the radiotherapy. This summary presents the update of a retrospective analysis in a population of adult patients (>18 years) suffering of a medulloblastoma presented in 2006 at the national congress of the Italian association of oncological radiotherapy. It confirms the efficiency of radiotherapy to treat the adult patients suffering of a medulloblastoma. (N.C.)

  20. Reappraisal of cerebellopontine angle medulloblastomas: Report of a fatal case and lessons learned

    Directory of Open Access Journals (Sweden)

    Sachin Ranganatha Goudihalli, M.Ch. Neurosurgery

    2018-06-01

    Full Text Available CPA Medulloblastomas are rare in adults. We describe a case of medulloblastoma in the right CPA in a middle aged male patient who presented with short history and was preoperatively diagnosed as vestibular schwannoma. Intra-operatively it turned out to be a highly vascular and malignant lesion. Histopathology demonstrated medulloblastoma with high ki67 index. Patient was re-explored for hematoma evacuation and remained vegetative postoperatively. This is a unique case considering the older age at presentation, short duration of symptoms with atypical presentation of only 7th, 8th and lower cranial nerve involvement. MRI showed a lobulated heterogeneous extra axial right CPA mass lesion extending in the right acoustic meatus and causing mass effect and effacement of the fourth ventricle with heterogeneous enhancement post-gadolinium, suggestive of vestibular schwannoma. The aggressive behaviour of this tumor with short history has to prompt one to keep less common lesions like medulloblastomas as differential diagnosis in the CPA region. Though medulloblastomas are rare lesions in the CPA they have to be considered in the differential diagnosis based on atypical clinical behaviour, a suspicion of such diagnosis preoperatively can alter the treatment strategy, focusing on tumor embolization, safe surgical excision and adjuvant chemoradiation, aiming towards a better quality of life, in the post-operative period. Keywords: Medulloblastoma, Cerebellopontine angle, Desmoplastic

  1. Sonic hedgehog-induced histone deacetylase activation is required for cerebellar granule precursor hyperplasia in medulloblastoma.

    Directory of Open Access Journals (Sweden)

    Seung Joon Lee

    Full Text Available Medulloblastoma, the most common pediatric brain tumor, is thought to arise from deregulated proliferation of cerebellar granule precursor (CGP cells. Sonic hedgehog (Shh is the primary mitogen that regulates proliferation of CGP cells during the early stages of postnatal cerebellum development. Aberrant activation of Shh signaling during this time has been associated with hyperplasia of CGP cells and eventually may lead to the development of medulloblastoma. The molecular targets of Shh signaling involved in medulloblastoma formation are still not well-understood. Here, we show that Shh regulates sustained activation of histone deacetylases (HDACs and that this activity is required for continued proliferation of CGP cells. Suppression of HDAC activity not only blocked the Shh-induced CGP proliferation in primary cell cultures, but also ameliorated aberrant CGP proliferation at the external germinal layer (EGL in a medulloblastoma mouse model. Increased levels of mRNA and protein of several HDAC family members were found in medulloblastoma compared to wild type cerebellum suggesting that HDAC activity is required for the survival/progression of tumor cells. The identification of a role of HDACs in the early steps of medulloblastoma formation suggests there may be a therapeutic potential for HDAC inhibitors in this disease.

  2. Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells.

    Science.gov (United States)

    Silva, Patrícia Benites Gonçalves da; Rodini, Carolina Oliveira; Kaid, Carolini; Nakahata, Adriana Miti; Pereira, Márcia Cristina Leite; Matushita, Hamilton; Costa, Silvia Souza da; Okamoto, Oswaldo Keith

    2016-08-01

    Medulloblastoma is a highly aggressive brain tumor and one of the leading causes of morbidity and mortality related to childhood cancer. These tumors display differential ability to metastasize and respond to treatment, which reflects their high degree of heterogeneity at the genetic and molecular levels. Such heterogeneity of medulloblastoma brings an additional challenge to the understanding of its physiopathology and impacts the development of new therapeutic strategies. This translational effort has been the focus of most pre-clinical studies which invariably employ experimental models using human tumor cell lines. Nonetheless, compared to other cancers, relatively few cell lines of human medulloblastoma are available in central repositories, partly due to the rarity of these tumors and to the intrinsic difficulties in establishing continuous cell lines from pediatric brain tumors. Here, we report the establishment of a new human medulloblastoma cell line which, in comparison with the commonly used and well-established cell line Daoy, is characterized by enhanced proliferation and invasion capabilities, stem cell properties, increased chemoresistance, tumorigenicity in an orthotopic metastatic model, replication of original medulloblastoma behavior in vivo, strong chromosome structural instability and deregulation of genes involved in neural development. These features are advantageous for designing biologically relevant experimental models in clinically oriented studies, making this novel cell line, named USP-13-Med, instrumental for the study of medulloblastoma biology and treatment.

  3. Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

    Directory of Open Access Journals (Sweden)

    Walderik W. Zomerman

    2018-03-01

    Full Text Available Summary: The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog, group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma. : Using peptide phosphorylation profiling, Zomerman et al. identify two medulloblastoma phosphoprotein-signaling profiles that have prognostic value and are potentially targetable. They find that these profiles extend across transcriptome-based subgroup borders. This suggests that diverse genetic information converges on common protein-signaling pathways and highlights protein-signaling as a unique information layer. Keywords: medulloblastoma, protein-signaling, protein synthesis, MYC, TP53, proteome, phosphoproteome

  4. Impact of radiation technique upon the outcome of treatment for medulloblastoma

    International Nuclear Information System (INIS)

    Halperin, Edward C.

    1996-01-01

    Craniospinal irradiation (CSI) is an essential component of the therapy of medulloblastoma. Because medulloblastoma disseminates via the cerebrospinal fluid (CSF), CSI technique involves the irradiation of all CSF-bearing areas which are at risk for tumor seeding. Underdosing with radiation because of inadequacies in CSI technique will produce dose 'cold spots' which have the potential of serving as a nidus for tumor recurrence. A simple mathematic model of subclinical disease in medulloblastoma based on the available data concerning the radiosensitivity of medulloblastoma cell lines as well as the known clinical dose-response relationships support the hypothesis that for most cases of medulloblastoma, the radiotherapist is working in a range of doses arrayed on the steep portion of the tumor control probability curve. Underdosing of CSF-bearing areas because of technical problems at the junction of the cranial and spinal fields of irradiation, placement of shielding blocks in the cribiform plate-sub frontal region, and/or anatomic errors in the design of the caudal end of the CSI fields may lead to significant risks of tumor relapse. One may debate the necessity of a posterior fossa boost encompassing the entire anatomic posterior fossa rather than the primary tumor volume with a margin. This review critically evaluates the potential impact of CSI technique upon the outcome of treatment for medulloblastoma, and suggests future areas of inquiry

  5. Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma.

    Directory of Open Access Journals (Sweden)

    Robert C Castellino

    Full Text Available BACKGROUND: Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. METHODOLOGY/PRINCIPAL FINDINGS: We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/-; Pten +/- medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/-; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression. CONCLUSIONS/SIGNIFICANCE: This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma.

  6. Epigenetic silencing of miRNA-9 is associated with HES1 oncogenic activity and poor prognosis of medulloblastoma

    Science.gov (United States)

    Fiaschetti, G; Abela, L; Nonoguchi, N; Dubuc, A M; Remke, M; Boro, A; Grunder, E; Siler, U; Ohgaki, H; Taylor, M D; Baumgartner, M; Shalaby, T; Grotzer, M A

    2014-01-01

    Background: microRNA-9 is a key regulator of neuronal development aberrantly expressed in brain malignancies, including medulloblastoma. The mechanisms by which microRNA-9 contributes to medulloblastoma pathogenesis remain unclear, and factors that regulate this process have not been delineated. Methods: Expression and methylation status of microRNA-9 in medulloblastoma cell lines and primary samples were analysed. The association of microRNA-9 expression with medulloblastoma patients' clinical outcome was assessed, and the impact of microRNA-9 restoration was functionally validated in medulloblastoma cells. Results: microRNA-9 expression is repressed in a large subset of MB samples compared with normal fetal cerebellum. Low microRNA-9 expression correlates significantly with the diagnosis of unfavourable histopathological variants and with poor clinical outcome. microRNA-9 silencing occurs via cancer-specific CpG island hypermethylation. HES1 was identified as a direct target of microRNA-9 in medulloblastoma, and restoration of microRNA-9 was shown to trigger cell cycle arrest, to inhibit clonal growth and to promote medulloblastoma cell differentiation. Conclusions: microRNA-9 is a methylation-silenced tumour suppressor that could be a potential candidate predictive marker for poor prognosis of medulloblastoma. Loss of microRNA-9 may confer a proliferative advantage to tumour cells, and it could possibly contribute to disease pathogenesis. Thus, re-expression of microRNA-9 may constitute a novel epigenetic regulation strategy against medulloblastoma. PMID:24346283

  7. Epigenetic silencing of miRNA-9 is associated with HES1 oncogenic activity and poor prognosis of medulloblastoma.

    Science.gov (United States)

    Fiaschetti, G; Abela, L; Nonoguchi, N; Dubuc, A M; Remke, M; Boro, A; Grunder, E; Siler, U; Ohgaki, H; Taylor, M D; Baumgartner, M; Shalaby, T; Grotzer, M A

    2014-02-04

    microRNA-9 is a key regulator of neuronal development aberrantly expressed in brain malignancies, including medulloblastoma. The mechanisms by which microRNA-9 contributes to medulloblastoma pathogenesis remain unclear, and factors that regulate this process have not been delineated. Expression and methylation status of microRNA-9 in medulloblastoma cell lines and primary samples were analysed. The association of microRNA-9 expression with medulloblastoma patients' clinical outcome was assessed, and the impact of microRNA-9 restoration was functionally validated in medulloblastoma cells. microRNA-9 expression is repressed in a large subset of MB samples compared with normal fetal cerebellum. Low microRNA-9 expression correlates significantly with the diagnosis of unfavourable histopathological variants and with poor clinical outcome. microRNA-9 silencing occurs via cancer-specific CpG island hypermethylation. HES1 was identified as a direct target of microRNA-9 in medulloblastoma, and restoration of microRNA-9 was shown to trigger cell cycle arrest, to inhibit clonal growth and to promote medulloblastoma cell differentiation. microRNA-9 is a methylation-silenced tumour suppressor that could be a potential candidate predictive marker for poor prognosis of medulloblastoma. Loss of microRNA-9 may confer a proliferative advantage to tumour cells, and it could possibly contribute to disease pathogenesis. Thus, re-expression of microRNA-9 may constitute a novel epigenetic regulation strategy against medulloblastoma.

  8. Gene expression analyses of the spatio-temporal relationships of human medulloblastoma subgroups during early human neurogenesis.

    Directory of Open Access Journals (Sweden)

    Cornelia M Hooper

    Full Text Available Medulloblastoma is the most common form of malignant paediatric brain tumour and is the leading cause of childhood cancer related mortality. The four molecular subgroups of medulloblastoma that have been identified - WNT, SHH, Group 3 and Group 4 - have molecular and topographical characteristics suggestive of different cells of origin. Definitive identification of the cell(s of origin of the medulloblastoma subgroups, particularly the poorer prognosis Group 3 and Group 4 medulloblastoma, is critical to understand the pathogenesis of the disease, and ultimately for the development of more effective treatment options. To address this issue, the gene expression profiles of normal human neural tissues and cell types representing a broad neuro-developmental continuum, were compared to those of two independent cohorts of primary human medulloblastoma specimens. Clustering, co-expression network, and gene expression analyses revealed that WNT and SHH medulloblastoma may be derived from distinct neural stem cell populations during early embryonic development, while the transcriptional profiles of Group 3 and Group 4 medulloblastoma resemble cerebellar granule neuron precursors at weeks 10-15 and 20-30 of embryogenesis, respectively. Our data indicate that Group 3 medulloblastoma may arise through abnormal neuronal differentiation, whereas deregulation of synaptic pruning-associated apoptosis may be driving Group 4 tumorigenesis. Overall, these data provide significant new insight into the spatio-temporal relationships and molecular pathogenesis of the human medulloblastoma subgroups, and provide an important framework for the development of more refined model systems, and ultimately improved therapeutic strategies.

  9. Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

    Science.gov (United States)

    2017-10-23

    Childhood Cerebral Anaplastic Astrocytoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma

  10. Radiotherapy of medulloblastoma combined with OK-432 (Picibanil)

    International Nuclear Information System (INIS)

    Aoki, Yoshiro

    1986-01-01

    The OK-432 group consists of 8 Medulloblastoma patients, 5 Pinealoma patients and 1 Pons glioma patient, while the historical control group consists of 12 Medulloblastoma patients who have been treated only with radiation at NIRS. The frequency of the week when the value of white blood cell counts decreased below 2,500 was 13 weeks per 98 weeks of total observation period (13.3 %) in the OK-432 group. However, it was 37 weeks per 103 weeks (35.9 %) in the control group. The frequency of the week when the value of the platelet counts decreased below 10 x 10 4 was 5 weeks per 98 weeks (5.1 %) in the OK-432 group, while it was 21 weeks per 103 weeks (20.4 %) in the control group. The OK-432 group received 54.4 ± 3.3 Gy/ 34 ± 2 fractions/ 51 ± 4 days to the cerebellar tumor, except a one-year-old girl who received only a half of the radiation dose as the other patients who were older than 5 years, while the control group received 47.2 ± 7.3 Gy/ 34 ± 7 fractions/ 49 ± 10 days. In terms of TDF, the OK-432 group received 83.5 ± 8.7 and the control group received 63.5 ± 10.2, whereby the difference between the OK-432 group and the control group is statistically significant at 2 % level. To the spinal cord, the OK-432 group received 27.1 ± 3.1 Gy/ 27 ± 5 fractions/ 41 ± 9 days, while the control group received 25.4 ± 7.5 Gy/ 27 ± 13 fractions/ 43 ± 25 days. The survival rate of 8 Medulloblastoma patients treated with radiation combined with OK-432 is as follows : the relative survival rate is 75.1 % in one year, 62.5 % in 3 years and 62.5 % in 5 years, in contrast to the rate of 73.3 % in one year, 20.0 % in 3 years and 20.0 % in 5 years in the control group. (J.P.N.)

  11. Medulloblastoma in adults. A retrospective single institution analysis

    Energy Technology Data Exchange (ETDEWEB)

    Hadi, Indrawati; Roengvoraphoj, Olarn; Niyazi, Maximilian; Nachbichler, Silke Birgit [LMU Munich, Department of Radiation Oncology, University Hospital, Munich (Germany); Roeder, Falk [LMU Munich, Department of Radiation Oncology, University Hospital, Munich (Germany); German Cancer Research Center (DKFZ), Molecular Radiation Oncology, Heidelberg (Germany); Schueller, Ulrich [University Medical Center, Institute of Neuropathology, Hamburg-Eppendorf (Germany); Research Institute Children' s Cancer Center, Hamburg (Germany); University Medical Center, Department of Pediatric Hematology and Oncology, Hamburg-Eppendorf (Germany); Belka, Claus [LMU Munich, Department of Radiation Oncology, University Hospital, Munich (Germany); German Cancer Consortium (DKTK), Munich (Germany)

    2018-03-15

    Adult medulloblastoma is a rare disease treated according to the current pediatric treatment guidelines. This retrospective analysis investigated the clinical outcomes and prognostic factors of adult medulloblastoma patients, who received multimodal therapy at our institution. Treatment charts of all patients over the age of 15 years of age with de novo medulloblastoma, who had been treated at our institution between 2001 and 2014, were retrospectively analyzed. Patients' demographic parameters, initial symptoms, treatment modalities, toxicities, and survival outcomes were investigated. In all, 21 patients with a median age of 30.2 years were identified. The most frequent histologies were desmoplastic and classic, and the most common molecular subtype was sonic hedgehog (SHH). After tumor resection, all patients received craniospinal irradiation (median dose 35.2 Gy) and a boost to the posterior fossa (median dose 19.8 Gy). Simultaneous chemotherapy with vincristine was given to 20 patients and sequential chemotherapy to 15 patients. The most common side effects were hematological toxicities. Median overall survival (OS) has not been reached after a median follow-up of 92 months. Estimated 5- and 10-year OS was 89 and 80%, respectively. Estimated 5- and 10-year progression-free survival (PFS) was 89 and 81%, respectively. In univariate analysis, a shorter interval between tumor resection and end of irradiation was significantly associated with improved OS and PFS, anaplastic histology with worse OS and PFS. The combined modality treatment showed a good outcome in adults with medulloblastoma. Treatment time was revealed to be prognostic and should be kept as short as possible. (orig.) [German] Das Medulloblastom des Erwachsenen ist eine seltene Erkrankung, die analog paediatrischer Behandlungsprotokolle therapiert wird. Diese retrospektive Analyse untersuchte die klinischen Ergebnisse und prognostischen Faktoren von erwachsenen Medulloblastompatienten, die eine

  12. The whole-genome landscape of medulloblastoma subtypes

    Science.gov (United States)

    Northcott, Paul A.; Buchhalter, Ivo; Morrissy, A. Sorana; Hovestadt, Volker; Weischenfeldt, Joachim; Ehrenberger, Tobias; Groebner, Susanne; Segura-Wang, Maia; Zichner, Thomas; Rudneva, Vasilisa; Warnatz, Hans-Jörg; Sidiropoulos, Nikos; Phillips, Aaron H.; Schumacher, Steven; Kleinheinz, Kortine; Waszak, Sebastian M.; Erkek, Serap; Jones, David T.W.; Worst, Barbara C.; Kool, Marcel; Zapatka, Marc; Jäger, Natalie; Chavez, Lukas; Hutter, Barbara; Bieg, Matthias; Paramasivam, Nagarajan; Heinold, Michael; Gu, Zuguang; Ishaque, Naveed; Jäger-Schmidt, Christina; Imbusch, Charles D.; Jugold, Alke; Hübschmann, Daniel; Risch, Thomas; Amstislavskiy, Vyacheslav; Gonzalez, Francisco German Rodriguez; Weber, Ursula D.; Wolf, Stephan; Robinson, Giles W.; Zhou, Xin; Wu, Gang; Finkelstein, David; Liu, Yanling; Cavalli, Florence M.G.; Luu, Betty; Ramaswamy, Vijay; Wu, Xiaochong; Koster, Jan; Ryzhova, Marina; Cho, Yoon-Jae; Pomeroy, Scott L.; Herold-Mende, Christel; Schuhmann, Martin; Ebinger, Martin; Liau, Linda M.; Mora, Jaume; McLendon, Roger E.; Jabado, Nada; Kumabe, Toshihiro; Chuah, Eric; Ma, Yussanne; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen L.; Thiessen, Nina; Tse, Kane; Wong, Tina; Jones, Steven J.M.; Witt, Olaf; Milde, Till; Von Deimling, Andreas; Capper, David; Korshunov, Andrey; Yaspo, Marie-Laure; Kriwacki, Richard; Gajjar, Amar; Zhang, Jinghui; Beroukhim, Rameen; Fraenkel, Ernest; Korbel, Jan O.; Brors, Benedikt; Schlesner, Matthias; Eils, Roland; Marra, Marco A.; Pfister, Stefan M.; Taylor, Michael D.; Lichter, Peter

    2018-01-01

    Summary Current therapies for medulloblastoma (MB), a highly malignant childhood brain tumor, impose debilitating effects on the developing child, warranting deployment of molecularly targeted treatments with reduced toxicities. Prior studies failed to disclose the full spectrum of driver genes and molecular processes operative in MB subgroups. Herein, we detail the somatic landscape across 491 sequenced MBs and molecular heterogeneity amongst 1,256 epigenetically analyzed cases, identifying subgroup-specific driver alterations including previously unappreciated actionable targets. Driver mutations explained the majority of Group 3 and Group 4 patients, remarkably enhancing previous knowledge. Novel molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions targeting KBTBD4 and ‘enhancer hijacking’ driving PRDM6 activation. Thus, application of integrative genomics to an unprecedented cohort of clinical samples derived from a single childhood cancer entity disclosed a series of new cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for treating MB patients. PMID:28726821

  13. Evaluation of the intraspinal enhancement for medulloblastoma on MR imaging

    International Nuclear Information System (INIS)

    Kim, Hwa Young; Kim, In One; Kim, Woo Sun; Cheon, Jung Eun; Yeon, Kyung Mo

    2004-01-01

    The purpose of this study was to analyze the enhancement pattern of the spinal cord for patients with medulloblastoma, and to correlate the enhancement pattern with cerebrospinal fluid (CSF) tumor seeding. We retrospectively reviewed 84 MR images, including the initial and follow-up studies after chemotherapy or radiation therapy, of 25 patients with medulloblastoma who were aged from 2 to 13 years. We analyzed the spinal leptomeningeal enhancement pattern on the MR images. The leptomeningeal enhancement patterns were categorized into three types: Type, I, fine or discontinuous linear enhancement, and type II, continuous linear or nodular enhancement, and type III, intradural mass formation. We correlated the enhancement pattern on MRI with the results of CSF cytology at the initial and follow-up examinations after treatment. Of total 25 patients, type I enhancement was observed for 14 patients. Twelve patients were negative on the initial CSF cytology and 2 patients were positive. On the follow-up MR studies, 14 patients showed no change or only a slight decrease of enhancement, and all were negative on the follow-up CSF cytology. Type II enhancement patterns were observed in seven patients, and all of them were positive on the initial CSF cytology. On follow-up MR study, one patient revealed an increased enhancement with the positive result on the follow-up CSF cytology, and six patients had decreased enhancement on the follow-up MR studies with negative conversion on the follow-up CSF cytology. Type III enhancement patterns were observed in four patients and all of them were positive on the initial CSF cytology. All four patients with tradural mass formations revealed progression of the lesions on follow-up MR studies, and all of them were positive on the follow-up CSF cytology. Type II and III enhancement patterns always represented CSF seeding and a type I enhancement pattern had a low probability of metastasis

  14. Further characterization of the ABR gene in medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Wright-White, E.C.; Haken, M.S. von; McDonald J.D. [Univ. of Chicago, IL (United States)] [and others

    1994-09-01

    Although brain tumors are the most common type of solid cancer in children, little is known about their etiology at the molecular genetic level. Using a panel of 20 chromosome 17p markers, we have previously determined that loss of distal chromosome 17p DNA sequences occurs in 14 of 35 specimens (40%) of medulloblastoma, one of the most common pediatric intracranial neoplasms. Analysis of these same tumors using a PCR-denaturing gradient gel electrophoresis technique has shown only two p53 gene mutations. These results suggest that a tumor suppressor gene in addition to p53 may be located on distal chromosome 17p. Consensus deletion mapping of our specimens suggests that the smallest site of chromosomal loss in defined distally by marker 144-D6, the most telomeric probe as yet identified on chromosome 17p, and proximally by the ABR marker, a BCR homologous gene containing two highly polymorphic VNTR regions. We have used fluorescence in situ hybridization and pulsed-field gel electrophoresis to determine that the ABR gene lies transcriptionally oriented 5{prime} to 3{prime} at a distance of 240 kb from marker 144-D6. We have also constructed a cosmid contig map spanning 120 kb of this region. Using one of these cosmids as a probe, we have detected breakpoints in three of the tumor specimens that lie between the two VNTR regions within the ABR gene. We have subsequently designed PCR primers to cover the breakpoint region which include the ABR exons which have the strongest homology to the BCR gene (Mbcr region), and are screening our tumor specimens for mutations. These results suggest that loss of ABR gene sequences may be involved in the etiology of medulloblastoma.

  15. Pre-Irradiation Chemotherapy in High Risk Medulloblastoma

    International Nuclear Information System (INIS)

    Abd-El-Aal, H.

    2006-01-01

    Rationale: The present study evaluates the effect of pre-irradiation chemotherapy in pediatric patients with high risk medulloblastoma. Twenty-four (24) pediatric patients attended the pediatric unit of Kasr-EI-Aini Center of Radiation Oncology and Nuclear Medicine (NEMROCK) from January 2000 to January 2003. Patients and Methods: Our patients were 13 boys and II girls aged 3-12 years with a median of 6.5 years. According to Chang staging system 6 cases had T2, 14 cases had T3 A and 4 cases had T3 B, 20 cases were M0, 3 cases were M I and I case was M2. All patients were treated by initial surgery, 2 cycles of pre-irradiation chemotherapy followed by craniospinal radiation then by 4 cycles of post-radiation chemotherapy. Results: Fifteen out of the 20 patients with M0 had objective response (10CR + 5PR) and no one had disease progression after pre-irradiation chemotherapy. Among 4 patients with M0 disease, 2 patients had PR and 2 had S.D. There was no disease progression among patients who received pre-irradiation chemotherapy. The 3-year overall survival and 3-year progression-free survival; (PFS) were 50% and 51 %, respectively, Myelosuppression was the main toxic effect observed during pre-irradiation chemotherapy; however, there was no delay or interruption of craniospinal irradiation. Conclusion: Pre-irradiation chemotherapy is effective in high risk medulloblastoma and is associated with acceptable side effects. The delay in craniospinal irradiation (CSI) for about 5 weeks to receive 2 courses of chemotherapy will not significantly increase disease progression. Multiple cycles of post-irradiation chemotherapy can be given safely after C51. A larger number of patients and longer follow-up is needed to confirm the results

  16. MiR-34a deficiency accelerates medulloblastoma formation in vivo.

    Science.gov (United States)

    Thor, Theresa; Künkele, Annette; Pajtler, Kristian W; Wefers, Annika K; Stephan, Harald; Mestdagh, Pieter; Heukamp, Lukas; Hartmann, Wolfgang; Vandesompele, Jo; Sadowski, Natalie; Becker, Lore; Garrett, Lillian; Hölter, Sabine M; Horsch, Marion; Calzada-Wack, Julia; Klein-Rodewald, Tanja; Racz, Ildiko; Zimmer, Andreas; Beckers, Johannes; Neff, Frauke; Klopstock, Thomas; De Antonellis, Pasqualino; Zollo, Massimo; Wurst, Wolfgang; Fuchs, Helmut; Gailus-Durner, Valérie; Schüller, Ulrich; de Angelis, Martin Hrabě; Eggert, Angelika; Schramm, Alexander; Schulte, Johannes H

    2015-05-15

    Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option. © 2014 UICC.

  17. Survival in pediatric medulloblastoma: a population-based observational study to improve prognostication.

    Science.gov (United States)

    Weil, Alexander G; Wang, Anthony C; Westwick, Harrison J; Ibrahim, George M; Ariani, Rojine T; Crevier, Louis; Perreault, Sebastien; Davidson, Tom; Tseng, Chi-Hong; Fallah, Aria

    2017-03-01

    Medulloblastoma is the most common form of brain malignancy of childhood. The mainstay of epidemiological data regarding childhood medulloblastoma is derived from case series, hence population-based studies are warranted to improve the accuracy of survival estimates. To utilize a big-data approach to update survival estimates in a contemporary cohort of children with medulloblastoma. We performed a population-based retrospective observational cohort study utilizing the Surveillance, Epidemiology, and End Results Program database that captures all children, less than 20 years of age, between 1973 and 2012 in 18 geographical regions representing 28% of the US population. We included all participants with a presumed or histologically diagnosis of medulloblastoma. The main outcome of interest is survivors at 1, 5 and 10 years following diagnosis. A cohort of 1735 children with a median (interquartile range) age at diagnosis of 7 (4-11) years, with a diagnosis of medulloblastoma were identified. The incidence and prevalence of pediatric medulloblastoma has remained stable over the past 4 decades. There is a critical time point at 1990 when the overall survival has drastically improved. In the contemporary cohort (1990 onwards), the percentage of participants alive was 86, 70 and 63% at 1, 5 and 10 years, respectively. Multivariate Cox-Regression model demonstrated Radiation (HR 0.37; 95% CI 0.30-0.46, p < 0.001) and Surgery (HR 0.42; 95% CI 0.30-0.58, p < 0.001) independently predict survival. The probability of mortality from a neurological cause is <5% in patients who are alive 8 years following diagnosis. The SEER cohort analysis demonstrates significant improvements in pediatric medulloblastoma survival. In contrast to previous reports, the majority of patients survive in the modern era, and those alive 8 years following initial diagnosis are likely a long-term survivor. The importance of minimizing treatment-related toxicity is increasingly apparent given

  18. Multicenter pilot study of radio-chemotherapy as first-line treatment for adults with medulloblastoma (NOA-07)

    DEFF Research Database (Denmark)

    Dagmar, Dagmar; Proescholdt, Martin; Reinert, Christiane

    2018-01-01

    Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radio-chemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptiv...

  19. Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo

    Directory of Open Access Journals (Sweden)

    Deckard Lindsey A

    2011-04-01

    Full Text Available Abstract Background Medulloblastoma is a highly malignant pediatric brain tumor that requires surgery, whole brain and spine irradiation, and intense chemotherapy for treatment. A more sophisticated understanding of the pathophysiology of medulloblastoma is needed to successfully reduce the intensity of treatment and improve outcomes. Nuclear factor kappa-B (NFκB is a signaling pathway that controls transcriptional activation of genes important for tight regulation of many cellular processes and is aberrantly expressed in many types of cancer. Methods To test the importance of NFκB to medulloblastoma cell growth, the effects of multiple drugs that inhibit NFκB, pyrrolidine dithiocarbamate, diethyldithiocarbamate, sulfasalazine, curcumin and bortezomib, were studied in medulloblastoma cell lines compared to a malignant glioma cell line and normal neurons. Expression of endogenous NFκB was investigated in cultured cells, xenograft flank tumors, and primary human tumor samples. A dominant negative construct for the endogenous inhibitor of NFκB, IκB, was prepared from medulloblastoma cell lines and flank tumors were established to allow specific pathway inhibition. Results We report high constitutive activity of the canonical NFκB pathway, as seen by Western analysis of the NFκB subunit p65, in medulloblastoma tumors compared to normal brain. The p65 subunit of NFκB is extremely highly expressed in xenograft tumors from human medulloblastoma cell lines; though, conversely, the same cells in culture have minimal expression without specific stimulation. We demonstrate that pharmacological inhibition of NFκB in cell lines halts proliferation and leads to apoptosis. We show by immunohistochemical stain that phosphorylated p65 is found in the majority of primary tumor cells examined. Finally, expression of a dominant negative form of the endogenous inhibitor of NFκB, dnIκB, resulted in poor xenograft tumor growth, with average tumor volumes

  20. Indian Society of Neuro-Oncology consensus guidelines for the contemporary management of medulloblastoma.

    Science.gov (United States)

    Gupta, Tejpal; Sarkar, Chitra; Rajshekhar, Vedantam; Chatterjee, Sandip; Shirsat, Neelam; Muzumdar, Dattatreya; Pungavkar, Sona; Chinnaswamy, Girish; Jalali, Rakesh

    2017-01-01

    The high success rate in the management medulloblastoma achieved in the western world is not exactly mirrored in developing countries including India. Socio-demographic differences, health-care disparity, and lack in uniformity of care with resultant widespread variations in the clinical practice are some of the reasons that may partly explain this difference in outcomes. Patients with medulloblastoma require a multi-disciplinary team approach involving but not limited to neuro-radiology, neurosurgery; neuropathology, molecular biology, radiation oncology, pediatric medical oncology and rehabilitative services for optimizing outcomes. The Indian Society of Neuro-Oncology (ISNO) constituted an expert multi-disciplinary panel with adequate representation from all stakeholders to prepare national consensus guidelines for the contemporary management of medulloblastoma. Minimum desirable, as well as preferable though optional recommendations (as appropriate), were developed and adopted for the pre-surgical work-up including neuroimaging; neurosurgical management including surgical principles, techniques, and complications; neuropathology reporting and molecular testing; contemporary risk-stratification in the molecular era; appropriate adjuvant therapy (radiotherapy and chemotherapy); and follow-up schedule in medulloblastoma. The current document represents a broad consensus reached amongst various stakeholders within the neuro-oncology community involved in the contemporary curative-intent management of children with medulloblastoma. It provides both general as well as specific guidelines and recommendations to be adopted by physicians and health care providers across India to achieve uniformity of care, improve disease-related outcomes, and compare results between institutions within the country.

  1. Concurrent IDH1 and SMARCB1 Mutations in Pediatric Medulloblastoma: A Case Report

    Directory of Open Access Journals (Sweden)

    Moatasem El-Ayadi

    2018-06-01

    Full Text Available Isocitrate Dehydrogenase-1 (IDH1 is a driver gene in several cancers including brain tumors such as low-grade and high-grade gliomas. Mutations of SMARCB1 were described in atypical teratoid rhabdoid tumors and to date have not been associated with the pathogenesis of medulloblastoma. We report concurrent IDH1 and SMARCB1 mutations in a medulloblastoma patient. We searched the catalog of somatic mutations in cancer (COSMIC database and other mutation databases and -to our knowledge- this is the first reported case of medulloblastoma harboring both mutations together. Our patient is a 13-year-old male presenting with headache and vomiting at diagnosis. MRI revealed left cerebellar expansive lesion with no evidence of metastasis. A histopathological diagnosis of desmoplastic/nodular medulloblastoma was made after complete resection of the tumor. Immunophenotypic characterization and methylation profiling suggested a medulloblastoma with SHH activation. Next generation sequencing of a panel of 400 genes revealed heterozygous somatic IDH1(p.R132C, SMARCB1(p.R201Q, and CDH11(p.L625T mutations. The patient was treated according to the HIT-SIOP PNET 4 protocol. He is in complete remission more than 2 years after diagnosis. In conclusion, increasing use of high throughput sequencing will certainly increase the frequency with which rare mutations or mutation combinations are identified. The exact frequency of this mutation combination and whether it has any particular therapeutic implications or prognostic relevance requires further investigation.

  2. Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma

    Directory of Open Access Journals (Sweden)

    Sara Badodi

    2017-12-01

    Full Text Available Summary: We describe molecular convergence between BMI1 and CHD7 in the initiation of medulloblastoma. Identified in a functional genomic screen in mouse models, a BMI1High;CHD7Low expression signature within medulloblastoma characterizes patients with poor overall survival. We show that BMI1-mediated repression of the ERK1/2 pathway leads to increased proliferation and tumor burden in primary human MB cells and in a xenograft model, respectively. We provide evidence that repression of the ERK inhibitor DUSP4 by BMI1 is dependent on a more accessible chromatin configuration in G4 MB cells with low CHD7 expression. These findings extend current knowledge of the role of BMI1 and CHD7 in medulloblastoma pathogenesis, and they raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of MB with low expression levels of CHD7. : Badodi et al. find convergence of the chromatin modifiers BMI1 and CHD7 in medulloblastoma pathogenesis, and they show that this pathway regulates tumor proliferation and growth via ERK signaling. Keywords: BMI1, CHD7, DUSP4, ERK, medulloblastoma, PcG genes, mouse models, epigenetics, chromatin

  3. Role of MXD3 in proliferation of DAOY human medulloblastoma cells.

    Directory of Open Access Journals (Sweden)

    Gustavo A Barisone

    Full Text Available A subset of medulloblastomas, the most common brain tumor in children, is hypothesized to originate from granule neuron precursors (GNPs in which the sonic hedgehog (SHH pathway is over-activated. MXD3, a basic helix-look-helix zipper transcription factor of the MAD family, has been reported to be upregulated during postnatal cerebellar development and to promote GNP proliferation and MYCN expression. Mxd3 is upregulated in mouse models of medulloblastoma as well as in human medulloblastomas. Therefore, we hypothesize that MXD3 plays a role in the cellular events that lead to medulloblastoma biogenesis. In agreement with its proliferative role in GNPs, MXD3 knock-down in DAOY cells resulted in decreased proliferation. Sustained overexpression of MXD3 resulted in decreased cell numbers due to increased apoptosis and cell cycle arrest. Structure-function analysis revealed that the Sin3 interacting domain, the basic domain, and binding to E-boxes are essential for this activity. Microarray-based expression analysis indicated up-regulation of 84 genes and down-regulation of 47 genes. Potential direct MXD3 target genes were identified by ChIP-chip. Our results suggest that MXD3 is necessary for DAOY medulloblastoma cell proliferation. However, increased level and/or duration of MXD3 expression ultimately reduces cell numbers via increased cell death and cell cycle arrest.

  4. Medulloblastoma in an Adult With Late Extraneural Metastases to the Mediastinum

    Directory of Open Access Journals (Sweden)

    Abhimanyu Ghose MD

    2014-04-01

    Full Text Available Background. Medulloblastoma, although the most common brain tumor of childhood, is exceedingly rare in adults. These tumors have a propensity for local recurrence and to metastasize along the leptomeninges; however, extraneural metastases are very rare and typically occur in the bone or bone marrow. We have not come across any case in literature of medulloblastoma with mediastinal metastases in an adult. Case Presentation. We report a case of medulloblastoma in a 38-year-old lady who was treated with surgery followed by craniospinal radiation. Ten years later she presented with hoarseness from true vocal cord paralysis. She was diagnosed to have infiltrating metastases of her medulloblastoma to the mediastinum, which was confirmed by biopsy. There was no local recurrence. This was treated with chemotherapy followed by stem cell rescue, and she remained progression free for 2 years. Conclusion. Medulloblastomas are rare in adults and can present with late extraneural metastases following treatment. Although most common reported sites are bone and bone marrow, late metastases to other unexpected areas like the mediastinum are possible too and warrant awareness. This can be treated with chemotherapy followed by high-dose chemotherapy and stem cell rescue in a young patient with good performance status.

  5. Progressive ototoxicity after combined modality treatment of medulloblastoma

    International Nuclear Information System (INIS)

    Dutton, S.C.; Neault, M.; Billett, A.E.; LaVally, B.; Scott, R.M.; Sallan, S.E.; Tarbell, N.J.

    1996-01-01

    Objective: Prospective study to evaluate the response rate, survival and toxicity of pre-irradiation chemotherapy in the treatment of children with seeding CNS tumors. Materials and Methods: Forty-two patients with medulloblastoma were enrolled on a prospective pre-irradiation chemotherapy protocol between 1984 and 1990. Patients (Median age 9.5 years; 29 males, 13 females) received post-operative chemotherapy [cisplatinum 100 mg/m2 q 3 weeks) and vincristine (1.5 mg/m2 weekly) for 9 weeks. Infants (4 patients) received nitrogen mustard (6 mg/m2), procarbazine (100 mg/m2) and vincristine (1.5 mg/m2) until age two followed by craniospinal radiation (CSI). Forty-one patients received CSI with ≥ 50 Gy to the posterior fossa (PF). The median doses to the whole brain, PF, and spine were 33.8 Gy, 55.3 Gy, 27.8 Gy, respectively. Results: Five-year overall survival was 86% and event-free survival was 65% (median follow-up for survivors, 61 months). Thirteen of 15 patients with complete surgical resection documented by post-operative imaging remained free of disease during chemotherapy (CT), and were considered unevaluable for response to CT. The response rate (complete plus partial) to pre-irradiation CT was 45% ((13(29))). Ten patients had stable disease and 6 had progressive disease (PD). Three of 6 patients with PD were long-term survivors after CSI. Thirteen patients relapsed with a median time to failure of 14.5 months. Sites of failure were PF (5 pts), spinal cord (3 pts), CNS/meninges (3 pts), PF/spinal cord (1 pt), and bone metastasis (1 pt). Ototoxicity analysis was performed using 24 patients who had normal hearing in the better ear before chemotherapy and at least one follow-up audiogram for comparison after therapy. 17 patients had an audiogram immediately after CT, and 71% of pts ((12(17))) had high frequency hearing impairment beginning in 3000-8000 Hz range. 18% ((3(17))) had hearing loss in the 500-2000 Hz range necessitating a hearing aid post-CT. 22

  6. Medulloblastoma in adults: treatment results and prognostic factors

    International Nuclear Information System (INIS)

    Abacioglu, Ufuk; Uzel, Omer; Sengoz, Meric; Turkan, Sedat; Ober, Ahmet

    2002-01-01

    Purpose: To investigate the treatment outcome and prognostic factors of adult medulloblastoma patients who received postoperative craniospinal irradiation (RT). Methods and Materials: Between 1983 and 2000, 30 adult patients (17 men and 13 women, age ≥16 years, median 27, range 16-45) underwent postoperative RT. The median duration of symptoms was 2 months (range 1-9). The tumor location was lateral in 16 (53%). A desmoplastic variant was seen in 12 (40%). Tumor resection was complete in 20 (67%) and incomplete in 10 (33%). All patients received craniospinal RT. The median dose to the whole brain was 40 Gy (range 36-51), to the posterior fossa 54 Gy (range 49-56), and to the spinal axis 36 Gy (range 24-40). The median interval between surgery and the start of RT was 31 days (range 12-69), and the median duration of RT was 45 days (range 34-89). Ten patients (33%) received adjuvant chemotherapy. The median follow-up was 51 months (range 5-215). Results: The 5- and 8-year overall survival and disease-free survival rates were 65% and 51% and 63% and 50%, respectively. Twelve patients (40%) developed relapse, with a median follow-up of 51 months. The posterior fossa was the most common site of relapse (6 patients). The median time to relapse was 26 months (range 4-78). Fifty percent of the relapses occurred after 2 years, 17% after 5 years. In univariate analysis, M stage and the interval between surgery and the start of RT were significant prognostic factors for disease-free survival. At 5 years, 70% of M0 patients were estimated to be disease-free, but none of the 3 M3 patients reached 5 years without recurrence (p=0.0002). The 5-year disease-free survival rate for the patients whose interval between surgery and the start of RT was 6 weeks was 0%, 85%, and 75%, respectively (p=0.002). The 5-year posterior fossa control rate for patients who received ≥54 Gy or <54 Gy to the posterior fossa was 91% and 33%, respectively (p=0.05). Conclusion: The survival results

  7. Deletion and aberrant CpG island methylation of Caspase 8 gene in medulloblastoma.

    Science.gov (United States)

    Gonzalez-Gomez, Pilar; Bello, M Josefa; Inda, M Mar; Alonso, M Eva; Arjona, Dolores; Amiñoso, Cinthia; Lopez-Marin, Isabel; de Campos, Jose M; Sarasa, Jose L; Castresana, Javier S; Rey, Juan A

    2004-09-01

    Aberrant methylation of promoter CpG islands in human genes is an alternative genetic inactivation mechanism that contributes to the development of human tumors. Nevertheless, few studies have analyzed methylation in medulloblastomas. We determined the frequency of aberrant CpG island methylation for Caspase 8 (CASP8) in a group of 24 medulloblastomas arising in 8 adult and 16 pediatric patients. Complete methylation of CASP8 was found in 15 tumors (62%) and one case displayed hemimethylation. Three samples amplified neither of the two primer sets for methylated or unmethylated alleles, suggesting that genomic deletion occurred in the 5' flanking region of CASP8. Our findings suggest that methylation commonly contributes to CASP8 silencing in medulloblastomas and that homozygous deletion or severe sequence changes involving the promoter region may be another mechanism leading to CASP8 inactivation in this neoplasm.

  8. Data on the number and frequency of scientific literature citations for established medulloblastoma cell lines

    Directory of Open Access Journals (Sweden)

    D.P. Ivanov

    2016-12-01

    Full Text Available This article collates information about the number of scientific articles mentioning each of the established medulloblastoma cell lines, derived through a systematic search of Web of Science, Scopus and Google Scholar in 2016. The data for each cell line have been presented as raw number of citations, percentage share of the total citations for each search engine and as an average percentage between the three search engines. In order to correct for the time since each cell line has been in use, the raw citation data have also been divided by the number of years since the derivation of each cell line. This is a supporting article for a review of in vitro models of medulloblastoma published in “in vitro models of medulloblastoma: choosing the right tool for the job” (D.P. Ivanov, D.A. Walker, B. Coyle, A.M. Grabowska, 2016 [1].

  9. Nevoid basal cell carcinoma syndrome with medulloblastoma and meningioma. Case report

    International Nuclear Information System (INIS)

    Fukushima, Yutaka; Oka, Hidehiro; Utsuki, Satoshi; Iwamoto, Kazuhisa; Fujii, Kiyotaka

    2004-01-01

    A 35-year-old man presented with a rare case of nevoid basal cell carcinoma syndrome, or Gorlin's syndrome, associated with both medulloblastoma and meningioma, manifesting as visual field constriction due to multiple parasellar tumors. He had undergone resection of a medulloblastoma at the age of 1 year 9 months, followed by adjunctive irradiation with a total dose of 40 Gy. He presented with multiple subcutaneous nodules on his face and neck. Histological examination of biopsy specimens established the diagnosis of nevoid basal cell carcinoma syndrome. Tuberculum sellae meningioma was removed through a craniotomy, and his symptoms improved. Meningioma is known to occur in the field of therapeutic irradiation, so chemotherapy may be a better option for medulloblastoma associated with nevoid basal cell carcinoma syndrome. (author)

  10. Dicer Is Required for Normal Cerebellar Development and to Restrain Medulloblastoma Formation.

    Directory of Open Access Journals (Sweden)

    Frederique Zindy

    Full Text Available Dicer, a ribonuclease III enzyme, is required for the maturation of microRNAs. To assess its role in cerebellar and medulloblastoma development, we genetically deleted Dicer in Nestin-positive neural progenitors and in mice lacking one copy for the Sonic Hedgehog receptor, Patched 1. We found that conditional loss of Dicer in mouse neural progenitors induced massive Trp53-independent apoptosis in all proliferative zones of the brain and decreased proliferation of cerebellar granule progenitors at embryonic day 15.5 leading to abnormal cerebellar development and perinatal lethality. Loss of one copy of Dicer significantly accelerated the formation of mouse medulloblastoma of the Sonic Hedgehog subgroup in Patched1-heterozygous mice. We conclude that Dicer is required for proper cerebellar development, and to restrain medulloblastoma formation.

  11. Goldenhar syndrome and medulloblastoma: a coincidental association? The first case report.

    Science.gov (United States)

    Aizenbud, Dror; Shoham, Natasha V; Constantini, Shlomi; Nevo, Neta; Ben Arush, Myriam; Raz, Michal; Rachmiel, Adi; Goldsher, Dorit

    2014-07-01

    Features of Goldenhar syndrome include several craniofacial anomalies of structures derived from the first and second pharyngeal arches, as well as vertebral, cardiac and renal systems abnormalities. In addition, Goldenhar patients were reported to manifest a variety of central nervous system anomalies and several types of neoplasias. The first case of medulloblastoma in a patient with Goldenhar syndrome is presented here. There is no clear association between these two pathologies. We speculate that aberrant events during the migration of neural crest cells in early stages of development could be the basis of an association between medulloblastoma and Goldenhar syndrome. The case history suggests other possible etiological contributing factors to the development of medulloblastoma, such as patient's history of trauma and/or early childhood exposure to ionizing radiation. Copyright © 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  12. Cauda equina syndrome as the initial presenting clinical feature of medulloblastoma: a case report

    Directory of Open Access Journals (Sweden)

    Al-Otaibi Faisal

    2012-05-01

    Full Text Available Abstract Introduction Medulloblastoma is one of the most common pediatric brain malignancies. The usual presenting clinical features are related to posterior fossa syndrome or/and hydrocephalus. Cauda equina syndrome is a very rare presentation for this disease. Case presentation We describe the case of a three-year-old boy with cauda equina syndrome as the initial presenting clinical feature for medulloblastoma. He was initially diagnosed as having a spinal tumor by magnetic resonance imaging scan. Subsequently, a cranial magnetic resonance imaging scan revealed a posterior fossa tumor with features of dissemination. He had substantial improvement after treatment. This case report is complemented by a literature review related to this unusual presentation. Conclusions Medulloblastoma primarily presenting with cauda equina syndrome is very rare. However, spinal drop metastasis should be considered in the pediatric age group to avoid suboptimal management.

  13. Metabolic analysis of radioresistant medulloblastoma stem-like clones and potential therapeutic targets.

    Directory of Open Access Journals (Sweden)

    Lue Sun

    Full Text Available Medulloblastoma is a fatal brain tumor in children, primarily due to the presence of treatment-resistant medulloblastoma stem cells. The energy metabolic pathway is a potential target of cancer therapy because it is often different between cancer cells and normal cells. However, the metabolic properties of medulloblastoma stem cells, and whether specific metabolic pathways are essential for sustaining their stem cell-like phenotype and radioresistance, remain unclear. We have established radioresistant medulloblastoma stem-like clones (rMSLCs by irradiation of the human medulloblastoma cell line ONS-76. Here, we assessed reactive oxygen species (ROS production, mitochondria function, oxygen consumption rate (OCR, energy state, and metabolites of glycolysis and tricarboxylic acid cycle in rMSLCs and parental cells. rMSLCs showed higher lactate production and lower oxygen consumption rate than parental cells. Additionally, rMSLCs had low mitochondria mass, low endogenous ROS production, and existed in a low-energy state. Treatment with the metabolic modifier dichloroacetate (DCA resulted in mitochondria dysfunction, glycolysis inhibition, elongated mitochondria morphology, and increased ROS production. DCA also increased radiosensitivity by suppression of the DNA repair capacity through nuclear oxidization and accelerated the generation of acetyl CoA to compensate for the lack of ATP. Moreover, treatment with DCA decreased cancer stem cell-like characters (e.g., CD133 positivity and sphere-forming ability in rMSLCs. Together, our findings provide insights into the specific metabolism of rMSLCs and illuminate potential metabolic targets that might be exploited for therapeutic benefit in medulloblastoma.

  14. Apparent diffusion coefficient mapping in medulloblastoma predicts non-infiltrative surgical planes.

    Science.gov (United States)

    Marupudi, Neena I; Altinok, Deniz; Goncalves, Luis; Ham, Steven D; Sood, Sandeep

    2016-11-01

    An appropriate surgical approach for posterior fossa lesions is to start tumor removal from areas with a defined plane to where tumor is infiltrating the brainstem or peduncles. This surgical approach minimizes risk of damage to eloquent areas. Although magnetic resonance imaging (MRI) is the current standard preoperative imaging obtained for diagnosis and surgical planning of pediatric posterior fossa tumors, it offers limited information on the infiltrative planes between tumor and normal structures in patients with medulloblastomas. Because medulloblastomas demonstrate diffusion restriction on apparent diffusion coefficient map (ADC map) sequences, we investigated the role of ADC map in predicting infiltrative and non-infiltrative planes along the brain stem and/or cerebellar peduncles by medulloblastomas prior to surgery. Thirty-four pediatric patients with pathologically confirmed medulloblastomas underwent surgical resection at our facility from 2004 to 2012. An experienced pediatric neuroradiologist reviewed the brain MRIs/ADC map, assessing the planes between the tumor and cerebellar peduncles/brain stem. An independent evaluator documented surgical findings from operative reports for comparison to the radiographic findings. The radiographic findings were statistically compared to the documented intraoperative findings to determine predictive value of the test in identifying tumor infiltration of the brain stem cerebellar peduncles. Twenty-six patients had preoperative ADC mapping completed and thereby, met inclusion criteria. Mean age at time of surgery was 8.3 ± 4.6 years. Positive predictive value of ADC maps to predict tumor invasion of the brain stem and cerebellar peduncles ranged from 69 to 88 %; negative predictive values ranged from 70 to 89 %. Sensitivity approached 93 % while specificity approached 78 %. ADC maps are valuable in predicting the infiltrative and non-infiltrative planes along the tumor and brain stem interface in

  15. Outcome and prognostic factors of desmoplastic medulloblastoma treated within a multidisciplinary treatment concept

    International Nuclear Information System (INIS)

    Rieken, Stefan; Gaiser, Timo; Mohr, Angela; Welzel, Thomas; Witt, Olaf; Kulozik, Andreas E; Wick, Wolfgang; Debus, Jürgen; Combs, Stephanie E

    2010-01-01

    Desmoplasia in medulloblastoma is often diagnosed in adult patients and was repeatedly associated with improved results. Today, all medulloblastoma patients receive intensive multimodal treatment including surgery, radiotherapy and chemotherapy. This study was set up to investigate treatment outcome and prognostic factors after radiation therapy in patients with desmoplastic medulloblastomas. Twenty patients treated for desmoplastic medulloblastoma in the Department of Radiation Oncology at the University of Heidelberg between 1984 and 2007 were included. Data were collected retrospectively. Tumor resection was performed in all patients. All patients underwent postsurgical radiotherapy (RT). Two patients underwent whole brain radiotherapy (WBRT), and 18 patients received craniospinal irradiation (CSI). In all patients, an additional boost was delivered to the posterior fossa. The median dose to the whole brain and the craniospinal axis was 35.2 Gray (Gy), and 54.4 Gy to the posterior fossa. Fourteen patients received chemotherapy, including seven who were treated with combined radiochemotherapy and twelve who received adjuvant chemotherapy. Statistical analysis was performed using the log-rank test and the Kaplan-Meier method. Median follow-up was 59 months. Overall (OS), local (LPFS) and distant progression-free survival (DPFS) was 80%, 71.2%, and 83.3% at 60 months. Patients who suffered from local or distant relapses had significantly worse outcome. Five patients died from recurrent medulloblastoma. Treatment-associated toxicity was acceptable. Multimodal approaches with surgical resection followed by chemoirradiation achieved high response rates with long OS in desmoplastic medulloblastoma patients. Staging parameters expected to predict for poor prognosis did not significantly influence outcome. However, success of any first line regimen had strong impact on disease control, and remission was achieved in no patient with relapsing disease. Multimodal concepts

  16. Medulloblastoma Presenting With Pure Word Deafness: Report of One Case and Review of Literature

    Directory of Open Access Journals (Sweden)

    Yen-Ting Chou

    2011-10-01

    Full Text Available Pure word deafness (PWD is a rare disorder characterized by impaired verbal comprehension sparing discrimination and recognition of nonverbal sounds with relatively normal spontaneous speech, writing, and reading comprehension. Etiologies of this syndrome are varied, and there are rare reports about brain tumor with PWD in children. We report a case of medulloblastoma presented with PWD in a 7-year-old girl. She visited our outpatient clinic because of English dictation performance deterioration. PWD was diagnosed by the otolaryngologist after examinations. Posterior fossa tumor and obstructive hydrocephalus were shown in the magnetic resonance imaging of the brain. The diagnosis of medulloblastoma was then made by pathology.

  17. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology.

    Science.gov (United States)

    Brandes, Alba A; Bartolotti, Marco; Marucci, Gianluca; Ghimenton, Claudio; Agati, Raffaele; Fioravanti, Antonio; Mascarin, Maurizio; Volpin, Lorenzo; Ammannati, Franco; Masotto, Barbara; Gardiman, Marina Paola; De Biase, Dario; Tallini, Giovanni; Crisi, Girolamo; Bartolini, Stefania; Franceschi, Enrico

    2015-06-01

    Medulloblastoma is the most common central nervous system tumor in children, while it is extremely rare in adults. Multimodal treatment involving surgery, radiotherapy and chemotherapy can improve the prognosis of this disease, and recent advances in molecular biology have allowed the identification of molecular subgroups (WNT, SHH, Groups 3 and 4), each of which have different cytogenetic, mutational and gene expression signatures, demographics, histology and prognosis. The present review focuses on the state of the art for adult medulloblastoma treatment and on novel molecular advances and their future implications in the treatment of this disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Recurrent medulloblastoma: Frequency of tumor enhancement on Gd-DTPA MR imaging

    International Nuclear Information System (INIS)

    Rollins, N.; Mendelsohn, D.; Mulne, A.; Barton, R.; Diehl, J.; Reyes, N.; Sklar, F.

    1990-01-01

    Thirty-two children with medulloblastoma were evaluated postoperatively with conventional and gadolinium-enhanced MR imaging. Eleven patients had abnormal cranial MR studies; nine of these had recurrent tumor. In six patients recurrent tumor enhanced with Gd, while in the other three patients recurrent tumor did not enhance. The remaining two patients had areas of abnormal Gd enhancement that were caused by radiation-induced breakdown of the blood-brain barrier rather than by recurrent tumor. This study shows that not all recurrent medulloblastoma enhances and that the absence of Gd enhancement does not necessarily indicate the absence of recurrent tumor

  19. SIOP PODC adapted treatment recommendations for standard-risk medulloblastoma in low and middle income settings.

    Science.gov (United States)

    Parkes, Jeannette; Hendricks, Marc; Ssenyonga, Peter; Mugamba, John; Molyneux, Elizabeth; Schouten-van Meeteren, Antoinette; Qaddoumi, Ibrahim; Fieggen, Graham; Luna-Fineman, Sandra; Howard, Scott; Mitra, Dipayan; Bouffet, Eric; Davidson, Alan; Bailey, Simon

    2015-04-01

    Effective treatment of children with medulloblastoma requires a functioning multi-disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition the treating centre should have the capacity to effectively screen and manage any tumour and treatment-associated complications. These requirements have made it difficult for many low and middle-income countries (LMIC) centres to offer curative treatment. This article provides management recommendations for children with standard-risk medulloblastoma (localised tumours in children over the age of 3-5 years) according to the level of facilities available. © 2014 Wiley Periodicals, Inc.

  20. Occurrence and prognosis of the medulloblastoma in adult persons

    Energy Technology Data Exchange (ETDEWEB)

    Boettcher, H.D.; Wagner, W.; Haverkamp, U.; Schadel, A.

    1983-03-01

    Between 1962 and 1981, 37 patients with histologically proved medulloblastomas have been treated at the hospitals of the University of Muenster. 17 patients died immediately after the operation or were, when admitted, in such bad condition that any therapy was impossible. Since about 1972, the therapy of choice is surgery and post-irradiation of the neurocranium with saturating irradiation of the posterior cranial fossa as well as irradiation of the complete cerebrospinal system down to the second sacral vertebra, because the tumor tends to spinal formation of metastases. Among our patients, twelve were treated in this manner. Before this time, patients were only operated on and submitted to an irradiation of the posterior cranial fossa. Eight patients were treated according to this incomplete therapy scheme, five of whom were younger than twelve and three older than forty years. The tumor was situated in one side of the cerebellum in the three adult patients. The children had a shorter survival time than the adults, except one four years old child who has survived for 228 months since treatment and has to be considered as cured. Our medical records showed at the same time that the course of this disease is considerably worse in infants up to three years than in older patients.

  1. Occurence and prognosis of the medulloblastoma in adult persons

    International Nuclear Information System (INIS)

    Boettcher, H.D.; Wagner, W.; Haverkamp, U.; Schadel, A.

    1983-01-01

    Between 1962 and 1981, 37 patients with histologically proved medulloblastomas have been treated at the hospitals of the University of Muenster. 17 patients died immediately after operation or were, when admitted, in such a bad condition that any therapy was impossible. Since about 1972, the therapy of choice is the operation and post-irradiation of the neurocranium with saturating irradiation of the posterior cranial fossa as well as irradiation of the complete cerebrospinal system down to the second sacral vertebra, because the tumor tends to spinal formation of metastases. Among our patients, twelve were treated in this manner. Before this time, patients were only operated and submitted to an irradiation of the posterior cranial fossa. Eight patients were treated according to this incomplete therapy scheme, five of whom were younger than twelve and three older than forty years. The tumor was situated in one side of the cerebellum in the three adult patients. The children had a shorter survival time than the adults, except one four years old child who survives already 228 months after the treatment and has to be considered as cured. Our medical records showed at the same time that the course of this disease is considerably worse in infants up to three years than in older patients. (orig.) [de

  2. Executive function in paediatric medulloblastoma: The role of cerebrocerebellar connections.

    Science.gov (United States)

    Law, Nicole; Smith, Mary Lou; Greenberg, Mark; Bouffet, Eric; Taylor, Michael D; Laughlin, Suzanne; Malkin, David; Liu, Fang; Moxon-Emre, Iska; Scantlebury, Nadia; Mabbott, Donald

    2017-06-01

    Executive functions (EFs) are involved in the attainment, maintenance, and integration of information; these functions may play a key role in cognitive and behavioural outcomes in children treated for medulloblastoma (MB). At present, it remains unclear which EFs are most sensitive to the treatment effects for MB and whether damage to cerebrocerebellar circuitry is associated with EF. We completed a comprehensive evaluation of EF in 24 children treated for MB and 20 age-matched healthy children (HC) and distilled these measures into components. Six components (C1-C6) were extracted from our model, reflecting dissociable constructs of EF: C1 = cognitive efficiency; C2 = planning/problem-solving; C3 = positive cognitive emotion regulation; C4 = working memory; C5 = negative cognitive emotion regulation; and C6 = mixed cognitive emotion regulation. Group differences were found for C1, C2, C3, and C4; the MB group showed poorer performance on EF tasks and made less use of positive cognitive emotion regulation strategies relative to HC. Compromise to cerebrocerebellar microstructure - cerebro-ponto-cerebellar and cerebello-thalamo-cerebral pathways - was evident in children treated for MB compared to HC. We found that cerebrocerebellar circuitry has a mediating effect on one component of EF following treatment for MB - working memory. © 2015 The British Psychological Society.

  3. Bmi1 overexpression in the cerebellar granule cell lineage of mice affects cell proliferation and survival without initiating medulloblastoma formation

    Directory of Open Access Journals (Sweden)

    Hourinaz Behesti

    2013-01-01

    BMI1 is a potent inducer of neural stem cell self-renewal and neural progenitor cell proliferation during development and in adult tissue homeostasis. It is overexpressed in numerous human cancers – including medulloblastomas, in which its functional role is unclear. We generated transgenic mouse lines with targeted overexpression of Bmi1 in the cerebellar granule cell lineage, a cell type that has been shown to act as a cell of origin for medulloblastomas. Overexpression of Bmi1 in granule cell progenitors (GCPs led to a decrease in cerebellar size due to decreased GCP proliferation and repression of the expression of cyclin genes, whereas Bmi1 overexpression in postmitotic granule cells improved cell survival in response to stress by altering the expression of genes in the mitochondrial cell death pathway and of Myc and Lef-1. Although no medulloblastomas developed in ageing cohorts of transgenic mice, crosses with Trp53−/− mice resulted in a low incidence of medulloblastoma formation. Furthermore, analysis of a large collection of primary human medulloblastomas revealed that tumours with a BMI1high TP53low molecular profile are significantly enriched in Group 4 human medulloblastomas. Our data suggest that different levels and timing of Bmi1 overexpression yield distinct cellular outcomes within the same cellular lineage. Importantly, Bmi1 overexpression at the GCP stage does not induce tumour formation, suggesting that BMI1 overexpression in GCP-derived human medulloblastomas probably occurs during later stages of oncogenesis and might serve to enhance tumour cell survival.

  4. c-Myc Enhances Sonic Hedgehog-Induced Medulloblastoma Formation from Nestin-Expressing Neural Progenitors in Mice

    Directory of Open Access Journals (Sweden)

    Ganesh Rao

    2003-05-01

    Full Text Available Medulloblastomas are malignant brain tumors that arise in the cerebella of children. The presumed cellsof-origin are undifferentiated precursors of granule neurons that occupy the external granule layer (EGL of the developing cerebellum. The overexpression of proteins that normally stimulate proliferation of neural progenitor cells may initiate medulloblastoma formation. Two known mitogens for neural progenitors are the c-Myc oncoprotein and Sonic hedgehog (Shh, a crucial determinant of embryonic pattern formation in the central nervous system. We modeled the ability of c-Myc and Shh to induce medulloblastoma in mice using the RCAS/tv-a system, which allows postnatal gene transfer and expression in a cell type-specific manner. We targeted the expression of Shh and c-Myc to nestin-expressing neural progenitor cells by injecting replication-competent ALV splice acceptor (RCAS vectors into the cerebella of newborn mice. Following injection with RCAS-Shh alone, 3/32 (9% mice developed medulloblastomas and 5/32 showed multifocal hyperproliferation of the EGL, possibly a precursor stage of medulloblastoma. Following injection with RCAS-Shh plus RCAS-Myc, 9/39 (23% mice developed medulloblastomas. We conclude that nestin-expressing neural progenitors, present in the cerebellum at birth, can act as the cells-of-origin for medulloblastoma, and that c-Myc cooperates with Shh to enhance tumorigenicity.

  5. Critical role of zinc finger protein 521 in the control of growth, clonogenicity and tumorigenic potential of medulloblastoma cells.

    Science.gov (United States)

    Spina, Raffaella; Filocamo, Gessica; Iaccino, Enrico; Scicchitano, Stefania; Lupia, Michela; Chiarella, Emanuela; Mega, Tiziana; Bernaudo, Francesca; Pelaggi, Daniela; Mesuraca, Maria; Pazzaglia, Simonetta; Semenkow, Samantha; Bar, Eli E; Kool, Marcel; Pfister, Stefan; Bond, Heather M; Eberhart, Charles G; Steinkühler, Christian; Morrone, Giovanni

    2013-08-01

    The stem cell-associated transcription co-factor ZNF521 has been implicated in the control of hematopoietic, osteo-adipogenic and neural progenitor cells. ZNF521 is highly expressed in cerebellum and in particular in the neonatal external granule layer that contains candidate medulloblastoma cells-of-origin, and in the majority of human medulloblastomas. Here we have explored its involvement in the control of human and murine medulloblastoma cells. The effect of ZNF521 on growth and tumorigenic potential of human medulloblastoma cell lines as well as primary Ptc1-/+ mouse medulloblastoma cells was investigated in a variety of in vitro and in vivo assays, by modulating its expression using lentiviral vectors carrying the ZNF521 cDNA, or shRNAs that silence its expression. Enforced overexpression of ZNF521 in DAOY medulloblastoma cells significantly increased their proliferation, growth as spheroids and ability to generate clones in single-cell cultures and semisolid media, and enhanced their migratory ability in wound-healing assays. Importantly, ZNF521-expressing cells displayed a greatly enhanced tumorigenic potential in nude mice. All these activities required the ZNF521 N-terminal motif that recruits the nucleosome remodeling and histone deacetylase complex, which might therefore represent an appealing therapeutic target. Conversely, silencing of ZNF521 in human UW228 medulloblastoma cells that display high baseline expression decreased their proliferation, clonogenicity, sphere formation and wound-healing ability. Similarly, Zfp521 silencing in mouse Ptc1-/+ medulloblastoma cells drastically reduced their growth and tumorigenic potential. Our data strongly support the notion that ZNF521, through the recruitment of the NuRD complex, contributes to the clonogenic growth, migration and tumorigenicity of medulloblastoma cells.

  6. Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells

    International Nuclear Information System (INIS)

    Harris, Peter S; Foreman, Nicholas K; Vibhakar, Rajeev; Venkataraman, Sujatha; Alimova, Irina; Birks, Diane K; Donson, Andrew M; Knipstein, Jeffrey; Dubuc, Adrian; Taylor, Michael D; Handler, Michael H

    2012-01-01

    Medulloblastoma is the most common malignant brain tumor in children and remains a therapeutic challenge due to its significant therapy-related morbidity. Polo-like kinase 1 (PLK1) is highly expressed in many cancers and regulates critical steps in mitotic progression. Recent studies suggest that targeting PLK1 with small molecule inhibitors is a promising approach to tumor therapy. We examined the expression of PLK1 mRNA in medulloblastoma tumor samples using microarray analysis. The impact of PLK1 on cell proliferation was evaluated by depleting expression with RNA interference (RNAi) or by inhibiting function with the small molecule inhibitor BI 2536. Colony formation studies were performed to examine the impact of BI 2536 on medulloblastoma cell radiosensitivity. In addition, the impact of depleting PLK1 mRNA on tumor-initiating cells was evaluated using tumor sphere assays. Analysis of gene expression in two independent cohorts revealed that PLK1 mRNA is overexpressed in some, but not all, medulloblastoma patient samples when compared to normal cerebellum. Inhibition of PLK1 by RNAi significantly decreased medulloblastoma cell proliferation and clonogenic potential and increased cell apoptosis. Similarly, a low nanomolar concentration of BI 2536, a small molecule inhibitor of PLK1, potently inhibited cell growth, strongly suppressed the colony-forming ability, and increased cellular apoptosis of medulloblastoma cells. Furthermore, BI 2536 pretreatment sensitized medulloblastoma cells to ionizing radiation. Inhibition of PLK1 impaired tumor sphere formation of medulloblastoma cells and decreased the expression of SRY (sex determining region Y)-box 2 (SOX2) mRNA in tumor spheres indicating a possible role in targeting tumor inititiating cells. Our data suggest that targeting PLK1 with small molecule inhibitors, in combination with radiation therapy, is a novel strategy in the treatment of medulloblastoma that warrants further investigation

  7. Group 3 medulloblastoma in a patient with a GYS2 germline mutation and glycogen storage disease 0a.

    Science.gov (United States)

    Holsten, Till; Tsiakas, Konstantinos; Kordes, Uwe; Bison, Brigitte; Pietsch, Torsten; Rutkowski, Stefan; Santer, René; Schüller, Ulrich

    2018-03-01

    Glycogen storage disease (GSD) 0a is a rare congenital metabolic disease with symptoms in infancy and childhood caused by biallelic GYS2 germline variants. A predisposition to cancer has not been described yet. We report here a boy with GSD 0a, who developed a malignant brain tumor at the age of 4.5 years. The tumor was classified as a group 3 medulloblastoma, and the patient died from cancer 27 months after initial tumor diagnosis. This case appears interesting as group 3 medulloblastoma is so far not known to arise in hereditary syndromes and the biology of sporadic group 3 medulloblastoma is largely unknown.

  8. Long-term neuro-endocrine sequelae after treatment for childhood medulloblastoma

    NARCIS (Netherlands)

    Heikens, J.; Michiels, E. M.; Behrendt, H.; Endert, E.; Bakker, P. J.; Fliers, E.

    1998-01-01

    The occurrence of neuro-endocrine deficiencies following craniospinal irradiation for medulloblastoma is well known, but data concerning the spectrum and prevalence of endocrine abnormalities in adulthood are scarce. We studied endocrine function in 20 (median age 25 years) adult subjects, 8-25

  9. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition

    NARCIS (Netherlands)

    Kool, Marcel; Jones, David T. W.; Jäger, Natalie; Northcott, Paul A.; Pugh, Trevor J.; Hovestadt, Volker; Piro, Rosario M.; Esparza, L. Adriana; Markant, Shirley L.; Remke, Marc; Milde, Till; Bourdeaut, Franck; Ryzhova, Marina; Sturm, Dominik; Pfaff, Elke; Stark, Sebastian; Hutter, Sonja; Seker-Cin, Huriye; Johann, Pascal; Bender, Sebastian; Schmidt, Christin; Rausch, Tobias; Shih, David; Reimand, Jüri; Sieber, Laura; Wittmann, Andrea; Linke, Linda; Witt, Hendrik; Weber, Ursula D.; Zapatka, Marc; König, Rainer; Beroukhim, Rameen; Bergthold, Guillaume; van Sluis, Peter; Volckmann, Richard; Koster, Jan; Versteeg, Rogier; Schmidt, Sabine; Wolf, Stephan; Lawerenz, Chris; Bartholomae, Cynthia C.; von Kalle, Christof; Unterberg, Andreas; Herold-Mende, Christel; Hofer, Silvia; Kulozik, Andreas E.; von Deimling, Andreas; Scheurlen, Wolfram; Felsberg, Jörg; Reifenberger, Guido; Hasselblatt, Martin; Crawford, John R.; Grant, Gerald A.; Jabado, Nada; Perry, Arie; Cowdrey, Cynthia; Croul, Sydney; Zadeh, Gelareh; Korbel, Jan O.; Doz, Francois; Delattre, Olivier; Bader, Gary D.; McCabe, Martin G.; Collins, V. Peter; Kieran, Mark W.; Cho, Yoon-Jae; Pomeroy, Scott L.; Witt, Olaf; Brors, Benedikt; Taylor, Michael D.; Schüller, Ulrich; Korshunov, Andrey; Eils, Roland; Wechsler-Reya, Robert J.; Lichter, Peter; Pfister, Stefan M.

    2014-01-01

    Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large

  10. A review of dosimetric and toxicity modeling of proton versus photon craniospinal irradiation for pediatrics medulloblastoma.

    Science.gov (United States)

    Ho, Evangeline S Q; Barrett, Sarah A; Mullaney, Laura M

    2017-08-01

    Craniospinal irradiation (CSI) is the standard radiation therapy treatment for medulloblastoma. Conventional CSI photon therapy (Photon-CSI) delivers significant dose to surrounding normal tissue (NT). Research into pediatric CSI with proton therapy (Proton-CSI) has increased, with the aim of exploiting the potential to reduce NT dose and associated post-treatment complications. This review aims to compare treatment outcomes of pediatric medulloblastoma patients between Proton- and Photon-CSI treatments. A search and review of studies published between 1990 and 2016 comparing pediatric (2-18 years) medulloblastoma Proton- and Photon-CSI in three aspects - normal organ sparing and target coverage; normal organ dysfunction and second malignancy risks - was completed. Fifteen studies were selected for review and the results were directly compared. Proton-CSI reported improved out-of-field organ sparing while target coverage improvements were inconsistent. Normal organ dysfunction risks were predicted to be lower following Proton-CSI. Secondary malignancy risks (SMRs) were generally lower with Proton-CSI based on several different risk models. Proton-CSI conferred better treatment outcomes than Photon-CSI for pediatric medulloblastoma patients. This review serves to compare the current literature in the absence of long-term data from prospective studies.

  11. Risk-based optimization of photon and proton radiotherapy for pediatric medulloblastoma

    DEFF Research Database (Denmark)

    Brodin, Nils Patrik

    Medulloblastoma (MB) is one of the most common brain tumors in children and most patients will survive their disease if treated with surgery, radio- and chemotherapy. This has resulted in a growing number of MB survivors who are at risk of developing severe late complications related to the aggre...

  12. Anaplasia is rare and does not influence prognosis in adult medulloblastoma.

    Science.gov (United States)

    Giordana, Maria Teresa; D'Agostino, Carla; Pollo, Bianca; Silvani, Antonio; Ferracini, Romano; Paiolo, Anna; Ghiglione, Paolo; Chiò, Adriano

    2005-10-01

    Histopathologic grading based on increasing anaplasia predicts clinical behavior of pediatric medulloblastomas. The present study was aimed at grading 86 medulloblastomas of adult patients (aged 18 and older) by anaplasia and analyzing the predictive power. Nodularity, desmoplasia, nuclear size, nuclear pleomorphism, necrosis, and endothelial proliferations have been evaluated. Morphometric analysis of nuclear size was performed using the Eclipse Net program. Patients treated with standard postoperative radiotherapy (35 Gy to craniospinal axis and 50 Gy to posterior fossa) were considered for correlation with survival. Pathologic data and total survival were compared by Kaplan-Meier and logrank analysis. No correlation was found between total survival duration and individual pathologic features. Cooccurrence of nuclear pleomorphism, large nuclear diameter, microvascular proliferations, and necroses did not predict outcome. Severe nuclear pleomorphism was found in 4 of 86 cases; the only large-cell medulloblastoma was from an 18-year-old patient. Histopathologic factors have no clinical use for stratification of patients in risk groups. The histologic spectrum of medulloblastoma in adults is different from that in children.

  13. Prognostic significance of anaplasia and angiogenesis in childhood medulloblastoma: a pediatric oncology group study.

    Science.gov (United States)

    Ozer, Erdener; Sarialioglu, Faik; Cetingoz, Riza; Yüceer, Nurullah; Cakmakci, Handan; Ozkal, Sermin; Olgun, Nur; Uysal, Kamer; Corapcioglu, Funda; Canda, Serefettin

    2004-01-01

    The purpose of this study was to investigate whether quantitative assessment of cytologic anaplasia and angiogenesis may predict the clinical prognosis in medulloblastoma and stratify the patients to avoid both undertreatment and overtreatment. Medulloblastomas from 23 patients belonging to the Pediatric Oncology Group were evaluated with respect to some prognostic variables, including histologic assessment of nodularity and desmoplasia, grading of anaplasia, measurement of nuclear size, mitotic cell count, quantification of angiogenesis, including vascular surface density (VSD) and microvessel number (NVES), and immunohistochemical scoring of vascular endothelial growth factor (VEGF) expression. Univariate and multivariate analyses for prognostic indicators for survival were performed. Univariate analysis revealed that extensive nodularity was a significant favorable prognostic factor, whereas the presence of anaplasia, increased nuclear size, mitotic rate, VSD, and NVES were significant unfavorable prognostic factors. Using multivariate analysis, increased nuclear size was found to be an independent unfavorable prognostic factor for survival. Neither the presence of desmoplasia nor VEGF expression was significantly related to patient survival. Although care must be taken not to overstate the importance of the results of this single-institution preliminary report, pathologic grading of medulloblastomas with respect to grading of anaplasia and quantification of nodularity, nuclear size, and microvessel profiles may be clinically useful for the treatment of medulloblastomas. Further validation of the independent prognostic significance of nuclear size in stratifying patients is required.

  14. High incidence of medulloblastoma in Māori and Pacific populations in New Zealand.

    Science.gov (United States)

    Elwood, J Mark; Aye, Phyu Sin

    2017-02-17

    In New Zealand from 1995-2010, the incidence of medulloblastoma at ages 1-19 years was significantly higher in Māori (relative risk 2.0) and in Pacific peoples (RR 2.1) than in New Zealand Europeans.

  15. Effect of motivation on academic fluency performance in survivors of pediatric medulloblastoma.

    Science.gov (United States)

    Holland, Alice Ann; Hughes, Carroll W; Harder, Lana; Silver, Cheryl; Bowers, Daniel C; Stavinoha, Peter L

    2016-01-01

    It has been proposed previously that extrinsic motivation may enable survivors of childhood medulloblastoma to significantly improve aspects of neurocognitive performance. In healthy populations, enhanced motivation has been shown to promote academic fluency, a domain likely more relevant to the educational outcomes of pediatric medulloblastoma survivors than academic skill development. The present study investigates the effect of enhanced extrinsic motivation on fluent (i.e., accurate and efficient) academic performance in pediatric medulloblastoma survivors. Participants were 36 children, ages 7-18, who had completed treatment for medulloblastoma. Participants completed a neuropsychological battery that included administration of equivalent tasks on Forms A and B of the Woodcock-Johnson III Tests of Achievement. Half were randomly assigned to an incentive condition prior to the administration of Form B. Provision of a performance-based incentive resulted in statistically significant improvement, but not normalization of function, in performance on measures of academic fluency. No demographic, treatment-related, academic, neuropsychological, or self-perception variables predicted response to incentive. Findings suggest that academic performance of survivors may significantly improve under highly motivating conditions. In addition to implications for educational services, this finding raises the novel possibility that decreased motivation represents an inherent neuropsychological deficit in this population and provides a rationale for further investigation of factors affecting individual differences in motivational processes. Further, by examining effort in a context where effort is not inherently suspect, present findings also significantly contribute to the debate regarding the effects of effort and motivation on neuropsychological performance.

  16. Relapsing tumefactive lesion in an adult with medulloblastoma previously treated with chemoradiotherapy and stem cell transplant.

    Science.gov (United States)

    Mahta, Ali; Qu, Yan; Nastic, Denis; Sundstrom, Maria; Kim, Ryan Y; Saria, Marlon; Santagata, Sandro; Kesari, Santosh

    2012-04-01

    Herein, we present an adult case of medulloblastoma who received chemotherapy, radiation therapy and stem cell transplantation, and underwent multiple surgical resections for what were thought to be recurrences; however pathology confirmed a diagnosis of relapsing tumefactive lesions. This phenomenon seems to be a consequence of stem cell transplantation rather than a simple radiation treatment effect.

  17. The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread.

    Science.gov (United States)

    Hatton, Beryl A; Villavicencio, Elisabeth H; Tsuchiya, Karen D; Pritchard, Joel I; Ditzler, Sally; Pullar, Barbara; Hansen, Stacey; Knoblaugh, Sue E; Lee, Donghoon; Eberhart, Charles G; Hallahan, Andrew R; Olson, James M

    2008-03-15

    Toward the goal of generating a mouse medulloblastoma model with increased tumor incidence, we developed a homozygous version of our ND2:SmoA1 model. Medulloblastomas form in 94% of homozygous Smo/Smo mice by 2 months of age. Tumor formation is, thus, predictable by age, before the symptomatic appearance of larger lesions. This high incidence and early onset of tumors is ideal for preclinical studies because mice can be enrolled before symptom onset and with a greater latency period before late-stage disease. Smo/Smo tumors also display leptomeningeal dissemination of neoplastic cells to the brain and spine, which occurs in many human cases. Despite an extended proliferation of granule neuron precursors (GNP) in the postnatal external granular layer (EGL), the internal granular layer formed normally in Smo/Smo mice and tumor formation occurred only in localized foci on the superficial surface of the molecular layer. Thus, tumor formation is not simply the result of over proliferation of GNPs within the EGL. Moreover, Smo/Smo medulloblastomas were transplantable and serially passaged in vivo, demonstrating the aggressiveness of tumor cells and their transformation beyond a hyperplastic state. The Smo/Smo model is the first mouse medulloblastoma model to show leptomeningeal spread. The adherence to human pathology, high incidence, and early onset of tumors thus make Smo/Smo mice an efficient model for preclinical studies.

  18. Medulloblastoma-change of prognosis in children at one center over the last 30 years

    International Nuclear Information System (INIS)

    Lechner-Pissenberger, S.

    2002-06-01

    Tumours of the central nervous system are the most common solid tumours in children. Medulloblastoma constitute about 20 % of all brain tumours in children. The peak of incidence is noted between the 4th and 8th year of life. There is a male/female predominancy of approximately 2 to 1. Medulloblastoma is a high-malignant tumour and originates in the posterior fossa. 87 patients were treated for a medulloblastoma at the Department of Neurosurgery at the General Hospital Vienna from January 1969 to December 2000. In this study the change of prognosis in children over the last 30 years should be explored. The 5-year event-free survival rate was between 1969 and 1979 33 %, between 1980 and 1990 64 % and between 1991 and 2000 59 %. Reasons for the improved survival rates from 1980 are the optimal surgical planning with CT and MRT, the MRT of the spinal cord before and after surgery for the purpose of tumor staging (metastases)and the advent of the surgical microscope in 1988. For all that the prognosis of medulloblastoma is poor now as before, because the mean 10-year survival rate is 60 %. Therefore it is necessary to improve the therapy to increase the long-term survival rates. This can be reached only with additional chemotherapy, which has been demonstrated in several studies of famous study groups. (author)

  19. EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion

    NARCIS (Netherlands)

    Sikkema, Arend H.; den Dunnen, Wilfred F. A.; Hulleman, Esther; van Vuurden, Dannis G.; Garcia-Manero, Guillermo; Yang, Hui; Scherpen, Frank J. G.; Kampen, Kim R.; Hoving, Eelco W.; Kamps, Willem A.; Diks, Sander H.; Peppelenbosch, Maikel P.; de Bont, Eve Line S. J. M.

    Eph/ephrin signaling has bcen implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinase-activity profiling data

  20. PTEN Signaling in the Postnatal Perivascular Progenitor Niche Drives Medulloblastoma Formation.

    Science.gov (United States)

    Zhu, Guo; Rankin, Sherri L; Larson, Jon D; Zhu, Xiaoyan; Chow, Lionel M L; Qu, Chunxu; Zhang, Jinghui; Ellison, David W; Baker, Suzanne J

    2017-01-01

    Loss of the tumor suppressor gene PTEN exerts diverse outcomes on cancer in different developmental contexts. To gain insight into the effect of its loss on outcomes in the brain, we conditionally inactivated the murine Pten gene in neonatal neural stem/progenitor cells. Pten inactivation created an abnormal perivascular proliferative niche in the cerebellum that persisted in adult animals but did not progress to malignancy. Proliferating cells showed undifferentiated morphology and expressed the progenitor marker Nestin but not Math1, a marker of committed granule neuron progenitors. Codeletion of Pten and Trp53 resulted in fully penetrant medulloblastoma originating from the perivascular niche, which exhibited abnormal blood vessel networks and advanced neuronal differentiation of tumor cells. EdU pulse-chase experiments demonstrated a perivascular cancer stem cell population in Pten/Trp53 double mutant medulloblastomas. Genetic analyses revealed recurrent somatic inactivations of the tumor suppressor gene Ptch1 and a recapitulation of the sonic hedgehog subgroup of human medulloblastomas. Overall, our results showed that PTEN acts to prevent the proliferation of a progenitor niche in postnatal cerebellum predisposed to oncogenic induction of medulloblastoma. Cancer Res; 77(1); 123-33. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma

    NARCIS (Netherlands)

    Remke, Marc; Hielscher, Thomas; Korshunov, Andrey; Northcott, Paul A.; Bender, Sebastian; Kool, Marcel; Westermann, Frank; Benner, Axel; Cin, Huriye; Ryzhova, Marina; Sturm, Dominik; Witt, Hendrik; Haag, Daniel; Toedt, Grischa; Wittmann, Andrea; Schöttler, Anna; von Bueren, André O.; von Deimling, Andreas; Rutkowski, Stefan; Scheurlen, Wolfram; Kulozik, Andreas E.; Taylor, Michael D.; Lichter, Peter; Pfister, Stefan M.

    2011-01-01

    Integrated genomics approaches have revealed at least four distinct biologic variants of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group C, and group D. Because of the remarkable clinical heterogeneity of group D tumors and the dismal prognosis of group C patients, it is vital to

  2. A chemical screen for medulloblastoma identifies quercetin as a putative radiosensitizer

    NARCIS (Netherlands)

    Lagerweij, Tonny; Hiddingh, Lotte; Biesmans, Dennis; Crommentuijn, Matheus H. W.; Cloos, Jacqueline; Li, Xiao-Nan; Kogiso, Mari; Tannous, Bakhos A.; Vandertop, W. Peter; Noske, David P.; Kaspers, Gertjan J. L.; Würdinger, Tom; Hulleman, Esther

    2016-01-01

    Treatment of medulloblastoma in children fails in approximately 30% of patients, and is often accompanied by severe late sequelae. Therefore, more effective drugs are needed that spare normal tissue and diminish long-term side effects. Since radiotherapy plays a pivotal role in the treatment of

  3. Central nervous system. Strategy for the management of medulloblastoma

    International Nuclear Information System (INIS)

    Green, D.

    1984-01-01

    Patients with medulloblastoma are treated by the sequential use of surgery and radiotherapy. The posterior cranial fossa is exposed by craniotomy and, provided that the risk of serious neurologic disability is not unduly increased, an attempt is made to remove as much of the tumour as possible. Such a procedure provides material for histological confirmation of the diagnosis, a means of reducing intracranial pressure by decompression and the removal of tumour which may be hypoxic and relatively radio-insensitive due to an inadequate blood supply. In about 10-14 days, when the craniotomy wound is soundly healed, irradiation of the cranio-spinal axis is commenced. The brain and entire spinal theca is treated in continuity. Using two opposed lateral fields the entire cranial contents and cervical spine are irradiated to give a midline dose of 30.0 Gy. Shielding is used to exclude the orbital contents, upper respiratory passages, the buccal cavity and laryngopharynx from the beam. A smaller direct posterior field is applied to the posterior fossa and brain stem to increase the midpoint dose to a minimum of 40.0 Gy (80%). The spinal theca from the lower cervical region above to the second sacral segment below is treatd by a direct posterior field to give a dose of 30.0 Gy at a depth of 4 cm (60% isodose in the cranio-spinal plan). The total dose is planned to be given over four weeks in 20 treatments. One cranio-cervical field and the spinal field are treated each day and the small field to the posterior cranial fossa twice weekly

  4. Wnt activation affects proliferation, invasiveness and radiosensitivity in medulloblastoma.

    Science.gov (United States)

    Salaroli, Roberta; Ronchi, Alice; Buttarelli, Francesca Romana; Cortesi, Filippo; Marchese, Valeria; Della Bella, Elena; Renna, Cristiano; Baldi, Caterina; Giangaspero, Felice; Cenacchi, Giovanna

    2015-01-01

    Medulloblastomas (MBs) associated with the Wnt activation represent a subgroup with a favorable prognosis, but it remains unclear whether Wnt activation confers a less aggressive phenotype and/or enhances radiosensitivity. To investigate this issue, we evaluated the biological behavior of an MB cell line, UW228-1, stably transfected with human β-catenin cDNA encoding a nondegradable form of β-catenin (UW-B) in standard culture conditions and after radiation treatment. We evaluated the expression, transcriptional activity, and localization of β-catenin in the stably transfected cells using immunofluorescence and WB. We performed morphological analysis using light and electron microscopy. We then analyzed changes in the invasiveness, growth, and mortality in standard culture conditions and after radiation. We demonstrated that (A) Wnt activation inhibited 97 % of the invasion capability of the cells, (B) the growth of the UW-B cells was statistically significantly lower than that of all the other control cells (p < 0.01), (C) the mortality of irradiated UW-B cells was statistically significantly higher than that of the controls and their nonirradiated counterparts (p < 0.05), and (D) morphological features of neuronal differentiation were observed in the Wnt-activated cells. In tissue samples, the Ki-67 labeling index (LI) was lower in β-catenin-positive samples compared to non-β-catenin positive ones. The Ki-67 LI median (LI = 40) of the nuclear β-catenin-positive tumor samples was lower than that of non-nuclear β-catenin-positive samples (LI = 50), but the difference was not statistically significant. Overall, our data suggest that activation of the Wnt pathway reduces the proliferation and invasion of MBs and increases the tumor's radiosensitivity.

  5. The cranial-spinal junction in medulloblastoma: does it matter?

    International Nuclear Information System (INIS)

    Narayana, Ashwatha; Jeswani, Sam; Paulino, Arnold C.

    1999-01-01

    Purpose: Late effects of treatment in children and young adults with medulloblastoma can be influenced by the technique employed in radiating the craniospinal axis. The purpose of this study is to determine whether the placement of the cranial-spinal junction has an impact on dose to the cervical spinal cord and surrounding organs. Methods and Materials: Five patients underwent computed tomography (CT) simulation in the prone position for craniospinal irradiation. A dose of 36 Gy was prescribed to the entire neuraxis. The doses to the cervical spinal cord and surrounding organs were calculated using a cranial-spinal junction at the C1-C2 vertebral interspace (high junction) or at the lowest point in the neck, with exclusion of the shoulders in the lateral cranial fields (low junction).The volume of critical organs at risk, as well as dose to these structures using the cranial and spinal field(s) were outlined and calculated using the CMS FOCUS 3-dimensional treatment planning system. Results: The average dose to the cervical spinal cord was 11.9% higher than the prescribed dose with the low junction, and 6.7% higher with the high junction. However, doses to the thyroid gland, mandible, pharynx, and larynx were increased by an average of 29.6%, 75.8%, 70.6%, and 227.7%, respectively, by the use of the high junction compared to the low junction. Conclusion: A higher dose to the cervical spinal cord can be minimized by using a high junction. However, this would be at the cost of substantially increased doses to surrounding organs such as the thyroid gland, mandible, pharynx, and larynx. This can be critical in children and young adults, where hypothyroidism, mandibular hypoplasia, and development of second malignancies may be a late sequela of radiation therapy

  6. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.

    Directory of Open Access Journals (Sweden)

    Marcel Kool

    Full Text Available BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. METHODS AND FINDINGS: To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases, SHH signaling (B; 15 cases, expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively or photoreceptor genes (D and E; both 11 cases. Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E

  7. microRNA-10b Is Overexpressed and Critical for Cell Survival and Proliferation in Medulloblastoma.

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    Rekha Pal

    Full Text Available This study demonstrates the effects of miRNA-10b on medulloblastoma proliferation through transcriptional induction of the anti-apoptotic protein BCL2. Using a cancer specific miRNA-array, high expression of miRNA-10b in medulloblastoma cell lines compared to a normal cerebellar control was shown, and this was confirmed with real time PCR (RT-PCR. Two medulloblastoma cell lines (DAOY and UW228 were transiently transfected with control miRNA, miRNA-10b inhibitor or miRNA-10b mimic and subjected to RT-PCR, MTT, apoptosis, clonogenic assay and western blot analysis. Transfection of miRNA-10b inhibitor induced a significant down-regulation of miRNA-10b expression, inhibited proliferation, and induced apoptosis, while miRNA-10b mimic exerted an opposite effect. Inhibition of miRNA-10b abrogated the colony-forming capability of medulloblastoma cells, and markedly down-regulated the expression of BCL2. Down-regulation of BCL2 by antisense oligonucleotides or siRNA also significantly down-regulated miRNA-10b, suggesting that BCL2 is a major mediator of the effects of miRNA-10b. ABT-737 and ABT-199, potent inhibitors of BCL2, downregulated the expression of miRNA-10b and increased apoptosis. Analysis of miRNA-10b levels in 13 primary medulloblastoma samples revealed that the 2 patients with the highest levels of miRNA-10b had multiple recurrences (4.5 and died within 8 years of diagnosis, compared with the 11 patients with low levels of miRNA-10b who had a mean of 1.2 recurrences and nearly 40% long-term survival. The data presented here indicate that miRNA-10b may act as an oncomir in medulloblastoma tumorigenesis, and reveal a previously unreported mechanism with Bcl-2 as a mediator of the effects of miRNA-10b upon medulloblastoma cell survival.

  8. Bmi1 Is Required for Hedgehog Pathway-Driven Medulloblastoma Expansion

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    Lowell Evan Michael

    2008-12-01

    Full Text Available Inappropriate Hedgehog (Hh signaling underlies development of a subset of medulloblastomas, and tumors with elevated HH signaling activity express the stem cell self-renewal gene BMI1. To test whether Bmi1 is required for Hh-driven medulloblastoma development, we varied Bmi1 gene dosage in transgenic mice expressing an oncogenic Hh effector, SmoA1, driven by a glial fibrillary acidic protein (GFAP promoter. Whereas 100% of SmoA1; Bmi1+/+ or SmoA1;Bmi1+/- mice examined between postnatal (P days 14 and 26 had typical medulloblastomas (N = 29, tumors were not detected in any of the SmoA1;Bmi1-/- animals examined (N = 6. Instead, small ectopic collections of cells were present in the region of greatest tumor load in SmoA1 animals, suggesting that medulloblastomas were initiated but failed to undergo expansion into frank tumors. Cells within these Bmi1-/- lesions expressed SmoA1 but were largely nonproliferative, in contrast to cells in Bmi1+/+ tumors (6.2% vs 81.9% PCNA-positive, respectively. Ectopic cells were negative for the progenitor marker nestin, strongly GFAP-positive, and highly apoptotic, relative to Bmi1+/+ tumor cells (29.6% vs 6.3% TUNEL-positive. The alterations in proliferation and apoptosis in SmoA1;Bmi1-/- ectopic cells are associated with reduced levels of Cyclin D1 and elevated expression of cyclin-dependent kinase inhibitor p19Arf, two inversely regulated downstream targets of Bmi1. These data provide the first demonstration that Bmi1 is required for spontaneous de novo development of a solid tumor arising in the brain, suggest a crucial role for Bmi1-dependent, nestin-expressing progenitor cells in medulloblastoma expansion, and implicate Bmi1 as a key factor required for Hh pathway-driven tumorigenesis.

  9. In vivo bioluminescence imaging using orthotopic xenografts towards patient's derived-xenograft Medulloblastoma models.

    Science.gov (United States)

    Asadzadeh, Fatemeh; Ferrucci, Veronica; DE Antonellis, Pasqualino; Zollo, Massimo

    2017-03-01

    Medulloblastoma is a cerebellar neoplasia of the central nervous system. Four molecular subgrups have been identified (MBWNT, MBSHH, MBgroup3 and MBgroup4) with distinct genetics and clinical outcome. Among these, MBgroup3-4 are highly metastatic with the worst prognosis. The current standard therapy includes surgery, radiation and chemotherapy. Thus, specific treatments adapted to cure those different molecular subgroups are needed. The use of orthotopic xenograft models, together with the non-invasive in vivo biolumiscence imaging (BLI) technology, is emerging during preclinical studies to test novel therapeutics for medulloblastoma treatment. Orthotopic MB xenografts were performed by injection of Daoy-luc cells, that had been previously infected with lentiviral particles to stably express luciferase gene, into the fourth right ventricle of the cerebellum of ten nude mice. For the implantation, specific stereotactic coordinates were used. Seven days after the implantation the mice were imaged by acquisitions of bioluminescence imaging (BLI) using IVIS 3D Illumina Imaging System (Xenogen). Tumor growth was evaluated by quantifying the bioluminescence signals using the integrated fluxes of photons within each area of interest using the Living Images Software Package 3.2 (Xenogen-Perkin Elmer). Finally, histological analysis using hematoxylin-eosin staining was performed to confirm the presence of tumorigenic cells into the cerebellum of the mice. We describe a method to use the in vivo bioluminescent imaging (BLI) showing the potential to be used to investigate the potential antitumorigenic effects of a drug for in vivo medulloblastoma treatment. We also discuss other studies in which this technology has been applied to obtain a more comprehensive knowledge of medulloblastoma using orthotopic xenograft mouse models. There is a need to develop patient's derived-xenograft (PDX) model systems to test novel drugs for medulloblastoma treatment within each molecular sub

  10. Study of hTERT and Histone 3 Mutations in Medulloblastoma.

    Science.gov (United States)

    Viana-Pereira, Marta; Almeida, Gisele Caravina; Stavale, João Norberto; Malheiro, Susana; Clara, Carlos; Lobo, Patrícia; Pimentel, José; Reis, Rui Manuel

    2017-01-01

    Hotspot activating mutations of the telomerase reverse transcriptase (hTERT) promoter region were recently described in several tumor types. These mutations lead to enhanced expression of telomerase, being responsible for telomere maintenance and allowing continuous cell division. Additionally, there are alternative telomere maintenance mechanisms, associated with histone H3 mutations, responsible for disrupting the histone code and affecting the regulation of transcription. Here, we investigated the clinical relevance of these mechanistically related molecules in medulloblastoma. Sixty-nine medulloblastomas, formalin fixed and paraffin embedded, from a cohort of patients aged 1.5-70 years, were used to investigate the hotspot mutations of the hTERT promoter region, i.e. H3F3A and HIST1H3B, using Sanger sequencing. We successfully sequenced hTERT in all 69 medulloblastoma samples and identified a total of 19 mutated cases (27.5%). c.-124:G>A and c.-146:G>A mutations were detected, respectively, in 16 and 3 samples. Similar to previous reports, hTERT mutations were more frequent in older patients (p < 0.0001), being found only in 5 patients <20 years of age. In addition, hTERT-mutated tumors were more frequently recurrent (p = 0.026) and hTERT mutations were significantly enriched in tumors located in the right cerebellar hemisphere (p = 0.039). No mutations were found on the H3F3A or HIST1H3B genes. hTERT promoter mutations are frequent in medulloblastoma and are associated with older patients, prone to recurrence and located in the right cerebellar hemisphere. On the other hand, histone 3 mutations do not seem to be present in medulloblastoma. © 2016 S. Karger AG, Basel.

  11. Diagnosis and treatment of adult medulloblastoma seeding in the intracranial-spinal subarachnoid space

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    Ji-wei WANG

    2015-10-01

    Full Text Available Objective To investigate the clinical diagnosis and treatment of adult medulloblastoma seeding in the intracranial-spinal subarachnoid space. Methods Eleven cases of adult medulloblastoma seeding in the intracranial-spinal subarachnoid space were retrospectively analyzed on the clinical features, cerebrospinal fluid (CSF cytology, radiological characteristics and treatments. Results All patients underment neurosurgical procedures to remove medulloblastomas. In 10 patients, tumor was removed through suboccipital posterior midline approach and in one patient through post-sigmoid sinus approach. In 7 patients tumor cell seeding was found in the intracranial-spinal subarachnoid space before postoperative radiotherapy and disappeared after radiological and chemical treatment, while in other 4 patients tumor cell seeding was found in the intracranial-spinal subarachnoid space at 3 months to 3 years follow-up period (average 20 months after radiotherapy. In 2 of all the patients tumor cells were found by CSF cytology before operation. All the patients were treated with radiotherapy and adjuvant chemotherapy. Two patients were still alive, while 9 patients were dead. Conclusions Patients with adult medulloblastoma seeding in intracranial-spinal subarachnoid space have a poor prognosis. In the diagnosis of adult medulloblastomas seeding in the intracranial-spinal subarachnoid space, MRI is more sensitive than CSF cytology. Once the seeding in intracranial-spinal subarachnoid space was found, the patients should be treated with radiotherapy and adjuvant chemotherapy, which can prolong the survival time and improve the quality of life. DOI: 10.3969/j.issn.1672-6731.2015.10.012 

  12. Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance.

    Science.gov (United States)

    Lindsey, J C; Kawauchi, D; Schwalbe, E C; Solecki, D J; Selby, M P; McKinnon, P J; Olson, J M; Hayden, J T; Grundy, R G; Ellison, D W; Williamson, D; Bailey, S; Roussel, M F; Clifford, S C

    2015-09-03

    The identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH pathway mutations, recent genome-wide sequencing studies have not revealed commonly mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.

  13. Sonic Hedgehog Signaling Drives Mitochondrial Fragmentation by Suppressing Mitofusins in Cerebellar Granule Neuron Precursors and Medulloblastoma.

    Science.gov (United States)

    Malhotra, Anshu; Dey, Abhinav; Prasad, Niyathi; Kenney, Anna Marie

    2016-01-01

    Sonic hedgehog (Shh) signaling is closely coupled with bioenergetics of medulloblastoma, the most common malignant pediatric brain tumor. Shh-associated medulloblastoma arises from cerebellar granule neuron precursors (CGNP), a neural progenitor whose developmental expansion requires signaling by Shh, a ligand secreted by the neighboring Purkinje neurons. Previous observations show that Shh signaling inhibits fatty acid oxidation although driving increased fatty acid synthesis. Proliferating CGNPs and mouse Shh medulloblastomas feature high levels of glycolytic enzymes in vivo and in vitro. Because both of these metabolic processes are closely linked to mitochondrial bioenergetics, the role of Shh signaling in mitochondrial biogenesis was investigated. This report uncovers a surprising decrease in mitochondrial membrane potential (MMP) and overall ATP production in CGNPs exposed to Shh, consistent with increased glycolysis resulting in high intracellular acidity, leading to mitochondrial fragmentation. Ultrastructural examination of mitochondria revealed a spherical shape in Shh-treated cells, in contrast to the elongated appearance in vehicle-treated postmitotic cells. Expression of mitofusin 1 and 2 was reduced in these cells, although their ectopic expression restored the MMP to the nonproliferating state and the morphology to a fused, interconnected state. Mouse Shh medulloblastoma cells featured drastically impaired mitochondrial morphology, restoration of which by ectopic mitofusin expression was also associated with a decrease in the expression of Cyclin D2 protein, a marker for proliferation. This report exposes a novel role for Shh in regulating mitochondrial dynamics and rescue of the metabolic profile of tumor cells to that of nontransformed, nonproliferating cells and represents a potential avenue for development of medulloblastoma therapeutics. ©2015 American Association for Cancer Research.

  14. Inhibition of STAT3 Expression and Signaling in Resveratrol-Differentiated Medulloblastoma Cells

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    Li-Jun Yu

    2008-07-01

    Full Text Available In this study, the potential influence of resveratrol (3,5,4′-trihydroxy-trans-stilbene in signal transducer and activator of transcription 3 (STAT3 signaling of medulloblastoma cells was evaluated by checking the status of STAT3 signaling and its downstream gene expression in two medulloblastoma cell lines (UW228-2 and UW228-3 with and without resveratrol treatment. The results revealed that resveratrol induced neuronal differentiation of medulloblastoma cells. Signal transducer and activator of transcription 3 expression and phosphorylation were detected in normally cultured UW228-2 and UW228-3 cells that were apparently attenuated after resveratrol treatment. The expression of STAT3 downstream genes, survivin, cyclin D1, Cox-2, and c-Myc, was suppressed but Bcl-2 was enhanced by resveratrol. Meanwhile, the production and secretion of leukemia inhibitory factor, a STAT3 activator, became active in resveratrol-treated cells. To further ascertain the significance of STAT3 signaling for medulloblastoma cells, AG490, a selective inhibitor of STAT3 phosphorylation, was used to treat UW228-3 cells. Phosphorylation of STAT3 was inhibited by AG490 accompanied with growth suppression, differentiation-like changes, and down-regulation of survivin, cyclin D1, Cox-2, and c-Myc. Our data thus suggest the importance of STAT3 signaling in maintenance and survival of medulloblastoma cells. This signaling may be the major target of resveratrol. Enhanced leukemia inhibitory factor and Bcl-2 expressions in resveratrol-treated cells might reflect a compensatory response to the loss of STAT3 function.

  15. Treatment of medulloblastoma using an oncolytic measles virus encoding the thyroidal sodium iodide symporter shows enhanced efficacy with radioiodine

    International Nuclear Information System (INIS)

    Hutzen, Brian; Pierson, Christopher R; Russell, Stephen J; Galanis, Evanthia; Raffel, Corey; Studebaker, Adam W

    2012-01-01

    Medulloblastoma is the most common malignant brain tumor of childhood. Although the clinical outcome for medulloblastoma patients has improved significantly, children afflicted with the disease frequently suffer from debilitating side effects related to the aggressive nature of currently available therapy. Alternative means for treating medulloblastoma are desperately needed. We have previously shown that oncolytic measles virus (MV) can selectively target and destroy medulloblastoma tumor cells in localized and disseminated models of the disease. MV-NIS, an oncolytic measles virus that encodes the human thyroidal sodium iodide symporter (NIS), has the potential to deliver targeted radiotherapy to the tumor site and promote a localized bystander effect above and beyond that achieved by MV alone. We evaluated the efficacy of MV-NIS against medulloblastoma cells in vitro and examined their ability to incorporate radioiodine at various timepoints, finding peak uptake at 48 hours post infection. The effects of MV-NIS were also evaluated in mouse xenograft models of localized and disseminated medulloblastoma. Athymic nude mice were injected with D283med-Luc medulloblastoma cells in the caudate putamen (localized disease) or right lateral ventricle (disseminated disease) and subsequently treated with MV-NIS. Subsets of these mice were given a dose of 131 I at 24, 48 or 72 hours later. MV-NIS treatment, both by itself and in combination with 131 I, elicited tumor stabilization and regression in the treated mice and significantly extended their survival times. Mice given 131 I were found to concentrate radioiodine at the site of their tumor implantations. In addition, mice with localized tumors that were given 131 I either 24 or 48 hours after MV-NIS treatment exhibited a significant survival advantage over mice given MV-NIS alone. These data suggest MV-NIS plus radioiodine may be a potentially useful therapy for the treatment of medulloblastoma

  16. Treatment of medulloblastoma using an oncolytic measles virus encoding the thyroidal sodium iodide symporter shows enhanced efficacy with radioiodine

    Directory of Open Access Journals (Sweden)

    Hutzen Brian

    2012-11-01

    Full Text Available Abstract Background Medulloblastoma is the most common malignant brain tumor of childhood. Although the clinical outcome for medulloblastoma patients has improved significantly, children afflicted with the disease frequently suffer from debilitating side effects related to the aggressive nature of currently available therapy. Alternative means for treating medulloblastoma are desperately needed. We have previously shown that oncolytic measles virus (MV can selectively target and destroy medulloblastoma tumor cells in localized and disseminated models of the disease. MV-NIS, an oncolytic measles virus that encodes the human thyroidal sodium iodide symporter (NIS, has the potential to deliver targeted radiotherapy to the tumor site and promote a localized bystander effect above and beyond that achieved by MV alone. Methods We evaluated the efficacy of MV-NIS against medulloblastoma cells in vitro and examined their ability to incorporate radioiodine at various timepoints, finding peak uptake at 48 hours post infection. The effects of MV-NIS were also evaluated in mouse xenograft models of localized and disseminated medulloblastoma. Athymic nude mice were injected with D283med-Luc medulloblastoma cells in the caudate putamen (localized disease or right lateral ventricle (disseminated disease and subsequently treated with MV-NIS. Subsets of these mice were given a dose of 131I at 24, 48 or 72 hours later. Results MV-NIS treatment, both by itself and in combination with 131I, elicited tumor stabilization and regression in the treated mice and significantly extended their survival times. Mice given 131I were found to concentrate radioiodine at the site of their tumor implantations. In addition, mice with localized tumors that were given 131I either 24 or 48 hours after MV-NIS treatment exhibited a significant survival advantage over mice given MV-NIS alone. Conclusions These data suggest MV-NIS plus radioiodine may be a potentially useful therapy for

  17. Pancreatic endoplasmic reticulum kinase activation promotes medulloblastoma cell migration and invasion through induction of vascular endothelial growth factor A.

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    Stephanie Jamison

    Full Text Available Evidence is accumulating that activation of the pancreatic endoplasmic reticulum kinase (PERK in response to endoplasmic reticulum (ER stress adapts tumor cells to the tumor microenvironment and enhances tumor angiogenesis by inducing vascular endothelial growth factor A (VEGF-A. Recent studies suggest that VEGF-A can act directly on certain tumor cell types in an autocrine manner, via binding to VEGF receptor 2 (VEGFR2, to promote tumor cell migration and invasion. Although several reports show that PERK activation increases VEGF-A expression in medulloblastoma, the most common solid malignancy of childhood, the role that either PERK or VEGF-A plays in medulloblastoma remains elusive. In this study, we mimicked the moderate enhancement of PERK activity observed in tumor patients using a genetic approach and a pharmacologic approach, and found that moderate activation of PERK signaling facilitated medulloblastoma cell migration and invasion and increased the production of VEGF-A. Moreover, using the VEGFR2 inhibitor SU5416 and the VEGF-A neutralizing antibody to block VEGF-A/VEGFR2 signaling, our results suggested that tumor cell-derived VEGF-A promoted medulloblastoma cell migration and invasion through VEGFR2 signaling, and that both VEGF-A and VEGFR2 were required for the promoting effects of PERK activation on medulloblastoma cell migration and invasion. Thus, these findings suggest that moderate PERK activation promotes medulloblastoma cell migration and invasion through enhancement of VEGF-A/VEGFR2 signaling.

  18. Inhibition of SIRT1 Transcription inResveratrol-differentiated Medulloblastoma Cells

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    Jing-Xin Ma

    2013-05-01

    Full Text Available ABSTRACTBackgrounds: Medulloblastoma(MB is the commonestbrain malignancyin childhood with poor prognosis, because of itsrapid aggressive growth and frequent occurrence. The current chemotherapeutic regimens for medulloblastoma patients involve a combination of lomustine, cisplatin, carboplatin, vincristine or cyclophosphamide, which have distinct short-and long-term side-effects. It is therefore in urgent need to explore safer and more effective adjuvant approach(s.Resveratrol, a polyphenol rich in numerous plants, has multiple biological activities including anticancer effects. Our previous data confirmed that resveratrolinhibited proliferation and induced differentiation and apoptosis of medulloblastoma cells. SIRT1 is a deacetylase of class III HDACs and the supposed molecular effecter of resveratrol. SIRT1 involves in aging prevention and cancer formation in a cell-context specific manner.Nevertheless, the datum concerningthe role(s ofSIRT1 in formation and prognosis of medulloblastomais still missing.Objective:The present study aimed to address the expression patterna of SIRT1 in medulloblastoma tissuesand non-cancerous counterpartsand to explorewhether resveratrol exerts its anti-medulloblastoma effects via regulating SIRT1 expression and bioactivity.Methods:The expression of SIRT1 in medulloblastoma and non-cancerous counterparts was elucidatedby immunohistochemical ataining (IHC.To clarify the function of SIRT1 in medulloblastomas, SIRT1 expression in UW228-3 medulloblastoma cells were suppressed by RNA interference(RNAi. The influence of resveratrol in SIRT1 expressionsin UW228-3 cellswas analyzedby reverse transcription-polymerase chain reaction (RT-PCR,immunocytochemistry (ICCand Western blotting(WB. The catalytic activity of deacetylase SIRT1was examined by measuring the acetylation ofthe main substrate p53.Results: IHC staining revealedthat SIRT1 was expressed in 64.17% of MB tissues,which was higher than that in

  19. Clinical characteristics and abandonment and outcome of treatment in 67 Chinese children with medulloblastoma.

    Science.gov (United States)

    Wang, Chen; Yuan, Xiao-Jun; Jiang, Ma-Wei; Wang, Li-Feng

    2016-01-01

    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

  20. c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients

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    Stearns Duncan

    2011-02-01

    Full Text Available Abstract Background To study whether and how c-MYC expression determines response to radio- and chemotherapy in childhood medulloblastoma (MB. Methods We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio- and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H-tetrazolium inner salt (MTS assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio- and chemotherapy as examined by neuroradiological imaging. Results In DAOY - and to a lesser extent in UW228 - cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation- and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio- (14 responders (CR, PR vs. 5 non-responders (SD, PD or chemotherapy (23 CR/PR vs. 20 SD/PD was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively. Conclusions c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment.

  1. Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas

    DEFF Research Database (Denmark)

    Bartek, Jiri; Fornara, Olesja; Merchut-Maya, Joanna Maria

    2017-01-01

    suppressor activation, across our medulloblastoma cohort. Most tumours showed high proliferation (Ki67 marker), variable oxidative DNA damage (8-oxoguanine lesions) and formation of 53BP1 nuclear 'bodies', the latter indicating (along with ATR-Chk1 signalling) endogenous replication stress. The bulk...... cell replication stress and DNA repair. Collectively, the scenario we report here likely fuels genomic instability and evolution of medulloblastoma resistance to standard-of-care genotoxic treatments....... eight established immunohistochemical markers to assess the status of the DDR machinery, we found pronounced endogenous DNA damage signalling (γH2AX marker) and robust constitutive activation of both the ATM-Chk2 and ATR-Chk1 DNA damage checkpoint kinase cascades, yet unexpectedly modest p53 tumour...

  2. Age at treatment and long-term performance results in medulloblastoma

    International Nuclear Information System (INIS)

    Chin, H.W.; Maruyama, Y.

    1984-01-01

    Medulloblastoma is highly radioresponsive, and recent treatment results have improved greatly since the introduction of megavoltage machine in 1960s. There is increasing evidence for the potential cure of medulloblastoma if properly treated in its early stages. The curable group represents approximately 75% of diagnosed patients. Long-term treatment effects were examined in this study. The study reveals age-dependent late effects in learning ability; the patients less than 4-years-old at treatment had major learning problems; patients of 5 to 7 years old performed at satisfactory-to-low passing levels in school work; patients older than 8 years old had no major intellectual impairment. Short stature was common when growth potential was present at the time of therapy, but endocrine tests were generally negative. These observations indicate special educational requirement needs, especially for children treated at a young age

  3. Computed tomography in the follow-up of medulloblastomas and ependymomas

    International Nuclear Information System (INIS)

    Enzmann, D.R.; Norman, D.; Levin, V.; Wilson, C.; Newton, T.H.

    1978-01-01

    The course of 36 patients with medulloblastoma and ependymoma was evaluated prospectively by clinical examination, radionuclide (RN) studies and computed tomography (CT). Seventeen of the 36 patients (47 percent) had tumor recurrence. Twelve (41 percent) of the 29 patients with medulloblastoma had recurrent tumors of which 7 of 12 (58 percent) were at the primary site and 2 of 12 (17 percent) were within the ventricles while 10 of 12 (83 percent) were in the subarachnoid space. Five of the 7 patients with ependymoma had recurrent tumors. In 4 of the 5 patients tumor recurred at the primary site while subarachnoid seeding occurred in 2 of 5 patients (40 percent) and intraventricular metastases were found in 4 of 5 patients (80 percent). Progressive ventricular enlargement often accompanied subarachnoid seeding, presumably secondary to obstruction of cerebrospinal fluid (CSF) flow in the subarachnoid pathways. CT and RN scans were frequently complementary in detecting tumor recurrence

  4. A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma.

    Science.gov (United States)

    Shou, Yaping; Robinson, Douglas M; Amakye, Dereck D; Rose, Kristine L; Cho, Yoon-Jae; Ligon, Keith L; Sharp, Thad; Haider, Asifa S; Bandaru, Raj; Ando, Yuichi; Geoerger, Birgit; Doz, François; Ashley, David M; Hargrave, Darren R; Casanova, Michela; Tawbi, Hussein A; Rodon, Jordi; Thomas, Anne L; Mita, Alain C; MacDonald, Tobey J; Kieran, Mark W

    2015-02-01

    Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma. Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed. Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded. This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment. ©2014 American Association for Cancer Research.

  5. Societal preferences in the treatment of pediatric medulloblastoma: Balancing risk of death and quality of life.

    Science.gov (United States)

    Khakban, Amir; Mohammadi, Tima; Lynd, Larry D; Mabbott, Don; Bouffet, Eric; Gastonguay, Louise; Zafari, Zafar; Malkin, David; Taylor, Michael; Marra, Carlo A

    2017-06-01

    Medulloblastoma is the most prevalent childhood brain cancer. Children with medulloblastoma typically receive a combination of surgery, radiation, and chemotherapy. The survival rate is high but survivors often have sequelae from radiotherapy of the entire developing brain and spinal cord. Ongoing genetic studies have suggested that decreasing the dose of radiation might be possible among children with favorable molecular variants; however, this may result in an increased disease recurrence. As such, there is a need to investigate the nature of trade-offs that individuals are willing to make regarding the treatment of medulloblastoma. We used best-worst scaling to estimate the importance of attributes affecting the general public's decision making around the treatment of medulloblastoma. After conducting focus groups, we selected three relevant attributes: (1) the accuracy of the genetic test; (2) the probability of serious adverse effects of the treatment(s); and (3) the survival rate. Using the paired method, we applied a conditional logit model to estimate preferences. In total, 3,006 respondents (51.3% female) with an average age of 43 years answered the questionnaires. All coefficients were statistically significantly different from zero and the attribute levels of adverse effects and the survival rate had the most impact on individuals' stated decision making. Overall, respondents showed high sensitivity to children experiencing disability particularly in the setting of a good prognosis. However, among children with poor prognostic molecular variants, participants showed tolerance about having a child with mild and partial disability compared to a low rate of survival. © 2016 Wiley Periodicals, Inc.

  6. Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog-Dependent Medulloblastoma Initiation and Maintenance

    Science.gov (United States)

    2015-12-01

    tumor suppressors and REST-targeted neuronal genes. Brg1 deletion led to the inhibition of Shh-type medulloblastoma growth by deregulation of the...China University of Rostock & Research Institute for the Biology of Farm Animals, Germany University of Texas Southwestern Medical Center at...of Rostock & Research Institute for the Biology of Farm Animals, Germany . Mentor: Prof. Dr. Hans-Martin Seyfert 2010- 2014 Postdoctoral

  7. Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma.

    Science.gov (United States)

    Markowitz, Daniel; Powell, Caitlin; Tran, Nhan L; Berens, Michael E; Ryken, Timothy C; Vanan, Magimairajan; Rosen, Lisa; He, Mingzu; Sun, Shan; Symons, Marc; Al-Abed, Yousef; Ruggieri, Rosamaria

    2016-08-01

    Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient-derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799-808. ©2016 AACR. ©2016 American Association for Cancer Research.

  8. Radiation treatment for medulloblastoma. A review of 64 cases at a single institute

    International Nuclear Information System (INIS)

    Liu Yueping; Gao Li; Xu Guozhen; Yi Junhin; Liu Xinfan; Li Yexiong

    2005-01-01

    Although the optimal treatment mode for medulloblastoma is frequently discussed, results based on large series of cases, especially those treated in Asia, have rarely been reported. Our purpose was to evaluate the efficacy of postoperative radiation therapy, and to identify prognostic factors, in a relatively large cohort of patients with limited-stage medulloblastoma treated at a single institute in China. Between January 1996 and April 2001, 69 patients with Chang stage M0/M1 medulloblastoma were referred to our hospital for radiation therapy after total or subtotal resection of the primary tumor. All patients received 30 Gy to the craniospinal axis followed by a 20-25 Gy boost to the posterior fossa (median fraction, 1.8 Gy). Sixty-four patients were followed for a median period of 38.5 months. The rates of 3-year and 5-year overall survival were 68.8% and 55.7%, respectively; corresponding disease-free survival were 57.8% and 51.4%, respectively. Patients who had received radiation treatment within 25 days after resection had a greater probability of 3-year survival (81.5% versus 59.5%; P=0.11) and 3-year disease-free survival (74.1% versus 46.0%; P=0.03) than patients who began radiation treatment later. No relationship was found between survival and age, sex or tumor size. This regimen was comparatively ineffective in preventing recurrence of postoperative medulloblastoma; however, we found that the interval between surgery and radiation is a significant prognostic factor for disease-free survival. (author)

  9. The expression of FAT1 is associated with overall survival in children with medulloblastoma.

    Science.gov (United States)

    Yu, Jianzhong; Li, Hao

    2017-01-21

    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. 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. 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). 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.

  10. Postoperative craniospinal radiotherapy of medulloblastoma in children and young adults

    Directory of Open Access Journals (Sweden)

    Golubičić Ivana V.

    2003-01-01

    Full Text Available PURPOSE The aim of this study was: 1. to evaluate treatment results of combined therapy (surgery, postoperative craniospinal radiotherapy with or without chemotherapy and 2. to assess factors affecting prognosis (extend of tumor removal, involvement of the brain stem, extent of disease postoperative meningitis, shunt placement, age, sex and time interval from surgery to start of postoperative radiotherapy. PATIENTS AND METHODS During the period 1986-1996, 78 patients with medulloblastoma, aged 1-22 years (median 8.6 years, were treated with combined modality therapy and 72 of them were evaluable for the study end-points. Entry criteria were histologically proven diagnosis, age under 22 years, and no history of previous malignant disease. The main characteristics of the group are shown in Table 1. Twenty-nine patients (37.2% have total, 8 (10.3% near total and 41 (52.5% partial removal. Seventy-two of 78 patients were treated with curative intent and received postoperative craniospinal irradiation. Radiotherapy started 13-285 days after surgery (median 36 days. Only 13 patients started radiotherapy after 60 days following surgery. Adjuvant chemotherapy was applied in 63 (80.7% patients. The majority of them (46 73% received chemotherapy with CCNU and Vincristine. The survival rates were calculated with the Kaplan-Meier method and the differences in survival were analyzed using the Wilcoxon test and log-rank test. RESULTS The follow-up period ranged from 1-12 years (median 3 years. Five-year overall survival (OS was 51% and disease-free survival (DFS 47% (Graph 1. During follow-up 32 relapses occurred. Patients having no brain stem infiltration had significantly better survival (p=0.0023 (Graph 2. Patients with positive myelographic findings had significantly poorer survival compared to dose with negative myelographic findings (p=0.0116. Significantly poorer survival was found in patients with meningitis developing in the postoperative period

  11. Medulloblastoma: evaluation of proliferative index by monoclonal antibody Mib-1, its prognostic correlation and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Ferrari Antonio Fernandes

    2003-01-01

    Full Text Available In the past few years, the monoclonal antibody MIB-1 has been used by researchers in order to retrospectively study paraffin imbibed tumor fragments. The medulloblastoma is the most common malignant central nervous system tumor in childhood. The objectives were: determination of the mean Mib-1 LI value from these patients, as well as the prognostic value of the method.This retrospective study represents an analysis of the cellular proliferation index of posterior fossa medulloblastomas collected from 22 patients at A.C. Camargo Hospital, from January 1990 to December 1999. The histopathological diagnosis was confirmed by H&E and proliferative index (LI was achived with Mib-1 which detects proliferating cells during G1, G2, S and M phases.The results demostrated that the mean Mib-1 was 30,1%, and ranged from 5,2% to 62,0%.In conclusion, this method has prognostic value, has to be used as routine for patients harboring medulloblastomas and the ones who have PI greater than the mean value found in this study, should be treated aggressively.

  12. MYC and MYCN amplification can be reliably assessed by aCGH in medulloblastoma.

    Science.gov (United States)

    Bourdeaut, Franck; Grison, Camille; Maurage, Claude-Alain; Laquerriere, Annie; Vasiljevic, Alexandre; Delisle, Marie-Bernadette; Michalak, Sophie; Figarella-Branger, Dominique; Doz, François; Richer, Wilfrid; Pierron, Gaelle; Miquel, Catherine; Delattre, Olivier; Couturier, Jérôme

    2013-04-01

    As prognostic factors, MYC and MYCN amplifications are routinely assessed in medulloblastomas. Fluorescence in situ hybridization (FISH) is currently considered as the technique of reference. Recently, array comparative genomic hybridization (aCGH) has been developed as an alternative technique to evaluate genomic abnormalities in other tumor types; however, this technique has not been widely adopted as a replacement for FISH in medulloblastoma. In this study, 34 tumors were screened by both FISH and aCGH. In all cases showing amplification by FISH, aCGH also unambiguously revealed the abnormality. The aCGH technique was also performed on tumors showing no amplification by FISH, and the absence of amplification was confirmed in all cases. Interestingly, one tumor showed a subclonal MYC amplification by FISH. This subclonal amplification was observed in approximately 20% of tumor cells and was clearly evident on aCGH. In conclusion, our analysis confirms that aCGH is as safe as FISH for the detection of MYC/MYCN gene amplification. Given its cost efficiency in comparison to two FISH tests and the global genomic information additionally provided by an aCGH experiment, this reproducible technique can be safely retained as an alternative to FISH for routine investigation of medulloblastoma. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Correlation of MRI and CSF cytology in the diagnosis of medulloblastoma spinal metastases

    International Nuclear Information System (INIS)

    Harrison, S.K.; Ditchfield, M.R.; Waters, K.

    1998-01-01

    Background. Medulloblastoma frequently spreads to involve the spinal cord, which significantly reduces patient survival and determines whether chemotherapy is utilised and the dose of irradiation to the neuraxis. Staging is usually achieved by MRI of the spine and/or cytology of CSF, both methods having their limitations. Objective. To determine whether there is a correlation between CSF cytology and the demonstration of spinal metastases by MRI and whether CSF cytology is useful when spinal MRI is equivocal. Materials and methods. All cases of medulloblastoma diagnosed at our hospital between 1992 and 1997 were identified. Of 26 cases, 11 presentations (age range 4 months to 12 years) had both CSF cytology (either from the cisterna magna or lumbar puncture) and spinal MRI. The MR studies were reviewed for the presence of metastases and the CSF cytology for the presence of tumour cells. Results. We found 100 % correlation between MRI and CSF cytology for samples taken by lumbar puncture (four negative and three positive on both investigations). No correlation was demonstrated when CSF samples were taken from the cisterna magna. Conclusions. Our data suggest that lumbar CSF cytology may be useful when the MRI is equivocal for the presence of metastatic involvement of the spine by medulloblastoma. (orig.)

  14. Distinctive clinical course and pattern of relapse in adolescents with medulloblastoma

    International Nuclear Information System (INIS)

    Tabori, Uri; Sung, Lillian; Hukin, Juliette; Laperriere, Normand; Crooks, Bruce; Carret, Anne-Sophie; Silva, Mariana; Odame, Isaac; Mpofu, Chris; Strother, Douglas; Wilson, Beverly; Samson, Yvan; Bouffet, Eric

    2006-01-01

    Purpose: To report the clinical course of adolescents with medulloblastoma, with specific emphasis on prognosis and pattern of relapse. Methods and Materials: We retrospectively studied the clinical course and outcomes of children aged 10-20 years with medulloblastoma, treated at centers throughout Canada between 1986 and 2003. To better assess time to relapse, a cohort of patients aged 3-20 years at diagnosis was generated. Results: A total of 72 adolescents were analyzed. Five-year overall survival and event-free survival rates were 78.3% ± 5.4% and 68.0% ± 6.2%, respectively. Late relapses occurred at a median of 3.0 years (range, 0.3-6.8 years). In univariate analysis, conventional risk stratification and the addition of chemotherapy to craniospinal radiation did not have prognostic significance. Female patients had improved overall survival (p = 0.007). Time to relapse increased with age in a linear fashion. After relapse, patients faired poorly regardless of treatment modality. Patients who did not receive chemotherapy initially had improved progression-free survival at relapse (p 0.05). Conclusions: Our study suggests that adolescents with medulloblastoma might have a unique prognosis and pattern of relapse, dissimilar to those in younger children. They might benefit from different risk stratifications and prolonged follow-up. These issues should be addressed in future prospective trials

  15. Paediatric medulloblastoma: patterns of care and radiotherapy quality assurance in Australia

    International Nuclear Information System (INIS)

    Ahern, V.; Koh, E-S.; Gebski, V.; Sathiyaseelan, Y.

    2007-01-01

    Full text: The purpose of this study was to document how children in Australia with medulloblastoma are being treated and to evaluate the quality of radiotherapy (RT) delivered. The Radiotherapy Database of the Australian and New Zealand Children's Haematology and Oncology Group was used to identify 46 children with medulloblastoma younger than the age of 15 years treated with radical intent by craniospinal irradiation between 1997 and 1999 inclusively. Twenty-six patients had completely resected disease without evidence of disease spread. Of these, 16 patients received a craniospinal RT dose of <25 Gy in addition to chemotherapy. RT treatment immobilization methods varied, as did planning methods. RT dose to critical structures was recorded on treatment plans for only 15% of patients. The average systematic error in shield placement at the posterior orbit was 5.2 mm, and two-thirds of patients were 'overshielded' at this site. Adequate coverage of the distal end of the thecal sac was achieved in fewer than 50% of on-treatment verification films for 21 of 45 patients. With a reduction in RT dose to the craniospinal axis for paediatric medulloblastoma, greater attention is needed for patient immobilization, documentation of RT dose to critical structures and the placement and reproducibility of shielding

  16. The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice

    Science.gov (United States)

    Dang, Mai T.; Wehrli, Suzanne; Dang, Chi V.; Curran, Tom

    2015-01-01

    The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice. PMID:26192445

  17. Patterns of failure in children with medulloblastoma treated with 3D conformal radiotherapy

    International Nuclear Information System (INIS)

    Skowronska-Gardas, Anna; Chojnacka, Marzanna; Morawska-Kaczynska, Marzena; Perek, Danuta; Perek-Polnik, Marta

    2007-01-01

    Background and purpose: Craniospinal irradiation for medulloblastoma is one of the most complex techniques employed in radiotherapy. Many reports stress the impact of irradiation quality on survival in these patients. Our report presents the outcome and patterns of failure for 95 patients treated with 3D conformal radiotherapy (3D-CRT). Materials and methods: From 1998 to 2003, 95 children with medulloblastoma received 3D conformal radiotherapy. All of them were previously treated with surgery and chemotherapy. The brain and upper spinal cord were treated with two lateral 6 MV photon fields. In four patients, the cribriform plate was irradiated by the additional field. For primary tumour bed we applied two or three photon beams. Spinal cord was irradiated either with 18-20 MeV electron fields or with a mixed beam. Results: With a median follow-up of 48 months, 32/95 patients suffered a multifocal (21) or isolated (11) recurrence. We evaluated every primary site of failure. In all patients, the recurrence appeared within the isodose level of 95-100%. Conclusions: Patterns of failure in medulloblastoma patients treated with 3D conformal radiotherapy indicated that the relapse was mainly associated with poor response to pre-irradiation chemotherapy. We believe that 3D conformal radiotherapy allows avoiding failures, related to radiotherapy uncertainties

  18. Evaluation of permanent alopecia in pediatric medulloblastoma patients treated with proton radiation

    International Nuclear Information System (INIS)

    Min, Chul Hee; Paganetti, Harald; Winey, Brian A; Adams, Judith; MacDonald, Shannon M; Tarbell, Nancy J; Yock, Torunn I

    2014-01-01

    To precisely calculate skin dose and thus to evaluate the relationship between the skin dose and permanent alopecia for pediatric medulloblastoma patients treated with proton beams. The dosimetry and alopecia outcomes of 12 children with medulloblastoma (ages 4-15 years) comprise the study cohort. Permanent alopecia was assessed and graded after completion of the entire therapy. Skin threshold doses of permanent alopecia were calculated based on the skin dose from the craniospinal irradiation (CSI) plan using the concept of generalized equivalent uniform dose (gEUD) and accounting for chemotherapy intensity. Monte Carlo simulations were employed to accurately assess uncertainties due to beam range prediction and secondary particles. Increasing the dose of the CSI field or the dose given by the boost field to the posterior fossa increased total skin dose delivered in that region. It was found that permanent alopecia could be correlated with CSI dose with a threshold of about 21 Gy (relative biological effectiveness, RBE) with high dose chemotherapy and 30 Gy (RBE) with conventional chemotherapy. Our results based on 12 patients provide a relationship between the skin dose and permanent alopecia for pediatric medulloblastoma patients treated with protons. The alopecia risk as assessed with gEUD could be predicted based on the treatment plan information

  19. Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4.

    Science.gov (United States)

    Ward, Stacey A; Warrington, Nicole M; Taylor, Sara; Kfoury, Najla; Luo, Jingqin; Rubin, Joshua B

    2017-03-15

    The CXCR4 chemokine and Sonic Hedgehog (SHH) morphogen pathways are well-validated therapeutic targets in cancer, including medulloblastoma. However, single-agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here, we discovered that dual inhibition of the SHH and CXCR4 pathways in a murine model of SHH-subtype medulloblastoma exerts potent antitumor effects. This therapeutic synergy resulted in the suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression. These results demonstrate that CXCR4 contributes to the epigenetic regulation of a tumor-propagating cell phenotype. Moreover, they provide a mechanistic rationale to evaluate the combination of SHH and CXCR4 inhibitors in clinical trials for the treatment of medulloblastoma, as well as other cancers driven by SHH that coexpress high levels of CXCR4. Cancer Res; 77(6); 1416-26. ©2016 AACR . ©2016 American Association for Cancer Research.

  20. Adaptations of energy metabolism during cerebellar neurogenesis are co-opted in medulloblastoma.

    Science.gov (United States)

    Tech, Katherine; Deshmukh, Mohanish; Gershon, Timothy R

    2015-01-28

    Recent studies show that metabolic patterns typical of cancer cells, including aerobic glycolysis and increased lipogenesis, are not unique to malignancy, but rather originate in physiologic development. In the postnatal brain, where sufficient oxygen for energy metabolism is scrupulously maintained, neural progenitors nevertheless metabolize glucose to lactate and prioritize lipid synthesis over fatty acid oxidation. Medulloblastoma, a cancer of neural progenitors that is the most common malignant brain tumor in children, recapitulates the metabolic phenotype of brain progenitor cells. During the physiologic proliferation of neural progenitors, metabolic enzymes generally associated with malignancy, including Hexokinase 2 (Hk2) and Pyruvate kinase M2 (PkM2) configure energy metabolism to support growth. In these non-malignant cells, expression of Hk2 and PkM2 is driven by transcriptional regulators that are typically identified as oncogenes, including N-myc. Importantly, N-myc continues to drive Hk2 and PkM2 in medulloblastoma. Similarly E2F transcription factors and PPARγ function in both progenitors and medulloblastoma to optimize energy metabolism to support proliferation. These findings show that the "metabolic transformation" that is a hallmark of cancer is not specifically limited to cancer. Rather, metabolic transformation represents a co-opting of developmental programs integral to physiologic growth. Despite their physiologic origins, the molecular mechanisms that mediate metabolic transformation may nevertheless present ideal targets for novel anti-tumor therapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy

    International Nuclear Information System (INIS)

    Moeller, Benjamin J; Chintagumpala, Murali; Philip, Jimmy J; Grosshans, David R; McAleer, Mary F; Woo, Shiao Y; Gidley, Paul W; Vats, Tribhawan S; Mahajan, Anita

    2011-01-01

    Hearing loss is common following chemoradiotherapy for children with medulloblastoma. Compared to photons, proton radiotherapy reduces radiation dose to the cochlea for these patients. Here we examine whether this dosimetric advantage leads to a clinical benefit in audiometric outcomes. From 2006-2009, 23 children treated with proton radiotherapy for medulloblastoma were enrolled on a prospective observational study, through which they underwent pre- and 1 year post-radiotherapy pure-tone audiometric testing. Ears with moderate to severe hearing loss prior to therapy were censored, leaving 35 ears in 19 patients available for analysis. The predicted mean cochlear radiation dose was 30 60 Co-Gy Equivalents (range 19-43), and the mean cumulative cisplatin dose was 303 mg/m 2 (range 298-330). Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (P < 0.05). There was partial sparing of mean post-radiation hearing thresholds at low-to-midrange frequencies and, consequently, the rate of high-grade (grade 3 or 4) ototoxicity at 1 year was favorable (5%). Ototoxicity did not correlate with predicted dose to the auditory apparatus for proton-treated patients, potentially reflecting a lower-limit threshold for radiation effect on the cochlea. Rates of high-grade early post-radiation ototoxicity following proton radiotherapy for pediatric medulloblastoma are low. Preservation of hearing in the audible speech range, as observed here, may improve both quality of life and cognitive functioning for these patients

  2. A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors

    Directory of Open Access Journals (Sweden)

    Jerome A. Staal

    2016-10-01

    Full Text Available Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC-amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities.

  3. A method for medulloblastoma tumor differentiation based on convolutional neural networks and transfer learning

    Science.gov (United States)

    Cruz-Roa, Angel; Arévalo, John; Judkins, Alexander; Madabhushi, Anant; González, Fabio

    2015-12-01

    Convolutional neural networks (CNN) have been very successful at addressing different computer vision tasks thanks to their ability to learn image representations directly from large amounts of labeled data. Features learned from a dataset can be used to represent images from a different dataset via an approach called transfer learning. In this paper we apply transfer learning to the challenging task of medulloblastoma tumor differentiation. We compare two different CNN models which were previously trained in two different domains (natural and histopathology images). The first CNN is a state-of-the-art approach in computer vision, a large and deep CNN with 16-layers, Visual Geometry Group (VGG) CNN. The second (IBCa-CNN) is a 2-layer CNN trained for invasive breast cancer tumor classification. Both CNNs are used as visual feature extractors of histopathology image regions of anaplastic and non-anaplastic medulloblastoma tumor from digitized whole-slide images. The features from the two models are used, separately, to train a softmax classifier to discriminate between anaplastic and non-anaplastic medulloblastoma image regions. Experimental results show that the transfer learning approach produce competitive results in comparison with the state of the art approaches for IBCa detection. Results also show that features extracted from the IBCa-CNN have better performance in comparison with features extracted from the VGG-CNN. The former obtains 89.8% while the latter obtains 76.6% in terms of average accuracy.

  4. School Competence and Fluent Academic Performance: Informing Assessment of Educational Outcomes in Survivors of Pediatric Medulloblastoma.

    Science.gov (United States)

    Holland, Alice Ann; Hughes, Carroll W; Stavinoha, Peter L

    2015-01-01

    Academic difficulties are widely acknowledged but not adequately studied in survivors of pediatric medulloblastoma. Although most survivors require special education services and are significantly less likely than healthy peers to finish high school, measured academic skills are typically average. This study sought to identify potential factors associated with academic difficulties in this population and focused on school competence and fluent academic performance. Thirty-six patients (ages 7-18 years old) were recruited through the Departments of Neurosurgery and Neuro-Oncology at Children's Medical Center Dallas and Cook Children's Medical Center in Fort Worth, TX. Participants completed a neuropsychological screening battery including selected Woodcock-Johnson III Tests of Achievement subtests. Parents completed the Child Behavior Checklist. School competence was significantly correlated with measured academic skills and fluency. Basic academic skill development was broadly average, in contrast to significantly worse fluent academic performance. School competence may have utility as a measure estimating levels of educational success in this population. Additionally, academic difficulties experienced by childhood medulloblastoma survivors may be better captured by measuring deficits in fluent academic performance rather than skills. Identification of these potential factors associated with educational outcomes of pediatric medulloblastoma survivors has significant implications for research, clinical assessment, and academic services/interventions.

  5. The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice.

    Directory of Open Access Journals (Sweden)

    Mai T Dang

    Full Text Available The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

  6. MicroRNA 128a increases intracellular ROS level by targeting Bmi-1 and inhibits medulloblastoma cancer cell growth by promoting senescence.

    Directory of Open Access Journals (Sweden)

    Sujatha Venkataraman

    Full Text Available BACKGROUND: MicroRNAs (miRNAs are a class of short non-coding RNAs that regulate cell homeostasis by inhibiting translation or degrading mRNA of target genes, and thereby can act as tumor suppressor genes or oncogenes. The role of microRNAs in medulloblastoma has only recently been addressed. We hypothesized that microRNAs differentially expressed during normal CNS development might be abnormally regulated in medulloblastoma and are functionally important for medulloblastoma cell growth. METHODOLOGY AND PRINCIPAL FINDINGS: We examined the expression of microRNAs in medulloblastoma and then investigated the functional role of one specific one, miR-128a, in regulating medulloblastoma cell growth. We found that many microRNAs associated with normal neuronal differentiation are significantly down regulated in medulloblastoma. One of these, miR-128a, inhibits growth of medulloblastoma cells by targeting the Bmi-1 oncogene. In addition, miR-128a alters the intracellular redox state of the tumor cells and promotes cellular senescence. CONCLUSIONS AND SIGNIFICANCE: Here we report the novel regulation of reactive oxygen species (ROS by microRNA 128a via the specific inhibition of the Bmi-1 oncogene. We demonstrate that miR-128a has growth suppressive activity in medulloblastoma and that this activity is partially mediated by targeting Bmi-1. This data has implications for the modulation of redox states in cancer stem cells, which are thought to be resistant to therapy due to their low ROS states.

  7. MR findings of medulloblastomas and the significance of contrast enhanced MR of brain and spine for the staging

    International Nuclear Information System (INIS)

    Chung, Jae Joon; Kim, Dong Ik; Chung, Tae Sub; Lee, Yeon Hee; Suh, Jung Ho

    1994-01-01

    The purpose of this study were to analyze the MR findings of medulloblastoma, and to evaluate the subarachnoid dissemination and the significance of contrast enhanced MR of brain and spine for tumor staging. The preoperative brain MR studies of 18 patients (9 males, 9 females; mean age, 9.4 years) with surgically proved medulloblastomas were retrospectively reviewed to characterize these neoplasms with regard to their location, size, MR signal intensity, appearance after contrast enhancement, presence of cyst and necrosis, subarachnoid dissemination, and other associated findings. In 14 patients postoperative spine MR studies were evaluated for staging and therapeutic planning. The most frequent location of medulloblastoma was the inferior vermis and the mean tumor size was 4.1 x 3.6 x 3.9 cm. On T1-weighted image, medulloblastomas generally had low to intermediate signal, predominantly hypointense relative to white matter. On T2-weighted image, medulloblastomas showed moderately high signal, hyperintense relative to white matter. Inhomogeneous contrast enhancement was demonstrated in 13 patients(72.2%) after injection of gadopentetate dimeglumine(Gadolinium). Cyst and necrosis within the tumor were visualized in 15 patients(83.3%). Subarachnoid disseminations of medulloblastomas were noted in 11 patients(61.1%), of which 6 demonstrated intracranial and 2 intraspinal dissemination. Three had both intracranial and intraspinal dissemination. In nine cases with intracranial lesions, there were intraparenchymal mass formation(7), subarachnoid nodules(5), infundibular lesions(2) and diffuse gyral enhancement(1). In five cases with intraspinal lesions, there were extramedullary intradural small nodules(3), central canal nodules(2), intradural masses(1) and fine nodular and sheet-like leptomeningeal enhancement(1). Other associated findings included intratumoral hemorrhage(11.1%), peritumoral edema(44.4%), tonsillar herniation(44.4%), hydrocephalus(88.9%) and

  8. Medulloblastoma: correlation among findings of conventional magnetic resonance imaging, diffusion-weighted imaging and proton magnetic resonance spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Fonte, Mariana Vieira de Melo da; Otaduy, Maria Concepcion Garcia; Lucato, Leandro Tavares; Reed, Umbertina Conti; Leite, Claudia da Costa [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil). Hospital das Clinicas. Inst. de Radiologia]. E-mail: mvmfonte@uol.com.br; Costa, Maria Olivia Rodrigues; Amaral, Raquel Portugal Guimaraes [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil). Faculdade de Medicina. Dept. de Radiologia; Reed, Umbertina Conti [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil). Faculdade de Medicina. Dept. de Neurologia; Rosemberg, Sergio [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil). Hospital das Clinicas. Dept. de Patologia

    2008-11-15

    To correlate imaging findings of medulloblastomas at conventional magnetic resonance imaging, diffusion-weighted imaging and proton magnetic resonance spectroscopy, comparing them with data in the literature. Preoperative magnetic resonance imaging studies of nine pediatric patients with histologically confirmed medulloblastomas (eight desmoplastic medulloblastoma, and one giant cell medulloblastoma) were retrospectively reviewed, considering demographics as well as tumors characteristics such as localization, morphology, signal intensity, contrast-enhancement, dissemination, and diffusion-weighted imaging and spectroscopy findings. In most of cases the tumors were centered in the cerebellar vermis (77.8%), predominantly solid (88.9%), hypointense on T 1-weighted images and intermediate/hyperintense on T 2-FLAIR-weighted images, with heterogeneous enhancement (100%), tumor dissemination/extension (77.8%) and limited water molecule mobility (100%). Proton spectroscopy acquired with STEAM technique (n = 6) demonstrated decreased Na a / Cr ratio (83.3%) and increased Co/Cr (100%) and ml/Cr (66.7%) ratios; and with PRESS technique (n = 7) demonstrated lactate peak (57.1%). Macroscopic magnetic resonance imaging findings in association with biochemical features of medulloblastomas have been useful in the differentiation among the most frequent posterior fossa tumors. (author)

  9. Medulloblastoma: correlation among findings of conventional magnetic resonance imaging, diffusion-weighted imaging and proton magnetic resonance spectroscopy

    International Nuclear Information System (INIS)

    Fonte, Mariana Vieira de Melo da; Otaduy, Maria Concepcion Garcia; Lucato, Leandro Tavares; Reed, Umbertina Conti; Leite, Claudia da Costa; Costa, Maria Olivia Rodrigues; Amaral, Raquel Portugal Guimaraes; Reed, Umbertina Conti; Rosemberg, Sergio

    2008-01-01

    To correlate imaging findings of medulloblastomas at conventional magnetic resonance imaging, diffusion-weighted imaging and proton magnetic resonance spectroscopy, comparing them with data in the literature. Preoperative magnetic resonance imaging studies of nine pediatric patients with histologically confirmed medulloblastomas (eight desmoplastic medulloblastoma, and one giant cell medulloblastoma) were retrospectively reviewed, considering demographics as well as tumors characteristics such as localization, morphology, signal intensity, contrast-enhancement, dissemination, and diffusion-weighted imaging and spectroscopy findings. In most of cases the tumors were centered in the cerebellar vermis (77.8%), predominantly solid (88.9%), hypointense on T 1-weighted images and intermediate/hyperintense on T 2-FLAIR-weighted images, with heterogeneous enhancement (100%), tumor dissemination/extension (77.8%) and limited water molecule mobility (100%). Proton spectroscopy acquired with STEAM technique (n = 6) demonstrated decreased Na a / Cr ratio (83.3%) and increased Co/Cr (100%) and ml/Cr (66.7%) ratios; and with PRESS technique (n = 7) demonstrated lactate peak (57.1%). Macroscopic magnetic resonance imaging findings in association with biochemical features of medulloblastomas have been useful in the differentiation among the most frequent posterior fossa tumors. (author)

  10. Differentiation of a medulloblastoma cell line towards an astrocytic lineage using the human T lymphotropic retrovirus-1.

    Science.gov (United States)

    Giraudon, P; Dufay, N; Hardin, H; Reboul, A; Tardy, M; Belin, M F

    1993-02-01

    Constituent cells of medulloblastoma, the most common brain tumor occurring in childhood, resemble the primitive neuroepithelial cells normally found in the developing nervous system. However, mutational events prevent their further differentiation. We used the human T cell lymphotrophic virus type 1 to activate these deregulated immature cells by means of its transactivating protein Tax. Concomitant with viral infection was a decrease in cell proliferation characterized by inhibition of [3H]thymidine incorporation and in the number of cells in the G2/M phase of the cell cycle. Morphological changes suggested that medulloblastoma cells differentiated along the astrocytic lineage. The glial phenotype was confirmed by the induction of the glial fibrillary acidic protein and the glial enzyme glutamine synthetase. A direct viral effect and/or secondary effects to viral infection via paracrine/autocrine pathways could counterbalance the maturational defect in these medulloblastoma cells.

  11. Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.

    Science.gov (United States)

    Hill, Rebecca M; Kuijper, Sanne; Lindsey, Janet C; Petrie, Kevin; Schwalbe, Ed C; Barker, Karen; Boult, Jessica K R; Williamson, Daniel; Ahmad, Zai; Hallsworth, Albert; Ryan, Sarra L; Poon, Evon; Robinson, Simon P; Ruddle, Ruth; Raynaud, Florence I; Howell, Louise; Kwok, Colin; Joshi, Abhijit; Nicholson, Sarah Leigh; Crosier, Stephen; Ellison, David W; Wharton, Stephen B; Robson, Keith; Michalski, Antony; Hargrave, Darren; Jacques, Thomas S; Pizer, Barry; Bailey, Simon; Swartling, Fredrik J; Weiss, William A; Chesler, Louis; Clifford, Steven C

    2015-01-12

    We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature

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    Giuseppe Privitera

    2009-01-01

    Full Text Available Medulloblastoma is a rare tumor in central nervous system, with an even rarer occurrence in adulthood. The management of a recurrent disease is a medical challenge; chemotherapy has been used as the treatment of choice, while reirradiation has been employed in selected cases. We report the case of a 51-year-old man with recurrent medulloblastoma. He was treated with local reirradiation, chemotherapy, and antiangiogenic drug, with the latter giving the longer progression-free interval. The aim of this report is to show that recurrent medulloblastoma in adults can be approached with a multimodality treatment and that antiangiogenic therapy should have a role in the management of this disease.

  13. Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update.

    Science.gov (United States)

    Bautista, Francisco; Fioravantti, Victoria; de Rojas, Teresa; Carceller, Fernando; Madero, Luis; Lassaletta, Alvaro; Moreno, Lucas

    2017-11-01

    Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early-phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0-100) and 6.5% (0-50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0-100). Smoothened inhibitors trials had a median ORR of 8% (3-8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  14. A novel small molecular STAT3 inhibitor, LY5, inhibits cell viability, cell migration, and angiogenesis in medulloblastoma cells.

    Science.gov (United States)

    Xiao, Hui; Bid, Hemant Kumar; Jou, David; Wu, Xiaojuan; Yu, Wenying; Li, Chenglong; Houghton, Peter J; Lin, Jiayuh

    2015-02-06

    Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated and could contribute to tumorigenesis of medulloblastoma. Numerous studies have demonstrated that inhibition of the persistent STAT3 signaling pathway results in decreased proliferation and increased apoptosis in human cancer cells, indicating that STAT3 is a viable molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable small molecule, named LY5, to target STAT3 in medulloblastoma cells. LY5 inhibited persistent STAT3 phosphorylation and induced apoptosis in human medulloblastoma cell lines expressing constitutive STAT3 phosphorylation. The inhibition of STAT3 signaling by LY5 was confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, bcl-XL, survivin, and micro-RNA-21. LY5 also inhibited the induction of STAT3 phosphorylation by interleukin-6 (IL-6), insulin-like growth factor (IGF)-1, IGF-2, and leukemia inhibitory factor in medulloblastoma cells, but did not inhibit STAT1 and STAT5 phosphorylation stimulated by interferon-γ (IFN-γ) and EGF, respectively. In addition, LY5 blocked the STAT3 nuclear localization induced by IL-6, but did not block STAT1 and STAT5 nuclear translocation mediated by IFN-γ and EGF, respectively. A combination of LY5 with cisplatin or x-ray radiation also showed more potent effects than single treatment alone in the inhibition of cell viability in human medulloblastoma cells. Furthermore, LY5 demonstrated a potent inhibitory activity on cell migration and angiogenesis. Taken together, these findings indicate LY5 inhibits persistent and inducible STAT3 phosphorylation and suggest that LY5 is a promising therapeutic drug candidate for medulloblastoma by inhibiting persistent STAT3 signaling. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines.

    Directory of Open Access Journals (Sweden)

    Walderik W Zomerman

    Full Text Available Recent clinical trials investigating receptor tyrosine kinase (RTK inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte growth factor receptor (MET and epidermal growth factor receptor family (ErbB1-4 inhibition in medulloblastoma cell lines. Medulloblastoma cell lines were treated with tyrosine kinase inhibitors crizotinib or canertinib, targeting MET and ErbB1-4, respectively. Upon treatment, cells were stimulated with VEGF-A, PDGF-AB, HGF, FGF-2 or EGF. Subsequently, we measured cell viability and expression levels of growth factors and downstream signaling proteins. Addition of HGF or EGF phosphorylated MET or EGFR, respectively, and demonstrated phosphorylation of Akt and ERK1/2 as well as increased tumor cell viability. Crizotinib and canertinib both inhibited cell viability and phosphorylation of Akt and ERK1/2. Specifically targeting MET using shRNA's resulted in decreased cell viability. Interestingly, addition of HGF to canertinib significantly enhanced cell viability as well as phosphorylation of Akt and ERK1/2. The HGF-induced bypass of canertinib was reversed by addition of crizotinib. HGF protein was hardly released by medulloblastoma cells itself. Addition of canertinib did not affect RTK cell surface or growth factor expression levels. This manuscript points to the bypassing capacity of exogenous HGF in medulloblastoma cell lines. It might be of great interest to anticipate on these results in developing novel clinical trials with a combination of MET and EGFR inhibitors in medulloblastoma.

  16. The anti-neoplastic activity of Vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition.

    Science.gov (United States)

    Craveiro, Rogerio B; Ehrhardt, Michael; Velz, Julia; Olschewski, Martin; Goetz, Barbara; Pietsch, Torsten; Dilloo, Dagmar

    2017-07-18

    Medulloblastoma is comprised of at least four molecular subgroups with distinct clinical outcome (WHO classification 2016). SHH-TP53-mutated as well as MYC-amplified Non-WNT/Non-SHH medulloblastoma show the worst prognosis.Here we present evidence that single application of the multi-kinase inhibitor Vandetanib displays anti-neoplastic efficacy against cell lines derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/Non-SHH medulloblastoma. The narrow target spectrum of Vandetanib along with a favourable toxicity profile renders this drug ideal for multimodal treatment approaches. In this context our investigation documents that Vandetanib in combination with the clinically available PI3K inhibitor GDC-0941 leads to enhanced cytotoxicity against MYC-amplified and SHH-TP53-mutated medulloblastoma. In line with these findings we show for MYC-amplified medulloblastoma a profound reduction in activity of the oncogenes STAT3 and AKT. Furthermore, we document that Vandetanib and the standard chemotherapeutic Etoposide display additive anti-neoplastic efficacy in the investigated medulloblastoma cell lines that could be further enhanced by PI3K inhibition. Of note, the combination of Vandetanib, GDC-0941 and Etoposide results in MYC-amplified and SHH-TP53-mutated cell lines in complete loss of cell viability. Our findings therefore provide a rational to further evaluate Vandetanib in combination with PI3K inhibitors as well as standard chemotherapeutics in vivo for the treatment of most aggressive medulloblastoma variants.

  17. Proton Beam Craniospinal Irradiation Reduces Acute Toxicity for Adults With Medulloblastoma

    International Nuclear Information System (INIS)

    Brown, Aaron P.; Barney, Christian L.; Grosshans, David R.; McAleer, Mary Frances; Groot, John F. de; Puduvalli, Vinay K.; Tucker, Susan L.; Crawford, Cody N.; Khan, Meena; Khatua, Soumen; Gilbert, Mark R.; Brown, Paul D.; Mahajan, Anita

    2013-01-01

    Purpose: Efficacy and acute toxicity of proton craniospinal irradiation (p-CSI) were compared with conventional photon CSI (x-CSI) for adults with medulloblastoma. Methods and Materials: Forty adult medulloblastoma patients treated with x-CSI (n=21) or p-CSI (n=19) at the University of Texas MD Anderson Cancer Center from 2003 to 2011 were retrospectively reviewed. Median CSI and total doses were 30.6 and 54 Gy, respectively. The median follow-up was 57 months (range 4-103) for x-CSI patients and 26 months (range 11-63) for p-CSI. Results: p-CSI patients lost less weight than x-CSI patients (1.2% vs 5.8%; P=.004), and less p-CSI patients had >5% weight loss compared with x-CSI (16% vs 64%; P=.004). p-CSI patients experienced less grade 2 nausea and vomiting compared with x-CSI (26% vs 71%; P=.004). Patients treated with x-CSI were more likely to have medical management of esophagitis than p-CSI patients (57% vs 5%, P<.001). p-CSI patients had a smaller reduction in peripheral white blood cells, hemoglobin, and platelets compared with x-CSI (white blood cells 46% vs 55%, P=.04; hemoglobin 88% vs 97%, P=.009; platelets 48% vs 65%, P=.05). Mean vertebral doses were significantly associated with reductions in blood counts. Conclusions: This report is the first analysis of clinical outcomes for adult medulloblastoma patients treated with p-CSI. Patients treated with p-CSI experienced less treatment-related morbidity including fewer acute gastrointestinal and hematologic toxicities

  18. Diffuse stenotic change in large intracranial arteries following irradiation therapy for medulloblastoma

    International Nuclear Information System (INIS)

    Yamakami, Iwao; Sugaya, Yuichi; Sato, Masanori; Osato, Katunobu; Yamaura, Akira; Makino, Hiroyasu.

    1990-01-01

    We reported a case of a patient who developed a diffuse stenotic change in the large intracranial arteries and repeated episodes of cerebral infarction after irradiation therapy for medulloblastoma. A three-year-old girl underwent the subtotal removal of cerebellar medulloblastoma and the subsequent irradiation therapy in the whole brain and spine (30 Gy in the whole brain, 20 Gy in the local brain, and 25 Gy in the whole spine). Two years later, she again underwent surgery and irradiation therapy because a recurrence of medulloblastoma had manifested itself in the frontal lobe; (40 Gy in the whole brain, 20 Gy in the local brain, and 25 Gy in the whole spine). One and half years after the second irradiation, she started suffering from frequent and refractory cerebral ischemic attacks. Cerebral angiography revealed a diffuse narrowing, and multifocal stenoses in the bilateral anterior and middle cerebral arteries. Computerized tomography demonstrated multiple cerebral infarctions. Her neurological condition deteriorated because of recurring strokes and she died at ten years of age. Most of the reported cases of patients who developed stenotic arteriopathy were children in the first decade of their life, and who were irradiated for parasellar brain tumor of low malignancy. Stenotic arteriopathy after irradiation has rarely been recognized in patients with malignant brain tumor. However, life expectancy is increasing even for those with malignant brain tumor, and it may make stenotic arteriopathy after irradiation recognized more commonly in patients with malignant brain tumor. Careful irradiation and subsequent angiographical examination should be required even in patients with malignant brain tumor. (author)

  19. Clinicopathological features of cerebellar lipidized medulloblastoma: a case report and review of literatures

    Directory of Open Access Journals (Sweden)

    LIU Li-yan

    2012-06-01

    Full Text Available Objective To explore the clinicopathological features of cerebellar lipidized medulloblastoma. Methods The clinical manifestations, neuroimaging, histopathological and immunohistochemical features were analysed in one case of lipidized medulloblastoma in the cerebellar vermis. Related literatures were reviewed. Results A 26-year-old man presented with intermittent headache,accompanied by dizziness, nausea and vomiting. The magnetic resonance imaging (MRI demonstrated a mass located the cerebellar vermis convex to the fourth ventricle. The tumor with well-demarcated boundary was homogeneous hypointense on T1 weighted and heterogeneous hyperintense on T2 weighted images, and enhanced brilliantly and homogenously on contrast. The patient subsequently underwent gross total mass resection. Microscopically,there was diffuse infiltration by high cellularity of tumor cells. The cytoplasm were thin eosinophilic to amphophilic. The neoplastic cells showed round to oval hyperchromatic nuclei with a delicately stippled chromatin and occasional conspicuous nucleoli and numerous mitotic figures were also present. Thin-wall vascular proliferation was detected. Lipid-laden cells were focally distributed in tumor tissue. On immunohistochemical examination, the neoplasm was reactive for CD56 and synaptophysin (Syn, focally positive for neurofilament protein (NF, weakly positive for oligodendrocyte lineage transcription factor 2 (Olig-2, and negtive for nestin, neuronal nuclei (NeuN, S-100 protein (S-100, glial fibrillary acidic protein (GFAP and epithelial membrane antigen (EMA. TP53 protein was over expressed in 10% of tumor cells. Ki-67 antigen labeling index were about 40% . Conclusion Cerebellar lipidized medulloblastoma is rare. Neuroimaging showed space occupying lesion in cerebellar vermis. Histologically, the tumor cells were consisted of monotonous, round cells with focal accumulations of lipidized cells. The differential diagnosis include

  20. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

    Science.gov (United States)

    Pham, Christina D; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M; Yearley, Jennifer H; Sayour, Elias J; Pei, Yanxin; Moore, Colin; McLendon, Roger E; Huang, Jianping; Sampson, John H; Wechsler-Reya, Robert; Mitchell, Duane A

    2016-02-01

    Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment. This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. ©2015 American Association for Cancer Research.

  1. Rubinstein-Taybi syndrome predisposing to non-WNT, non-SHH, group 3 medulloblastoma.

    Science.gov (United States)

    Bourdeaut, Franck; Miquel, Catherine; Richer, Wilfrid; Grill, Jacques; Zerah, Michel; Grison, Camille; Pierron, Gaelle; Amiel, Jeanne; Krucker, Clementine; Radvanyi, Francois; Brugieres, Laurence; Delattre, Olivier

    2014-02-01

    Medulloblastomas (MB) are classified in four subgroups: the well defined WNT and Sonic Hedgehog (SHH) subgroups, and the less defined groups 3 and 4. They occasionally occur in the context of a cancer predisposition syndrome. While germline APC mutations predispose to WNT MB, germline mutations in SUFU, PTCH1, and TP53 predispose to SHH tumors. We report on a child with a Rubinstein-Taybi syndrome (RTS) due to a germline deletion in CREBBP, who developed a MB. Biological profilings demonstrate that this tumor belongs to the group 3. RTS may therefore be the first predisposition syndrome identified for non-WNT/non-SHH MB. © 2013 Wiley Periodicals, Inc.

  2. Late-onset radiation-induced vasculopathy and stroke in a child with medulloblastoma.

    Science.gov (United States)

    Bansal, Lalit R; Belair, Jeffrey; Cummings, Dana; Zuccoli, Giulio

    2015-05-01

    We report a case of a 15-year-old boy who presented to our institution with left-sided weakness and slurred speech. He had a history of medulloblastoma diagnosed at 3 years of age, status postsurgical resection and craniospinal radiation. Magnetic resonance imaging (MRI) of brain revealed a right paramedian pontine infarction, suspected secondary to late-onset radiation-induced vasculopathy of the vertebrobasilar system. Radiation to the brain is associated with increased incidence of ischemic stroke. Clinicians should have a high index of suspicion for stroke when these patients present with new neurologic symptoms. © The Author(s) 2014.

  3. Post-operative diffusion weighted imaging as a predictor of posterior fossa syndrome permanence in paediatric medulloblastoma.

    Science.gov (United States)

    Chua, Felicia H Z; Thien, Ady; Ng, Lee Ping; Seow, Wan Tew; Low, David C Y; Chang, Kenneth T E; Lian, Derrick W Q; Loh, Eva; Low, Sharon Y Y

    2017-03-01

    Posterior fossa syndrome (PFS) is a serious complication faced by neurosurgeons and their patients, especially in paediatric medulloblastoma patients. The uncertain aetiology of PFS, myriad of cited risk factors and therapeutic challenges make this phenomenon an elusive entity. The primary objective of this study was to identify associative factors related to the development of PFS in medulloblastoma patient post-tumour resection. This is a retrospective study based at a single institution. Patient data and all related information were collected from the hospital records, in accordance to a list of possible risk factors associated with PFS. These included pre-operative tumour volume, hydrocephalus, age, gender, extent of resection, metastasis, ventriculoperitoneal shunt insertion, post-operative meningitis and radiological changes in MRI. Additional variables included molecular and histological subtypes of each patient's medulloblastoma tumour. Statistical analysis was employed to determine evidence of each variable's significance in PFS permanence. A total of 19 patients with appropriately complete data was identified. Initial univariate analysis did not show any statistical significance. However, multivariate analysis for MRI-specific changes reported bilateral DWI restricted diffusion changes involving both right and left sides of the surgical cavity was of statistical significance for PFS permanence. The authors performed a clinical study that evaluated possible risk factors for permanent PFS in paediatric medulloblastoma patients. Analysis of collated results found that post-operative DWI restriction in bilateral regions within the surgical cavity demonstrated statistical significance as a predictor of PFS permanence-a novel finding in the current literature.

  4. Simultaneous colonic adenocarcinoma and medulloblastoma in a 12-year-old with biallelic deletions in PMS2.

    Science.gov (United States)

    Lindsay, Holly; Jubran, Rima F; Wang, Larry; Kipp, Benjamin R; May, William A

    2013-08-01

    We describe a 12-year-old girl, simultaneously presenting with colonic adenocarcinoma and medulloblastoma from bialleic deletions in the mismatch repair gene PMS2. Her distinctive physical and clinical findings are characteristic of constitutional mismatch repair deficiency syndrome. Earlier recognition of such findings may permit better screening and more effective treatment. Copyright © 2013 Mosby, Inc. All rights reserved.

  5. Clinical, pathological, and molecular data on desmoplastic/nodular medulloblastoma: case studies and a review of the literature.

    Science.gov (United States)

    Siegfried, Aurore; Bertozzi, Anne Isabelle; Bourdeaut, Franck; Sevely, Annick; Loukh, Najat; Grison, Camille; Miquel, Catherine; Lafon, Delphine; Sevenet, Nicolas; Pietsch, Torsten; Dufour, Christelle; Delisle, Marie-Bernadette

    2016-01-01

    The aim of this study was to better define the clinical and biopathological features of patients with desmoplastic/nodular medulloblastoma (DNMB) and to further characterize this subgroup. 17 children aged 3 years, and residual tumor may also have been an explanation for recurrence.

  6. In vitro stemness characterization of radio-resistant clones isolated from a medulloblastoma cell line ONS-76

    International Nuclear Information System (INIS)

    Sun, Lue; Suzuki, Kenshi; Gerelchuluun, Ariungerel; Hong, Zhengshan; Moritake, Takashi; Zenkoh, Junko; Tsuboi, Koji; Zheng, Yun-Wen; Taniguchi, Hideki

    2013-01-01

    One-third of patients with medulloblastoma die due to recurrence after various treatments including radiotherapy. Although it has been postulated that cancer stem-like cells are radio-resistant and play an important role in tumor recurrence, the 'stemness' of medulloblastoma cells surviving irradiation has not yet been elucidated. Using a medulloblastoma cell line ONS-76, cells that survived gamma irradiation were investigated on their 'stemness' in vitro. From 10 500 cells, 20 radio-resistant clones were selected after gamma ray irradiation (5 Gy x two fractions) using the replica micro-well technique. These 20 resistant clones were screened for CD133 positivity by flow cytometry followed by side population assay, tumor sphere formation assay and clonogenic survival assay. Results revealed CD133 fractions were significantly elevated in three clones, which also exhibited significantly increased levels of tumor sphere formation ability and side population fraction. Clonogenic survival assay demonstrated that their radio-resistance was significantly higher than the parental ONS-76. This may support the hypothesis that a small number of cancer stem-like cells (CSCs) are the main culprits in local recurrence after radiotherapy, and disruption of the resistance mechanism of these CSCs is a critical future issue in improving the outcome of patients with medulloblastoma. (author)

  7. Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma

    DEFF Research Database (Denmark)

    Brodin, N Patrik; Munck af Rosenschöld, Per Martin; Aznar, Marianne C

    2011-01-01

    The aim of this model study was to estimate and compare the risk of radiation-induced adverse late effects in pediatric patients with medulloblastoma (MB) treated with either three-dimensional conformal radiotherapy (3D CRT), inversely-optimized arc therapy (RapidArc(®) (RA)) or spot...

  8. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: A retrospective integrated clinical and molecular analysis

    NARCIS (Netherlands)

    E.M. Thompson (Eric M.); T. Hielscher (Thomas); E. Bouffet (Eric); M. Remke (Marc); P. Luu (Phan); S. Gururangan (Sridharan); R.E. McLendon (Roger E.); D.D. Bigner (Darell); E.S. Lipp (Eric S.); S. Perreault (Sebastien); Y.-J. Cho (Yoon-Jae); G. Grant (Gerald); S.-K. Kim (Seung-Ki); J.Y. Lee (Ji Yeoun); A.A.N. Rao (Amulya A. Nageswara); C. Giannini (Caterina); K.K.W. Li (Kay Ka Wai); H.-K. Ng (Ho-Keung); Y. Yao (Yu); T. Kumabe (Toshihiro); T. Tominaga (Teiji); W.A. Grajkowska (Wieslawa); M. Perek-Polnik (Marta); D.C.Y. Low (David C.Y.); W.T. Seow (Wan Tew); K.T.E. Chang (Kenneth T.E.); J. Mora (Jaume); A. Pollack (Aaron); R.L. Hamilton (Ronald L.); S. Leary (Sarah); A.S. Moore (Andrew S.); W.J. Ingram (Wendy J.); A.R. Hallahan (Andrew R.); A. Jouvet (Anne); M. Fèvre-Montange (Michelle); A. Vasiljevic (Alexandre); C. Faure-Conter (Cecile); T. Shofuda (Tomoko); N. Kagawa (Naoki); N. Hashimoto (Naoya); N. Jabado (Nada); A.G. Weil (Alexander G.); T. Gayden (Tenzin); T. Wataya (Takafumi); T. Shalaby (Tarek); M. Grotzer (Michael); K. Zitterbart (Karel); J. Sterba; L. Kren (Leos); T. Hortobágyi (Tibor); A. Klekner (Almos); L. Bognár (László); T. Pócza (Tímea); P. Hauser (Peter); U. Schüller (Ulrich); S. Jung (Shin); W.-Y. Jang (Woo-Youl); P.J. French (Pim); J.M. Kros (Johan); M.L.C. van Veelen-Vincent (Marie-Lise); L. Massimi (Luca); J.R. Leonard (Jeffrey); J.B. Rubin (Joshua); R. Vibhakar (Rajeev); L.B. Chambless (Lola B.); M.K. Cooper (Michael); R.C. Thompson (Reid); R. Faria (Rui); A. Carvalho (Alice); S. Nunes (Sofia); J. Pimentel; X. Fan (Xing); K.M. Muraszko (Karin); E. López-Aguilar (Enrique); D. Lyden (David); L. Garzia (Livia); D.J.H. Shih (David J.); N. Kijima (Noriyuki); C. Schneider (Christian); J. Adamski (Jennifer); P.A. Northcott (Paul A.); M. Kool (Marcel); D. Jones (David); J.A. Chan (Jennifer A.); A. Nikolic (Ana); M.L. Garre (Maria Luisa); E.G. Van Meir (Erwin G.); S. Osuka (Satoru); J.J. Olson (Jeffrey J.); A. Jahangiri (Arman); B.A. Castro (Brandyn A.); N. Gupta (Nalin); W.A. Weiss (William A.); I. Moxon-Emre (Iska); D.J. Mabbott (Donald J.); A. Lassaletta (Alvaro); C.E. Hawkins (Cynthia); U. Tabori (Uri); J. Drake (James); A. Kulkarni (Abhaya); M. Dirks (Maaike); J.T. Rutka (James); A. Korshunov (Andrey); S.M. Pfister (Stefan); R.J. Packer (Roger J.); E.A. Ramaswamy; M.D. Taylor (Michael)

    2016-01-01

    textabstractBackground: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All

  9. Actual and future strategies in interdisciplinary treatment of medulloblastomas, supratentorial PNET and intracranial germ cell tumors in childhood

    International Nuclear Information System (INIS)

    Kortmann, R.D.; Timmermann, B.; Bamberg, M.; Kuehl, J.; Calaminus, G.; Goebel, U.; Dieckmann, K.; Wurm, R.; Soerensen, N.; Urban, C.

    2001-01-01

    Methods: Systemic irradiation of neuroaxis is an essential part in the management of medulloblastoma, stPNET and intracranial germ cell tumors. The introduction of quality assurance programs in radiooncology assures a precise radiotherapy of target volumes and is a prerequisite to improve survival. Results: Hyperfractionated radiotherapy has the potential of increasing dose to tumor more safely without increasing the risk for late adverse effects. Pilot studies revealed excellent tumor control in medulloblastoma with acceptable acute toxicity and a long-term survival of up to 96%. In medulloblastoma stereotactic radiation techniques reveal an acceptable toxicity and promising results in tumor control in recurrent disease or as primary treatment. They are now part of future treatment protocols in case of persisting residual tumor. Radiotherapy alone in pure germinoma is continuously yielding high cure rates. In secreting germ cell tumors cisplatin containing chemotherapies in conjunction with radiotherapy achieve a long-term survival rate of 80% today. Especially in high risk medulloblastoma and secreting germ cell tumors chemotherapies are playing an increasingly important role in the interdisciplinary management. It can be expected that future developments of chemotherapeutic protocols and the introduction of new cytostatic substances will further improve the therapeutic outcome. (orig.) [de

  10. Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines

    NARCIS (Netherlands)

    Zomerman, Waldrik W; Plasschaert, Sabine L. A.; Diks, Sander H.; Lourens, Harm-Jan; Meeuwsen-de Boer, Tiny; Hoving, Eelco W.; den Dunnen, Wilfred F. A.; de Bont, Eveline S. J. M.

    2015-01-01

    Recent clinical trials investigating receptor tyrosine kinase (RTK) inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte

  11. Modeling freedom from progression for standard-risk medulloblastoma: a mathematical tumor control model with multiple modes of failure

    DEFF Research Database (Denmark)

    Brodin, Nils Patrik; Vogelius, Ivan R.; Bjørk-Eriksson, Thomas

    2013-01-01

    As pediatric medulloblastoma (MB) is a relatively rare disease, it is important to extract the maximum information from trials and cohort studies. Here, a framework was developed for modeling tumor control with multiple modes of failure and time-to-progression for standard-risk MB, using published...

  12. Molecular risk stratification of medulloblastoma patients based on immunohistochemical analysis of MYC, LDHB, and CCNB1 expression

    NARCIS (Netherlands)

    de Haas, Talitha; Hasselt, Nancy; Troost, Dirk; Caron, Huib; Popovic, Mara; Zadravec-Zaletel, Lorna; Grajkowska, Wieslawa; Perek, Marta; Osterheld, Maria-Chiara; Ellison, David; Baas, Frank; Versteeg, Rogier; Kool, Marcel

    2008-01-01

    PURPOSE: Medulloblastoma is the most common malignant embryonal brain tumor in children. The current clinical risk stratification to select treatment modalities is not optimal because it does not identify the standard-risk patients with resistant disease or the unknown number of high-risk patients

  13. High resolution array-based comparative genomic hybridisation of medulloblastomas and supra-tentorial primitive neuroectodermal tumours

    Science.gov (United States)

    McCabe, Martin Gerard; Ichimura, Koichi; Liu, Lu; Plant, Karen; Bäcklund, L Magnus; Pearson, Danita M; Collins, Vincent Peter

    2010-01-01

    Medulloblastomas and supratentorial primitive neuroectodermal tumours are aggressive childhood tumours. We report our findings using array comparative genomic hybridisation (CGH) on a whole-genome BAC/PAC/cosmid array with a median clone separation of 0.97Mb to study 34 medulloblastomas and 7 supratentorial primitive neuroectodermal tumours. Array CGH allowed identification and mapping of numerous novel small regions of copy number change to genomic sequence, in addition to the large regions already known from previous studies. Novel amplifications were identified, some encompassing oncogenes, MYCL1, PDGFRA, KIT and MYB, not previously reported to show amplification in these tumours. In addition, one supratentorial primitive neuroectodermal tumour had lost both copies of the tumour suppressor genes CDKN2A & CDKN2B. Ten medulloblastomas had findings suggestive of isochromosome 17q. In contrast to previous reports using conventional CGH, array CGH identified three distinct breakpoints in these cases: Ch 17: 17940393-19251679 (17p11.2, n=6), Ch 17: 20111990-23308272 (17p11.2-17q11.2, n=4) and Ch 17: 38425359-39091575 (17q21.31, n=1). Significant differences were found in the patterns of copy number change between medulloblastomas and supratentorial primitive neuroectodermal tumours, providing further evidence that these tumours are genetically distinct despite their morphological and behavioural similarities. PMID:16783165

  14. BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma.

    Directory of Open Access Journals (Sweden)

    Gregory M Shackleford

    Full Text Available Medulloblastomas are the most common malignant pediatric brain tumor and have been divided into four major molecular subgroups. Animal models that mimic the principal molecular aberrations of these subgroups will be important tools for preclinical studies and allow greater understanding of medulloblastoma biology. We report a new transgenic model of medulloblastoma that possesses a unique combination of desirable characteristics including, among others, the ability to incorporate multiple and variable genes of choice and to produce bioluminescent tumors from a limited number of somatic cells within a normal cellular environment. This model, termed BarTeL, utilizes a Barhl1 homeobox gene promoter to target expression of a bicistronic transgene encoding both the avian retroviral receptor TVA and an eGFP-Luciferase fusion protein to neonatal cerebellar granule neuron precursor (cGNP cells, which are cells of origin for the sonic hedgehog (SHH subgroup of human medulloblastomas. The Barhl1 promoter-driven transgene is expressed strongly in mammalian cGNPs and weakly or not at all in mature granule neurons. We efficiently induced bioluminescent medulloblastomas expressing eGFP-luciferase in BarTeL mice by infection of a limited number of somatic cGNPs with avian retroviral vectors encoding the active N-terminal fragment of SHH and a stabilized MYCN mutant. Detection and quantification of the increasing bioluminescence of growing tumors in young BarTeL mice was facilitated by the declining bioluminescence of their uninfected maturing cGNPs. Inclusion of eGFP in the transgene allowed enriched sorting of cGNPs from neonatal cerebella. Use of a single bicistronic avian vector simultaneously expressing both Shh and Mycn oncogenes increased the medulloblastoma incidence and aggressiveness compared to mixed virus infections. Bioluminescent tumors could also be produced by ex vivo transduction of neonatal BarTeL cerebellar cells by avian retroviruses and

  15. The use of stereotactic radiosurgical boost in the treatment of medulloblastomas

    International Nuclear Information System (INIS)

    Woo, Charles; Stea, Baldassarre; Lulu, Bruce; Hamilton, Allan; Cassady, J. Robert

    1997-01-01

    Purpose: Starting in 1992, we began using a stereotactic radiosurgical (SRS) boost for the treatment of medulloblastomas. Four patients ranging in age from 7 to 42 years old have since been treated and are the subject of this retrospective study. Methods and Materials: All patients were initially treated with a maximally debulking surgery and external beam radiotherapy, which were then followed by a stereotactic radiosurgical boost using a modified 6 MeV linear accelerator. Radiosurgical boost doses ranged from 4.50 to 10.0 Gy. Target volumes ranged from 1.1 to 8.1 cc. The procedure was well tolerated with minimal acute toxicities. Results: All four patients are alive without evidence of recurrence (at 8 to 35 months). Acute nausea and vomiting was elicited during the radiosurgical procedure in the first patient treated. We have since begun premedicating patients with antiemetics or treating under general anesthesia. Late complications consisted of panhypopituitarism in one patient, which was thought to be attributable to the previous course of whole-brain radiotherapy. We have not observed any incidence of radionecrosis in this small cohort of patients. Conclusions: Our preliminary results with the use of radiosurgery for medulloblastomas are optimistic, and we would like to suggest the inclusion of a radiosurgery boost in future clinical trials for treatment of this disease

  16. Cost-effectiveness analysis of cochlear dose reduction by proton beam therapy for medulloblastoma in childhood

    International Nuclear Information System (INIS)

    Hirano, Emi; Kawabuchi, Koichi; Fuji, Hiroshi; Onoe, Tsuyoshi; Kumar, Vinay; Shirato, Hiroki

    2014-01-01

    The aim of this study is to evaluate the cost-effectiveness of proton beam therapy with cochlear dose reduction compared with conventional X-ray radiotherapy for medulloblastoma in childhood. We developed a Markov model to describe health states of 6-year-old children with medulloblastoma after treatment with proton or X-ray radiotherapy. The risks of hearing loss were calculated on cochlear dose for each treatment. Three types of health-related quality of life (HRQOL) of EQ-5D, HUI3 and SF-6D were used for estimation of quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) for proton beam therapy compared with X-ray radiotherapy was calculated for each HRQOL. Sensitivity analyses were performed to model uncertainty in these parameters. The ICER for EQ-5D, HUI3 and SF-6D were $21 716/QALY, $11 773/QALY, and $20 150/QALY, respectively. One-way sensitivity analyses found that the results were sensitive to discount rate, the risk of hearing loss after proton therapy, and costs of proton irradiation. Cost-effectiveness acceptability curve analysis revealed a 99% probability of proton therapy being cost effective at a societal willingness-to-pay value. Proton beam therapy with cochlear dose reduction improves health outcomes at a cost that is within the acceptable cost-effectiveness range from the payer's standpoint. (author)

  17. Combined chemotherapy including platinum derivatives for medulloblastoma. The usefulness as maintenance chemotherapy

    International Nuclear Information System (INIS)

    Sasaki, Hikaru; Otani, Mitsuhiro; Yoshida, Kazunari; Kagami, Hiroshi; Shimazaki, Kenji; Toya, Shigeo; Kawase, Takeshi

    1997-01-01

    The authors reviewed 24 cerebellar medulloblastoma patients treated at Keio University to determine usefulness of combined chemotherapy including platinum derivatives (cisplatin, carboplatin) as the induction and maintenance treatment. All patients underwent radical surgery and craniospinal irradiation. Ten received adjuvant chemotherapy other than platinum derivatives (mainly with nitrosourea compounds), five were treated by induction and maintenance chemotherapy including platinum derivatives, and nine patients did not undergo chemotherapy. The progression-free survival rate of patients treated with platinum derivatives was better than that of patients treated with other modes of chemotherapy and also that of patients who did not receive chemotherapy. The results were especially good in the case of four patients treated with maintenance chemotherapy consisting of carboplatin and etoposide, two of whom had been free from relapse beyond the risk period of Collins. The occurrences of toxicity in maintenance chemotherapy with carboplatin and etoposide were limited to transient leucopenia. The present study indicates combined chemotherapy including platinum derivatives benefits patients with medulloblastoma, and could be useful, especially as maintenance treatment. (author)

  18. Intraoperative Tumoral Bleeding of Hypervascular Medulloblastoma after Ventricular Drainage: A Case Report.

    Science.gov (United States)

    Ryu, Han-Seung; Jung, Tae-Young; Han, Moon-Soo; Kim, Seul-Ki; Lee, Kyung-Hwa

    2017-01-01

    We report a rare case of intraoperative tumoral bleeding of a hypervascular medulloblastoma. A 12-year-old girl presented with dizziness and nausea. Brain magnetic resonance (MR) images revealed an approximately 4.2-cm enhanced mass on the cerebellar vermis associated with mild perilesional edema and increased cerebral blood volume. Angiography showed tumoral staining and developed occipital and circular dural sinuses in the venous phase. A suboccipital craniotomy was performed. To relieve the intracranial pressure, cerebrospinal fluid (CSF) was drained via a lateral ventricular catheter in the occipital horn. During the opening of the dura, the brain swelling had progressed, and brain computed tomography revealed an intratumoral hemorrhage with brainstem compression. The patient was in a stuporous mental state. A reoperation was performed, and the mass was totally removed. The pathologic findings revealed a medulloblastoma with abnormal enlarged arterial vascular structures. Postoperatively, the patient recovered to an alert mental state. She underwent chemotherapy and radiotherapy. There was no recurrence after 1 year. Pre-resectional CSF drainage should not be routinely performed in posterior fossa tumors, especially with increased cerebral blood volume on MR perfusion images. Complete removal should be performed quickly while CSF drainage should be performed slowly. An intratumoral hemorrhage should be considered in posterior fossa tumors when severe brain swelling suddenly develops after CSF drainage. © 2016 S. Karger AG, Basel.

  19. Imaging mass spectrometry identifies prognostic ganglioside species in rodent intracranial transplants of glioma and medulloblastoma.

    Directory of Open Access Journals (Sweden)

    Leonardo Ermini

    Full Text Available Matrix-assisted laser desorption ionization (MALDI imaging mass spectrometry (MALDI-MSI allows us to investigate the distribution of lipid molecules within tissues. We used MALDI-MSI to identify prognostic gangliosides in tissue sections of rat intracranial allografts of rat glioma and mouse intracranial xenografts of human medulloblastoma. In the healthy adult rodent brain, GM1 and GD1 were the main types of glycolipids. Both gangliosides were absent in both intracranial transplants. The ganglioside GM3 was not present in the healthy adult brain but was highly expressed in rat glioma allografts. In combination with tandem mass spectrometry GM3 (d18:1/C24:0 was identified as the most abundant ganglioside species in the glioma allotransplant. By contrast, mouse xenografts of human medulloblastoma were characterized by prominent expression of the ganglioside GM2 (d18:0/C18:0. Together, these data demonstrate that tissue-based MALDI-MSI of gangliosides is able to discriminate between different brain tumors and may be a useful clinical tool for their classification and grading.

  20. Metachronous medulloblastoma and glioblastoma: Implications for clinical and technical aspects of re-irradiation.

    Science.gov (United States)

    Verma, Vivek; Kulkarni, Rajesh R; Bhirud, Abhijeet R; Bennion, Nathan R; McComb, Rodney D; Lin, Chi

    2016-01-01

    A seven-year-old male underwent surgical resection and chemoradiation for average risk medulloblastoma; twelve years later, the presence of a necrotic and infiltrative mass in the same area and invading the brainstem prompted a subtotal resection. Pathology was indicative of glioblastoma. He was then treated with concurrent temozolomide and using biologically effective dose calculations for gross residual tumor tissue in the brainstem as well as brainstem tolerance, a radiotherapy dose of 3750 cGy was chosen, fractionated in twice-daily fractions of 125 cGy each. The gross tumor volume was expanded with a 5 mm margin to the planning target volume, which was also judiciously subtracted from the normal brainstem. He completed his radiotherapy course with subsequent imaging free of residual tumor and continued adjuvant temozolomide and remains under follow-up surveillance. This case underscores the rarity of metachronous medulloblastoma and glioblastoma, of which only five known cases heretofore have been described. We discuss the technicalities of radiotherapy planning in this patient, including common hurdles for radiation oncologists in similar patients.

  1. Comparison of supine and prone craniospinal irradiation in children with medulloblastoma.

    Science.gov (United States)

    Verma, Jonathan; Mazloom, Ali; Teh, Bin S; South, Michael; Butler, E Brian; Paulino, Arnold C

    2015-01-01

    To compare port film rejection and treatment outcome according to craniospinal irradiation (CSI) position for medulloblastoma. We retrospectively searched for patients ≤19 years treated with CSI for medulloblastoma at 1 department. We collected the following data: age; sex; risk group; need for general anesthesia; radiation therapy (RT) dose and fractionation; and the acceptance or rejection of weekly port films during treatment. We also collected data on outcomes, including neuraxis recurrence and possible complications such as myelitis. Of 46 children identified, 23 were treated prone (median age, 8.1 years) and 23 supine (median age, 7.2 years). High-risk disease was seen in 26% of prone and 35% of supine patients (P = .25). There was no difference in use of general anesthesia between those treated prone versus supine (57% vs 61%). The rejection rate of cranial port films in the prone position was 35%, which was significantly higher than the rate of 8% in patients treated supine (P < .0001). The 5-year progression-free (P = .37) and overall survival (P = .18) rates were 62% and 67% for prone and 76% and 84% for supine patients. There were no isolated junctional failures or radiation myelitis in either CSI position. The supine position for CSI was found to have similar survival outcomes compared with the prone position. A higher proportion of rejected cranial port films was seen in children treated in the prone position. Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

  2. Tipifarnib in Treating Young Patients With Recurrent or Progressive High-Grade Glioma, Medulloblastoma, Primitive Neuroectodermal Tumor, or Brain Stem Glioma

    Science.gov (United States)

    2013-10-07

    Childhood High-grade Cerebral Astrocytoma; Childhood Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  3. [Undifferentiated soft tissue tumor with rhabdoid phenotype (extra-renal rhabdoid tumor). Report of a congenital case associated with medulloblastoma in a brother].

    Science.gov (United States)

    Costes, V; Medioni, D; Durand, L; Sarran, N; Marguerite, G; Baldet, P

    1997-03-01

    We report a case of congenital cervical rhabdoid tumor with association of a medulloblastoma in a brother. The immunohistochemical features of this tumor are compatible with a neuroectodermal differentiation (MIC 2+, Leu 7+). Extrarenal rhabdoid tumors share a common morphology but do not represent a single entity with only one histogenesis. Most of them are now considered to be of neuroectodermal origin. In our case, the association with a medulloblastoma in a brother seems to confirm this concept.

  4. Nevoid basal cell carcinoma syndrome with medulloblastoma in an African-American boy: A rare case illustrating gene-environment interaction

    Energy Technology Data Exchange (ETDEWEB)

    Korczak, J.F.; Goldstein, A.M. [National Institutes of Health, Bethesda, MD (United States); Kase, R.G. [Westat Inc., Rockville, MD (United States)] [and others

    1997-03-31

    We present an 8-year-old African-American boy with medulloblastoma and nevoid basal cell carcinoma syndrome (NBCCS) who exhibited the radiosensitive response of basal cell carcinoma (BCC) formation in the area irradiated for medulloblastoma. Such a response is well-documented in Caucasian NBCCS patients with medulloblastoma. The propositus was diagnosed with medulloblastoma at the age of 2 years and underwent surgery, chemotherapy, and craniospinal irradiation. At the age of 6 years, he was diagnosed with NBCCS following his presentation with a large odontogenic keratocyst of the mandible, pits of the palms and soles and numerous BCCs in the area of the back and neck that had been irradiated previously for medulloblastoma. Examination of other relatives showed that the propositus mother also had NBCCS but was more mildly affected; in particular, she had no BCCs. This case illustrates complex gene-environment interaction, in that increased skin pigmentation in African-Americans is presumably protective against ultraviolet, but not ionizing, radiation. This case and other similar cases in the literature show the importance of considering NBCCS in the differential diagnosis of any patient who presents with a medulloblastoma, especially before the age of 5 years, and of examining other close relatives for signs of NBCCS to determine the patient`s at-risk status. Finally, for individuals who are radiosensitive, protocols that utilize chemotherapy in lieu of radiotherapy should be considered. 27 refs., 4 figs.

  5. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

    Science.gov (United States)

    Waszak, Sebastian M; Northcott, Paul A; Buchhalter, Ivo; Robinson, Giles W; Sutter, Christian; Groebner, Susanne; Grund, Kerstin B; Brugières, Laurence; Jones, David T W; Pajtler, Kristian W; Morrissy, A Sorana; Kool, Marcel; Sturm, Dominik; Chavez, Lukas; Ernst, Aurelie; Brabetz, Sebastian; Hain, Michael; Zichner, Thomas; Segura-Wang, Maia; Weischenfeldt, Joachim; Rausch, Tobias; Mardin, Balca R; Zhou, Xin; Baciu, Cristina; Lawerenz, Christian; Chan, Jennifer A; Varlet, Pascale; Guerrini-Rousseau, Lea; Fults, Daniel W; Grajkowska, Wiesława; Hauser, Peter; Jabado, Nada; Ra, Young-Shin; Zitterbart, Karel; Shringarpure, Suyash S; De La Vega, Francisco M; Bustamante, Carlos D; Ng, Ho-Keung; Perry, Arie; MacDonald, Tobey J; Hernáiz Driever, Pablo; Bendel, Anne E; Bowers, Daniel C; McCowage, Geoffrey; Chintagumpala, Murali M; Cohn, Richard; Hassall, Timothy; Fleischhack, Gudrun; Eggen, Tone; Wesenberg, Finn; Feychting, Maria; Lannering, Birgitta; Schüz, Joachim; Johansen, Christoffer; Andersen, Tina V; Röösli, Martin; Kuehni, Claudia E; Grotzer, Michael; Kjaerheim, Kristina; Monoranu, Camelia M; Archer, Tenley C; Duke, Elizabeth; Pomeroy, Scott L; Shelagh, Redmond; Frank, Stephan; Sumerauer, David; Scheurlen, Wolfram; Ryzhova, Marina V; Milde, Till; Kratz, Christian P; Samuel, David; Zhang, Jinghui; Solomon, David A; Marra, Marco; Eils, Roland; Bartram, Claus R; von Hoff, Katja; Rutkowski, Stefan; Ramaswamy, Vijay; Gilbertson, Richard J; Korshunov, Andrey; Taylor, Michael D; Lichter, Peter; Malkin, David; Gajjar, Amar; Korbel, Jan O; Pfister, Stefan M

    2018-06-01

    Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MB WNT ), SHH (MB SHH ), group 3 (MB Group3 ), and group 4 (MB Group4 ). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105

  6. Differential prefrontal-like deficit in children after cerebellar astrocytoma and medulloblastoma tumor

    Directory of Open Access Journals (Sweden)

    Quintero Eliana A

    2008-04-01

    Full Text Available Abstract Background This study was realized thanks to the collaboration of children and adolescents who had been resected from cerebellar tumors. The medulloblastoma group (CE+, n = 7 in addition to surgery received radiation and chemotherapy. The astrocytoma group (CE, n = 13 did not receive additional treatments. Each clinical group was compared in their executive functioning with a paired control group (n = 12. The performances of the clinical groups with respect to controls were compared considering the tumor's localization (vermis or hemisphere and the affectation (or not of the dentate nucleus. Executive variables were correlated with the age at surgery, the time between surgery-evaluation and the resected volume. Methods The executive functioning was assessed by means of WCST, Complex Rey Figure, Controlled Oral Word Association Test (letter and animal categories, Digits span (WISC-R verbal scale and Stroop test. These tests are very sensitive to dorsolateral PFC and/or to medial frontal cortex functions. The scores for the non-verbal Raven IQ were also obtained. Direct scores were corrected by age and transformed in standard scores using normative data. The neuropsychological evaluation was made at 3.25 (SD = 2.74 years from surgery in CE group and at 6.47 (SD = 2.77 in CE+ group. Results The Medulloblastoma group showed severe executive deficit (≤ 1.5 SD below normal mean in all assessed tests, the most severe occurring in vermal patients. The Astrocytoma group also showed executive deficits in digits span, semantic fluency (animal category and moderate to slight deficit in Stroop (word and colour tests. In the astrocytoma group, the tumor's localization and dentate affectation showed different profile and level of impairment: moderate to slight for vermal and hemispheric patients respectively. The resected volume, age at surgery and the time between surgery-evaluation correlated with some neuropsychological executive variables

  7. Comparison of therapeutic dosimetric data from passively scattered proton and photon craniospinal irradiations for medulloblastoma

    Directory of Open Access Journals (Sweden)

    Howell Rebecca M

    2012-07-01

    Full Text Available Abstract Background For many decades, the standard of care radiotherapy regimen for medulloblastoma has been photon (megavoltage x-rays craniospinal irradiation (CSI. The late effects associated with CSI are well-documented in the literature and are in-part attributed to unwanted dose to healthy tissue. Recently, there is growing interest in using proton therapy for CSI in pediatric and adolescent patients to reduce this undesirable dose. Previous comparisons of dose to target and non-target organs from conventional photon CSI and passively scattered proton CSI have been limited to small populations (n ≤ 3 and have not considered the use of age-dependent target volumes in proton CSI. Methods Standard of care treatment plans were developed for both photon and proton CSI for 18 patients. This cohort included both male and female medulloblastoma patients whose ages, heights, and weights spanned a clinically relevant and representative spectrum (age 2–16, BMI 16.4–37.9 kg/m2. Differences in plans were evaluated using Wilcoxon signed rank tests for various dosimetric parameters for the target volumes and normal tissue. Results Proton CSI improved normal tissue sparing while also providing more homogeneous target coverage than photon CSI for patients across a wide age and BMI spectrum. Of the 24 parameters (V5, V10, V15, and V20 in the esophagus, heart, liver, thyroid, kidneys, and lungs Wilcoxon signed rank test results indicated 20 were significantly higher for photon CSI compared to proton CSI (p ≤ 0.05 . Specifically, V15 and V20 in all six organs and V5, V10 in the esophagus, heart, liver, and thyroid were significantly higher with photon CSI. Conclusions Our patient cohort is the largest, to date, in which CSI with proton and photon therapies have been compared. This work adds to the body of literature that proton CSI reduces dose to normal tissue compared to photon CSI for pediatric patients who are at substantial risk for

  8. Comparison of therapeutic dosimetric data from passively scattered proton and photon craniospinal irradiations for medulloblastoma

    International Nuclear Information System (INIS)

    Howell, Rebecca M; Giebeler, Annelise; Koontz-Raisig, Wendi; Mahajan, Anita; Etzel, Carol J; D’Amelio, Anthony M Jr; Homann, Kenneth L

    2012-01-01

    For many decades, the standard of care radiotherapy regimen for medulloblastoma has been photon (megavoltage x-rays) craniospinal irradiation (CSI). The late effects associated with CSI are well-documented in the literature and are in-part attributed to unwanted dose to healthy tissue. Recently, there is growing interest in using proton therapy for CSI in pediatric and adolescent patients to reduce this undesirable dose. Previous comparisons of dose to target and non-target organs from conventional photon CSI and passively scattered proton CSI have been limited to small populations (n ≤ 3) and have not considered the use of age-dependent target volumes in proton CSI. Standard of care treatment plans were developed for both photon and proton CSI for 18 patients. This cohort included both male and female medulloblastoma patients whose ages, heights, and weights spanned a clinically relevant and representative spectrum (age 2–16, BMI 16.4–37.9 kg/m2). Differences in plans were evaluated using Wilcoxon signed rank tests for various dosimetric parameters for the target volumes and normal tissue. Proton CSI improved normal tissue sparing while also providing more homogeneous target coverage than photon CSI for patients across a wide age and BMI spectrum. Of the 24 parameters (V 5 , V 10 , V 15 , and V 20 in the esophagus, heart, liver, thyroid, kidneys, and lungs) Wilcoxon signed rank test results indicated 20 were significantly higher for photon CSI compared to proton CSI (p ≤ 0.05) . Specifically, V 15 and V 20 in all six organs and V 5 , V 10 in the esophagus, heart, liver, and thyroid were significantly higher with photon CSI. Our patient cohort is the largest, to date, in which CSI with proton and photon therapies have been compared. This work adds to the body of literature that proton CSI reduces dose to normal tissue compared to photon CSI for pediatric patients who are at substantial risk for developing radiogenic late effects. Although the present study

  9. Cerebellopontine angle medulloblastoma with extensive nodularity in a child: case report and review of the literature.

    Science.gov (United States)

    Noiphithak, Raywat; Yindeedej, Vich; Thamwongskul, Chatchai

    2017-05-01

    Cerebellar medulloblastomas (MBs) are one of the most common posterior fossa tumors in children but rarely occur in the cerebellopontine angle (CPA). Only 39 cases of CPA MBs were reported in the literature, and most of them were classic and desmoplastic MBs. A 22-month-old girl presented with progressive cerebellar ataxia. Magnetic resonance imaging showed a large tumor in the right CPA and obstructive hydrocephalus. Surgical resection was performed and achieved total tumor removal. Microscopic examination and immunohistochemical staining revealed the diagnosis of MB with extensive nodularity. The patient recovered from her symptoms during follow-up and was transferred for adjuvant chemotherapy. MB should be considered as a differential diagnosis of a lesion in the CPA. The treatment and outcome of CPA MBs are similar to cerebellar MBs.

  10. Synchronous glioblastoma and medulloblastoma in a child with mismatch repair mutation.

    Science.gov (United States)

    Amayiri, Nisreen; Al-Hussaini, Maysa; Swaidan, Maisa; Jaradat, Imad; Qandeel, Monther; Tabori, Uri; Hawkins, Cynthia; Musharbash, Awni; Alsaad, Khulood; Bouffet, Eric

    2016-03-01

    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.

  11. An adult multifocal medulloblastoma with diffuse acute postoperative cerebellar swelling: immunohistochemical and molecular genetics analysis.

    Science.gov (United States)

    Balik, Vladimir; Trojanec, Radek; Holzerova, Milena; Tuckova, Lucie; Sulla, Igor; Megova, Magdalena; Vaverka, Miroslav; Hrabalek, Lumir; Ehrmann, Jiri

    2015-01-01

    Medulloblastoma (MB), the most common malignant tumor typically affecting children, occurs only exceptionally in adults. Multifocal presentation of this malignancy in adulthood is even much rarer—only four cases with favorable postoperative course have been reported, so far. The study illustrates a very rare rapid postoperative clinical deterioration due to diffuse cerebellar swelling (DCS) in an adult multifocal MB (MMB). To the best of their knowledge, authors for the first time performed genetic analysis of MMB and demonstrated expression patterns of selected markers that put the patient within the sonic hedgehog (SHH) molecular subgroup and at least partially explain her unsatisfactory clinical course. Herein, authors summarized the relevant literature concerning this issue with the aim to determine features that would facilitate diagnosis and therapy of such a scarce clinical entity.

  12. Contrast enhanced MR imaging of postoperative medulloblastoma in childhood: emphasis on meningeal enhancement

    International Nuclear Information System (INIS)

    Choi, Choong Gon; Kim, In One; Kim, Woo Sun; Kim, Ho Chul; Yeon, Kyung Mo

    1993-01-01

    To differentiate the postoperative changes from the recurrence of tumor and to evaluate MR imaging of early postoperative leptomeningeal seeding in medulloblastoma, We have retrospectively analysed 34 cases of MR images of 17 patients who were confirmed as medulloblastoma by histopathology. Noncontrast and postcontrast T1 weighted MR images were obtained in all patients. In 11 patients follow-up MR was done more than once (average: 1.5 times) and average interval of MR imaging was 6 months. The timing of 34 MR images was as follow: 6 case within 2 months, 9 cases between 2 months and 1 year, 19 cases more than 1 year after surgery respectively. MR images within 2 month after surgery revealed contrast enhancement at operation site and adjacent meninges, hemorrhage, residual tumor. In patients who had no evidence of tumor recurrence, these early postoperative changes were markedly decreased within 6 month after surgery. MR images obtained more than 1 year after surgery showed no abnormal contrast enhancement or mild focal dural enhancement at operation site. Diffuse moderate dural enhancement was noted in one patient who had the history of post-surgical subdural hemorrhage. In six patients with tumor recurrences which were detected from as early as 9 months to 6 years after surgery, the findings of recurrence included leptomeningeal enhancement of brain stem and cerebellar surface at early stage, variable sized enhancing leptomeningeal nodules, linear or irregular sulcus obliterating enhancing lesions, enhancing mass at primary or metastatic site. We have concluded that leptomeningeal enhancement detected after 6 months of surgery is an important MR finding suggesting the possibility of tumor recurrence. Small nodular and linear enhancement of leptomeninges at brainstem or cerebellar surface is considered as the early manifestation of intracranial tumor seeding

  13. Long-term effects of whole brain radiation on intellectual function in children with medulloblastoma

    International Nuclear Information System (INIS)

    Uozumi, Akimasa; Okimura, Yoshitaka; Ohsato, Katsunobu; Yamaura, Akira; Hasegawa, Keiko

    1992-01-01

    Neuropsychological tests were administered to four children 4 to 10 years after treatment of medulloblastoma with surgery, radiation, and natural alpha-interferon. The age at the time of treatment ranged from 2 years and 4 months to 11 years. The radiation doses were 26-34 Gy to the whole brain, 48-52 Gy to the posterior fossa and 26-34 Gy to the whole spine. Uneventful follow-up periods ranged from 4 years and 8 months to 10 years and 6 months. At present they attend regular classes at local schools. The neuropsychological tests used were: Wechsler Intelligence Scale for Children-Revised (WISC-R), Frostig developmental test of visual perception and Uchida-Kraepelin psychometric test. The WISC-R showed a marked decrease of full-scale IQ in two of the four children (scores of 72 and 73). Their performance IQ scores were significantly lower than their verbal scores. This may reflect less ability to manage visual and spatial information than verbal information. The other two patients had full-scale IQ scores of 91 and 92 (within the normal range). The test of visual perception showed decreased ability in the three patients who were younger than 8 years, of age at the time of treatment but normal ability in the child who had been treated at 11 years of age. The Uchida-Kraepelin test showed reduced amounts of work accomplished and poor learning ability in all four patients. These findings suggest that intellectual function in children with medulloblastoma is affected by the failure of visual perception to develop normally because of whole brain radiation at an early age and that their problem is aggravated by secondary learning difficulties. It is necessary to provide these patients with individual learning programs based on the results of neuropsychological evaluations. (author)

  14. Contrast enhanced MR imaging of postoperative medulloblastoma in childhood: emphasis on meningeal enhancement

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Choong Gon; Kim, In One; Kim, Woo Sun; Kim, Ho Chul; Yeon, Kyung Mo [College of Medicine, Seoul National University, Seoul (Korea, Republic of)

    1993-03-15

    To differentiate the postoperative changes from the recurrence of tumor and to evaluate MR imaging of early postoperative leptomeningeal seeding in medulloblastoma, We have retrospectively analysed 34 cases of MR images of 17 patients who were confirmed as medulloblastoma by histopathology. Noncontrast and postcontrast T1 weighted MR images were obtained in all patients. In 11 patients follow-up MR was done more than once (average: 1.5 times) and average interval of MR imaging was 6 months. The timing of 34 MR images was as follow: 6 case within 2 months, 9 cases between 2 months and 1 year, 19 cases more than 1 year after surgery respectively. MR images within 2 month after surgery revealed contrast enhancement at operation site and adjacent meninges, hemorrhage, residual tumor. In patients who had no evidence of tumor recurrence, these early postoperative changes were markedly decreased within 6 month after surgery. MR images obtained more than 1 year after surgery showed no abnormal contrast enhancement or mild focal dural enhancement at operation site. Diffuse moderate dural enhancement was noted in one patient who had the history of post-surgical subdural hemorrhage. In six patients with tumor recurrences which were detected from as early as 9 months to 6 years after surgery, the findings of recurrence included leptomeningeal enhancement of brain stem and cerebellar surface at early stage, variable sized enhancing leptomeningeal nodules, linear or irregular sulcus obliterating enhancing lesions, enhancing mass at primary or metastatic site. We have concluded that leptomeningeal enhancement detected after 6 months of surgery is an important MR finding suggesting the possibility of tumor recurrence. Small nodular and linear enhancement of leptomeninges at brainstem or cerebellar surface is considered as the early manifestation of intracranial tumor seeding.

  15. Long-term effects of whole brain radiation on intellectual function in children with medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Uozumi, Akimasa; Okimura, Yoshitaka; Ohsato, Katsunobu; Yamaura, Akira; Hasegawa, Keiko (Chiba Univ. (Japan). School of Medicine)

    1992-10-01

    Neuropsychological tests were administered to four children 4 to 10 years after treatment of medulloblastoma with surgery, radiation, and natural alpha-interferon. The age at the time of treatment ranged from 2 years and 4 months to 11 years. The radiation doses were 26-34 Gy to the whole brain, 48-52 Gy to the posterior fossa and 26-34 Gy to the whole spine. Uneventful follow-up periods ranged from 4 years and 8 months to 10 years and 6 months. At present they attend regular classes at local schools. The neuropsychological tests used were: Wechsler Intelligence Scale for Children-Revised (WISC-R), Frostig developmental test of visual perception and Uchida-Kraepelin psychometric test. The WISC-R showed a marked decrease of full-scale IQ in two of the four children (scores of 72 and 73). Their performance IQ scores were significantly lower than their verbal scores. This may reflect less ability to manage visual and spatial information than verbal information. The other two patients had full-scale IQ scores of 91 and 92 (within the normal range). The test of visual perception showed decreased ability in the three patients who were younger than 8 years, of age at the time of treatment but normal ability in the child who had been treated at 11 years of age. The Uchida-Kraepelin test showed reduced amounts of work accomplished and poor learning ability in all four patients. These findings suggest that intellectual function in children with medulloblastoma is affected by the failure of visual perception to develop normally because of whole brain radiation at an early age and that their problem is aggravated by secondary learning difficulties. It is necessary to provide these patients with individual learning programs based on the results of neuropsychological evaluations. (author).

  16. Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma.

    Science.gov (United States)

    Mascaro-Cordeiro, Bruna; Oliveira, Indhira Dias; Tesser-Gamba, Francine; Pavon, Lorena Favaro; Saba-Silva, Nasjla; Cavalheiro, Sergio; Dastoli, Patrícia; Toledo, Silvia Regina Caminada

    2018-05-22

    Histone deacetylate inhibitors (HDACi), as valproic acid (VA), have been reported to enhance efficacy and to prevent drug resistance in some tumors, including medulloblastoma (MB). In the present study, we investigated VA role, combined to cisplatin (CDDP) in cell viability and gene expression of MB cell lines. Dose-response curve determined IC 50 values for each treatment: (1) VA single, (2) CDDP single, and (3) VA and CDDP combined. Cytotoxicity and flow cytometry evaluated cell viability after exposure to treatments. Quantitative PCR evaluated gene expression levels of AKT, CTNNB1, GLI1, KDM6A, KDM6B, NOTCH2, PTCH1, and TERT, before and after treatment. Besides, we performed next-generation sequencing (NGS) for PTCH1, TERT, and TP53 genes. The most effective treatment to reduce viability was combined for D283MED and ONS-76; and CDDP single for DAOY cells (p AKT genes were overexpressed after treatments with VA. D283MED and ONS-76 cells presented variants in TERT and PTCH1, respectively and DAOY cell line presented a TP53 mutation. MB tumors belonging to SHH molecular subgroup, with TP53 MUT , would be the ones that present high risk in relation to VA use during the treatment, while TP53 WT MBs can benefit from VA therapy, both SHH and groups 3 and 4. Our study shows a new perspective about VA action in medulloblastoma cells, raising the possibility that VA may act in different patterns. According to the genetic background of MB cell, VA can stimulate cell cycle arrest and apoptosis or induce resistance to treatment via signaling pathways activation.

  17. Mental and growth retardation after medulloblastoma radiation therapy. MRI assessment of radiation injuries

    International Nuclear Information System (INIS)

    Miyagi, Koichi; Mukawa, Jiro; Mekaru, Susumu; Harakuni, Tsuyoshi; Yamaguchi, Keiichiro; Tominaga, Daisuke; Nakasone, Susumu.

    1996-01-01

    We report on 3 cases of a medulloblastoma and discuss the usefulness of calculating the T2 value from long-term follow-up MRIs of 1.5 T in order to analyze the cause of mental retardation. Of 13 medulloblastoma patients who were treated at our hospital from 1970 through 1984, 4 patients survived. Excluding 1 of these patients, a 2-year-old child, the remaining 3 cases are discussed. The 3 patients underwent surgery and received postoperative craniospinal irradiation and chemotherapy. The radiation dose (tumoral dose) was 40 to 85 Gy to the posterior fossa, 0 to 30.4 Gy to the spinal cord, and 25.6 to 35.2 Gy to the whole brain. The long-term effects were evaluated by calculating the T2 value and conducting a psychometric analysis from 2 to 11 years after radiation therapy. Their respective Tanaka-Vineland IQ test results were 32, 46, and 102 and their respective growth heights were -3.6 SD, -6.4 SD, and +0.18 SD. Growth hormone deficiencies were identified in all 3 patients. The decline in ability and failure to grow became more pronounced with time. The calculated T2 values showed alterations in the hippocampus, the occipital white matter, and the hypothalamus of all 3 patients. The hippocampal alteration contributed to a decline in intellectual ability and resulted in learning difficulties at school. It should be noted that in addition to whole-brain radiation that was pursued, the focal radiation provided delivers the same radiation dose to the hippocampus as to the tumor. Such a high radiation dose thus might be responsible for the decline in intellectual ability. Therefore, to avoid radiation injury to these areas, stereotactic radiosurgery must be planned for focal radiation therapy. (K.H.)

  18. Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity

    International Nuclear Information System (INIS)

    Huang, Eugene; Teh, Bin S.; Strother, Douglas R.; Davis, Quillin G.; Chiu, J. Kam; Lu, Hsin H.; Carpenter, L. Steven; Mai Weiyuan; Chintagumpala, Murali M.; South, Michael; Grant, Walter H. III; Butler, E. Brian; Woo, Shiao Y.

    2002-01-01

    Purpose: The combination of cisplatin chemotherapy and radiation therapy for the treatment of medulloblastoma has been shown to cause significant ototoxicity, impairing a child's cognitive function and quality of life. Our purpose is to determine whether the new conformal technique of intensity-modulated radiation therapy (IMRT) can achieve lower rates of hearing loss by decreasing the radiation dose delivered to the cochlea and eighth cranial nerve (auditory apparatus). Patients and Methods: Twenty-six pediatric patients treated for medulloblastoma were retrospectively divided into two groups that received either conventional radiotherapy (Conventional-RT Group) or IMRT (IMRT Group). One hundred thirteen pure-tone audiograms were evaluated retrospectively, and hearing function was graded on a scale of 0 to 4 according to the Pediatric Oncology Group's toxicity criteria. Statistical analysis comparing the rates of ototoxicity was performed using Fisher's exact test with two-tailed analysis. Results: When compared to conventional radiotherapy, IMRT delivered 68% of the radiation dose to the auditory apparatus (mean dose: 36.7 vs. 54.2 Gy). Audiometric evaluation showed that mean decibel hearing thresholds of the IMRT Group were lower at every frequency compared to those of the Conventional-RT Group, despite having higher cumulative doses of cisplatin. The overall incidence of ototoxicity was lower in the IMRT Group. Thirteen percent of the IMRT Group had Grade 3 or 4 hearing loss, compared to 64% of the Conventional-RT Group (p<0.014). Conclusion: The conformal technique of IMRT delivered much lower doses of radiation to the auditory apparatus, while still delivering full doses to the desired target volume. Our findings suggest that, despite higher doses of cisplatin, and despite radiotherapy before cisplatin therapy, treatment with IMRT can achieve a lower rate of hearing loss

  19. Medulloblastoma subgroup-specific outcomes in irradiated children: who are the true high-risk patients?

    Science.gov (United States)

    Ramaswamy, Vijay; Remke, Marc; Adamski, Jennifer; Bartels, Ute; Tabori, Uri; Wang, Xin; Huang, Annie; Hawkins, Cynthia; Mabbott, Donald; Laperriere, Normand; Taylor, Michael D; Bouffet, Eric

    2016-02-01

    The advent of integrated genomics has fundamentally changed our understanding of medulloblastoma. Although survival differences exist among the 4 principal subgroups, this has yet to be elucidated in a North American cohort of irradiated patients. Ninety-two consecutive patients between the ages of 3 and 17 treated with surgery, craniospinal irradiation, and chemotherapy were identified at the Hospital for Sick Children. Molecular subgrouping was performed using nanoString. Two treatment periods were identified: prior to 2006 as per the protocols of the Children's Oncology Group, and after 2006 per the St Jude Medulloblastoma 03 protocol. Five-year progression-free survival (PFS) over the entire cohort was 0.801 (95% CI: 0.692-0.875) with no significant difference between treatment protocols. Strikingly, we found that Group 4 patients had excellent 5-year PFS of 0.959 (95% CI: 0.744-0.994) for average risk and 0.887 (95% CI: 0.727-0.956) across all Group 4 patients. Group 3 patients had 5-year PFS of 0.733 (95% CI: 0.436-0.891). Sonic hedgehog patients did poorly across both treatment protocols, with 5-year PFS of 0.613 (95% CI: 0.333-0.804), likely owing to a high proportion of TP53 mutated patients in this age group. In a cohort of irradiated patients over 3 years of age, PFS for Group 4 patients was significantly improved compared with initial reports. The impact of subgroup affiliation in these children needs to be assessed in large prospectively treated cooperative protocols to determine if more than just WNT patients can be safely selected for de-escalation of therapy. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. 111In-Pentetreotide scintigraphy in medulloblastoma: A comparison with magnetic resonance imaging

    International Nuclear Information System (INIS)

    Yueksel, Mahmut; Lutterbey, Goetz; Biersack, Hans Juergen; Elke, Urs; Ezziddin, Samer; Hasan, Carola; Bode, Udo; Zairong Gao

    2007-01-01

    Medulloblastoma (MB) is a primitive neuroectodermal tumour constituting a grade IV brain malignancy. Early and correct detection of recurrence or metastasis is desirable for follow-up of patients in this entity. Frequent expression of somatostatin receptors by MB lesions facilitates functional tumour imaging by somatostatin receptor scintigraphy (SRS). To investigate the value of SRS in the follow-up of MB, the results of ten consecutive patients (seven children and three adults) undergoing additional imaging with 111 In-pentetreotide were reviewed. Four, 24 and 48 h p.i. planar and whole body images as well as a SPECT study at 4 h p.i. were acquired after intravenous injection of 109±35 MBq 111 In-pentetreotide (Octreoscan). SRS yielded 11 positive and ten negative imaging results, compared to 17 positive and four negative in magnetic resonance imaging (MRI). The lesion-by-lesion analysis with a total of 44 lesions revealed a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 42%, 83%, 94%, 18% for SRS and 89.5%, 50%, 92%, 43% for MRI. Based on a per-patient analysis, considering the patient as to be either tumour-free or tumour-positive by one imaging modality, the following values for sensitivity, specificity, PPV and NPV were obtained: 61%, 100%, 100%, 30% for SRS and 94%, 67%, 94%, 67% for MRI. MRI remains the first step imaging technique in medulloblastoma patients before and after surgery and during the follow-up providing the highest sensitivity. However, to improve specificity and contribute to correct diagnosis in MB 111 In-pentetreotide scintigraphy should be considered as a confirmatory second step imaging tool, especially in case of equivocal MRI results. Moreover, a positive SRS scan might serve as a reference before and after somatostatin receptor targeted radiotherapy

  1. Musashi1 modulates cell proliferation genes in the medulloblastoma cell line Daoy

    Directory of Open Access Journals (Sweden)

    Hung Jaclyn Y

    2008-09-01

    Full Text Available Abstract Background Musashi1 (Msi1 is an RNA binding protein with a central role during nervous system development and stem cell maintenance. High levels of Msi1 have been reported in several malignancies including brain tumors thereby associating Msi1 and cancer. Methods We used the human medulloblastoma cell line Daoy as model system in this study to knock down the expression of Msi1 and determine the effects upon soft agar growth and neurophere formation. Quantitative RT-PCR was conducted to evaluate the expression of cell proliferation, differentiation and survival genes in Msi1 depleted Daoy cells. Results We observed that MSI1 expression was elevated in Daoy cells cultured as neurospheres compared to those grown as monolayer. These data indicated that Msi1 might be involved in regulating proliferation in cancer cells. Here we show that shRNA mediated Msi1 depletion in Daoy cells notably impaired their ability to form colonies in soft agar and to grow as neurospheres in culture. Moreover, differential expression of a group of Notch, Hedgehog and Wnt pathway related genes including MYCN, FOS, NOTCH2, SMO, CDKN1A, CCND2, CCND1, and DKK1, was also found in the Msi1 knockdown, demonstrating that Msi1 modulated the expression of a subset of cell proliferation, differentiation and survival genes in Daoy. Conclusion Our data suggested that Msi1 may promote cancer cell proliferation and survival as its loss seems to have a detrimental effect in the maintenance of medulloblastoma cancer cells. In this regard, Msi1 might be a positive regulator of tumor progression and a potential target for therapy.

  2. Hippocampal sparing radiotherapy for pediatric medulloblastoma: impact of treatment margins and treatment technique.

    Science.gov (United States)

    Brodin, N Patrik; Munck af Rosenschöld, Per; Blomstrand, Malin; Kiil-Berthlesen, Anne; Hollensen, Christian; Vogelius, Ivan R; Lannering, Birgitta; Bentzen, Søren M; Björk-Eriksson, Thomas

    2014-04-01

    We investigated how varying the treatment margin and applying hippocampal sparing and proton therapy impact the risk of neurocognitive impairment in pediatric medulloblastoma patients compared with current standard 3D conformal radiotherapy. We included 17 pediatric medulloblastoma patients to represent the variability in tumor location relative to the hippocampal region. Treatment plans were generated using 3D conformal radiotherapy, hippocampal sparing intensity-modulated radiotherapy, and spot-scanned proton therapy, using 3 different treatment margins for the conformal tumor boost. Neurocognitive impairment risk was estimated based on dose-response models from pediatric CNS malignancy survivors and compared among different margins and treatment techniques. Mean hippocampal dose and corresponding risk of cognitive impairment were decreased with decreasing treatment margins (P < .05). The largest risk reduction, however, was seen when applying hippocampal sparing proton therapy-the estimated risk of impaired task efficiency (95% confidence interval) was 92% (66%-98%), 81% (51%-95%), and 50% (30%-70%) for 3D conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy, respectively, for the smallest boost margin and 98% (78%-100%), 90% (60%-98%), and 70% (39%-90%) if boosting the whole posterior fossa. Also, the distance between the closest point of the planning target volume and the center of the hippocampus can be used to predict mean hippocampal dose for a given treatment technique. We estimate a considerable clinical benefit of hippocampal sparing radiotherapy. In choosing treatment margins, the tradeoff between margin size and risk of neurocognitive impairment quantified here should be considered.

  3. Electromagnetic navigation-guided neuroendoscopic removal of radiation-induced intraforniceal cavernoma as a late complication of medulloblastoma treatment.

    Science.gov (United States)

    Liby, Petr; Zamecnik, J; Kyncl, M; Zackova, J; Tichy, M

    2017-11-01

    Medulloblastoma is the most frequent malignant brain tumour in children. Radiation-induced cavernous haemangiomas (RICHs) are a known late complication of radiation exposure, especially in young children. We present a patient who underwent subtotal resection of posterior fossa medulloblastoma with subsequent chemotherapy and radiotherapy at the age of 10 years. A new lesion in the region of the left foramen of Monro appeared 16 years later. Based on the imaging results, metastasis or radiation-induced cavernoma was considered. The lesion had the same appearance on imaging as a rarely published intraventricular cavernoma of the foramen of Monro. Unlike the cavernoma of the foramen of Monro, this lesion was subependymal and intraforniceal. Using electromagnetic navigation and neuroendoscopy, the lesion was completely removed. Histopathological examination revealed a cavernous haemangioma. This is a unique case of intraforniceal paraforaminal cavernoma that was successfully removed endoscopically using electromagnetic neuronavigation and without neurological sequelae.

  4. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

    Science.gov (United States)

    Thompson, Eric M; Hielscher, Thomas; Bouffet, Eric; Remke, Marc; Luu, Betty; Gururangan, Sridharan; McLendon, Roger E; Bigner, Darell D; Lipp, Eric S; Perreault, Sebastien; Cho, Yoon-Jae; Grant, Gerald; Kim, Seung-Ki; Lee, Ji Yeoun; Rao, Amulya A Nageswara; Giannini, Caterina; Li, Kay Ka Wai; Ng, Ho-Keung; Yao, Yu; Kumabe, Toshihiro; Tominaga, Teiji; Grajkowska, Wieslawa A; Perek-Polnik, Marta; Low, David C Y; Seow, Wan Tew; Chang, Kenneth T E; Mora, Jaume; Pollack, Ian F; Hamilton, Ronald L; Leary, Sarah; Moore, Andrew S; Ingram, Wendy J; Hallahan, Andrew R; Jouvet, Anne; Fèvre-Montange, Michelle; Vasiljevic, Alexandre; Faure-Conter, Cecile; Shofuda, Tomoko; Kagawa, Naoki; Hashimoto, Naoya; Jabado, Nada; Weil, Alexander G; Gayden, Tenzin; Wataya, Takafumi; Shalaby, Tarek; Grotzer, Michael; Zitterbart, Karel; Sterba, Jaroslav; Kren, Leos; Hortobágyi, Tibor; Klekner, Almos; László, Bognár; Pócza, Tímea; Hauser, Peter; Schüller, Ulrich; Jung, Shin; Jang, Woo-Youl; French, Pim J; Kros, Johan M; van Veelen, Marie-Lise C; Massimi, Luca; Leonard, Jeffrey R; Rubin, Joshua B; Vibhakar, Rajeev; Chambless, Lola B; Cooper, Michael K; Thompson, Reid C; Faria, Claudia C; Carvalho, Alice; Nunes, Sofia; Pimentel, José; Fan, Xing; Muraszko, Karin M; López-Aguilar, Enrique; Lyden, David; Garzia, Livia; Shih, David J H; Kijima, Noriyuki; Schneider, Christian; Adamski, Jennifer; Northcott, Paul A; Kool, Marcel; Jones, David T W; Chan, Jennifer A; Nikolic, Ana; Garre, Maria Luisa; Van Meir, Erwin G; Osuka, Satoru; Olson, Jeffrey J; Jahangiri, Arman; Castro, Brandyn A; Gupta, Nalin; Weiss, William A; Moxon-Emre, Iska; Mabbott, Donald J; Lassaletta, Alvaro; Hawkins, Cynthia E; Tabori, Uri; Drake, James; Kulkarni, Abhaya; Dirks, Peter; Rutka, James T; Korshunov, Andrey; Pfister, Stefan M; Packer, Roger J; Ramaswamy, Vijay; Taylor, Michael D

    2016-04-01

    Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival

  5. Severe vincristine-induced polyneuropathy in a teenager with anaplastic medulloblastoma and undiagnosed Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Aghajan, Yasmin; Yoon, Janet M; Crawford, John Ross

    2017-04-24

    Severe neuropathy is a known adverse effect of vincristine in patients with Charcot-Marie-Tooth disease (CMT). We present the case of a 16-year-old girl with anaplastic medulloblastoma treated with gross total resection and high-dose craniospinal radiation with adjuvant vincristine chemotherapy who developed acute-onset severe quadriplegia and vocal cord paralysis. Vincristine and radiation therapy were discontinued. Although her neuropathy slowly improved over several weeks, she developed metastatic extraneural medulloblastoma and died 5 months after diagnosis. Subsequent genetic testing revealed previously asymptomatic and undiagnosed CMT1A. Our case highlights the importance of early recognition of acute vincristine neurotoxicity that should raise suspicion of an underlying hereditary neuropathy. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  6. Metastatic Group 3 Medulloblastoma in a Patient With Tuberous Sclerosis Complex: Case Description and Molecular Characterization of the Tumor.

    Science.gov (United States)

    Moavero, Romina; Folgiero, Valentina; Carai, Andrea; Miele, Evelina; Ferretti, Elisabetta; Po, Agnese; Diomedi Camassei, Francesca; Lepri, Francesca Romana; Vigevano, Federico; Curatolo, Paolo; Valeriani, Massimiliano; Colafati, Giovanna S; Locatelli, Franco; Tornesello, Assunta; Mastronuzzi, Angela

    2016-04-01

    Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment-induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; H&E, haematoxilin and eosin; Gd, gadolinium. © 2015 Wiley Periodicals, Inc.

  7. Large cell/anaplastic medulloblastoma with myogenic, melanotic and neuronal differentiation: A case report of a rare tumor

    Directory of Open Access Journals (Sweden)

    Amany A. Fathaddin

    2014-01-01

    Full Text Available Medulloblastoma is an embryonal neuroepithelial tumor of the cerebellum and is the most common malignant central nervous system tumor in children. Different histological variants and patterns have been described. The classic variant represents the majority of cases. This report describes a rare case of large cell/anaplastic medulloblastoma with myogenic, melanotic and neuronal differentiation arising in the cerebellum of a 3-year-old boy who presented with headache and vomiting. Magnetic resonance imaging demonstrated a heterogeneously enhanced lesion in the fourth ventricle. Surgical resection of the tumor was accomplished, but a residual tumor was left behind because of the involvement of the brainstem. Postoperatively, the patient received chemotherapy and radiotherapy. Currently, 20 months after treatment, the patient has survived without further progression. Pathological examination revealed a high grade primitive neuronal tumor with foci of myogenic features, melanin containing epithelial elements and ganglion-like cells, which were confirmed by immunohistochemistry.

  8. Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses.

    Science.gov (United States)

    Friedman, Gregory K; Moore, Blake P; Nan, Li; Kelly, Virginia M; Etminan, Tina; Langford, Catherine P; Xu, Hui; Han, Xiaosi; Markert, James M; Beierle, Elizabeth A; Gillespie, G Yancey

    2016-02-01

    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. 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. 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. Pediatric medulloblastoma, including Group 3 tumors, may be an excellent target for oHSV virotherapy, and a clinical trial in medulloblastoma is warranted. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. MR signal of the solid portion of pilocytic astrocytoma on T2-weighted images: is it useful for differentiation from medulloblastoma?

    International Nuclear Information System (INIS)

    Arai, Kiyokazu; Yagi, Akiko; Taketomi-Takahashi, Ayako; Morita, Hideo; Koyama, Yoshinori; Endo, Keigo; Sato, Noriko; Aoki, Jun; Oba, Hiroshi; Ishiuchi, Shogo; Saito, Nobuhito

    2006-01-01

    Background and purpose: Although imaging features of cerebellar pilocytic astrocytoma and medulloblastoma have been described in many texts, original comparisons of magnetic resonance intensity between these two tumours are limited. In the present study the results of magnetic resonance imaging (MRI) were reviewed, focusing especially on the signal intensity of the solid portion of these neoplasms. Methods: MR images of ten cerebellar pilocytic astrocytomas and ten medulloblastomas were reviewed. The signal intensities of the solid components were graded on a scale of 1 to 5, with higher scores indicating a signal intensity closer to that of water. The degree of enhancement, tumour cysts and peripheral oedema were evaluated on MR images. When the solid portion was heterogeneous (i.e. mixed signal intensity or degree of enhancement), the dominant area was selected for evaluation. On T2-weighted images, the signal intensity of the solid portion was equal to that of cerebrospinal fluid (CSF) in 50% of pilocytic astrocytomas. No medulloblastomas showed such hyperintensity. Most medulloblastomas (80%) were isointense to grey matter. On T1-weighted images, the signal intensity varied widely in pilocytic astrocytomas; however, all medulloblastomas were iso- or hypointense to grey matter. The MR enhancement pattern, cystic component and peripheral oedema all varied in both tumour types and no specific features were identified. A signal intensity of the solid portion isointense to CSF on T2-weighted images was characteristic of cerebellar pilocytic astrocytomas; this was not observed in medulloblastomas. Attention to T2-weighted imaging of the solid portions of a tumour is easy and helpful in differentiating between cerebellar pilocytic astrocytoma and medulloblastoma. (orig.)

  10. Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia.

    Science.gov (United States)

    Eberhart, Charles G; Kratz, John; Wang, Yunyue; Summers, Krista; Stearns, Duncan; Cohen, Kenneth; Dang, Chi V; Burger, Peter C

    2004-05-01

    Several molecular and histopathological prognostic markers have been proposed for the therapeutic stratification of medulloblastoma patients. Amplification of the c-myc oncogene, elevated levels of c-myc mRNA, or tumor anaplasia have been associated with worse clinical outcomes. In contrast, high TrkC mRNA expression generally presages longer survival. The goal of this study was to evaluate the prognostic value of c-myc, N-myc and TrkC expression in medulloblastomas and compare them to histopathological classification. We used in situ hybridization to measure expression of these molecular markers. c-myc mRNA was detected in 18 of 59 (31%) cases, and was significantly associated with shorter patient survival times on both univariate and multivariate analyses (p = 0.04). The presence of c-myc mRNA was also significantly associated with tumor anaplasia. While survival rates were higher for patients with low N-myc or high TrkC expression, these differences were not statistically significant. The group of patients with either moderate or severely anaplastic tumors showed only a trend towards shorter survival (p = 0.11). However, severe anaplasia alone was significantly prognostic (p = 0.002). Given the prognostic import of c-myc, we investigated 2 potential mechanisms by which its expression might be regulated: Wnt signaling and Mxi-1 mutation. Nuclear translocation of beta-catenin, a marker of Wnt pathway activation, was more common in medulloblastomas with high c-myc than in tumors overall, but the difference was not statistically significant. No Mxi-1 mutations were detected in the 22 cases examined. The association we describe between c-myc expression, tumor anaplasia, and worse clinical outcomes provides further evidence for the importance of this oncogene in medulloblastoma pathobiology.

  11. Acute toxicity profile of craniospinal irradiation with intensity-modulated radiation therapy in children with medulloblastoma: A prospective analysis

    International Nuclear Information System (INIS)

    Cox, Maurice C.; Kusters, Johannes M.; Gidding, Corrie E.; Schieving, Jolanda H.; Lindert, Erik J. van; Kaanders, Johannes H.; Janssens, Geert O.

    2015-01-01

    To report on the acute toxicity in children with medulloblastoma undergoing intensity-modulated radiation therapy (IMRT) with daily intrafractionally modulated junctions. Newly diagnosed patients, aged 3–21, with standard-risk (SR) or high-risk (HR) medulloblastoma were eligible. A dose of 23.4 or 36.0Gy in daily fractions of 1.8Gy was prescribed to the craniospinal axis, followed by a boost to the primary tumor bed (54 or 55.8Gy) and metastases (39.6–55.8Gy), 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. 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. 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

  12. Survival and neurologic outcome of infants with medulloblastoma treated with surgery and MOPP chemotherapy. A preliminary report.

    Science.gov (United States)

    Baram, T Z; van Eys, J; Dowell, R E; Cangir, A; Pack, B; Bruner, J M

    1987-07-15

    The results of treatment of infants with medulloblastoma using surgery and chemotherapy, without the use of radiation therapy, are reported. Both survival and outcome, in terms of growth, neurologic deficit, and intelligence are compared with the same parameters in children treated conventionally. Although preliminary, our results suggest that chemotherapy combined with surgery is a valid option for the treatment of infants with this type of neoplasm.

  13. Proton Radiation Therapy for Pediatric Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors: Outcomes for Very Young Children Treated With Upfront Chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Jimenez, Rachel B., E-mail: rbjimenez@partners.org [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Sethi, Roshan [Harvard Medical School, Boston, Massachusetts (United States); Depauw, Nicolas [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Pulsifer, Margaret B. [Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts (United States); Adams, Judith [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); McBride, Sean M. [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Ebb, David [Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts (United States); Fullerton, Barbara C.; Tarbell, Nancy J.; Yock, Torunn I.; MacDonald, Shannon M. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2013-09-01

    Purpose: To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). Methods and Materials: All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. Results: Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients had medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. Conclusions: Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity.

  14. The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Sarah Ball

    Full Text Available Tumors of the central nervous system represent a major source of cancer-related deaths, with medulloblastoma and glioblastoma being the most common malignant brain tumors in children and adults respectively. While significant advances in treatment have been made, with the 5-year survival rate for medulloblastoma at 70-80%, treating patients under 3 years of age still poses a problem due to the deleterious effects of radiation on the developing brain, and the median survival for patients with glioblastoma is only 15 months. The transcription factor, STAT3, has been found constitutively activated in a wide variety of cancers and in recent years it has become an attractive therapeutic target. We designed a non-peptide small molecule STAT3 inhibitor, LLL12, using structure-based design. LLL12 was able to inhibit STAT3 phosphorylation, decrease cell viability and induce apoptosis in medulloblastoma and glioblastoma cell lines with elevated levels of p-STAT3 (Y705. IC(50 values for LLL12 were found to be between 1.07 µM and 5.98 µM in the five cell lines expressing phosphorylated STAT3. STAT3 target genes were found to be downregulated and a decrease in STAT3 DNA binding was observed following LLL12 treatment, indicating that LLL12 is an effective STAT3 inhibitor. LLL12 was also able to inhibit colony formation, wound healing and decreased IL-6 and LIF secretion. Our results suggest that LLL12 is a potent STAT3 inhibitor and that it may be a potential therapeutic treatment for medulloblastoma and glioblastoma.

  15. Survival of very young children with medulloblastoma (primitive neuroectodermal tumor of the posterior fossa) treated with craniospinal irradiation

    International Nuclear Information System (INIS)

    Saran, Frank H.; Driever, Pablo Herniz; Thilmann, Christoph; Mose, Stephan; Wilson, Paula; Sharpe, Geoff; Adamietz, Irenaeus A.; Boettcher, Heinz D.

    1998-01-01

    Purpose: Very young children with medulloblastoma are considered to have a worse prognosis than older children. As radiotherapy remains an important part of the treatment, the adverse prognosis could be due to inadequate radiation treatment rather than biological factors. We analyzed the published literature to examine the impact of radiotherapy on survival in this group. Methods and Materials: A Medline search was performed and we reviewed studies of treatment of medulloblastoma where radiotherapy was delivered using megavoltage equipment and the minimum follow-up allowed the calculation of 5-year survival rates. Results: Thirty-nine studies were published between 1979 and 1996 with a treatment including craniospinal irradiation and boost to the posterior fossa. Eleven studies comprising 1366 patients analyzed survival by age at diagnosis. Eight of 11 studies showed a worse 5-year survival for the younger patient group which reached statistical significance in two. There is also a suggestion of a higher proportion of children with metastatic disease at presentation in the very young age group. The usual policy in younger children was to give a lower dose of radiotherapy to the craniospinal axis (CSA) and posterior fossa (PF) with reduction of dose in the range of 15 to 25% compared to standard treatment. As dose reduction to the posterior fossa is associated with worse survival and local recurrence is the predominant site of failure, the major determinant of worse survival in very young children with medulloblastoma may be suboptimal radiotherapy. Protocols including postoperative chemotherapy with delayed, omitted, or only local tumor irradiation do not reach survival rates of protocols with standard radiotherapy, also suggesting a continued importance for irradiation. Conclusion: Very young children with medulloblastoma have a worse prognosis than older children. Inadequate radiation dose and technique to the primary tumor region may be a major contributing

  16. Chromosome 17 alterations identify good-risk and poor-risk tumors independently of clinical factors in medulloblastoma

    Science.gov (United States)

    McCabe, Martin G.; Bäcklund, L. Magnus; Leong, Hui Sun; Ichimura, Koichi; Collins, V. Peter

    2011-01-01

    Current risk stratification schemas for medulloblastoma, based on combinations of clinical variables and histotype, fail to accurately identify particularly good- and poor-risk tumors. Attempts have been made to improve discriminatory power by combining clinical variables with cytogenetic data. We report here a pooled analysis of all previous reports of chromosomal copy number related to survival data in medulloblastoma. We collated data from previous reports that explicitly quoted survival data and chromosomal copy number in medulloblastoma. We analyzed the relative prognostic significance of currently used clinical risk stratifiers and the chromosomal aberrations previously reported to correlate with survival. In the pooled dataset metastatic disease, incomplete tumor resection and severe anaplasia were associated with poor outcome, while young age at presentation was not prognostically significant. Of the chromosomal variables studied, isolated 17p loss and gain of 1q correlated with poor survival. Gain of 17q without associated loss of 17p showed a trend to improved outcome. The most commonly reported alteration, isodicentric chromosome 17, was not prognostically significant. Sequential multivariate models identified isolated 17p loss, isolated 17q gain, and 1q gain as independent prognostic factors. In a historical dataset, we have identified isolated 17p loss as a marker of poor outcome and 17q gain as a novel putative marker of good prognosis. Biological markers of poor-risk and good-risk tumors will be critical in stratifying treatment in future trials. Our findings should be prospectively validated independently in future clinical studies. PMID:21292688

  17. Medulloblastoma -- Childhood

    Science.gov (United States)

    ... to Content ASCO.org Conquer Cancer Foundation ASCO Journals Donate eNews Signup f Cancer.net on Facebook t Cancer.net on Twitter q Cancer.net on YouTube g Cancer.net on Google Menu Home Types of Cancer Navigating Cancer Care Coping With Cancer Research and Advocacy Survivorship Blog About ...

  18. Risk factors for development of postoperative cerebellar mutism syndrome in children after medulloblastoma surgery.

    Science.gov (United States)

    Pols, San Y C V; van Veelen, Marie Lise C; Aarsen, Femke K; Gonzalez Candel, Antonia; Catsman-Berrevoets, Coriene E

    2017-07-01

    OBJECTIVE Postoperative cerebellar mutism syndrome (pCMS) occurs in 7%-50% of children after cerebellar tumor surgery. Typical features include a latent onset of 1-2 days after surgery, transient mutism, emotional lability, and a wide variety of motor and neurobehavioral abnormalities. Sequelae of this syndrome usually persist long term. The principal causal factor is bilateral surgical damage (regardless of tumor location) to any component of the proximal efferent cerebellar pathway, which leads to temporary dysfunction of cerebral cortical regions as a result of diaschisis. Tumor type, cerebellar midline location, and brainstem involvement are risk factors for pCMS that have been identified repeatedly, but they do not explain its latent onset. Ambiguous or negative results for other factors, such as hydrocephalus, postoperative meningitis, length of vermian incision, and tumor size, have been reached. The aim of this study was to identify perioperative clinical, radiological, and laboratory factors that also increase risk for the development of pCMS. The focus was on factors that might explain the delayed onset of pCMS and thus might provide a time window for taking precautionary measures to prevent pCMS or reduce its severity. The study was focused specifically on children who had undergone surgery for medulloblastoma. METHODS In this single-center retrospective cohort study, the authors included 71 children with medulloblastoma, 28 of whom developed pCMS after primary resection. Clinical and laboratory data were collected prospectively and analyzed systematically. Variables were included for univariate and multivariate analysis. RESULTS Univariate regression analysis revealed 7 variables that had a significant influence on pCMS onset, namely, tumor size, maximum tumor diameter > 5 cm, tumor infiltration or compression of the brainstem, significantly larger decreases in hemoglobin (p = 0.010) and hematocrit (p = 0.003) in the pCMS group after surgery than in the

  19. Combined radiotherapy and chemotherapy for pediatric medulloblastoma: a clinical study of 33 cases

    Directory of Open Access Journals (Sweden)

    Wei ZHENG

    2011-06-01

    Full Text Available Objective To retrospectively review the clinical characteristics of medulloblastoma,discuss the optimized treatment regimen,and analyze the prognostic influential factors.Methods Thirty-three children with pathologically certified medulloblastoma(aged 3-14 years with average of 6.5 years,admitted from Aug.2004 to Dec.2007,received radiotherapy within 3 weeks post surgery.Ratiotherapy consisted of 28~36Gy whole craniospinal radiation and a supplementary radiation aimed at tumors by three-dimensional conformal radiotherapy(3D-CRT for a total dose of 50~54Gy(conventional fraction dose of 1.8-2.0Gy.A part of patients received hyperfractionation radiotherapy(1.0Gy/f,2f/d for alleviating the tardive adverse events.Meanwhile,a synchronized chemotherapy,consisting of lomustine + vincristine + cisplatin,or isophosphamide + carboplatin + etoposide,was administered after the completion of whole craniospinal radiation,and 3-5 courses of sequential chemotherapy were given after the overall radiotherapy was finished.According to the metastasis,and the residual tumor and its size,the 33 patients were divided into 2 groups as follows: low-risk group(n=24: no metastases,total or sub-total excision of tumors(residual tumors ≤1.5cm3;high-risk group(n=9: either metastases or residual tumor > 1.5cm3.The 3-year survival rates of two groups were then compared.Results The combined radiotherapy and chemotherapy was effective to 10 of the 11 patients(90.9% with residual tumors.Out of the 33 patients,31 obtained complete remission(93.9%,and 2 patients showed partial remission or stable status(3.0%,respectively.The median survival time of 33 patients was 51 months,3-year disease free survival(DFS was 75.8%,and 3-year overall survival(OS was 78.8%,including 33.3% in high-risk group and 95.8% in low-risk group(P < 0.01.The major side effects occurred in haematological system and digestive system,such as an incidence of 21.2%(7/33 with grade Ⅲ-Ⅳ bone marrow suppression

  20. Hypothyroidism in children with medulloblastoma: a comparison of 3600 and 2340 cGy craniospinal radiotherapy

    International Nuclear Information System (INIS)

    Paulino, Arnold C.

    2002-01-01

    Purpose: To determine if low-dose craniospinal irradiation (2340 cGy) with chemotherapy is associated with a lower incidence of hypothyroidism compared to standard dose (3600 cGy) with or without chemotherapy in children with medulloblastoma. Patients and Methods: Between 1980 and 1999, 32 patients ≤20 years old survived after craniospinal irradiation with or without chemotherapy. Twenty patients received 3600 cGy craniospinal irradiation (CSI), whereas 12 had 2340 cGy CSI; all patients received a posterior fossa boost to a total dose 5040-5580 cGy. The median ages at the time of CSI for those receiving 2340 cGy and 3600 cGy were 7.2 and 10.2 years, respectively. Chemotherapy (CT) was employed in 22 children. All children who received 2340 cGy had CT consisting of vincristine, CCNU, and either cisplatin or cyclophosphamide. Ten of 20 (50%) patients receiving 3600 cGy had CT; the most common regimen was vincristine, CCNU, and prednisone. Serum-free thyroxine and thyroid-stimulating hormone concentrations were measured in all children at variable times after radiotherapy. Thyroid-stimulating hormone responses to i.v. thyrotrophin-releasing hormone were assessed in those suspected of having central hypothyroidism. Median follow-up for children receiving 2340 cGy was 5 years (range: 2-11.2 years), whereas for those receiving 3600 cGy, follow-up was 12.5 years (range: 2.4-20 years). Results: Eighteen patients (56%) developed hypothyroidism at a median time after radiotherapy of 41 months (range: 10 months to 18 years). Primary hypothyroidism was more common than central hypothyroidism (38% and 19%). All 7 children 10 years had hypothyroidism (p<0.001). Hypothyroidism was documented in 10 of 12 (83%) who had 2340 cGy + CT, 6 of 10 (60%) who had 3600 cGy + CT, and 2 of 10 (20%) who had 3600 cGy without CT (p<0.025). Conclusions: Current treatment regimens consisting of chemotherapy and 2340 cGy craniospinal irradiation followed by a posterior fossa boost for

  1. Medulloblastoma outcome is adversely associated with overexpression of EEF1D, RPL30, and RPS20 on the long arm of chromosome 8

    International Nuclear Information System (INIS)

    De Bortoli, Massimiliano; Man, Tsz-Kwong; Rao, Pulivarthi H; Kim, John YH; Castellino, Robert C; Lu, Xin-Yan; Deyo, Jeffrey; Sturla, Lisa Marie; Adesina, Adekunle M; Perlaky, Laszlo; Pomeroy, Scott L; Lau, Ching C

    2006-01-01

    Medulloblastoma is the most common malignant brain tumor of childhood. Improvements in clinical outcome require a better understanding of the genetic alterations to identify clinically significant biological factors and to stratify patients accordingly. In the present study, we applied cytogenetic characterization to guide the identification of biologically significant genes from gene expression microarray profiles of medulloblastoma. We analyzed 71 primary medulloblastomas for chromosomal copy number aberrations (CNAs) using comparative genomic hybridization (CGH). Among 64 tumors that we previously analyzed by gene expression microarrays, 27 were included in our CGH series. We analyzed clinical outcome with respect to CNAs and microarray results. We filtered microarray data using specific CNAs to detect differentially expressed candidate genes associated with survival. The most frequent lesions detected in our series involved chromosome 17; loss of 16q, 10q, or 8p; and gain of 7q or 2p. Recurrent amplifications at 2p23-p24, 2q14, 7q34, and 12p13 were also observed. Gain of 8q is associated with worse overall survival (p = 0.0141), which is not entirely attributable to MYC amplification or overexpression. By applying CGH results to gene expression analysis of medulloblastoma, we identified three 8q-mapped genes that are associated with overall survival in the larger group of 64 patients (p < 0.05): eukaryotic translation elongation factor 1D (EEF1D), ribosomal protein L30 (RPL30), and ribosomal protein S20 (RPS20). The complementary use of CGH and expression profiles can facilitate the identification of clinically significant candidate genes involved in medulloblastoma growth. We demonstrate that gain of 8q and expression levels of three 8q-mapped candidate genes (EEF1D, RPL30, RPS20) are associated with adverse outcome in medulloblastoma

  2. Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway

    International Nuclear Information System (INIS)

    Zhan, Meixiao; Sun, Xiaohan; Liu, Jinxiao; Li, Yan; Li, Yong; He, Xu; Zhou, Zizhang; Lu, Ligong

    2017-01-01

    The ubiquitin-specific protease Usp7 plays roles in multiple cellular processes through deubiquitinating and stabilizing numerous substrates, including P53, Pten and Gli. Aberrant Usp7 activity has been implicated in many disorders and tumorigenesis, making it as a potential target for therapeutic intervention. Although it is clear that Usp7 is involved in many types of cancer, its role in regulating medulloblastoma (MB) is still unknown. In this study, we show that knockdown of Usp7 inhibits the proliferation and migration of MB cells, while Usp7 overexpression exerts an opposite effect. Furthermore, we establish Usp7 knockout MB cell line using the CRISPR/Cas9 system and further confirm that Usp7 knockout also blocks MB cell proliferation and metastasis. In addition, we reveal that knockdown of Usp7 compromises Shh pathway activity and decrease Gli protein levels, while P53 level and P53 target gene expression have no obvious changes. Finally, we find that Usp7 inhibitors apparently inhibit MB cell viability and migration. Taken together, our findings suggest that Usp7 is important for MB cell proliferation and metastasis by activating Shh pathway, and is a putative therapeutic target for MBs. - Highlights: • Loss of usp7 blocks the proliferation and metastasis of MB cells. • Usp7 regulates MB cell growth and migration through stimulating Shh pathway. • Usp7 inhibitors hamper MB cell proliferation and migration. • Usp7 inhibitors could attenuate Shh pathway activity.

  3. A comparative evaluation of supervised and unsupervised representation learning approaches for anaplastic medulloblastoma differentiation

    Science.gov (United States)

    Cruz-Roa, Angel; Arevalo, John; Basavanhally, Ajay; Madabhushi, Anant; González, Fabio

    2015-01-01

    Learning data representations directly from the data itself is an approach that has shown great success in different pattern recognition problems, outperforming state-of-the-art feature extraction schemes for different tasks in computer vision, speech recognition and natural language processing. Representation learning applies unsupervised and supervised machine learning methods to large amounts of data to find building-blocks that better represent the information in it. Digitized histopathology images represents a very good testbed for representation learning since it involves large amounts of high complex, visual data. This paper presents a comparative evaluation of different supervised and unsupervised representation learning architectures to specifically address open questions on what type of learning architectures (deep or shallow), type of learning (unsupervised or supervised) is optimal. In this paper we limit ourselves to addressing these questions in the context of distinguishing between anaplastic and non-anaplastic medulloblastomas from routine haematoxylin and eosin stained images. The unsupervised approaches evaluated were sparse autoencoders and topographic reconstruct independent component analysis, and the supervised approach was convolutional neural networks. Experimental results show that shallow architectures with more neurons are better than deeper architectures without taking into account local space invariances and that topographic constraints provide useful invariant features in scale and rotations for efficient tumor differentiation.

  4. Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma.

    Science.gov (United States)

    Coco, Simona; De Mariano, Marilena; Valdora, Francesca; Servidei, Tiziana; Ridola, Vita; Andolfo, Immacolata; Oberthuer, André; Tonini, Gian Paolo; Longo, Luca

    2012-10-01

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

  5. Medulloblastoma. The identification of prognostic subgroups and implications for multimodality management

    International Nuclear Information System (INIS)

    Kopelson, G.; Linggood, R.M.; Kleinman, G.M.

    1983-01-01

    For 43 medulloblatoma patients who had five-and ten-year actuarial survival rates of 56%, prognostic factors of statistical significance included: T-stage, M-stage and histopathologic tumor score. Posterior fossa local control rates were also function of T-stage and TS. Combining TS with T-stage, patients fell into three prognostic and local control groups, which may have different future management implications: Small (T1,2) tumors of favorable (TS less than or equal to 5) histology had a 92% ten-year actuarial survival rate with 100% (8/8) local control; no change from current management is suggested. For the intermediate prognosis group, increasing the irradiation dose alone may improve survival because these tumors exhibited an irradiation dose-response relationship. However, it is the poor prognosis group which might be suitable for future adjuvant chemotherapy or radiosensitizer trials since there is no evidence that higher irradiation doses improve local control. This article identifies prognostic subgroups based on histologic type and TM staging in medulloblastoma patients which potentially may be utilized to improve therapeutic results, and confirms the value of staging patients with central nervous system malignancies

  6. Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis.

    Science.gov (United States)

    Wiederschain, Dmitri; Chen, Lin; Johnson, Brett; Bettano, Kimberly; Jackson, Dowdy; Taraszka, John; Wang, Y Karen; Jones, Michael D; Morrissey, Michael; Deeds, James; Mosher, Rebecca; Fordjour, Paul; Lengauer, Christoph; Benson, John D

    2007-07-01

    Bmi-1 and Mel-18 are structural homologues that belong to the Polycomb group of transcriptional regulators and are believed to stably maintain repression of gene expression by altering the state of chromatin at specific promoters. While a number of clinical and experimental observations have implicated Bmi-1 in human tumorigenesis, the role of Mel-18 in cancer cell growth has not been investigated. We report here that short hairpin RNA-mediated knockdown of either Bmi-1 or Mel-18 in human medulloblastoma DAOY cells results in the inhibition of proliferation, loss of clonogenic survival, anchorage-independent growth, and suppression of tumor formation in nude mice. Furthermore, overexpression of both Bmi-1 and Mel-18 significantly increases the clonogenic survival of Rat1 fibroblasts. In contrast, stable downregulation of Bmi-1 or Mel-18 alone does not affect the growth of normal human WI38 fibroblasts. Proteomics-based characterization of Bmi-1 and Mel-18 protein complexes isolated from cancer cells revealed substantial similarities in their respective compositions. Finally, gene expression analysis identified a number of cancer-relevant pathways that may be controlled by Bmi-1 and Mel-18 and also showed that these Polycomb proteins regulate a set of common gene targets. Taken together, these results suggest that Bmi-1 and Mel-18 may have overlapping functions in cancer cell growth.

  7. Primary Cilia in the Murine Cerebellum and in Mutant Models of Medulloblastoma.

    Science.gov (United States)

    Di Pietro, Chiara; Marazziti, Daniela; La Sala, Gina; Abbaszadeh, Zeinab; Golini, Elisabetta; Matteoni, Rafaele; Tocchini-Valentini, Glauco P

    2017-01-01

    Cellular primary cilia crucially sense and transduce extracellular physicochemical stimuli. Cilium-mediated developmental signaling is tissue and cell type specific. Primary cilia are required for cerebellar differentiation and sonic hedgehog (Shh)-dependent proliferation of neuronal granule precursors. The mammalian G-protein-coupled receptor 37-like 1 is specifically expressed in cerebellar Bergmann glia astrocytes and participates in regulating postnatal cerebellar granule neuron proliferation/differentiation and Bergmann glia and Purkinje neuron maturation. The mouse receptor protein interacts with the patched 1 component of the cilium-associated Shh receptor complex. Mice heterozygous for patched homolog 1 mutations, like heterozygous patched 1 humans, have a higher incidence of Shh subgroup medulloblastoma (MB) and other tumors. Cerebellar cells bearing primary cilia were identified during postnatal development and in adulthood in two mouse strains with altered Shh signaling: a G-protein-coupled receptor 37-like 1 null mutant and an MB-susceptible, heterozygous patched homolog 1 mutant. In addition to granule and Purkinje neurons, primary cilia were also expressed by Bergmann glia astrocytes in both wild-type and mutant animals, from birth to adulthood. Variations in ciliary number and length were related to the different levels of neuronal and glial cell proliferation and maturation, during postnatal cerebellar development. Primary cilia were also detected in pre-neoplastic MB lesions in heterozygous patched homolog 1 mutant mice and they could represent specific markers for the development and analysis of novel cerebellar oncogenic models.

  8. Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma.

    Science.gov (United States)

    Ozawa, Patricia Midori Murobushi; Ariza, Carolina Batista; Ishibashi, Cintya Mayumi; Fujita, Thiago Cezar; Banin-Hirata, Bruna Karina; Oda, Julie Massayo Maeda; Watanabe, Maria Angelica Ehara

    2016-01-01

    Chemokines and its receptors have significant impact on physiological and pathological processes and studies concerning their association with tumor biology are subject of great interest in scientific community. CXCL12/CXCR4 axis has been widely studied due to its significant role in tumor microenvironment, but it is also important to development and maintenance of tissues and organs, for example, in the brain and cerebellum. Studies have demonstrated that CXCL12 and CXCR4 are required for normal cerebellar development and that dysfunction in this pathway may be involved with medulloblastoma pathogenesis. In this context, a new molecular subgroup has been suggested based on the importance of the association between CXCR4 overexpression and sonic hedgehog subgroup. Treatment using CXCR4 antagonists showed significant results, evidencing the important role and possible therapeutic capacity of CXCR4 in MB. This review summarizes studies on MB cell biology, focusing on a chemokine-receptor axis, CXCL12/CXCR4, that may have implications for treatment strategies once it can improve life expectancy and reduce neurocognitive sequelae of patients with this neoplasia. © 2014 UICC.

  9. Cavernous angioma after chemotherapy for desmoplastic/nodular medulloblastoma associated with anhidrotic ectodermal dysplasia.

    Science.gov (United States)

    Yamasaki, Fumiyuki; Takayasu, Takeshi; Nosaka, Ryo; Kawaguchi, Hiroshi; Sugiyama, Kazuhiko; Kobayashi, Masao; Kurisu, Kaoru

    2016-02-01

    While cavernous angioma (CVA) after cranial irradiation has been documented, its development after high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) has not. We present a patient with desmoplastic/nodular medulloblastoma (DNMB) associated with anhidrotic ectodermal dysplasia (AED) who developed CVA 2 years after high-dose chemotherapy and PBSCT. A 1-year-old boy with ingravescent vomiting was admitted to our institute. He presented with a large head, a depressed nasal bridge, low-set ears, thick lips with peg-shaped teeth, hypohidrosis, sparse hair, thin atrophic skin, scaly dermatitis with frontal bossing, and a bulging anterior fontanel. Neuroradiological examination revealed multiple cerebellar masses with heterogeneous enhancement and speckled calcifications and severe obstructive hydrocephalus. The histological diagnosis of surgical specimens was DNMB, and he underwent postoperative multiple-drug chemotherapy with autologous PBSCT. The outcome was favorable and he did not undergo radiotherapy. After 2 years, intracranial hemorrhage was detected at his regular radiological check-up and he again underwent surgery. The histological diagnosis was CVA. To our knowledge, this is the first report of AED-associated DNMB and CVA.

  10. Albumin nanoparticles for glutathione-responsive release of cisplatin: New opportunities for medulloblastoma.

    Science.gov (United States)

    Catanzaro, Giuseppina; Curcio, Manuela; Cirillo, Giuseppe; Spizzirri, Umile Gianfranco; Besharat, Zein Mersini; Abballe, Luana; Vacca, Alessandra; Iemma, Francesca; Picci, Nevio; Ferretti, Elisabetta

    2017-01-30

    Redox-responsive nanoparticles were synthesized by desolvation of bovine serum albumin followed by disulfide-bond crosslinking with N, N'-Bis (acryloyl) cystamine. Dynamic light scattering and transmission electron microscopy studies revealed spherical nanoparticles (mean diameter: 83nm, polydispersity index: 0.3) that were glutathione-responsive. Confocal microscopy revealed rapid, efficient internalization of the nanoparticles by Daoy medulloblastoma cells and healthy controls (HaCaT keratinocytes). Cisplatin-loaded nanoparticles with drug:carrier ratios of 5%, 10%, and 20% were tested in both cell lines. The formulation with the highest drug:carrier ratio reduced Daoy and HaCaT cell viability with IC 50 values of 6.19 and 11.17μgmL -1 , respectively. The differential cytotoxicity reflects the cancer cells' higher glutathione content, which triggers more extensive disruption of the disulfide bond-mediated intra-particle cross-links, decreasing particle stability and increasing their cisplatin release. These findings support continuing efforts to improve the safety and efficacy of antineoplastic drug therapy for pediatric brain tumors using selective nanoparticle-based drug delivery systems. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Fatal Gastrointestinal Hemorrhage in a Young Boy with Newly Diagnosed Metastatic Medulloblastoma on High Dose Dexamethasone

    Directory of Open Access Journals (Sweden)

    Victor Wong

    2014-01-01

    Full Text Available A 10-year-old boy with newly diagnosed metastatic medulloblastoma was placed on high dose dexamethasone and ranitidine prior to surgery. The child underwent subtotal resection and was discharged 5 days postoperatively with an uneventful hospital course on a tapering dose of dexamethasone and ranitidine. Over the next 2 days the patient complained of mild abdominal distension with flatulence, without pain, vomiting, or dysmotility. On follow-up in clinic 5 days after discharge, he had normal vital signs when he suddenly became pale and had loss of consciousness. Emergent computerized tomography of the head showed no acute hemorrhage and complete blood count revealed hemoglobin of 4.2 gm/dL. In spite of maximum resuscitation with copious blood products the patient died. Autopsy revealed evidence of duodenal perforation with intraluminal hemorrhage. This case demonstrates a rare fatal complication of high dose dexamethasone therapy even with concurrent gastrointestinal prophylactic therapy. We provide a review of the limited literature on steroid use in pediatric neurooncology with regard to gastrointestinal bleeding.

  12. The ubiquitin-proteasome system and chromosome 17 in cerebellar granule cells and medulloblastoma subgroups.

    Science.gov (United States)

    Vriend, Jerry; Marzban, Hassan

    2017-02-01

    Chromosome 17 abnormalities are often observed in medulloblastomas (MBs), particularly those classified in the consensus Groups 3 and 4. Herein we review MB signature genes associated with chromosome 17 and the relationship of these signature genes to the ubiquitin-proteasome system. While clinical investigators have not focused on the ubiquitin-proteasome system in relation to MB, a substantial amount of data on the topic has been hidden in the form of supplemental datasets of gene expression. A supplemental dataset associated with the Thompson classification of MBs shows that a subgroup of MB with 17p deletions is characterized by reduced expression of genes for several core particle subunits of the beta ring of the proteasome (β1, β4, β5, β7). One of these genes (PSMB6, the gene for the β1 subunit) is located on chromosome 17, near the telomeric end of 17p. By comparison, in the WNT group of MBs only one core proteasome subunit, β6, associated with loss of a gene (PSMB1) on chromosome 6, was down-regulated in this dataset. The MB subgroups with the worst prognosis have a significant association with chromosome 17 abnormalities and irregularities of APC/C cyclosome genes. We conclude that the expression of proteasome subunit genes and genes for ubiquitin ligases can contribute to prognostic classification of MBs. The therapeutic value of targeting proteasome subunits and ubiquitin ligases in the various subgroups of MB remains to be determined separately for each classification of MB.

  13. Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

    Science.gov (United States)

    Brun, S N; Markant, S L; Esparza, L A; Garcia, G; Terry, D; Huang, J-M; Pavlyukov, M S; Li, X-N; Grant, G A; Crawford, J R; Levy, M L; Conway, E M; Smith, L H; Nakano, I; Berezov, A; Greene, M I; Wang, Q; Wechsler-Reya, R J

    2015-07-01

    Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.

  14. PROGNOSTIC SIGNIFICANCE OF CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR CHARACTERISTICS OF MEDULLOBLASTOMAS IN THE PROSPECTIVE HIT2000 MULTICENTER CLINICAL TRIAL COHORT

    Science.gov (United States)

    Pietsch, Torsten; Schmidt, Rene; Remke, Marc; Korshunov, Andrey; Hovestadt, Volker; Jones, David TW; Felsberg, Jörg; Kaulich, Kerstin; Goschzik, Tobias; Kool, Marcel; Northcott, Paul A.; von Hoff, Katja; von Bueren, André O.; Friedrich, Carsten; Skladny, Heyko; Fleischhack, Gudrun; Taylor, Michael D.; Cremer, Friedrich; Lichter, Peter; Faldum, Andreas; Reifenberger, Guido; Rutkowski, Stefan; Pfister, Stefan M.

    2014-01-01

    BACKGROUND: This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. METHODS: Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a validation (n = 57) dataset. All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. RESULTS: By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, TOP2A copy-number, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining “intermediate molecular risk” population dependent on age, M-stage, pattern of synaptophysin expression, and MYCN copy-number status was identified and validated, with speckled synaptophysin expression indicating worse outcome. CONCLUSIONS: Methylation subgrouping and CTNNB1 mutation status represent robust tools for the risk-stratification of medulloblastoma. A simple clinico-pathological risk score for “intermediate molecular risk” patients was identified, which deserves further validation

  15. Early recurrence in standard-risk medulloblastoma patients with the common idic(17)(p11.2) rearrangement

    Science.gov (United States)

    Bien-Willner, Gabriel A.; López-Terrada, Dolores; Bhattacharjee, Meena B.; Patel, Kayuri U.; Stankiewicz, Paweł; Lupski, James R.; Pfeifer, John D.; Perry, Arie

    2012-01-01

    Medulloblastoma is diagnosed histologically; treatment depends on staging and age of onset. Whereas clinical factors identify a standard- and a high-risk population, these findings cannot differentiate which standard-risk patients will relapse and die. Outcome is thought to be influenced by tumor subtype and molecular alterations. Poor prognosis has been associated with isochromosome (i)17q in some but not all studies. In most instances, molecular investigations document that i17q is not a true isochromosome but rather an isodicentric chromosome, idic(17)(p11.2), with rearrangement breakpoints mapping within the REPA/REPB region on 17p11.2. This study explores the clinical utility of testing for idic(17)(p11.2) rearrangements using an assay based on fluorescent in situ hybridization (FISH). This test was applied to 58 consecutive standard- and high-risk medulloblastomas with a 5-year minimum of clinical follow-up. The presence of i17q (ie, including cases not involving the common breakpoint), idic(17)(p11.2), and histologic subtype was correlated with clinical outcome. Overall survival (OS) and disease-free survival (DFS) were consistent with literature reports. Fourteen patients (25%) had i17q, with 10 (18%) involving the common isodicentric rearrangement. The presence of i17q was associated with a poor prognosis. OS and DFS were poor in all cases with anaplasia (4), unresectable disease (7), and metastases at presentation (10); however, patients with standard-risk tumors fared better. Of these 44 cases, tumors with idic(17)(p11.2) were associated with significantly worse patient outcomes and shorter mean DFS. FISH detection of idic(17)(p11.2) may be useful for risk stratification in standard-risk patients. The presence of this abnormal chromosome is associated with early recurrence of medulloblastoma. PMID:22573308

  16. Alleviating action of OK-432 (Picibanil) on the myelosuppression in medulloblastoma patients induced by whole axis irradiation

    International Nuclear Information System (INIS)

    Aoki, Yoshiro

    1982-01-01

    The test subjects termed as OK-432 group which consist of 4 patients of Medulloblastoma and 2 of Pinealoma, underwent the whole axis irradiation in combination with OK-432. The control group consisting of 9 Medulloblastoma patients was subjected to the same radiation treatment without OK-432. Six of the nine patients (66.7%) irradiated showed the decrease of peripheral white blood cell counts down to 2,500, whereas, only two of six patients showed a similar decrement in OK-432 group. Three of the nine patients (33.3%) in the control group showed the decrease of white blood cell down to 2,000, but only one of the six patients in OK-432 group. The neutrophil counts decreased below the level of 1,000 in three of the nine patients (33.3%) in the control group, but none in the OK-432 group. The platelet counts decreased below the level of 100,000 in five of the nine patients (55.6%) in the control group during the irradiation period, but only one patient in the OK-432 group showed a decrease down to 100,000 counts. Three of the nine patients (33.3%) in the control group had to be stopped irradiation due to the severe leukopenia and thrombocytopenia, in contrast to the OK-432 group, which completed whole axis irradiation without interruption. These results seem to indicate that OK-432 alleviated the myelosuppression induced in patients by whole axis irradiation. This alleviating action of OK-432 is considered to be applicable to the treatment of Medulloblastoma patients. (J.P.N.)

  17. Alleviating action of OK-432 (Picibanil) on the myelosuppression in Medulloblastoma patients induced by whole axis irradiation

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    Aoki, Yoshiro (National Inst. of Radiological Sciences, Chiba (Japan))

    1982-11-01

    The test subjects termed as OK-432 group which consist of 4 patients of Medulloblastoma and 2 of Pinealoma, underwent the whole axis irradiation in combination with OK-432. The control group consisting of 9 Medulloblastoma patients was subjected to the same radiation treatment without OK-432. Six of the nine patients (66.7%) irradiated showed the decrease of peripheral white blood cell counts down to 2,500, whereas, only two of six patients showed a similar decrement in OK-432 group. Three of the nine patients (33.3%) in the control group showed the decrease of white blood cell down to 2,000, but only one of the six patients in OK-432 group. The neutrophil counts decreased below the level of 1,000 in three of the nine patients (33.3%) in the control group, but none in the OK-432 group. The platelet counts decreased below the level of 100,000 in five of the nine patients (55.6%) in the control group during the irradiation period, but only one patient in the OK-432 group showed a decrease down to 100,000 counts. Three of the nine patients (33.3%) in the control group had to be stopped irradiation due to the severe leukopenia and thrombocytopenia, in contrast to the OK-432 group, which completed whole axis irradiation without interruption. These results seem to indicate that OK-432 alleviated the myelosuppression induced in patients by whole axis irradiation. This alleviating action of OK-432 is considered to be applicable to the treatment of Medulloblastoma patients.

  18. Early Clinical Outcomes Demonstrate Preserved Cognitive Function in Children With Average-Risk Medulloblastoma When Treated With Hyperfractionated Radiation Therapy

    International Nuclear Information System (INIS)

    Gupta, Tejpal; Jalali, Rakesh; Goswami, Savita; Nair, Vimoj; Moiyadi, Aliasgar; Epari, Sridhar; Sarin, Rajiv

    2012-01-01

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

  19. Suppression of medulloblastoma lesions by forced migration of preneoplastic precursor cells with intracerebellar administration of the chemokine Cxcl3

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    Manuela Ceccarelli

    2016-12-01

    Full Text Available Medulloblastoma (MB, tumor of the cerebellum, remains a leading cause of cancer-related mortality in childhood.We previously showed, in a mouse model of spontaneous MB (Ptch1+/-/Tis21-/-, that a defect of the migration of cerebellar granule neuron precursor cells (GCPs correlates with an increased frequency of MB. This occurs because GCPs, rather than migrating internally and differentiating, remain longer in the proliferative area at the cerebellar surface, becoming targets of transforming insults. Furthermore, we identified the chemokine Cxcl3 as responsible for the inward migration of GCPs. As it is known that preneoplastic GCPs (pGCPs can still migrate and differentiate like normal GCPs, thus exiting the neoplastic program, in this study we tested the hypothesis that pGCPs within a MB lesion could be induced by Cxcl3 to migrate and differentiate. We observed that the administration of Cxcl3 for 28 days within the cerebellum of one-month-old Ptch1+/-/Tis21-/- mice, i.e., when MB lesions are already formed, leads to complete disappearance of the lesions. However, a shorter treatment with Cxcl3 (two weeks was ineffective, suggesting that the suppression of MB lesions is dependent on the duration of Cxcl3 application. We verified that the treatment with Cxcl3 causes a massive migration of pGCPs from the lesion to the internal granular layer (IGL, where they differentiate.Thus, the induction of migration of pGCPs in medulloblastoma lesions may open new ways to treat MB that exploit the plasticity of the pGCPs, forcing their differentiation. It remains to be tested whether this plasticity continues at advanced stages of medulloblastoma. If so, these findings would set a potential use of the chemokine Cxcl3 as therapeutic agent against MB development in human preclinical studies.

  20. Long time to diagnosis of medulloblastoma in children is not associated with decreased survival or with worse neurological outcome.

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    Jean-Francois Brasme

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

  1. Early Clinical Outcomes Demonstrate Preserved Cognitive Function in Children With Average-Risk Medulloblastoma When Treated With Hyperfractionated Radiation Therapy

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    Gupta, Tejpal, E-mail: tejpalgupta@rediffmail.com [Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Jalali, Rakesh [Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Goswami, Savita [Department of Clinical Psychology and Psychiatry Unit, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Nair, Vimoj [Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Moiyadi, Aliasgar [Division of Neuro-Surgery, Department of Surgical Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Epari, Sridhar [Department of Pathology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Sarin, Rajiv [Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India)

    2012-08-01

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

  2. Patterns of Failure After Proton Therapy in Medulloblastoma; Linear Energy Transfer Distributions and Relative Biological Effectiveness Associations for Relapses

    International Nuclear Information System (INIS)

    Sethi, Roshan V.; Giantsoudi, Drosoula; Raiford, Michael; Malhi, Imran; Niemierko, Andrzej; Rapalino, Otto; Caruso, Paul; Yock, Torunn I.; Tarbell, Nancy J.; Paganetti, Harald; MacDonald, Shannon M.

    2014-01-01

    Purpose: The pattern of failure in medulloblastoma patients treated with proton radiation therapy is unknown. For this increasingly used modality, it is important to ensure that outcomes are comparable to those in modern photon series. It has been suggested this pattern may differ from photons because of variations in linear energy transfer (LET) and relative biological effectiveness (RBE). In addition, the use of matching fields for delivery of craniospinal irradiation (CSI) may influence patterns of relapse. Here we report the patterns of failure after the use of protons, compare it to that in the available photon literature, and determine the LET and RBE values in areas of recurrence. Methods and Materials: Retrospective review of patients with medulloblastoma treated with proton radiation therapy at Massachusetts General Hospital (MGH) between 2002 and 2011. We documented the locations of first relapse. Discrete failures were contoured on the original planning computed tomography scan. Monte Carlo calculation methods were used to estimate the proton LET distribution. Models were used to estimate RBE values based on the LET distributions. Results: A total of 109 patients were followed for a median of 38.8 months (range, 1.4-119.2 months). Of the patients, 16 experienced relapse. Relapse involved the supratentorial compartment (n=8), spinal compartment (n=11), and posterior fossa (n=5). Eleven failures were isolated to a single compartment; 6 failures in the spine, 4 failures in the supratentorium, and 1 failure in the posterior fossa. The remaining patients had multiple sites of disease. One isolated spinal failure occurred at the spinal junction of 2 fields. None of the 70 patients treated with an involved-field-only boost failed in the posterior fossa outside of the tumor bed. We found no correlation between Monte Carlo-calculated LET distribution and regions of recurrence. Conclusions: The most common site of failure in patients treated with protons for

  3. Life years lost-comparing potentially fatal late complications after radiotherapy for pediatric medulloblastoma on a common scale

    DEFF Research Database (Denmark)

    Brodin, N. Patrik; Vogelius, Ivan R.; Maraldo, Maja V.

    2012-01-01

    The authors developed a framework for estimating and comparing the risks of various long-term complications on a common scale and applied it to 3 different techniques for craniospinal irradiation in patients with pediatric medulloblastoma. METHODS: Radiation dose-response parameters related......-modulated proton therapy (IMPT). RESULTS: Lung cancer contributed most to the estimated LYL, followed by myocardial infarction, and stomach cancer. The estimates of breast or thyroid cancer incidence were higher than those for lung and stomach cancer incidence, but LYL were lower because of the relatively good...

  4. Oncolytic Herpes Virus rRp450 Shows Efficacy in Orthotopic Xenograft Group 3/4 Medulloblastomas and Atypical Teratoid/Rhabdoid Tumors

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    Adam W. Studebaker

    2017-09-01

    Full Text Available Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA-approved to treat melanoma in adults. We evaluated the therapeutic potential of the clinically available oncolytic herpes simplex vector rRp450 in cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor. Cells of both tumor types were supportive of virus replication and virus-mediated cytotoxicity. Orthotopic xenograft models of medulloblastoma and atypical teratoid/rhabdoid tumors displayed significantly prolonged survival following a single, stereotactic intratumoral injection of rRp450. Furthermore, addition of the chemotherapeutic prodrug cyclophosphamide (CPA enhanced rRp450’s in vivo efficacy. In conclusion, oncolytic herpes viruses with the ability to bioactivate the prodrug CPA within the tumor microenvironment warrant further investigation as a potential therapy for pediatric brain tumors.

  5. Identification and Characterization of KCASH2 and KCASH3, 2 Novel Cullin3 Adaptors Suppressing Histone Deacetylase and Hedgehog Activity in Medulloblastoma

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    Enrico De Smaele

    2011-04-01

    Full Text Available Medulloblastoma is the most common pediatric malignant brain tumor, arising from aberrant cerebellar precursors' development, a process mainly controlled by Hedgehog (Hh signaling pathway. Histone deacetylase HDAC1 has been recently shown to modulate Hh signaling, deacetylating its effectors Gli1/2 and enhancing their transcriptional activity. Therefore, HDAC may represent a potential therapeutic target for Hh-dependent tumors, but still little information is available on the physiological mechanisms of HDAC regulation. The putative tumor suppressor RENKCTD11 acts through ubiquitination-dependent degradation of HDAC1, thereby affecting Hh activity and medulloblastoma growth. We identify and characterize here two RENKCTD11 homologues, defining a new family of proteins named KCASH, as “KCTD containing, Cullin3 adaptor, suppressor of Hedgehog.” Indeed, the novel genes (KCASH2KCTD21 and KCASH3KCTD6 share with RENKCTD11 a number of features, such as a BTB domain required for the formation of a Cullin3 ubiquitin ligase complex and HDAC1 ubiquitination and degradation capability, suppressing the acetylation-dependent Hh/Gli signaling. Expression of KCASH2 and -3 is observed in cerebellum, whereas epigenetic silencing and allelic deletion are observed in human medulloblastoma. Rescuing KCASHs expression reduces the Hedgehog-dependent medulloblastoma growth, suggesting that loss of members of this novel family of native HDAC inhibitors is crucial in sustaining Hh pathway-mediated tumorigenesis. Accordingly, they might represent a promising class of endogenous “agents” through which this pathway may be targeted.

  6. Treatment Results of Adults and Children with Medulloblastoma NCI, Cairo University Experience

    International Nuclear Information System (INIS)

    KHALIL, E.M.

    2008-01-01

    Purpose: To evaluate treatment outcome and prognostic factors of adults and pediatric medulloblastoma patients treated by adjuvant postoperative craniospinal irradiation (CSI) and chemotherapy. Patients and Methods: Between 1997 and 2004, 67 patients were treated in the National cancer Institute- Cairo University; 51 pediatric patients with a median age of 7 years and 16 adult patients with a median age of 25 years. According to the Chang staging system; 50%-35%, 37.5%-47% and 12.5%-18% had T2, T3 and T4 tumors of adults and pediatric patient's population respectively. M1, M2 and M4 were reported in 16%, 3% and in 1.5% respectively. All patients underwent primary surgical resection; near total resection in 25%, Subtotal resection in 61%; with tumor residual 2 in 49% compared to 51% with >1.5 cm 2 residual tumor and 14%, had biopsy only. All patients were treated by craniospinal radiotherapy (RT); with a median dose of 34 Gy to the whole brain, 54 Gy to the posterior fossa and 32 Gy to the spinal axis. The median interval between surgery and RT was 45 days and 38 days for the pediatric and adult groups respectively. The median duration of RT was 54 days and 52 days for pediatric and adult patients respectively. Thirty four pediatric patients (67%) received concomitant chemotherapy, while 61% received adjuvant (postoperative) chemotherapy and 57% received sequential chemotherapy. Only 33% of patients did not receive chemotherapy. The median follow-up was 49 months for the whole group of patients (range 11-121). Results: For the pediatric and adult patients, the 5- and 7-year overall and disease-free survival rates were 89% and 78% Vs. 84% and 56% and 80% and 68% Vs. 79% and 52% respectively. Fourteen patients (21%) relapsed (10 pediatric and 4 adults) at a median time of 11 months vs. 23 months and a median follow-up period of 8 and 12 months respectively; Neuro-axis was the most common site of relapse (11 patients). Ninety percent (9/10) of the pediatric relapses

  7. Medulloblastoma: time-dose relationship based on a 30-year review

    International Nuclear Information System (INIS)

    Charco, John O. del; Bolek, Timothy W.; McCollough, W. Mark; Maria, Bernard L.; Kedar, Amos; Braylan, Raul C.; Mickle, J. Parker; Buatti, John M.; Mendenhall, Nancy P.; Marcus, Robert B.

    1998-01-01

    Purpose: Time-dose relationships have proven important in many cancer sites. This study evaluates the time factors involved in the successful postoperative radiotherapy of medulloblastoma, based on a 30-year experience in a single institution. Methods and Materials: Fifty-three patients with medulloblastoma received postoperative craniospinal radiotherapy with curative intent between 1963 and 1993. Seven patients (13%) underwent biopsy alone, 28 patients (53%) had subtotal excision, and 18 patients (34%) had gross total excision. Eleven patients received adjuvant chemotherapy. The mean posterior fossa dose was 53.1 Gy; most patients received 54.0 Gy (range, 34.3 to 69.6 Gy). For 41 patients receiving once-a-day therapy, the mean dose was 50.6 Gy (range, 34.3 to 56.0 Gy). For 12 patients receiving twice-a-day therapy, the mean dose was 61.8 Gy (range, 52.6 to 69.6 Gy). Minimum follow-up was 2 years, and median follow-up was 10.7 years. Survival, freedom from relapse, and disease control in the posterior fossa were calculated using the Kaplan-Meier method, and multivariate analysis was performed for prognostic factors. Variables related to radiotherapy were examined, including dose to the craniospinal axis, dose to the posterior fossa, fractionation (once-a-day vs. twice-a-day), use of adjuvant chemotherapy, risk group [high (≥T3b or ≥M1) or low (≤T3a and M0-MX)], interval between surgery and radiotherapy (excluding patients receiving chemotherapy before radiotherapy), and duration of radiotherapy. Results: At 5 and 10 years, overall survival rates were 68 and 64%, respectively, and freedom-from-relapse rates were 61 and 52%, respectively. Rates of disease control in the posterior fossa at 5 and 10 years were 79 and 68%, respectively. At 5 years, absolute survival rates after biopsy alone, subtotal excision, and gross total excision were 43, 67, and 78%, respectively (p = 0.04), and posterior fossa control rates were 27, 89, and 83%, respectively (p = 0

  8. Chronic subdural hematoma associated with moyamoya phenomenon after radiotherapy for medulloblastoma; A case report

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    Fuse, Takahisa; Takagi, Takuji; Fukushima, Tsuneyuki; Mizuno, Shiroh; Hashimoto, Nobukazu; Suzuki, Osamu (Nagoya City Higashi General Hospital (Japan))

    1994-04-01

    A 9-year-old boy had been diagnosed at the age of 9 months as having a cerebellar medulloblastoma and had received 40 Gy of radiation therapy to the brain after removal of the tumor. Cerebral angiography at the time of initial diagnosis did not show any evidence of occlusive disease involving the internal carotid circulation. At the age of 6 years, the patient developed generalized seizures. On examination, he was drowsy and had right hemiparesis. CT scan demonstrated a low-density area in the left frontal lobe. Cerebral angiography showed a marked narrowing of the bilateral internal carotid arteries with moyamoya vessels. The patient was treated medically with aspirin (100 mg/day) and anticonvulsants. His neurological deficits improved gradually. At the age of 8 years, there was no recurrence of the tumor although a slight left subdural hematoma was seen on CT scan. On August 10, 1993, at the age of 9 years, he was admitted for treatment of a developing subdural hematoma. MRI showed a chronic subdural hematoma with thick outer and inner membranes. Cerebral angiography showed occlusion of the left internal carotid artery which fed the right frontal lobe through moyamoya vessels, marked narrowing of the right internal carotid artery distal to the ophthalmic artery, moyamoya vessels at the base, and cortical revascularization througth the ophthalmic, posterior cerebral and middle meningeal arteries. Trepanation and aspiration of the hematoma were performed. The outer membrane of the hematoma was about 2 mm thick and the hematoma cavity was filled with a partially organized hematoma. In this case, we speculate that development of the chronic subdural hematoma involved the following factors: (1) transdural external-internal carotid anastomosis after radiation-induced cerebrovasculopathy; (2) repeated mild head trauma due to gait disturbance after removal of the cerebellar tumor; and (3) administration of acetylsalicylic acid. (author).

  9. Differential immune microenvironments and response to immune checkpoint blockade amongst molecular subtypes of murine medulloblastoma

    Science.gov (United States)

    Pham, Christina D.; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M.; Yearley, Jennifer H.; Sayour, Elias J.; Pei, Yanxin; Moore, Colin; McLendon, Roger E.; Huang, Jianping; Sampson, John H.; Wechsler-Reya, Robert; Mitchell, Duane A.

    2016-01-01

    PURPOSE Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma (MB), the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and Group 3 MB for preclinical evaluation in immunocompetent C57BL/6 mice. METHODS AND RESULTS Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid derived suppressor cells and tumor-associated macrophages in murine SHH model tumors compared with Group 3 tumors. However, murine Group 3 tumors had higher percentages of CD8+ PD-1+ T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial Group 3 tumors compared to SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1+ peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3+ T cells within the tumor microenvironment. CONCLUSIONS This is the first immunologic characterization of preclinical models of molecular subtypes of MB and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. PMID:26405194

  10. High promoter hypermethylation frequency of p14/ARF in supratentorial PNET but not in medulloblastoma.

    Science.gov (United States)

    Inda, M M; Muñoz, J; Coullin, P; Fauvet, D; Danglot, G; Tuñón, T; Bernheim, A; Castresana, J S

    2006-04-01

    Medulloblastoma (MB) is the most common primitive neuroectodermal tumour (PNET) of the central nervous system. Although supratentorial PNET (sPNET) and MB are histologically similar, their clinical behaviour differs, sPNET being more aggressive than MB. The aim of this study was to determine whether sPNET and MB are genetically different entities. We investigated 32 PNET primary tumour samples (23 MB and nine sPNET) and four PNET cell lines, for the presence of CDKN2A homozygous deletions at exon 1-alpha of p16/INK4 and exon 1-beta of p14/ARF, and promoter hypermethylation of both genes. No homozygous deletion of either p16/INK4 or p14/ARF was demonstrated in any of the PNET primary tumour samples. Methylation of p16/INK4 was found in one of six sPNET and in one of 23 MB, while p14/ARF methylation was observed in three of six sPNET and in three of 21 MB. No methylation of p16/INK4 or p14/ARF was found in any of the PNET cell lines analysed. The three MB cell lines did not show p16/INK4 expression, and only the MB Daoy cell line (homozygously deleted at CDKN2A) presented loss of p14/ARF expression. Our results in this limited series of central PNET show that p14/ARF is frequently involved in PNET carcinogenesis, with a higher frequency, but not statistically significant, for sPNET than for MB.

  11. Role of the miR-17∼92 cluster family in cerebellar and medulloblastoma development

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    Frederique Zindy

    2014-06-01

    Full Text Available The miR-17∼92 cluster family is composed of three members encoding microRNAs that share seed sequences. To assess their role in cerebellar and medulloblastoma (MB development, we deleted the miR-17∼92 cluster family in Nestin-positive neural progenitors and in mice heterozygous for the Sonic Hedgehog (SHH receptor Patched 1 (Ptch1+/−. We show that mice in which we conditionally deleted the miR-17∼92 cluster (miR-17∼92floxed/floxed; Nestin-Cre+ alone or together with the complete loss of the miR-106b∼25 cluster (miR-106b∼25−/− were born alive but with small brains and reduced cerebellar foliation. Remarkably, deletion of the miR-17∼92 cluster abolished the development of SHH-MB in Ptch1+/− mice. Using an orthotopic transplant approach, we showed that granule neuron precursors (GNPs purified from the cerebella of postnatal day 7 (P7 Ptch1+/−; miR-106b∼25−/− mice and overexpressing Mycn induced MBs in the cortices of naïve recipient mice. In contrast, GNPs purified from the cerebella of P7 Ptch1+/−; miR-17∼92floxed/floxed; Nestin-Cre+ animals and overexpressing Mycn failed to induce tumors in recipient animals. Taken together, our findings demonstrate that the miR-17∼92 cluster is dispensable for cerebellar development, but required for SHH-MB development.

  12. Ototoxicity After Intensity-Modulated Radiation Therapy and Cisplatin-Based Chemotherapy in Children With Medulloblastoma

    International Nuclear Information System (INIS)

    Paulino, Arnold C.; Lobo, Mark; Teh, Bin S.; Okcu, M. Fatih; South, Michael; Butler, E. Brian; Su, Jack; Chintagumpala, Murali

    2010-01-01

    Purpose: To report the incidence of Pediatric Oncology Group (POG) Grade 3 or 4 ototoxicity in a cohort of patients treated with craniospinal irradiation (CSI) followed by posterior fossa (PF) and/or tumor bed (TB) boost using intensity-modulated radiation therapy (IMRT). Methods and Materials: From 1998 to 2006, 44 patients with medulloblastoma were treated with CSI followed by IMRT to the PF and/or TB and cisplatin-based chemotherapy. Patients with standard-risk disease were treated with 18 to 23.4 Gy CSI followed by either a (1) PF boost to 36 Gy and TB boost to 54 to 55.8 Gy or (2) TB boost to 55.8 Gy. Patients with high-risk disease received 36 to 39.6 Gy CSI followed by a (1) PF boost to 54 to 55.8 Gy, (2) PF boost to 45 Gy and TB boost to 55.8 Gy, or (3) TB boost to 55.8 Gy. Median audiogram follow-up was 41 months (range, 11-92.4 months). Results: POG Grade Ototoxicity 0, 1, 2, 3. and 4 was found in 29, 32, 11, 13. and 3 ears. respectively, with POG Grade 3 or 4 accounting for 18.2% of cases. There was a statistically significant difference in mean radiation dose (D mean ) cochlea according to degree of ototoxicity, with D mean cochlea increasing with severity of hearing loss (p = 0.027). Conclusions: Severe ototoxicity was seen in 18.2% of ears in children treated with IMRT boost and cisplatin-based chemotherapy. Increasing dose to the cochlea was associated with increasing severity of hearing loss.

  13. The clinical significance of equivocal findings on spinal MRI in children with medulloblastoma.

    Science.gov (United States)

    Bennett, Julie; Ashmawy, Ramy; Ramaswamy, Vijay; Stephens, Derek; Bouffet, Eric; Laperriere, Normand; Taylor, Michael; Shroff, Manohar; Bartels, Ute

    2017-08-01

    Medulloblastoma (MB) is the most common malignant brain tumor of childhood, with cerebrospinal fluid spread the most common site of metastasis. Currently, children diagnosed with MB and evidence of spinal metastasis are treated with an increased dose of craniospinal radiation (CSI). This report reviewed equivocal abnormalities including nerve root clumping, linear vascular enhancement, nerve root enhancement and/or other vague findings on spinal magnetic resonance imaging (MRI) to elucidate their prognostic significance and aid in risk stratification. This retrospective cohort study identified children (≥3 years) diagnosed with MB between 1988 and 2012. Children treated with upfront CSI were included, and staging spine MRI must have been done preoperatively or within 72 hr of primary tumor resection. Initial MRI of the spine was assessed by two independent reviewers blinded to outcome to evaluate for equivocal findings. Survival analysis was done to determine impact on prognosis. One hundred of 157 patients were eligible for the analysis. Equivocal findings were identified in 48 (48%) patients, with MRI done preoperatively in 45 (94%) patients. Analysis by subgroup identified a higher proportion of equivocal findings in the sonic hedgehog (SHH) subgroup (P = 0.007). Five-year overall survival (OS) in children with equivocal findings compared to those with normal MRI was not different, 80 vs. 84.8% respectively, while OS in M3 patients was worse at 54.7% (P = 0.02). A higher proportion of equivocal findings was identified in the SHH subgroup. This institutional retrospective review demonstrates equivocal findings are common, not associated with decreased OS and should not prompt increased dose of CSI. © 2017 Wiley Periodicals, Inc.

  14. Downregulation of 14q32 microRNAs in primary human desmoplastic medulloblastoma.

    Directory of Open Access Journals (Sweden)

    Danielle Ribeiro Lucon

    2013-09-01

    Full Text Available Medulloblastoma (MB is one of the most common pediatric cancers, likely originating from abnormal development of cerebellar progenitor neurons. MicroRNA (miRNA has been shown to play an important role in the development of the central nervous system. Microarray analysis was used to investigate miRNA expression in desmoplastic MB from patients diagnosed at a young age (1 or 2 years old. Normal fetal or newborn cerebellum was used as control. A total of 84 differentially expressed miRNAs (64 downregulated and 20 upregulated were found. Most downregulated miRNAs (32/64 were found to belong to the cluster of miRNAs at the 14q32 locus, suggesting that this miRNA locus is regulated as a module in MB. Possible mechanisms of 14q32 miRNAs downregulation were investigated by the analysis of publicly available gene expression data sets. First, expression of estrogen-related receptor γ (ESRRG, a reported positive transcriptional regulator of some 14q32 miRNAs, was found downregulated in desmoplastic MB. Second, expression of the parentally imprinted gene MEG3 was lower in MB in comparison to normal cerebellum, suggesting a possible epigenetic silencing of the 14q32 locus. miR-129-5p (11p11.2/7q32.1, miR-206 (6p12.2, and miR-323-3p (14q32.2, were chosen for functional studies in DAOY cells. Overexpression of miR-129-5p using mimics decreased DAOY proliferation. No effect was found with miR-206 or miR-323 mimics.

  15. Ecto-5'-Nucleotidase Overexpression Reduces Tumor Growth in a Xenograph Medulloblastoma Model.

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    Angélica R Cappellari

    Full Text Available Ecto-5'-nucleotidase/CD73 (ecto-5'-NT participates in extracellular ATP catabolism by converting adenosine monophosphate (AMP into adenosine. This enzyme affects the progression and invasiveness of different tumors. Furthermore, the expression of ecto-5'-NT has also been suggested as a favorable prognostic marker, attributing to this enzyme contradictory functions in cancer. Medulloblastoma (MB is the most common brain tumor of the cerebellum and affects mainly children.The effects of ecto-5'-NT overexpression on human MB tumor growth were studied in an in vivo model. Balb/c immunodeficient (nude 6 to 14-week-old mice were used for dorsal subcutaneous xenograph tumor implant. Tumor development was evaluated by pathophysiological analysis. In addition, the expression patterns of adenosine receptors were verified.The human MB cell line D283, transfected with ecto-5'-NT (D283hCD73, revealed reduced tumor growth compared to the original cell line transfected with an empty vector. D283hCD73 generated tumors with a reduced proliferative index, lower vascularization, the presence of differentiated cells and increased active caspase-3 expression. Prominent A1 adenosine receptor expression rates were detected in MB cells overexpressing ecto-5'-NT.This work suggests that ecto-5'-NT promotes reduced tumor growth to reduce cell proliferation and vascularization, promote higher differentiation rates and initiate apoptosis, supposedly by accumulating adenosine, which then acts through A1 adenosine receptors. Therefore, ecto-5'-NT might be considered an important prognostic marker, being associated with good prognosis and used as a potential target for therapy.

  16. Molecular and in vivo characterization of cancer-propagating cells derived from MYCN-dependent medulloblastoma.

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    Zai Ahmad

    Full Text Available Medulloblastoma (MB is the most common malignant pediatric brain tumor. While the pathways that are deregulated in MB remain to be fully characterized, amplification and/or overexpression of the MYCN gene, which is has a critical role in cerebellar development as a regulator of neural progenitor cell fate, has been identified in several MB subgroups. Phenotypically, aberrant expression of MYCN is associated with the large-cell/anaplastic MB variant, which accounts for 5-15% of cases and is associated with aggressive disease and poor clinical outcome. To better understand the role of MYCN in MB in vitro and in vivo and to aid the development of MYCN-targeted therapeutics we established tumor-derived neurosphere cell lines from the GTML (Glt1-tTA/TRE-MYCN-Luc genetically engineered mouse model. A fraction of GTML neurospheres were found to be growth factor independent, expressed CD133 (a marker of neural stem cells, failed to differentiate upon MYCN withdrawal and were highly tumorigenic when orthotopically implanted into the cerebellum. Principal component analyzes using single cell RNA assay data suggested that the clinical candidate aurora-A kinase inhibitor MLN8237 converts GTML neurospheres to resemble non-MYCN expressors. Correlating with this, MLN8237 significantly extended the survival of mice bearing GTML MB allografts. In summary, our results demonstrate that MYCN plays a critical role in expansion and survival of aggressive MB-propagating cells, and establish GTML neurospheres as an important resource for the development of novel therapeutic strategies.

  17. EphrinB1 expression is dysregulated and promotes oncogenic signaling in medulloblastoma.

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    McKinney, Nicole; Yuan, Liangping; Zhang, Hongying; Liu, Jingbo; Cho, Yoon-Jae; Rushing, Elisabeth; Schniederjan, Matthew; MacDonald, Tobey J

    2015-01-01

    Eph receptors and ephrin ligands are master regulators of oncogenic signaling required for proliferation, migration, and metastasis. Yet, Eph/ephrin expression and activity in medulloblastoma (MB), the most common malignant brain tumor of childhood, remains poorly defined. We hypothesized that Eph/ephrins are differentially expressed by sonic hedgehog (SHH) and non-SHH MB and that specific members contribute to the aggressive phenotype. Affymetrix gene expression profiling of 29 childhood MB, separated into SHH (N = 11) and non-SHH (N = 18), was performed followed by protein validation of selected Eph/ephrins in another 60 MB and two MB cell lines (DAOY, D556). Functional assays were performed using MB cells overexpressing or deleted for selected ephrins. We found EPHB4 and EFNA4 almost exclusively expressed by SHH MB, whereas EPHA2, EPHA8, EFNA1 and EFNA3 are predominantly expressed by non-SHH MB. The remaining family members, except EFNB1, are ubiquitously expressed by over 70-90 % MB, irrespective of subgroup. EFNB1 is the only member differentially expressed by 28 % of SHH and non-SHH MB. Corresponding protein expression for EphB/ephrinB1 and B2 was validated in MB. Only ephrinB2 was also detected in fetal cerebellum, indicating that EphB/ephrinB1 expression is MB-specific. EphrinB1 immunopositivity localizes to tumor cells within MB with the highest proliferative index. EphrinB1 overexpression promotes EphB activation, alters F-actin distribution and morphology, decreases adhesion, and significantly promotes proliferation. Either silencing or overexpression of ephrinB1 impairs migration. These results indicate that EphrinB1 is uniquely dysregulated in MB and promotes oncogenic responses in MB cells, implicating ephrinB1 as a potential target.

  18. Diffusion profiling of tumor volumes using a histogram approach can predict proliferation and further microarchitectural features in medulloblastoma.

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    Schob, Stefan; Beeskow, Anne; Dieckow, Julia; Meyer, Hans-Jonas; Krause, Matthias; Frydrychowicz, Clara; Hirsch, Franz-Wolfgang; Surov, Alexey

    2018-05-31

    Medulloblastomas are the most common central nervous system tumors in childhood. Treatment and prognosis strongly depend on histology and transcriptomic profiling. However, the proliferative potential also has prognostical value. Our study aimed to investigate correlations between histogram profiling of diffusion-weighted images and further microarchitectural features. Seven patients (age median 14.6 years, minimum 2 years, maximum 20 years; 5 male, 2 female) were included in this retrospective study. Using a Matlab-based analysis tool, histogram analysis of whole apparent diffusion coefficient (ADC) volumes was performed. ADC entropy revealed a strong inverse correlation with the expression of the proliferation marker Ki67 (r = - 0.962, p = 0.009) and with total nuclear area (r = - 0.888, p = 0.044). Furthermore, ADC percentiles, most of all ADCp90, showed significant correlations with Ki67 expression (r = 0.902, p = 0.036). Diffusion histogram profiling of medulloblastomas provides valuable in vivo information which potentially can be used for risk stratification and prognostication. First of all, entropy revealed to be the most promising imaging biomarker. However, further studies are warranted.

  19. Late effects of craniospinal irradiation for standard risk medulloblastoma in paediatric patients: A comparison of treatment techniques

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    Leman, J.

    2016-01-01

    Background: Survival rates for standard risk medulloblastoma are favourable, but craniospinal irradiation (CSI) necessary to eradicate microscopic spread causes life limiting late effects. Aims: The aim of this paper is to compare CSI techniques in terms of toxicity and quality of life for survivors. Methods and materials: A literature search was conducted using synonyms of ‘medulloblastoma’, ’craniospinal’, ‘radiotherapy’ and ‘side effects’ to highlight 29 papers that would facilitate this discussion. Results and discussion: Intensity modulated radiotherapy (IMRT), tomotherapy and protons all provide CSI which can reduce dose to normal tissue, however photon methods cannot eliminate exit dose as well as protons can. Research for each technique requires longer term follow up in order to prove that survival rates remain high whilst reducing late effects. Findings/conclusion: Proton therapy is the superior method of CSI in term of late effects, but more research is needed to evidence this. Until proton therapy is available in the UK IMRT should be utilised. - Highlights: • Craniospinal irradiation is vital in the treatment of medulloblastoma. • Survivors often suffer long term side effects which reduce quality of life. • Tomotherapy, IMRT and proton therapy reduce late effects by sparing normal tissue. • Proton therapy offers superior dose distribution but further research is necessary. • IMRT should be employed for photon radiotherapy.

  20. A female survivor of childhood medulloblastoma presenting with growth-hormone-induced edema and inflammatory lesions: a case report

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    Biassoni Veronica

    2009-01-01

    Full Text Available Abstract Introduction The improved survival of children with brain tumors has increased concerns about treatment-related sequelae. Growth hormone deficiency is frequently observed after craniospinal irradiation for medulloblastoma. It has been widely reported that growth hormone replacement therapy does not increase the risk of second tumors, but there are reports in the literature of growth hormone, and its downstream mediator insulin-like Growth Factor 1, having an important proinflammatory action. There are few reports, however, on the "in-vivo" induction of edema and symptomatic inflammatory lesions during replacement therapy. Case presentation We report the case of a 7-year-old girl treated for metastatic medulloblastoma who developed growth hormone deficiency 2 years after oncological treatment. Three months after replacement therapy, magnetic resonance imaging showed exacerbation of her brain edema, which was already present after oncological treatment. We consequently suspended the growth hormone until a new magnetic resonance image obtained 3 months later documented a reduction of the inflammatory areas. We then re-introduced somatotropin at lower doses with no further increase in brain edema in subsequent radiological controls. Conclusion This case and its iconography suggest a strong association between growth hormone administration and the exacerbation of inflammatory reactions within the tumor bed. Replacement therapy should be carefully monitored in this particular subset of patients.

  1. Comparison of risk of radiogenic second cancer following photon and proton craniospinal irradiation for a pediatric medulloblastoma patient

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    Zhang, Rui; Howell, Rebecca M.; Giebeler, Annelise; Taddei, Phillip J.; Mahajan, Anita; Newhauser, Wayne D.

    2013-02-01

    Pediatric patients who received radiation therapy are at risk of developing side effects such as radiogenic second cancer. We compared proton and photon therapies in terms of the predicted risk of second cancers for a 4 year old medulloblastoma patient receiving craniospinal irradiation (CSI). Two CSI treatment plans with 23.4 Gy or Gy (RBE) prescribed dose were computed: a three-field 6 MV photon therapy plan and a four-field proton therapy plan. The primary doses for both plans were determined using a commercial treatment planning system. Stray radiation doses for proton therapy were determined from Monte Carlo simulations, and stray radiation doses for photon therapy were determined from measured data. Dose-risk models based on the Biological Effects of Ionization Radiation VII report were used to estimate the risk of second cancer in eight tissues/organs. Baseline predictions of the relative risk for each organ were always less for proton CSI than for photon CSI at all attained ages. The total lifetime attributable risk of the incidence of second cancer considered after proton CSI was much lower than that after photon CSI, and the ratio of lifetime risk was 0.18. Uncertainty analysis revealed that the qualitative findings of this study were insensitive to any plausible changes of dose-risk models and mean radiation weighting factor for neutrons. Proton therapy confers lower predicted risk of second cancer than photon therapy for the pediatric medulloblastoma patient.

  2. Nos2 inactivation promotes the development of medulloblastoma in Ptch1(+/- mice by deregulation of Gap43-dependent granule cell precursor migration.

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    Daniel Haag

    Full Text Available Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1(+/- mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1(+/- mice with mice lacking inducible nitric oxide synthase (Nos2 to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1(+/- Nos2(-/- mice compared to Ptch1(+/- Nos2(+/+ mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1(+/+ Nos2(-/- mice but not from Ptch1(+/- Nos2(-/- mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43. Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1(+/+ Nos2(-/- mice but increased in Ptch1(+/- Nos2(-/ (- mice relative to Ptch1(+/- Nos2(+/+ mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1(+/- mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during

  3. Differential induction of p53-mediated apoptosis in medulloblastomas and gliomas correlates with their ability to induce bax

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    Shu, H.-K.G.; Furman, Felix; Dee, Suzanne; Israel, Mark A.

    1997-01-01

    Purpose/Objective: Medulloblastoma cell lines readily undergo a p53-mediated apoptosis following exposure to ionizing radiation, while glioma cell lines do not undergo significant levels of apoptosis following irradiation. This study attempts to define some of the molecular events that characterize the differential ability medulloblastomas and gliomas to undergo radiation-induced apoptosis. Materials and Methods: The medulloblastoma cell lines D283 and D341 and the glioma cell lines U87, U343 and U563 were used in this study. All five cell lines were confirmed to have a wild type p53 by their ability to induce p21 protein levels and to undergo a cell-cycle arrest in G1 following treatment with ionizing radiation. Also, 3 clonal derivatives of D283 were used. Two of the clones were derived following transfection with an expression plasmid containing a dominant negative mutant p53 (Arg175 --> His) expressed from the CMV promoter (D283/53.6 and D283/53.7), while the remaining clone was derived following transfection with that same expression plasmid without mutant p53 (D283/vec). All irradiation experiments were performed on Phillips RT-250 X-ray unit using 250 Kvp X-rays. In each case, 5 Gy of ionizing radiation was given at a dose rate of 250 cGy/minute. Apoptosis was quantitated by staining fixed cells with propidium iodide and determining the percentage of cells with subdiploid DNA content by flow cytometry. Northern blot analysis was performed using standard methods. Results: The D283 and D341 cell lines exhibited a significant induction of apoptosis when assayed 2 days following treatment with radiation while the U87, U343 and U563 cell lines displayed only minimal induction of apoptosis when assayed following treatment at that time. RNA was prepared from the different cell lines that were unirradiated, 6 hours or 24 hours post-irradiation. Northern blots were made of the total RNAs and probed for bax, bcl-2 and bcl-x mRNA. This analysis detected no significant

  4. Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells

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    Helson Lawrence

    2007-01-01

    Full Text Available Abstract Background With current treatment strategies, nearly half of all medulloblastoma (MB patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to correlate with anaplasia and unfavorable prognosis. In neuroblastoma – an embryonal tumor with biological similarities to MB – the quassinoid NBT-272 has been demonstrated to inhibit cellular proliferation and to down-regulate c-MYC protein expression. Methods To study MB cell responses to NBT-272 and their dependence on the level of c-MYC expression, DAOY (wild-type, empty vector transfected or c-MYC transfected, D341 (c-MYC amplification and D425 (c-MYC amplification human MB cells were used. The cells were treated with different concentrations of NBT-272 and the impact on cell proliferation, apoptosis and c-MYC expression was analyzed. Results NBT-272 treatment resulted in a dose-dependent inhibition of cellular proliferation (IC50 in the range of 1.7 – 9.6 ng/ml and in a dose-dependent increase in apoptotic cell death in all human MB cell lines tested. Treatment with NBT-272 resulted in up to 90% down-regulation of c-MYC protein, as demonstrated by Western blot analysis, and in a significant inhibition of c-MYC binding activity. Anti-proliferative effects were slightly more prominent in D341 and D425 human MB cells with c-MYC amplification and slightly more pronounced in c-MYC over-expressing DAOY cells compared to DAOY wild-type cells. Moreover, treatment of synchronized cells by NBT-272 induced a marked cell arrest at the G1/S boundary. Conclusion In human MB cells, NBT-272 treatment inhibits cellular proliferation at nanomolar concentrations, blocks cell cycle progression, induces apoptosis, and down-regulates the expression of the oncogene c-MYC. Thus, NBT-272 may represent a novel drug candidate to inhibit

  5. Craniospinal versus whole brain irradiation in Medulloblastoma patients, with introduction of utilizing a simple immobilization device

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    Haddad P

    2001-05-01

    Full Text Available Craniospinal irradiation plus posterior fossa boost (CS1 is the standard modality of post-operative treatment of patient with medulloblastoma, but considering the technical difficulties and limited facilities, often whole- brain irradiation plus posterior fossa boost (WBI had been used in our institution until 1991. Tust a retrospective study was undertaken to compare the patients treated by By WBI and CSI for recurrences and disease-free survival (DFS. Files of all medullobalstoma patients treated post-operatively in our department in the 10 – year period of 1986-1996 were reviewed. To obtain the best possible follow- up, a formal inquiry letter was mailed to all patients’ addresses.Total of 72 patients had been treated, with a mean age of 14.7 years and male-to-female ratio of 1.5:1 Thirty –seven patients had been treated by WBI and 35 by CS. A simple wooden device designed and made in our department was used for CSI patients’ set-up and immobilization. Mean radiation dose to posterior fossa was 4, 765 cGy in WBT and 5, 071 cGY in CSI (180-200 cGy fractions. Sixty-two patients (85% came back for follow-up, with 24 recurrences. Only 24% of CSI patients had recurrences, versus 51% in WBI Nearly all Wbi recurrences versus half of the CSI recurrences were spinal. DFS was 39 months in CSI and 26 months in WBI (P<0.001 . in multi-factorial analysis, only the extent of radiation (CSI versus WBI, P<0.001 was statistically significant. Mean age in our patients was higher than what is commonly reported in literature. The immobilization device introduce was a simple and useful accessory to CSI. Considering DFS, CSI in our department was acceptabley comparable to literature results and significantly superior to WBI. With regard to relatively high spinal recurrence rate even in CSI, the importance of suitable spinal cytological and imaging evaluation is again emphasized.

  6. In vivo bioluminescence imaging for leptomeningeal dissemination of medulloblastoma in mouse models

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    Choi, Seung Ah; Kwak, Pil Ae; Kim, Seung-Ki; Park, Sung-Hye; Lee, Ji Yeoun; Wang, Kyu-Chang; Oh, Hyun Jeong; Kim, Kyuwan; Lee, Dong Soo; Hwang, Do Won; Phi, Ji Hoon

    2016-01-01

    The primary cause of treatment failure in medulloblastomas (MB) is the development of leptomeningeal dissemination (seeding). For translational research on MB seeding, one of the major challenges is the development of reliable experimental models that simulate the seeding and growth characteristics of MBs. To overcome this obstacle, we improved an experimental mouse model by intracisternal inoculation of human MB cells and monitoring with in vivo live images. Human MB cells (UW426, D283 and MED8A) were transfected with a firefly luciferase gene and a Thy1.1 (CD90.1) marker linked with IRES under the control of the CMV promoter in a retroviral DNA backbone (effLuc). The MB-effLuc cells were injected into the cisterna magna using an intrathecal catheter, and bioluminescence images were captured. We performed histopathological analysis to confirm the extent of tumor seeding. The luciferase activity of MB-effLuc cells displayed a gradually increasing pattern, which correlated with a quantitative luminometric assay. Live imaging showed that the MB-effLuc cells were diffusely distributed in the cervical spinal cord and the lumbosacral area. All mice injected with UW426-effLuc, D283-effLuc and MED8A-effLuc died within 51 days. The median survival was 22, 41 and 12 days after injection of 1.2 × 10 6 UW426-effLuc, D283-effLuc and MED8A-effLuc cells, respectively. The histopathological studies revealed that the MB-effLuc cells spread extensively and diffusely along the leptomeninges of the brain and spinal cord, forming tumor cell-coated layers. The tumor cells in the subarachnoid space expressed a human nuclei marker and Ki-67. Compared with the intracerebellar injection method in which the subfrontal area and distal spinal cord were spared by tumor cell seeding in some mice, the intracisternal injection model more closely resembled the widespread leptomeningeal seeding observed in MB patients. The results and described method are valuable resources for further

  7. Importance of radiation time and dose factors on outcome for childhood medulloblastoma

    International Nuclear Information System (INIS)

    Back, M.; Barton, M.

    2005-01-01

    The purpose of this study was to investigate the relationship of posterior fossa radiation therapy duration (PFRTD) and relapse-free survival (RFS) following adjuvant craniospinal RT for childhood medulloblastoma. A retrospective audit was performed assessing all children aged 180days) pre-RT chemotherapy were excluded. Data were obtained for potential prognostic factors in domains of patient, tumour and treatment factors. Radiation therapy time factors assessed were PFRTD and time interval from surgery to commencement of RT (SRTD). The end-point assessed was RFS and analysis was performed using Cox regression and Kaplan-Meier survival. One hundred and eighty-nine children were identified from 10 oncology units, with data available from 182 children for analysis. Median follow up was 5.3 years. Seventy-three per cent of children presented with disease confined to the cerebellum; 13% had initial neuraxis disease. Macroscopic resection was described in 54%; 42% received adjuvant chemotherapy. Median RT dose and RT duration to PF was 55 Gy and 45 days, respectively. Seventy-eight relapses occurred with a 10-year actuarial RFS of 58.2% (standard error±4%). On univariate analysis, increasing PF dose (P = 0.002), age >5 years (P 0.006), and more thorough extent of surgical resection (P - 0.043) were associated with improved RFS; PFRTD (P = 0.20) and SRTD (P = 0.51) were not associated with RFS. On multivariate analysis, although both PF dose (P 0.004) and extent of surgery (P = 0.045) remained strongly significant, RT duration was now associated with RFS (P = 0.049). Other factors assessed that did not reach significance were patient age, local tumour extent, presence of internal shunt and use of chemotherapy. The importance of local treatment factors was confirmed in this audit with established prognostic factors such as primary tumour macroscopic resection and adequate PF RT dose being associated with RFS. A treatment time effect is weakly suggested, although less

  8. Apoptosis induced by knockdown of uPAR and MMP-9 is mediated by inactivation of EGFR/STAT3 signaling in medulloblastoma.

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    Ramaprasada Rao Kotipatruni

    Full Text Available Medulloblastoma is a highly invasive cancer of central nervous system diagnosed mainly in children. Matrix metalloproteinase-9 (MMP-9 and urokinase plasminogen activator receptor (uPAR are over expressed in several cancers and well established for their roles in tumor progression. The present study is aimed to determine the consequences of targeting these molecules on medulloblastoma progression.Radiation is one of the foremost methods applied for treating cancer and considerable evidence showed that radiation elevated uPAR and MMP-9 expression in medulloblastoma cell. Therefore efforts are made to target these molecules in non-irradiated and irradiated medulloblastoma cells. Our results showed that siRNA-mediated knockdown of uPAR and MMP-9, either alone or in combination with radiation modulated a series of events leading to apoptosis. Down regulation of uPAR and MMP-9 inhibited the expression of anti-apoptotic molecules like Bcl-2, Bcl-xL, survivin, XIAP and cIAPI; activated BID cleavage, enhanced the expression of Bak and translocated cyctochrome C to cytosol. Capsase-3 and -9 activities were also increased in uPAR- and MMP-9-downregulated cells. The apoptosis induced by targeting MMP-9 and uPAR was initiated by inhibiting epidermal growth factor receptor (EGFR mediated activation of STAT3 and NF-κB related signaling molecules. Silencing uPAR and MMP-9 inhibited DNA binding activity of STAT3 and also reduced the recruitment of STAT3 protein at the promoter region of Bcl-2 and survivin genes. Our results suggest that inhibiting uPAR and MMP-9 reduced the expression of anti-apoptotic molecules by inactivating the transcriptional activity of STAT3. In addition, treating pre-established medulloblastoma with siRNAs against uPAR and MMP-9 both alone or in combination with radiation suppressed uPAR, MMP-9, EGFR, STAT3 expression and induced Bak activation leading to apoptosis.Taken together, our results illustrated that RNAi mediated targeting of

  9. Patterns of failure following treatment for medulloblastoma: is it necessary to treat the entire posterior fossa?

    International Nuclear Information System (INIS)

    Fukunaga-Johnson, Nina; Lee, Jason H.; Robertson, Patricia; Sandler, Howard M.; McNeil, Elizabeth; Goldwein, Joel W.

    1997-01-01

    Purpose: Craniospinal radiation (CSRT) followed by a boost to the entire posterior fossa (PF) is standard post-operative therapy for patients with medulloblastoma. A large proportion of recurrences after treatment are local with approximately 50-70% of recurrences occurring in the PF. It is unclear, however, whether these failures are occurring in the original tumor bed, or outside the tumor bed but still within the PF. With improved diagnostic imaging, better definition of tumor volumes, and the use of 3D conformal therapy, we may be able to restrict the boost volume to the tumor bed plus a margin without compromising local control. This retrospective study analyzes the patterns of failure within the PF of a series of patients treated with radiation therapy (RT). Methods: From (7(86)) through (2(96)), 27 of 114 (24%) patients > 18 mo and < 18 yr with medulloblastoma, who were treated at the University of Michigan and Children's Hospital of Philadelphia, with RT following surgical resection were found to have a recurrence. RT consisted of CSRT followed by a boost to the entire posterior fossa. Patient's preoperative MRI and/or CT studies were used to compare the original tumor volume with the specific region of local relapse. Failure was defined as MRI or CT evidence of recurrence or positive cerebrospinal fluid cytology. Relapse was scored as local, if it was within the original tumor bed and regional, if it was outside of the tumor bed but still within the PF. Results: The median age of the patients was 8.6 years. Three patients were < 3 years old. (21(27)) had disease localized to the PF. (19(21)) patients received chemotherapy during their treatment regimen; 6 patients did not have information on systemic treatment. The median dose of RT to the craniospinal axis was 32.5 Gy and to the PF was 55.2 Gy. The median time to recurrence was 19.5 months. Local failure within the tumor bed as any component of first failure occurred in 52% ((14(27))) of all failures but

  10. Hyperfractionated craniospinal radiotherapy and adjuvant chemotherapy for children with newly diagnosed medulloblastoma and other primitive neuroectodermal tumors

    International Nuclear Information System (INIS)

    Allen, Jeffrey C.; Donahue, Bernadine; DaRosso, Robert; Nirenberg, Anita

    1996-01-01

    Purpose: This single-institution Phase I/II study conducted from 1989 to 1995 evaluates the feasibility of a multi-modality protocol combining hyperfractionated craniospinal radiotherapy (HFRT) followed by adjuvant chemotherapy in 23 patients with newly diagnosed primitive neuroectodermal tumors (PNET) arising in the central nervous system. Methods and Materials: All 23 patients had a histologically confirmed PNET and were over 3 years of age at diagnosis. The eligibility criteria for PNET patients with cerebellar primaries (medulloblastoma) included either a high T stage (T3b or 4) or high M stage (M1-3). All patients with noncerebellar primaries were eligible regardless of T or M stage. The median age of the 23 patients was 9 years (mean 3-25); 11 were female. The primary tumor arose in the cerebellum in 19. Of these medulloblastoma patients, 15 had high T stages (T3b or T4) with large locally invasive tumors and no evidence of metastases (M0), constituting Group 1. Thirteen (86%) of these patients had gross total resections. Four other medulloblastoma patients had both high T and high M stages, constituting Group 2. Group 3 consisted of four other patients with exocerebellar primaries (two brain, one brain stem, and one cauda equina), three of whom were M3. Hyperfractionated radiotherapy was administered within 4 weeks of surgery. Twice-daily 1-Gy fractions were administered separated by 4-6 h. The total dose to the primary intracranial tumor and other areas of measurable intracranial disease was 72 Gy. The prophylactic craniospinal axis dose was 36 Gy, and boosts of 44-56 Gy were administered to metastatic spinal deposits. Following radiotherapy, monthly courses of multiagent chemotherapy were administered sequentially (cyclophosphamide-vincristine followed by cisplatin-etoposide followed by carboplatin-vincristine) for a total of 9 months. Results: All patients completed radiotherapy as planned. Only three patients lost >10% of their body weight. One patient

  11. Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: How do protons compare with other conformal techniques?

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    Lee, Catherine T.; Bilton, Stephen D.; Famiglietti, Robin M.; Riley, Beverly A.; Mahajan, Anita; Chang, Eric L.; Maor, Moshe H.; Woo, Shiao Y.; Cox, James D.; Smith, Alfred R.

    2005-01-01

    Purpose: To calculate treatment plans and compare the dose distributions and dose-volume histograms (DVHs) for photon three-dimensional conformal radiation therapy (3D-CRT), electron therapy, intensity-modulated radiation therapy (IMRT), and standard (nonintensity modulated) proton therapy in three pediatric disease sites. Methods and Materials: The tumor volumes from 8 patients (3 retinoblastomas, 2 medulloblastomas, and 3 pelvic sarcomas) were studied retrospectively to compare DVHs from proton therapy with 3D-CRT, electron therapy, and IMRT. In retinoblastoma, several planning techniques were analyzed: A single electron appositional beam was compared with a single 3D-CRT lateral beam, a 3D-CRT anterior beam paired with a lateral beam, IMRT, and protons. In medulloblastoma, three posterior fossa irradiation techniques were analyzed: 3D-CRT, IMRT, and protons. Craniospinal irradiation (which consisted of composite plans of both the posterior fossa and craniospinal components) was also evaluated, primarily comparing spinal irradiation using 3D-CRT electrons, 3D-CRT photons, and protons. Lastly, in pelvic sarcoma, 3D-CRT, IMRT, and proton plans were assessed. Results: In retinoblastoma, protons resulted in the best target coverage combined with the most orbital bone sparing (10% was the mean orbital bone volume irradiated at ≥5 Gy for protons vs. 25% for 3D-CRT electrons, 69% for IMRT, 41% for a single 3D lateral beam, 51% for a 3D anterolateral beam with a lens block, and 65% for a 3D anterolateral beam without a lens block). A single appositional electron field was the next best technique followed by other planning approaches. In medulloblastoma, for posterior fossa and craniospinal irradiation, protons resulted in the least dose to the cochlea (for only posterior fossa irradiation at ≥20 Gy, 34% was the mean cochlear volume irradiated for protons, 87% for IMRT, 89% for 3D-CRT) and hypothalamus-pituitary axis (for only posterior fossa irradiation at ≥10 Gy

  12. Hepatic Sinusoidal Obstruction Syndrome During Chemotherapy for Childhood Medulloblastoma: Report of a Case and Review of the Literature

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    Buckland, Amy; Phillips, Marianne B.; Cole, Catherine H.; Gottardo, Nicholas G.

    2014-01-01

    Hepatic sinusoidal obstruction syndrome (HSOS), also known as veno-occlusive disease, is a well-recognized toxic complication after autologous and allogeneic hematopoietic stem cell transplant, during treatment of Wilms tumor and rhabdomyosarcoma associated with actinomycin-D, and during acute lymphoblastic leukemia therapy due to oral 6-thioguanine. However, its occurrence in the context of chemotherapy regimens for other childhood malignancies is rare. We report a 5-year-old girl with high-risk anaplastic medulloblastoma, who developed severe HSOS during her second cycle of maintenance chemotherapy, consisting of vincristine, cisplatin, and cyclophosphamide. She was treated with defibrotide with complete resolution of the HSOS. These findings and a review of the literature, highlight the occurrence of HSOS in children outside the established settings of hematopoietic stem cell transplantation, Wilms tumor, rhabdomyosarcoma, and acute lymphoblastic leukemia. PMID:24276042

  13. Medulloblastoma: Long-term follow-up of patients treated with electron irradiation of the spinal field

    International Nuclear Information System (INIS)

    Gaspar, L.E.; Dawson, D.J.; Tilley-Gulliford, S.A.; Banerjee, P.

    1991-01-01

    Thirty-two patients with posterior fossa medulloblastoma underwent treatment with electron irradiation to the spinal field. The 5- and 10-year actuarial survival rates were 57% and 50%, respectively. Late complications observed in the 15 patients followed up for more than 5 years were short stature (six patients), decreased sitting-standing height ratio (four patients), scoliosis (two patients), poor school performance (seven patients), xerostomia (one patient), esophageal stricture (one patient), pituitary dysfunction (four patients), primary hypothyroidism (one patient), bilateral eighth-nerve deafness (one patient), and carcinoma of the thyroid (one patient). Complications following treatment with electrons to a spinal field are compared with reported complications following treatment with photons to the spinal field. Although short-term reactions were minimal, the authors found no difference in late complications. More sophisticated treatment planning may show such a long-term benefit in the future

  14. An Integrated Approach Identifies Nhlh1 and Insm1 as Sonic Hedgehog-regulated Genes in Developing Cerebellum and Medulloblastoma

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    Enrico De Smaele

    2008-01-01

    Full Text Available Medulloblastoma (MB is the most common malignant brain tumor of childhood arising from deregulated cerebellar development. Sonic Hedgehog (Shh pathway plays a critical role in cerebellar development and its aberrant expression has been identified in MB. Gene expression profiling of cerebella from 1- to 14-day-old mice unveiled a cluster of genes whose expression correlates with the levels of Hedgehog (HH activity. From this cluster, we identified Insm1 and Nhlh1/NSCL1 as novel HH targets induced by Shh treatment in cultured cerebellar granule cell progenitors. Nhlh1 promoter was found to be bound and activated by Gli1 transcription factor. Remarkably, the expression of these genes is also upregulated in mouse and human HH-dependent MBs, suggesting that they may be either a part of the HH-induced tumorigenic process or a specific trait of HH-dependent tumor cells.

  15. CD133+ brain tumor-initiating cells are dependent on STAT3 signaling to drive medulloblastoma recurrence.

    Science.gov (United States)

    Garg, N; Bakhshinyan, D; Venugopal, C; Mahendram, S; Rosa, D A; Vijayakumar, T; Manoranjan, B; Hallett, R; McFarlane, N; Delaney, K H; Kwiecien, J M; Arpin, C C; Lai, P-S; Gómez-Biagi, R F; Ali, A M; de Araujo, E D; Ajani, O A; Hassell, J A; Gunning, P T; Singh, S K

    2017-02-02

    Medulloblastoma (MB), the most common malignant paediatric brain tumor, is currently treated using a combination of surgery, craniospinal radiotherapy and chemotherapy. Owing to MB stem cells (MBSCs), a subset of MB patients remains untreatable despite standard therapy. CD133 is used to identify MBSCs although its functional role in tumorigenesis has yet to be determined. In this work, we showed enrichment of CD133 in Group 3 MB is associated with increased rate of metastasis and poor clinical outcome. The signal transducers and activators of transcription-3 (STAT3) pathway are selectively activated in CD133 + MBSCs and promote tumorigenesis through regulation of c-MYC, a key genetic driver of Group 3 MB. We screened compound libraries for STAT3 inhibitors and treatment with the selected STAT3 inhibitors resulted in tumor size reduction in vivo. We propose that inhibition of STAT3 signaling in MBSCs may represent a potential therapeutic strategy to treat patients with recurrent MB.

  16. A novel method for sensing metastatic cells in the CSF of pediatric population with medulloblastoma by frequency domain FLIM system

    Science.gov (United States)

    Yahav, Gilad; Fixler, Dror; Gershanov, Sivan; Goldenberg-Cohen, Nitza

    2016-03-01

    Brain tumors are the second leading cause of cancer-related deaths in children, after leukemia. Patients with cancer in the central nervous system have a very low recovery rate. Today known imaging and cytology techniques are not always sensitive enough for an early detection of both tumor and its metastatic spread, moreover the detection is generally limited, reviewer dependent and takes a relatively long time. Medulloblastoma (MB) is the most common malignant brain tumor in children. The aim of our talk is to present the frequency domain fluorescence lifetime imaging microscopy system as a possible method for an early detection of MB and its metastatic spread in the cerebrospinal fluids within the pediatric population.

  17. SU-E-J-274: Responses of Medulloblastoma Cells to Radiation Dosimetric Parameters in Intensity-Modulated Radiation Therapy

    International Nuclear Information System (INIS)

    Park, J; Park, J; Rogalla, S; Contag, C; Woo, D; Lee, D; Park, H; Suh, T

    2015-01-01

    Purpose: To evaluate radiation responses of the medulloblastoma cell line Daoy in intensity-modulated radiation therapy (IMRT), quantitative variations to variable radiation dosimetic parameters were tracked by bioluminescent images (BLIs). Methods: The luciferase and green fluorescent protein positive Daoy cells were cultured on dishes. The medulloblastoma cells irradiated to different dose rate, interval of fractionated doses, field margin and misalignment, and dose uniformity in IMRT were monitored using bioluminescent images. The cultured cells were placed into a dedicated acrylic phantom to deliver intensity-modulated fluences and calculate accurate predicted dose distribution. The radiation with dose rate from 0.5 Gy/min to 15 Gy/min was irradiated by adjusting monitor unit per minute and source-to-surface distances. The intervals of fractionated dose delivery were changed considering the repair time of double strand breaks (DSB) revealed by straining of gamma-H2AX.The effect of non-uniform doses on the cells were visualized by registering dose distributions and BLIs. The viability according to dosimetric parameters was correlated with bioluminescent intensities for cross-check of radiation responses. Results: The DSB and cell responses due to the first fractionated dose delivery significantly affected final tumor control rather than other parameters. The missing tumor volumes due to the smaller field margin than the tumor periphery or field misalignment caused relapse of cell responses on BLIs. The dose rate and gradient had effect on initial responses but could not bring out the distinguishable killing effect on cancer cells. Conclusion: Visualized and quantified bioluminescent images were useful to correlate the dose distributions with spatial radiation effects on cells. This would derive the effective combination of dose delivery parameters and fractionation. Radiation responses in particular IMRT configuration could be reflected to image based-dose re-optimization

  18. Ototoxicity evaluation in medulloblastoma patients treated with involved field boost using intensity-modulated radiation therapy (IMRT): a retrospective review

    International Nuclear Information System (INIS)

    Vieira, Wilson Albieri; Nadalin, Wladimir; Odone Filho, Vicente; Petrilli, Antonio Sergio; Weltman, Eduardo; Chen, Michael Jenwei; Silva, Nasjla Saba da; Cappellano, Andrea Maria; Pereira, Liliane Desgualdo; Gonçalves, Maria Ines Rabelo; Ferrigno, Robson; Hanriot, Rodrigo Morais

    2014-01-01

    Ototoxicity is a known side effect of combined radiation therapy and cisplatin chemotherapy for the treatment of medulloblastoma. The delivery of an involved field boost by intensity modulated radiation therapy (IMRT) may reduce the dose to the inner ear when compared with conventional radiotherapy. The dose of cisplatin may also affect the risk of ototoxicity. A retrospective study was performed to evaluate the impact of involved field boost using IMRT and cisplatin dose on the rate of ototoxicity. Data from 41 medulloblastoma patients treated with IMRT were collected. Overall and disease-free survival rates were calculated by Kaplan-Meier method Hearing function was graded according to toxicity criteria of Pediatric Oncology Group (POG). Doses to inner ear and total cisplatin dose were correlated with hearing function by univariate and multivariate data analysis. After a mean follow-up of 44 months (range: 14 to 72 months), 37 patients remained alive, with two recurrences, both in spine with CSF involvement, resulting in a disease free-survival and overall survival of 85.2% and 90.2%, respectively. Seven patients (17%) experienced POG Grade 3 or 4 toxicity. Cisplatin dose was a significant factor for hearing loss in univariate analysis (p < 0.03). In multivariate analysis, median dose to inner ear was significantly associated with hearing loss (p < 0.01). POG grade 3 and 4 toxicity were uncommon with median doses to the inner ear bellow 42 Gy (p < 0.05) and total cisplatin dose of less than 375 mg/m 2 (p < 0.01). IMRT leads to a low rate of severe ototoxicity. Median radiation dose to auditory apparatus should be kept below 42 Gy. Cisplatin doses should not exceed 375 mg/m 2

  19. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuro-ectodermal tumors: spinal theca irradiation

    International Nuclear Information System (INIS)

    Miralbell, Raymond; Lomax, Anthony; Russo, Mariateresa

    1997-01-01

    Purpose: Conventional postoperative photon-beam radiotherapy to the spine in children with medulloblastoma/PNET is associated with severe late effects. This morbidity (growth and developmental) is related to the exit dose of the beams and is particularly severe in young children. With the purpose of reducing this toxicity, a dosimetric study was undertaken in which proton therapy was compared to standard megavoltage photon treatment. Methods and materials: The results of a comparative dosimetric study are presented in such a way that the dose distribution achievable with a posterior modulated 100 MeV proton beam (spot scanning method) is compared with that of a standard set of posterior 6 MV x-ray fields. The potential improvements with protons are evaluated, using dose-volume histograms to examine the coverage of the target as well as the dose to the vertebral bodies (growth plates), lungs, heart, and liver. Results: The target (i.e., the spinal dural sac) received the full prescribed dose in both treatment plans. However, the proportions of the vertebral body volume receiving ≥50% of the prescribed dose were 100 and 20% for 6 MV x-rays and protons, respectively. For 6 MV x-rays >60% of the dose prescribed to the target was delivered to 44% of the heart volume, while the proton beam was able to completely avoid the heart, the liver, and in all likelihood the thyroid and gonads as well. Conclusion: The present study demonstrates a potential role of proton therapy in decreasing the dose (and toxicity) to the critical structures in the irradiation of the spinal neuraxis in medulloblastoma/PNET. The potential bone marrow and growth arrest sparing effects make this approach specially attractive for intensive chemotherapy protocols and for very young children. Sparing the thyroid gland, the posterior heart wall, and the gonads may be additional advantages in assuring a long-term posttreatment morbidity-free survival

  20. Permeability of PEGylated immunoarsonoliposomes through in vitro blood brain barrier-medulloblastoma co-culture models for brain tumor therapy.

    Science.gov (United States)

    Al-Shehri, Abdulghani; Favretto, Marco E; Ioannou, Panayiotis V; Romero, Ignacio A; Couraud, Pierre-Olivier; Weksler, Babette Barbash; Parker, Terry L; Kallinteri, Paraskevi

    2015-03-01

    Owing to restricted access of pharmacological agents into the brain due to blood brain barrier (BBB) there is a need: 1. to develop a more representative 3-D-co-culture model of tumor-BBB interaction to investigate drug and nanoparticle transport into the brain for diagnostic and therapeutic evaluation. 2. to address the lack of new alternative methods to animal testing according to replacement-reduction-refinement principles. In this work, in vitro BBB-medulloblastoma 3-D-co-culture models were established using immortalized human primary brain endothelial cells (hCMEC/D3). hCMEC/D3 cells were cultured in presence and in absence of two human medulloblastoma cell lines on Transwell membranes. In vitro models were characterized for BBB formation, zonula occludens-1 expression and permeability to dextran. Transferrin receptors (Tfr) expressed on hCMEC/D3 were exploited to facilitate arsonoliposome (ARL) permeability through the BBB to the tumor by covalently attaching an antibody specific to human Tfr. The effect of anticancer ARLs on hCMEC/D3 was assessed. In vitro BBB and BBB-tumor co-culture models were established successfully. BBB permeability was affected by the presence of tumor aggregates as suggested by increased permeability of ARLs. There was a 6-fold and 8-fold increase in anti-Tfr-ARL uptake into VC312R and BBB-DAOY co-culture models, respectively, compared to plain ARLs. The three-dimensional models might be appropriate models to study the transport of various drugs and nanocarriers (liposomes and immunoarsonoliposomes) through the healthy and diseased BBB. The immunoarsonoliposomes can be potentially used as anticancer agents due to good tolerance of the in vitro BBB model to their toxic effect.

  1. Thyroid dysfunction as a late effect in childhood medulloblastoma: a comparison of hyperfractionated versus conventionally fractionated craniospinal radiotherapy

    International Nuclear Information System (INIS)

    Ricardi, Umberto; Corrias, Andrea; Einaudi, Silvia; Genitori, Lorenzo; Sandri, Alessandro; Cordero Di Montezemolo, Luca; Besenzon, Luigi; Madon, Enrico; Urgesi, Alessandro

    2001-01-01

    Purpose: Primary hypothyroidism is a common sequela of craniospinal radiotherapy in the treatment of childhood medulloblastoma. Due to the strong radiobiologic rationale, hyperfractionation can reduce the delayed effects of radiation injury. Methods and Materials: The authors compared the incidence of thyroid dysfunction after conventionally fractionated radiotherapy (Group A, n=20 patients) vs. hyperfractionated radiotherapy (Group B, n=12 patients) in a group of pediatric patients with posterior fossa primitive neuroectodermal tumor (PNET). Results: The mean age at the time of tumor diagnosis was 7.4 years in Group A and 8.4 years in Group B. Thyroid function was evaluated yearly, with ultrasonographic examination every 2 years. The patients were followed after diagnosis for a mean of 10.8 years for Group A and 6.0 years for Group B. Approximately 80% of the Group A (16/20) and 33.3% of the Group B (4/12) patients developed primary hypothyroidism within a similar period after irradiation (4.2 vs. 3.5 years, respectively). Analysis by cumulative incidence function demonstrated a significant difference in the risk of developing thyroid dysfunction between these two groups of patients (p<0.05). Ultrasonography showed reduced thyroid volume in 7 Group A patients and structural changes in 21 patients (17 Group A, 4 Group B cases); a thyroid benign nodule was detected in 2 Group A patients. Conclusions: The current study findings suggest that the use of hyperfractionated craniospinal radiotherapy in the treatment of childhood medulloblastoma is associated with a lower risk of these patients' developing late thyroid dysfunction

  2. The FDA approved PI3K inhibitor GDC-0941 enhances in vitro the anti-neoplastic efficacy of Axitinib against c-myc-amplified high-risk medulloblastoma.

    Science.gov (United States)

    Ehrhardt, Michael; Craveiro, Rogerio B; Velz, Julia; Olschewski, Martin; Casati, Anna; Schönberger, Stefan; Pietsch, Torsten; Dilloo, Dagmar

    2018-04-01

    Aberrant receptor kinase signalling and tumour neovascularization are hallmarks of medulloblastoma development and are both considered valuable therapeutic targets. In addition to VEGFR1/2, expression of PDGFR α/β in particular has been documented as characteristic of metastatic disease correlating with poor prognosis. Therefore, we have been suggested that the clinically approved multi-kinase angiogenesis inhibitor Axitinib, which specifically targets these kinases, might constitute a promising option for medulloblastoma treatment. Indeed, our results delineate anti-neoplastic activity of Axitinib in medulloblastoma cell lines modelling the most aggressive c-myc-amplified Non-WNT/Non-SHH and SHH-TP53-mutated tumours. Exposure of medulloblastoma cell lines to Axitinib results in marked inhibition of proliferation and profound induction of cell death. The differential efficacy of Axitinib is in line with target expression of medulloblastoma cells identifying VEGFR 1/2, PDGFR α/β and c-kit as potential markers for drug application. The high specificity of Axitinib and the consequential low impact on the haematopoietic and immune system render this drug ideal multi-modal treatment approaches. In this context, we demonstrate that the clinically available PI3K inhibitor GDC-0941 enhances the anti-neoplastic efficacy of Axitinib against c-myc-amplified medulloblastoma. Our findings provide a rational to further evaluate Axitinib alone and in combination with other therapeutic agents for the treatment of most aggressive medulloblastoma subtypes. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  3. Medulloblastoma in China: clinicopathologic analyses of SHH, WNT, and non-SHH/WNT molecular subgroups reveal different therapeutic responses to adjuvant chemotherapy.

    Directory of Open Access Journals (Sweden)

    Zhen-Yu Zhang

    Full Text Available Medulloblastoma (MB is one of the most common primary central nervous system tumors in children. Data is lacking of a large cohort of medulloblastoma patients in China. Also, our knowledge on the sensitivity of different molecular subgroups of MB to adjuvant radiation therapy (RT or chemotherapy (CHT is still limited. The authors performed a retrospective study of 173 medulloblastoma patients treated at two institutions from 2002 to 2011. Formalin-fixed paraffin embedded (FFPE tissues were available in all the cases and sections were stained to classify histological and molecular subgroups. Univariate and multivariate analyses were used to investigate prognostic factors. Of 173 patients, there were 118 children and 55 adults, 112 males and 61 females. Estimated 5-year overall survival (OS rates for all patients, children and adults were 52%, 48% and 63%, respectively. After multivariate analysis, postoperative primary radiation therapy (RT and chemotherapy (CHT were revealed as favorable prognostic factors influencing OS and EFS. Postoperative primary chemotherapy (CHT was found significantly improving the survival of children (p<0.001 while it was not a significant prognostic factor for adult patients. Moreover, patients in WNT subtype had better OS (p = 0.028 than others (SHH and Non-SHH/WNT subtypes given postoperative adjuvant therapies. Postoperative primary RT was found to be a strong prognostic factor influencing the survival in all histological and molecular subgroups (p<0.001. Postoperative primary CHT was found significantly to influence the survival of classic medulloblastoma (CMB (OS p<0.001, EFS p<0.001, SHH subgroup (OS p = 0.020, EFS p = 0.049 and WNT subgroup (OS p = 0.003, EFS p = 0.016 but not in desmoplastic/nodular medulloblastoma (DMB (OS p = 0.361, EFS p = 0.834 and Non-SHH/WNT subgroup (OS p = 0.127, EFS p = 0.055. Our study showed postoperative primary CHT significantly influence the

  4. The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma.

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    Fabiana Salm

    Full Text Available Medulloblastoma (MB is the most common malignant brain tumor in childhood and represents the main cause of cancer-related death in this age group. The phosphoinositide 3-kinase (PI3K pathway has been shown to play an important role in the regulation of medulloblastoma cell survival and proliferation, but the molecular mechanisms and downstream effectors underlying PI3K signaling still remain elusive. The impact of RNA interference (RNAi-mediated silencing of PI3K isoforms p110α and p110δ on global gene expression was investigated by DNA microarray analysis in medulloblastoma cell lines. A subset of genes with selectively altered expression upon p110α silencing in comparison to silencing of the closely related p110δ isoform was revealed. Among these genes, the leukemia inhibitory factor receptor α (LIFR α was validated as a novel p110α target in medulloblastoma. A network involving c-Myc and miR-125b was shown to be involved in the control of LIFRα expression downstream of p110α. Targeting the LIFRα by RNAi, or by using neutralizing reagents impaired medulloblastoma cell proliferation in vitro and induced a tumor volume reduction in vivo. An analysis of primary tumors revealed that LIFRα and p110α expression were elevated in the sonic hedgehog (SHH subgroup of medulloblastoma, indicating its clinical relevance. Together, these data reveal a novel molecular signaling network, in which PI3K isoform p110α controls the expression of LIFRα via c-Myc and miR-125b to promote MB cell proliferation.

  5. Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma

    Directory of Open Access Journals (Sweden)

    Eberhart Charles G

    2010-11-01

    Full Text Available Abstract Background The Sonic hedgehog (Shh signaling pathway is critical for cell growth and differentiation. Impairment of this pathway can result in both birth defects and cancer. Despite its importance in cancer development, the Shh pathway has not been thoroughly investigated in tumorigenesis of brain tumors. In this study, we sought to understand the regulatory roles of GLI1, the immediate downstream activator of the Shh signaling pathway on its downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6 in medulloblastoma and astrocytic tumors. Methods We silenced GLI1 expression in medulloblastoma and astrocytic cell lines by transfection of siRNA against GLI1. Subsequently, we performed RT-PCR and quantitative real time RT-PCR (qRT-PCR to assay the expression of downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6. We also attempted to correlate the pattern of expression of GLI1 and its regulated genes in 14 cell lines and 41 primary medulloblastoma and astrocytoma tumor samples. We also assessed the methylation status of the Cyclin D2 and PTCH1 promoters in these 14 cell lines and 58 primary tumor samples. Results Silencing expression of GLI1 resulted up-regulation of all target genes in the medulloblastoma cell line, while only PTCH1 was up-regulated in astrocytoma. We also observed methylation of the cyclin D2 promoter in a significant number of astrocytoma cell lines (63% and primary astrocytoma tumor samples (32%, but not at all in any medulloblastoma samples. PTCH1 promoter methylation was less frequently observed than Cyclin D2 promoter methylation in astrocytomas, and not at all in medulloblastomas. Conclusions Our results demonstrate different regulatory mechanisms of Shh-GLI1 signaling. These differences vary according to the downstream target gene affected, the origin of the tissue, as well as epigenetic regulation of some of these genes.

  6. Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma

    International Nuclear Information System (INIS)

    Shahi, Mehdi H; Afzal, Mohammad; Sinha, Subrata; Eberhart, Charles G; Rey, Juan A; Fan, Xing; Castresana, Javier S

    2010-01-01

    The Sonic hedgehog (Shh) signaling pathway is critical for cell growth and differentiation. Impairment of this pathway can result in both birth defects and cancer. Despite its importance in cancer development, the Shh pathway has not been thoroughly investigated in tumorigenesis of brain tumors. In this study, we sought to understand the regulatory roles of GLI1, the immediate downstream activator of the Shh signaling pathway on its downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6 in medulloblastoma and astrocytic tumors. We silenced GLI1 expression in medulloblastoma and astrocytic cell lines by transfection of siRNA against GLI1. Subsequently, we performed RT-PCR and quantitative real time RT-PCR (qRT-PCR) to assay the expression of downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6. We also attempted to correlate the pattern of expression of GLI1 and its regulated genes in 14 cell lines and 41 primary medulloblastoma and astrocytoma tumor samples. We also assessed the methylation status of the Cyclin D2 and PTCH1 promoters in these 14 cell lines and 58 primary tumor samples. Silencing expression of GLI1 resulted up-regulation of all target genes in the medulloblastoma cell line, while only PTCH1 was up-regulated in astrocytoma. We also observed methylation of the cyclin D2 promoter in a significant number of astrocytoma cell lines (63%) and primary astrocytoma tumor samples (32%), but not at all in any medulloblastoma samples. PTCH1 promoter methylation was less frequently observed than Cyclin D2 promoter methylation in astrocytomas, and not at all in medulloblastomas. Our results demonstrate different regulatory mechanisms of Shh-GLI1 signaling. These differences vary according to the downstream target gene affected, the origin of the tissue, as well as epigenetic regulation of some of these genes

  7. Viability of D283 medulloblastoma cells treated with a histone deacetylase inhibitor combined with bombesin receptor antagonists.

    Science.gov (United States)

    Jaeger, Mariane; Ghisleni, Eduarda C; Fratini, Lívia; Brunetto, Algemir L; Gregianin, Lauro José; Brunetto, André T; Schwartsmann, Gilberto; de Farias, Caroline B; Roesler, Rafael

    2016-01-01

    Medulloblastoma (MB) comprises four distinct molecular subgroups, and survival remains particularly poor in patients with Group 3 tumors. Mutations and copy number variations result in altered epigenetic regulation of gene expression in Group 3 MB. Histone deacetylase inhibitors (HDACi) reduce proliferation, promote cell death and neuronal differentiation, and increase sensitivity to radiation and chemotherapy in experimental MB. Bombesin receptor antagonists potentiate the antiproliferative effects of HDACi in lung cancer cells and show promise as experimental therapies for several human cancers. Here, we examined the viability of D283 cells, which belong to Group 3 MB, treated with an HDACi alone or combined with bombesin receptor antagonists. D283 MB cells were treated with different doses of the HDACi sodium butyrate (NaB), the neuromedin B receptor (NMBR) antagonist BIM-23127, the gastrin releasing peptide receptor (GRPR) antagonist RC-3095, or combinations of NaB with each receptor antagonist. Cell viability was examined by cell counting. NaB alone or combined with receptor antagonists reduced cell viability at all doses tested. BIM-23127 alone did not affect cell viability, whereas RC-3095 at an intermediate dose significantly increased cell number. Although HDACi are promising agents to inhibit MB growth, the present results provide preliminary evidence that combining HDACi with bombesin receptor antagonists is not an effective strategy to improve the effects of HDACi against MB cells.

  8. Long-term safety of growth hormone replacement therapy after childhood medulloblastoma and PNET: it is time to set aside old concerns.

    Science.gov (United States)

    Indini, Alice; Schiavello, Elisabetta; Biassoni, Veronica; Bergamaschi, Luca; Magni, Maria Chiara; Puma, Nadia; Chiaravalli, Stefano; Pallotti, Federica; Seregni, Ettore; Diletto, Barbara; Pecori, Emilia; Gandola, Lorenza; Poggi, Geraldina; Massimino, Maura

    2017-01-01

    To assess the long-term safety of administering growth hormone (GH) in patients with GH deficiency due to treatment for childhood medulloblastoma and primitive neuroectodermal tumor (PNET). Data were retrospectively retrieved on children receiving GH supplementation, assessing their disease-free and overall survival outcomes and risk of secondary malignancies using Kaplan-Meier and Cox models. Overall 65 children were consecutively collected from May 1981 to April 2013. All patients had undergone craniospinal irradiation (total dose 18-39 Gy), and subsequently received GH for a median (interquartile range, IQR) of 81 (50.6-114.9) months. At a median (IQR) of 122.4 months (74.4-149.5) after the end of their adjuvant cancer treatment, two patients (3 %) experienced recurrent disease and 8 (12.3 %) developed secondary malignancies, all but one of them (an osteosarcoma) related to radiation exposure and occurring within the radiation fields. There was no apparent correlation between the administration of GH replacement therapy (or its duration) and primary tumor relapse or the onset of secondary malignancies [HR: 1.01 (95 % CI: 0.98, 1.03) for every additional 12 months of GH supplementation; p = 0.36). At univariate analysis, the large cell or anaplastic medulloblastoma subtype, metastases and myeloablative chemotherapy correlated with a higher risk of secondary malignancies (p < 0.1), but multivariate analysis failed to identify any factors independently associated with this risk. Our data supports once more the safety of long-term GH replacement therapy in children treated for medulloblastoma/PNET, previously reported in larger data sets. The neurooncology community now need to warrant large-scale meta-analyses or international prospective trials in order to consolidate our knowledge of factors other than GH, such as genetic predisposition, high-grade/metastatic disease, high-dose chemotherapy and era of treatment, in promoting the occurrence of

  9. OS7.7 Feasibility and toxicity of concomitant radiochemotherapy with vincristine in adult patients with medulloblastoma - results from the NOA-07 trial

    Science.gov (United States)

    Seidel, C.; Reimers, C.; Beier, D.; Pietsch, T.; Warmuth-Metz, M.; Bogdahn, U.; Kortmann, R.; Hau, P.

    2016-01-01

    Abstract Introduction: Medulloblastoma is a tumor of the cerebellum that is rare in adults with an incidence of about 0.6 cases per million per year. In children the introduction of chemotherapy with cisplatin, lomustine and vincristine in combination with craniospinal radiotherapy led to a significant improvement of overall survival. In adults, this regimen was never prospectively investigated in a clinical trial. Methods. The NOA-07 trial is a prospective single arm Phase II study to evaluate toxicity of craniospinal irradiation (1.6 Gy/35.2 Gy, posterior fossa boost 1.8 Gy/55.0 Gy) in combination with vincristine (1.5 mg/m2 weekly, ceiling dose 2.0 mg) followed by adjuvant chemotherapy with a maximum 8 of 6-weekly cycles of cisplatin (70 mg/m2, day 1), lomustine (75 mg/m2, day 1) and vincristine (1.5 g/m2, ceiling dose 2.0 mg, day 1, 8, 15) in adults with medulloblastoma. Here, we report on feasibility and toxicity of the concomitant radiochemotherapy. Results. 30 patients with medulloblastoma were recruited in 15 German centers. Radiotherapy was completed in all patients. Treatment interruptions occurred in 3/30 patients (toxicity related: 2, compliance: 1). Leukopenia was the major toxicity with grade 3 and 4 (CTC Version 3.0) occurring in 11 of 30 patients and 1 of 30 patients, respectively. Grade 3 to 4 thrombocytopenia occurred in 1 patient. Grade 3 to 4 infections occurred in 3 patients. Polyneuropathy due to vincristine was the most prevalent adverse event (Grade 1: 5, Grade 2: 4, Grade 3: 5 of 30 patients). Frequent but less severe toxicities involved sickness, dermatitis and alopecia. Conclusion. Concomitant radiochemotherapy with vincristine was feasible in adults with medulloblastoma. Leukopenia and polyneuropathy are major complications, pointing out that polyneuropathy occurs already early in treatment after application of only 1 to 6 doses in a substantial number of patients. Toxicity of the complete treatment protocol including

  10. Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Brodin, N. Patrik (Radiation Medicine Research Center, Dept. of Radiation Oncology, Rigshospitalet, Univ. of Copenhagen (Denmark); Niels Bohr Inst., Faculty of Sciences, Univ. of Copenhagen (Denmark)), e-mail: brodin.patrik@gmail.com; Munck af Rosenschoeld, Per; Aznar, Marianne C.; Vogelius, Ivan R. (Radiation Medicine Research Center, Dept. of Radiation Oncology, Rigshospitalet, Univ. of Copenhagen (Denmark)); Kiil-Berthelsen, Anne (Radiation Medicine Research Center, Dept. of Radiation Oncology, Rigshospitalet, Univ. of Copenhagen (Denmark); Dept. of Clinical Physiology and Nuclear Medicine, Centre of Diagnostic Investigations, Rigshospitalet, Univ. of Copenhagen (Denmark)); Nilsson, Per; Bjoerk-Eriksson, Thomas (Dept. of Oncology, Skaane Univ. Hospital and Lund Univ., Lund (Sweden)); Lannering, Birgitta (Dept. of Paediatric Oncology, The Queen Silvia Children' s Hospital, Gothenburg (Sweden))

    2011-08-15

    Introduction. The aim of this model study was to estimate and compare the risk of radiation-induced adverse late effects in pediatric patients with medulloblastoma (MB) treated with either three-dimensional conformal radiotherapy (3D CRT), inversely-optimized arc therapy (RapidArc (RA)) or spot-scanned intensity-modulated proton therapy (IMPT). The aim was also to find dose-volume toxicity parameters relevant to children undergoing RT to be used in the inverse planning of RA and IMPT, and to use in the risk estimations. Material and methods. Treatment plans were created for all three techniques on 10 pediatric patients that have been treated with craniospinal irradiation (CSI) at our institution in 2007-2009. Plans were generated for two prescription CSI doses, 23.4 Gy and 36 Gy. Risk estimates were based on childhood cancer survivor data when available and secondary cancer (SC) risks were estimated as a function of age at exposure and attained age according to the organ-equivalent dose (OED) concept. Results. Estimates of SC risk was higher for the RA plans and differentiable from the estimates for 3D CRT at attained ages above 40 years. The risk of developing heart failure, hearing loss, hypothyroidism and xerostomia was highest for the 3D CRT plans. The risks of all adverse effects were estimated as lowest for the IMPT plans, even when including secondary neutron (SN) irradiation with high values of the neutron radiation weighting factors (WR{sub neutron}). Conclusions. When comparing RA and 3D CRT treatment for pediatric MB it is a matter of comparing higher SC risk against higher risks of non-cancer adverse events. Considering time until onset of the different complications is necessary to fully assess patient benefit in such a comparison. The IMPT plans, including SN dose contribution, compared favorably to the photon techniques in terms of all radiobiological risk estimates

  11. A School Passport as Part of a Protocol to Assist Educational Reintegration After Medulloblastoma Treatment in Childhood.

    Science.gov (United States)

    Tresman, Rachel; Brown, Morven; Fraser, Faye; Skinner, Roderick; Bailey, Simon

    2016-09-01

    Medulloblastoma is the most common malignant brain tumour in children and is treated with a combination of surgery, radiotherapy and chemotherapy. These children frequently experience long-term cognitive, social and physical sequelae, which significantly affect school reintegration. This study aimed to explore school-return experiences to create a more structured school reintegration protocol for children postmedulloblastoma. A cohort of nine patients who had completed treatment and for whom full neuropsychometric data were available was included in the study (median time since diagnosis 8 years). Data were collected using qualitative parental questionnaires, semistructured interviews with teachers (n = 12) and healthcare professionals (HCPs) (n = 6) involved in their school reintegration. Thematic analysis was employed. A focus group with five HCPs was then used for data validation. This study uncovered the following four main subjects: (1) Information sharing; (2) education and empowerment (of educational professionals (EP) and parents); (3) communication between parents, HCPs and EPs; and (4) long-term difficulties. Implementation of a standardised protocol delivered within the structure of a school passport document would aid uniform follow-up. The proposed multistage protocol includes early communication and reintegration planning followed by meetings at school re-entry. Follow-up meetings are suggested to reduce information loss and reassess the child's needs. Hospital support at school transitions, inclusion of school data in long-term clinical follow-up and long-term rehabilitation are also recommended. Each stage would be supported by school passport documentation and would facilitate school and parental empowerment, paramount to the long-term sustainability of successful schooling. © 2016 Wiley Periodicals, Inc.

  12. Prognostic value of Ki-67 index in adult medulloblastoma after accounting for molecular subgroup: a retrospective clinical and molecular analysis.

    Science.gov (United States)

    Zhao, Fu; Zhang, Jing; Li, Peng; Zhou, Qiangyi; Zhang, Shun; Zhao, Chi; Wang, Bo; Yang, Zhijun; Li, Chunde; Liu, Pinan

    2018-04-23

    Medulloblastoma (MB) is a rare primary brain tumor in adults. We previously evaluated that combining both clinical and molecular classification could improve current risk stratification for adult MB. In this study, we aimed to identify the prognostic value of Ki-67 index in adult MB. Ki-67 index of 51 primary adult MBs was reassessed using a computer-based image analysis (Image-Pro Plus). All patients were followed up ranging from 12 months up to 15 years. Gene expression profiling and immunochemistry were used to establish the molecular subgroups in adult MB. Combined risk stratification models were designed based on clinical characteristics, molecular classification and Ki-67 index, and identified by multivariable Cox proportional hazards analysis. In our cohort, the mean Ki-67 value was 30.0 ± 11.3% (range 6.56-63.55%). The average Ki-67 value was significantly higher in LC/AMB than in CMB and DNMB (P = .001). Among three molecular subgroups, Group 4-tumors had the highest average Ki-67 value compared with WNT- and SHH-tumors (P = .004). Patients with Ki-67 index large than 30% displayed poorer overall survival (OS) and progression free survival (PFS) than those with Ki-67 less than 30% (OS: P = .001; PFS: P = .006). Ki-67 index (i.e. > 30%, < 30%) was identified as an independent significant prognostic factor (OS: P = .017; PFS: P = .024) by using multivariate Cox proportional hazards model. In conclusion, Ki-67 index can be considered as a valuable independent prognostic biomarker for adult patients with MB.

  13. Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma

    International Nuclear Information System (INIS)

    Brodin, N. Patrik; Munck af Rosenschoeld, Per; Aznar, Marianne C.; Vogelius, Ivan R.; Kiil-Berthelsen, Anne; Nilsson, Per; Bjoerk-Eriksson, Thomas; Lannering, Birgitta

    2011-01-01

    Introduction. The aim of this model study was to estimate and compare the risk of radiation-induced adverse late effects in pediatric patients with medulloblastoma (MB) treated with either three-dimensional conformal radiotherapy (3D CRT), inversely-optimized arc therapy (RapidArc (RA)) or spot-scanned intensity-modulated proton therapy (IMPT). The aim was also to find dose-volume toxicity parameters relevant to children undergoing RT to be used in the inverse planning of RA and IMPT, and to use in the risk estimations. Material and methods. Treatment plans were created for all three techniques on 10 pediatric patients that have been treated with craniospinal irradiation (CSI) at our institution in 2007-2009. Plans were generated for two prescription CSI doses, 23.4 Gy and 36 Gy. Risk estimates were based on childhood cancer survivor data when available and secondary cancer (SC) risks were estimated as a function of age at exposure and attained age according to the organ-equivalent dose (OED) concept. Results. Estimates of SC risk was higher for the RA plans and differentiable from the estimates for 3D CRT at attained ages above 40 years. The risk of developing heart failure, hearing loss, hypothyroidism and xerostomia was highest for the 3D CRT plans. The risks of all adverse effects were estimated as lowest for the IMPT plans, even when including secondary neutron (SN) irradiation with high values of the neutron radiation weighting factors (WR neutron ). Conclusions. When comparing RA and 3D CRT treatment for pediatric MB it is a matter of comparing higher SC risk against higher risks of non-cancer adverse events. Considering time until onset of the different complications is necessary to fully assess patient benefit in such a comparison. The IMPT plans, including SN dose contribution, compared favorably to the photon techniques in terms of all radiobiological risk estimates

  14. Modeling Freedom From Progression for Standard-Risk Medulloblastoma: A Mathematical Tumor Control Model With Multiple Modes of Failure

    International Nuclear Information System (INIS)

    Brodin, N. Patrik; Vogelius, Ivan R.; Björk-Eriksson, Thomas; Munck af Rosenschöld, Per; Bentzen, Søren M.

    2013-01-01

    Purpose: As pediatric medulloblastoma (MB) is a relatively rare disease, it is important to extract the maximum information from trials and cohort studies. Here, a framework was developed for modeling tumor control with multiple modes of failure and time-to-progression for standard-risk MB, using published pattern of failure data. Methods and Materials: Outcome data for standard-risk MB published after 1990 with pattern of relapse information were used to fit a tumor control dose-response model addressing failures in both the high-dose boost volume and the elective craniospinal volume. Estimates of 5-year event-free survival from 2 large randomized MB trials were used to model the time-to-progression distribution. Uncertainty in freedom from progression (FFP) was estimated by Monte Carlo sampling over the statistical uncertainty in input data. Results: The estimated 5-year FFP (95% confidence intervals [CI]) for craniospinal doses of 15, 18, 24, and 36 Gy while maintaining 54 Gy to the posterior fossa was 77% (95% CI, 70%-81%), 78% (95% CI, 73%-81%), 79% (95% CI, 76%-82%), and 80% (95% CI, 77%-84%) respectively. The uncertainty in FFP was considerably larger for craniospinal doses below 18 Gy, reflecting the lack of data in the lower dose range. Conclusions: Estimates of tumor control and time-to-progression for standard-risk MB provides a data-driven setting for hypothesis generation or power calculations for prospective trials, taking the uncertainties into account. The presented methods can also be applied to incorporate further risk-stratification for example based on molecular biomarkers, when the necessary data become available

  15. Impact of radiation technique, radiation fraction dose, and total cisplatin dose on hearing. Retrospective analysis of 29 medulloblastoma patients

    International Nuclear Information System (INIS)

    Scobioala, Sergiu; Kittel, Christopher; Ebrahimi, Fatemeh; Wolters, Heidi; Eich, Hans Theodor; Parfitt, Ross; Matulat, Peter; Am Zehnhoff-Dinnesen, Antoinette

    2017-01-01

    To analyze the incidence and degree of sensorineural hearing loss (SNHL) resulting from different radiation techniques, fractionation dose, mean cochlear radiation dose (D mean ), and total cisplatin dose. In all, 29 children with medulloblastoma (58 ears) with subclinical pretreatment hearing thresholds participated. Radiotherapy (RT) and cisplatin had been applied sequentially according to the HIT MED Guidance. Audiological outcomes up to the latest follow-up (median 2.6 years) were compared. Bilateral high-frequency SNHL was observed in 26 patients (90%). No significant differences were found in mean hearing threshold between left and right ears at any frequency. A significantly better audiological outcome (p < 0.05) was found after tomotherapy at the 6 kHz bone-conduction threshold (BCT) and left-sided 8 kHz air-conduction threshold (ACT) than after a combined radiotherapy technique (CT). Fraction dose was not found to have any impact on the incidence, degree, and time-to-onset of SNHL. Patients treated with CT had a greater risk of SNHL at high frequencies than tomotherapy patients even though D mean was similar. Increase in severity of SNHL was seen when the total cisplatin dose reached above 210 mg/m 2 , with the highest abnormal level found 8-12 months after RT regardless of radiation technique or fraction dose. The cochlear radiation dose should be kept as low as possible in patients who receive simultaneous cisplatin-based chemotherapy. The risk of clinically relevant HL was shown when D mean exceeds 45 Gy independent of radiation technique or radiation regime. Cisplatin ototoxicity was shown to have a dose-dependent effect on bilateral SNHL, which was more pronounced in higher frequencies. (orig.) [de

  16. Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3.

    Science.gov (United States)

    Ceccarelli, Manuela; Micheli, Laura; Tirone, Felice

    2016-01-01

    Medulloblastoma (MB), tumor of the cerebellum, remains a leading cause of cancer-related mortality in childhood. We previously showed, in a mouse model of spontaneous MB ( Ptch1 +/- / Tis21 -/- ), that a defect of the migration of cerebellar granule neuron precursor cells (GCPs) correlates with an increased frequency of MB. This occurs because GCPs, rather than migrating internally and differentiating, remain longer in the proliferative area at the cerebellar surface, becoming targets of transforming insults. Furthermore, we identified the chemokine Cxcl3 as responsible for the inward migration of GCPs. As it is known that preneoplastic GCPs (pGCPs) can still migrate and differentiate like normal GCPs, thus exiting the neoplastic program, in this study we tested the hypothesis that pGCPs within a MB lesion could be induced by Cxcl3 to migrate and differentiate. We observed that the administration of Cxcl3 for 28 days within the cerebellum of 1-month-old Ptch1 +/- / Tis21 -/- mice, i.e., when MB lesions are already formed, leads to complete disappearance of the lesions. However, a shorter treatment with Cxcl3 (2 weeks) was ineffective, suggesting that the suppression of MB lesions is dependent on the duration of Cxcl3 application. We verified that the treatment with Cxcl3 causes a massive migration of pGCPs from the lesion to the internal granular layer, where they differentiate. Thus, the induction of migration of pGCPs in MB lesions may open new ways to treat MB that exploit the plasticity of the pGCPs, forcing their differentiation. It remains to be tested whether this plasticity continues at advanced stages of MB. If so, these findings would set a potential use of the chemokine Cxcl3 as therapeutic agent against MB development in human preclinical studies.

  17. Immunological low-dose radiation modulates the pediatric medulloblastoma antigens and enhances antibody-dependent cellular cytotoxicity.

    Science.gov (United States)

    Das, Arabinda; McDonald, Daniel; Lowe, Stephen; Bredlau, Amy-Lee; Vanek, Kenneth; Patel, Sunil J; Cheshier, Samuel; Eskandari, Ramin

    2017-03-01

    Immunotherapy can be an effective treatment for pediatric medulloblastoma (MB) patients. However, major subpopulations do not respond to immunotherapy, due to the lack of antigenic mutations or the immune-evasive properties of MB cells. Clinical observations suggest that radiation therapy (RT) may expand the therapeutic reach of immunotherapy. The aim of the present investigation is to study the effect of low-dose X-ray radiation (LDXR, 1 Gy) on the functional immunological responses of MB cells (DAOY, D283, and D341). Induction of MB cell death was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Production of reactive oxygen species (ROS) was measured by fluorescent probes. Changes in the expression of  human leukocyte antigen (HLA) molecules and caspase-3 activities during treatment were analyzed using Western blotting and caspase-3 assay. Western blot analysis demonstrated that LDXR upregulated the expression of HLA class I and HLA II molecules by more than 20% compared with control and high-dose (12 Gy) groups in vitro. Several of these HLA subtypes, such as MAGE C1, CD137, and ICAM-1, have demonstrated upregulation. In addition, LDXR increases ROS production in association with phosphorylation of NF-κB and cell surface expression of mAb target molecules (HER2 and VEGF). These data suggest that a combined LDXR and mAb therapy can create a synergistic effect in vitro. These results suggest that LDXR modulates HLA molecules, leading to alterations in T-cell/tumor-cell interaction and enhancement of T-cell-mediated MB cell death. Also, low-dose radiotherapy combined with monoclonal antibody therapy may one day augment the standard treatment for MB, but more investigation is needed to prove its utility as a new therapeutic combination for MB patients.

  18. Characterization of ectonucleotidases in human medulloblastoma cell lines: ecto-5'NT/CD73 in metastasis as potential prognostic factor.

    Directory of Open Access Journals (Sweden)

    Angélica Regina Cappellari

    Full Text Available Medulloblastoma (MB is the most common malignant brain tumor in children and occurs mainly in the cerebellum. Important intracellular signaling molecules, such those present in the Sonic Hedgehog and Wnt pathways, are involved in its development and can also be employed to determine tumor grade and prognosis. Ectonucleotidases, particularly ecto-5'NT/CD73, are important enzymes in the malignant process of different tumor types regulating extracellular ATP and adenosine levels. Here, we investigated the activity of ectonucleotidases in three malignant human cell lines: Daoy and ONS76, being representative of primary MB, and the D283 cell line, derived from a metastatic MB. All cell lines secreted ATP into the extracellular medium while hydrolyze poorly this nucleotide, which is in agreement with the low expression and activity of pyrophosphate/phosphodiesterase, NTPDases and alkaline phosphatase. The analysis of AMP hydrolysis showed that Daoy and ONS76 completely hydrolyzed AMP, with parallel adenosine production (Daoy and inosine accumulation (ONS76. On the other hand, D283 cell line did not hydrolyze AMP. Moreover, primary MB tumor cells, Daoy and ONS76 express the ecto-5'NT/CD73 while D283 representative of a metastatic tumor, revealed poor expression of this enzyme, while the ecto-adenosine deaminase showed higher expression in D283 compared to Daoy and ONS76 cells. Nuclear beta-catenin has been suggested as a marker for MB prognosis. Further it can promotes expression of ecto-5'NT/CD73 and suppression of adenosine deaminase. It was observed that Daoy and ONS76 showed greater nuclear beta-catenin immunoreactivity than D283, which presented mainly cytoplasmic immunoreactivity. In summary, the absence of ecto-5'NT/CD73 in the D283 cell line, a metastatic MB phenotype, suggests that high expression levels of this ectonucleotidase could be correlated with a poor prognosis in patients with MB.

  19. Chemotherapy increases long-term survival in patients with adult medulloblastoma--a literature-based meta-analysis.

    Science.gov (United States)

    Kocakaya, Selin; Beier, Christoph Patrick; Beier, Dagmar

    2016-03-01

    Adult medulloblastoma is a potentially curable malignant entity with an incidence of 0.5-1 per million. Valid data on prognosis, treatment, and demographics are lacking, as most current knowledge stems from retrospective studies. Surgical resection followed by radiotherapy are accepted parts of treatment regimes; however, established prognostic factors and data clarifying the role of chemotherapy are missing. We investigated 227 publications from 1969-2013, with 907 identifiable, individual patients being available for meta-analysis. Demographic data, risk stratification, and treatment of these patients were similar to previous cohorts. The median overall survival (mOS) was 65 months (95% CI: 54.6-75.3) , the 5-year overall survival was 50.9% with 16% of the patients dying more than 5 years after diagnosis. Incomplete resection, clinical and radiological signs for brainstem infiltration, and abstinence from radiotherapy were predictive of worse outcome. Metastatic disease at tumor recurrence was identified as a new prognostic factor, while neither metastasis at initial diagnosis nor desmoplastic/classic histology was correlated with survival. Patients receiving chemotherapy first-line survived significantly longer (mOS: 108 mo, 95% CI: 68.6-148.4) than patients treated with radiation alone (mOS: 57 mo, 95% CI: 39.6-74.4) or patients who received chemotherapy at tumor recurrence. This effect was not biased by tumor stage or decade of treatment. Importantly, (neo)adjuvant chemotherapy also significantly increased the chance for long-term survival (>5 y) compared with radiotherapy alone or chemotherapy at tumor recurrence. This meta-analysis clarifies relevant prognostic factors and suggests that chemotherapy as part of first-line therapy improves overall survival and increases the proportion of patients with long-term survival. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions

  20. Patterns of Failure Following Multimodal Treatment for Medulloblastoma: Long-Term Follow-up Results at a Single Institution.

    Science.gov (United States)

    Lee, Dong Soo; Cho, Jaeho; Kim, Se Hoon; Kim, Dong-Seok; Shim, Kyu Won; Lyu, Chuhl Joo; Han, Jung Woo; Suh, Chang-Ok

    2015-10-01

    The purpose of this study is to investigate the long-term results and appropriateness of radiation therapy (RT) for medulloblastoma (MB) at a single institution. We analyzed the clinical outcomes of 106 patients with MB who received RT between January 1992 and October 2009. The median age was 7 years (range, 0 to 50 years), and the proportion of M0, M1, M2, and M3 stages was 60.4%, 8.5%, 4.7%, and 22.6%, respectively. The median total craniospinal irradiation (CSI) and posterior fossa tumor bed dose in 102 patients (96.2%) treated with CSI was 36 Gy and 54 Gy, respectively. The median follow-up period in survivors was 132 months (range, 31 to 248 months). A gradual improvement in survival outcomes was observed, with 5-year overall survival rates of 61.5% in 1990s increasing to 73.6% in 2000s. A total of 29 recurrences (27.4%) developed at the following sites: five (17.2%) in the tumor bed; five (17.2%) in the posterior fossa other than the tumor bed; nine (31%) in the supratentorium; and six (20.7%) in the spinal subarachnoid space only. The four remaining patients showed multiple site recurrences. Among 12 supratentorial recurrences, five cases recurred in the subfrontal areas. Although the frequency of posterior fossa/tumor bed recurrences was significantly high among patients treated with subtotal resection, other site (other intracranial/spinal) recurrences were more common among patients treated with gross tumor removal (p=0.016). There was no case of spinal subarachnoid space relapse from desmoplastic/extensive nodular histological subtypes. Long-term follow-up results and patterns of failure confirmed the importance of optimal RT dose and field arrangement. More tailored multimodal strategies and proper CSI technique may be the cornerstones for improving treatment outcomes in MB patients.

  1. The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma.

    Science.gov (United States)

    Andrade, Augusto Faria; Borges, Kleiton Silva; Suazo, Veridiana Kiill; Geron, Lenisa; Corrêa, Carolina Alves Pereira; Castro-Gamero, Angel Mauricio; de Vasconcelos, Elton José Rosas; de Oliveira, Ricardo Santos; Neder, Luciano; Yunes, José Andres; Dos Santos Aguiar, Simone; Scrideli, Carlos Alberto; Tone, Luiz Gonzaga

    2017-02-01

    Medulloblastoma (MB) is the most common solid tumor among pediatric patients and corresponds to 20 % of all pediatric intracranial tumors in this age group. Its treatment currently involves significant side effects. Epigenetic changes such as DNA methylation may contribute to its development and progression. DNA methyltransferase (DNMT) inhibitors have shown promising anticancer effects. The agent Zebularine acts as an inhibitor of DNA methylation and shows low toxicity and high efficacy, being a promising adjuvant agent for anti-cancer chemotherapy. Several studies have reported its effects on different types of tumors; however, there are no studies reporting its effects on MB. We analyzed its potential anticancer effects in four pediatric MB cell lines. The treatment inhibited proliferation and clonogenicity, increased the apoptosis rate and the number of cells in the S phase (p < 0.05), as well as the expression of p53, p21, and Bax, and decreased cyclin A, Survivin and Bcl-2 proteins. In addition, the combination of zebularine with the chemotherapeutic agents vincristine and cisplatin resulted in synergism and antagonism, respectively. Zebularine also modulated the activation of the SHH pathway, reducing SMO and GLI1 levels and one of its targets, PTCH1, without changing SUFU levels. A microarray analysis revealed different pathways modulated by the drug, including the Toll-Like Receptor pathway and high levels of the BATF2 gene. The low expression of this gene was associated with a worse prognosis in MB. Taken together, these data suggest that Zebularine may be a potential drug for further in vivo studies of MB treatment.

  2. Oncolytic effects of parvovirus H-1 in medulloblastoma are associated with repression of master regulators of early neurogenesis.

    Science.gov (United States)

    Lacroix, Jeannine; Schlund, Franziska; Leuchs, Barbara; Adolph, Kathrin; Sturm, Dominik; Bender, Sebastian; Hielscher, Thomas; Pfister, Stefan M; Witt, Olaf; Rommelaere, Jean; Schlehofer, Jörg R; Witt, Hendrik

    2014-02-01

    Based on extensive pre-clinical studies, the oncolytic parvovirus H-1 (H-1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high-risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H-1PV on MB cells in vitro and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non-transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H-1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H-1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H-1PV. H-1PV induced down-regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H-1PV infection. H-1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. Copyright © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  3. FUNCTIONAL GENOMICS IDENTIFIES TIS21-DEPENDENT MECHANISMS AND PUTATIVE CANCER DRUG TARGETS UNDERLYING MEDULLOBLASTOMA SHH-TYPE DEVELOPMENT

    Directory of Open Access Journals (Sweden)

    Giulia Gentile

    2016-11-01

    Full Text Available We have recently generated a novel medulloblastoma (MB mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+-Tis21KO.ts main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs. By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+-is21 wild-type versus Ptch1+-Tis21 knockout, among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets.The data analysis using bioinformatic tools revealed: i a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; ii a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype the neural cell type involved in group 3 MB; iii the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.

  4. Physical mapping of chromosome 17p13.3 in the region of a putative tumor suppressor gene important in medulloblastoma

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    McDonald, J.D.; Daneshvar, L.; Willert, J.R. [Univ. of California, San Franciso, CA (United States)] [and others

    1994-09-01

    Deletion mapping of a medulloblastoma tumor panel revealed loss of distal chromosome 17p13.3 sequences in tumors from 14 of 32 patients (44%). Of the 14 tumors showing loss of heterozygosity by restriction fragment length polymorphism analysis, 14 of 14 (100%) displayed loss of the telomeric marker p144-D6 (D17S34), while a probe for the ABR gene on 17p13.3 was lost in 7 of 8 (88%) informative cases. Using pulsed-field gel electrophoresis, we localized the polymorphic marker (VNTR-A) of the ABR gene locus to within 220 kb of the p144-D6 locus. A cosmid contig constructed in this region was used to demonstrate by fluorescence in situ hybridization that the ABR gene is oriented transcriptionally 5{prime} to 3{prime} toward the telomere. This report provides new physical mapping data for the ABR gene, which has not been previously shown to be deleted in medulloblastoma. These results provide further evidence for the existence of a second tumor suppressor gene distinct from p53 on distal chromosome 17p. 12 refs., 3 figs.

  5. Application of probabilistic fiber-tracking method of MR imaging to measure impact of cranial irradiation on structural brain connectivity in children treated for medulloblastoma

    Science.gov (United States)

    Duncan, Elizabeth C.; Reddick, Wilburn E.; Glass, John O.; Hyun, Jung Won; Ji, Qing; Li, Yimei; Gajjar, Amar

    2016-03-01

    We applied a modified probabilistic fiber-tracking method for the extraction of fiber pathways to quantify decreased white matter integrity as a surrogate of structural loss in connectivity due to cranial radiation therapy (CRT) as treatment for pediatric medulloblastoma. Thirty subjects were examined (n=8 average-risk, n=22 high-risk) and the groups did not differ significantly in age at examination. The pathway analysis created a structural connectome focused on sub-networks within the central executive network (CEN) for comparison between baseline and post-CRT scans and for comparison between standard and high dose CRT. A paired-wise comparison of the connectivity between baseline and post-CRT scans showed the irradiation did have a significant detrimental impact on white matter integrity (decreased fractional anisotropy (FA) and decreased axial diffusivity (AX)) in most of the CEN sub-networks. Group comparisons of the change in the connectivity revealed that patients receiving high dose CRT experienced significant AX decreases in all sub-networks while the patients receiving standard dose CRT had relatively stable AX measures across time. This study on pediatric patients with medulloblastoma demonstrated the utility of this method to identify specific sub-networks within the developing brain affected by CRT.

  6. Diffusion Tensor Magnetic Resonance Imaging Finding of Discrepant Fractional Anisotropy Between the Frontal and Parietal Lobes After Whole-Brain Irradiation in Childhood Medulloblastoma Survivors: Reflection of Regional White Matter Radiosensitivity?

    International Nuclear Information System (INIS)

    Qiu Deqiang; Kwong, Dora; Chan, Godfrey; Leung, Lucullus; Khong, P.-L.

    2007-01-01

    Purpose: To test the hypothesis that fractional anisotropy (FA) is more severely reduced in white matter of the frontal lobe compared with the parietal lobe after receiving the same whole-brain irradiation dose in a cohort of childhood medulloblastoma survivors. Methods and Materials: Twenty-two medulloblastoma survivors (15 male, mean [± SD] age = 12.1 ± 4.6 years) and the same number of control subjects (15 male, aged 12.0 ± 4.2 years) were recruited for diffusion tensor magnetic resonance imaging scans. Using an automated tissue classification method and the Talairach Daemon atlas, FA values of frontal and parietal lobes receiving the same radiation dose, and the ratio between them were quantified and denoted as FFA, PFA, and FA f/p , respectively. The Mann-Whitney U test was used to test for significant differences of FFA, PFA, and FA f/p between medulloblastoma survivors and control subjects. Results: Frontal lobe and parietal lobe white matter FA were found to be significantly less in medulloblastoma survivors compared with control subjects (frontal p = 0.001, parietal p = 0.026). Moreover, these differences were found to be discrepant, with the frontal lobe having a significantly larger difference in FA compared with the parietal lobe. The FA f/p of control and medulloblastoma survivors was 1.110 and 1.082, respectively (p = 0.029). Conclusion: Discrepant FA changes after the same irradiation dose suggest radiosensitivity of the frontal lobe white matter compared with the parietal lobe. Special efforts to address the potentially vulnerable frontal lobe after treatment with whole-brain radiation may be needed so as to balance disease control and treatment-related morbidity

  7. Pituitary adenylyl cyclase activating polypeptide inhibits gli1 gene expression and proliferation in primary medulloblastoma derived tumorsphere cultures

    Directory of Open Access Journals (Sweden)

    Dong Hongmei

    2010-12-01

    Full Text Available Abstract Background Hedgehog (HH signaling is critical for the expansion of granule neuron precursors (GNPs within the external granular layer (EGL during cerebellar development. Aberrant HH signaling within GNPs is thought to give rise to medulloblastoma (MB - the most commonly-observed form of malignant pediatric brain tumor. Evidence in both invertebrates and vertebrates indicates that cyclic AMP-dependent protein kinase A (PKA antagonizes HH signalling. Receptors specific for the neuropeptide pituitary adenylyl cyclase activating polypeptide (PACAP, gene name ADCYAP1 are expressed in GNPs. PACAP has been shown to protect GNPs from apoptosis in vitro, and to interact with HH signaling to regulate GNP proliferation. PACAP/ptch1 double mutant mice exhibit an increased incidence of MB compared to ptch1 mice, indicating that PACAP may regulate HH pathway-mediated MB pathogenesis. Methods Primary MB tumorsphere cultures were prepared from thirteen ptch1+/-/p53+/- double mutant mice and treated with the smoothened (SMO agonist purmorphamine, the SMO antagonist SANT-1, the neuropeptide PACAP, the PKA activator forskolin, and the PKA inhibitor H89. Gene expression of gli1 and [3H]-thymidine incorporation were assessed to determine drug effects on HH pathway activity and proliferation, respectively. PKA activity was determined in cell extracts by Western blotting using a phospho-PKA substrate antibody. Results Primary tumor cells cultured for 1-week under serum-free conditions grew as tumorspheres and were found to express PAC1 receptor transcripts. Gli1 gene expression was significantly reduced by SANT-1, PACAP and forskolin, but was unaffected by purmorphamine. The attenuation of gli1 gene expression by PACAP was reversed by the PKA inhibitor H89, which also blocked PKA activation. Treatment of tumorsphere cultures with PACAP, forskolin, and SANT-1 for 24 or 48 hours reduced proliferation. Conclusions Primary tumorspheres derived from ptch1+/-/p53

  8. Pituitary adenylyl cyclase activating polypeptide inhibits gli1 gene expression and proliferation in primary medulloblastoma derived tumorsphere cultures

    International Nuclear Information System (INIS)

    Cohen, Joseph R; Resnick, Daniel Z; Niewiadomski, Pawel; Dong, Hongmei; Liau, Linda M; Waschek, James A

    2010-01-01

    Hedgehog (HH) signaling is critical for the expansion of granule neuron precursors (GNPs) within the external granular layer (EGL) during cerebellar development. Aberrant HH signaling within GNPs is thought to give rise to medulloblastoma (MB) - the most commonly-observed form of malignant pediatric brain tumor. Evidence in both invertebrates and vertebrates indicates that cyclic AMP-dependent protein kinase A (PKA) antagonizes HH signalling. Receptors specific for the neuropeptide pituitary adenylyl cyclase activating polypeptide (PACAP, gene name ADCYAP1) are expressed in GNPs. PACAP has been shown to protect GNPs from apoptosis in vitro, and to interact with HH signaling to regulate GNP proliferation. PACAP/ptch1 double mutant mice exhibit an increased incidence of MB compared to ptch1 mice, indicating that PACAP may regulate HH pathway-mediated MB pathogenesis. Primary MB tumorsphere cultures were prepared from thirteen ptch1 +/- /p53 +/- double mutant mice and treated with the smoothened (SMO) agonist purmorphamine, the SMO antagonist SANT-1, the neuropeptide PACAP, the PKA activator forskolin, and the PKA inhibitor H89. Gene expression of gli1 and [ 3 H]-thymidine incorporation were assessed to determine drug effects on HH pathway activity and proliferation, respectively. PKA activity was determined in cell extracts by Western blotting using a phospho-PKA substrate antibody. Primary tumor cells cultured for 1-week under serum-free conditions grew as tumorspheres and were found to express PAC1 receptor transcripts. Gli1 gene expression was significantly reduced by SANT-1, PACAP and forskolin, but was unaffected by purmorphamine. The attenuation of gli1 gene expression by PACAP was reversed by the PKA inhibitor H89, which also blocked PKA activation. Treatment of tumorsphere cultures with PACAP, forskolin, and SANT-1 for 24 or 48 hours reduced proliferation. Primary tumorspheres derived from ptch1 +/- /p53 +/- mice exhibit constitutive HH pathway activity

  9. Additive effects of 5-Aza-2'-deoxycytidine and irradiation on clonogenic survival of human medulloblastoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Patties, Ina; Jahns, Jutta; Kortmann, Rolf-Dieter; Glasow, Annegret [Dept. of Radiotherapy and Radiooncology, Universitaetsklinikum Leipzig AoeR (Germany); Hildebrandt, Guido [Dept. of Radiotherapy and Radiooncology, Universitaetsklinikum Leipzig AoeR (Germany); Dept. of Radiotherapy, Univ. of Rostock (Germany)

    2009-05-15

    Background and purpose: in recent years, epigenetic modulators were introduced into tumor therapy. Here, the authors investigated the antitumor effect of 5-aza-2'-deoxycytidine-(5-aza-dC-)induced demethylation combined with irradiation on human medulloblastoma (MB) cells, which form the most common malignant brain tumor in children. Material and methods: three MB cell lines were treated with 5-aza-dC in a low-dose (0.1 {mu}M, 6 days) or high-dose (3/5 {mu}M, 3 days) setting and irradiated with 2, 4, 6, or 8 Gy single dose on an X-ray unit. Methylation status and mRNA expression of three candidate genes were analyzed by methylation-specific PCR (polymerase chain reaction) and quantitative real-time RT-PCR. Cell survival and mortality were determined by trypan blue exclusion test. Proliferation was analyzed by BrdU incorporation assay, and long-term cell survival was assessed by clonogenic assay. Results: 5-aza-dC treatment resulted in partial promoter demethylation and increased expression of hypermethylated candidate genes. A significant decrease of vital cell count, proliferation inhibition and increase of mortality was observed in 5-aza-dC-treated as well as in irradiated MB cells, whereby combination of both treatments led to additive effects. Although high-dose 5-aza-dC treatment was more effective in terms of demethylation, clonogenic assay revealed no differences between high- and low-dose settings indicating no relevance of 5-aza-dC-induced demethylation for decreased cell survival. MB cells pretreated with 5-aza-dC showed significantly lower plating efficiencies than untreated cells at all irradiation doses investigated. Analysis of surviving curves in irradiated MB cells, however, revealed no significant differences of {alpha}-, {beta}-values and 2-Gy surviving fraction with or without 5-aza-dC treatment. Conclusion: 5-aza-dC did not enhance radiation sensitivity of MB cells but significantly reduced the clonogenicity versus irradiation alone, which

  10. Integrated analysis of miRNA and mRNA expression in childhood medulloblastoma compared with neural stem cells.

    Directory of Open Access Journals (Sweden)

    Laura A Genovesi

    Full Text Available Medulloblastoma (MB is the most common malignant brain tumor in children and a leading cause of cancer-related mortality and morbidity. Several molecular sub-types of MB have been identified, suggesting they may arise from distinct cells of origin. Data from animal models indicate that some MB sub-types arise from multipotent cerebellar neural stem cells (NSCs. Hence, microRNA (miRNA expression profiles of primary MB samples were compared to CD133+ NSCs, aiming to identify deregulated miRNAs involved in MB pathogenesis. Expression profiling of 662 miRNAs in primary MB specimens, MB cell lines, and human CD133+ NSCs and CD133- neural progenitor cells was performed by qRT-PCR. Clustering analysis identified two distinct sub-types of MB primary specimens, reminiscent of sub-types obtained from their mRNA profiles. 21 significantly up-regulated and 12 significantly down-regulated miRNAs were identified in MB primary specimens relative to CD133+ NSCs (p<0.01. The majority of up-regulated miRNAs mapped to chromosomal regions 14q32 and 17q. Integration of the predicted targets of deregulated miRNAs with mRNA expression data from the same specimens revealed enrichment of pathways regulating neuronal migration, nervous system development and cell proliferation. Transient over-expression of a down-regulated miRNA, miR-935, resulted in significant down-regulation of three of the seven predicted miR-935 target genes at the mRNA level in a MB cell line, confirming the validity of this approach. This study represents the first integrated analysis of MB miRNA and mRNA expression profiles and is the first to compare MB miRNA expression profiles to those of CD133+ NSCs. We identified several differentially expressed miRNAs that potentially target networks of genes and signaling pathways that may be involved in the transformation of normal NSCs to brain tumor stem cells. Based on this integrative approach, our data provide an important platform for future

  11. Updated results of a pilot study of low dose craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive neuroectodermal tumors (medulloblastoma)

    International Nuclear Information System (INIS)

    Goldwein, Joel W.; Radcliffe, Jerilynn; Johnson, James; Moshang, Thomas; Packer, Roger J.; Sutton, Leslie N.; Rorke, Lucy B.; D'Angio, Giulio J.

    1996-01-01

    Purpose: Children under 5 years old with medulloblastoma (MB) have a poor prognosis. They are more susceptible to the deleterious effects of craniospinal irradiation (CSART) and have a higher relapse rate when treated with low-dose CSART alone. We, thus, embarked on a prospective trial testing the usefulness of very low dose CSART and adjuvant chemotherapy. This is an update of a previous report on these patients. Methods and Materials: Between January 1988 and March 1990, 10 patients with medulloblastoma were treated using 18 Gy radiation therapy (RT) to the craniospinal axis, a posterior fossa (PF) boost to 50.4-55.8 Gy and chemotherapy consisting of vincristine (VCR) weekly during RT. This was followed by VCR, cis-diamminedichloroplatinum (CDDP), and lomustine (CCNU) for eight, 6-week cycles. Patients between 18 and 60 months of age without evidence of tumor dissemination were eligible for study. Follow-up was available until September 1994 with a median follow-up for living patients of 6.3 years from diagnosis. Results: Actuarial survival at over 6 years is 70 ± 20%. Three of the 10 patients relapsed and died. In one patient, the relapse developed in the spine and brain outside the posterior fossa, in the second, concurrently in the posterior fossa, brain and spine, and the third, only in the spine. One surviving child developed a brain stem infarct 4.8 years after diagnosis and has since almost fully recovered. A mean intelligence quotient (IQ) score of 103 in six patients surviving at least 1 year is unchanged from the baseline group score of 107. Five children tested at baseline and 2 years following treatment had IQ scores of 101 and 102, respectively. Six children tested at baseline and at 3 years had IQ scores of 106 and 96, respectively. Excluding the child tested shortly after his brain stem infarct, baseline and 3 year IQ scores were 103 and 97, respectively. Five of the seven long-term survivors grew at rates significantly below their expected

  12. Medulloblastoma: Conventional Radiation Therapy in Comparison to Chemo Radiation Therapy in The Post-operative Treatment of High-Risk Patients

    International Nuclear Information System (INIS)

    Abd El-Aal, H.H.; Mokhtar, M.M.; Habib, E.E.; El-Kashef, A.T.; Fahmy, E.S.

    2005-01-01

    The aim of this study is to assess treatment results of 48 pediatric high-risk medulloblastoma cases that were treated by surgery, radiotherapy with or without chemotherapy. The impact of adjuvant combination chemotherapy on treatment results will be assessed. Forty-eight cases of pediatric high-risk medulloblastoma treated from July 2001 to July 2004 were randomized into two groups. The first (group I) included 21 patients who received postoperative craniospinal radiation therapy (36 Gy + boost 20 Gy to the posterior fossa). The second (group II) included 27 cases who received postoperative combination cranio-spinal radiation therapy (with the same dose as the first group) and chemotherapy (vincristine, etoposide, cisplatin). Both groups were compared as regards overall survival (OS), disease free survival (DFS), response rate and treatment toxicity. In-group I, complete remission (CR) was achieved in 71.4% of the cases; partial remission (PR) in 14.3% of the patients; stationary disease (SD) in 14.3% and none of the cases suffered from progressive disease. The three year OS was 69.5% and the three-year OFS was 61.3%. In-group II, CR was achieved in 59.3% of the cases; PR in 3.7%; SO in 3.7% and PO in 37.3% of the cases. The three-year OS was 48.4% and the 3-year OFS was 48.9%. Regarding acute treatment toxicity in group I, nine patients (31.5%) developed grade I myelo-suppression and seven cases (24.5%) developed grade II myelo-suppression with three to five days treatment interruption. Whereas in group II, 13 patients (45.5%) developed grade I myelosuppression and seven cases (24.5%) developed grade II myelo-suppression requiring interruption of treatment for a period ranging from five to seven days with spontaneous recovery. In group I no other acute toxicity was recognized, whereas in group II other toxicities related to chemotherapy were noticed. For example, three patients (II %) developed peripheral neuritis during the course of treatment and two patients

  13. Optimizing the radiation therapy dose prescription for pediatric medulloblastoma: Minimizing the life years lost attributable to failure to control the disease and late complication risk

    DEFF Research Database (Denmark)

    Brodin, N. Patrik; Vogelius, Ivan R.; Bjork-Eriksson, Thomas

    2014-01-01

    Background. A mathematical framework is presented for simultaneously quantifying and evaluating the trade-off between tumor control and late complications for risk-based radiation therapy (RT) decision-support. To demonstrate this, we estimate life years lost (LYL) attributable to tumor recurrence...... is important, with 0.75 LYL (95% CI 0.60-7.2 years) for standard uniform 24 Gy CS irradiation. However, recurrence risk dominates the total LYL with 14.2 years (95% CI 13.4-16.6 years). Compared to standard treatment, a risk-adapted strategy prescribing 12 Gy to the spinal volume encompassing the 1st-10th......, late cardiac toxicity and secondary cancers for standard-risk pediatric medulloblastoma (MB) patients and compare the effect of dose re-distribution on a common scale. Methods. Total LYL were derived, based on the LYL attributable to radiation-induced late complications and the LYL from not controlling...

  14. OS02.1 Multicenter pilot study of radio-chemotherapy as first-line treatment for adults with medulloblastoma - the NOA-07 trial

    Science.gov (United States)

    Beier, D.; Proescholdt, M.; Reinert, C.; Hattingen, E.; Seidel, C.; Dirven, L.; Lürding, R.; Pfister, S.; Pietsch, T.; Hau, P.

    2017-01-01

    Abstract Background: Medulloblastoma in adult patients has a low incidence, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. In contrast to children, no prospective data on the feasibility of radio-chemotherapy in adults exists. The German Neuro-Oncology Working Group (NOA) performed a prospective multicenter single-arm Phase II trial to evaluate the feasibility and toxicity of radio-chemotherapy in this population. Methods: The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by a maximum of eight cycles of cisplatin, lomustine and vincristine. Adverse events, imaging and progression patterns, combined histological and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated prospectively. The primary endpoints were the rate of toxicity-related treatment terminations after four cycles of chemotherapy, and the toxicity profile. Findings: Thirty patients were evaluable. Fifty percent of patients showed classic, and 50% desmoplastic-nodular histology. Sixty-eight percent of patients were genetically classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13.6% in wingless (WNT), and 17.7% in Non-WNT/Non-SHH (Group 4). Four cycles of chemotherapy were feasible in the majority of patients (n=21; 70.0%). Leukopenia was the major toxicity, with 79 events of CTC grade 3 and 4 in 17 patients. Polyneuropathy and ototoxicity were the only grade 3 or 4 non-haematological toxicities during the active treatment phase and occurred 12 times in eight patients and one time in one patient, respectively. Events were also calculated per cycle and showed an increase of toxicity over treatment time. Feasibility appeared to be age-dependent, leading to application of four cycles of chemotherapy in 72.7% of patients below age 45 and 62.5% of patients 45 or above. Testing for all eight adjuvant cycles revealed that 45.5% of all patients younger than 45 years completed

  15. BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells.

    Science.gov (United States)

    Thomaz, Amanda; Jaeger, Mariane; Buendia, Marienela; Bambini-Junior, Victorio; Gregianin, Lauro José; Brunetto, Algemir Lunardi; Brunetto, André T; de Farias, Caroline Brunetto; Roesler, Rafael

    2016-07-01

    Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling has been associated with increased proliferative capabilities, invasiveness, and chemoresistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide (ANA-12) markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide the first evidence supporting further investigation of TrkB inhibition as a potential novel strategy for MB treatment.

  16. Feasibility and efficacy of a computer-based intervention aimed at preventing reading decoding deficits among children undergoing active treatment for medulloblastoma: results of a randomized trial.

    Science.gov (United States)

    Palmer, Shawna L; Leigh, Laurie; Ellison, Susan C; Onar-Thomas, Arzu; Wu, Shengjie; Qaddoumi, Ibrahim; Armstrong, Gregory T; Wright, Karen; Wetmore, Cynthia; Broniscer, Alberto; Gajjar, Amar

    2014-05-01

    To investigate the feasibility of a computer-based reading intervention completed by patients diagnosed with a brain tumor. Patients were randomized to the intervention (n = 43) or standard of care group (n = 38). The intervention consisted of 30 sessions using Fast ForWord® exercises in a game-like format. Change in reading decoding scores over time since diagnosis was examined. Gender, race, parent education, parent marital status, and age at diagnosis were examined as covariates. 17 patients (39.5%) were able to complete the target goal of 30 intervention sessions. Females had significantly greater training time than males (p = .022). Age at diagnosis was associated with average training time/session for females (r = .485, p = .041). No significant differences were found in reading scores between the randomized groups. The study was well accepted by families and adherence by patients undergoing radiation therapy for medulloblastoma was moderate. Suggestions for improved methodology are discussed.

  17. Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury

    Energy Technology Data Exchange (ETDEWEB)

    Giantsoudi, Drosoula; Sethi, Roshan V. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Yeap, Beow Y. [Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts (United States); Eaton, Bree R. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Ebb, David H. [Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts (United States); Caruso, Paul A.; Rapalino, Otto [Department of Radiology (O.R.) at the Massachusetts General Hospital, Boston, Massachusetts (United States); Chen, Yen-Lin E.; Adams, Judith A.; Yock, Torunn I.; Tarbell, Nancy J.; Paganetti, Harald [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); MacDonald, Shannon M., E-mail: smacdonald@mgh.harvard.edu [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2016-05-01

    Background: Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. Methods and Materials: We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. Results: At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). Conclusions: Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

  18. Critical combinations of radiation dose and volume predict intelligence quotient and academic achievement scores after craniospinal irradiation in children with medulloblastoma.

    Science.gov (United States)

    Merchant, Thomas E; Schreiber, Jane E; Wu, Shengjie; Lukose, Renin; Xiong, Xiaoping; Gajjar, Amar

    2014-11-01

    To prospectively follow children treated with craniospinal irradiation to determine critical combinations of radiation dose and volume that would predict for cognitive effects. Between 1996 and 2003, 58 patients (median age 8.14 years, range 3.99-20.11 years) with medulloblastoma received risk-adapted craniospinal irradiation followed by dose-intense chemotherapy and were followed longitudinally with multiple cognitive evaluations (through 5 years after treatment) that included intelligence quotient (estimated intelligence quotient, full-scale, verbal, and performance) and academic achievement (math, reading, spelling) tests. Craniospinal irradiation consisted of 23.4 Gy for average-risk patients (nonmetastatic) and 36-39.6 Gy for high-risk patients (metastatic or residual disease >1.5 cm(2)). The primary site was treated using conformal or intensity modulated radiation therapy using a 2-cm clinical target volume margin. The effect of clinical variables and radiation dose to different brain volumes were modeled to estimate cognitive scores after treatment. A decline with time for all test scores was observed for the entire cohort. Sex, race, and cerebrospinal fluid shunt status had a significant impact on baseline scores. Age and mean radiation dose to specific brain volumes, including the temporal lobes and hippocampi, had a significant impact on longitudinal scores. Dichotomized dose distributions at 25 Gy, 35 Gy, 45 Gy, and 55 Gy were modeled to show the impact of the high-dose volume on longitudinal test scores. The 50% risk of a below-normal cognitive test score was calculated according to mean dose and dose intervals between 25 Gy and 55 Gy at 10-Gy increments according to brain volume and age. The ability to predict cognitive outcomes in children with medulloblastoma using dose-effects models for different brain subvolumes will improve treatment planning, guide intervention, and help estimate the value of newer methods of irradiation. Copyright © 2014

  19. Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury

    International Nuclear Information System (INIS)

    Giantsoudi, Drosoula; Sethi, Roshan V.; Yeap, Beow Y.; Eaton, Bree R.; Ebb, David H.; Caruso, Paul A.; Rapalino, Otto; Chen, Yen-Lin E.; Adams, Judith A.; Yock, Torunn I.; Tarbell, Nancy J.; Paganetti, Harald; MacDonald, Shannon M.

    2016-01-01

    Background: Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. Methods and Materials: We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. Results: At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). Conclusions: Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

  20. A comparative study on the risks of radiogenic second cancers and cardiac mortality in a set of pediatric medulloblastoma patients treated with photon or proton craniospinal irradiation

    International Nuclear Information System (INIS)

    Zhang, Rui; Howell, Rebecca M.; Taddei, Phillip J.; Giebeler, Annelise; Mahajan, Anita; Newhauser, Wayne D.

    2014-01-01

    Purpose: To compare the risks of radiogenic second cancers and cardiac mortality in 17 pediatric medulloblastoma patients treated with passively scattered proton or field-in-field photon craniospinal irradiation (CSI). Material/methods: Standard of care photon or proton CSI treatment plans were created for all 17 patients in a commercial treatment planning system (TPS) (Eclipse version 8.9; Varian Medical Systems, Palo Alto, CA) and prescription dose was 23.4 or 23.4 Gy (RBE) to the age specific target volume at 1.8 Gy/fraction. The therapeutic doses from proton and photon CSI plans were estimated from TPS. Stray radiation doses were determined from Monte Carlo simulations for proton CSI and from measurements and TPS for photon CSI. The Biological Effects of Ionization Radiation VII report and a linear model based on childhood cancer survivor data were used for risk predictions of second cancer and cardiac mortality, respectively. Results: The ratios of lifetime attributable risk (RLARs) (proton/photon) ranged from 0.10 to 0.22 for second cancer incidence and ranged from 0.20 to 0.53 for second cancer mortality, respectively. The ratio of relative risk (RRR) (proton/photon) of cardiac mortality ranged from 0.12 to 0.24. The RLARs of both cancer incidence and mortality decreased with patient’s age at exposure (e), while the RRRs of cardiac mortality increased with e. Girls had a significantly higher RLAR of cancer mortality than boys. Conclusion: Passively scattered proton CSI provides superior predicted outcomes by conferring lower predicted risks of second cancer and cardiac mortality than field-in-field photon CSI for all medulloblastoma patients in a large clinically representative sample in the United States, but the magnitude of superiority depends strongly on the patients’ anatomical development status

  1. Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury.

    Science.gov (United States)

    Giantsoudi, Drosoula; Sethi, Roshan V; Yeap, Beow Y; Eaton, Bree R; Ebb, David H; Caruso, Paul A; Rapalino, Otto; Chen, Yen-Lin E; Adams, Judith A; Yock, Torunn I; Tarbell, Nancy J; Paganetti, Harald; MacDonald, Shannon M

    2016-05-01

    Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET. Published by Elsevier Inc.

  2. A Phase 1 Trial of TPI 287 as a Single Agent and in Combination With Temozolomide in Patients with Refractory or Recurrent Neuroblastoma or Medulloblastoma.

    Science.gov (United States)

    Mitchell, Deanna; Bergendahl, Genevieve; Ferguson, William; Roberts, William; Higgins, Timothy; Ashikaga, Takamaru; DeSarno, Mike; Kaplan, Joel; Kraveka, Jacqueline; Eslin, Don; Werff, Alyssa Vander; Hanna, Gina K; Sholler, Giselle L Saulnier

    2016-01-01

    The primary aim of this Phase I study was to determine the maximum tolerated dose (MTD) of TPI 287 and the safety and tolerability of TPI 287 alone and in combination with temozolomide (TMZ) in pediatric patients with refractory or recurrent neuroblastoma or medulloblastoma. The secondary aims were to evaluate the pharmacokinetics of TPI 287 and the treatment responses. Eighteen patients were enrolled to a phase I dose escalation trial of weekly intravenous infusion of TPI 287 for two 28-day cycles with toxicity monitoring to determine the MTD, followed by two cycles of TPI 287 in combination with TMZ. Samples were collected to determine the pharmacokinetic parameters C(max), AUC(0-24), t(1/2), CL, and Vd on day 1 of cycles 1 (TPI 287 alone) and 3 (TPI 287 + TMZ) following TPI 287 infusion. Treatment response was evaluated by radiographic (CT or MRI) and radionuclide (MIBG) imaging for neuroblastoma. We determined the MTD of TPI 287 alone and in combination with temozolomide to be 125 mg/m(2). The non-dose-limiting toxicities at this dose were mainly anorexia and pain. The dose-limiting toxicities (DLTs) of two patients at 135 mg/m(2) were grade 3 hemorrhagic cystitis and grade 3 sensory neuropathy. Overall, TPI 287 was well tolerated by pediatric patients with refractory and relapsed neuroblastoma and medulloblastoma at a dose of 125 mg/m(2) IV on days 1, 8, and 15 of a 28 day cycle. © 2015 Wiley Periodicals, Inc.

  3. Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia

    International Nuclear Information System (INIS)

    Blazek, Ed R.; Foutch, Jennifer L.; Maki, Guitta

    2007-01-01

    Purpose: Primary medulloblastoma and glioblastoma multiforme tumor cells that express the surface marker CD133 are believed to be enriched for brain tumor stem cells because of their unique ability to initiate or reconstitute tumors in immunodeficient mice. This study sought to characterize the radiobiological properties and marker expression changes of CD133+ vs. CD133- cells of an established medulloblastoma cell line. Methods and Materials: Daoy and D283 Med cell lines were stained with fluorescently labeled anti-CD133 antibody and sorted into CD133+ and CD133- populations. The effect of oxygen (2% vs. 20%) on CD133 expression was measured. Both populations were analyzed for marker stability, cell cycle distribution, and radiosensitivity. Results: CD133+ Daoy cells restored nearly native CD133+ and CD133- populations within 18 days, whereas CD133- cells remained overwhelmingly CD133-. Culturing Daoy cells in 2% oxygen rather than the standard 20% oxygen increased their CD133 expression 1.6-fold. CD133+ Daoy cells were radioresistant via the β-parameter of the linear-quadratic model relative to CD133- Daoy cells, although their α-parameters and cell cycle distributions were identical. Conclusions: Restoration of the original CD133+ and CD133- populations from CD133+ Daoy cells in serum is further evidence that CD133+ cells are functionally distinct from CD133- cells. The radioresistance of CD133+ compared with CD133- Daoy cells is consistent with better repair of sublethal damage. Enlargement of the CD133+ sector is a new feature of the hypoxic response

  4. Clinical Outcomes Among Children With Standard-Risk Medulloblastoma Treated With Proton and Photon Radiation Therapy: A Comparison of Disease Control and Overall Survival.

    Science.gov (United States)

    Eaton, Bree R; Esiashvili, Natia; Kim, Sungjin; Weyman, Elizabeth A; Thornton, Lauren T; Mazewski, Claire; MacDonald, Tobey; Ebb, David; MacDonald, Shannon M; Tarbell, Nancy J; Yock, Torunn I

    2016-01-01

    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. 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. 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). Disease control with proton and photon radiation therapy appears equivalent for standard risk medulloblastoma. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Impact of radiation technique, radiation fraction dose, and total cisplatin dose on hearing. Retrospective analysis of 29 medulloblastoma patients

    Energy Technology Data Exchange (ETDEWEB)

    Scobioala, Sergiu; Kittel, Christopher; Ebrahimi, Fatemeh; Wolters, Heidi; Eich, Hans Theodor [University Hospital of Muenster, Department of Radiotherapy and Radiooncology, Muenster (Germany); Parfitt, Ross; Matulat, Peter; Am Zehnhoff-Dinnesen, Antoinette [University Hospital of Muenster, Department of Phoniatrics and Pediatric Audiology, Muenster (Germany)

    2017-11-15

    To analyze the incidence and degree of sensorineural hearing loss (SNHL) resulting from different radiation techniques, fractionation dose, mean cochlear radiation dose (D{sub mean}), and total cisplatin dose. In all, 29 children with medulloblastoma (58 ears) with subclinical pretreatment hearing thresholds participated. Radiotherapy (RT) and cisplatin had been applied sequentially according to the HIT MED Guidance. Audiological outcomes up to the latest follow-up (median 2.6 years) were compared. Bilateral high-frequency SNHL was observed in 26 patients (90%). No significant differences were found in mean hearing threshold between left and right ears at any frequency. A significantly better audiological outcome (p < 0.05) was found after tomotherapy at the 6 kHz bone-conduction threshold (BCT) and left-sided 8 kHz air-conduction threshold (ACT) than after a combined radiotherapy technique (CT). Fraction dose was not found to have any impact on the incidence, degree, and time-to-onset of SNHL. Patients treated with CT had a greater risk of SNHL at high frequencies than tomotherapy patients even though D{sub mean} was similar. Increase in severity of SNHL was seen when the total cisplatin dose reached above 210 mg/m{sup 2}, with the highest abnormal level found 8-12 months after RT regardless of radiation technique or fraction dose. The cochlear radiation dose should be kept as low as possible in patients who receive simultaneous cisplatin-based chemotherapy. The risk of clinically relevant HL was shown when D{sub mean} exceeds 45 Gy independent of radiation technique or radiation regime. Cisplatin ototoxicity was shown to have a dose-dependent effect on bilateral SNHL, which was more pronounced in higher frequencies. (orig.) [German] Analyse von Inzidenz und Schweregrad einer sensorineuralen Schwerhoerigkeit (''sensorineural hearing loss'', SNHL) infolge der Wirkung unterschiedlicher Bestrahlungstechniken, Fraktionierungen, mittlerer

  6. Medulloblastoma: long-term results for patients treated with definitive radiation therapy during the computed tomography era

    International Nuclear Information System (INIS)

    Merchant, Thomas E.; Wang, M.-H.; Haida, Toni; Lindsley, Karen L.; Finlay, Jonathan; Dunkel, Ira J.; Rosenblum, Marc K.; Leibel, Steven A.

    1996-01-01

    Purpose: We performed a retrospective evaluation of the patterns of failure and outcome for medulloblastoma patients treated with craniospinal irradiation therapy during the computed tomography (CT) era. Materials and Methods: The records of 100 patients treated at Memorial Sloan-Kettering Cancer Center between 1979 and 1994 were reviewed. CT scans or magnetic resonance imaging were used to guide surgical intervention and evaluate the extent of resection postoperatively. All patients were treated with conventional fractionation (1.8 Gy/day) and the majority received full-dose neuraxis radiation therapy and > 50 Gy to the primary site. Results: With a median follow-up of 100 months, the median, 5-year, and 10-year actuarial overall survival for the entire group were 58 months, 50%, and 25%, respectively. The median, 5- and 10-year actuarial disease-free survivals were 37 months, 41%, and 27%, respectively. Patients with localized disease (no evidence of disease beyond the primary site) had significantly improved overall (p < 0.02) and disease-free (p < 0.02) survivals compared to those with non localized disease. For patients with localized disease, the 5- and 10-year overall survival rates were 59% and 31%, whereas the disease-free survivals were 49% and 31%, respectively. Disease-free and overall survivals at similar intervals for patients with non localized disease were 29% and 30% (5 years), and 29% and 20% (10 years), respectively. Sixty-four of 100 patients failed treatment. Local failure as any component of first failure occurred in 35% of patients or 55% (35 of 64) of all failures and as the only site of first failure in 14% or 22% (14 of 64) of all failures. For patients presenting with localized disease (n = 68), local failure as any component of first failure occurred in 32% (22 of 68) and in 18% (12 of 68) as the only site. A multivariate analysis showed that M stage was the only prognostic factor to influence overall survival. For disease-free survival

  7. Clinical Outcomes Among Children With Standard-Risk Medulloblastoma Treated With Proton and Photon Radiation Therapy: A Comparison of Disease Control and Overall Survival

    International Nuclear Information System (INIS)

    Eaton, Bree R.; Esiashvili, Natia; Kim, Sungjin; Weyman, Elizabeth A.; Thornton, Lauren T.; Mazewski, Claire; MacDonald, Tobey; Ebb, David; MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I.

    2016-01-01

    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.

  8. Critical Combinations of Radiation Dose and Volume Predict Intelligence Quotient and Academic Achievement Scores After Craniospinal Irradiation in Children With Medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Merchant, Thomas E., E-mail: thomas.merchant@stjude.org [Division of Radiation Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Schreiber, Jane E. [Department of Psychology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Wu, Shengjie [Department of Biostatistcs, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Lukose, Renin [Division of Radiation Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Xiong, Xiaoping [Department of Biostatistcs, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Gajjar, Amar [Department of Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States)

    2014-11-01

    Purpose: To prospectively follow children treated with craniospinal irradiation to determine critical combinations of radiation dose and volume that would predict for cognitive effects. Methods and Materials: Between 1996 and 2003, 58 patients (median age 8.14 years, range 3.99-20.11 years) with medulloblastoma received risk-adapted craniospinal irradiation followed by dose-intense chemotherapy and were followed longitudinally with multiple cognitive evaluations (through 5 years after treatment) that included intelligence quotient (estimated intelligence quotient, full-scale, verbal, and performance) and academic achievement (math, reading, spelling) tests. Craniospinal irradiation consisted of 23.4 Gy for average-risk patients (nonmetastatic) and 36-39.6 Gy for high-risk patients (metastatic or residual disease >1.5 cm{sup 2}). The primary site was treated using conformal or intensity modulated radiation therapy using a 2-cm clinical target volume margin. The effect of clinical variables and radiation dose to different brain volumes were modeled to estimate cognitive scores after treatment. Results: A decline with time for all test scores was observed for the entire cohort. Sex, race, and cerebrospinal fluid shunt status had a significant impact on baseline scores. Age and mean radiation dose to specific brain volumes, including the temporal lobes and hippocampi, had a significant impact on longitudinal scores. Dichotomized dose distributions at 25 Gy, 35 Gy, 45 Gy, and 55 Gy were modeled to show the impact of the high-dose volume on longitudinal test scores. The 50% risk of a below-normal cognitive test score was calculated according to mean dose and dose intervals between 25 Gy and 55 Gy at 10-Gy increments according to brain volume and age. Conclusions: The ability to predict cognitive outcomes in children with medulloblastoma using dose-effects models for different brain subvolumes will improve treatment planning, guide intervention, and help

  9. Critical Combinations of Radiation Dose and Volume Predict Intelligence Quotient and Academic Achievement Scores After Craniospinal Irradiation in Children With Medulloblastoma

    International Nuclear Information System (INIS)

    Merchant, Thomas E.; Schreiber, Jane E.; Wu, Shengjie; Lukose, Renin; Xiong, Xiaoping; Gajjar, Amar

    2014-01-01

    Purpose: To prospectively follow children treated with craniospinal irradiation to determine critical combinations of radiation dose and volume that would predict for cognitive effects. Methods and Materials: Between 1996 and 2003, 58 patients (median age 8.14 years, range 3.99-20.11 years) with medulloblastoma received risk-adapted craniospinal irradiation followed by dose-intense chemotherapy and were followed longitudinally with multiple cognitive evaluations (through 5 years after treatment) that included intelligence quotient (estimated intelligence quotient, full-scale, verbal, and performance) and academic achievement (math, reading, spelling) tests. Craniospinal irradiation consisted of 23.4 Gy for average-risk patients (nonmetastatic) and 36-39.6 Gy for high-risk patients (metastatic or residual disease >1.5 cm 2 ). The primary site was treated using conformal or intensity modulated radiation therapy using a 2-cm clinical target volume margin. The effect of clinical variables and radiation dose to different brain volumes were modeled to estimate cognitive scores after treatment. Results: A decline with time for all test scores was observed for the entire cohort. Sex, race, and cerebrospinal fluid shunt status had a significant impact on baseline scores. Age and mean radiation dose to specific brain volumes, including the temporal lobes and hippocampi, had a significant impact on longitudinal scores. Dichotomized dose distributions at 25 Gy, 35 Gy, 45 Gy, and 55 Gy were modeled to show the impact of the high-dose volume on longitudinal test scores. The 50% risk of a below-normal cognitive test score was calculated according to mean dose and dose intervals between 25 Gy and 55 Gy at 10-Gy increments according to brain volume and age. Conclusions: The ability to predict cognitive outcomes in children with medulloblastoma using dose-effects models for different brain subvolumes will improve treatment planning, guide intervention, and help estimate

  10. Premature Epiphyseal Closure of the Lower Ext