WorldWideScience

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. [The medulloblastoma].

    Science.gov (United States)

    Figols-Ladrón de Guevara, J; Lafuente-Sánchez, J V

    Medulloblastoma is a cerebellar small cell tumor, whose ancestor cell has not been yet identified in the human normal embriology: its exact origin is, in fact, still unknown. Nevertheless, one of the most acceptable possibilities facing the origin of the tumor is the remaining rests of cerebellar outer granular sheet. It is a predominantly infantile tumor, less frequent in young adults, and World Health Organization (WHO) classification has assignated grade IV of malignancy. In this publication of the WHO, medulloblastomas have been subclassified into: classic, desmoplastic, medulloblastomas with extensive nodularity and advanced neuronal differentiation and large cell medulloblastomas. Real differences dealing with survival and prognosis amidst these subvarieties have been noted in extensive series. The most frequently genetic alteration is the presence of isochromosome 17q in most of 50% of the cases.

  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. 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.)

  13. 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.

  14. 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...

  15. 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...... in MR imaging biomarkers identified in pediatric medulloblastomas. MATERIALS AND METHODS: 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......-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. RESULTS: There were 19 SHH TP53 wild type (69%), 4 WNT-activated (14%), and 5 Group 4 (17%) medulloblastomas. Six...

  16. 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

  17. Cerebellar medulloblastoma presenting with skeletal metastasis

    Directory of Open Access Journals (Sweden)

    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.

  18. 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.

  19. 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.

    2014-01-01

    Purpose 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. Patients and Methods 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. Results 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. Conclusion 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. PMID

  20. 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)

  1. 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

  2. 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.)

  3. 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...

  4. 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.

  5. 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

  6. 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

  7. 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)

  8. 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)

  9. 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.)

  10. 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

  11. 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.)

  12. 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.)

  13. 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.

  14. 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,

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449

    OpenAIRE

    Rudin, Charles M.; Hann, Christine L.; Laterra, John; Yauch, Robert L.; Callahan, Christopher A.; Fu, Ling; Holcomb, Thomas; Stinson, Jeremy; Gould, Stephen E.; Coleman, Barbara; LoRusso, Patricia M.; Von Hoff, Daniel D.; de Sauvage, Frederic J.; Low, Jennifer A.

    2009-01-01

    Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms. Molecular analyses of tumor specimens obta...

  5. 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.

  6. [Congenital medulloblastoma associated with intracranial arachnoid cyst].

    Science.gov (United States)

    Gelabert González, Miguel; Serramito-García, Ramón; Liñares Paz, Mercedes; Aran-Echabe, Eduardo; García-Allut, Alfredo

    2014-01-01

    Arachnoid cysts are very common lesions in paediatric patients, with treatment depending on their location and symptomatology. They are usually solitary cysts but may be associated with other central nervous system diseases such as tumours and congenital deformities. We describe the case of a neonate diagnosed with an arachnoid cyst of the quadrigeminal cistern treated by endoscopy. After the operation, the child's condition worsened; a CT scan revealed a midline posterior fossa tumour not visible in the preoperative neuroradiological tests. The tumour, a medulloblastoma, was partially removed. Given the child's age and the poor prognosis, oncological treatment was not undertaken. The association between medulloblastoma and arachnoid cyst is very rare, and we could find only one such case in the literature. Copyright © 2012 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

  7. 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

  8. 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

  9. 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.

  10. 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...

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. [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.

  19. 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.

  20. Cerebellar Medulloblastoma in Middle-to-Late Adulthood

    OpenAIRE

    Aljoghaiman, Majid; Taha, Mahmoud S.; Abdulkader, Marwah M.

    2018-01-01

    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 posterio...

  1. A Rare Case of Adult Medulloblastoma with Spinal Metastasis

    Directory of Open Access Journals (Sweden)

    K. Quenum

    2012-01-01

    Full Text Available Medulloblastoma is a relatively common malignant brain tumor of childhood and relatively rare in adulthood, with a propensity for neuraxial spread via cerebrospinal fluid pathways. Osseous extraneural metastasis is uncommon and when it happens, radiologic findings are of sclerotic (60%, lytic (35%, and mixed patterns (5% (Algra et al. (1992. In this paper, we present a case of medulloblastoma metastiaszing to the lumbar spine and describe the magnetic resonance appearance, with emphasis on the image findings mimicking spondylodiscitis.

  2. 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.

  3. Modeling Aggressive Medulloblastoma Using Human-Induced Pluripotent Stem Cells

    Science.gov (United States)

    2015-07-01

    significant neurological, intellectual  and physical  disabilities . Recent gene expression studies have identified four MB subgroups, many of which have...investigate the role of individual’s distinctive genetic background in carcinogen sensitivity and medulloblastoma susceptibility. none provided 14...tumors are the most common cause of childhood oncological death, and medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB

  4. 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

  5. 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.

  6. MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS

    OpenAIRE

    Pugh, Trevor J.; Weeraratne, Shyamal Dilhan; Archer, Tenley C.; Pomeranz Krummel, Daniel A.; Auclair, Daniel; Bochicchio, James; Carneiro, Mauricio O.; Carter, Scott L.; Cibulskis, Kristian; Erlich, Rachel L.; Greulich, Heidi; Lawrence, Michael S.; Lennon, Niall J.; McKenna, Aaron; Meldrim, James

    2012-01-01

    Medulloblastomas are the most common malignant brain tumors in children 1 . Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles 2?5 . Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across t...

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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)

  14. 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)

  15. 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)

  16. 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)

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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

  7. 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

  8. The whole-genome landscape of medulloblastoma subtypes

    DEFF Research Database (Denmark)

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

    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 ...

  9. 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 ...

  10. 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…

  11. 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

  12. 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)

  13. 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.)

  14. MRI features of primary, secondary and metastatic medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Buehring, U.; Strayle-Batra, M.; Kueker, W. [Department of Neuroradiology, University of Tuebingen (Germany); Freudenstein, D. [Department of Neursurgery, University of Tuebingen (Germany); Scheel-Walter, H.-G. [Department of Pediatric Oncology, University of Tuebingen (Germany)

    2002-06-01

    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.)

  15. 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.)

  16. The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors.

    Science.gov (United States)

    Mille, Frédéric; Tamayo-Orrego, Lukas; Lévesque, Martin; Remke, Marc; Korshunov, Andrey; Cardin, Julie; Bouchard, Nicolas; Izzi, Luisa; Kool, Marcel; Northcott, Paul A; Taylor, Michael D; Pfister, Stefan M; Charron, Frédéric

    2014-10-13

    During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. 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

  18. 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.

  19. 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

  20. 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.

  1. Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem.

    Science.gov (United States)

    Grammel, Daniel; Warmuth-Metz, Monika; von Bueren, André O; Kool, Marcel; Pietsch, Torsten; Kretzschmar, Hans A; Rowitch, David H; Rutkowski, Stefan; Pfister, Stefan M; Schüller, Ulrich

    2012-04-01

    Medulloblastoma is a malignant brain tumor of childhood that comprises at least four molecularly distinct subgroups. We have previously described that cerebellar granule neuron precursors may give rise to the subgroup with a molecular fingerprint of Sonic hedgehog (Shh) signaling. Other recent data indicate that precursor cells within the dorsal brain stem may serve as cellular origins for Wnt-associated medulloblastomas. To see whether Shh-associated medulloblastomas are also able to develop in the dorsal brainstem, we analyzed two lines of transgenic mice with constitutive Shh signaling in hGFAP- and Math1-positive brainstem precursor populations, respectively. Our results show that in both of these lines, medulloblastomas arise from granule neuron precursors of the cochlear nuclei, a derivative of the auditory lower rhombic lip. This region is distinct from derivatives of precerebellar lower rhombic lip where medulloblastomas arise in mice with constitutive-active Wnt signaling. With respect to their histology and the expression of appropriate markers, Shh tumors from the murine cochlear nuclei perfectly resemble human Shh-associated medulloblastomas. Moreover, we find that in a series of 63 human desmoplastic medulloblastomas, 21 (33%) have a very close contact to the cochlear nuclei on MR imaging. In conclusion, we demonstrate that precursors of the murine rhombic lip, which either develop into cerebellar or into cochlear granule neurons, may give rise to Shh-associated medulloblastoma, and this has important implications for the cellular origin of human medulloblastomas.

  2. 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

  3. RalA is overactivated in medulloblastoma.

    Science.gov (United States)

    Ginn, Kevin F; Fangman, Ben; Terai, Kaoru; Wise, Amanda; Ziazadeh, Daniel; Shah, Kushal; Gartrell, Robyn; Ricke, Brandon; Kimura, Kyle; Mathur, Sharad; Borrego-Diaz, Emma; Farassati, Faris

    2016-10-01

    Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies. We have studied an important effector down-stream of Ras, namely RalA (Ras-Like), for the first time and revealed overactivation of RalA in MDB. Affinity precipitation analysis of active RalA (RalA-GTP) in eight MDB cell lines (DAOY, RES256, RES262, UW228-1, UW426, UW473, D283 and D425) revealed that the majority contained elevated levels of active RalA (RalA-GTP) as compared with fetal cerebellar tissue as a normal control. Additionally, total RalA levels were shown to be elevated in 20 MDB patient samples as compared to normal brain tissue. The overall expression of RalA, however, was comparable in cancerous and normal samples. Other important effectors of RalA pathway including RalA binding protein-1 (RalBP1) and protein phosphatase A (PP2A) down-stream of Ral and Aurora kinase A (AKA) as an upstream RalA activator were also investigated in MDB. Considering the lack of specific inhibitors for RalA, we used gene specific silencing in order to inhibit RalA expression. Using a lentivirus expressing anti-RalA shRNA we successfully inhibited RalA expression in MDB and observed a significant reduction in proliferation and invasiveness. Similar results were observed using inhibitors of AKA and geranyl-geranyl transferase (non-specific inhibitors of RalA signaling) in terms of loss of in vivo tumorigenicity in heterotopic nude mouse model. Finally, once tested in cells expressing CD133 (a marker for MDB cancer stem cells

  4. 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 descriptive......-polychemotherapy of adult patients with medulloblastoma....

  5. 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.

  6. 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.

  7. 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.

  8. 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.)

  9. Medulloblastoma: seeding of VP shunt tract and peritoneum.

    Science.gov (United States)

    Pettersson, David; Schmitz, Kelli R; Pollock, Jeffrey M; Hopkins, Katharine L

    2012-03-30

    We report on a 5-year-old boy with seeding of the peritoneum and a ventriculoperitoneal shunt tract by anaplastic medulloblastoma. The role of ventriculoperitoneal shunting in the spread of primary central nervous system tumors has been controversial. In the case reported here, the unique distribution of tumor implants on ultrasound and multiplanar computed tomography gives further credence to the argument that ventriculoperitoneal shunting is a pathway for extraneural metastases of primary central nervous system tumors.

  10. Modeling Aggressive Medulloblastoma Using Human Induced Pluripotent Stem Cells

    Science.gov (United States)

    2017-09-01

    Determine if AngII promotes MB cell tumorigenicity through a AT1R-MYC positive feedback loop. This aim will build on our working model that AngII...AWARD NUMBER: W81XWH-14-1-0176 TITLE: Modeling Aggressive Medulloblastoma Using Human-Induced Pluripotent Stem Cells PRINCIPAL INVESTIGATOR...DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response

  11. [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.

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

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    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.

  13. Cognitive disorders in pediatric medulloblastoma: what neuroimaging has to offer.

    Science.gov (United States)

    Hoang, Duc Ha; Pagnier, Anne; Guichardet, Karine; Dubois-Teklali, Fanny; Schiff, Isabelle; Lyard, Geneviève; Cousin, Emilie; Krainik, Alexandre

    2014-08-01

    Medulloblastomas are the most common malignant childhood brain tumors arising in the posterior fossa. Treatment improvements for these tumors have meant that there are a greater number of survivors, but this long-term patient survival has increased the awareness of resulting neurocognitive deficits. Impairments in attention, memory, executive functions, and intelligence quotient demonstrate that the cerebellum likely plays a significant role in numerous higher cognitive functions such as language, cognitive, and emotional functions. In addition, children with medulloblastoma not only have cerebellar lesions but also brain white matter damages due to radiation and chemotherapy. Functional neuroimaging, a noninvasive method with many advantages, has become the standard tool in clinical and cognitive neuroscience research. By reviewing functional neuroimaging studies, this review aims to clarify the role of the cerebellum in cognitive function and explain more clearly cognitive sequelae due to polytherapy in children with medulloblastoma. This review suggests that the posterior cerebellar lobes are crucial to maintaining cognitive performance. Clinical investigations could help to better assess the involvement of these lobes in cognitive functions.

  14. 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.

  15. 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.)

  16. 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.

  17. 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...

  18. 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.

  19. 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)

  20. Medulloblastomas of the Cerebellum in Children: Clinicopathologic Comparison

    Directory of Open Access Journals (Sweden)

    V. V. Morgun

    2017-04-01

    Full Text Available Embryonal neuroepithelial tumours of the brain, grade IV are mainly observed in children and are characterized by rapid metastatic spread and frequent recurrence. The aim of the work is to compare structural features of medulloblastomas of the cerebellum in children of different age groups taking into account localization, metastatic spread and treatment outcomes. Materials and methods. The results of complete examination and surgical treatment of 289 children with medulloblastoma of the cerebellum at the Department of Pediatric Neurosurgery of Institute of neurosurgery named after A.P. Romodanov over the period of 1993–2013 were analysed. The children’s age ranged from 1 month to 17 years: peak of medulloblastoma detection was registered at the age of 4–7. Results. As part of the study all the patients were divided into four age groups. Younger children rarely had brainstem lesion. In children of older age brainstem lesion, invasion into cerebral aqueduct with the development of noncommunicating hydrocephalus were registered. Total resection of medulloblastoma in younger children was performed in 40 % of cases, subtotal – in 42 %, partial – in 18 %. In children of older age total resection of medulloblastoma was carried out in 36%, subtotal – in 52 %, partial – in 12 % of cases. Histological analysis of tumours involved morphological characteristics of general histoarchitecture, correlation between parenchymal and stromal component, presence of Homer Wright pseudorosettes, collonar structures, pale insulas, true ependymal rosettes, formation of braided collonar structures, prevalence of small low-differentiated structures, number of mitoses, neoangiogenesis and angioproliferation, presence of colliquative and coagulation necroses, evidence and type of invasion, lymphocytic infiltration of tumour tissue. The following variations were defined histologically: classical – 9470/3 in 34 cases (17.9 %, desmoplastic/nodular – 9471

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. Late effects of radiotherapy on patients with cerebellar medulloblastoma

    International Nuclear Information System (INIS)

    Silverman, C.L.; Palkes, H.; Talent, B.; Kovnar, E.; Clouse, J.W.; Thomas, P.R.

    1984-01-01

    Nine long-term survivors of cerebellar medulloblastoma treated with surgery and irradiation were retrospectively examined with a complete battery of neuropsychological tests and the results compared with their nonirradiated siblings. Significant decreased scores were found in the full-scale intelligence quotients (IQ), performance IQ, and verbal IQ with all nine irradiated patients scoring below their siblings. Also, educational quotients (EQ) of the irradiated patients were 12 to 17 points below the nonirradiated siblings with arithmetic EQ significantly decreased. Most severely affected were those children younger than 8 years at time of irradiation. No correlation was found with whole-brain dose, or objective physical or neurologic findings

  10. 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

  11. 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

  12. 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.

  13. 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

  14. 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

    Medulloblastomas are the most common, and often fatal, paediatric brain tumours that feature high genomic instability, frequent infection by human cytomegalovirus (HCMV) and resistance to radiation and chemotherapy. The causes of the pronounced chromosomal instability and its potential links...... with HCMV infection and/or resistance to genotoxic therapies remain largely unknown. To address these issues, here we have combined immunohistochemical analysis of a series of 25 paediatric medulloblastomas, complemented by medulloblastoma cell culture models including experimental HCMV infection. Using...... 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...

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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.)

  1. 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

  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. 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.

  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. 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.

  11. In vitro Natural Killer cell immunotherapy for medulloblastoma

    Directory of Open Access Journals (Sweden)

    Lucia eFernandez

    2013-04-01

    Full Text Available How the immune system attacks medulloblastoma (MB tumours effectively is unclear, although natural killer (NK cells play an important role in immune defence against tumour cells. Interactions between receptors on NK cells and ligands expressed by tumour cells are critical for tumour control by immunotherapy. In this study, we analysed tumour samples from 54 MB patients for expression of major histocompatibility complex class I-related chains A (MICA and UL16 binding protein (ULPB-2, which are ligands for the NK group 2 member D activatory receptor (NKG2D. The percentage of MICA and ULBP-2 positive cells was higher than 25% in 68% and 6% of MB patients, respectively. A moderate-high intensity of MICA cytoplasmic staining was observed in 46% MB patients and weak ULBP-2 staining was observed in 8% MB patients. No correlation between MICA/ULBP-2 expression and patient outcome was found. We observed that HTB-186, a medulloblastoma cell line, was moderately resistant to NK cell cytotoxicity in vitro. Blocking MICA/ULBP-2 on HTB-186, and NKG2D receptor on NK cells increased resistance to NK cell lysis in vitro. However, HLA class I blocking on HTB-186 and overnight incubation with IL-15 stimulated NK cells efficiently to kill tumour cells in vitro. We conclude that although NKG2D/MICA-ULBP-2 interactions have a role in NK cell cytotoxicity against MB, high expression of HLA class I can protect MB from NK cell cytotoxicity. Even so, our in vitro data indicate that if NK cells are appropriately stimulated, they may have the potential to target MB in vivo.

  12. 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

  13. RT-12OUTCOMES IN MEDULLOBLASTOMA: SINGLE INSTITUTION CASE SERIES

    Science.gov (United States)

    Kannan, V.; Bajpai, Ranjeet; Anand, Vivek; Deshpande, Sudesh; Misra, Basant K.; Kapadia, Asha; Almel, Sachin; Sankhe, Milind; Desai, Ketan; Kannan, Aarthi; Dubey, Sandhya; Ashok, P.P.; Shinde, Sandip

    2014-01-01

    BACKGROUND: We have seen a paradigm shift in terms of use of radiation technology for the treatment of patients with medulloblastoma, from conventional 2-D shifting fields to 3-D CRT, IMRT and proton therapy. Similarly from prone to supine position and reduced dose to the cranio-spinal axis with an intent to have equivalent outcomes with reduced probability of late sequelae including second malignancies. METHODS: We have analysed data of 21 consecutive patients in May 2014, registered and treated in our hospital between 2002 and 2011. The cohort consisted of 14 male and 7 female patients with a median age of 8 (Range 3-30) Years. With no known co-morbidities and median KPS of 70 they all had tumors mostly in the IV ventricle(43%) and cerebellum(38%), for which they underwent surgery including decompression(72%) subtotal excision(9%), near total or total excision(19%). All patients were histologically grade IV medulloblastoma who underwent adjuvant radiation alone (40%) or followed by chemotherapy (60%) based on the risk stratification. 57% received 3D CRT in supine position while rest are treated with conventional techniques, median dose given to cranio-spinal axis was 23.4 Gy, posterior fossa was 36 Gy and to the tumor bed was 55.8 Gy at 1.8Gy per fraction. Chemotherapy was usually procarbazine/cisplatin/vincristine based regimen. Regular IQ, endocrine, ophthalmic and auditory evaluation was done in all the patients on follow-up. RESULT: Overall survival at 5 year was documented at 45% and 10 year survival at 35% for the entire cohort taking worst case scenario.3/13 patients developed IQ problems, 7/13 developed endocrine dysfunction, 3/12 developed auditory abnormality. CONCLUSION: Outcome of this cohort is comparable to the literature on risk group stratification. More importantly, risk adapted strategy for the treatment was found to be technically and logistically feasible and effective for a comparatively rare tumor in our setup.

  14. 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.

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

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    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

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

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    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

  17. 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.

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

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    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.

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

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    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.

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

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    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

  1. 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

  2. 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

  3. 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.

  4. 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)

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

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    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.

  6. 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.

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

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    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.

  8. SPARC expression induces cell cycle arrest via STAT3 signaling pathway in medulloblastoma cells

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    Chetty, Chandramu [Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL-61605 (United States); Dontula, Ranadheer [Section of Hematology/Oncology, Department of Medicine, University of Illinois College of Medicine at Chicago, 840 South Wood Street, Suite 820-E, Chicago, IL-60612 (United States); Ganji, Purnachandra Nagaraju [Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL-61605 (United States); Gujrati, Meena [Department of Pathology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL-61605 (United States); Lakka, Sajani S., E-mail: slakka@uic.edu [Section of Hematology/Oncology, Department of Medicine, University of Illinois College of Medicine at Chicago, 840 South Wood Street, Suite 820-E, Chicago, IL-60612 (United States)

    2012-01-13

    Highlights: Black-Right-Pointing-Pointer Ectopic expression of SPARC impaired cell proliferation in medulloblastoma cells. Black-Right-Pointing-Pointer SPARC expression induces STAT3 mediated cell cycle arrest in medulloblastoma cells. Black-Right-Pointing-Pointer SPARC expression significantly inhibited pre-established tumor growth in nude-mice. -- Abstract: Dynamic cell interaction with ECM components has profound influence in cancer progression. SPARC is a component of the ECM, impairs the proliferation of different cell types and modulates tumor cell aggressive features. We previously reported that SPARC expression significantly impairs medulloblastoma tumor growth in vivo. In this study, we demonstrate that expression of SPARC inhibits medulloblastoma cell proliferation. MTT assay indicated a dose-dependent reduction in tumor cell proliferation in adenoviral mediated expression of SPARC full length cDNA (Ad-DsRed-SP) in D425 and UW228 cells. Flow cytometric analysis showed that Ad-DsRed-SP-infected cells accumulate in the G2/M phase of cell cycle. Further, immunoblot and immunoprecipitation analyses revealed that SPARC induced G2/M cell cycle arrest was mediated through inhibition of the Cyclin-B-regulated signaling pathway involving p21 and Cdc2 expression. Additionally, expression of SPARC decreased STAT3 phosphorylation at Tyr-705; constitutively active STAT3 expression reversed SPARC induced G2/M arrest. Ad-DsRed-SP significantly inhibited the pre-established orthotopic tumor growth and tumor volume in nude-mice. Immunohistochemical analysis of tumor sections from mice treated with Ad-DsRed-SP showed decreased immunoreactivity for pSTAT3 and increased immunoreactivity for p21 compared to tumor section from mice treated with mock and Ad-DsRed. Taken together our studies further reveal that STAT3 plays a key role in SPARC induced G2/M arrest in medulloblastoma cells. These new findings provide a molecular basis for the mechanistic understanding of the

  9. 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

  10. 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.

  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......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...

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    Harris Peter S

    2012-03-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusions Our data suggest that targeting PLK1 with small molecule inhibitors, in combination with radiation therapy, is a novel strategy in the treatment of

  19. 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

  20. Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.

    Science.gov (United States)

    Lee, Michelle J; Hatton, Beryl A; Villavicencio, Elisabeth H; Khanna, Paritosh C; Friedman, Seth D; Ditzler, Sally; Pullar, Barbara; Robison, Keith; White, Kerry F; Tunkey, Chris; LeBlanc, Michael; Randolph-Habecker, Julie; Knoblaugh, Sue E; Hansen, Stacey; Richards, Andrew; Wainwright, Brandon J; McGovern, Karen; Olson, James M

    2012-05-15

    The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.

  1. 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

  2. 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)

  3. 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

  4. Chemotherapy increases long-term survival in patients with adult medulloblastoma

    DEFF Research Database (Denmark)

    Kocakaya, Selin; Beier, Christoph Patrick; Beier, Dagmar

    2016-01-01

    BACKGROUND: 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...

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  13. 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

  14. 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

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    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 

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

    Directory of Open Access Journals (Sweden)

    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.

  18. 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.

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

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    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.

  20. 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.

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

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    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

  2. 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

  3. 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.

  4. 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

  5. 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

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

    International Nuclear Information System (INIS)

    Bueren, André O von; Eberhart, Charles G; Kortmann, Rolf D; Rutkowski, Stefan; Grotzer, Michael A; Oehler, Christoph; Shalaby, Tarek; Hoff, Katja von; Pruschy, Martin; Seifert, Burkhardt; Gerber, Nicolas U; Warmuth-Metz, Monika; Stearns, Duncan

    2011-01-01

    To study whether and how c-MYC expression determines response to radio- and chemotherapy in childhood medulloblastoma (MB). 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. 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). 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

  7. The evolution of medulloblastoma therapy to personalized medicine [version 1; referees: 3 approved

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    Soma Sengupta

    2017-04-01

    Full Text Available Recent advances in cancer genomics have revolutionized the characterization and classification of medulloblastomas. According to the current WHO guidelines, medulloblastomas are now classified into the following molecularly defined groups: Wnt signaling pathway (WNT-activated, sonic hedgehog signaling pathway (SHH-activated and tumor suppressor protein p53 (TP53-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH (i.e. group 3 and group 4. Importantly, genomic, epigenomic, and proteomic advances have created a potential paradigm shift in therapeutic options. The challenge now is to (i translate these observations into new therapeutic approaches and (ii employ these observations in clinical practice, utilizing the classification following a molecular analysis for diagnosis and application of new subgroup-specific targeted therapeutics.

  8. Patterns of neuropsychological deficits in children with medulloblastoma according to craniospatial irradiation doses.

    Science.gov (United States)

    Kieffer-Renaux, V; Bulteau, C; Grill, J; Kalifa, C; Viguier, D; Jambaque, I

    2000-11-01

    This study aimed to analyse the relationship between supratentorial irradiation dose and the intellectual outcome in 36 children (aged between 5 and 15 years) treated for medulloblastoma. The supratentorial radiation dose was reduced to 25 Gy in 23 children and given at the standard dose, 35 Gy, in 13 other children. Neuropsychological evaluation was performed at a mean of 4.3 years (SD 4.7 years) after radiotherapy. The supratentorial radiation dose was the principal risk factor associated with impaired intellectual outcome. Verbal fluency, immediate word list recall, block design, and fine motricity of the dominant hand were significantly lower in children irradiated at the standard doses than in those irradiated at reduced doses. These findings suggest that the dose of radiotherapy applied to the brain strongly influences later verbal and non-verbal skills in children with medulloblastoma. This should be taken into account in treatment planning and in rehabilitation programs.

  9. 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

  10. 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

  11. Neuroblastomas and medulloblastomas exhibit more Coxsackie adenovirus receptor expression than gliomas and other brain tumors.

    Science.gov (United States)

    Persson, Annette; Fan, Xiaolong; Salford, Leif G; Widegren, Bengt; Englund, Elisabet

    2007-06-01

    Adenoviral vector-mediated treatment is a potential therapy for tumors of the central nervous system. To obtain a significant therapeutic effect by adenoviral vectors, a sufficient infection is required, the power of which depends predominantly on the level of Coxsackie adenovirus receptors. We stained surgical biopsies of central nervous system tumors and neuroblastomas for Coxsackie adenovirus receptors. For gliomas, the level of the receptor was low and markedly variable among individual tumors. By contrast, neuroblastomas and medulloblastomas exhibited a higher degree of Coxsackie adenovirus receptor expression than gliomas and other brain tumors. We conclude that neuroblastomas and medulloblastomas could be suitable for adenovirus-mediated gene therapy. Adverse effects of the treatment, however, must be considered because neurons and reactive astrocytes also express a significant amount of the receptor.

  12. 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.

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

    OpenAIRE

    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...

  14. 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)

  15. 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.

  16. 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.

  17. 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

  18. 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.

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

    Science.gov (United States)

    Staal, Jerome A.; Pei, Yanxin; Rood, Brian R.

    2016-01-01

    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. PMID:27775567

  20. 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

  1. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas.

    Science.gov (United States)

    Leung, Carly; Lingbeek, Merel; Shakhova, Olga; Liu, James; Tanger, Ellen; Saremaslani, Parvin; Van Lohuizen, Maarten; Marino, Silvia

    2004-03-18

    Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf) tumour suppressors. Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-repression of the ink4a/Arf locus is critically implicated. Here, we show that Bmi1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1-null mice we demonstrate a crucial role for Bmi1 in clonal expansion of granule cell precursors both in vivo and in vitro. Deregulated proliferation of these progenitor cells, by activation of the sonic hedgehog (Shh) pathway, leads to medulloblastoma development. We also demonstrate linked overexpression of BMI1 and patched (PTCH), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas. Together with the rapid induction of Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 in cerebellar granule cell cultures, these findings implicate BMI1 overexpression as an alternative or additive mechanism in the pathogenesis of medulloblastomas, and highlight a role for Bmi1-containing polycomb complexes in proliferation of cerebellar precursor cells.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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

  15. 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)

  16. 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)

  17. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study.

    Science.gov (United States)

    Schwalbe, Edward C; Lindsey, Janet C; Nakjang, Sirintra; Crosier, Stephen; Smith, Amanda J; Hicks, Debbie; Rafiee, Gholamreza; Hill, Rebecca M; Iliasova, Alice; Stone, Thomas; Pizer, Barry; Michalski, Antony; Joshi, Abhijit; Wharton, Stephen B; Jacques, Thomas S; Bailey, Simon; Williamson, Daniel; Clifford, Steven C

    2017-07-01

    International consensus recognises four medulloblastoma molecular subgroups: WNT (MB WNT ), SHH (MB SHH ), group 3 (MB Grp3 ), and group 4 (MB Grp4 ), each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0-16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3-16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MB WNT remained unchanged and each remaining consensus subgroup was split in two. MB SHH was split into age-dependent subgroups corresponding to infant (Star for Harris, Action

  18. 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.

    2015-01-01

    Summary 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. PMID:25533335

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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.

  2. 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.

  3. 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.

  4. 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-scanned inte......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...

  5. Management and outcomes of treating pediatric medulloblastoma: an eight years' experience in an Iranian pediatric center.

    Science.gov (United States)

    Mehrvar, Azim; Tashvighi, Maryam; Hedayati Asl, Amir Abbas; Niktoreh-Mofrad, Naghmeh; Mehrvar, Narjes; Afsar, Negar; Naderi, Ali; Allebouyeh, Mardawig; Qaddoumi, Ibrahim; Faranoush, Mohammad

    2018-04-01

    The clinical management of pediatric medulloblastoma requires a multidisciplinary approach, which can be challenging, especially in low- and middle-income countries. The aim of this study was to identify current challenges and describe the treatment and outcomes of Iranian pediatric patients with medulloblastoma who were referred to our center in Tehran, Iran. Our retrospective review included 126 patient records from April 2007 to May 2015. The records were analyzed for epidemiologic features, treatment modalities, overall survival, and progression-free survival. Data were analyzed using SPSS 22.0 software. Median age at diagnosis was 6 years (male:female ratio, 2.3:1). At the time of diagnosis, 7 patients were 2 years or younger, and 76 (60.3%) were categorized as having high-risk disease. Overall, 100 patients had gross or near-total surgical resection. Cerebral spinal fluid involvement was detected in 22.2% of the patients tested, and spinal involvement was detected in 25% of the patients who underwent spinal MRI. Metastasis stages at the time of diagnosis were as follows: M0: 48.4% patients, M1: 16.7%, M2: 5.5%, and M3: 21.4%. Median times of follow-up and progression-free survival were 16 and 12 months, respectively. Probability of 7-year overall survival and progression-free survival were 59 and 53.8%, respectively. Results of the current retrospective study emphasize the need for implementing measures to improve outcome for our patients with medulloblastoma. Such measures include a multidisciplinary approach, unified national treatment guidelines, better disease and metastasis staging, twinning initiatives, and seeking a second opinion when needed.

  6. Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07).

    Science.gov (United States)

    Beier, Dagmar; Proescholdt, Martin; Reinert, Christiane; Pietsch, Torsten; Jones, David T W; Pfister, Stefan M; Hattingen, Elke; Seidel, Clemens; Dirven, Linda; Luerding, Ralf; Reijneveld, Jaap; Warmuth-Metz, Monika; Bonsanto, Matteo; Bremer, Michael; Combs, Stephanie E; Rieken, Stefan; Herrlinger, Ulrich; Kuntze, Holger; Mayer-Steinacker, Regine; Moskopp, Dag; Schneider, Thomas; Beringer, Andreas; Schlegel, Uwe; Stummer, Walter; Welker, Helmut; Weyerbrock, Astrid; Paulsen, Frank; Rutkowski, Stefan; Weller, Michael; Wick, Wolfgang; Kortmann, Rolf-Dieter; Bogdahn, Ulrich; Hau, Peter

    2018-02-19

    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 radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock. Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma. © The Author(s) 2017. 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

  7. 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

  8. 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

  9. 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.

  10. 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)

  11. Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma

    DEFF Research Database (Denmark)

    Blomstrand, M.; Berthelsen, Anne Kiil; Munck af Rosenschöld, Per Martin

    2012-01-01

    to the whole-brain irradiation that is part of standard management. Neurogenesis is very sensitive to radiation, and limiting the radiation dose to the hippocampus and the subventricular zone (SVZ) may preserve neurocognitive function. Radiotherapy plans were created using 4 techniques: standard opposing......We sought to assess the feasibility and estimate the benefit of sparing the neurogenic niches when irradiating the brain of pediatric patients with medulloblastoma (MB) based on clinical outcome data. Pediatric MB survivors experience a high risk of neurocognitive adverse effects, often attributed...

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. Joint binding of OTX2 and MYC in promotor regions is associated with high gene expression in medulloblastoma

    NARCIS (Netherlands)

    Bunt, Jens; Hasselt, Nancy E.; Zwijnenburg, Danny A.; Koster, Jan; Versteeg, Rogier; Kool, Marcel

    2011-01-01

    Both OTX2 and MYC are important oncogenes in medulloblastoma, the most common malignant brain tumor in childhood. Much is known about MYC binding to promoter regions, but OTX2 binding is hardly investigated. We used ChIP-on-chip data to analyze the binding patterns of both transcription factors in

  17. 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

  18. 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)

  19. 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

  20. 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...

  1. 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...

  2. 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

  3. 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

  4. 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

  5. Prognostic Value of Medulloblastoma Extent of Resection After Accounting for Molecular Subgroup: An 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, Seung-Ki Kim 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 CY; Seow, Wan Tew; Chang, Kenneth TE; 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 JH; Kijima, Noriyuki; Schneider, Christian; Adamski, Jennifer; Northcott, Paul A; Kool, Marcel; Jones, David TW; 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

    2016-01-01

    Summary Background Incomplete surgical resection of medulloblastoma is controversially considered a marker of high-risk disease; driving aggressive surgical resections, “second-look” surgeries, and/or intensified chemoradiotherapy. All prior publications evaluating the clinical importance of extent of resection (EOR) failed to account for molecular subgroup. We analysed the prognostic value of EOR across 787 medulloblastoma samples in a subgroup-specific manner. Methods We retrospectively identified patients from Medulloblastoma Advanced Genomics International Consortium (MAGIC) centres with a histological diagnosis of medulloblastoma and complete extent of resection and survival data. Specimens were collected from 35 international institutions. Medulloblastoma subgroup affiliation was determined using nanoString gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. Extent of resection (EOR) based on post-operative imaging was classified as gross total (GTR), near total (NTR, <1·5cm2), or subtotal (STR, ≥ 1·5cm2). Overall survival (OS) and progression-free survival (PFS) multivariable analyses including subgroup, age, metastatic status, geographical location of therapy (North America/Australia vs world), and adjuvant therapy regimen were performed. The primary endpoint was the impact of surgical EOR by molecular subgroup and other clinical variables on OS and PFS. Findings 787 medulloblastoma patients (86 WNT, 242 SHH, 163 Group 3, and 296 Group 4) were included in a multivariable Cox model of PFS and OS. The marked benefit of EOR in the overall cohort was greatly attenuated after including molecular subgroup in the multivariable analysis. There was an observed PFS benefit of GTR over STR (hazard ration [HR] 1·45, 95% CI; 1·07–1·96, p=0·02) but there was no observed PFS or OS benefit of GTR over NTR (HR 1·05, 0·71–1·53, p=0·82 and HR 1·14, 0·75–1·72, p=0.55). There was no statistically significant survival benefit

  6. 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)

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. Radiation-induced glioblastoma in a medulloblastoma patient: a case report with molecular features.

    Science.gov (United States)

    Gessi, Marco; Maderna, Emanuela; Guzzetti, Sara; Cefalo, Graziella; Massimino, Maura; Solero, Carlo L; Finocchiaro, Gaetano; Pollo, Bianca

    2008-12-01

    We report a case of glioblastoma (GBM) occurring 8 years after radiation therapy for a medulloblastoma. A 15-year-old boy underwent surgery and radiotherapy for a medulloblastoma and 8 years later he developed a second tumor at the same site. The second lesion showed different histological and molecular features, was diagnosed as a glioblastoma and fulfilled the criteria of radiation-induced neoplasm. Mutational analysis of the p53 gene showed a C to G transition at codon 176 in tumor DNA. LOH was detected at 17p and 19q. The tumor also showed O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation and no amplification of EGF receptor. In conclusion, the radiation-induced MGMT hyper-methylation and p53 mutations may have a role in the development of a subgroup of radio-induced glioma (RIG), suggesting that these molecular alterations directly cooperate in the genesis of the post-irradiation GBM. Moreover RIGs seem to be a heterogeneous group of tumors that may resemble either primary or secondary GBM.

  13. Tropomyosin receptor kinase C (TrkC) expression in medulloblastoma: relation to the molecular subgroups and impact on treatment response.

    Science.gov (United States)

    Friedrich, Carsten; Shalaby, Tarek; Oehler, Christoph; Pruschy, Martin; Seifert, Burkhardt; Picard, Daniel; Remke, Marc; Warmuth-Metz, Monika; Kortmann, Rolf-Dieter; Rutkowski, Stefan; Grotzer, Michael A; von Bueren, André O

    2017-09-01

    High messenger RNA (mRNA) expression of the tropomyosin receptor kinase C gene (TrkC) has been associated with favorable survival in medulloblastoma patients. Untested is whether it plays a role through modulating the response to therapy or whether it might be a surrogate marker for a favorable molecular subgroup. The medulloblastoma-derived cell line DAOY was stably transfected to overexpress TrkC (clone DAOY-TrkC) and compared to a control (clone DAOY-EV, empty vector transfected). Cell viability (MTS assay) was tested after irradiation or incubation with chemotherapeutic drugs. Neuroradiologic response to postoperative chemotherapy or craniospinal irradiation (CSI) of medulloblastoma patients aged 3-21 years with postoperative residual disease treated within the consecutive trials HIT'91/HIT2000 was compared to TrkC mRNA expression in their tumor samples. Five well-characterized independent expression-profiling studies covering together 686 medulloblastoma patients were analyzed for TrkC levels according to the molecular subgroups. Cell viability of DAOY-TrkC compared to DAOY-EV was not different after exposure to increasing doses of irradiation, cisplatin, etoposide, or vincristine. While TrkC mRNA expression tended to be higher in non-responders (n = 5/19) to postoperative CSI (p = 0.03, ratio 15.5, 95% CI 9-267), this was the case in responders (n = 23/43) to chemotherapy (p = 0.04, ratio 6.1, 95% CI 1.1-35), both analyzed with Mann-Whitney U test (not significant after Bonferroni adjustment). The highest TrkC mRNA levels were found in the SHH subgroup across all expression-profiling studies. High TrkC mRNA expression appears to be frequent in the SHH subgroup and seems not to have a major effect on therapy responsiveness in medulloblastoma patients.

  14. 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

  15. Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

    Science.gov (United States)

    Ferrucci, Veronica; de Antonellis, Pasqualino; Pennino, Francesco Paolo; Asadzadeh, Fatemeh; Virgilio, Antonella; Montanaro, Donatella; Galeone, Aldo; Boffa, Iolanda; Pisano, Ida; Scognamiglio, Iolanda; Navas, Luigi; Diana, Donatella; Pedone, Emilia; Gargiulo, Sara; Gramanzini, Matteo; Brunetti, Arturo; Danielson, Laura; Carotenuto, Marianeve; Liguori, Lucia; Verrico, Antonio; Quaglietta, Lucia; Errico, Maria Elena; Del Monaco, Valentina; D'Argenio, Valeria; Tirone, Felice; Mastronuzzi, Angela; Donofrio, Vittoria; Giangaspero, Felice; Picard, Daniel; Remke, Marc; Garzia, Livia; Daniels, Craig; Delattre, Olivier; Swartling, Fredrik J; Weiss, William A; Salvatore, Francesco; Fattorusso, Roberto; Chesler, Louis; Taylor, Michael D; Cinalli, Giuseppe; Zollo, Massimo

    2018-02-27

    Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.

  16. 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

  17. Medulloblastoma and gliomatosis cerebri: rare brain tumors in multiple sclerosis patients.

    Science.gov (United States)

    da Silva, Ana Alexandra Duarte Martins; dos Santos Cavaco, Sara Marta Pereira; Taipa, Ricardo Jorge Ferreira; Pinto, Pedro Ricardo Soares; Pires, Manuel Jorge Rocha Melo

    2011-10-01

    The simultaneous appearance of both multiple sclerosis (MS) and central nervous system (CNS) tumors is relatively uncommon. Whether the co-existence of two diseases is due to chance alone or the result of a causal relationship is still a matter of debate. There is also controversy about the effect of long-term exposure of MS patients to immunomodulatory drugs on the incidence of cancer. This paper reports two cases of rare CNS tumors (i.e., medulloblastoma and gliomatosis cerebri) in adult MS patients. Our cases emphasize that when uncommon neurological features appear in patients with MS, brain magnetic resonance imaging (MRI) ought to be done and brain biopsy should be considered to exclude a concomitant CNS disorder. These procedures are essential for the differential diagnosis and early treatment.

  18. Case report: treatment of medulloblastoma using a computer-controlled tracking cobalt unit

    International Nuclear Information System (INIS)

    Tate, T.; Brace, J.A.; Davy, T.J.; Morgan, H.M.; Skeggs, D.B.L.; Tookman, A.J.

    1985-01-01

    Radiation therapy of the length of the spinal column presents various clinical and physical problems. The completed plan may be complicated to set up, be time-consuming and require daily variation to achieve reasonable dose homogeneity. A case of medulloblastoma is used to illustrate the steps in producing a plan for dynamic treatment using a computer-controlled tracking cobalt unit. After definition by computed tomography, the target is considered in segments in order to develop a plan which keeps the spinal cord constantly positioned at the beam isocentre. The main computer is used to develop the patient treatment file and information is transferred to a second computer which controls and monitors the safe functioning of the cobalt unit. The cranial fields are treated separately in a conventional way. Good and consistent control of the dose distribution is achieved along the entire target volume. This technique is a marked improvement over all existing methods of treating the spinal axis. (author)

  19. 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.

  20. 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.

  1. 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.

  2. Treatment developments and the unfolding of the quality of life discussion in childhood medulloblastoma: a review.

    Science.gov (United States)

    Gudrunardottir, Thora; Lannering, Birgitta; Remke, Marc; Taylor, Michael D; Wells, Elizabeth M; Keating, Robert F; Packer, Roger J

    2014-06-01

    To describe how the quality of life (QOL) discussion in childhood medulloblastoma (MB) relates to treatment developments, survival and sequelae from 1920 to 2014. Articles containing "childhood medulloblastoma" and "quality of life" were identified in PubMed. Those containing phrases pertaining to psychological, emotional, behavioral or social adjustment in the title, abstract or keywords were selected. Inclusion of relevant older publications was assured by cross-checking references. 1920-1930s: suction, electro-surgery, kilovolt (KV) irradiation. Survival = months. Focus on operative mortality, symptoms and survival. 1940s: radiotherapy improved. 1950s: chemotherapy and intubation. Survival = years. Opinions oscillated between optimism/awareness of physical sequelae of radiotherapy. 1960s: magnified vision, ventriculo-peritoneal (VP) shunts, megavolt (MV) irradiation. Long-term survival shifted the attention towards neurological problems, disability and carcinogenesis of radiotherapy. 1970s: CT, microscope, bipolar coagulation, shunt filters, neuroanesthesia, chemotherapy trials and staging studies. Operative mortality decreased and many patients (re)entered school; emphasis on neuropsychological sequelae, IQ and academic performance. 1980s: magnetic resonance imaging (MRI), Cavitron ultrasonic aspiration (CUSA), laser surgery, hyper-fractionated radiotherapy (HFRT). Cerebellar mutism, psychological and social issues. 1990s: pediatric neurosurgery, proton beams, stem cell rescue. Reflections on QOL as such. 21st century: molecular genetics. Premature aging, patterns of decline, risk- and resilience factors. QOL is a critical outcome measure. Focus depends on survival and sequelae, determined after years of follow-up. Detailed measurements are limited by time, money and human resources, and self-reporting questionnaires represent a crude measure limited by subjectivity. Therapeutic improvements raise the question of QOL versus cure. QOL is a potential primary

  3. 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.)

  4. 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

  5. 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

  6. 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)

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.)

  16. 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.

  17. 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

  18. 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

  19. 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 ...

  20. 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

  1. Combined radiotherapy and chemotherapy for pediatric medulloblastoma: a clinical study of 33 cases

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    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

  2. 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

  3. Medulloblastoma outcome is adversely associated with overexpression of EEF1D, RPL30, and RPS20 on the long arm of chromosome 8

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    De Bortoli Massimiliano

    2006-09-01

    Full Text Available Abstract Background 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. Methods 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. Results 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 EEF1D, ribosomal protein L30 (RPL30, and ribosomal protein S20 (RPS20. Conclusion 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.

  4. 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

  5. Unravelling the Mechanism of TrkA-Induced Cell Death by Macropinocytosis in Medulloblastoma Daoy Cells.

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    Li, Chunhui; MacDonald, James I S; Talebian, Asghar; Leuenberger, Jennifer; Seah, Claudia; Pasternak, Stephen H; Michnick, Stephen W; Meakin, Susan O

    2016-10-15

    Macropinocytosis is a normal cellular process by which cells internalize extracellular fluids and nutrients from their environment and is one strategy that Ras-transformed pancreatic cancer cells use to increase uptake of amino acids to meet the needs of rapid growth. Paradoxically, in non-Ras transformed medulloblastoma brain tumors, we have shown that expression and activation of the receptor tyrosine kinase TrkA overactivates macropinocytosis, resulting in the catastrophic disintegration of the cell membrane and in tumor cell death. The molecular basis of this uncontrolled form of macropinocytosis has not been previously understood. Here, we demonstrate that the overactivation of macropinocytosis is caused by the simultaneous activation of two TrkA-mediated pathways: (i) inhibition of RhoB via phosphorylation at Ser(185) by casein kinase 1, which relieves actin stress fibers, and (ii) FRS2-scaffolded Src and H-Ras activation of RhoA, which stimulate actin reorganization and the formation of lamellipodia. Since catastrophic macropinocytosis results in brain tumor cell death, improved understanding of the mechanisms involved will facilitate future efforts to reprogram tumors, even those resistant to apoptosis, to die. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  6. Primary Cilia in the Murine Cerebellum and in Mutant Models of Medulloblastoma.

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    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.

  7. 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.

  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

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    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. 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.)

  15. 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.

  16. Suppression of medulloblastoma lesions by forced migration of preneoplastic precursor cells with intracerebellar administration of the chemokine Cxcl3

    Directory of Open Access Journals (Sweden)

    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.

  17. Long time to diagnosis of medulloblastoma in children is not associated with decreased survival or with worse neurological outcome.

    Directory of Open Access Journals (Sweden)

    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.

  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. 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

  20. The use of 5-ALA to assist complete removal of residual non-enhancing part of childhood medulloblastoma

    DEFF Research Database (Denmark)

    Skjøth-Rasmussen, Jane; Bøgeskov, Lars; Sehested, Astrid

    2015-01-01

    . METHODS: The child was pretreated with 3 × 4 mg dexamethasone for 4 days prior to the second surgery. At 5 a.m. on the day of surgery, a freshly prepared solution of 5-ALA (20 mg/kg body weight; Medac, Germany) was given orally. RESULTS: At surgery, through the original opening, the vague red fluorescence...... changed from the high-risk medulloblastoma regimen to the standard-risk regimen. CONCLUSIONS: In this particular difficult case of non-contrast-enhancing tumor, 5-ALA was of vital importance to improve rate of resection and change the aggressiveness needed in postsurgery radiation therapy....

  1. Patterns of Failure After Proton Therapy in Medulloblastoma; Linear Energy Transfer Distributions and Relative Biological Effectiveness Associations for Relapses

    Energy Technology Data Exchange (ETDEWEB)

    Sethi, Roshan V. [Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts (United States); Giantsoudi, Drosoula; Raiford, Michael; Malhi, Imran; Niemierko, Andrzej [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Rapalino, Otto; Caruso, Paul [Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts (United States); 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@partners.org [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2014-03-01

    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

  2. Sonic hedgehog inhibition reduces in vitro tumorigenesis and alters expression of Gli1-target genes in a desmoplastic medulloblastoma cell line

    Directory of Open Access Journals (Sweden)

    García-López R

    2013-03-01

    Full Text Available Medulloblastoma is one of the most frequent and aggressive tumors of childhood. The Sonic hedgehog (Shh pathway, related to human development, is altered in most medulloblastomas: genes like Ptch, Smo, or Sufu suffer mutations in 15% to 25% of these tumors. We tested Shh inhibition in the Daoy medulloblastoma cell line by two methods: a molecular one, direct Gli1 siRNA inhibition; and a pharmacological inhibition of Smo, upstream of Gli1, by cyclopamine. Afterwards, a comparison of cellular and molecular responses was done. In general, we proved that cell viability, cell migration and cell colony formation decreased after Shh inhibition, which might confer a less tumorigenic status to Daoy cells. Moreover, we assessed the expression of different Gli1 target genes and other genes and found that Shh shows a crosstalk with oncogenes and tumor suppressor genes that have been described in numerous tumors. All these experiments give an overview of the Shh pathway in medulloblastoma, together with the demonstration of the efficacy of cyclopamine and Gli1 siRNA Shh inhibition in vitro.

  3. 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.

  4. 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

    , 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...

  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. 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.

  8. 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.

  9. Ecto-5'-Nucleotidase Overexpression Reduces Tumor Growth in a Xenograph Medulloblastoma Model.

    Directory of Open Access Journals (Sweden)

    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.

  10. Molecular and in vivo characterization of cancer-propagating cells derived from MYCN-dependent medulloblastoma.

    Directory of Open Access Journals (Sweden)

    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.

  11. EphrinB1 expression is dysregulated and promotes oncogenic signaling in medulloblastoma.

    Science.gov (United States)

    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.

  12. Ecto-5’-Nucleotidase Overexpression Reduces Tumor Growth in a Xenograph Medulloblastoma Model

    Science.gov (United States)

    Cappellari, Angélica R.; Pillat, Micheli M.; Souza, Hellio D. N.; Dietrich, Fabrícia; Oliveira, Francine H.; Figueiró, Fabrício; Abujamra, Ana L.; Roesler, Rafael; Lecka, Joanna; Sévigny, Jean; Battastini, Ana Maria O.; Ulrich, Henning

    2015-01-01

    Background 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. Materials and Methods 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. Results 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. Conclusion 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. PMID:26491983

  13. Chronic subdural hematoma associated with moyamoya phenomenon after radiotherapy for medulloblastoma; A case report

    Energy Technology Data Exchange (ETDEWEB)

    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).

  14. Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma.

    Science.gov (United States)

    Nair, Smita K; Driscoll, Timothy; Boczkowski, David; Schmittling, Robert; Reynolds, Renee; Johnson, Laura A; Grant, Gerald; Fuchs, Herbert; Bigner, Darell D; Sampson, John H; Gururangan, Sridharan; Mitchell, Duane A

    2015-10-01

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

  15. Late effects of craniospinal irradiation for standard risk medulloblastoma in paediatric patients: A comparison of treatment techniques

    International Nuclear Information System (INIS)

    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.

  16. A female survivor of childhood medulloblastoma presenting with growth-hormone-induced edema and inflammatory lesions: a case report

    Directory of Open Access Journals (Sweden)

    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.

  17. 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.

  18. 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

  19. Differential induction of p53-mediated apoptosis in medulloblastomas and gliomas correlates with their ability to induce bax

    International Nuclear Information System (INIS)

    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

  20. 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.

  1. Increased focal hemosiderin deposition in pediatric medulloblastoma patients receiving radiotherapy at a later age.

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    Yeom, Kristen W; Lober, Robert M; Partap, Sonia; Telischak, Nicholas; Tsolinas, Rachel; Barnes, Patrick D; Edwards, Michael S B

    2013-11-01

    Focal hemosiderin deposition (FHD) is commonly observed on brain MRI scans of patients treated for childhood medulloblastoma (MB). The authors sought to determine the clinical significance of FHD and its relationship to patient age, radiation dose, and cognitive outcomes. A single-institution retrospective study of 93 MB patients at Lucile Packard Children's Hospital at Stanford from 1998 to 2011 identified 41 patients with a negative baseline MRI scan and at least 2 posttreatment MRI scans obtained with T2* gradient recalled echo (GRE). The number and cumulative rate of FHDs detectable by GRE were compared between patients aged 6 years and younger (early age) and aged 7-21 years (late age) at the time of radiotherapy (RT) and between low-dose (1800-2340 cGy) and high-dose (2920-3960 cGy) RT. The median age at MB diagnosis was 7.3 years (range 0.9-21.0 years), the median clinical follow-up period was 5.8 years (range 0.8-13.4 years), and the median 5-year overall survival was 81% ± 7%. Of 30 school-aged children with MB, 21 (70%) required special education, and the median IQ of 10 tested patients was 100 (range 50-118). Thirty-three patients (80%) had FHD after a median latency of 1.9 years (range 0.1-5.9 years). Ninety-four percent (436 of 466) of the lesions arose in the supratentorial region of the brain, whereas 29 (6%) resided in the brainstem or the cerebellum. No spinal lesions were observed on routine spine MRI scans using T2 fast spin echo imaging. The mean cumulative lesion rate per year was 2.23 ± 3.05, and this rate was higher in older children at the time of RT compared with younger children (3.23 vs 0.67 per year, p = 0.002) but did not differ among different RT doses (p = 0.395). A child's IQ or need for special education showed no significant correlation with the rate of lesion development or number of lesions. None of the lesions resulted in symptomatic hemorrhage that required surgical intervention. More FHD was observed in children treated for

  2. In vivo bioluminescence imaging for leptomeningeal dissemination of medulloblastoma in mouse models

    International Nuclear Information System (INIS)

    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

  3. 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

  4. Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells.

    Science.gov (United States)

    von Bueren, André O; Shalaby, Tarek; Rajtarova, Julia; Stearns, Duncan; Eberhart, Charles G; Helson, Lawrence; Arcaro, Alexandre; Grotzer, Michael A

    2007-01-25

    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. 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. 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. 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 proliferation of human MB cells in vivo.

  5. 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

  6. 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

  7. 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

  8. High dose ACNU and radiation therapy with autologous bone marrow rescue for a patient with cerebellar medulloblastoma

    International Nuclear Information System (INIS)

    Matsumoto, Masahito; Yamashita, Junkoh; Okamoto, Shin-ichiro; Handa, Hajime; Sawada, Hitoshi; Abe, Mitsuyuki

    1984-01-01

    High dose ACNU and radiation therapy with auto-logous bone marrow rescue was performed in a 3-year-old boy suffering from cerebellar medulloblastoma, whose main mass had been removed at operation when widespread subarachnoid tumor dissemination was already present. The myelosuppression, which is a major side effect of high dose chemotherapy, was successfully prevented by the autologous bone marrow grafting and the serial CT scans showed complete dissappearance of the tumor. However, the patient died on the 53rd day after the administration of ACNU of respiratory complication which was most likely due to pulmonary fibrosis. Although the autologous bone marrow rescue therapy is a technical advance to cope with myelosuppression secondary to chemotherapy, side effects of the other organs, particularly of the respiratory system, remain to be solved. The optimal treatment schedule should be established as soon as possible. (author)

  9. Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: How do protons compare with other conformal techniques?

    International Nuclear Information System (INIS)

    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

  10. 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

  11. An Integrated Approach Identifies Nhlh1 and Insm1 as Sonic Hedgehog-regulated Genes in Developing Cerebellum and Medulloblastoma

    Directory of Open Access Journals (Sweden)

    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.

  12. 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.

  13. 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.

  14. Medulloblastoma: Long-term follow-up of patients treated with electron irradiation of the spinal field

    Energy Technology Data Exchange (ETDEWEB)

    Gaspar, L.E.; Dawson, D.J.; Tilley-Gulliford, S.A.; Banerjee, P. (London Regional Cancer Centre, Ontario (Canada))

    1991-09-01

    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.

  15. Effects of vertebral-body-sparing proton craniospinal irradiation on the spine of young pediatric patients with medulloblastoma.

    Science.gov (United States)

    MacEwan, Iain; Chou, Brian; Moretz, Jeremy; Loredo, Lilia; Bush, David; Slater, Jerry D

    2017-01-01

    To investigate the long-term effects of vertebral-body-sparing proton craniospinal irradiation (CSI) on the spine of young patients with medulloblastoma. Six children between the ages of 3 and 5 years with medulloblastoma were treated with vertebral-body-sparing proton CSI after maximal safe resection. Radiation therapy was delivered in the supine position with posterior beams targeting the craniospinal axis, and the proton beam was stopped anterior to the thecal sac. Patients were treated with a dose of either 23.4 Gy or 36 Gy to the craniospinal axis followed by a boost to the posterior fossa and any metastatic lesions. Chemotherapy varied by protocol. Radiographic effects on the spine were evaluated with serial imaging, either with magnetic resonance imaging scans or plain film using Cobb angle calculations, the presence of thoracic lordosis, lumbar vertebral body-to-disc height ratios, and anterior-posterior height ratios. Clinical outcomes were evaluated by patient/family interview and medical chart review. Overall survival and disease free survival were 83% (5/6) at follow-up. Median clinical and radiographic follow-up were 13.6 years and 12.3 years, respectively. Two patients were clinically diagnosed with scoliosis and treated conservatively. At the time of follow-up, no patients had experienced chronic back pain or required spine surgery. No patients were identified to have thoracic lordosis. Diminished growth of the posterior portions of vertebral bodies was identified in all patients, with an average posterior to anterior ratio of 0.88, which was accompanied by compensatory hypertrophy of the posterior intervertebral discs. Vertebral-body-sparing CSI with proton beam did not appear to cause increased severe spinal abnormalities in patients treated at our institution. This approach could be considered in future clinical trials in an effort to reduce toxicity and the risk of secondary malignancy and to improve adult height.

  16. 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.

  17. 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

  18. Real-time PCR assay based on the differential expression of microRNAs and protein-coding genes for molecular classification of formalin-fixed paraffin embedded medulloblastomas.

    Science.gov (United States)

    Kunder, Ratika; Jalali, Rakesh; Sridhar, Epari; Moiyadi, Aliasgar; Goel, Naina; Goel, Atul; Gupta, Tejpal; Krishnatry, Rahul; Kannan, Sadhana; Kurkure, Purna; Deopujari, Chandrashekhar; Shetty, Prakash; Biyani, Naresh; Korshunov, Andrey; Pfister, Stefan M; Northcott, Paul A; Shirsat, Neelam Vishwanath

    2013-12-01

    Medulloblastoma has recently been found to consist of 4 molecularly and clinically distinct subgroups: WNT, Sonce hedgehog (SHH), Group 3, and Group 4. Deregulated microRNA expression is known to contribute to pathogenesis and has been shown to have diagnostic and prognostic potential in the classification of various cancers. Molecular subgrouping and microRNA expression analysis of 44 frozen and 59 formalin-fixed paraffin embedded medulloblastomas from an Indian cohort were carried out by real-time RT-PCR assay. The differential expression of 9 microRNAs in the 4 molecular subgroups was validated in a set of 101 medulloblastomas. The tumors in the WNT subgroup showed significant (P classification of medulloblastomas into the 4 molecular subgroups was obtained using a set of 12 protein-coding genes and 9 microRNAs as markers in a real-time RT-PCR assay with an accuracy of 97% as judged by the Prediction Analysis of Microarrays. Age at diagnosis, histology, gender-related incidence, and the relative survival rates of the 4 molecular subgroups in the present Indian cohort were found to be similar to those reported for medulloblastomas from the American and European subcontinent. Non-WNT, non-SHH medulloblastomas underexpressing miR-592 or overexpressing miR-182 were found to have significantly inferior survival rates, indicating utility of these miRNAs as markers for risk stratification. The microRNA based real-time PCR assay is rapid, simple, inexpensive, and useful for molecular classification and risk stratification of medulloblastomas, in particular formalin-fixed paraffin embedded tissues, wherein the expression profile of protein-coding genes is often less reliable due to RNA fragmentation.

  19. Analysis of the intracellular localization of p73 N-terminal protein isoforms TAp73 and ∆Np73 in medulloblastoma cell lines.

    Science.gov (United States)

    Nekulová, Marta; Zitterbart, Karel; Sterba, Jaroslav; Veselská, Renata

    2010-10-01

    The protein homologous to the tumor suppressor p53, p73, has essential roles in development and tumorigenesis. This protein exists in a wide range of isoforms with different, even antagonistic, functions. However, there are virtually no detailed morphological studies analyzing the endogenous expression of p73 isoforms at the cellular level in cancer cells. In this study, we investigated the expression and subcellular distribution of two N-terminal isoforms, TAp73 and ΔNp73, in medulloblastoma cells using immunofluorescence microscopy. Both proteins were observed in all cell lines examined, but differences were noted in their intracellular localization between the reference Daoy cell line and four newly established medulloblastoma cell lines (MBL-03, MBL-06, MBL-07 and MBL-10). In the new cell lines, TAp73 and ΔNp73 were located predominantly in cell nuclei. However, there was heterogeneity in TAp73 distribution in the cells of all MBL cell lines, with the protein located in the nucleus and also in a limited non-random area in the cytoplasm. In a small percentage of cells, we detected cytoplasmic localization of TAp73 only, i.e., nuclear exclusion was observed. Our results provide a basis for future studies on the causes and function of distinct intracellular localization of p73 protein isoforms with respect to different protein-protein interactions in medulloblastoma cells.

  20. 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

  1. The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma.

    Directory of Open Access Journals (Sweden)

    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.

  2. 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.

  3. 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

  4. Do we still need IQ-scores? Misleading interpretations of neurocognitive outcome in pediatric patients with medulloblastoma: a retrospective study.

    Science.gov (United States)

    Wegenschimmel, Barbara; Leiss, Ulrike; Veigl, Michaela; Rosenmayr, Verena; Formann, Anton; Slavc, Irene; Pletschko, Thomas

    2017-11-01

    Over the past decades, many studies used global outcome measures like the IQ when reporting cognitive outcome of pediatric brain tumor patients, assuming that intelligence is a singular and homogeneous construct. In contrast, especially in clinical neuropsychology, the assessment and interpretation of distinct neurocognitive domains emerged as standard. By definition, the full scale IQ (FIQ) is a score attempting to measure intelligence. It is established by calculating the average performance of a number of subtests. Therefore, FIQ depends on the subtests that are used and the influence neurocognitive functions have on these performances. Consequently, the present study investigated the impact of neuropsychological domains on the singular "g-factor" concept and analysed the consequences for interpretation of clinical outcome. The sample consisted of 37 pediatric patients with medulloblastoma, assessed 0-3 years after diagnosis with the Wechsler Intelligence Scales. Information processing speed and visuomotor function were measured by the Trailmaking Test, Form A. Our findings indicate that FIQ was considerably impacted by processing speed and visuomotor coordination, which leaded to an underestimation of the general cognitive performance of many patients. One year after diagnosis, when patients showed the largest norm-deviation, this effect seemed to be at its peak. As already recommended in international guidelines, a comprehensive neuropsychological test battery is necessary to fully understand cognitive outcome. If IQ-tests are used, a detailed subtest analysis with respect to the impact of processing speed seems essential. Otherwise patients may be at risk for wrong decision making, especially in educational guidance.

  5. 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.

  6. SU-E-T-375: Passive Scattering to Pencil-Beam-Scanning Comparison for Medulloblastoma Proton Therapy: LET Distributions and Radiobiological Implications

    Energy Technology Data Exchange (ETDEWEB)

    Giantsoudi, D; MacDonald, S; Paganetti, H [Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)

    2014-06-01

    Purpose: To compare the linear energy transfer (LET) distributions between passive scattering and pencil beam scanning proton radiation therapy techniques for medulloblastoma patients and study the potential radiobiological implications. Methods: A group of medulloblastoma patients, previously treated with passive scattering (PS) proton craniospinal irradiation followed by prosterior fossa or involved field boost, were selected from the patient database of our institution. Using the beam geometry and planning computed tomography (CT) image sets of the original treatment plans, pencil beam scanning (PBS) treatment plans were generated for the cranial treatment for each patient, with average beam spot size of 8mm (sigma in air at isocenter). 3-dimensional dose and LET distributions were calculated by Monte Carlo methods (TOPAS) both for the original passive scattering and new pencil beam scanning treatment plans. LET volume histograms were calculated for the target and OARs and compared for the two delivery methods. Variable RBE weighted dose distributions and volume histograms were also calculated using a variable dose and LET-based model. Results: Better dose conformity was achieved with PBS planning compared to PS, leading to increased dose coverage for the boost target area and decreased average dose to the structures adjacent to it and critical structures outside the whole brain treatment field. LET values for the target were lower for PBS plans. Elevated LET values for OARs close to the boosted target areas were noticed, due to end of range of proton beams falling inside these structures, resulting in higher RBE weighted dose for these structures compared to the clinical RBE value of 1.1. Conclusion: Transitioning from passive scattering to pencil beam scanning proton radiation treatment can be dosimetrically beneficial for medulloblastoma patients. LET–guided treatment planning could contribute to better decision making for these cases, especially for

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. Characterization of ectonucleotidases in human medulloblastoma cell lines: ecto-5'NT/CD73 in metastasis as potential prognostic factor.

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    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.

  14. Chemotherapy increases long-term survival in patients with adult medulloblastoma--a literature-based meta-analysis.

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    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

  15. Patterns of Failure Following Multimodal Treatment for Medulloblastoma: Long-Term Follow-up Results at a Single Institution.

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    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.

  16. The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma.

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    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.

  17. 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.

  18. FUNCTIONAL GENOMICS IDENTIFIES TIS21-DEPENDENT MECHANISMS AND PUTATIVE CANCER DRUG TARGETS UNDERLYING MEDULLOBLASTOMA SHH-TYPE DEVELOPMENT

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    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.

  19. 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

  20. Formation of telomeric repeat-containing RNA (TERRA) foci in highly proliferating mouse cerebellar neuronal progenitors and medulloblastoma.

    Science.gov (United States)

    Deng, Zhong; Wang, Zhuo; Xiang, Chaomei; Molczan, Aliah; Baubet, Valérie; Conejo-Garcia, Jose; Xu, Xiaowei; Lieberman, Paul M; Dahmane, Nadia

    2012-09-15

    Telomeres play crucial roles in the maintenance of genome integrity and control of cellular senescence. Most eukaryotic telomeres can be transcribed to generate a telomeric repeat-containing RNA (TERRA) that persists as a heterogeneous nuclear RNA and can be developmentally regulated. However, the precise function and regulation of TERRA in normal and cancer cell development remains poorly understood. Here, we show that TERRA accumulates in highly proliferating normal and cancer cells, and forms large nuclear foci, which are distinct from previously characterized markers of DNA damage or replication stress. Using a mouse model for medulloblastoma driven by chronic Sonic hedgehog (SHH) signaling, TERRA RNA was detected in tumor, but not adjacent normal cells using both RNA fluorescence in situ hybridization (FISH) and northern blotting. RNA FISH revealed the formation of TERRA foci (TERFs) in the nuclear regions of rapidly proliferating tumor cells. In the normal developing cerebellum, TERRA aggregates could also be detected in highly proliferating zones of progenitor neurons. SHH could enhance TERRA expression in purified granule progenitor cells in vitro, suggesting that proliferation signals contribute to TERRA expression in responsive tissue. TERRA foci did not colocalize with γH2AX foci, promyelocytic leukemia (PML) or Cajal bodies in mouse tumor tissue. We also provide evidence that TERRA is elevated in a variety of human cancers. These findings suggest that elevated TERRA levels reflect a novel early form of telomere regulation during replication stress and cancer cell evolution, and the TERRA RNA aggregates may form a novel nuclear body in highly proliferating mammalian cells.

  1. ME-16IS AQUAPORIN4 (AQP4) INVOLVED IN ADULT HUMAN MEDULLOBLASTOMA DISSEMINATION OR IN A BENEFICIAL BARRIER FORMATION?

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    Pollo, Bianca; Mazzetti, Samanta; Patanè, Monica; Calatozzolo, Chiara; Di Meco, Francesco; Silvani, Antonio

    2014-01-01

    Medulloblastoma (MDB) is a highly malignant embryonal brain tumor located in the cerebellum with tendency to leptomeningeal dissemination, common in children, rare in adults. Recent genetic analysis suggested classification into four subgroups according to gene expression profiles, including the Wingless signaling pathway-activated group (WNT group), the Sonic Hedgehog signaling pathway-activated group (SHH group), group 3and 4, with distinct molecular, clinicopathological, and prognostic characteristics. AQP4 is the main water channel in the normal central nervous system (CNS) responsible for salt and water balance maintaining. When the blood-brain barrier become disrupted, as in gliomas, water moves from the vasculature into the extracellular space in an AQP4-independent manner, down a hydrostatic gradient to form a vasogenic edema. Moreover, AQPs have a role promoting tumor progression, cell migration and metastasis. Aim of our study was to evaluate for the first time AQP4 expression in adult MDB to focus its role in edema, tumor invasion and dissemination. We analyzed by immunohistochemistry AQP4 expression in 40 adult MDBs, also investigated for GAB1, ß-catenin, filamin-A, NPR3, according to molecular subgroups. Desmoplastic histology and Sonic hedgehog (SHH) pathway activation were more common feature, with GAB-1 and filamin-A expression. Only one case showed nuclear staining for ß-catenin. None expressed NPR3. In classical MDB, AQP4 staining was localized in glial endfoot surrounding tumor vessels. This AQP4 distribution was lost in the desmoplastic type, where the nodular areas were negatives, surrounded by glial elements AQP4 intensely stained. In the molecular layer of the cerebellar cortex in the tumor proximity in classic type MDB it has been observed migrating tumor cells along glial processes AQP4 stained. This finding was mainly observed in patients with early dissemination. These observations could suggest a role for AQP4 in adult MDB, not only in

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. Pituitary adenylyl cyclase activating polypeptide inhibits gli1 gene expression and proliferation in primary medulloblastoma derived tumorsphere cultures

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    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

  7. Integrated analysis of miRNA and mRNA expression in childhood medulloblastoma compared with neural stem cells.

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    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

  8. 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

  9. 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......, 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...... in this context, the gain is small compared to estimated uncertainty, this study demonstrates a framework for all-cause mortality risk estimation, rather than evaluates direct clinical applicability of risk-adapted strategies....

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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.

  4. Premature Epiphyseal Closure of the Lower Extremities Contributing to Short Stature after cis-Retinoic Acid Therapy in Medulloblastoma: A Case Report.

    Science.gov (United States)

    Noyes, Jessica J; Levine, Michael A; Belasco, Jean B; Mostoufi-Moab, Sogol

    2016-01-01

    Prolonged cis-retinoic acid (RA) exposure contributes to premature epiphyseal closure. cis-RA is administered in various treatment regimens for pediatric cancers, thus increasing the risk for bone deformities and compromised growth. We present a case of premature epiphyseal closure in a 9-year-old female with a history of medulloblastoma and treatment with a multimodal regimen including cis-RA. She was subsequently diagnosed with radiation-induced endocrine late effects including hypothyroidism and growth hormone deficiency (GHD). Seven months after initiation of GH therapy, an increased prominence of the wrists and knees combined with a deceleration in growth velocity prompted further evaluation; radiographs revealed bilateral premature closure of the distal femur and proximal tibia growth plates despite normal left wrist bone age. High doses of vitamin A and its analogs are linked to premature closure of the lower-extremity growth plates in animals and children. Pediatric brain tumor patients are at increased risk of growth failure due to concurrent radiation-induced GHD, damage to the spinal bones, and cis-RA-associated premature closure of the lower-extremity growth plates, with significant reduction in adult stature. A better appreciation of the detrimental effect of cis-RA on the growing skeleton is needed to monitor at-risk patients and to provide timely interventions. © 2015 S. Karger AG, Basel.

  5. Meduloblastoma em adultos: análise de uma casuística e resultados cirúrgicos Medulloblastoma in adulthood: analysis of a casuistics and surgical results

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    PAULO HENRIQUE AGUIAR

    1999-12-01

    Full Text Available Analisamos 15 casos de meduloblastoma em adultos (8 homens e 7 mulheres, com idade média de 23,7 anos (variação de 13 a 46 submetidos a ressecção cirúrgica no período de fevereiro de 1988 a outubro de 1995. Os tumores se localizavam no hemisfério cerebelar em 7 casos (1 com extensão supratentorial e outro atingindo a cisterna do ângulo pontocerebelar, no vermis e hemisférico em 4 e apenas no vermis em outros 4. A ressecção foi considerada radical em 7 casos, subtotal em 7 e parcial em um. Não houve mortalidade operatória. Aspectos relativos ao comportamento biológico e prognóstico são discutidos.We report on 15 cases of medulloblastoma of adult onset (8 male and 7 female operated upon posterior fossa approach from February 1988 to October 1995. Tumors were localized in cerebellar hemisphere in 7 cases (one with extension to supratentorial notch and another case reaching the cerebello-pontine angle cistern, in vermis and hemisphere in four, only in vermis in another four. Resection was total in seven patients, subtotal in other seven, and partial in one.There was no operative mortality. Aspects regarding biological behavior, diagnosis, pathological findings, surgery and survival are discussed as well as prognostic factors.

  6. Multi-Institution Prospective Trial of Reduced-Dose Craniospinal Irradiation (23.4 Gy) Followed by Conformal Posterior Fossa (36 Gy) and Primary Site Irradiation (55.8 Gy) and Dose-Intensive Chemotherapy for Average-Risk Medulloblastoma

    International Nuclear Information System (INIS)

    Merchant, Thomas E.; Kun, Larry E.; Krasin, Matthew J.; Wallace, Dana; Chintagumpala, Murali M.; Woo, Shiao Y.; Ashley, David M.; Sexton, Maree; Kellie, Stewart J.; Ahern, Verity M.B.B.S.; Gajjar, Amar

    2008-01-01

    Purpose: Limiting the neurocognitive sequelae of radiotherapy (RT) has been an objective in the treatment of medulloblastoma. Conformal RT to less than the entire posterior fossa (PF) after craniospinal irradiation might reduce neurocognitive sequelae and requires evaluation. Methods and Materials: Between October 1996 and August 2003, 86 patients, 3-21 years of age, with newly diagnosed, average-risk medulloblastoma were treated in a prospective, institutional review board-approved, multi-institution trial of risk-adapted RT and dose-intensive chemotherapy. RT began within 28 days of definitive surgery and consisted of craniospinal irradiation (23.4 Gy), conformal PF RT (36.0 Gy), and primary site RT (55.8 Gy). The planning target volume for the primary site included the postoperative tumor bed surrounded by an anatomically confined margin of 2 cm that was then expanded with a geometric margin of 0.3-0.5 cm. Chemotherapy was initiated 6 weeks after RT and included four cycles of high-dose cyclophosphamide, cisplatin, and vincristine. Results: At a median follow-up of 61.2 months (range, 5.2-115.0 months), the estimated 5-year event-free survival and cumulative incidence of PF failure rate was 83.0% ± 5.3% and 4.9% ± 2.4% (± standard error), respectively. The targeting guidelines used in this study resulted in a mean reduction of 13% in the volume of the PF receiving doses >55 Gy compared with conventionally planned RT. The reductions in the dose to the temporal lobes, cochleae, and hypothalamus were statistically significant. Conclusion: This prospective trial has demonstrated that irradiation of less than the entire PF after 23.4 Gy craniospinal irradiation for average-risk medulloblastoma results in disease control comparable to that after treatment of the entire PF

  7. Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032.

    Science.gov (United States)

    Robinson, Giles W; Orr, Brent A; Wu, Gang; Gururangan, Sridharan; Lin, Tong; Qaddoumi, Ibrahim; Packer, Roger J; Goldman, Stewart; Prados, Michael D; Desjardins, Annick; Chintagumpala, Murali; Takebe, Naoko; Kaste, Sue C; Rusch, Michael; Allen, Sariah J; Onar-Thomas, Arzu; Stewart, Clinton F; Fouladi, Maryam; Boyett, James M; Gilbertson, Richard J; Curran, Tom; Ellison, David W; Gajjar, Amar

    2015-08-20

    Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB). Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available. A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH-MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses. Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit. © 2015 by American Society of Clinical Oncology.

  8. Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog–Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032

    Science.gov (United States)

    Robinson, Giles W.; Orr, Brent A.; Wu, Gang; Gururangan, Sridharan; Lin, Tong; Qaddoumi, Ibrahim; Packer, Roger J.; Goldman, Stewart; Prados, Michael D.; Desjardins, Annick; Chintagumpala, Murali; Takebe, Naoko; Kaste, Sue C.; Rusch, Michael; Allen, Sariah J.; Onar-Thomas, Arzu; Stewart, Clinton F.; Fouladi, Maryam; Boyett, James M.; Gilbertson, Richard J.; Curran, Tom; Ellison, David W.; Gajjar, Amar

    2015-01-01

    Purpose Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB). Patients and Methods Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available. Results A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH–MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses. Conclusion Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH–MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit. PMID:26169613

  9. Quality of Survival and Growth in Children and Young Adults in the PNET4 European Controlled Trial of Hyperfractionated Versus Conventional Radiation Therapy for Standard-Risk Medulloblastoma

    International Nuclear Information System (INIS)

    Kennedy, Colin; Bull, Kim; Chevignard, Mathilde; Culliford, David; Dörr, Helmuth G.; Doz, François; Kortmann, Rolf-Dieter; Lannering, Birgitta; Massimino, Maura; Navajas Gutiérrez, Aurora; Rutkowski, Stefan; Spoudeas, Helen A.; Calaminus, Gabriele

    2014-01-01

    Purpose: To compare quality of survival in “standard-risk” medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial. Methods and Materials: Participants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded. Results: Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011). Conclusions: Hyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life

  10. Does electron and proton therapy reduce the risk of radiation induced cancer after spinal irradiation for childhood medulloblastoma? A comparative treatment planning study

    International Nuclear Information System (INIS)

    Xiangkui Mu; Zackrisson, Bjoern; Bjoerk-Eriksson, Thomas; Johansson, Lennart; Karlsson, Mikael; Nill, Simeon; Oelfke, Uwe; Johansson, Karl-Axel; Gagliardi, Giovanna

    2005-01-01

    The aim of this treatment planning comparison study was to explore different spinal irradiation techniques with respect to the risk of late side-effects, particularly radiation-induced cancer. The radiotherapy techniques compared were conventional photon therapy, intensity modulated x-ray therapy (IMXT), conventional electron therapy, intensity/energy modulated electron therapy (IMET) and proton therapy (IMPT). CT images for radiotherapy use from five children, median age 8 and diagnosed with medulloblastoma, were selected for this study. Target volumes and organs at risk were defined in 3-D. Treatment plans using conventional photon therapy, IMXT, conventional electron therapy, IMET and IMPT were set up. The probability of normal tissue complication (NTCP) and the risk of cancer induction were calculated using models with parameters-sets taken from published data for the general population; dose data were taken from dose volume histograms (DVH). Similar dose distributions in the targets were achieved with all techniques but the absorbed doses in the organs-at-risk varied significantly between the different techniques. The NTCP models based on available data predicted very low probabilities for side-effects in all cases. However, the effective mean doses outside the target volumes, and thus the predicted risk of cancer induction, varied significantly between the techniques. The highest lifetime risk of secondary cancers was estimated for IMXT (30%). The lowest risk was found with IMPT (4%). The risks associated with conventional photon therapy, electron therapy and IMET were 20%, 21% and 15%, respectively. This model study shows that spinal irradiation of young children with photon and electron techniques results in a substantial risk of radiation-induced secondary cancers. Multiple beam IMXT seems to be associated with a particularly high risk of secondary cancer induction. To minimise this risk, IMPT should be the treatment of choice. If proton therapy is not

  11. Radiotherapy for Adult Medulloblastoma: Evaluation of Helical Tomotherapy, Volumetric Intensity Modulated Arc Therapy, and Three-Dimensional Conformal Radiotherapy and the Results of Helical Tomotherapy Therapy

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    Sun Zong-wen

    2018-01-01

    Full Text Available Introduction. All adult medulloblastoma (AMB patients should be treated with craniospinal irradiation (CSI postoperatively. Because of the long irradiation range, multiple radiation fields must be designed for conventional radiotherapy technology. CSI can be completed in only one session with helical tomotherapy (HT. We evaluated the dose of HT, volumetric intensity modulated arc therapy (VMAT, and three-dimensional conformal radiotherapy (3D-CRT of AMB and the results of 5 cases of AMB treated with HT. Methods. Complete craniospinal and posterior cranial fossa irradiation with HT, VMAT, and 3D-CRT and dose evaluation were performed. And results of 5 cases of AMB treated with HT were evaluated. Results. A large volume of tissue was exposed to low dose radiation in the organs at risk (OAR, while a small volume was exposed to high dose radiation with HT. The conformity and uniformity of the targets were good with HT and VMAT, and the volume of targets exposed to high dose with VMAT was larger than that of HT. The uniformity of 3D-CRT was also good, but the dose conformity was poor. The main toxicity was hematologic toxicity, without 4th-degree bone marrow suppression. There was 3rd-degree inhibition in the white blood cells, hemoglobin, and platelets. The three female patients suffered menstrual disorders during the course of radiation. Two female patients with heavy menstruation suffered 3rd-degree anemia inhibition, and 2 patients suffered amenorrhea after radiotherapy. Although menstrual cycle was normal, the third patient was not pregnant. Conclusion. CSI with HT is convenient for clinical practice, and the side effects are mild. With good conformity and uniformity, VMAT can also be used for selection in CSI. For poor conformity, 3D-CRT should not be the priority selection for CSI. In female patients, the ovaries should be protected.

  12. Concordance between the chang and the International Society of Pediatric Oncology (SIOP) ototoxicity grading scales in patients treated with cisplatin for medulloblastoma.

    Science.gov (United States)

    Bass, Johnnie K; Huang, Jie; Onar-Thomas, Arzu; Chang, Kay W; Bhagat, Shaum P; Chintagumpala, Murali; Bartels, Ute; Gururangan, Sridharan; Hassall, Tim; Heath, John A; McCowage, Geoffrey; Cohn, Richard J; Fisher, Michael J; Robinson, Giles; Broniscer, Alberto; Gajjar, Amar; Gurney, James G

    2014-04-01

    Reporting ototoxicity is frequently complicated by use of various ototoxicity criteria. The International Society of Pediatric Oncology (SIOP) ototoxicity grading scale was recently proposed for standardized use in reporting hearing loss outcomes across institutions. The aim of this study was to evaluate the concordance between the Chang and SIOP ototoxicity grading scales. Differences between the two scales were identified and the implications these differences may have in the clinical setting were discussed. Audiological evaluations were reviewed for 379 patients with newly diagnosed medulloblastoma (ages 3-21 years). Each patient was enrolled on one of two St. Jude clinical protocols that included craniospinal radiation therapy and four courses of 75 mg/m(2) cisplatin chemotherapy. The latest audiogram conducted 5.5-24.5 months post-protocol treatment initiation was graded using the Chang and SIOP ototoxicity criteria. Clinically significant hearing loss was defined as Chang grade ≥2a and SIOP ≥2. Hearing loss was considered serious (requiring a hearing aid) at the level of Chang grade ≥2b and SIOP ≥3. A strong concordance was observed between the Chang and SIOP ototoxicity scales (Stuart's tau-c statistic = 0.89, 95% CI: 0.86, 0.91). Among those patients diagnosed with serious hearing loss, the two scales were in good agreement. However, the scales deviated from one another in classifying patients with less serious or no hearing loss. Although discrepancies between the Chang and SIOP ototoxicity scales exist primarily for patients with no or minimal hearing loss, the scales share a strong concordance overall. © 2013 Wiley Periodicals, Inc.

  13. RADIATION THERAPY QUALITY IN CCG/POG INTERGROUP 9961: IMPLICATIONS FOR CRANIOSPINAL IRRADIATION AND THE POSTERIOR FOSSA BOOST IN FUTURE MEDULLOBLASTOMA TRIALS

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    Bernadine eDonahue

    2012-12-01

    Full Text Available Purpose: Associations of RT deviations and outcomes in medulloblastoma have not been defined well, particularly in the era of reduced-dose CSI and chemotherapy. The aim of this study is to evaluate the quality of RT on CCG/POG 9961 and analyze associations of RT deviations with outcome.Methods and Materials: Major volume deviations were assessed based on the distance from specified anatomical region to field edge. We investigated associations of RT deviations with progression-free survival (PFS, overall survival (OS, and explored associations with demographics and clinical variables.Results: Of the 308 patients who were evaluable for volume deviations, 101 patients (33% did not have any. Of the remaining 207 patients, 50% had only minor deviations, 29% had only major deviations, and 21% had both minor and major deviations. Of the patients with major deviations, 73% had a single major deviation. The most common major deviation was in the cribriform plate region, followed by the posterior fossa; posterior fossa deviations resulted from treating less than whole posterior fossa. There were no significant differences in PFS or OS between patients with deviations and those without. There was no evidence of associations of deviations with patient age. Conclusions: Approximately one-third of patients had major volume deviations. There was no evidence of a significant association between these and outcome. This lack of correlation likely reflects the current high quality of radiation therapy delivered in COG institutions, our strict definition of volume deviations, and the relatively few instances of multiple major deviations in individual patients. In is noteworthy that the types of posterior fossa volume deviations observed in this study were not adversely associated with outcome. As we move forward, quality assurance will continue to play an important role to ensure that deviations on study do not influence study outcome.

  14. OTX2 exhibits cell-context-dependent effects on cellular and molecular properties of human embryonic neural precursors and medulloblastoma cells

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    Ravinder Kaur

    2015-10-01

    Full Text Available Medulloblastoma (MB is the most common malignant primary pediatric brain tumor and is currently divided into four subtypes based on different genomic alterations, gene expression profiles and response to treatment: WNT, Sonic Hedgehog (SHH, Group 3 and Group 4. This extensive heterogeneity has made it difficult to assess the functional relevance of genes to malignant progression. For example, expression of the transcription factor Orthodenticle homeobox2 (OTX2 is frequently dysregulated in multiple MB variants; however, its role may be subtype specific. We recently demonstrated that neural precursors derived from transformed human embryonic stem cells (trans-hENs, but not their normal counterparts (hENs, resemble Groups 3 and 4 MB in vitro and in vivo. Here, we tested the utility of this model system as a means of dissecting the role of OTX2 in MB using gain- and loss-of-function studies in hENs and trans-hENs, respectively. Parallel experiments with MB cells revealed that OTX2 exerts inhibitory effects on hEN and SHH MB cells by regulating growth, self-renewal and migration in vitro and tumor growth in vivo. This was accompanied by decreased expression of pluripotent genes, such as SOX2, and was supported by overexpression of SOX2 in OTX2+ SHH MB and hENs that resulted in significant rescue of self-renewal and cell migration. By contrast, OTX2 is oncogenic and promotes self-renewal of trans-hENs and Groups 3 and 4 MB independent of pluripotent gene expression. Our results demonstrate a novel role for OTX2 in self-renewal and migration of hENs and MB cells and reveal a cell-context-dependent link between OTX2 and pluripotent genes. Our study underscores the value of human embryonic stem cell derivatives as alternatives to cell lines and heterogeneous patient samples for investigating the contribution of key developmental regulators to MB progression.

  15. Quality of survival and growth in children and young adults in the PNET4 European controlled trial of hyperfractionated versus conventional radiation therapy for standard-risk medulloblastoma.

    Science.gov (United States)

    Kennedy, Colin; Bull, Kim; Chevignard, Mathilde; Culliford, David; Dörr, Helmuth G; Doz, François; Kortmann, Rolf-Dieter; Lannering, Birgitta; Massimino, Maura; Navajas Gutiérrez, Aurora; Rutkowski, Stefan; Spoudeas, Helen A; Calaminus, Gabriele

    2014-02-01

    To compare quality of survival in "standard-risk" medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial. Participants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded. Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011). Hyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Ovarian function in survivors of childhood medulloblastoma: Impact of reduced dose craniospinal irradiation and high-dose chemotherapy with autologous stem cell rescue.

    Science.gov (United States)

    Balachandar, Sadana; Dunkel, Ira J; Khakoo, Yasmin; Wolden, Suzanne; Allen, Jeffrey; Sklar, Charles A

    2015-02-01

    Data on ovarian function (OvF) in medulloblastoma (MB) survivors is limited, with most studies describing outcomes in survivors treated with craniospinal irradiation (CSI) doses >24 Gy ± standard chemotherapy. The objective of the current study is to report on OvF: (i) across a range of CSI doses; and (ii) following high-dose chemotherapy with autologous stem cell rescue (ASCR). Retrospective review of female MB survivors who were diagnosed in childhood and followed at Memorial Sloan Kettering Cancer Center. Patients were divided into three groups: (i) CSI ≤24 Gy +/- standard chemotherapy; (ii) CSI ≥35 Gy +/- standard chemotherapy; and (iii) high-dose chemotherapy with ASCR +/- CSI. Primary ovarian dysfunction (POD) occurred in 2/17 subjects in group 1, 3/9 subjects in group 2 and 5/5 subjects in group 3 (P < 0.01). Normalization of function was noted in four subjects with POD. Persistent POD requiring hormone replacement (POF) was observed in 1/17 subjects in group 1, 2/9 in group 2, and 3/5 in group 3 (P = 0.02). Neither age at treatment nor type of standard chemotherapy correlated with risk of POD or POF. Both POD and POF appear to occur in a small proportion of patients who are treated with contemporary doses of CSI +/- standard chemotherapy. However, ovarian dysfunction requiring hormone replacement therapy is common following high-dose chemotherapy associated with ASCR. These findings will assist clinicians in counseling patients regarding fertility preservation and risk of impaired ovarian function/future fertility. Pediatr Blood Cancer 2015;62:317-321. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

  17. Characterization of Ectonucleotidases in Human Medulloblastoma Cell Lines: ecto-5′NT/CD73 in Metastasis as Potential Prognostic Factor

    Science.gov (United States)

    Cappellari, Angélica Regina; Rockenbach, Liliana; Dietrich, Fabrícia; Clarimundo, Vanessa; Glaser, Talita; Braganhol, Elizandra; Abujamra, Ana Lúcia; Roesler, Rafael; Ulrich, Henning; liveira Battastini, Ana Maria

    2012-01-01

    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. PMID:23094051

  18. Quantitative assessment of inter-clinician variability of target volume delineation for medulloblastoma: quality assurance for the SIOP PNET 4 trial protocol

    International Nuclear Information System (INIS)

    Coles, Charlotte E.; Hoole, Andrew C.F.; Harden, Susan V; Burnet, Neil G.; Twyman, Nicola; Taylor, Roger E.; Kortmann, Rolf D.; Williams, Michael V.

    2003-01-01

    Background and purpose: To assess inter-clinician variability amongst specialist paediatric radiation oncologists in delineating clinical target volumes for treating medulloblastoma as a quality assurance exercise prior to the introduction of the SIOP PNET 4 trial protocol of conformal radiotherapy to the posterior fossa and tumour bed. Patients and methods: Participants from 17 UK centres attended an educational meeting and then completed a clinical planning exercise to outline: (1) the whole posterior fossa and (2) the tumour bed. Quantitative analysis of the volumes, lengths, spatial positioning and axial planes for each individual was carried out and variation between individuals analysed. Results: Outlining of the posterior fossa was reasonably consistent, although most variation was seen in defining the superior border of the tentorium. A major difference was the decision whether or not to include the post-surgical meningocoele in the clinical target volume (CTV). The CTV for the tumour bed was under treated by all participants due to lack of inclusion of pre-operative tumour extent. Conclusions: This exercise demonstrated several ambiguities in the draft protocol and highlighted particular areas of inter-clinician variation. Consequently the protocol was revised and improved to take account of these findings. We recommend that planning exercises, in conjunction with education and training, should be implemented before the start of any new radiotherapy trial. In the future, the use of image transfer will allow prospective peer review of target volumes before treatment commences. These measures are essential to ensure that alterations in clinical practice are achieved in a uniform way

  19. Quality of Survival and Growth in Children and Young Adults in the PNET4 European Controlled Trial of Hyperfractionated Versus Conventional Radiation Therapy for Standard-Risk Medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Kennedy, Colin, E-mail: crk1@soton.ac.uk [University of Southampton Faculty of Medicine and University Hospital Southampton National Health Service Foundation Trust, Southampton (United Kingdom); Bull, Kim [University of Southampton Faculty of Medicine and University Hospital Southampton National Health Service Foundation Trust, Southampton (United Kingdom); Chevignard, Mathilde [Hôpitaux de Saint Maurice, Saint Maurice (France); Neurophysiology, University of Pierre et Marie-Curie Paris 6, Paris (France); Culliford, David [University of Southampton Faculty of Medicine and University Hospital Southampton National Health Service Foundation Trust, Southampton (United Kingdom); Dörr, Helmuth G. [Kinder- und Jugendklinik der Universität Erlangen, Erlangen (Germany); Doz, François [Institut Curie and University Paris Descartes, Sorbonne Paris Cité (France); Kortmann, Rolf-Dieter [Department of Radiation Therapy, University of Leipzig, Leipzig (Germany); Lannering, Birgitta [Department of Pediatrics, The Sahlgren Academy, University of Gothenburg, Gothenburg (Sweden); Massimino, Maura [Fondazione Istituto di Ricovero e Cura a Carattere Scientifico IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Navajas Gutiérrez, Aurora [Hospital Universitario Cruces, Baracaldo-Vizcaya (Spain); Rutkowski, Stefan [University Medical Center Hamburg-Eppendorf, Hamburg (Germany); Spoudeas, Helen A. [Center for Pediatric Endocrinology, University College London, London (United Kingdom); Calaminus, Gabriele [Pediatric Oncology, University of Muenster, Muenster (Germany)

    2014-02-01

    Purpose: To compare quality of survival in “standard-risk” medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial. Methods and Materials: Participants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded. Results: Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011). Conclusions: Hyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life.

  20. RNA interference-mediated c-MYC inhibition prevents cell growth and decreases sensitivity to radio- and chemotherapy in childhood medulloblastoma cells

    International Nuclear Information System (INIS)

    Bueren, André O von; Shalaby, Tarek; Oehler-Jänne, Christoph; Arnold, Lucia; Stearns, Duncan; Eberhart, Charles G; Arcaro, Alexandre; Pruschy, Martin; Grotzer, Michael A

    2009-01-01

    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 cause anaplasia and correlate with unfavorable prognosis. To study the role of c-MYC in MB biology, we down-regulated c-MYC expression by using small interfering RNA (siRNA) and investigated changes in cellular proliferation, cell cycle analysis, apoptosis, telomere maintenance, and response to ionizing radiation (IR) and chemotherapeutics in a representative panel of human MB cell lines expressing different levels of c-MYC (DAOY wild-type, DAOY transfected with the empty vector, DAOY transfected with c-MYC, D341, and D425). siRNA-mediated c-MYC down-regulation resulted in an inhibition of cellular proliferation and clonogenic growth, inhibition of G1-S phase cell cycle progression, and a decrease in human telomerase reverse transcriptase (hTERT) expression and telomerase activity. On the other hand, down-regulation of c-MYC reduced apoptosis and decreased the sensitivity of human MB cells to IR, cisplatin, and etoposide. This effect was more pronounced in DAOY cells expressing high levels of c-MYC when compared with DAOY wild-type or DAOY cells transfected with the empty vector. In human MB cells, in addition to its roles in growth and proliferation, c-MYC is also a potent inducer of apoptosis. Therefore, targeting c-MYC might be of therapeutic benefit when used sequentially with chemo- and radiotherapy rather than concomitantly

  1. SU-F-T-218: Validation of An In-Vivo Proton Range Verification Method for Reducing the Risk of Permanent Alopecia in the Treatment of Pediatric Medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Lucconi, G [Department of Medical Physics, S. Orsola-Malpighi University Hospital, Bologna (Italy); Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States); Bentefour, E; Janssens, G [Advanced Technology Group, Ion Beam Applications (IBA), Louvain la Neuve (Belgium); Deepak, S [Department of Physics, Central University of Karnataka, Karnataka 585367 (India); Weaver, K; Moteabbed, M; Lu, H-M [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States)

    2016-06-15

    Purpose: The clinical commissioning of a workflow for pre-treatment range verification/adjustment for the head treatment of pediatric medulloblastoma patients, including dose monitoring during treatment. Methods: An array of Si-diodes (DIODES Incorporated) is placed on the patient skin on the opposite side to the beam entrance. A “scout” SOBP beam, with a longer beam range to cover the diodes in its plateau, is delivered; the measured signal is analyzed and the extracted water equivalent path lengths (WEPL) are compared to the expected values, revealing if a range correction is needed. Diodes stay in place during treatment to measure dose. The workflow was tested in solid water and head phantoms and validated against independent WEPL measurements. Both measured WEPL and skin doses were compared to computed values from the TPS (XiO); a Markus chamber was used for reference dose measurements. Results: The WEPL accuracy of the method was verified by comparing it with the dose extinction method. It resulted, for both solid water and head phantom, in the sub-millimeter range, with a deviation less than 1% to the value extracted from the TPS. The accuracy of dose measurements in the fall-off part of the dose profile was validated against the Markus chamber. The entire range verification workflow was successfully tested for the mock-treatment of head phantom with the standard delivery of 90 cGy per field per fraction. The WEPL measurement revealed no need for range correction. The dose measurements agreed to better than 4% with the prescription dose. The robustness of the method and workflow, including detector array, hardware set and software functions, was successfully stress-tested with multiple repetitions. Conclusion: The performance of the in-vivo range verification system and related workflow meet the clinical requirements in terms of the needed WEPL accuracy for pretreatment range verification with acceptable dose to the patient.

  2. Neuropsychological Outcome of Children Treated for Standard Risk Medulloblastoma in the PNET4 European Randomized Controlled Trial of Hyperfractionated Versus Standard Radiation Therapy and Maintenance Chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Câmara-Costa, Hugo, E-mail: hugocamaracosta@gmail.com [National Institute of Health and Medical Research, INSERM U1178, Paris (France); Resch, Anika [University Medical Center Hamburg-Eppendorf, Hamburg (Germany); Kieffer, Virginie [Saint Maurice Hospitals, Saint Maurice (France); Lalande, Clémence [Institut Gustave Roussy, Villejuif (France); Poggi, Geraldina [Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco (Italy); Kennedy, Colin; Bull, Kim [University of Southampton, Faculty of Medicine, Southampton (United Kingdom); Calaminus, Gabriele [Paediatric Oncology, University of Muenster, Muenster (Germany); Grill, Jacques [Institut Gustave Roussy, Villejuif (France); Doz, François [Institut Curie and University Paris Descartes, Sorbonne Paris Cité, Paris (France); Rutkowski, Stefan [University Medical Center Hamburg-Eppendorf, Hamburg (Germany); Massimino, Maura [Fondazione IRCCS, Istituto Nazionale Tumori, Milan (Italy); Kortmann, Rolf-Dieter [Department of Radiation Therapy, University of Leipzig, Leipzig (Germany); Lannering, Birgitta [Paediatric Oncology, University of Gothenburg, Gothenburg (Sweden); Dellatolas, Georges [National Institute of Health and Medical Research, INSERM U1178, Paris (France); Chevignard, Mathilde [Rehabilitation Department for Children With Acquired Neurological Injury, Saint Maurice Hospitals, Saint Maurice, and Sorbonne Universités, UPMC Universités Paris, INSERM CNRS, Paris (France)

    2015-08-01

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

  3. Neuropsychological Outcome of Children Treated for Standard Risk Medulloblastoma in the PNET4 European Randomized Controlled Trial of Hyperfractionated Versus Standard Radiation Therapy and Maintenance Chemotherapy

    International Nuclear Information System (INIS)

    Câmara-Costa, Hugo; Resch, Anika; Kieffer, Virginie; Lalande, Clémence; Poggi, Geraldina; Kennedy, Colin; Bull, Kim; Calaminus, Gabriele; Grill, Jacques; Doz, François; Rutkowski, Stefan; Massimino, Maura; Kortmann, Rolf-Dieter; Lannering, Birgitta; Dellatolas, Georges; Chevignard, Mathilde

    2015-01-01

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

  4. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: reduction of the supratentorial target volume

    International Nuclear Information System (INIS)

    Miralbell, Raymond; Lomax, Anthony; Bortfeld, Thomas; Rouzaud, Michel; Carrie, Christian

    1997-01-01

    Purpose: One of the components of radiotherapy (RT) in medulloblastoma/primitive neuroectodermal tumors is the prophylactic irradiation of the whole brain (WBI). With the aim of reducing late neuropsychologic morbidity a CT-scan-based dosimetric study was undertaken in which treatment was confined mainly or exclusively to supratentorial sites considered at high risk for disease recurrence. Methods and Materials: A comparative dosimetric study is presented in which a three field (two laterals and one posterior) proton plan (spot scanning method) is compared with a two-field conventional WBI 6 MV x-ray plan, to a 6-field 'hand-made' 6 MV x-ray plan, and to a computer-optimized 9-field 'inverse' 15 MV x-ray plan. For favorable patients, 30 Gy were delivered to the ventricles and main cisterns, the subfrontal and subtemporal regions, and the posterior fossa. For the unfavorable patients, 10 Gy WBI preceded a boost to 30 Gy to the same treatment volume chosen for favorable patients. The dose distribution was evaluated with dose-volume histograms to examine the coverage of the targets as well as the dose to the nontarget brain and optical structures. In addition, the risks of radiation-related late neuropsychologic effects after WBI were collected from the literature and used to predict normal tissue complication probabilities (NTCPs) for an intelligence quotient deficit after treatment with photon or proton beams. Results: Proton beams succeeded better in reducing the dose to the brain hemispheres and eye than any of the photon plans. A 25.1% risk of an IQ score <90 was predicted after 30 Gy WBI. Almost a 10% drop in the predicted risk was observed when using proton beams in both favorable and unfavorable patients. However, predicted NTCPs for both optimized photon plans ('hand made' and 'inverse') were only slightly higher (0.3-2.5%) than those of proton beams. An age-modifying factor was introduced in the predictive NTCP model to assess for IQ differences in relation

  5. Challenges of Treating Childhood Medulloblastoma in a Country With Limited Resources: 20 Years of Experience at a Single Tertiary Center in Malaysia

    Directory of Open Access Journals (Sweden)

    Revathi Rajagopal

    2017-04-01

    Full Text Available Purpose: Pediatric medulloblastoma (MB treatment has evolved over the past few decades; however, treating children in countries with limited resources remains challenging. Until now, the literature regarding childhood MB in Malaysia has been nonexistent. Our objectives were to review the demographics and outcome of pediatric MB treated at the University Malaya Medical Center between January 1994 and December 2013 and describe the challenges encountered. Methods: Fifty-one patients with childhood MB were seen at University Malaya Medical Center. Data from 43 patients were analyzed; eight patients were excluded because their families refused treatment after surgery. Results: Headache and vomiting were the most common presenting symptoms, and the mean interval between symptom onset and diagnosis was 4 weeks. Fourteen patients presented with metastatic disease. Five-year progression-free survival (± SE for patients ≥ 3 years old was 41.7% ± 14.2% (95% CI, 21.3% to 81.4% in the high-risk group and 68.6% ± 18.6% (95% CI, 40.3% to 100% in the average-risk group, and 5-year overall survival (± SE in these two groups was 41.7% ± 14.2% (95% CI, 21.3% to 81.4% and 58.3% ± 18.6% (95% CI, 31.3% to 100%, respectively. Children younger than 3 years old had 5-year progression-free and overall survival rates (± SE of 47.6% ± 12.1% (95% CI, 28.9% to 78.4% and 45.6% ± 11.7% (95% CI, 27.6% to 75.5%, respectively. Time to relapse ranged from 4 to 132 months. Most patients who experienced relapse died within 1 year. Febrile neutropenia, hearing loss, and endocrinopathy were the most common treatment-related complications. Conclusion: The survival rate of childhood MB in Malaysia is inferior to that usually reported in the literature. We postulate that the following factors contribute to this difference: lack of a multidisciplinary neuro-oncology team, limited health care facilities, inconsistent risk assessment, insufficient data in the National Cancer

  6. MiR-34a targeting of Notch ligand delta-like 1 impairs CD15+/CD133+ tumor-propagating cells and supports neural differentiation in medulloblastoma.

    Directory of Open Access Journals (Sweden)

    Pasqualino de Antonellis

    Full Text Available Through negative regulation of gene expression, microRNAs (miRNAs can function as oncosuppressors in cancers, and can themselves show altered expression in various tumor types. Here, we have investigated medulloblastoma tumors (MBs, which arise from an early impairment of developmental processes in the cerebellum, where Notch signaling is involved in many of the cell-fate-determining stages. Notch regulates a subset of MB cells that have stem-cell-like properties and can promote tumor growth. On the basis of this evidence, we hypothesized that miRNAs targeting the Notch pathway can regulate these phenomena, and can be used in anti-cancer therapies.In a screening of potential targets within Notch signaling, miR-34a was seen to be a regulator of the Notch pathway through its targeting of Notch ligand Delta-like 1 (Dll1. Down-regulation of Dll1 expression by miR-34a negatively regulates cell proliferation, and induces apoptosis and neural differentiation in MB cells. Using an inducible tetracycline on-off model of miR-34a expression, we show that in Daoy MB cells, Dll1 is the first target that is regulated in MB, as compared to the other targets analyzed here: Cyclin D1, cMyc and CDK4. MiR-34a expression negatively affects CD133(+/CD15(+ tumor-propagating cells, then we assay through reverse-phase proteomic arrays, Akt and Stat3 signaling hypo-phosphorylation. Adenoviruses carrying the precursor miR-34a induce neurogenesis of tumor spheres derived from a genetic animal model of MB (Patch1(+/- p53(-/-, thus providing further evidence that the miR-34a/Dll1 axis controls both autonomous and non autonomous signaling of Notch. In vivo, miR-34a overexpression carried by adenoviruses reduces tumor burden in cerebellum xenografts of athymic mice, thus demonstrating an anti-tumorigenic role of miR-34a in vivo.Despite advances in our understanding of the pathogenesis of MB, one-third of patients with MB remain incurable. Here, we show that stable nucleic

  7. Challenges of Treating Childhood Medulloblastoma in a Country With Limited Resources: 20 Years of Experience at a Single Tertiary Center in Malaysia.

    Science.gov (United States)

    Rajagopal, Revathi; Abd-Ghafar, Sayyidatul; Ganesan, Dharmendra; Bustam Mainudin, Anita Zarina; Wong, Kum Thong; Ramli, Norlisah; Jawin, Vida; Lum, Su Han; Yap, Tsiao Yi; Bouffet, Eric; Qaddoumi, Ibrahim; Krishnan, Shekhar; Ariffin, Hany; Abdullah, Wan Ariffin

    2017-04-01

    Pediatric medulloblastoma (MB) treatment has evolved over the past few decades; however, treating children in countries with limited resources remains challenging. Until now, the literature regarding childhood MB in Malaysia has been nonexistent. Our objectives were to review the demographics and outcome of pediatric MB treated at the University Malaya Medical Center between January 1994 and December 2013 and describe the challenges encountered. Fifty-one patients with childhood MB were seen at University Malaya Medical Center. Data from 43 patients were analyzed; eight patients were excluded because their families refused treatment after surgery. Headache and vomiting were the most common presenting symptoms, and the mean interval between symptom onset and diagnosis was 4 weeks. Fourteen patients presented with metastatic disease. Five-year progression-free survival (± SE) for patients ≥ 3 years old was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) in the high-risk group and 68.6% ± 18.6% (95% CI, 40.3% to 100%) in the average-risk group, and 5-year overall survival (± SE) in these two groups was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) and 58.3% ± 18.6% (95% CI, 31.3% to 100%), respectively. Children younger than 3 years old had 5-year progression-free and overall survival rates (± SE) of 47.6% ± 12.1% (95% CI, 28.9% to 78.4%) and 45.6% ± 11.7% (95% CI, 27.6% to 75.5%), respectively. Time to relapse ranged from 4 to 132 months. Most patients who experienced relapse died within 1 year. Febrile neutropenia, hearing loss, and endocrinopathy were the most common treatment-related complications. The survival rate of childhood MB in Malaysia is inferior to that usually reported in the literature. We postulate that the following factors contribute to this difference: lack of a multidisciplinary neuro-oncology team, limited health care facilities, inconsistent risk assessment, insufficient data in the National Cancer Registry and pathology reports, inadequate long

  8. Irradiation-induced angiogenesis is associated with an MMP-9-miR-494-syndecan-1 regulatory loop in medulloblastoma cells.

    Science.gov (United States)

    Asuthkar, S; Velpula, K K; Nalla, A K; Gogineni, V R; Gondi, C S; Rao, J S

    2014-04-10

    Matrix metalloproteinase-9 (MMP-9) represents one of the most prominent proteins associated with tumorigenesis and is a modulator of the tumor microenvironment during angiogenesis. Recently, syndecan-1 (SDC1), a transmembrane heparan sulfate-bearing proteoglycan, was also speculated to have a critical role in contributing to angiogenesis when associated with MMP-9. However, the mechanism behind their synergistic regulation is not fully understood. In the current study, we report for the first time that ionizing radiation (IR)-induced MMP-9 enhances SDC1 shedding, corroborating to tube-inducing ability of medulloblastoma (MB) cells. Furthermore, we observed that the tumor angiogenesis is associated with higher MMP-9-SDC1 interactions on both the cell surface and extracellular medium. Our results also revealed the existence of a novel regulatory mechanism where MMP-9 drives the suppression of miR-494, resulting in enhanced SDC1 shedding and angiogenesis. From the in situ hybridization analysis, we found that MMP-9-specific shRNA (shMMP-9) treatment of mouse intracranial tumors resulted in elevated expression of miR-494. This negative correlation between MMP-9 and miR-494 levels was observed to be dependent on the methylation status of a miR-494 promoter-associated CpG island region (-186 to -20), which was confirmed by bisulfite-sequencing and methylation-specific PCR (MSP) analysis. Further, validation of MMP-9 and SDC1 3'-untranslated region (3'-UTR) targets with luciferase reporter assay provided a more favorable result for miR-494-mediated regulation of SDC1 but not of MMP-9, suggesting that the 3'-UTR of SDC1 mRNA is a direct target of miR-494. Overall, our results indicate that angiogenesis induced by radiotherapy is associated with an MMP-9-miR-494-SDC1 regulatory loop and that MMP-9-SDC1 activity creates a negative feedback loop by regulating the expression of miR-494.

  9. 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.

    Science.gov (United States)

    Brodin, N Patrik; Vogelius, Ivan R; Björk-Eriksson, Thomas; Munck Af Rosenschöld, Per; Maraldo, Maja V; Aznar, Marianne C; Specht, Lena; Bentzen, Søren M

    2014-04-01

    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, 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. Total LYL were derived, based on the LYL attributable to radiation-induced late complications and the LYL from not controlling the primary disease. We compared the estimated LYL for three different treatments in 10 patients: 1) standard 3D conformal RT; 2) proton therapy; 3) risk-adaptive photon treatment lowering the dose to part of the craniospinal (CS) target volume situated close to critical risk organs. Late toxicity 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 thoracic vertebrae (Th1-Th10), and 36 Gy to the remaining CS volume, estimated a LYL reduction of 0.90 years (95% CI -0.18-2.41 years). Proton therapy with 36 Gy to the whole CS volume was associated with significantly fewer LYL compared to the risk-adapted photon strategies, with a mean LYL difference of 0.50 years (95% CI 0.25-2.60 years). Optimization of RT prescription strategies considering both late complications and the risk of recurrence, an all-cause mortality dose painting approach, was demonstrated. The risk-adapted techniques compared favorably to the standard, and although in this context, the gain is small compared to estimated uncertainty, this study demonstrates a framework for all-cause mortality risk estimation, rather than evaluates direct clinical applicability of risk

  10. A Phase II Study of Preradiotherapy Chemotherapy Followed by Hyperfractionated Radiotherapy for Newly Diagnosed High-Risk Medulloblastoma/Primitive Neuroectodermal Tumor: A Report From the Children's Oncology Group (CCG 9931)

    International Nuclear Information System (INIS)

    Allen, Jeffrey; Donahue, Bernadine; Mehta, Minesh; Miller, Douglas C.; Rorke, Lucy B.; Jakacki, Regina; Robertson, Patricia; Sposto, Richard; Holmes, Emi; Vezina, Gilbert; Muraszko, Karin; Puccetti, Diane; Prados, Michael; Chan, K.-W.

    2009-01-01

    Purpose: To verify feasibility and monitor progression-free survival and overall survival in children with high-risk medulloblastoma and noncerebellar primitive neuroectodermal tumors (PNETs) treated in a Phase II study with preradiotherapy chemotherapy (CHT) followed by high-dose, hyperfractionated craniospinal radiotherapy (CSRT). Methods and Materials: Eligibility criteria included age >3 years at diagnosis, medulloblastoma with either high M stage and/or >1.5 cm 2 postoperative residual disease, and all patients with noncerebellar PNET. Treatment was initiated with five alternating monthly cycles of CHT (A [cisplatin, cyclophosphamide, etoposide, and vincristine], B [carboplatin and etoposide], A, B, and A) followed by hyperfractionated CSRT (40 Gy) with a boost to the primary tumor (72 Gy) given in twice-daily 1-Gy fractions. Results: The valid study group consisted of 124 patients whose median age at diagnosis was 7.8 years. Eighty-four patients (68%) completed the entire protocol according to study guidelines (within 9 months), and the median time to complete CSRT was 1.6 months. Major reasons for failure to complete CHT included progressive disease (17%) and toxic death (2.4%). The 5-year progression-free survival and overall survival rates were 43% ± 5% and 52% ± 5%, respectively. No significant differences were detected in subset analysis related to response to CHT, site of primary tumor, postoperative residual disease, or M stage. Conclusions: The feasibility of this intensive multimodality protocol was confirmed, and response to pre-RT CHT did not impact on survival. Survival data from this protocol can not be compared with data from other studies, given the protocol design.

  11. A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children's Oncology Group.

    Science.gov (United States)

    Esbenshade, Adam J; Kocak, Mehmet; Hershon, Linda; Rousseau, Pierre; Decarie, Jean-Claude; Shaw, Susan; Burger, Peter; Friedman, Henry S; Gajjar, Amar; Moghrabi, Albert

    2017-06-01

    Children with high-risk medulloblastoma historically have had a poor prognosis. The Children's Oncology Group completed a Phase II study using oral etoposide given with radiotherapy followed by intensive chemotherapy. Patients enrolled in the study had high-risk disease defined as ≥1.5 cm 2 of residual disease postsurgery or definite evidence of central nervous metastasis. All patients underwent surgery followed by radiotherapy. During radiation, the patients received oral etoposide (21 days on, 7 off) at an initial dose of 50 mg/m 2 per day (treatment 1), which was reduced to 35 mg/m 2 per day (treatment 2) due to toxicity. After radiotherapy, the patients received chemotherapy with three cycles of cisplatin and oral etoposide, followed by eight courses of cyclophosphamide and vincristine. Between November 1998 and October 2002, 53 patients were accrued; 15 received treatment 1 and 38 treatment 2. Forty-seven patients (89%) were eligible. Response to radiation was excellent, with 19 (40.4%) showing complete response, 24 (51.1%) partial response, and four (8.5%) no recorded response. The overall 2- and 5-year progression-free survival (PFS) was 76.6 ± 6% and 70.2 ± 7%, respectively. The 2- and 5-year overall survival (OS) was 80.9 ± 6% and 76.6 ± 6%, respectively. Clinical response postradiation and PFS/OS were not significantly different between the treatment groups. There was a trend toward a difference in 5-year PFS between those without and with metastatic disease (P = 0.072). Oral etoposide was tolerable at 35 mg/m 2 (21 days on and 7 days off) when given during full-dose irradiation in patients with high-risk medulloblastoma with encouraging survival data. © 2016 Wiley Periodicals, Inc.

  12. Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1.

    Directory of Open Access Journals (Sweden)

    Frank Götschel

    Full Text Available Aberrant activation of Hedgehog (HH signaling has been identified as a key etiologic factor in many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling depend profoundly on interactions with other pathways, such as epidermal growth factor receptor-mediated signaling, which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. Our experimental data demonstrated that the Daoy human medulloblastoma cell line possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic HH or Smoothened agonist induced expression of GLI1 protein and simultaneously prevented the processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed at the transcriptomic and proteomic levels. The Daoy cells responded to the HH/EGF co-treatment by downregulating GLI1, PTCH, and HHIP at the transcript level; this was also observed when Amphiregulin (AREG was used instead of EGF. We identified a novel crosstalk mechanism whereby EGFR signaling silences proteins acting as negative regulators of HH signaling, as AKT- and ERK-signaling independent process. EGFR/HH signaling maintained high GLI1 protein levels which contrasted the GLI1 downregulation on the transcript level. Conversely, a high-level synergism was also observed, due to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile. This suggests that there are more wide-spread, yet context-dependent interactions, between HH/GLI and growth factor receptor signaling in human malignancies.

  13. Suppression of STAT3 NH2-terminal domain chemosensitizes medulloblastoma cells by activation of protein inhibitor of activated STAT3 via de-repression by microRNA-21.

    Science.gov (United States)

    Ray, Sutapa; Coulter, Don W; Gray, Shawn D; Sughroue, Jason A; Roychoudhury, Shrabasti; McIntyre, Erin M; Chaturvedi, Nagendra K; Bhakat, Kishor K; Joshi, Shantaram S; McGuire, Timothy R; Sharp, John G

    2018-04-01

    Medulloblastoma (MB) is a malignant pediatric brain tumor with poor prognosis. Signal transducers and activators of transcription-3 (STAT3) is constitutively activated in MB where it functions as an oncoprotein, mediating cancer progression and metastasis. Here, we have delineated the functional role of activated STAT3 in MB, by using a cell permeable STAT3-NH 2 terminal domain inhibitor (S3-NTDi) that specifically perturbs the structure/function of STAT3. We have implemented several biochemical experiments using human MB tumor microarray (TMA) and pediatric MB cell lines, derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/SHH tumors. Treatment of MB cells with S3-NTDi leads to growth inhibition, cell cycle arrest, and apoptosis. S3-NTDi downregulated expression of STAT3 target genes, delayed migration of MB cells, attenuated epithelial-mesenchymal transition (EMT) marker expressions and reduced cancer stem-cell associated protein expressions in MB-spheres. To elucidate mechanisms, we showed that S3-NTDi induce expression of pro-apoptotic gene, C/EBP-homologous protein (CHOP), and decrease association of STAT3 to the proximal promoter of CCND1 and BCL2. Of note, S3-NTDi downregulated microRNA-21, which in turn, de-repressed Protein Inhibitor of Activated STAT3 (PIAS3), a negative regulator of STAT3 signaling pathway. Furthermore, combination therapy with S3-NTDi and cisplatin significantly decreased highly aggressive MYC-amplified MB cell growth and induced apoptosis by downregulating STAT3 regulated proliferation and anti-apoptotic gene expression. Together, our results revealed an important role of STAT3 in regulating MB pathogenesis. Disruption of this pathway with S3-NTDi, therefore, may serves as a promising candidate for targeted MB therapy by enhancing chemosensitivity of MB cells and potentially improving outcomes in high-risk patients. © 2017 Wiley Periodicals, Inc.

  14. Disabling c-Myc in childhood medulloblastoma and atypical teratoid/rhabdoid tumor cells by the potent G-quadruplex interactive agent S2T1-6OTD.

    Science.gov (United States)

    Shalaby, Tarek; von Bueren, André O; Hürlimann, Marie-Louise; Fiaschetti, Giulio; Castelletti, Deborah; Masayuki, Tera; Nagasawa, Kazuo; Arcaro, Alexandre; Jelesarov, Ilian; Shin-ya, Kazuo; Grotzer, Michael

    2010-01-01

    We investigated here the effects of S2T1-6OTD, a novel telomestatin derivative that is synthesized to target G-quadruplex-forming DNA sequences, on a representative panel of human medulloblastoma (MB) and atypical teratoid/rhabdoid (AT/RT) childhood brain cancer cell lines. S2T1-6OTD proved to be a potent c-Myc inhibitor through its high-affinity physical interaction with the G-quadruplex structure in the c-Myc promoter. Treatment with S2T1-6OTD reduced the mRNA and protein expressions of c-Myc and hTERT, which is transcriptionally regulated by c-Myc, and decreased the activities of both genes. In remarkable contrast to control cells, short-term (72-hour) treatment with S2T1-6OTD resulted in a dose- and time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC(50), 0.25-0.39 micromol/L). Under conditions where inhibition of both proliferation and c-Myc activity was observed, S2T1-6OTD treatment decreased the protein expression of the cell cycle activator cyclin-dependent kinase 2 and induced cell cycle arrest. Long-term treatment (5 weeks) with nontoxic concentrations of S2T1-6OTD resulted in a time-dependent (mainly c-Myc-dependent) telomere shortening. This was accompanied by cell growth arrest starting on day 28 followed by cell senescence and induction of apoptosis on day 35 in all of the five cell lines investigated. On in vivo animal testing, S2T1-6OTD may well represent a novel therapeutic strategy for childhood brain tumors.

  15. Meduloblastoma: correlação entre ressonância magnética convencional, difusão e espectroscopia de prótons Medulloblastoma: correlation among findings of conventional magnetic resonance imaging, diffusion-weighted imaging and proton magnetic resonance spectroscopy

    Directory of Open Access Journals (Sweden)

    Mariana Vieira de Melo da Fonte

    2008-12-01

    Full Text Available OBJETIVO: Correlacionar os achados de ressonância magnética convencional, difusão e espectroscopia de prótons nos meduloblastomas, e compará-los aos dados da literatura. MATERIAIS E MÉTODOS: Análise retrospectiva de exames de ressonância magnética pré-operatórios de nove pacientes na faixa pediátrica com diagnóstico histológico de meduloblastoma (oito desmoplásicos e um de células gigantes. Foram considerados dados demográficos e características do tumor como localização, característica morfológica, intensidade de sinal, realce, disseminação e achados na difusão e espectroscopia. RESULTADOS: Na maioria dos casos os tumores apresentaram epicentro no vermis cerebelar (77,8%, sendo predominantemente sólido (88,9%, com hipossinal nas seqüências ponderadas em T1 e iso/hipersinal nas seqüências ponderadas em T2 e FLAIR, realce heterogêneo (100%, sinais de disseminação/extensão tumoral (77,8% e restrição à movimentação das moléculas de água (100%. A espectroscopia de prótons pela técnica STEAM (n = 6 demonstrou redução da relação Naa/Cr (83,3% e aumento de Co/Cr (100% e mI/Cr (66,7%, e pela técnica PRESS (n = 7 evidenciou pico de lactato (57,1%. CONCLUSÃO: O conjunto dos achados macroscópicos obtidos pela ressonância magnética, somado às características bioquímicas dos meduloblastomas, têm sido úteis na tentativa de diferenciação entre os principais tumores da fossa posterior.OBJECTIVE: 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. MATERIALS AND METHODS: 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

  16. The role of OTX2 in medulloblastoma

    NARCIS (Netherlands)

    Bunt, J.

    2012-01-01

    Het onderdrukken van het gen OTX2 lijkt een potentiële therapie voor medulloblastomen, een kwaadaardige hersentumor. Jens Bunt stelt dat OTX2 door binding aan het DNA de expressie van genen die nodig zijn voor celdeling aanzet, terwijl het indirect de differentiatie van cellen remt. Uit proeven met

  17. Medulloblastoma: evaluation of proliferative index by monoclonal antibody Mib-1, its prognostic correlation and therapeutic implications Meduloblastoma: avaliação do padrão proliferativo pelo anticorpo monoclonal Mib-1, correlação prognóstica e implicações terapêuticas

    Directory of Open Access Journals (Sweden)

    Antonio Fernandes Ferrari

    2003-09-01

    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.Nos últimos anos, o anticorpo monoclonal Mib1 tem sido bastante utilizado pelos pesquisadores para estudo retro e prospectivo, pela possibilidade de se obter um índice de proliferação de fragmentos tumorais conservados em parafina. O meduloblastoma é o tumor maligno mais freqüente do sistema nervoso central na infância. Os objetivos do trabalho foram determinar a média IP através do Mib-1 destas neoplasias, e estabelecer seu valor prognóstico. Neste trabalho foi determinado retrospectivamente o índice de proliferação celular de tumores extraídos de 22 pacientes portadores de meduloblastoma da fossa craniana posterior, tratados no Departamento de Neurocirurgia do Hospital A.C. Camargo de S. Paulo, no período de janeiro de 90 a dezembro de 99. O diagnóstico histopatológico de meduloblastoma foi confirmado pela coloração pela hematoxilina e eosina (HE e o IP foi determinado através do marcador

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

    Science.gov (United States)

    2015-07-01

    patient-derived xenografts (PDX) as an improved system to quantify rates of tumor subclonal population evolution. Specific Aims: 1: Spatial and...Temporal Dissection of Subclonal Heterogeneity in Breast Cancer Xenografts - a. Characterization of spatially and temporally separated breast cancer...of Subclonal Evolution During Drug Treatment - a. Genomic and histological characterization of spatially and temporally separated xenografts under

  19. Social Behavior in Medulloblastoma: Functional Analysis of Tumor-Supporting

    Science.gov (United States)

    2013-07-01

    used MADM to probe into early phases of gliomagenesis, and surprisingly found the lack of overpopulation of mutant NSCs. Among NSC-derived cell types...focus is on brain tumors. Several Berlin-based research groups have specialized on investigating the impact of parenchymal interactions of brain tumor

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

    Science.gov (United States)

    2017-09-01

    developing organs produce tumors with distinct molecular and cellular characteristics even when the initiating oncogenic event is the same. To test the...proposed to analyze both bulk tumor cells and CSCs from each of these models and compare their molecular and cellular characteristics , including CSC...resource for those studying this syndrome and knowledge gained from our analyses will reveal new insights into early stages of tumorigenesis in the

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

    International Nuclear Information System (INIS)

    Hope-Stone, H.F.

    1984-01-01

    Initially surgery will be required to establish the diagnosis and, by removal of at least some of the neoplastic mass, to produce sufficient decompression to allow radiation to be given. Complete surgical removal is unnecessary and may be dangerous if vital structures are involved, and by manipulation of the tumour may increase the risk of seedling metastasis. Since these tumours spread by seedling metastasis throughout the CSF, irradiation of the whole cerebro-spinal axis is required. Although this can be carried out by a series of matched contiguous fields, truly homogeneous irradiation cannot easily be achieved, especially at field junctions. A modification of the Manchester method is used. The technique comprises two fields, an anterior cranial field given with cobalt-60 and a posterior cranial/spinal field given with 250 kV orthovoltage X-rays

  2. Differential expression of gamma-tubulin and class III beta-tubulin in medulloblastomas and human medulloblastoma cell lines

    Czech Academy of Sciences Publication Activity Database

    Caracciolo, V.; D´Agostino, L.; Dráberová, Eduarda; Sládková, Vladimíra; Crozier-Fitzgerald, C.; Agamanolis, D.P.; De Chadarévian, J.P.; Legido, A.; Giordano, A.; Dráber, Pavel; Katsetos, C.D.

    2010-01-01

    Roč. 223, č. 2 (2010), s. 519-529 ISSN 0021-9541 R&D Projects: GA AV ČR KAN200520701 Institutional research plan: CEZ:AV0Z50520514 Keywords : gamma-tubulin * beta III-tubulin * meduloblastoma Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.986, year: 2010

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

    Science.gov (United States)

    2015-10-01

    overpopulation of mutant NSCs. Among NSC-derived cell types, we only detected dramatic over-expansion of mutant oligodendrocyte precursor cells (OPCs) at... Solution was injected subcutaneously at the nape. For adult mice, tamoxifen citrate tablets (10 mg/tablet; Mylan) were ground and dissolved at 200 mg/mL...minutes before addition of blocking solution (10% NDS in 0.1%PBT) for 20 minutes at RT. Appropriate primary antibodies (Table S1) were incubated on

  4. Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma

    International Nuclear Information System (INIS)

    Merchant, Thomas E.; Kiehna, Erin N.; Li Chenghong; Shukla, Hemant; Sengupta, Saikat; Xiong Xiaoping; Gajjar, Amar; Mulhern, Raymond K.

    2006-01-01

    Purpose: Model the effects of radiation dosimetry on IQ among pediatric patients with central nervous system (CNS) tumors. Methods and Materials: Pediatric patients with CNS embryonal tumors (n = 39) were prospectively evaluated with serial cognitive testing, before and after treatment with postoperative, risk-adapted craniospinal irradiation (CSI) and conformal primary-site irradiation, followed by chemotherapy. Differential dose-volume data for 5 brain volumes (total brain, supratentorial brain, infratentorial brain, and left and right temporal lobes) were correlated with IQ after surgery and at follow-up by use of linear regression. Results: When the dose distribution was partitioned into 2 levels, both had a significantly negative effect on longitudinal IQ across all 5 brain volumes. When the dose distribution was partitioned into 3 levels (low, medium, and high), exposure to the supratentorial brain appeared to have the most significant impact. For most models, each Gy of exposure had a similar effect on IQ decline, regardless of dose level. Conclusions: Our results suggest that radiation dosimetry data from 5 brain volumes can be used to predict decline in longitudinal IQ. Despite measures to reduce radiation dose and treatment volume, the volume that receives the highest dose continues to have the greatest effect, which supports current volume-reduction efforts

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

    Science.gov (United States)

    2015-12-01

    neural precursor proliferation. Genes Dev 2009; 23: 2729-2741. 14 Flora A, Klisch TJ, Schuster G, Zoghbi HY. Deletion of Atoh1 disrupts Sonic Hedgehog...29 Klisch TJ, Xi Y, Flora A, Wang L, Li W, Zoghbi HY. In vivo Atoh1 targetome reveals how a proneural transcription factor regulates cerebellar... definitively exclude the possibility that Hck phosphorylates other Gli1 regulators and activates Gli1 indirectly. In the study, we observed that Hck

  6. Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations

    NARCIS (Netherlands)

    Rausch, Tobias; Jones, David T. W.; Zapatka, Marc; Stütz, Adrian M.; Zichner, Thomas; Weischenfeldt, Joachim; Jäger, Natalie; Remke, Marc; Shih, David; Northcott, Paul A.; Pfaff, Elke; Tica, Jelena; Wang, Qi; Massimi, Luca; Witt, Hendrik; Bender, Sebastian; Pleier, Sabrina; Cin, Huriye; Hawkins, Cynthia; Beck, Christian; von Deimling, Andreas; Hans, Volkmar; Brors, Benedikt; Eils, Roland; Scheurlen, Wolfram; Blake, Jonathon; Benes, Vladimir; Kulozik, Andreas E.; Witt, Olaf; Martin, Dianna; Zhang, Cindy; Porat, Rinnat; Merino, Diana M.; Wasserman, Jonathan; Jabado, Nada; Fontebasso, Adam; Bullinger, Lars; Rücker, Frank G.; Döhner, Konstanze; Döhner, Hartmut; Koster, Jan; Molenaar, Jan J.; Versteeg, Rogier; Kool, Marcel; Tabori, Uri; Malkin, David; Korshunov, Andrey; Taylor, Michael D.; Lichter, Peter; Pfister, Stefan M.; Korbel, Jan O.

    2012-01-01

    Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of

  7. Endocrine outcomes with proton and photon radiotherapy for standard risk medulloblastoma.

    Science.gov (United States)

    Eaton, Bree R; Esiashvili, Natia; Kim, Sungjin; Patterson, Briana; Weyman, Elizabeth A; Thornton, Lauren T; Mazewski, Claire; MacDonald, Tobey J; Ebb, David; MacDonald, Shannon M; Tarbell, Nancy J; Yock, Torunn I

    2016-06-01

    Endocrine dysfunction is a common sequela of craniospinal irradiation (CSI). Dosimetric data suggest that proton radiotherapy (PRT) may reduce radiation-associated endocrine dysfunction but clinical data are limited. Seventy-seven children were treated with chemotherapy and proton (n = 40) or photon (n = 37) radiation between 2000 and 2009 with ≥3 years of endocrine screening. The incidence of multiple endocrinopathies among the proton and photon cohorts is compared. Multivariable analysis and propensity score adjusted analysis are performed to estimate the effect of radiotherapy type while adjusting for other variables. The median age at diagnosis was 6.2 and 8.3 years for the proton and photon cohorts, respectively (P = .010). Cohorts were similar with respect to gender, histology, CSI dose, and total radiotherapy dose and whether the radiotherapy boost was delivered to the posterior fossa or tumor bed. The median follow-up time was 5.8 years for proton patients and 7.0 years for photon patients (P = .010). PRT was associated with a reduced risk of hypothyroidism (23% vs 69%, P < .001), sex hormone deficiency (3% vs 19%, P = .025), requirement for any endocrine replacement therapy (55% vs 78%, P = .030), and a greater height standard deviation score (mean (± SD) -1.19 (± 1.22) vs -2 (± 1.35), P = .020) on both univariate and multivariate and propensity score adjusted analysis. There was no significant difference in the incidence of growth hormone deficiency (53% vs 57%), adrenal insufficiency (5% vs 8%), or precocious puberty (18% vs 16%). Proton radiotherapy may reduce the risk of some, but not all, radiation-associated late endocrine abnormalities. © 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.

  8. Application of optical coherence tomography attenuation imaging for quantification of optical properties in medulloblastoma

    Science.gov (United States)

    Vuong, Barry; Skowron, Patryk; Kiehl, Tim-Rasmus; Kyan, Matthew; Garzia, Livia; Genis, Helen; Sun, Cuiru; Taylor, Michael D.; Yang, Victor X. D.

    2015-03-01

    The hemodynamic environment is known to play a crucial role in the progression, rupture, and treatment of intracranial aneurysms. Currently there is difficulty assessing and measuring blood flow profiles in vivo. An emerging high resolution imaging modality known as split spectrum Doppler optical coherence tomography (ssDOCT) has demonstrated the capability to quantify hemodynamic patterns as well as arterial microstructural changes. In this study, we present a novel in vitro method to acquire precise blood flow patterns within a patient- specific aneurysm silicone flow models using ssDOCT imaging. Computational fluid dynamics (CFD) models were generated to verify ssDOCT results.

  9. I