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Sample records for irradiated recurrent medulloblastoma

  1. 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.

  2. Divergent clonal selection dominates medulloblastoma at recurrence

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

    2016-01-01

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

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

    Science.gov (United States)

    2018-06-18

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

  4. 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

  5. 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

  6. 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

  7. Medulloblastoma.

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    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.

  8. 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)

  9. 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

  10. 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

  11. 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%...

  12. 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

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

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    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.

  14. 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

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

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    Giuseppe Privitera

    2009-01-01

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

  16. 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.

  17. Radiotherapy for the medulloblastoma

    International Nuclear Information System (INIS)

    Gose, Kyuhei; Imajo, Yoshinari; Imanaka, Kazufumi

    1983-01-01

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

  18. Ovarian irradiation in recurrent endometriosis

    International Nuclear Information System (INIS)

    Kochbati, L.; Chaari, N.; Besbes, M.; Maalej, M.; Neji, K.; Ben Amara, F.; Ben Romdhane, N.K.

    2005-01-01

    We describe a case of a young woman with a history of an aplastic anaemia in which pelvic radiotherapy was used successfully in the management of a recurrent and inoperable endometriosis. The use of therapeutic pelvic or ovarian irradiation in endometriosis may be considered, when surgical and medical treatments have been exhausted and have failed. (authors)

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

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

    2017-08-01

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

  20. 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

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

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    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.

  2. Early recurrence in standard-risk medulloblastoma patients with the common idic(17)(p11.2) rearrangement

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    Bien-Willner, Gabriel A.; López-Terrada, Dolores; Bhattacharjee, Meena B.; Patel, Kayuri U.; Stankiewicz, Paweł; Lupski, James R.; Pfeifer, John D.; Perry, Arie

    2012-01-01

    Medulloblastoma is diagnosed histologically; treatment depends on staging and age of onset. Whereas clinical factors identify a standard- and a high-risk population, these findings cannot differentiate which standard-risk patients will relapse and die. Outcome is thought to be influenced by tumor subtype and molecular alterations. Poor prognosis has been associated with isochromosome (i)17q in some but not all studies. In most instances, molecular investigations document that i17q is not a true isochromosome but rather an isodicentric chromosome, idic(17)(p11.2), with rearrangement breakpoints mapping within the REPA/REPB region on 17p11.2. This study explores the clinical utility of testing for idic(17)(p11.2) rearrangements using an assay based on fluorescent in situ hybridization (FISH). This test was applied to 58 consecutive standard- and high-risk medulloblastomas with a 5-year minimum of clinical follow-up. The presence of i17q (ie, including cases not involving the common breakpoint), idic(17)(p11.2), and histologic subtype was correlated with clinical outcome. Overall survival (OS) and disease-free survival (DFS) were consistent with literature reports. Fourteen patients (25%) had i17q, with 10 (18%) involving the common isodicentric rearrangement. The presence of i17q was associated with a poor prognosis. OS and DFS were poor in all cases with anaplasia (4), unresectable disease (7), and metastases at presentation (10); however, patients with standard-risk tumors fared better. Of these 44 cases, tumors with idic(17)(p11.2) were associated with significantly worse patient outcomes and shorter mean DFS. FISH detection of idic(17)(p11.2) may be useful for risk stratification in standard-risk patients. The presence of this abnormal chromosome is associated with early recurrence of medulloblastoma. PMID:22573308

  3. 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

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

    International Nuclear Information System (INIS)

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

    2012-01-01

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

  5. 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.

  6. 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.)

  7. Alleviating action of OK-432 (Picibanil) on the myelosuppression in Medulloblastoma patients induced by whole axis irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Aoki, Yoshiro (National Inst. of Radiological Sciences, Chiba (Japan))

    1982-11-01

    The test subjects termed as OK-432 group which consist of 4 patients of Medulloblastoma and 2 of Pinealoma, underwent the whole axis irradiation in combination with OK-432. The control group consisting of 9 Medulloblastoma patients was subjected to the same radiation treatment without OK-432. Six of the nine patients (66.7%) irradiated showed the decrease of peripheral white blood cell counts down to 2,500, whereas, only two of six patients showed a similar decrement in OK-432 group. Three of the nine patients (33.3%) in the control group showed the decrease of white blood cell down to 2,000, but only one of the six patients in OK-432 group. The neutrophil counts decreased below the level of 1,000 in three of the nine patients (33.3%) in the control group, but none in the OK-432 group. The platelet counts decreased below the level of 100,000 in five of the nine patients (55.6%) in the control group during the irradiation period, but only one patient in the OK-432 group showed a decrease down to 100,000 counts. Three of the nine patients (33.3%) in the control group had to be stopped irradiation due to the severe leukopenia and thrombocytopenia, in contrast to the OK-432 group, which completed whole axis irradiation without interruption. These results seem to indicate that OK-432 alleviated the myelosuppression induced in patients by whole axis irradiation. This alleviating action of OK-432 is considered to be applicable to the treatment of Medulloblastoma patients.

  8. 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

  9. 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)

  10. 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.

  11. 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.

  12. 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

  13. Comparison of risk of radiogenic second cancer following photon and proton craniospinal irradiation for a pediatric medulloblastoma patient

    Science.gov (United States)

    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.

  14. 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

  15. 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.)

  16. 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.)

  17. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuro-ectodermal tumors: spinal theca irradiation

    International Nuclear Information System (INIS)

    Miralbell, Raymond; Lomax, Anthony; Russo, Mariateresa

    1997-01-01

    Purpose: Conventional postoperative photon-beam radiotherapy to the spine in children with medulloblastoma/PNET is associated with severe late effects. This morbidity (growth and developmental) is related to the exit dose of the beams and is particularly severe in young children. With the purpose of reducing this toxicity, a dosimetric study was undertaken in which proton therapy was compared to standard megavoltage photon treatment. Methods and materials: The results of a comparative dosimetric study are presented in such a way that the dose distribution achievable with a posterior modulated 100 MeV proton beam (spot scanning method) is compared with that of a standard set of posterior 6 MV x-ray fields. The potential improvements with protons are evaluated, using dose-volume histograms to examine the coverage of the target as well as the dose to the vertebral bodies (growth plates), lungs, heart, and liver. Results: The target (i.e., the spinal dural sac) received the full prescribed dose in both treatment plans. However, the proportions of the vertebral body volume receiving ≥50% of the prescribed dose were 100 and 20% for 6 MV x-rays and protons, respectively. For 6 MV x-rays >60% of the dose prescribed to the target was delivered to 44% of the heart volume, while the proton beam was able to completely avoid the heart, the liver, and in all likelihood the thyroid and gonads as well. Conclusion: The present study demonstrates a potential role of proton therapy in decreasing the dose (and toxicity) to the critical structures in the irradiation of the spinal neuraxis in medulloblastoma/PNET. The potential bone marrow and growth arrest sparing effects make this approach specially attractive for intensive chemotherapy protocols and for very young children. Sparing the thyroid gland, the posterior heart wall, and the gonads may be additional advantages in assuring a long-term posttreatment morbidity-free survival

  18. 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.

  19. Multimodality therapy for medulloblastoma

    International Nuclear Information System (INIS)

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

    1980-01-01

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

  20. [Medulloblastoma. Pathology].

    Science.gov (United States)

    Siegfried, A; Delisle, M-B

    2018-04-24

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

  1. Additive effects of 5-Aza-2'-deoxycytidine and irradiation on clonogenic survival of human medulloblastoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Patties, Ina; Jahns, Jutta; Kortmann, Rolf-Dieter; Glasow, Annegret [Dept. of Radiotherapy and Radiooncology, Universitaetsklinikum Leipzig AoeR (Germany); Hildebrandt, Guido [Dept. of Radiotherapy and Radiooncology, Universitaetsklinikum Leipzig AoeR (Germany); Dept. of Radiotherapy, Univ. of Rostock (Germany)

    2009-05-15

    Background and purpose: in recent years, epigenetic modulators were introduced into tumor therapy. Here, the authors investigated the antitumor effect of 5-aza-2'-deoxycytidine-(5-aza-dC-)induced demethylation combined with irradiation on human medulloblastoma (MB) cells, which form the most common malignant brain tumor in children. Material and methods: three MB cell lines were treated with 5-aza-dC in a low-dose (0.1 {mu}M, 6 days) or high-dose (3/5 {mu}M, 3 days) setting and irradiated with 2, 4, 6, or 8 Gy single dose on an X-ray unit. Methylation status and mRNA expression of three candidate genes were analyzed by methylation-specific PCR (polymerase chain reaction) and quantitative real-time RT-PCR. Cell survival and mortality were determined by trypan blue exclusion test. Proliferation was analyzed by BrdU incorporation assay, and long-term cell survival was assessed by clonogenic assay. Results: 5-aza-dC treatment resulted in partial promoter demethylation and increased expression of hypermethylated candidate genes. A significant decrease of vital cell count, proliferation inhibition and increase of mortality was observed in 5-aza-dC-treated as well as in irradiated MB cells, whereby combination of both treatments led to additive effects. Although high-dose 5-aza-dC treatment was more effective in terms of demethylation, clonogenic assay revealed no differences between high- and low-dose settings indicating no relevance of 5-aza-dC-induced demethylation for decreased cell survival. MB cells pretreated with 5-aza-dC showed significantly lower plating efficiencies than untreated cells at all irradiation doses investigated. Analysis of surviving curves in irradiated MB cells, however, revealed no significant differences of {alpha}-, {beta}-values and 2-Gy surviving fraction with or without 5-aza-dC treatment. Conclusion: 5-aza-dC did not enhance radiation sensitivity of MB cells but significantly reduced the clonogenicity versus irradiation alone, which

  2. 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...

  3. 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)

  4. 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.

  5. 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)

  6. 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

  7. The child medulloblastoma in Tunisia

    International Nuclear Information System (INIS)

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

    2000-01-01

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

  8. Critical combinations of radiation dose and volume predict intelligence quotient and academic achievement scores after craniospinal irradiation in children with medulloblastoma.

    Science.gov (United States)

    Merchant, Thomas E; Schreiber, Jane E; Wu, Shengjie; Lukose, Renin; Xiong, Xiaoping; Gajjar, Amar

    2014-11-01

    To prospectively follow children treated with craniospinal irradiation to determine critical combinations of radiation dose and volume that would predict for cognitive effects. Between 1996 and 2003, 58 patients (median age 8.14 years, range 3.99-20.11 years) with medulloblastoma received risk-adapted craniospinal irradiation followed by dose-intense chemotherapy and were followed longitudinally with multiple cognitive evaluations (through 5 years after treatment) that included intelligence quotient (estimated intelligence quotient, full-scale, verbal, and performance) and academic achievement (math, reading, spelling) tests. Craniospinal irradiation consisted of 23.4 Gy for average-risk patients (nonmetastatic) and 36-39.6 Gy for high-risk patients (metastatic or residual disease >1.5 cm(2)). The primary site was treated using conformal or intensity modulated radiation therapy using a 2-cm clinical target volume margin. The effect of clinical variables and radiation dose to different brain volumes were modeled to estimate cognitive scores after treatment. A decline with time for all test scores was observed for the entire cohort. Sex, race, and cerebrospinal fluid shunt status had a significant impact on baseline scores. Age and mean radiation dose to specific brain volumes, including the temporal lobes and hippocampi, had a significant impact on longitudinal scores. Dichotomized dose distributions at 25 Gy, 35 Gy, 45 Gy, and 55 Gy were modeled to show the impact of the high-dose volume on longitudinal test scores. The 50% risk of a below-normal cognitive test score was calculated according to mean dose and dose intervals between 25 Gy and 55 Gy at 10-Gy increments according to brain volume and age. The ability to predict cognitive outcomes in children with medulloblastoma using dose-effects models for different brain subvolumes will improve treatment planning, guide intervention, and help estimate the value of newer methods of irradiation. Copyright © 2014

  9. 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

  10. 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

  11. 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.

  12. 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

  13. 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

  14. Ovarian irradiation in recurrent endometriosis; Irradiation ovarienne pour endometriose refractaire inoperable

    Energy Technology Data Exchange (ETDEWEB)

    Kochbati, L.; Chaari, N.; Besbes, M.; Maalej, M. [Institut Salah-Azaiz, Service de Radiotherapie Carcinologique Tunis (Tunisia); Neji, K.; Ben Amara, F. [Centre de Maternite et de Neonatologie de Tunis, Service B (Tunisia); Ben Romdhane, N.K. [Hopital La-Rabta, Service d' Hematologie, Tunis (Tunisia)

    2005-09-15

    We describe a case of a young woman with a history of an aplastic anaemia in which pelvic radiotherapy was used successfully in the management of a recurrent and inoperable endometriosis. The use of therapeutic pelvic or ovarian irradiation in endometriosis may be considered, when surgical and medical treatments have been exhausted and have failed. (authors)

  15. 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

  16. 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)

  17. 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

  18. 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

  19. 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

  20. Salvage Re-Irradiation for Recurrent Head and Neck Cancer

    International Nuclear Information System (INIS)

    Lee, Nancy; Chan, Kelvin; Bekelman, Justin E.; Zhung, Joanne; Mechalakos, James; Narayana, Ashwatha; Wolden, Suzanne; Venkatraman, Ennapadam S.; Pfister, David; Kraus, Dennis; Shah, Jatin; Zelefsky, Michael J.

    2007-01-01

    Purpose: To present a retrospective review of treatment outcomes for recurrent head and neck (HN) cancer patients treated with re-irradiation (re-RT) at a single medical center. Methods and Materials: From July 1996-September 2005, 105 patients with recurrent HN cancer underwent re-RT at our institution. Sites included were: the neck (n = 21), nasopharynx (n 21), paranasal sinus (n = 18), oropharynx (n = 16), oral cavity (n = 9), larynx (n = 10), parotid (n = 6), and hypopharynx (n = 4). The median prior RT dose was 62 Gy. Seventy-five patients received chemotherapy with their re-RT (platinum-based in the majority of cases). The median re-RT dose was 59.4 Gy. In 74 (70%), re-RT utilized intensity-modulated radiation therapy (IMRT). Results: With a median follow-up of 35 months, 18 patients were alive with no evidence of disease. The 2-year loco-regional progression-free survival (LRPFS) and overall survival rates were 42% and 37%, respectively. Patients who underwent IMRT, compared to those who did not, had a better 2-year LRPF (52% vs. 20%, p < 0.001). On multivariate analysis, non-nasopharynx and non-IMRT were associated with an increased risk of loco-regional (LR) failure. Patients with LR progression-free disease had better 2-year overall survival vs. those with LR failure (56% vs. 21%, p < 0.001). Acute and late Grade 3-4 toxicities were reported in 23% and 15% of patients. Severe Grade 3-4 late complications were observed in 12 patients, with a median time to development of 6 months after re-RT. Conclusions: Based on our data, achieving LR control is crucial for improved overall survival in this patient population. The use of IMRT predicted better LR tumor control. Future aggressive efforts in maximizing tumor control in the recurrent setting, including dose escalation with IMRT and improved chemotherapy, are warranted

  1. 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

  2. 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)

  3. 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

  4. Vaginal vault recurrences of endometrial cancer in non-irradiated patients

    DEFF Research Database (Denmark)

    Hardarson, Hordur Alexander; Nyhøj Heidemann, Lene; Christensen, René dePont

    2015-01-01

    are few and limited to previously irradiated patients or patients with advanced disease. Investigation of surgical treatment for isolated vaginal vault recurrence is practically nonexistent. The aim of this study is to evaluate the efficacy of RT and ST in a non-irradiated group with recurrent endometrial...... cancer limited to the vaginal vault. METHODS: Patients treated for recurrent endometrial cancer at Odense University Hospital, Denmark between 2003 and 2012 were identified, n = 118. Thirty-three patients had an isolated vaginal vault recurrence and were treated with either RT, ST or both. Re...

  5. 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...

  6. Adult medulloblastoma with myogenic differentiation

    Directory of Open Access Journals (Sweden)

    Xia-ling ZHANG

    2015-09-01

    labeling index was about 10% . Pathological diagnosis was medulloblastoma with myogenic differentiation (WHO Ⅳ. The patient was not given further treatment including chemotherapy or radiotherapy after surgery. Nine-month follow-up showed no tumor recurrence.  Conclusions Medulloblastoma is a malignant, invasive embryonal tumor commonly occuring in the cerebellum of children. Medulloblastoma with myogenic differentiation occurs very rarely in adult, which is characterized by containing primitive neuroectodermal and rhabdomyoblastic elements. The diagnosis should be differentiated from central nervous system primitive neuroectodermal tumor (PNET, atypical teratoid/rhabdoid tumor (AT/RT and rhabdomyosarcoma. DOI: 10.3969/j.issn.1672-6731.2015.09.009

  7. 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.

  8. Studies on quantitative characters of pea varieties affected by acute and recurrent gamma irradiation

    International Nuclear Information System (INIS)

    Mazik-Toekei, K.; Fueredi, J.

    1991-01-01

    The influence of acute and recurrent gamma irradiation was investigated on the quantitative characters of Dukat, Paloma, BR 52, Ujmajor early and Marro pea varieties. All five varieties were irradiated with 25, 50, 75 and 100 Gy of gamma rays. The influence of recurrent irradiation was investigated in two and three subsequent generations. Varietal differences in radiation sensitivity were observed. The yield components of different varieties changed under similar dose conditions. The Dukat variety was found to be most sensitive to acute irradiation, so the quantitative characters of Dukat may be improved by using this method. Recurrent irradiation in two subsequent generations was succesful in the Paloma variety while treating three subsequent generations proved to be less succesful in improving yield components than in two generations. (author) 18 refs.; 3 tabs

  9. Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients

    International Nuclear Information System (INIS)

    Haddock, Michael G.; Gunderson, Leonard L.; Nelson, Heidi; Cha, Stephen S.; Devine, Richard M.; Dozois, Roger R.; Wolff, Bruce G.

    2001-01-01

    Purpose: Information in the literature regarding salvage treatment for patients with locally recurrent colorectal cancer who have previously been treated with high or moderate dose external beam irradiation (EBRT) is scarce. A retrospective review was therefore performed in our institution to determine disease control, survival, and tolerance in patients treated aggressively with surgical resection and intraoperative electron irradiation (IOERT) ± additional EBRT and chemotherapy. Methods and Materials: From 1981 through 1994, 51 previously irradiated patients with recurrent locally advanced colorectal cancer without evidence of distant metastatic disease were treated at Mayo Clinic Rochester with surgical resection and IOERT ± additional EBRT. An attempt was made to achieve a gross total resection before IOERT if it could be safely accomplished. The median IOERT dose was 20 Gy (range, 10-30 Gy). Thirty-seven patients received additional EBRT either pre- or postoperatively with doses ranging from 5 to 50.4 Gy (median 25.2 Gy). Twenty patients received 5-fluorouracil ± leucovorin during EBRT. Three patients received additional cycles of 5-fluorouracil ± leucovorin as maintenance chemotherapy. Results: Thirty males and 21 females with a median age of 55 years (range 31-73 years) were treated. Thirty-four patients have died; the median follow-up in surviving patients is 21 months. The median, 2-yr, and 5-yr actuarial overall survivals are 23 months, 48% and 12%, respectively. The 2-yr actuarial central control (within IOERT field) is 72%. Local control at 2 years has been maintained in 60% of patients. There is a trend toward improved local control in patients who received ≥30 Gy EBRT in addition to IOERT as compared to those who received no EBRT or <30 Gy with 2-yr local control rates of 81% vs. 54%. Distant metastatic disease has developed in 25 patients, and the actuarial rate of distant progression at 2 and 4 years is 56% and 76%, respectively. Peripheral

  10. 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)

  11. Pattern of local recurrence after conservative surgery and whole-breast irradiation

    International Nuclear Information System (INIS)

    Freedman, Gary M.; Anderson, Penny R.; Hanlon, Alexandra L.; Eisenberg, Debra F.; Nicolaou, Nicos

    2005-01-01

    Purpose: Most recurrences in the breast after conservative surgery and whole-breast irradiation have been reported to occur within the same quadrant as the initial primary tumor. We analyzed the long-term risk of recurrence by area of the breast after whole-breast irradiation. Materials and Methods: In all, 1,990 women with Stage 0-II breast cancer were treated with conservative surgery and whole-breast irradiation from 1970-1998. Stage was ductal carcinoma in situ in 237, T1 in 1273, and T2 in 480 patients. Of 120 local recurrences, 71 were classified as true local (confined to the original quadrant) and 49 as elsewhere (involving outside the original quadrant). Kaplan-Meier methodology was used to calculate 5-year, 10-year, and 15-year rates of recurrence (95% confidence intervals in parentheses). The median follow-up is 80 months. Results: There was no apparent difference in the 15-year rate of true local vs. elsewhere recurrence, but the time to recurrence was different. The rate of true local recurrence was 2%, 5%, and 7% (5-9%) at 5, 10, and 15 years, respectively. The recurrences elsewhere in the breast were rare at 5 (1%) and 10 (2%) years, but increased to 6 (3-9%) at 15 years. This 15-year rate of elsewhere recurrence was half the rate of contralateral breast cancers of 13% (10-16%). Conclusions: Recurrence elsewhere in the breast is rare for the first 10 years, but by 15 years is nearly equal to true local recurrence even after whole-breast irradiation. The 15-year rate of elsewhere recurrence was half the rate of contralateral breast cancers. This may indicate a therapeutic effect of whole-breast radiation for other areas of the breast. Very long follow-up will be needed for partial breast irradiation with or without tamoxifen to show that the risk of elsewhere recurrence is not significantly different than after whole-breast irradiation

  12. Medulloblastoma: progress over time

    International Nuclear Information System (INIS)

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

    2012-01-01

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

  13. Prognosis in patients with local recurrence after definitive irradiation for prostatic carcinoma

    International Nuclear Information System (INIS)

    Kuban, D.A.; el-Mahdi, A.M.; Schellhammer, P.F.

    1989-01-01

    Of 414 patients with Stage A2-C disease, all with a minimum follow-up period of 3 years, who have been definitively irradiated by external beam therapy or iodine-125 (I-125) implantation for biopsy-proven prostatic adenocarcinoma, 83 patients (20%) have experienced local recurrences. The incidence of distant metastasis was significantly higher in patients with local tumor recurrence (56 of 83; 68%), as compared with those with local control (64 of 331; 19%; P less than 0.001). This difference remained significant within each tumor grade and stage. Subsequently, survival in patients with local recurrence was significantly shorter than in those with local tumor control (66% vs. 89% at 5 years; P = 0.001). Of the 83 patients with local tumor recurrence, 56 had local recurrence and distant metastasis, and 27 had local failure alone, with a median follow-up of 76 months for the latter group. Fifteen of 83 patients with local recurrence (18%) developed major complications secondary to local disease. Three of the 83 (4%) patients were known to die of prostatic recurrence alone and another 11 of 83 (13%) as a result of some combination of local and distant disease. Therefore, in reference to the entire group of definitively irradiated patients, only 0.72% expired solely of complications associated with local tumor recurrence and an additional 2.7% expired of a combination of both local and distant disease

  14. Proton Radiation Therapy for Pediatric Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors: Outcomes for Very Young Children Treated With Upfront Chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Jimenez, Rachel B., E-mail: rbjimenez@partners.org [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Sethi, Roshan [Harvard Medical School, Boston, Massachusetts (United States); Depauw, Nicolas [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Pulsifer, Margaret B. [Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts (United States); Adams, Judith [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); McBride, Sean M. [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Ebb, David [Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts (United States); Fullerton, Barbara C.; Tarbell, Nancy J.; Yock, Torunn I.; MacDonald, Shannon M. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2013-09-01

    Purpose: To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). Methods and Materials: All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. Results: Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients had medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. Conclusions: Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity.

  15. Radiation induced chimeric rearrangement flower structure of Rhododendron simsii Planch. (Azaleaindica L. ) Use of recurrent irradiation

    Energy Technology Data Exchange (ETDEWEB)

    de Loose, R [IWONL (IRSIA) Irradiation Laboratory, Institute of Ornamental Plant Growing, Melle (Belgium)

    1979-02-01

    A radiation-induced chimeric flower colour sport of vegetatively propagated Rhododendron simsii Planch was recurrently irradiated (up to three times in three consecutive years) with soft X-rays (50kV-30mA), as compared to a single treatment. Because of the low true flower colour mutation frequency the efficiency of the different radiation treatments was compared on the basis of the number of chimeric rearrangements in flower structure i.e. the flower colour change from red with broad white edge towards either homogeneous carminered or white. It is quite clear that recurrent irradiation with appropiate doses is most efficient.

  16. Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients

    Energy Technology Data Exchange (ETDEWEB)

    Haddock, M G; Gunderson, L L; Nelson, H; Cha, S; Devine, R M; Dozois, R R; Wolff, B G

    1995-07-01

    Purpose/Objective: Little information exists in the literature on salvage treatment for patients with pelvic recurrences of colorectal cancer who have previously received high dose radiation therapy (RT). A retrospective review of such patients treated aggressively with surgical resection and intraoperative electrons (IOERT) was undertaken. Material and Methods: From 1981 through 1994, 52 previously irradiated patients with recurrent locally advanced colorectal cancer without evidence of distant metastatic disease were treated with surgical resection and intraoperative electrons (IOERT) {+-} additional external beam RT. Every attempt was made to achieve a gross total resection prior to IOERT if it could be safely accomplished. IOERT doses ranged from 1000-3000 cGy with a median of 2000 cGy. 37 patients received additional external beam radiotherapy either pre- or post-operatively with doses ranging from 500-5040 cGy (median 2520 cGy). 20 patients received 5FU {+-} leukovorin during external beam RT. Three patients received 5FU+leukovorin after completion of RT. Results: 31 males and 21 females with a median age of 55 years (range 31-73 years) were treated. 71% of patients have been followed until death or for > 2 years. The median, 2-year and 5-year actuarial overall survival is 23 months, 48% and 13%, respectively. Actuarial central disease control (IOERT field) at 2 and 4 years is 72 and 57%; pelvic control at 2 and 4 years is 60 and 34%. Pelvic control rates are better in patients who received {>=} 3000 cGy external beam RT in addition to IOERT as compared to patients who received no external beam RT or < 3000 cGy, with 2 year pelvic control rates of 81% vs. 54%. 25 patients have developed distant metastases. The actuarial rate of appearance of distant metastatic disease at 2 and 4 years is 60 and 80%. Late complications attributable to IOERT include neuropathies in 13 patients (5 mild, 5 moderate, 3 severe) and narrowing or obstruction of the ureter in four

  17. Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients

    International Nuclear Information System (INIS)

    Haddock, M.G.; Gunderson, L.L.; Nelson, H.; Cha, S.; Devine, R.M.; Dozois, R.R.; Wolff, B.G.

    1995-01-01

    Purpose/Objective: Little information exists in the literature on salvage treatment for patients with pelvic recurrences of colorectal cancer who have previously received high dose radiation therapy (RT). A retrospective review of such patients treated aggressively with surgical resection and intraoperative electrons (IOERT) was undertaken. Material and Methods: From 1981 through 1994, 52 previously irradiated patients with recurrent locally advanced colorectal cancer without evidence of distant metastatic disease were treated with surgical resection and intraoperative electrons (IOERT) ± additional external beam RT. Every attempt was made to achieve a gross total resection prior to IOERT if it could be safely accomplished. IOERT doses ranged from 1000-3000 cGy with a median of 2000 cGy. 37 patients received additional external beam radiotherapy either pre- or post-operatively with doses ranging from 500-5040 cGy (median 2520 cGy). 20 patients received 5FU ± leukovorin during external beam RT. Three patients received 5FU+leukovorin after completion of RT. Results: 31 males and 21 females with a median age of 55 years (range 31-73 years) were treated. 71% of patients have been followed until death or for > 2 years. The median, 2-year and 5-year actuarial overall survival is 23 months, 48% and 13%, respectively. Actuarial central disease control (IOERT field) at 2 and 4 years is 72 and 57%; pelvic control at 2 and 4 years is 60 and 34%. Pelvic control rates are better in patients who received ≥ 3000 cGy external beam RT in addition to IOERT as compared to patients who received no external beam RT or < 3000 cGy, with 2 year pelvic control rates of 81% vs. 54%. 25 patients have developed distant metastases. The actuarial rate of appearance of distant metastatic disease at 2 and 4 years is 60 and 80%. Late complications attributable to IOERT include neuropathies in 13 patients (5 mild, 5 moderate, 3 severe) and narrowing or obstruction of the ureter in four patients

  18. 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)

  19. Reirradiation, surgery and IORT for recurrent rectal cancer in previously irradiated patients

    International Nuclear Information System (INIS)

    Vermaas, Maarten; Nuyttens, Joost J.M.E.; Ferenschild, Floris T.J.; Verhoef, Cornelis; Eggermont, Alexander M.M.; Wilt, Johannes H.W. de

    2008-01-01

    A total of 11 patients with recurrent rectal cancer who had been previously irradiated were treated with preoperative reirradiation (median dose 30 Gy), surgery and IORT. This treatment was related with high morbidity, a short pain-free survival (5 months) and poor local control (27% after 3 years), although some patients have long-term distant control and survival

  20. 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.

  1. Recurrent pneumonias following intrauterine irradiation of the thymus

    International Nuclear Information System (INIS)

    Rieger, H.L.; Eife, R.F.; Muenchen Univ.

    1978-01-01

    A 9 year old girl is described who was born without thyroid function as a result of maternal 131 I treatment during early pregnancy. The patient had 15 pneumonias since her second year of life. Immunological investigations showed normal humoral immunity and a normal in vitro responsiveness of circulating lymphocytes. The patient was, however, anergic to 5 skintest antigens and exhibited a primary vaccination reaction after a smallpox revaccination. The findings suggest that intrauterine irradiation primarily affected memory-lymphocytes. (orig.) [de

  2. Treatment of recurrences in head and neck cancers occurring in irradiated site

    International Nuclear Information System (INIS)

    Pernot, M.

    1994-01-01

    We'll consider as recurrences the elevate relapses occurring at least six months after the first treatment end. The recurrences however frequent it is, is bad codified and everybody does what he can in the presence of a relapse. The number of retreated lesions should be in inverse proportion of the efficiency of the initial treatment. The surgery made large progresses during these last 15 years. The external radiotherapy is seldom a very good treatment indication of head and neck cancer recurrences in previously irradiated site. Iridium 192 wires may be used as implantations with low dose rate. For the cavity proper of mouth, we have counted 159 relapses at the level of the sole primary tumour. The tonsil neoplasms are often treated by a sole external irradiation or in association with curietherapy. For a larynx neoplasm the ideal starting treatment is that one which allows to cure the tumour while protecting the speaking and the swallowing. 83 refs

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

    African Journals Online (AJOL)

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

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

    Science.gov (United States)

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

    2016-04-01

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

  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. 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.

  7. 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.

  8. Intertumoral Heterogeneity within Medulloblastoma Subgroups.

    Science.gov (United States)

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

    2017-06-12

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

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

    Directory of Open Access Journals (Sweden)

    Yukiko Nakahara

    2010-01-01

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

  10. 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.)

  11. c-myc overexpression causes anaplasia in medulloblastoma.

    Science.gov (United States)

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

    2006-01-15

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

  12. Study of hourly and daily solar irradiation forecast using diagonal recurrent wavelet neural networks

    International Nuclear Information System (INIS)

    Cao Jiacong; Lin Xingchun

    2008-01-01

    An accurate forecast of solar irradiation is required for various solar energy applications and environmental impact analyses in recent years. Comparatively, various irradiation forecast models based on artificial neural networks (ANN) perform much better in accuracy than many conventional prediction models. However, the forecast precision of most existing ANN based forecast models has not been satisfactory to researchers and engineers so far, and the generalization capability of these networks needs further improving. Combining the prominent dynamic properties of a recurrent neural network (RNN) with the enhanced ability of a wavelet neural network (WNN) in mapping nonlinear functions, a diagonal recurrent wavelet neural network (DRWNN) is newly established in this paper to perform fine forecasting of hourly and daily global solar irradiance. Some additional steps, e.g. applying historical information of cloud cover to sample data sets and the cloud cover from the weather forecast to network input, are adopted to help enhance the forecast precision. Besides, a specially scheduled two phase training algorithm is adopted. As examples, both hourly and daily irradiance forecasts are completed using sample data sets in Shanghai and Macau, and comparisons between irradiation models show that the DRWNN models are definitely more accurate

  13. Initial results of CyberKnife treatment for recurrent previously irradiated head and neck cancer

    International Nuclear Information System (INIS)

    Himei, Kengo; Katsui, Kuniaki; Yoshida, Atsushi

    2003-01-01

    The purpose of this study was to evaluate the efficacy of CyberKnife for recurrent previously irradiated head and neck cancer. Thirty-one patients with recurrent previously irradiated head and neck cancer were treated with a CyberKnife from July 1999 to March 2002 at Okayama Kyokuto Hospital were retrospectively studied. The accumulated dose was 28-80 Gy (median 60 Gy). The interval between CyberKnife treatment and previous radiotherapy was 0.4-429.5 months (median 16.3 months). Primary lesions were nasopharynx: 7, maxillary sinus: 6, tongue: 5, ethmoid sinus: 3, and others: 1. The pathology was squamous cell carcinoma: 25, adenoid cystic carcinoma: 4, and others: 2. Symptoms were pain: 8, and nasal bleeding: 2. The prescribed dose was 15.0-40.3 Gy (median 32.3 Gy) as for the marginal dose. The response rate (complete response (CR)+partial response (PR)) and local control rate (CR+PR+no change (NC)) was 74% and 94% respectively. Pain disappeared for 4 cases, relief was obtained for 4 cases and no change for 2 cases and nasal bleeding disappeared for 2 cases for an improvement of symptoms. An adverse effects were observed as mucositis in 5 cases and neck swelling in one case. Prognosis of recurrent previously irradiated head and neck cancer was estimated as poor. Our early experience shows that CyberKnife is expected to be feasible treatment for recurrent previously irradiated head and neck cancer, and for the reduction adverse effects and maintenance of useful quality of life (QOL) for patients. (author)

  14. Local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer.

    Science.gov (United States)

    Kimoto, Takuya; Yamazaki, Hideya; Suzuki, Gen; Aibe, Norihiro; Masui, Koji; Tatekawa, Kotoha; Sasaki, Naomi; Fujiwara, Hitoshi; Shiozaki, Atsushi; Konishi, Hirotaka; Nakamura, Satoaki; Yamada, Kei

    2017-09-01

    Radiotherapy is an effective treatment for the postoperative loco-regional recurrence of esophageal cancer; however, the optimal treatment field remains controversial. This study aims to evaluate the outcome of local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer. We retrospectively investigated 35 patients treated for a postoperative loco-regional recurrence of esophageal cancer with local field radiotherapy between December 2008 and March 2016. The median irradiation dose was 60 Gy (range: 50-67.5 Gy). Thirty-one (88.6%) patients received concurrent chemotherapy. The median follow-up period was 18 months (range: 5-94 months). The 2-year overall survival was 55.7%, with a median survival time of 29.9 months. In the univariate analysis, the maximal diameter ≤20 mm (P = 0.0383), solitary lesion (P = 0.0352), and the complete remission after treatment (P = 0.00411) had a significantly better prognosis. A total of 27 of 35 patients (77.1%) had progressive disease (loco-regional failure [n = 9], distant metastasis [n = 7], and both loco-regional failure and distant metastasis [n = 11]). No patients had Grade 3 or greater mucositis. Local field radiotherapy is a considerable treatment option for postoperative loco-regional recurrence of esophageal cancer. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  15. 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.

  16. Anaplasia and grading in medulloblastomas.

    Science.gov (United States)

    Eberhart, Charles G; Burger, Peter C

    2003-07-01

    The variable clinical outcomes of medulloblastoma patients have prompted a search for markers with which to tailor therapies to individuals. In this review, we discuss clinical, histological and molecular features that can be used in such treatment customization, focusing on how histopathological grading can impact both patient care and research on the molecular basis of CNS embryonal tumors. Medulloblastomas span a histological spectrum ending in overtly malignant large cell/anaplastic lesions characterized by increased nuclear size, marked cytological anaplasia, and increased mitotic and apoptotic rates. These "high-grade" lesions make up approximately one quarter of medulloblastomas, and recur and metastasize more frequently than tumors lacking anaplasia. We believe anaplastic change represents a type of malignant progression common to many medulloblastoma subtypes and to other CNS embryonal lesions as well. Correlation of these histological changes with the accumulation of genetic events suggests a model for the histological and molecular progression of medulloblastoma.

  17. 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.)

  18. Re-irradiation and hyperthermia after surgery for recurrent breast cancer

    International Nuclear Information System (INIS)

    Linthorst, Marianne; Geel, Albert N. van; Baaijens, Margreet; Ameziane, Ali; Ghidey, Wendim; Rhoon, Gerard C. van; Zee, Jacoba van der

    2013-01-01

    Purpose: Evaluation of efficacy and side effects of combined re-irradiation and hyperthermia electively or for subclinical disease in the management of locoregional recurrent breast cancer. Methods and materials: Records of 198 patients with recurrent breast cancer treated with re-irradiation and hyperthermia from 1993 to 2010 were reviewed. Prior treatments included surgery (100%), radiotherapy (100%), chemotherapy (42%), and hormonal therapy (57%). Ninety-one patients were treated for microscopic residual disease following resection or systemic therapy and 107 patients were treated electively for areas at high risk for local recurrences. All patients were re-irradiated to 28–36 Gy (median 32) and treated with 3–8 hyperthermia treatments (mean 4.36). Forty percent of the patients received concurrent hormonal therapy. Patient and tumor characteristics predictive for actuarial local control (LC) and toxicity were studied in univariate and multivariate analysis. Results: The median follow-up was 42 months. Three and 5 year LC-rates were 83% and 78%. Mean of T90 (tenth percentile of temperature distribution), maximum and average temperatures were 39.8 °C, 43.6 °C, and 41.2 °C, respectively. Mean of the cumulative equivalent minutes (CEM43) at T90 was 4.58 min. Number of previous chemotherapy and surgical procedures were most predictive for LC. Cumulative incidence of grade 3 and 4 late toxicity at 5 years was 11.9%. The number of thermometry sensors and depth of treatment volume were associated with acute hyperthermia toxicity. Conclusions: The combination of re-irradiation and hyperthermia results in a high LC-rate with acceptable toxicity

  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. Total lymphoid irradiation in the treatment of early or recurrent heart transplant rejection

    International Nuclear Information System (INIS)

    Salter, Susan P.; Salter, Merle M.; Kirklin, James K.; Bourge, Robert C.; Naftel, David C.

    1995-01-01

    Purpose: Recurrent acute cardiac allograft rejection is an important cause of repeat hospitalization and a major mode of mortality, particularly during the 6 months immediately following transplant. Total lymphoid irradiation (TLI) has been shown experimentally to induce a state of partial tolerance when administered prior to transplantation. Anecdotal reports of clinical experience have also suggested efficacy of TLI in treatment of recurrent cardiac rejection. The purpose of this study is to evaluate the safety and efficacy of TLI for treatment of early or recurrent heart transplant rejection. Materials and Methods: Between January 1990 and June 1992, 49 patients postallograft cardiac transplant were given courses of TLI for treatment of early or recurrent rejection after conventional therapy with Methylprednisolone, antithymocyte globulin, OKT3, and methotrexate. Two patients failed to complete their therapy and were not evaluated. Two other patients received a second TLI course, making a total of 49 courses delivered. Indications for TLI were early rejection (n = 5), recurrent rejection (n = 38), and recurrent rejection with vasculitis (n = 6). The dose goal of the TLI protocol was 8 Gy in 10 fractions given twice weekly. Three separate fields were used to encompass all major lymph node-bearing areas. The actual mean dose was 7 Gy (range 2.4-8.4 Gy), and the duration of treatment was 8 to 106 days. These variations were secondary to leukopenia or thrombocytopenia. Results: The mean posttransplant follow-up is 15 ± 1.2 months (maximum 27 months). Among patients initiating TLI within 1 month posttransplant (n = 15), the rejection frequency decreased from 1.83 episodes/patient/month pre-TLI to 0.13 episodes/patient/month post-TLI (p < 0.0001). For those who began TLI 1-3 months after transplant (n = 21), rejection decreased from 1.43 to 0.10 episodes/patient/month (p < 0.0001). When TLI was started more than 3 months posttransplant (n = 11), the pre-TLI and post

  1. Hyperthermia of locally advanced or recurrent gynecological cancer. The effect of combination with irradiation or chemotherapy

    International Nuclear Information System (INIS)

    Terashima, Hiromi; Imada, Hajime; Egashira, Kanji; Nakata, Hajime; Kunugita, Naoki; Matsuura, Yuusuke; Kashimura, Masamichi

    1995-01-01

    Between May 1986 and April 1994, 15 patients with advanced or recurrent gynecological cancer were treated with combined therapy of hyperthermia and irradiation or chemotherapy at UOEH Hospital. Initial cases were treated by hyperthermia combined with irradiation in 4 and with chemotherapy in 2. Recurrent 9 cases were treated by hyperthermia combined with chemotherapy or by hyperthermia alone. Radiotherapy was given in a conventional way 5 fractions per week and hyperthermia was performed using RF capacitive heating equipment, Thermotron RF-8, once or twice a week. Intratumoral temperature was measured by thermocouple inserted into the tumor and kept at 42-44degC for 30-40 minutes. Complete response (CR) and partial response (PR), defined as 50% or more regression, was obtained in 8/15 (53%). Response rates (CR+PR/all cases) were good in initially treated cases (5/6, 83%), irradiated cases (7/8, 88%) and cases hearted over 42degC (7/9, 78%). Combined therapy of hyperthermia and radiotherapy seemed to be useful for controlling advanced gynecological cancers. (author)

  2. Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors

    Science.gov (United States)

    2017-09-27

    Childhood Choroid Plexus Tumor; Childhood Ependymoblastoma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor

  3. Re-irradiation of recurrent esophageal cancer after primary definitive radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young Suk; Lee, Chang Geol; Kim, Kyung Hwan; Kim, Tae Hyung [Dept. of Radiation Oncology, Yonsei University Health System, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2012-12-15

    For recurrent esophageal cancer after primary definitive radiotherapy, no general treatment guidelines are available. We evaluated the toxicities and clinical outcomes of re-irradiation (re-RT) for recurrent esophageal cancer. We analyzed 10 patients with recurrent esophageal cancer treated with re-RT after primary definitive radiotherapy. The median time interval between primary radiotherapy and re-RT was 15.6 months (range, 4.8 to 36.4 months). The total dose of primary radiotherapy was a median of 50.4 Gy (range, 50.4 to 63.0 Gy). The total dose of re-RT was a median of 46.5 Gy (range, 44.0 to 50.4 Gy). The median follow-up period was 4.9 months (range, 2.6 to 11.4 months). The tumor response at 3 months after the end of re-RT was complete response (n = 2), partial response (n = 1), stable disease (n = 2), and progressive disease (n = 5). Grade 5 tracheoesophageal fistula developed in three patients. The time interval between primary radiotherapy and re-RT was less than 12 months in two of these three patients. Late toxicities included grade 1 dysphagia (n = 1). Re-RT of recurrent esophageal cancer after primary radiotherapy can cause severe toxicity.

  4. Re-irradiation of recurrent esophageal cancer after primary definitive radiotherapy

    International Nuclear Information System (INIS)

    Kim, Young Suk; Lee, Chang Geol; Kim, Kyung Hwan; Kim, Tae Hyung

    2012-01-01

    For recurrent esophageal cancer after primary definitive radiotherapy, no general treatment guidelines are available. We evaluated the toxicities and clinical outcomes of re-irradiation (re-RT) for recurrent esophageal cancer. We analyzed 10 patients with recurrent esophageal cancer treated with re-RT after primary definitive radiotherapy. The median time interval between primary radiotherapy and re-RT was 15.6 months (range, 4.8 to 36.4 months). The total dose of primary radiotherapy was a median of 50.4 Gy (range, 50.4 to 63.0 Gy). The total dose of re-RT was a median of 46.5 Gy (range, 44.0 to 50.4 Gy). The median follow-up period was 4.9 months (range, 2.6 to 11.4 months). The tumor response at 3 months after the end of re-RT was complete response (n = 2), partial response (n = 1), stable disease (n = 2), and progressive disease (n = 5). Grade 5 tracheoesophageal fistula developed in three patients. The time interval between primary radiotherapy and re-RT was less than 12 months in two of these three patients. Late toxicities included grade 1 dysphagia (n = 1). Re-RT of recurrent esophageal cancer after primary radiotherapy can cause severe toxicity.

  5. Evaluation of lens dose in medulloblastoma radiotherapy

    International Nuclear Information System (INIS)

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

    2007-01-01

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

  6. Time distributions of recurrences of immunogenic and nonimmunogenic tumors following local irradiation

    International Nuclear Information System (INIS)

    Suit, H.D.; Sedlacek, R.; Fagundes, L.; Goitein, M.; Rothman, K.J.

    1978-01-01

    Three hundred and fourteen mice received single-dose irradiation of the right leg and thigh as treatment of an 8-mm mammary carcinoma isotransplant, and were then observed until death, usually by 1000 days. The time distributions of death due to local recurrence, radiation-induced sarcoma, distant metastasis in the absence of local regrowth, second primary, intercurrent disease, and unknown causes have been evaluated. The times for the transplant tumor inoculum to grow to an 8-mm tumor and the times of death due to local regrowth, distant metastasis, or induced tumor were all approximately log-normally distributed. Of the 128 recurrences, the latest-appearing 3 were at 300, 323, and 436 days; no recurrences were noted during the time period from 436 to 1000 days. These findings have been interpreted to mean that in some cases absolute cure of mice of the tumor in the leg was achieved by radiation alone at the dose levels employed. Radiation-induced sarcomas began to appear after 300 days. The time of appearance of the radiation-induced tumors was inversely related to radiation dose. Similar data for an immunogenic fibrosarcoma show that recurrences appeared earlier and were more closely bunched with respect to time than the recurrences of mammary carcinoma. The time distribution of the development of radiation-induced tumors in non-tumor-bearing animals was also approximately long-normally distributed; the slope of the time distribution curve was the same as that for radiation-induced tumors in mice which had been treated for tumor

  7. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  9. The Use of Re-irradiation in Locally Recurrent, Non-metastatic Rectal Cancer.

    Science.gov (United States)

    Susko, Matthew; Lee, Jason; Salama, Joseph; Thomas, Samantha; Uronis, Hope; Hsu, David; Migaly, John; Willett, Christopher; Czito, Brian; Palta, Manisha

    2016-10-01

    The optimal approach to patients with locally recurrent, non-metastatic rectal cancer is unclear. This study evaluates the outcomes and toxicity associated with pelvic re-irradiation. Patients undergoing re-irradiation for locally recurrent, non-metastatic, rectal cancer between 2000 and 2014 were identified. Acute and late toxicities were assessed using common terminology criteria for adverse events version 4.0. Disease-related endpoints included palliation of local symptoms, surgical outcomes, and local progression-free survival (PFS), distant PFS and overall survival (OS) using the Kaplan-Meier method. Thirty-three patients met the criteria for inclusion in this study. Two (6 %) experienced early grade 3+ toxicity and seven (21 %) experienced late grade 3+ toxicity. Twenty-three patients presented with symptomatic local recurrence and 18 (78 %) reported symptomatic relief. Median local PFS was 8.7 (95 % CI 3.8-15.2) months, with a 2-year rate of 15.7 % (4.1-34.2), and median time to distant progression was 4.4 (2.2-33.3) months, with a 2-year distant PFS rate of 38.9 % (20.1-57.3). Median OS time for patients was 23.1 (11.1-33.0) months. Of the 14 patients who underwent surgery, median survival was 32.3 (13.8-48.0) months compared with 13.3 (2.2-33.0) months in patients not undergoing surgery (p = 0.10). A margin-negative (R0) resection was achieved in 10 (71 %) of the surgeries. Radiation treatment modality (intensity-modulated radiation therapy, three-dimensional conformal radiotherapy, intraoperative radiation therapy) did not influence local or distant PFS or OS. Re-irradiation is a beneficial treatment modality for the management of locally recurrent, non-metastatic rectal cancer. It is associated with symptom improvement, low rates of toxicity, and similar benefits among radiation modalities.

  10. Re-irradiation of recurrent anaplastic ependymoma using radiosurgery or fractionated stereotactic radiotherapy.

    Science.gov (United States)

    Murai, Taro; Sato, Kengo; Iwabuchi, Michio; Manabe, Yoshihiko; Ogino, Hiroyuki; Iwata, Hiromitsu; Tatewaki, Koshi; Yokota, Naoki; Ohta, Seiji; Shibamoto, Yuta

    2016-03-01

    Recurrent ependymomas were retreated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). The efficacy, toxicities, and differences between SRS and FSRT were analyzed. Eight patients with recurrent ependymomas fulfilling the criteria described below were evaluated. Inclusion criteria were: (1) the patient had previously undergone surgery and conventional radiotherapy as first-line treatment; (2) targets were located in or adjacent to the eloquent area or were deep-seated; and (3) the previously irradiated volume overlapped the target lesion. FSRT was delivered to 18 lesions, SRS to 20 lesions. A median follow-up period was 23 months. The local control rate was 76 % at 3 years. No significant differences in local control were observed due to tumor size or fractionation schedule. Lesions receiving >25 Gy/5 fr or 21 Gy/3 fr did not recur within 1 year, whereas no dose-response relationship was observed in those treated with SRS. No grade ≥2 toxicity was observed. Our treatment protocol provided an acceptable LC rate and minimal toxicities. Because local recurrence of tumors may result in patient death, a minimum dose of 21 Gy/3 fr or 25 Gy/5 fr or higher may be most suitable for treatment of these cases.

  11. Safety and Efficacy of Bevacizumab With Hypofractionated Stereotactic Irradiation for Recurrent Malignant Gliomas

    International Nuclear Information System (INIS)

    Gutin, Philip H.; Iwamoto, Fabio M.; Beal, Kathryn; Mohile, Nimish A.; Karimi, Sasan; Hou, Bob L.; Lymberis, Stella; Yamada, Yoshiya; Chang, Jenghwa

    2009-01-01

    Purpose: Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination in malignant gliomas. Methods and Materials: After prior treatment with standard radiation therapy patients with recurrent glioblastoma (GBM) and anaplastic gliomas (AG) received bevacizumab (10 mg/kg intravenous) every 2 weeks of 28-day cycles until tumor progression. Patients also received 30 Gy of hypofractionated stereotactic radiotherapy (HFSRT) in five fractions after the first cycle of bevacizumab. Results: Twenty-five patients (20 GBM, 5 AG; median age 56 years; median Karnofsky Performance Status 90) received a median of seven cycles of bevacizumab. One patient did not undergo HFSRT because overlap with prior radiotherapy would exceed the safe dose allowed to the optic chiasm. Three patients discontinued treatment because of Grade 3 central nervous system intratumoral hemorrhage, wound dehiscence, and bowel perforation. Other nonhematologic and hematologic toxicities were transient. No radiation necrosis was seen in these previously irradiated patients. For the GBM cohort, overall response rate was 50%, 6-month progression-free survival was 65%; median overall survival was 12.5 months, and 1-year survival was 54%. Discussion: Bevacizumab with HFSRT is safe and well tolerated. Radiographic responses, duration of disease control, and survival suggest that this regimen is active in recurrent malignant glioma.

  12. 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

  13. 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

  14. 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.

  15. Locoregional recurrences following radical external beam irradiation and interstitial implantation for operable breast cancer - a twenty three year experience

    International Nuclear Information System (INIS)

    Leung, S.; Otmezguine, Y.; Calitchi, E.; Mazeron, J.J.; Le Bourgeois, J.P.; Pierquin, B.

    1986-01-01

    Locoregional recurrences are reported in 493 consecutive with T1 T2 N0 N1 breast cancer patients who were treated with radical external beam irradiation and interstitial 192 Ir implant between 1961 and 1979. Follow-up ranges from 5-23 years (mean 10 years) with 195 patients having 10-23 years follow up (mean 12 years). There were 51 (10%) locoregional recurrences with 34 mammary, 14 combined mammary/axillary and 3 isolated axillary recurrences. The 10 year relapse rate was 20/195 (10%). The results have been compared with other series in the literature and changes in the authors' current protocol are described. (Auth.)

  16. Predictors of Local Recurrence Following Accelerated Partial Breast Irradiation: A Pooled Analysis

    International Nuclear Information System (INIS)

    Shah, Chirag; Wilkinson, John Ben; Lyden, Maureen; Beitsch, Peter; Vicini, Frank A.

    2012-01-01

    Purpose: To analyze a pooled set of nearly 2,000 patients treated on the American Society of Breast Surgeons (ASBS) Mammosite Registry Trial and at William Beaumont Hospital (WBH) to identify factors associated with local recurrence following accelerated partial breast irradiation (APBI). Methods and Materials: A total of 1,961 women underwent partial breast irradiation between April 1993 and November 2010 as part of the ASBS Registry Trial or at WBH. Rates of ipsilateral breast tumor recurrence (IBTR), regional recurrence (RR), distant metastases (DM), disease-free survival (DFS), cause-specific survival (CSS), and overall survival (OS) were analyzed for each group and for the pooled cohort. Clinical, pathologic, and treatment-related variables were analyzed including age, tumor stage/size, estrogen receptor status, surgical margins, and lymph node status to determine their association with IBTR. Results: The two groups weres similar, but WBH patients were more frequently node positive, had positive margins, and were less likely to be within the American Society for Radiation Oncology-unsuitable group. At 5 years, the rates of IBTR, RR, DM, DFS, CSS, and OS for the pooled group of patients were 2.9%, 0.5%, 2.4%, 89.1%, 98.5%, and 91.8%, respectively. The 5-year rate of true recurrence/marginal miss was 0.8%. Univariate analysis of IBTR found that negative estrogen receptor status (odds ratio [OR], 2.83, 95% confidence interval 1.55–5.13, p = 0.0007) was the only factor significantly associated with IBTR, while a trend was seen for age less than 50 (OR 1.80, 95% confidence interval 0.90–3.58, p = 0.10). Conclusions: Excellent 5-year outcomes were seen following APBI in over 1,900 patients. Estrogen receptor negativity was the only factor associated with IBTR, while a trend for age less than 50 was noted. Significant differences in factors associated with IBTR were noted between cohorts, suggesting that factors driving IBTR may be predicated based on the risk

  17. Optimizing the radiation therapy dose prescription for pediatric medulloblastoma: Minimizing the life years lost attributable to failure to control the disease and late complication risk

    DEFF Research Database (Denmark)

    Brodin, N. Patrik; Vogelius, Ivan R.; Bjork-Eriksson, Thomas

    2014-01-01

    Background. A mathematical framework is presented for simultaneously quantifying and evaluating the trade-off between tumor control and late complications for risk-based radiation therapy (RT) decision-support. To demonstrate this, we estimate life years lost (LYL) attributable to tumor recurrence...... is important, with 0.75 LYL (95% CI 0.60-7.2 years) for standard uniform 24 Gy CS irradiation. However, recurrence risk dominates the total LYL with 14.2 years (95% CI 13.4-16.6 years). Compared to standard treatment, a risk-adapted strategy prescribing 12 Gy to the spinal volume encompassing the 1st-10th......, late cardiac toxicity and secondary cancers for standard-risk pediatric medulloblastoma (MB) patients and compare the effect of dose re-distribution on a common scale. Methods. Total LYL were derived, based on the LYL attributable to radiation-induced late complications and the LYL from not controlling...

  18. 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

  19. Intrathecal chemotherapy for refractory disseminated medulloblastoma.

    Science.gov (United States)

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

    2008-05-01

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

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    Abhimanyu Ghose MD

    2014-04-01

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

  2. 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.

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

    Science.gov (United States)

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

    2012-04-01

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

  4. 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

  5. Re-irradiation for oligo-recurrence from esophageal cancer with radiotherapy history: a multi-institutional study.

    Science.gov (United States)

    Jingu, Keiichi; Niibe, Yuzuru; Yamashita, Hideomi; Katsui, Kuniaki; Matsumoto, Toshihiko; Nishina, Tomohiro; Terahara, Atsuro

    2017-09-05

    Neoadjuvant chemoradiotherapy following surgery has recently become a standard therapy. The purpose of the present study was to determine the effectiveness and toxicity of re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy. We reviewed retrospectively 248 patients treated with (chemo)radiotherapy for oligo-recurrence in lymph nodes from esophageal cancer in five Japanese high-volume centers between 2000 and 2015. Thirty-three patients in whom re-irradiation was performed were enrolled in this study, and the results for patients in whom re-irradiation was performed were compared with the results for other patients. Median maximum lymph node diameter was 22 mm. Median total radiation dose was 60 Gy. The median calculated biological effective dose using the LQ model with α/β = 10 Gy (BED10) in patients in whom re-irradiation was performed was significantly lower than the median BED10 in others. There was no different factor except for BED10, histology and irradiation field between patients with a past irradiation history and patients without a past irradiation history. The median observation period in surviving patients in whom re-irradiation was performed was 21.7 months. The 3-year overall survival rate in the 33 patients with a past irradiation history was 17.9%, with a median survival period of 16.0 months. Overall survival rate and local control rate in patients with a past irradiation history were significantly worse than those in patients without a past irradiation history (log-rank test, p = 0.016 and p = 0.0007, respectively). One patient in whom re-irradiation was performed died from treatment-related gastric hemorrhage. Results in the present study suggested that re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy might be acceptable but

  6. Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma

    Energy Technology Data Exchange (ETDEWEB)

    Combs, Stephanie E.; Welzel, Thomas; Debus, Juergen [Univ. Hospital of Heidelberg, Dept. of Radiation Oncology, Heidelberg (Germany)], E-mail: Stephanie.combs@med.uni-heidelberg.de; Edler, Lutz; Rausch, Renate [German Cancer Research Center (dkfz), Dept. of Biostatistics, Heidelberg (Germany); Wick, Wolfgang [Univ. Hospital of Heidelberg, Dept. of Neurooncology, Heidelberg (Germany)

    2013-01-15

    Re-irradiation using high-precision radiation techniques has been established within the clinical routine for patients with recurrent gliomas. In the present work, we developed a practical prognostic score to predict survival outcome after re-irradiation. Patients and methods. Fractionated stereotactic radiotherapy (FSRT) was applied in 233 patients. Primary histology included glioblastoma (n = 89; 38%), WHO Grade III gliomas (n = 52; 22%) and low-grade glioma (n = 92; 40%). FSRT was applied with a median dose of 36 Gy in 2 Gy single fractions. We evaluated survival after re-irradiation as well as progression-free survival after re-irradiation; prognostic factors analyzed included age, tumor volume at re-irradiation, histology, time between initial radiotherapy and re-irradiation, age and Karnofsky Performance Score. Results. Median survival after FSRT was 8 months for glioblastoma, 20 months for anaplastic gliomas, and 24 months for recurrent low-grade patients. The strongest prognostic factors significantly impacting survival after re-irradiation were histology (p <0.0001) and age (<50 vs. ={>=}50, p < 0.0001) at diagnosis and the time between initial radiotherapy and re-irradiation {<=}12 vs. >12 months (p < 0.0001). We generated a four-class prognostic score to distinguish patients with excellent (0 points), good (1 point), moderate (2 points) and poor (3-4 points) survival after re-irradiation. The difference in outcome was highly significant (p < 0.0001). Conclusion. We generated a practical prognostic score index based on three clinically relevant factors to predict the benefit of patients from re-irradiation. This score index can be helpful in patient counseling, and for the design of further clinical trials. However, individual treatment decisions may include other patient-related factors not directly influencing outcome.

  7. 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)

  8. Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma

    International Nuclear Information System (INIS)

    Combs, Stephanie E.; Welzel, Thomas; Debus, Juergen; Edler, Lutz; Rausch, Renate; Wick, Wolfgang

    2013-01-01

    Re-irradiation using high-precision radiation techniques has been established within the clinical routine for patients with recurrent gliomas. In the present work, we developed a practical prognostic score to predict survival outcome after re-irradiation. Patients and methods. Fractionated stereotactic radiotherapy (FSRT) was applied in 233 patients. Primary histology included glioblastoma (n = 89; 38%), WHO Grade III gliomas (n = 52; 22%) and low-grade glioma (n = 92; 40%). FSRT was applied with a median dose of 36 Gy in 2 Gy single fractions. We evaluated survival after re-irradiation as well as progression-free survival after re-irradiation; prognostic factors analyzed included age, tumor volume at re-irradiation, histology, time between initial radiotherapy and re-irradiation, age and Karnofsky Performance Score. Results. Median survival after FSRT was 8 months for glioblastoma, 20 months for anaplastic gliomas, and 24 months for recurrent low-grade patients. The strongest prognostic factors significantly impacting survival after re-irradiation were histology (p 12 months (p < 0.0001). We generated a four-class prognostic score to distinguish patients with excellent (0 points), good (1 point), moderate (2 points) and poor (3-4 points) survival after re-irradiation. The difference in outcome was highly significant (p < 0.0001). Conclusion. We generated a practical prognostic score index based on three clinically relevant factors to predict the benefit of patients from re-irradiation. This score index can be helpful in patient counseling, and for the design of further clinical trials. However, individual treatment decisions may include other patient-related factors not directly influencing outcome.

  9. 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 ...

  10. 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

  11. 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.)

  12. 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

  13. Feasibility of carbon-ion radiotherapy for re-irradiation of locoregionally recurrent, metastatic, or secondary lung tumors.

    Science.gov (United States)

    Hayashi, Kazuhiko; Yamamoto, Naoyoshi; Karube, Masataka; Nakajima, Mio; Tsuji, Hiroshi; Ogawa, Kazuhiko; Kamada, Tadashi

    2018-03-02

    Intrathoracic recurrence after carbon-ion radiotherapy for primary or metastatic lung tumors remains a major cause of cancer-related deaths. However, treatment options are limited. Herein, we report on the toxicity and efficacy of re-irradiation with carbon-ion radiotherapy for locoregionally recurrent, metastatic, or secondary lung tumors. Data of 95 patients with prior intrathoracic carbon-ion radiotherapy who were treated with re-irradiation with carbon-ion radiotherapy at our institution between 2006 and 2016 were retrospectively analyzed. Seventy-three patients (76.8%) had primary lung tumors and 22 patients (23.2%) had metastatic lung tumors. The median dose of initial carbon-ion radiotherapy was 52.8 Gy (relative biological effectiveness) and the median dose of re-irradiation was 66.0 Gy (relative biological effectiveness). None of the patients received concurrent chemotherapy. The median follow-up period after re-irradiation was 18 months. In terms of grade ≥3 toxicities, one patient experienced each of the following: grade 5 bronchopleural fistula, grade 4 radiation pneumonitis, grade 3 chest pain, and grade 3 radiation pneumonitis. The 2-year local control and overall survival rates were 54.0% and 61.9%, respectively. In conclusion, re-irradiation with carbon-ion radiotherapy was associated with relatively low toxicity and moderate efficacy. Re-irradiation with carbon-ion radiotherapy might be an effective treatment option for patients with locoregionally recurrent, metastatic, or secondary lung tumors. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  14. Re-irradiation with 36 Gy (1.5 Gy Twice Daily) Plus Paclitaxel for Advanced Recurrent and Previously Irradiated SCCHN is Feasible.

    Science.gov (United States)

    Rades, Dirk; Bartscht, Tobias; Idel, Christian; Hakim, Samer G

    2018-01-01

    Many patients developing a loco-regional recurrence of squamous cell carcinoma of head and neck (SCCHN) have a poor prognosis. Often, recurrences are unresectable, and patients require a second course of radiotherapy or chemoradiation. We present an approach of chemoradiation including mainly 30 Gy of radiotherapy (1.5 Gy twice daily) plus concurrent paclitaxel. To further improve the prognoses of these patients, we increased the radiation dose from 30 to 36 Gy. In four patients with recurrent and previously irradiated SCCHN (60-70 Gy) chemoradiation was carried out using 36 Gy (1.5 Gy twice daily) and concurrent paclitaxel (4-5 times 20-25 mg/m 2 ). One-year loco-regional control rates were 75% inside and 67% outside re-irradiated regions. One-year survival was 50%, and median survival time 11 months. Toxicities were mild (grade 0-2). Re-irradiation with 36 Gy (1.5 Gy twice daily) plus paclitaxel appears feasible and may lead to promising outcomes. This study is preceding a phase I trial. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  15. Clinical potential of boron neutron capture therapy for locally recurrent inoperable previously irradiated head and neck cancer

    International Nuclear Information System (INIS)

    Lim, Diana; Quah, Daniel SC; Leech, Michelle; Marignol, Laure

    2015-01-01

    This review compares the safety and efficacy of boron neutron capture therapy (BNCT) in the treatment of previously irradiated, inoperable locoregional recurrent HNC patients and compares BNCT against the standard treatment of platinum-based chemotherapy. Our analysis of published clinical trials highlights efficacy of BNCT associated with mild side effects. However, the use of BNCT should be explored in stratified randomised trials. - Highlights: • BNCT can prolong median overall survival. • BNCT can be associated with severe adverse effects. • BNCT may be comparable to chemotherapy-based regimens. • BNCT may be comparable to re-irradiation techniques regimens in patients with low performance status.

  16. 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

  17. Clinical Impact of Re-irradiation with Carbon-ion Radiotherapy for Lymph Node Recurrence of Gynecological Cancers.

    Science.gov (United States)

    Shiba, Shintaro; Okonogi, Noriyuki; Kato, Shingo; Wakatsuki, Masaru; Kobayashi, Daijiro; Kiyohara, Hiroki; Ohno, Tatsuya; Karasawa, Kumiko; Nakano, Takashi; Kamada, Tadashi

    2017-10-01

    To evaluate the safety and efficacy of re-irradiation with carbon-ion radiotherapy (C-ion RT) for lymph node recurrence of gynecological cancers after definitive radiotherapy. Data regarding patients with unresectable and isolated recurrent lymph node from gynecological cancer after definitive radiotherapy were analyzed. Total dose of C-ion RT was 48-57.6 Gy (RBE) in 12 or 16 fractions. Sixteen patients received re-irradiation by C-ion RT were analyzed. Median follow-up was 37 months. Median tumor size was 27 mm. None developed Grade 1 or higher acute toxicities and Grade 3 or higher late toxicities. The 3-year overall survival, local control and disease-free survival rates after C-ion RT were 74%, 94% and 55%, respectively. Re-irradiation with C-ion RT for lymph node recurrence of gynecological cancers after definitive radiotherapy can be safe and effective. This result suggested that C-ion RT could be a curative treatment option for conventionally difficult-to-cure patients. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  18. 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...

  19. 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

  20. Re-irradiation after gross total resection of recurrent glioblastoma. Spatial pattern of recurrence and a review of the literature as a basis for target volume definition

    Energy Technology Data Exchange (ETDEWEB)

    Straube, Christoph; Elpula, Greeshma [Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Klinikum rechts der Isar, Muenchen (Germany); Gempt, Jens; Gerhardt, Julia; Meyer, Bernhard [Technische Universitaet Muenchen (TUM), Department of Neurosurgery, Klinikum rechts der Isar, Muenchen (Germany); Bette, Stefanie; Zimmer, Claus [Technische Universitaet Muenchen (TUM), Department of Neuroradiology, Klinikum rechts der Isar, Muenchen (Germany); Schmidt-Graf, Friederike [Technische Universitaet Muenchen (TUM), Department of Neurology, Klinikum rechts der Isar, Muenchen (Germany); Combs, Stephanie E. [Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Klinikum rechts der Isar, Muenchen (Germany); Helmholtz Zentrum Muenchen, Institute for Innovative Radiotherapy (iRT), Department of Radiation Sciences (DRS), Oberschleissheim (Germany)

    2017-11-15

    Currently, patients with gross total resection (GTR) of recurrent glioblastoma (rGBM) undergo adjuvant chemotherapy or are followed up until progression. Re-irradiation, as one of the most effective treatments in macroscopic rGBM, is withheld in this situation, as uncertainties about the pattern of re-recurrence, the target volume, and also the efficacy of early re-irradiation after GTR exist. Imaging and clinical data from 26 consecutive patients with GTR of rGBM were analyzed. The spatial pattern of recurrences was analyzed according to the RANO-HGG criteria (''response assessment in neuro-oncology criteria for high-grade gliomas''). Progression-free (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. Furthermore, a systematic review was performed in PubMed. All but 4 patients underwent adjuvant chemotherapy after GTR. Progression was diagnosed in 20 of 26 patients and 70% of recurrent tumors occurred adjacent to the resection cavity. The median extension beyond the edge of the resection cavity was 20 mm. Median PFS was 6 months; OS was 12.8 months. We propose a target volume containing the resection cavity and every contrast enhancing lesion as the gross tumor volume (GTV), a spherical margin of 5-10 mm to generate the clinical target volume (CTV), and a margin of 1-3 mm to generate the planning target volume (PTV). Re-irradiation of this volume is deemed to be safe and likely to prolong PFS. Re-irradiation is worth considering also after GTR, as the volumes that need to be treated are limited and re-irradiation has already proven to be a safe treatment option in general. The strategy of early re-irradiation is currently being tested within the GlioCave/NOA 17/Aro 2016/03 trial. (orig.) [German] Patienten mit einem rezidivierten Glioblastom (rGBM) werden, wenn eine komplette Resektion (GTR) des makroskopischen Rezidivs durchgefuehrt wurde, aktuell meist systemisch adjuvant behandelt oder einer engmaschigen Nachsorge

  1. 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.

  2. Multimodal approaches including three-dimensional conformal re-irradiation for recurrent or persistent esophageal cancer. Preliminary results

    International Nuclear Information System (INIS)

    Yamaguchi, Shinsaku; Ohguri, Takayuki; Imada, Hajime

    2011-01-01

    The purpose of this study was to assess the toxicity and efficacy of multimodal approaches, including three-dimensional conformal re-irradiation, for patients with recurrent or persistent esophageal cancer after radiotherapy. Thirty-one patients with esophageal cancer treated with three-dimensional conformal re-irradiation were retrospectively analyzed. Of the 31 patients, 27 patients received concurrent chemotherapy, and 14 patients underwent regional hyperthermia during the re-irradiation. We divided the patients into two groups on the basis of their clinical condition: the curative group (n=11) or the palliative group (n=20). Severe toxicities were detected in one patient with Grade 3 esophageal perforation in the curative group, and 5 patients had a Grade 3 or higher toxicity of the esophagus in the palliative group. Advanced T stage at the time of re-irradiation was found to be significantly correlated with Grade 3 or higher toxicity in the esophagus. For the curative group, 10 (91%) of 11 patients had an objective response. For the palliative group, symptom relief was recognized in 8 (57%) of 14 patients with obvious swallowing difficulty. In conclusion, in the curative group with early-stage recurrent or persistent esophageal cancer, the multimodal approaches, including three-dimensional conformal re-irradiation, may be feasible, showing acceptable toxicity and a potential value of promising results, although further evaluations especially for the toxicities of the organs at risk are required. In the palliative group, the benefit of our therapy may be restrictive because severe esophageal toxicities were not uncommon in the patients with advanced T stage at the time of re-irradiation. (author)

  3. 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

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

    Science.gov (United States)

    Lee, Dong Soo; Cho, Jaeho; Kim, Se Hoon; Kim, Dong-Seok; Shim, Kyu Won; Lyu, Chuhl Joo; Han, Jung Woo; Suh, Chang-Ok

    2015-10-01

    The purpose of this study is to investigate the long-term results and appropriateness of radiation therapy (RT) for medulloblastoma (MB) at a single institution. We analyzed the clinical outcomes of 106 patients with MB who received RT between January 1992 and October 2009. The median age was 7 years (range, 0 to 50 years), and the proportion of M0, M1, M2, and M3 stages was 60.4%, 8.5%, 4.7%, and 22.6%, respectively. The median total craniospinal irradiation (CSI) and posterior fossa tumor bed dose in 102 patients (96.2%) treated with CSI was 36 Gy and 54 Gy, respectively. The median follow-up period in survivors was 132 months (range, 31 to 248 months). A gradual improvement in survival outcomes was observed, with 5-year overall survival rates of 61.5% in 1990s increasing to 73.6% in 2000s. A total of 29 recurrences (27.4%) developed at the following sites: five (17.2%) in the tumor bed; five (17.2%) in the posterior fossa other than the tumor bed; nine (31%) in the supratentorium; and six (20.7%) in the spinal subarachnoid space only. The four remaining patients showed multiple site recurrences. Among 12 supratentorial recurrences, five cases recurred in the subfrontal areas. Although the frequency of posterior fossa/tumor bed recurrences was significantly high among patients treated with subtotal resection, other site (other intracranial/spinal) recurrences were more common among patients treated with gross tumor removal (p=0.016). There was no case of spinal subarachnoid space relapse from desmoplastic/extensive nodular histological subtypes. Long-term follow-up results and patterns of failure confirmed the importance of optimal RT dose and field arrangement. More tailored multimodal strategies and proper CSI technique may be the cornerstones for improving treatment outcomes in MB patients.

  5. Partial breast irradiation as second conservative treatment for local breast cancer recurrence

    International Nuclear Information System (INIS)

    Hannoun-Levi, Jean-Michel; Houvenaeghel, Gilles; Ellis, Steve; Teissier, Eric; Alzieu, Claude; Lallement, Michel; Cowen, Didier

    2004-01-01

    Purpose: Mastectomy is the treatment of reference for local relapse after breast cancer (BC). The aim of this study was to document the feasibility and the results of associating lumpectomy with partial breast irradiation by interstitial brachytherapy (IB) as local treatment for an isolated ipsilateral BC local recurrence (LR). Methods and materials: Between 1975 and 1996 at Marseille and Nice Cancer Institutes, 4026 patients received lumpectomy and radiotherapy (RT) (50-80 Gy) for a localized breast cancer of which 473 presented a LR. Among these patients, 69 (14.6%) received a second lumpectomy followed by IB, which delivered 30 Gy (Nice, n = 24) or 45-50 Gy (Marseille, n = 45) with 3 to 8 192 Ir wires in 1 or 2 planes on the 85% isodose. Results: Median age at LR was 58.2 years, median follow-up since primary BC was 10 years, and median follow-up after the second conservative treatment was 50.2 months (range, 2-139 months). Immediate tolerance was good in all cases. Grade 2 to 3 long-term complications (LTC) according to IB dose were 0%, 28%, and 32%, respectively, for 30 Gy, 45 to 46 Gy, and 50 Gy (p 0.01). Grade 2 to 3 LTC according to total dose were 4% and 30%, respectively, for total doses (initial RT plus IB) ≤ 100 Gy or >100 Gy (p = 0.008). Logistic regression showed that the only factor associated with Grade 2 to 3 complications was higher IB doses (p = 0.01). We noted 11 second LRs (LR2), 10 distant metastases (DM), and 5 specific deaths. LR2 occurred either in the tumor bed (50.8%) or close to the tumor bed (34.3%) or in another quadrant (14.9%). Kaplan-Meier 5-year freedom from (FF) LR2 (FFLR2), FFDM, and DFS were 77.4%, 86.7%, and 68.9%, respectively. Overall 5-year survival (OS) was 91.8%. Univariate analysis showed the following factors associated with a higher FFLR2: (1) number of wires used for IB (3-4 vs. 5-8 wires, p = 0.006), (2) IB doses (30-45 Gy vs. 46-60 Gy, p = 0.05), (3) number of planes (1 vs. 2, p = 0.05), (4) interval between

  6. Managing a small recurrence in the previously irradiated breast. Is there a second chance for breast conservation?

    Science.gov (United States)

    Chadha, Manjeet; Trombetta, Mark; Boolbol, Susan; Osborne, Michael P

    2009-10-01

    Over the past 30 years, lumpectomy and radiation therapy (breast-conservation therapy, or BCT) has been the preferred treatment for early-stage breast cancer. With accumulating follow-up, we have an ever-expanding pool of patients with history of an irradiated intact breast. Routine use of every-6-month or annual screening in this population has identified an emerging clinical dilemma with respect to managing a small recurrence or a second primary tumor in the treated breast. Most women diagnosed with a second cancer in a previously irradiated breast are advised to undergo mastectomy. More recently, with an improved understanding of the patterns of in-breast failure, and with advances in the delivery of conformal radiation dose there is an opportunity to reevaluate treatment alternatives for managing a small in-breast recurrence. A limited number of publications have reported on patient outcomes after a second lumpectomy and radiation therapy for this clinical scenario. In this report, we review the controversial subject of a second chance at breast conservation for women with a prior history of breast irradiation.

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

    Directory of Open Access Journals (Sweden)

    Deckard Lindsey A

    2011-04-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  9. Vaginal vault recurrences of endometrial cancer in non-irradiated patients — Radiotherapy or surgery

    Directory of Open Access Journals (Sweden)

    Hordur Alexander Hardarson

    2015-01-01

    Conclusion: This study indicates that ST is an appropriate treatment for locally recurrent endometrial cancer. Our study involves a limited number of patients and is made retrospectively, therefore prospective and ideally randomized trials evaluating both survival and complications are warranted.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1997-03-31

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

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

    Directory of Open Access Journals (Sweden)

    Lue Sun

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

  12. 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.

  13. Delayed metamorphosis and recurrence of bacterial infection in irradiated Rana clamitans tadpoles

    International Nuclear Information System (INIS)

    Hart, D.R.

    1982-03-01

    X-ray doses of 5 and 10 Gy (1 Gy/min) given to premetamorphic Green Frog (Rana clamitans) tadpoles delayed their metamorphosis relative to unirradiated controls. Previous pathogenic bacterial infections recurred in irradiated animals prior to metamorphic climax. Limited mortality occurred during metamorphic climax, 80-105 days after irradiation

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. The location of locoregional recurrence in pathologic T3N0, non-irradiated lower rectal cancer

    International Nuclear Information System (INIS)

    Kim, Mi Sun; Keum, Ki Chang; Rhee, Woo Joong; Kim, Hyun Ju; Kim, Min Ji; Choi, Seo Hee; Nam, Ki Chang; Koom, Woong Sub

    2013-01-01

    To investigate the patterns of locoregional recurrence of pathologic T3N0 (pT3N0) lower rectal cancer omitting postoperative radiotherapy (RT) and explore the potential of modification of a RT field. From Jan 2003 to Nov 2011, 35 patients omitting preoperative or postoperative RT for pT3N0 lower rectal cancer were included. We defined the lower rectal cancer as the tumor with the inferior margin located below the virtual line-a convergent level between rectal wall and levator ani muscle. All patients had radiologic examinations for recurrence evaluation during the follow-up duration. The median follow-up duration was 66.4 months (range, 1.4 to 126.1 months). Eight (22.9%) of the 35 patients had recurrence. Three (8.6%) was local recurrence (LR) only, 3 (8.6%) was distant metastasis (DM) only, and 2 (5.7%) was LR with DM. All LR were located at primary tumor sites. The overall survival rate, LR-free survival rate, and DM-free survival rate at 5 years was 79.8%, 83%, and 87%, respectively. All LR developed from tumors over 5 cm. However, there was no statistical significance (p = 0.065). There was no other risk factor for LR. Even though the patients included in this study had pathologically favorable pT3N0 rectal cancer, LR developed in 14.3% of patients. Most of the LR was located at primary tumor sites prior to surgery. Based on these findings, it might seem reasonable to consider postoperative RT with a smaller radiation field to the primary tumor site rather than the conventional whole pelvic irradiation.

  19. 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.

  20. 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.)

  1. 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.)

  2. Re-irradiation associated to cetuximab and paclitaxel in the recurrences in irradiated field of upper aero-digestive ducts tumors resistant to platina salts; Re-irradiation associee au cetuximab et au paclitaxel dans les recidives en territoire irradie des tumeurs des voies aero-digestives superieures resistantes aux sels de platine

    Energy Technology Data Exchange (ETDEWEB)

    Martin, L.M. [Centre Guillaume-Le-Conquerant, 76 - Le Havre (France); Moran, A.R.; Pavlovitch, J.M. [Clinique du Petit-Colmoulin, 76 - Harfleur (France); El Amarti, R. [Hopital Monod, 76 - Montivilliers (France); Damour, M. [CMC Ormeaux-Vauban, 76 - Le Havre (France)

    2007-11-15

    The objective of this study is to present the preliminary results of the toxicity and efficiency evaluation of the association 're-irradiation-cetuximab-paclitaxel' in the recurrences of upper aero-digestive ducts tumors in irradiated field resistant to platinum salts. (N.C.)

  3. Medulloblastomas - primitive neuroectodermal tumours in the adult population

    International Nuclear Information System (INIS)

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

    2008-01-01

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

  4. 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,

  5. Local recurrences after conservative surgery and irradiation for breast cancer: Diagnosis with mammography and ultrasound. Mammographie und Sonographie in der Rezidivdiagnostik nach brusterhaltender Therapie des Mammakarzinoms

    Energy Technology Data Exchange (ETDEWEB)

    Buchberger, W; Hamberger, L; Schoen, G [Innsbruck Univ. (Austria). Universitaetsklinik fuer Radiodiagnostik; Steixner, G; Fritsch, E [Innsbruck Univ. (Austria). Universitaetsklinik fuer Strahlentherapie

    1991-06-01

    89 patients, who underwent conservative surgery for breast cancer were followed up with mammography and real-time sonography. 78 patients underwent postoperative irradiation. Depending on the time interval between irradiation and examination various alterations in mammographic and sonographic patterns were evident. Of 14 biospy-confirmed local recurrences, 11 were diagnosed by mammography and 12 by sonography. Combined use of mammography and sonography should therefore lead to better results in the diagnosis of local recurrences and to a reduction of unnecessary biopsies. (orig./GDG).

  6. Stereotactic Body Radiation Therapy for Re-irradiation of Persistent or Recurrent Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Trovo, Marco, E-mail: marcotrovo33@hotmail.com [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Minatel, Emilio; Durofil, Elena [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Polesel, Jerry [Department of Epidemiology and Biostatistics, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Avanzo, Michele [Department of Medical Physics, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Baresic, Tania [Department of Nuclear Medicine, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Bearz, Alessandra [Department of Medical Oncology, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy); Del Conte, Alessandro [Department of Medical Oncology, Pordenone General Hospital, Aviano, Pordenone (Italy); Franchin, Giovanni; Gobitti, Carlo; Rumeileh, Imad Abu; Trovo, Mauro G. [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Pordenone (Italy)

    2014-04-01

    Purpose: To retrospectively assess toxicity and outcome of re-irradiation with stereotactic body radiation therapy (SBRT) in patients with recurrent or persistent non-small cell lung cancer (NSCLC), who were previously treated with radical radiation therapy (50-60 Gy). The secondary endpoint was to investigate whether there are dosimetric parameter predictors of severe radiation toxicity. Methods and Materials: The analysis was conducted in 17 patients with “in-field” recurrent/persistent centrally located NSCLC, who underwent re-irradiation with SBRT. SBRT consisted of 30 Gy in 5 to 6 fractions; these prescriptions would be equivalent for the tumor to 37.5 to 40 Gy, bringing the total 2-Gy-per-fraction cumulative dose to 87 to 100 Gy, considering the primary radiation therapy treatment. Actuarial analyses and survival were calculated by the Kaplan-Meier method, and P values were estimated by the log-rank test, starting from the date of completion of SBRT. Dosimetric parameters from the subgroups with and without grade ≥3 pulmonary toxicity were compared using a 2-tailed Student t test. Results: The median follow-up was 18 months (range, 4-57 months). Only 2 patients had local failure, corresponding to a local control rate of 86% at 1 year. The Kaplan-Meier estimates of overall survival (OS) rates at 1 and 2 years were 59% and 29%, respectively; the median OS was 19 months. Four patients (23%) experienced grade 3 radiation pneumonitis, and 1 patient developed fatal pneumonitis. One patient died of fatal hemoptysis 2 months after the completion of SBRT. Unexpectedly, heart maximum dose, D5 (minimum dose to at least 5% of the heart volume), and D10 were correlated with risk of radiation pneumonitis (P<.05). Conclusions: Re-irradiation with SBRT for recurrent/persistent centrally located NSCLC achieves excellent results in terms of local control. However, the high rate of severe toxicity reported in our study is of concern.

  7. Stereotactic Body Radiation Therapy for Re-irradiation of Persistent or Recurrent Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Trovo, Marco; Minatel, Emilio; Durofil, Elena; Polesel, Jerry; Avanzo, Michele; Baresic, Tania; Bearz, Alessandra; Del Conte, Alessandro; Franchin, Giovanni; Gobitti, Carlo; Rumeileh, Imad Abu; Trovo, Mauro G.

    2014-01-01

    Purpose: To retrospectively assess toxicity and outcome of re-irradiation with stereotactic body radiation therapy (SBRT) in patients with recurrent or persistent non-small cell lung cancer (NSCLC), who were previously treated with radical radiation therapy (50-60 Gy). The secondary endpoint was to investigate whether there are dosimetric parameter predictors of severe radiation toxicity. Methods and Materials: The analysis was conducted in 17 patients with “in-field” recurrent/persistent centrally located NSCLC, who underwent re-irradiation with SBRT. SBRT consisted of 30 Gy in 5 to 6 fractions; these prescriptions would be equivalent for the tumor to 37.5 to 40 Gy, bringing the total 2-Gy-per-fraction cumulative dose to 87 to 100 Gy, considering the primary radiation therapy treatment. Actuarial analyses and survival were calculated by the Kaplan-Meier method, and P values were estimated by the log-rank test, starting from the date of completion of SBRT. Dosimetric parameters from the subgroups with and without grade ≥3 pulmonary toxicity were compared using a 2-tailed Student t test. Results: The median follow-up was 18 months (range, 4-57 months). Only 2 patients had local failure, corresponding to a local control rate of 86% at 1 year. The Kaplan-Meier estimates of overall survival (OS) rates at 1 and 2 years were 59% and 29%, respectively; the median OS was 19 months. Four patients (23%) experienced grade 3 radiation pneumonitis, and 1 patient developed fatal pneumonitis. One patient died of fatal hemoptysis 2 months after the completion of SBRT. Unexpectedly, heart maximum dose, D5 (minimum dose to at least 5% of the heart volume), and D10 were correlated with risk of radiation pneumonitis (P<.05). Conclusions: Re-irradiation with SBRT for recurrent/persistent centrally located NSCLC achieves excellent results in terms of local control. However, the high rate of severe toxicity reported in our study is of concern

  8. Results of external beam irradiation for rectal carcinomas locally recurrent after local excision or electrocoagulation

    International Nuclear Information System (INIS)

    Shun Wong, C.; Cummings, B.J.; Keane, T.J.; O'Sullivan, Brian; Catton, C.N.

    1991-01-01

    The outcome of 42 patients who developed locally recurrent rectal carcinoma after initial local excision or electrocoagulation was presented. Five patients received combined surgery and radiotherapy (XRT). The remaining 37 patients were managed by XRT alone. The overall 5 years actuarial survival and local control rates were 21 and 22 percent, respectively. For patients who received XRT alone, the 5 year actuarial survival and local control rates were 20 and 15 percent, resp. The corresponding figures were 35 and 40 percent for patients who received a total XRT dose of 50 Gy or more. One patient who underwent combined treatment developed rectal and bladder incontinence requiring surgery. For patients with rectal recurrence after initial conservative surgery, XRT is an alternative to abdominoperipheral resection if major resection is contraindicated. (author). 13 refs.; 2 tabs

  9. 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

  10. 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

  11. 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

  12. Distinguishing tumor recurrence from irradiation sequelae with positron emission tomography in patients treated for larynx cancer

    International Nuclear Information System (INIS)

    Greven, K.M.; Williams, D.W. III; Keyes, J.W. Jr.; McGuirt, W.F.; Harkness, B.A.; Watson, N.E. Jr.; Raben, M.; Frazier, L.C.; Geisinger, K.R.; Capellari, J.O.

    1994-01-01

    Distinguishing persistent or recurrent tumor from postradiation edema, or soft tissue/cartilage necrosis in patients treated for carcinoma of the larynx can be difficult. Because recurrent tumor is often submucosal, multiple deep biopsies may be necessary before a diagnosis can be established. Positron emission tomography with 18F-2-fluro-2-deoxglucose (FDG) was studied for its ability to aid in this problem. Positron emission tomography (18FDG) scans were performed on 11 patients who were suspected of having persistent or recurrent tumor after radiation treatment for carcinoma of the larynx. Patients underwent thorough history and physical examinations, scans with computerized tomography, and pathologic evaluation when indicated. Standard uptake values were used to quantitate the FDG uptake in the larynx. The time between completion of radiation treatment and positron emission tomography examination ranged from 2 to 26 months with a median of 6 months. Ten patients underwent computed tomography (CT) of the larynx, which revealed edema of the larynx (six patients), glottic mass (four patients), and cervical nodes (one patient). Positron emission tomography scans revealed increased FDG uptake in the larynx in five patients and laryngectomy confirmed the presence of carcinoma in these patients. Five patients had positron emission tomography results consistent with normal tissue changes in the larynx, and one patient had increased FDG uptake in neck nodes. This patient underwent laryngectomy, and no cancer was found in the primary site, but nodes were pathologically positive. One patient had slightly elevated FDG uptake and negative biopsy results. The remaining patients have been followed for 11 to 14 months since their positron emission studies and their examinations have remained stable. In patients without tumor, average standard uptake values of the larynx ranged from 2.4 to 4.7, and in patients with tumor, the range was 4.9 to 10.7. 18 refs., 3 figs., 1 tab

  13. 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

  14. 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

  15. Pattern of recurrence in children with midline posterior fossa malignant neoplasms

    Energy Technology Data Exchange (ETDEWEB)

    Wootton-Gorges, S.L.; Foreman, N.K.; Albano, E.A.; Dertina, D.M.; Nein, P.K.; Shukert, B.; Cesario, K.B.; Gage, S.; Rumack, C.M.; Strain, J.D. [Children' s Hospital, Department of Radiology, Denver, CO (United States)

    2000-02-01

    Background. Surveillance imaging of the brain and spinal neuraxis in patients with posterior fossa malignant tumors is commonly performed, with the assumption that early detection of tumor recurrence will improve outcome. However, the benefit of this imaging has not been proven. To evaluate the usefulness of spinal surveillance imaging in children with nonmetastatic (at diagnosis, M0) posterior fossa ependymoma and medulloblastoma. Materials and methods. This retrospective study included 65 children (3 months to 16 years, mean 5.7 years) treated between 1985 and 1997 for ependymoma (22) and medulloblastoma (43). Medical records were reviewed for pathology and treatment data. Serial imaging of the head and spine was reviewed for evidence of tumor recurrence. Results. Twenty-four patients (37 %) had tumor recurrence, including 13 with ependymoma and 11 with medulloblastoma. Of the 17/24 recurrent patients initially diagnosed as M0 (6 medulloblastoma and 11 ependymoma), 13 (76 %) had a cranial recurrence only, and 4 (24 %) presented with concomitant cranial and spinal recurrence. No M0 patient presented solely with spinal metastases at recurrence. Conclusion. This study suggests that spinal surveillance imaging in patients with posterior fossa ependymoma or medulloblastoma initially staged as M0 may not be useful, as these patients initially recur intracranially. Thus, until an intracranial recurrence is detected, these patients may be spared the time, expense and sedation risk necessary for spinal imaging. (orig.)

  16. Pattern of recurrence in children with midline posterior fossa malignant neoplasms

    International Nuclear Information System (INIS)

    Wootton-Gorges, S.L.; Foreman, N.K.; Albano, E.A.; Dertina, D.M.; Nein, P.K.; Shukert, B.; Cesario, K.B.; Gage, S.; Rumack, C.M.; Strain, J.D.

    2000-01-01

    Background. Surveillance imaging of the brain and spinal neuraxis in patients with posterior fossa malignant tumors is commonly performed, with the assumption that early detection of tumor recurrence will improve outcome. However, the benefit of this imaging has not been proven. To evaluate the usefulness of spinal surveillance imaging in children with nonmetastatic (at diagnosis, M0) posterior fossa ependymoma and medulloblastoma. Materials and methods. This retrospective study included 65 children (3 months to 16 years, mean 5.7 years) treated between 1985 and 1997 for ependymoma (22) and medulloblastoma (43). Medical records were reviewed for pathology and treatment data. Serial imaging of the head and spine was reviewed for evidence of tumor recurrence. Results. Twenty-four patients (37 %) had tumor recurrence, including 13 with ependymoma and 11 with medulloblastoma. Of the 17/24 recurrent patients initially diagnosed as M0 (6 medulloblastoma and 11 ependymoma), 13 (76 %) had a cranial recurrence only, and 4 (24 %) presented with concomitant cranial and spinal recurrence. No M0 patient presented solely with spinal metastases at recurrence. Conclusion. This study suggests that spinal surveillance imaging in patients with posterior fossa ependymoma or medulloblastoma initially staged as M0 may not be useful, as these patients initially recur intracranially. Thus, until an intracranial recurrence is detected, these patients may be spared the time, expense and sedation risk necessary for spinal imaging. (orig.)

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. Intermittent hormonal therapy in the treatment of post-irradiation residual/recurrent prostate cancer

    International Nuclear Information System (INIS)

    Williams, Aaron O; Kocherill, Paul G; Wallace, Michelle; Forman, Jeffrey D

    1996-01-01

    Purpose: To evaluate the efficacy and toxicity of intermittent hormonal therapy in the treatment of residual/recurrent prostate cancer. Materials and Methods: Seventeen patients with biochemical evidence of residual/recurrent prostate cancer were initially treated with radiation therapy (RT)(13), neo-adjuvant hormonal therapy and RT (3), or RT following prostatectomy (1). The mean follow-up time was 19.4 months from the initiation of hormonal therapy. Hormonal therapy consisted of an LH-RH agonist alone (7), an anti-androgen alone (1) or a combination of both (9). Hormonal therapy was continued until the prostatic specific antigen (PSA) level became undetectable. IHT was reinstituted when the PSA reached a pre-determined level, usually greater than or equal to 10ng/ml. Results: The mean time from completion of primary treatment to the initiation of hormonal therapy was 32.5 months. The mean PSA at the start of the first cycle of hormonal therapy was 43.9ng/ml, the second cycle, 11.9ng/ml and the third cycle, 24ng/ml. The mean PSA levels at the end of the first and second cycle of hormonal therapy were .48 and .42ng/ml, respectively. No patient has yet completed the third cycle of hormonal therapy. The average duration of hormonal therapy was 10 months for the first cycle and 4 months for the second cycle. The mean intermittent time off hormones were 9.3 months between cycles 1 and 2, and 10 months between cycles 2 and 3. No patient has yet become refractory to hormonal therapy. Currently all patients are alive. All patients experienced hot flashes and decreased libido at varying degrees during treatment. Thirty-five percent experienced gynecomastia. During the intervals between hormonal therapy, most patients reported a decrease in hot flashes. Conclusion: This analysis supplies preliminary evidence that intermittent hormonal therapy is a viable option in patients with biochemical evidence of disease following initial therapy. It is associated with less treatment

  2. Case Report and Dosimetric Analysis of an Axillary Recurrence After Partial Breast Irradiation with Mammosite Catheter

    International Nuclear Information System (INIS)

    Shah, Anand P.; Dickler, Adam; Kirk, Michael C.; Chen, Sea S.; Strauss, Jonathan B.; Coon, Alan B.; Turian, Julius V.; Siziopikou, Kalliopi; Dowlat, Kambiz; Griem, Katherine L.

    2008-01-01

    Partial breast irradiation (PBI) was designed in part to decrease overall treatment times associated with whole breast radiation therapy (WBRT). WBRT treats the entire breast and usually portions of the axilla. The goal of PBI is to treat a smaller volume of breast tissue in less time, focusing the dose around the lumpectomy cavity. The following is a case of a 64-year-old woman with early-stage breast cancer treated with PBI who failed regionally in the ipsilateral axilla. With our dosimetric analysis, we found that the entire area of this axillary failure would have likely received at least 45 Gy if WBRT had been used, enough to sterilize microscopic disease. With PBI, this area received a mean dose of only 2.8 Gy, which raises the possibility that this regional failure may have been prevented had WBRT been used instead of PBI

  3. 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.

  4. The challenge in treating locally recurrent T3-4 nasopharyngeal carcinoma: the survival benefit and severe late toxicities of re-irradiation with intensity-modulated radiotherapy.

    Science.gov (United States)

    Tian, Yun-Ming; Huang, Wei-Zeng; Yuan, Xia; Bai, Li; Zhao, Chong; Han, Fei

    2017-06-27

    Effective treatments for patients with advanced locally recurrent nasopharyngeal carcinoma (NPC) are limited. This investigation was to determine the potential benefits from re-irradiation by intensity-modulated radiotherapy (IMRT) on survival and the effects of severe late toxicities. A retrospective study was conducted in 245 patients diagnosed with locally recurrent T3-T4 NPC who had undergone re-irradiation with IMRT. Follow-up data was colletedand factors associated with survival and severe late toxicities were analyzed. The 5-year local-regional failure-free survival, distant failure-free survival and overall survival rates were 60.9%, 78.3% and 27.5%, respectively. The presence of severe late complications, recurrent T4 disease and gross tumor volume >30 cm3 were associated with poor survival. The incidences of mucosal necrosis, temporal lobe necrosis, cranial neuropathy and trismus were 22.0%, 14.6%, 27.0% and 14.6% respectively. Re-irradiation with IMRT is an effective choice in patients with locally recurrent T3-T4 NPC. However, the survival benefits can be partly offset by severe late complications and optimum treatments in these patients remain a challenge.

  5. Occurrence and prognosis of the medulloblastoma in adult persons

    Energy Technology Data Exchange (ETDEWEB)

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

    1983-03-01

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

  6. Occurence and prognosis of the medulloblastoma in adult persons

    International Nuclear Information System (INIS)

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

    1983-01-01

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

  7. Re-irradiation of the chest wall for local breast cancer recurrence. Results of salvage brachytherapy with hyperthermia

    Energy Technology Data Exchange (ETDEWEB)

    Auoragh, A. [University Hospital Erlangen, Department of Radiation Oncology, Erlangen (Germany); Hospital Fuerth, Department of Radiation Oncology, Fuerth (Germany); Strnad, V.; Ott, O.J.; Fietkau, R. [University Hospital Erlangen, Department of Radiation Oncology, Erlangen (Germany); Beckmann, M.W. [University Hospital Erlangen, Department of Gynecology and Obstetrics, Erlangen (Germany)

    2016-09-15

    Following mastectomy and adjuvant external beam radiation therapy in patients with breast cancer, the incidence of local or locoregional recurrence is approximately 9 % (2-20 %). Alongside the often limited possibilities of surgical treatment, radiation therapy combined with superficial hyperthermia is the most effective local therapy. In the present work, a retrospective analysis of salvage brachytherapy combined with superficial hyperthermia for chest wall recurrences is presented. Between 2004 and 2011, 18 patients with a total of 23 target volumes resulting from chest wall recurrences after previously mastectomy and external beam radiation therapy (median 56 Gy, range 50-68 Gy) were treated with superficial brachytherapy as salvage treatment: 8 patients (44 %) had macroscopic tumor, 3 (17 %) had microscopic tumor (R1), and 7 (39 %) had undergone R0 resection and were treated due to risk factors. A dose of 50 Gy was given (high-dose rate [HDR] and pulsed-dose rate [PDR] procedures). In all, 5 of 23 patients (22 %) received additional concurrent chemotherapy, and in 20 of 23 (87 %) target volumes additional superficial hyperthermia was carried out twice weekly. The 5-year local recurrence-free survival was 56 %, the disease-free survival was 28 %, and a 5-year overall survival was 22 %. Late side effects Common Toxicity Criteria (CTC) grade 3 were reported in 17 % of the patients: 2 of 18 (11 %) had CTC grade 3 fibrosis, and 1 of 18 (6 %) had a chronic wound healing disorder. Re-irradiation as salvage brachytherapy with superficial hyperthermia for chest wall recurrences is a feasible and safe treatment with good local control results and acceptable late side effects. (orig.) [German] Nach einer Mastektomie und adjuvanter Strahlentherapie bei Patientinnen mit Mammakarzinom kommt es bei 9 % (2-20 %) zum lokalen bzw. lokoregionaeren Rezidiv. Neben den oft limitierten operativen Behandlungsmoeglichkeiten ist die Strahlentherapie mit Oberflaechenhyperthermie die

  8. Using deep recurrent neural network for direct beam solar irradiance cloud screening

    Science.gov (United States)

    Chen, Maosi; Davis, John M.; Liu, Chaoshun; Sun, Zhibin; Zempila, Melina Maria; Gao, Wei

    2017-09-01

    Cloud screening is an essential procedure for in-situ calibration and atmospheric properties retrieval on (UV-)MultiFilter Rotating Shadowband Radiometer [(UV-)MFRSR]. Previous study has explored a cloud screening algorithm for direct-beam (UV-)MFRSR voltage measurements based on the stability assumption on a long time period (typically a half day or a whole day). To design such an algorithm requires in-depth understanding of radiative transfer and delicate data manipulation. Recent rapid developments on deep neural network and computation hardware have opened a window for modeling complicated End-to-End systems with a standardized strategy. In this study, a multi-layer dynamic bidirectional recurrent neural network is built for determining the cloudiness on each time point with a 17-year training dataset and tested with another 1-year dataset. The dataset is the daily 3-minute cosine corrected voltages, airmasses, and the corresponding cloud/clear-sky labels at two stations of the USDA UV-B Monitoring and Research Program. The results show that the optimized neural network model (3-layer, 250 hidden units, and 80 epochs of training) has an overall test accuracy of 97.87% (97.56% for the Oklahoma site and 98.16% for the Hawaii site). Generally, the neural network model grasps the key concept of the original model to use data in the entire day rather than short nearby measurements to perform cloud screening. A scrutiny of the logits layer suggests that the neural network model automatically learns a way to calculate a quantity similar to total optical depth and finds an appropriate threshold for cloud screening.

  9. P08.52 Proton therapy re-Irradiation in large-volume recurrent glioblastoma.

    Science.gov (United States)

    Amelio, D.; Widesott, L.; Vennarini, S.; Fellin, F.; Maines, F.; Righetto, R.; Lorentini, S.; Farace, P.; Schwarz, M.; Amichetti, M.

    2016-01-01

    Abstract Purpose: To report preliminary results of re-irradiation with proton therapy (PT) in large-volume recurrent glioblastoma (rGBM). Matherial/Methods: Between January and December 2015 ten patients (pts) with rGBM were re-irradiated with PT. All pts were previously treated with photon radiotherapy (60 Gy) with concomitant and adjuvant TMZ for 1–20 cycles (median, 7). Seven pts were re-irradiated at first relapse/progression. Four patients were re-irradiated after partial tumor resection. Median age and Karnofsky performance status at re-irradiation were 57 years (range, 41–68) and 80%, (range, 70–100), respectively. Median time between prior radiotherapy and PT was 9 months (range, 5–24). Target definition was based on CT, MR, and 18F-DOPA PET imaging. GTV included any area of contrast enhancement after contrast medium administration plus any pathological PET uptake regions. CTV was generated by adding to GTV a 3-mm uniform margin manually corrected in proximity of anatomical barriers. CTV was expanded by 4 mm to create PTV. Median PTV volume was 90 cc (range, 46–231). All pts received 36 GyRBE in 18 fractions. Four pts also received concomitant temozolomide (75 mg/m2/die, 7 days/week). All pts were treated with active beam scanning PT using 2–3 fields with single field optimization technique. Results: All pts completed the treatment without breaks. Registered acute side effects (according to Common Terminology Criteria for Adverse Events version 4.0 - CTCAE) include grade 1–2 skin erythema, alopecia, fatigue, conjunctivitis, concentration impairment, dysphasia, and headache. There were no grade 3 or higher toxicities. One patient developed grade 1 neutropenia. Five pts started PT under steroids (2–7 mg/daily); two of them reduced the dose during PT, while three kept the same steroids dose. None of remaining pts needed steroids therapy. Registered late side effects (according to CTCAE version 4.0) include grade 1–2 alopecia, fatigue

  10. 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.

  11. Medulloblastoma in adults. A retrospective single institution analysis

    Energy Technology Data Exchange (ETDEWEB)

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

    2018-03-15

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

  12. 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.

  13. 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)

  14. Re-irradiation with cetuximab or cisplatin-based chemotherapy for recurrent squamous cell carcinoma of the head and neck

    Energy Technology Data Exchange (ETDEWEB)

    Dornoff, Nicolas; Weiss, Christian; Roedel, Franz [J. W. Goethe University, Department of Radiotherapy and Oncology, Frankfurt a. M. (Germany); Wagenblast, Jens [J. W. Goethe University, Department of Otorhinolaryngology, Frankfurt a. M. (Germany); Ghanaati, Shahram [J. W. Goethe University, Department of Maxillofacial Surgery, Frankfurt a. M. (Germany); Atefeh, Nateghian; Roedel, Claus; Balermpas, Panagiotis [J. W. Goethe University, Department of Radiotherapy and Oncology, Frankfurt a. M. (Germany); German Cancer Research Center (DKFZ), Heidelberg (Germany); German Cancer Consortium (DKTK) partner site: Frankfurt, Frankfurt a. M. (Germany)

    2015-08-15

    Locoregional recurrence remains the main pattern of failure after primary combined modality treatment of squamous cell carcinoma of the head and neck (SCCHN). We compared the efficacy and toxicity of either cisplatin or cetuximab in combination with re-irradiation (ReRT) for recurrent unresectable SCCHN. Various clinicopathological factors were investigated to establish a prognostic score. Between 2007 and 2014, 66 patients with recurrent SCCHN originating in a previously irradiated area received cetuximab (n = 33) or cisplatin-based chemotherapy (n = 33) concomitant with ReRT. Toxicity was evaluated weekly and at every follow-up visit. Physical examination, endoscopy, CT or MRI scans were used to evaluate response and disease control. With a mean follow-up of 18.3 months, the 1-year overall survival (OS) rates for Re-RT with cetuximab and cisplatin-based chemotherapy were 44.4 and 45.5 % (p = 0.352), respectively. At 1 year, local control rates (LCR) were 46.4 and 54.2 % (p = 0.625), freedom from metastases (FFM) rates 73.6 and 81 % (p = 0.842), respectively. Haematological toxicity ≥ grade 3 occurred more often in the cisplatin group (p < 0.001), pain ≥ grade 3 was increased in the cetuximab group (p = 0.034). A physiological haemoglobin level and a longer interval between primary RT and ReRT, proved to be significant prognostic factors for OS (multivariate: p = 0.003, p = 0.002, respectively). Site of the recurrence and gross target volume (GTV) did not show a significant impact on OS in multivariate analysis (p = 0.160, p = 0.167, respectively). A prognostic-score (1-4 points) based on these four variables identified significantly different subgroups: 1-year OS for 0/1/2/3/4 prognostic points: 10, 38, 76, 80 and 100 %, respectively (p < 0.001). Both cetuximab- and cisplatin-based ReRT of SCCHN recurrences are feasible and effective treatment options with comparable results in terms of tumour control and survival. Acute adverse events may differ slightly

  15. Re-irradiation combined with capecitabine in locally recurrent squamous cell carcinoma of the head and neck. A prospective phase II trial

    Energy Technology Data Exchange (ETDEWEB)

    Vormittag, L.; Kornek, G. [Medical Univ. Vienna (Austria). Div. of Clinical Oncology; Lemaire, C.; Radonjic, D.; Selzer, E. [Medical Univ. Vienna (Austria). Dept. for Radiotherapy and Radiobiology

    2012-03-15

    We performed a prospective phase II trial to investigate the safety and efficacy of radiotherapy combined with capecitabine in patients suffering from a recurrence of a squamous cell carcinoma of the head and neck (SCCHN) within a previously irradiated field. A total of 31 evaluable patients with recurrent SCCHN received re-irradiation with a total dose of 50 Gy (25 fractions over 5 weeks) up to a maximum of 60 Gy combined with 900 mg/m{sup 2}/day capecitabine given on the days of radiotherapy. The median time to relapse after the first course of radiotherapy was 15 months. The overall response rate in our study was 68% including 6 patients with a complete response. The median overall survival was 8.4 months. Grade 3 or 4 mucositis occurred in 4 patients and 1 patient, respectively. No grade 4 hematological toxicities were observed; 1 patient had grade 3 anemia. The cumulative median lifetime dose was 116 Gy. Capecitabine combined with re-irradiation is a well-tolerated treatment in patients with recurrent SCCHN. In light of its good tolerability, it appears to be a potential option for patients with a reduced performance status and may also serve as a basis for novel treatment concepts, such as in combination with targeted therapies.

  16. 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

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

    International Nuclear Information System (INIS)

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

    1998-01-01

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

  18. 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

  19. 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

  20. A Pilot Study of Hypofractionated Stereotactic Radiation Therapy and Sunitinib in Previously Irradiated Patients With Recurrent High-Grade Glioma

    International Nuclear Information System (INIS)

    Wuthrick, Evan J.; Curran, Walter J.; Camphausen, Kevin; Lin, Alexander; Glass, Jon; Evans, James; Andrews, David W.; Axelrod, Rita; Shi, Wenyin; Werner-Wasik, Maria; Haacke, E. Mark; Hillman, Gilda G.; Dicker, Adam P.

    2014-01-01

    Purpose/Objective(s): Angiogenic blockade with irradiation may enhance the therapeutic ratio of radiation therapy (RT) through vascular normalization. We sought to determine the safety and toxicity profile of continuous daily-dosed sunitinib when combined with hypofractionated stereotactic RT (fSRT) for recurrent high-grade gliomas (rHGG). Methods and Materials: Eligible patients had malignant high-grade glioma that recurred or progressed after primary surgery and RT. All patients received a minimum of a 10-day course of fSRT, had World Health Organization performance status of 0 to 1, and a life expectancy of >3 months. During fSRT, sunitinib was administered at 37.5 mg daily. The primary endpoint was acute toxicity, and response was assessed via serial magnetic resonance imaging. Results: Eleven patients with rHGG were enrolled. The fSRT doses delivered ranged from 30 to 42 Gy in 2.5- to 3.75-Gy fractions. The median follow-up time was 40 months. Common acute toxicities included hematologic disorders, fatigue, hypertension, and elevated liver transaminases. Sunitinib and fSRT were well tolerated. One grade 4 mucositis toxicity occurred, and no grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. One patient had a nearly complete response, and 4 patients had stable disease for >9 months. Two patients (18%) remain alive and progression-free >3 years from enrollment. The 6-month progression-free survival was 45%. Conclusions: Sunitinib at a daily dose of 37.5 mg given concurrently with hypofractionated stereotactic reirradiation for rHGG yields acceptable toxicities and an encouraging 6-month progression-free survival

  1. Nomogram for Predicting the Risk of Locoregional Recurrence in Patients Treated With Accelerated Partial-Breast Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Wobb, Jessica L. [Department of Radiation Oncology, Beaumont Health System, Royal Oak, Michigan (United States); Chen, Peter Y., E-mail: PChen@beaumont.edu [Department of Radiation Oncology, Beaumont Health System, Royal Oak, Michigan (United States); Shah, Chirag [Department of Radiation Oncology, Summa Health System, Akron, Ohio (United States); Moran, Meena S. [Department of Therapeutic Radiology, Yale School of Medicine, Norwich, Connecticut (United States); Shaitelman, Simona F. [Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas (United States); Vicini, Frank A. [Department of Radiation Oncology, Michigan Healthcare Professionals/21st Century Oncology, Farmington, Michigan (United States); Mbah, Alfred K.; Lyden, Maureen [Biostat International Inc, Tampa, Florida (United States); Beitsch, Peter [Department of Surgery, Dallas Breast Center, Dallas, Texas (United States)

    2015-02-01

    Purpose: To develop a nomogram taking into account clinicopathologic features to predict locoregional recurrence (LRR) in patients treated with accelerated partial-breast irradiation (APBI) for early-stage breast cancer. Methods and Materials: A total of 2000 breasts (1990 women) were treated with APBI at William Beaumont Hospital (n=551) or on the American Society of Breast Surgeons MammoSite Registry Trial (n=1449). Techniques included multiplanar interstitial catheters (n=98), balloon-based brachytherapy (n=1689), and 3-dimensional conformal radiation therapy (n=213). Clinicopathologic variables were gathered prospectively. A nomogram was formulated utilizing the Cox proportional hazards regression model to predict for LRR. This was validated by generating a bias-corrected index and cross-validated with a concordance index. Results: Median follow-up was 5.5 years (range, 0.9-18.3 years). Of the 2000 cases, 435 were excluded because of missing data. Univariate analysis found that age <50 years, pre-/perimenopausal status, close/positive margins, estrogen receptor negativity, and high grade were associated with a higher frequency of LRR. These 5 independent covariates were used to create adjusted estimates, weighting each on a scale of 0-100. The total score is identified on a points scale to obtain the probability of an LRR over the study period. The model demonstrated good concordance for predicting LRR, with a concordance index of 0.641. Conclusions: The formulation of a practical, easy-to-use nomogram for calculating the risk of LRR in patients undergoing APBI will help guide the appropriate selection of patients for off-protocol utilization of APBI.

  2. A Pilot Study of Hypofractionated Stereotactic Radiation Therapy and Sunitinib in Previously Irradiated Patients With Recurrent High-Grade Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Wuthrick, Evan J., E-mail: evan.wuthrick@osumc.edu [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Curran, Walter J. [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Camphausen, Kevin [Department of Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland (United States); Lin, Alexander [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Glass, Jon; Evans, James; Andrews, David W. [Department of Neurological Surgery, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Axelrod, Rita [Department of Medical Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Shi, Wenyin; Werner-Wasik, Maria [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Haacke, E. Mark [Department of Radiology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan (United States); Department of Biomedical Engineering, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan (United States); Hillman, Gilda G. [Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan (United States); Dicker, Adam P. [Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2014-10-01

    Purpose/Objective(s): Angiogenic blockade with irradiation may enhance the therapeutic ratio of radiation therapy (RT) through vascular normalization. We sought to determine the safety and toxicity profile of continuous daily-dosed sunitinib when combined with hypofractionated stereotactic RT (fSRT) for recurrent high-grade gliomas (rHGG). Methods and Materials: Eligible patients had malignant high-grade glioma that recurred or progressed after primary surgery and RT. All patients received a minimum of a 10-day course of fSRT, had World Health Organization performance status of 0 to 1, and a life expectancy of >3 months. During fSRT, sunitinib was administered at 37.5 mg daily. The primary endpoint was acute toxicity, and response was assessed via serial magnetic resonance imaging. Results: Eleven patients with rHGG were enrolled. The fSRT doses delivered ranged from 30 to 42 Gy in 2.5- to 3.75-Gy fractions. The median follow-up time was 40 months. Common acute toxicities included hematologic disorders, fatigue, hypertension, and elevated liver transaminases. Sunitinib and fSRT were well tolerated. One grade 4 mucositis toxicity occurred, and no grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. One patient had a nearly complete response, and 4 patients had stable disease for >9 months. Two patients (18%) remain alive and progression-free >3 years from enrollment. The 6-month progression-free survival was 45%. Conclusions: Sunitinib at a daily dose of 37.5 mg given concurrently with hypofractionated stereotactic reirradiation for rHGG yields acceptable toxicities and an encouraging 6-month progression-free survival.

  3. Prospective evaluation of patient-reported quality-of-life outcomes following SBRT ± cetuximab for locally-recurrent, previously-irradiated head and neck cancer

    International Nuclear Information System (INIS)

    Vargo, John A.; Heron, Dwight E.; Ferris, Robert L.; Rwigema, Jean-Claude M.; Wegner, Rodney E.; Kalash, Ronny; Ohr, James; Kubicek, Greg J.; Burton, Steven

    2012-01-01

    Purpose: Stereotactic body radiotherapy (SBRT) has emerged as a promising salvage strategy for unresectable, previously-irradiated recurrent squamous cell carcinomas of the head and neck (rSCCHN). Here-in, we report the first prospective evaluation of patient-reported quality-of-life (PR-QoL) following re-irradiation with SBRT ± cetuximab for rSCCHN. Materials and methods: From November 2004 to May 2011, 150 patients with unresectable, rSCCHN in a previously-irradiated field receiving >40 Gy were treated with SBRT to 40–50 Gy in 5 fractions ± concurrent cetuximab. PR-QoL was prospectively acquired using University of Washington Quality-of-Life Revised (UW-QoL-R). Results: Overall PR-QoL, health-related PR-QoL, and select domains commonly affected by re-irradiation progressively increase following an initial 1-month decline with statistically significant improvements noted in swallowing (p = 0.025), speech (p = 0.017), saliva (p = 0.041), activity (p = 0.032) and recreation (p = 0.039). Conclusions: Especially for patients surviving >1-year, improved tumor control associated with SBRT re-irradiation may ameliorate decreased PR-QoL resulting from rSCCHN. These improvements in PR-QoL transcend all measured domains in a validated PR-QoL assessment tool independent of age, use of cetuximab, tumor volume, and interval since prior irradiation.

  4. 18F-fluorocholine PET-guided target volume delineation techniques for partial prostate re-irradiation in local recurrent prostate cancer

    International Nuclear Information System (INIS)

    Wang Hui; Vees, Hansjoerg; Miralbell, Raymond; Wissmeyer, Michael; Steiner, Charles; Ratib, Osman; Senthamizhchelvan, Srinivasan; Zaidi, Habib

    2009-01-01

    Background and purpose: We evaluate the contribution of 18 F-choline PET/CT in the delineation of gross tumour volume (GTV) in local recurrent prostate cancer after initial irradiation using various PET image segmentation techniques. Materials and methods: Seventeen patients with local-only recurrent prostate cancer (median = 5.7 years) after initial irradiation were included in the study. Rebiopsies were performed in 10 patients that confirmed the local recurrence. Following injection of 300 MBq of 18 F-fluorocholine, dynamic PET frames (3 min each) were reconstructed from the list-mode acquisition. Five PET image segmentation techniques were used to delineate the 18 F-choline-based GTVs. These included manual delineation of contours (GTV man ) by two teams consisting of a radiation oncologist and a nuclear medicine physician each, a fixed threshold of 40% and 50% of the maximum signal intensity (GTV 40% and GTV 50% ), signal-to-background ratio-based adaptive thresholding (GTV SBR ), and a region growing (GTV RG ) algorithm. Geographic mismatches between the GTVs were also assessed using overlap analysis. Results: Inter-observer variability for manual delineation of GTVs was high but not statistically significant (p = 0.459). In addition, the volumes and shapes of GTVs delineated using semi-automated techniques were significantly higher than those of GTVs defined manually. Conclusions: Semi-automated segmentation techniques for 18 F-choline PET-guided GTV delineation resulted in substantially higher GTVs compared to manual delineation and might replace the latter for determination of recurrent prostate cancer for partial prostate re-irradiation. The selection of the most appropriate segmentation algorithm still needs to be determined.

  5. 18F-fluorocholine PET-guided target volume delineation techniques for partial prostate re-irradiation in local recurrent prostate cancer.

    Science.gov (United States)

    Wang, Hui; Vees, Hansjörg; Miralbell, Raymond; Wissmeyer, Michael; Steiner, Charles; Ratib, Osman; Senthamizhchelvan, Srinivasan; Zaidi, Habib

    2009-11-01

    We evaluate the contribution of (18)F-choline PET/CT in the delineation of gross tumour volume (GTV) in local recurrent prostate cancer after initial irradiation using various PET image segmentation techniques. Seventeen patients with local-only recurrent prostate cancer (median=5.7 years) after initial irradiation were included in the study. Rebiopsies were performed in 10 patients that confirmed the local recurrence. Following injection of 300 MBq of (18)F-fluorocholine, dynamic PET frames (3 min each) were reconstructed from the list-mode acquisition. Five PET image segmentation techniques were used to delineate the (18)F-choline-based GTVs. These included manual delineation of contours (GTV(man)) by two teams consisting of a radiation oncologist and a nuclear medicine physician each, a fixed threshold of 40% and 50% of the maximum signal intensity (GTV(40%) and GTV(50%)), signal-to-background ratio-based adaptive thresholding (GTV(SBR)), and a region growing (GTV(RG)) algorithm. Geographic mismatches between the GTVs were also assessed using overlap analysis. Inter-observer variability for manual delineation of GTVs was high but not statistically significant (p=0.459). In addition, the volumes and shapes of GTVs delineated using semi-automated techniques were significantly higher than those of GTVs defined manually. Semi-automated segmentation techniques for (18)F-choline PET-guided GTV delineation resulted in substantially higher GTVs compared to manual delineation and might replace the latter for determination of recurrent prostate cancer for partial prostate re-irradiation. The selection of the most appropriate segmentation algorithm still needs to be determined.

  6. Patterns of Recurrence in Electively Irradiated Lymph Node Regions After Definitive Accelerated Intensity Modulated Radiation Therapy for Head and Neck Squamous Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Bosch, Sven van den, E-mail: sven.vandenbosch@radboudumc.nl; Dijkema, Tim; Verhoef, Lia C.G.; Zwijnenburg, Ellen M.; Janssens, Geert O.; Kaanders, Johannes H.A.M.

    2016-03-15

    Purpose: To provide a comprehensive risk assessment on the patterns of recurrence in electively irradiated lymph node regions after definitive radiation therapy for head and neck cancer. Methods and Materials: Two hundred sixty-four patients with stage cT2-4N0-2M0 squamous cell carcinoma of the oropharynx, larynx, or hypopharynx treated with accelerated intensity modulated radiation therapy between 2008 and 2012 were included. On the radiation therapy planning computed tomography (CT) scans from all patients, 1166 lymph nodes (short-axis diameter ≥5 mm) localized in the elective volume were identified and delineated. The exact sites of regional recurrences were reconstructed and projected on the initial radiation therapy planning CT scan by performing coregistration with diagnostic imaging of the recurrence. Results: The actuarial rate of recurrence in electively irradiated lymph node regions at 2 years was 5.1% (95% confidence interval 2.4%-7.8%). Volumetric analysis showed an increased risk of recurrence with increasing nodal volume. Receiver operating characteristic analysis demonstrated that the summed long- and short-axis diameter is a good alternative for laborious volume calculations, using ≥17 mm as cut-off (hazard ratio 17.8; 95% confidence interval 5.7-55.1; P<.001). Conclusions: An important risk factor was identified that can help clinicians in the pretreatment risk assessment of borderline-sized lymph nodes. Not overtly pathologic nodes with a summed diameter ≥17 mm may require a higher than elective radiation therapy dose. For low-risk elective regions (all nodes <17 mm), the safety of dose de-escalation below the traditional 45 to 50 Gy should be investigated.

  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. Re-irradiation after salvage mastectomy for local recurrence after a conservative treatment: a retrospective analysis of twenty patients (Nancy: 1988-2001)

    International Nuclear Information System (INIS)

    Racadot, S.; Marchal, C.; Charra-Brunaud, C.; Peiffert, D.; Bey, P.; Verhaeghe, J.L.

    2003-01-01

    Purpose. - To retrospectively assess the efficacy of post-mastectomy re-irradiation for local relapse of breast cancer. Patients and methods. - Twenty patients, initially treated by conservative surgery and radiotherapy (50 Gy in 25 fractions over 5 weeks) were treated from 1998 to 2001 for a local relapse by salvage mastectomy and re-irradiation (either electron or photon beams). Mean age was 53 years (31-71). Reasons for re-irradiation were that the local relapses were inflammatory (4 pts), multifocal (5 pts), cutaneous (5 pts), involved the nipple (3 pts) or because the surgical margins (either muscle or skin) were involved (3 pts). The median dose of re-irradiation was 45 Gy (33-65) in 15 fractions over 33 days. Mean follow-up was 48 months (5-97). Results. - Fifteen patients remained free of a second local recurrence and 10 were still alive, without metastasis. Neither the dose of re-irradiation nor the irradiated surfaces were prognostic factors of local control (P = 0.877 and P = 0.424). Five patients developed radiation-induced pneumonitis without functional respiratory impairment. The incidence of pneumonitis seemed to be related to the biological dose of re-irradiation (P = 0.037). Other late complications occurred such as pigmentation changes (12 pts), telangiectasia (8 pts), chondritis (2 pts), parietal fibrosis (7 pts), rib fractures (4 pts), severe pain (11 pts) and lymphedema (2 pts). The increase in biological equivalent dose was highly statistically linked with the occurrence of disabling pain (P = 0.0123). Conclusion. - Parietal re-irradiation achieves good and lasting local control with an acceptable rate of acute complications but with a risk of disabling late sequelae such as severe pain. (author)

  9. 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

  10. Postponed Is Not Canceled: Role of Craniospinal Radiation Therapy in the Management of Recurrent Infant Medulloblastoma—An Experience From the HIT-REZ 1997 and 2005 Studies

    Energy Technology Data Exchange (ETDEWEB)

    Müller, Klaus, E-mail: Klaus.Mueller@medizin.uni-leipzig.de [Department of Radiation Oncology, University of Leipzig Medical Center, Leipzig (Germany); Mynarek, Martin [Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg (Germany); Zwiener, Isabella [Institute for Medical Biostatistics, Epidemiology and Informatics, University of Mainz Medical Center, Mainz (Germany); Siegler, Nele [University Hospital of Essen, Pediatrics III, Essen (Germany); Zimmermann, Martina [Department of Pediatric Hematology and Oncology, Children' s Hospital, University Hospital of Bonn, Bonn (Germany); Christiansen, Hans [Department of Radiotherapy, Hannover Medical School, Hannover (Germany); Budach, Wilfried [Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Düsseldorf (Germany); Henke, Guido [Department of Radiation Oncology, Kantonsspital St. Gallen, St. Gallen (Switzerland); Warmuth-Metz, Monika [Department of Neuroradiology, University of Würzburg, Würzburg (Germany); Pietsch, Torsten [Department of Neuropathology, University of Bonn Medical Center, Bonn (Germany); Hoff, Katja von [Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg (Germany); Bueren, Andre von [Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg (Germany); Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Göttingen (Germany); Bode, Udo [Department of Pediatric Hematology and Oncology, Children' s Hospital, University Hospital of Bonn, Bonn (Germany); and others

    2014-04-01

    Purpose: To evaluate the efficacy of craniospinal irradiation (CSI) in the management of recurrent infant medulloblastoma after surgery and chemotherapy alone. Methods and Materials: Seventeen pediatric medulloblastoma patients registered in the HIT-REZ 1997 and 2005 studies underwent CSI as salvage treatment at first recurrence. All patients had achieved complete remission after first-line treatment consisting of surgery and chemotherapy. Eleven patients showed metastatic disease at relapse. Five patients underwent surgery prior to radiation therapy, which resulted in complete resection in 1 case. In 1 patient, complete resection of the residual tumor was performed after CSI. Eleven patients received chemotherapy prior, 6 patients during and 8 patients after CSI. All patients received CSI with a median total dose of 35.2 Gy, and all but 1 received a boost to the posterior fossa (median total dose, 55.0 Gy). Metastases were boosted with an individual radiation dose, depending on their location and extent. Results: During a median follow-up time of 6.2 years since recurrence, 11 patients showed progressive disease and died. Median progression-free (overall) survival was 2.9 ± 1.1 (3.8 ± 0.8) years. Progression-free survival (PFS) rates at 1, 3, and 5 years were 88% ± 8%, 46% ± 12%, and 40% ± 12%, respectively. Overall survival (OS) rates at 1, 3, and 5 years were 94% ± 6%, 58% ± 12%, and 39% ± 12%, respectively. For 11 patients with classic medulloblastoma, 3-year (and 5-year) PFS and OS were 62% ± 15% and 72% ± 14% (52% ± 16% and 51% ± 16%), respectively. On univariate analysis, metastatic disease was not associated with poorer progression-free and overall survival. Conclusions: Our results suggest that salvage treatment of relapsed medulloblastomas consisting of CSI and chemotherapy offers a second chance for cure, even for patients with classic histological findings. Metastatic disease at relapse did not have an impact

  11. 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.

  12. 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...

  13. 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

  14. The incidence of late neck recurrence in N0 maxillary sinus squamous cell carcinomas after superselective intra-arterial chemoradiotherapy without prophylactic neck irradiation.

    Science.gov (United States)

    Sakashita, Tomohiro; Homma, Akihiro; Hatakeyama, Hiromitsu; Kano, Satoshi; Mizumachi, Takatsugu; Furusawa, Jun; Yoshida, Daisuke; Fujima, Noriyuki; Onimaru, Rikiya; Tsuchiya, Kazuhiko; Yasuda, Koichi; Shirato, Hiroki; Fukuda, Satoshi

    2014-10-01

    The efficacy of elective neck irradiation (ENI) for patients with N0 carcinoma of the maxillary sinus has been controversial. The purpose of our study was to investigate the incidence of late neck recurrence and the mortality rate from regional disease in patients with N0 maxillary sinus cancer after superselective cisplatin infusion and concomitant radiotherapy (RADPLAT) without ENI. We retrospectively analyzed 48 patients with N0 maxillary sinus cancer who underwent RADPLAT. Chemotherapy consisted of 100-120 mg/m(2) superselective intra-arterial cisplatin administered at a median rate of four times weekly. Concurrent radiation therapy was administered at a median dose of 65 Gy without ENI. Late neck recurrence was observed in 8.3% (4/48). Three patients underwent salvage neck dissection and survived without any evidence of disease. The remaining patient did not undergo neck dissection due to coexistence with distant metastasis, and he died of regional disease. The mortality rate from regional disease was calculated to be 2% (1/48). The incidence of late neck recurrence was not frequent, and the mortality rate from regional disease was low. Salvage neck dissection was considered to be feasible for patients with late neck recurrence. When definitive radiotherapy and concomitant chemotherapy are applied, it is considered that ENI is not required for cases of N0 maxillary sinus cancer.

  15. 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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1993-03-15

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

  17. 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

  18. 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

  19. 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

  20. Preoperative irradiation and surgery for recurrent rectal cancer. Will intraoperative radiotherapy (IORT) be of additional benefit? A prospective study

    International Nuclear Information System (INIS)

    Wiig, Johan Nicolay; Tveit, Kjell Magne; Poulsen, Jan Peter; Olsen, Dag Rune; Giercksky, Karl-Erik

    2002-01-01

    Background: The therapeutic gain of surgery for recurrent rectal cancer is not clear, particularly with regard to the addition of intraoperative radiotherapy (IORT). Methods: Patients (107) with isolated pelvic recurrence of rectal cancer received preoperative external radiotherapy of 46-50 in 2 Gy fractions. At surgery 59 patients had IORT 12-18 Gy. Survival and local recurrence was analysed with regard to surgical resection stages and IORT. Results: Patients (44) had R0- and 39 R1-resections, 24 R2-resections or exploratory laparotomy. IORT was given most often after R1-resections, least in R0-patients. Estimated 5-year survival was overall around 30%, around 60% in the R0-, around 25% for R1- and 0% in R2-patients. Local recurrence was around 30% in the R0- and around 65% in R1-stage patients. R0-/R1-stage patients survived statistically significantly longer than the R2-group otherwise there was no statistical significant difference between IORT and non-IORT groups in any R-stages regarding overall survival or local recurrence. Conclusions: Macroscopic removal of the recurrence improves survival. Whether R0- is better than R1-resections is not clear. The effect of IORT is not a major one. IORT need be evaluated in randomised controlled trials

  1. Intraoperative Spillage of Favorable Histology Wilms Tumor Cells: Influence of Irradiation and Chemotherapy Regimens on Abdominal Recurrence. A Report From the National Wilms Tumor Study Group

    International Nuclear Information System (INIS)

    Kalapurakal, John A.; Li, Sierra M.; Breslow, Norman E.; Beckwith, J. Bruce; Ritchey, Michael L.; Shamberger, Robert C.; Haase, Gerald M.; Thomas, Patrick R.M.; Grundy, Paul; Green, Daniel M.; D'Angio, Giulio J.

    2010-01-01

    Purpose: We undertook this study to determine (1) the frequency with which spilled tumor cells of favorable histology produced intra-abdominal disease in patients treated with differing chemotherapy regimens and abdominal radiation therapy (RT) and (2) the patterns of relapse and outcomes in such patients. Methods and Materials: The influence of RT dose (0, 10, and 20 Gy), RT fields (flank, whole abdomen), and chemotherapy with dactinomycin and vincristine (2 drugs) vs. added doxorubicin (three drugs) on intra-abdominal tumor recurrence rates was analyzed by logistic regression in 450 patients. Each patient was considered at risk for two types of failure: flank and subdiaphragmatic beyond-flank recurrence, with the correlation between the two outcomes accounted for in the analyses. Results: The crude odds ratio for the risk of recurrence relative to no RT was 0.35 (0.15-0.78) for 10Gy and 0.08 (0.01-0.58) for 20Gy. The odds ratio for the risk of recurrence for doxorubicin to two drugs after adjusting for RT was not significant. For Stage II patients (NWTS-4), the 8-year event rates with and without spillage, respectively, were 79% and 87% for relapse-free survival (p = 0.07) and 90% and 95% for overall survival (p = 0.04). Conclusions: Irradiation (10 Gy or 20 Gy) reduced abdominal tumor recurrence rates after tumor spillage. Tumor spillage in Stage II patients reduced relapse-free survival and overall survival, but only the latter was of statistical significance. These data provide a basis for assessing the risks vs. benefits when considering treatment for children with favorable histology Wilms tumor and surgical spillage.

  2. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-09-03

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

  3. 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.

  4. 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.

  5. 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.

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

    Science.gov (United States)

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

    2002-01-15

    Medulloblastomas are small cell embryonal tumors of the cerebellum found predominantly in children, only slightly more than half of whom survive. Predicting favorable outcome has been difficult, and improved stratification clearly is required to avoid both undertreatment and overtreatment. Patients currently are staged clinically, but no pathologic staging system is in use. Two rare subtypes at extreme ends of the histologic spectrum, i.e., medulloblastomas with extensive nodularity and large cell/anaplastic medulloblastomas, are associated with better and worse clinical outcomes, respectively. However, there is little data about correlations between histologic features and clinical outcome for most patients with medulloblastomas that fall between these histologic extremes of nodularity and anaplasia. Therefore, the authors evaluated the clinical effects of increasing anaplasia and nodularity in a large group of children with medulloblastomas, hypothesizing that increasing nodularity would predict better clinical outcomes and that increasing anaplasia would presage less favorable results. Medulloblastomas from 330 Pediatric Oncology Group patients were evaluated histologically with respect to extent of nodularity, presence of desmoplasia, grade of anaplasia, and extent of anaplasia. Pathologic and clinical data were then compared using Kaplan-Meier and log-rank analyses. Increasing grade of anaplasia and extent of anaplasia were associated strongly with progressively worse clinical outcomes (P anaplasia (moderate or severe) was identified in 24% of medulloblastoma specimens. Neither increasing degrees of nodularity nor desmoplasia were associated significantly with longer survival. Moderate anaplasia and severe anaplasia were associated with aggressive clinical behavior in patients with medulloblastomas and were detected in a significant number of specimens (24%). Pathologic grading of medulloblastomas with respect to anaplasia may be of clinical utility.

  7. 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.

  8. 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

  9. 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.

  10. Dose Sparing of Brainstem and Spinal Cord for Re-Irradiating Recurrent Head and Neck Cancer with Intensity-Modulated Radiotherapy

    International Nuclear Information System (INIS)

    Chen, Chin-Cheng; Lee, Chen-Chiao; Mah, Dennis; Sharma, Rajiv; Landau, Evan; Garg, Madhur; Wu, Andrew

    2011-01-01

    Because of the dose limit for critical structures such as brainstem and spinal cord, administering a dose of 60 Gy to patients with recurrent head and neck cancer is challenging for those who received a previous dose of 60-70 Gy. Specifically, previously irradiated head and neck patients may have received doses close to the tolerance limit to their brainstem and spinal cord. In this study, a reproducible intensity-modulated radiation therapy (IMRT) treatment design is presented to spare the doses to brainstem and spinal cord, with no compromise of prescribed dose delivery. Between July and November 2008, 7 patients with previously irradiated, recurrent head and neck cancers were treated with IMRT. The jaws of each field were set fixed with the goal of shielding the brainstem and spinal cord at the sacrifice of partial coverage of the planning target volume (PTV) from any particular beam orientation. Beam geometry was arranged to have sufficient coverage of the PTV and ensure that the constraints of spinal cord o , patients could be treated by 18 fields. Six patients met these criteria and were treated in 25 minutes per fraction. One patient exceeded a 30 o Cobb's angle and was treated by 31 fields in 45 minutes per fraction. We have demonstrated a new technique for retreatment of head and neck cancers. The angle of cervical spine curvature plays an important role in the efficiency and effectiveness of our approach.

  11. Detection of tumor recurrence using technetium99m-tetrofosmin brain SPECT in patients with previously irradiated brain tumors

    International Nuclear Information System (INIS)

    Llamas A; Reyes A; Uribe, L F; Martinez T

    2004-01-01

    Objective: to assess the clinical utility of brain SPECT with Tc-99m Tetrofosmin to differentiate between tumor recurrence and radionecrosis in patients with primary brain tumors previously treated with external beam radiotherapy. Materials and methods: thirteen patients with clinical or radiological suspicion of tumor recurrence were studied with brain SPECT using 20-mCi of Tc-99m Tetrofosmin. Obtained images were interpreted by consensus between two experienced observers and subsequently classified as positive or negative for tumor viability. Results were compared to those of conventional diagnostic imaging techniques. Diagnostic test values and 95% confidence intervals were quantified. Results: SPECT results included 7 true-positives, 5 true-negatives and 1 false negative result. Conclusions: Tc-99m Tetrofosmin brain SPECT night be a useful alternative to diagnose recurrent brain tumors, especially with non-conclusive clinical and radiological findings

  12. [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.

  13. Irradiation with and without razoxane in the treatment of incompletely resected or inoperable recurrent rectal cancer. Results of a small randomized multicenter study

    International Nuclear Information System (INIS)

    Rhomberg, W.; Eiter, H.; Hammer, J.; Seewald, D.; Sedlmayer, F.; Schneider, B.

    2007-01-01

    Background and Purpose: In an earlier phase II study, irradiation together with razoxane was shown to improve local control in recurrent rectal cancer. Therefore, the Austrian Society of Radiooncology (OeGRO) initiated a randomized controlled trial in 1992 to compare this combined treatment versus radiation therapy alone. Patients and Methods: Between 1992 and 1999, 36 patients with localized recurrences of rectal cancer were randomized to receive radiotherapy without (group A) or with razoxane (group B). The prognostic variables of the two groups were similar except for a longer median latency period from initial surgery to local recurrence in group A. High-energy photons with daily fractions between 170 and 200 cGy were used. The median total radiation dose was 60 Gy in each group. The patients in group B received a median razoxane dose of 9.6 g (range, 5-12 g). Main outcome measures were local control, overall survival, and toxicity. Results: The combined treatment with razoxane increased the local control rate compared to radiotherapy alone (39% vs. 8%; p = 0.05). The median survival time was not different between the groups (20 months each). No patient in arm A but four of 18 patients in arm B survived 5 years. Acute toxic effects were of moderate degree in both groups. There were no substantial differences as to late side effects. Conclusion: Radiotherapy together with razoxane is superior to radiation treatment alone in recurrent rectal cancer as far as local control is concerned. In some patients, long-term survival was achieved with razoxane and radiotherapy. (orig.)

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  15. 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.

  16. Temporal lobe injury after re-irradiation of locally recurrent nasopharyngeal carcinoma using intensity modulated radiotherapy: clinical characteristics and prognostic factors.

    Science.gov (United States)

    Liu, Shuai; Lu, Taixiang; Zhao, Chong; Shen, Jingxian; Tian, Yunming; Guan, Ying; Zeng, Lei; Xiao, Weiwei; Huang, Shaomin; Han, Fei

    2014-09-01

    Temporal lobe injury (TLI) is a debilitating complication after radiotherapy for nasopharyngeal carcinoma (NPC), especially in patients who suffer treatment relapses and receive re-irradiation. We explored the clinical characteristics and prognostic factors of TLI in locally recurrent NPC (rNPC) patients after re-irradiation using intensity modulated radiotherapy (IMRT). A total of 454 temporal lobes (TLs) from 227 locally rNPC patients were reviewed. The clinical characteristics of TLI were analyzed. In the two radiotherapy courses, the equivalent dose in 2 Gy per fraction (EQD2) for the TLs was recalculated to facilitate comparison of the individual data. The median follow-up time was 31 (range, 3-127) months. After re-irradiation using IMRT, 31.3 % (71/227) of patients developed TLI. The median latency of TLI was 15 (range, 4-100) months. Univariate and multivariate analysis showed that the interval time (IT) between the two courses of radiotherapy and the summation of the maximum doses of the two radiotherapy courses (EQD2 - ∑max) were independent factors influencing TLI. The 5-year incidence of TLI for an IT ≤26 or >26 months was 35.9 and 53.7 % respectively (p = 0.024). The median maximum doses delivered to the injured TLs were significantly higher than was the case for the uninjured TLs after two courses of radiotherapy (135.3 and 129.8 Gy, respectively: p 2-year interval was found to be relatively safe.

  17. 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

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

    Science.gov (United States)

    2015-07-01

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

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

    Science.gov (United States)

    2017-09-01

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

  20. 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.

  1. 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

  2. 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.

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

    Science.gov (United States)

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

    2014-01-01

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

  4. 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.

  5. 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

  6. 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.

  7. Clinical Outcomes Among Children With Standard-Risk Medulloblastoma Treated With Proton and Photon Radiation Therapy: A Comparison of Disease Control and Overall Survival

    International Nuclear Information System (INIS)

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

    2016-01-01

    Purpose: The purpose of this study was to compare long-term disease control and overall survival between children treated with proton and photon radiation therapy (RT) for standard-risk medulloblastoma. Methods and Materials: This multi-institution cohort study includes 88 children treated with chemotherapy and proton (n=45) or photon (n=43) RT between 2000 and 2009. Overall survival (OS), recurrence-free survival (RFS), and patterns of failure were compared between the 2 cohorts. Results: Median (range) age was 6 years old at diagnosis (3-21 years) for proton patients versus 8 years (3-19 years) for photon patients (P=.011). Cohorts were similar with respect to sex, histology, extent of surgical resection, craniospinal irradiation (CSI) RT dose, total RT dose, whether the RT boost was delivered to the posterior fossa (PF) or tumor bed (TB), time from surgery to RT start, or total duration of RT. RT consisted of a median (range) CSI dose of 23.4 Gy (18-27 Gy) and a boost of 30.6 Gy (27-37.8 Gy). Median follow-up time is 6.2 years (95% confidence interval [CI]: 5.1-6.6 years) for proton patients versus 7.0 years (95% CI: 5.8-8.9 years) for photon patients. There was no significant difference in RFS or OS between patients treated with proton versus photon RT; 6-year RFS was 78.8% versus 76.5% (P=.948) and 6-year OS was 82.0% versus 87.6%, respectively (P=.285). On multivariate analysis, there was a trend for longer RFS with females (P=.058) and higher CSI dose (P=.096) and for longer OS with females (P=.093). Patterns of failure were similar between the 2 cohorts (P=.908). Conclusions: Disease control with proton and photon radiation therapy appears equivalent for standard risk medulloblastoma.

  8. Results of external beam irradiation for rectal carcinomas locally recurrent after local excision or electrocoagulation; Short communication

    Energy Technology Data Exchange (ETDEWEB)

    Shun Wong, C.; Cummings, B.J.; Keane, T.J.; O' Sullivan, Brian; Catton, C.N. (Princess Margaret Hospital, Toronto, ON (Canada))

    1991-10-01

    The outcome of 42 patients who developed locally recurrent rectal carcinoma after initial local excision or electrocoagulation was presented. Five patients received combined surgery and radiotherapy (XRT). The remaining 37 patients were managed by XRT alone. The overall 5 years actuarial survival and local control rates were 21 and 22 percent, respectively. For patients who received XRT alone, the 5 year actuarial survival and local control rates were 20 and 15 percent, resp. The corresponding figures were 35 and 40 percent for patients who received a total XRT dose of 50 Gy or more. One patient who underwent combined treatment developed rectal and bladder incontinence requiring surgery. For patients with rectal recurrence after initial conservative surgery, XRT is an alternative to abdominoperipheral resection if major resection is contraindicated. (author). 13 refs.; 2 tabs.

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  10. 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.

  11. 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

  12. 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.

  13. 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)

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

    International Nuclear Information System (INIS)

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

    1997-01-01

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

  15. Effects of recurrent irradiation and cross fertilization on improvement of cultivated tomato (Solanum lycopersicon L.) and wild tomato (Solanum pimpinellifolium L.)

    International Nuclear Information System (INIS)

    Nunoo, J.

    2010-01-01

    Two separate experiments were conducted to determine the effects of recurrent irradiation and cross fertilization on the improvement of fruit quality and plant architecture of two tomato species (Solanum lycopersicon L.) and (Solanum pimpinellifolium L.) in Ghana. In the first experiment, a variant line of the wild tomato (Solanum pimpinellifolium L.) (SP 300/30.4.2.4) previously obtained through irradiation with gamma rays at 300 Gy was re-irradiated with gamma rays at 150 Gy and 300 Gy using gamma irradiation. The second experiment involved hybridization of the same variant line (SP 300/30.4.2.4) with five cultivars of the cultivated tomato (Solanum lycopersicon L). Progeny were assessed in both M1 and M2 generations for the first experiment but only at the F 2 generation for the second experiment. Significant variations were observed in number of days to first flowering and 50% fruiting. Fruit size increased from 1.36 g and 1.67 g to 1.77 g and 2.66 g in the M 1 and M 2 generations respectively following re-irradiation at 300 Gy. Three 150 Gy treated plants at the M 1 generation and two 300 Gy treated plants at the M 2 generations exhibited erect growth habit compared to the parental line (SP 300/30.4.2.4) which was sprawling. A variant line among the 300 Gy treated plants had a fused fruit of fruit weight of 3.57 g with four locules. Also, hybridization involving five cultivars of the cultivated tomato (S. lycopersicon L.) as female parents and the variant line (SP 300/30.4.2.4) generated variability in several traits including plant architecture, days to flowering and fruiting, fruit weight and number of seeds per fruit in the F 2 generation. Variations in style-length, number of locules, fruit shape and colour were also observed among the plants in the F 2 generation. Generally, significant improvements were obtained with respect to plant architecture (that is reduced plant height), earliness and fruit quality (that is fruit size and colour). Although no

  16. 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.

  17. 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

  18. Radiobiological restrictions and tolerance doses of repeated single-fraction hdr-irradiation of intersecting small liver volumes for recurrent hepatic metastases

    Directory of Open Access Journals (Sweden)

    Wust Peter

    2010-05-01

    Full Text Available Abstract Background To assess radiobiological restrictions and tolerance doses as well as other toxic effects derived from repeated applications of single-fraction high dose rate irradiation of small liver volumes in clinical practice. Methods Twenty patients with liver metastases were treated repeatedly (2 - 4 times at identical or intersecting locations by CT-guided interstitial brachytherapy with varying time intervals. Magnetic resonance imaging using the hepatocyte selective contrast media Gd-BOPTA was performed before and after treatment to determine the volume of hepatocyte function loss (called pseudolesion, and the last acquired MRI data set was merged with the dose distributions of all administered brachytherapies. We calculated the BED (biologically equivalent dose for a single dose d = 2 Gy for different α/β values (2, 3, 10, 20, 100 based on the linear-quadratic model and estimated the tolerance dose for liver parenchyma D90 as the BED exposing 90% of the pseudolesion in MRI. Results The tolerance doses D90 after repeated brachytherapy sessions were found between 22 - 24 Gy and proved only slightly dependent on α/β in the clinically relevant range of α/β = 2 - 10 Gy. Variance analysis showed a significant dependency of D90 with respect to the intervals between the first irradiation and the MRI control (p 90 and the pseudolesion's volume. No symptoms of liver dysfunction or other toxic effects such as abscess formation occurred during the follow-up time, neither acute nor on the long-term. Conclusions Inactivation of liver parenchyma occurs at a BED of approx. 22 - 24 Gy corresponding to a single dose of ~10 Gy (α/β ~ 5 Gy. This tolerance dose is consistent with the large potential to treat oligotopic and/or recurrent liver metastases by CT-guided HDR brachytherapy without radiation-induced liver disease (RILD. Repeated small volume irradiation may be applied safely within the limits of this study.

  19. Randomized phase III trial (GORTEC 98-03) comparing re-irradiation plus chemotherapy versus methotrexate in patients with recurrent or a second primary head and neck squamous cell carcinoma, treated with a palliative intent

    International Nuclear Information System (INIS)

    Tortochaux, Jacques; Tao Yungan; Tournay, Elodie; Lapeyre, Michel; Lesaunier, Francois; Bardet, Etienne; Janot, Francois; Lusinchi, Antoine; Benhamou, Ellen; Bontemps, Patrick; Maingon, Philippe; Calais, Gilles; Daly-Schveitzer, Nicolas; Verrelle, Pierre; Bourhis, Jean

    2011-01-01

    Purpose: This randomized phase III trial investigated the potential benefit of concurrent re-irradiation, fluorouracil and hydroxyurea versus methotrexate for patients treated with palliative intent for recurrent or second primary head and neck squamous cell carcinoma (HNSCC) in previously irradiated area. Patients and methods: Patients with recurrent HNSCC or a second primary not amenable to curative-intent treatment were randomized to the R-RT arm (concurrent re-irradiation, fluorouracil and hydroxyurea) or to the Ch-T arm (methotrexate). The primary endpoint was overall survival (OS). Due to a very slow accrual, the trial was closed after inclusion of 57 patients. Results: Fifty-seven patients were included. All patients died in the two arms with a maximal follow-up of 5 years. Although four complete responses were achieved in R-RT arm, (none in Ch-T arm) re-irradiation did not improve OS compared with methotrexate (23% versus 22% at 1 year, NS). Sixteen patients experienced clinical grade ≥3 late toxicities (>6 months), 11 in R-RT arm and five in Ch-T arm. Conclusions: Premature discontinuation of the trial did not allow us to draw firm conclusions. However, there was no suggestion that concurrent re-irradiation, fluorouracil and hydroxyurea improved OS compared to methotrexate alone in patients treated with palliative intent for a recurrent or second primary HNSCC.

  20. Contralateral regional recurrence after elective unilateral neck irradiation in oropharyngeal carcinoma: A literature-based critical review.

    Science.gov (United States)

    Al-Mamgani, Abrahim; van Werkhoven, Erik; Navran, Arash; Karakullukcu, Baris; Hamming-Vrieze, Olga; Machiels, Melanie; van der Velden, Lilly-Ann; Vogel, Wouter V; Klop, W Martin

    2017-09-01

    The head and neck region has rich regional lymphatic network, with a theoretical risk on contralateral metastasis from oropharyngeal cancer (OPC). There is a long-standing convention to irradiate the great majority of these tumors electively to both sides of the neck to reduce the risk of contralateral regional failure (cRF), but this can induce significant toxicity. We aimed to identify patient groups where elective contralateral irradiation may safely be omitted. PubMed and EMBASE were searched for original full-text articles in English with a combination of search terms related to the end points: cRF in OPC primarily treated by radiotherapy only to the ipsilateral neck and identifying predictive factors for increased incidence of cRF. The data from the identified studies were pooled, the incidence of cRF was calculated and the correlation with different predictive factors was investigated. Eleven full-text articles met the inclusion criteria. In these studies, 1116 patients were treated to the ipsilateral neck alone. The mean incidence of cRF was 2.42% (range 0-5.9%, 95% CI 1.6-3.5%). The incidence of cRF correlated only with T-stage (p=0.008), and involvement of midline (p=0.001). However, the significant correlation with T-stage can be explained by the very low incidence of cRF among T1 (0.77%), and disappeared when the incidence of cRF was compared between T2, T3,and T4 (p=0.344). The incidence of cRF in patients with OPC is very low, with involvement of midline providing the most significant prognosticator. These results call for trials on unilateral elective irradiation in selected groups. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2016-04-01

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

  2. Targeting the Enhancer of Zeste Homologue 2 in Medulloblastoma

    Science.gov (United States)

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

    2012-01-01

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

  3. 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)

  4. Life years lost-comparing potentially fatal late complications after radiotherapy for pediatric medulloblastoma on a common scale

    DEFF Research Database (Denmark)

    Brodin, N. Patrik; Vogelius, Ivan R.; Maraldo, Maja V.

    2012-01-01

    The authors developed a framework for estimating and comparing the risks of various long-term complications on a common scale and applied it to 3 different techniques for craniospinal irradiation in patients with pediatric medulloblastoma. METHODS: Radiation dose-response parameters related......-modulated proton therapy (IMPT). RESULTS: Lung cancer contributed most to the estimated LYL, followed by myocardial infarction, and stomach cancer. The estimates of breast or thyroid cancer incidence were higher than those for lung and stomach cancer incidence, but LYL were lower because of the relatively good...

  5. 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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2003-06-01

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

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

    International Nuclear Information System (INIS)

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

    1993-01-01

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

  8. Protein kinase A regulatory subunit distribution in medulloblastoma

    International Nuclear Information System (INIS)

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

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Carvalho Neto Arnolfo de

    2003-01-01

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

  10. Evasion of Cell Senescence Leads to Medulloblastoma Progression

    Directory of Open Access Journals (Sweden)

    Lukas Tamayo-Orrego

    2016-03-01

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

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

    International Nuclear Information System (INIS)

    Carvalho Neto, Arnolfo de; Bertoldi, Guilherme A.

    2003-01-01

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

  12. ASC deficiency suppresses proliferation and prevents medulloblastoma incidence.

    Science.gov (United States)

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

    2015-01-15

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

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

    Science.gov (United States)

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

    2015-04-01

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

  14. Epigenetic Silencing of DKK3 in Medulloblastoma

    Directory of Open Access Journals (Sweden)

    André Oberthuer

    2013-04-01

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

  15. 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

  16. Apoptosis induced by knockdown of uPAR and MMP-9 is mediated by inactivation of EGFR/STAT3 signaling in medulloblastoma.

    Directory of Open Access Journals (Sweden)

    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

  17. A case of recurrent metastasis in the supraclavicular and axillary lymph nodes and vertebrae following irradiation and paclitaxel plus bevacizumab administration

    International Nuclear Information System (INIS)

    Nishiyama, Yasuyuki; Nishimura, Reiki; Ohsako, Tomofumi; Tashima, Rumiko; Nakano, Masahiro; Fujisue, Mamiko

    2013-01-01

    A 48-year-old woman with invasive ductal carcinoma of the left breast underwent breast-conserving surgery and axillary dissection; 19 months after surgery, she developed local recurrence. Subsequently, she underwent mastectomy and received endocrine therapy and chemotherapy. At 47 years of age, she developed pleural metastasis, which directly invaded the vertebrae as well as the right supraclavicular and right axillary lymph nodes. In addition, liver metastasis was observed. To avoid acute transverse myelopathy, the patient received radiation therapy to the vertebrae and the right supraclavicular and right axillary lymph nodes followed by paclitaxel plus bevacizumab administration. After 2 courses of paclitaxel plus bevacizumab, we observed a remarkable shrinkage of the vertebral tumor, and skin necrosis was observed in the right supraclavicular and right axillary region; in contrast, the liver metastasis had increased in size. After discontinuation of the combination therapy, the patient died of blood loss from the axillary skin defect. This wound healing complication might have arisen because of the synergistic effects of paclitaxel plus bevacizumab and irradiation. (author)

  18. 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

  19. 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

  20. 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.

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

    Science.gov (United States)

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

    2006-07-01

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

  2. 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

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

  4. 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.)

  5. 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 ...

  6. 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…

  7. 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

  8. The whole-genome landscape of medulloblastoma subtypes

    NARCIS (Netherlands)

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

    2017-01-01

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

  9. 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

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

    Science.gov (United States)

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

    2006-07-01

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

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

    Science.gov (United States)

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

    2017-04-25

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2000-01-01

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

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

    International Nuclear Information System (INIS)

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

    2000-01-01

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

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

    Science.gov (United States)

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

    2015-02-26

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

  16. Medulloblastoma. The identification of prognostic subgroups and implications for multimodality management

    International Nuclear Information System (INIS)

    Kopelson, G.; Linggood, R.M.; Kleinman, G.M.

    1983-01-01

    For 43 medulloblatoma patients who had five-and ten-year actuarial survival rates of 56%, prognostic factors of statistical significance included: T-stage, M-stage and histopathologic tumor score. Posterior fossa local control rates were also function of T-stage and TS. Combining TS with T-stage, patients fell into three prognostic and local control groups, which may have different future management implications: Small (T1,2) tumors of favorable (TS less than or equal to 5) histology had a 92% ten-year actuarial survival rate with 100% (8/8) local control; no change from current management is suggested. For the intermediate prognosis group, increasing the irradiation dose alone may improve survival because these tumors exhibited an irradiation dose-response relationship. However, it is the poor prognosis group which might be suitable for future adjuvant chemotherapy or radiosensitizer trials since there is no evidence that higher irradiation doses improve local control. This article identifies prognostic subgroups based on histologic type and TM staging in medulloblastoma patients which potentially may be utilized to improve therapeutic results, and confirms the value of staging patients with central nervous system malignancies

  17. A Prospective Phase 2 Trial of Reirradiation With Stereotactic Body Radiation Therapy Plus Cetuximab in Patients With Previously Irradiated Recurrent Squamous Cell Carcinoma of the Head and Neck

    Energy Technology Data Exchange (ETDEWEB)

    Vargo, John A. [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Ferris, Robert L. [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Department of Otolaryngology, Head and Neck Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Ohr, James [Division Medical Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Clump, David A. [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Davis, Kara S.; Duvvuri, Umamaheswar; Kim, Seungwon; Johnson, Jonas T. [Department of Otolaryngology, Head and Neck Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Bauman, Julie E.; Gibson, Michael K. [Division Medical Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Branstetter, Barton F. [Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (United States); Heron, Dwight E., E-mail: herond2@umpc.edu [Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (United States); Department of Otolaryngology, Head and Neck Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States)

    2015-03-01

    Purpose: Salvage options for unresectable locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN) are limited. Although the addition of reirradiation may improve outcomes compared to chemotherapy alone, significant toxicities limit salvage reirradiation strategies, leading to suboptimal outcomes. We therefore designed a phase 2 protocol to evaluate the efficacy of stereotactic body radiation therapy (SBRT) plus cetuximab for rSCCHN. Methods and Materials: From July 2007 to March 2013, 50 patients >18 years of age with inoperable locoregionally confined rSCCHN within a previously irradiated field receiving ≥60 Gy, with a Zubrod performance status of 0 to 2, and normal hepatic and renal function were enrolled. Patients received concurrent cetuximab (400 mg/m{sup 2} on day −7 and then 250 mg/m{sup 2} on days 0 and +8) plus SBRT (40-44 Gy in 5 fractions on alternating days over 1-2 weeks). Primary endpoints were 1-year locoregional progression-free survival and National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 graded toxicity. Results: Median follow-up for surviving patients was 18 months (range: 10-70). The 1-year local PFS rate was 60% (95% confidence interval [CI]: 44%-75%), locoregional PFS was 37% (95% CI: 23%-53%), distant PFS was 71% (95% CI: 54%-85%), and PFS was 33% (95% CI: 20%-49%). The median overall survival was 10 months (95% CI: 7-16), with a 1-year overall survival of 40% (95% CI: 26%-54%). At last follow-up, 69% died of disease, 4% died with disease, 15% died without progression, 10% were alive without progression, and 2% were alive with progression. Acute and late grade 3 toxicity was observed in 6% of patients respectively. Conclusions: SBRT with concurrent cetuximab appears to be a safe salvage treatment for rSCCHN of short overall treatment time.

  18. A Prospective Phase 2 Trial of Reirradiation With Stereotactic Body Radiation Therapy Plus Cetuximab in Patients With Previously Irradiated Recurrent Squamous Cell Carcinoma of the Head and Neck

    International Nuclear Information System (INIS)

    Vargo, John A.; Ferris, Robert L.; Ohr, James; Clump, David A.; Davis, Kara S.; Duvvuri, Umamaheswar; Kim, Seungwon; Johnson, Jonas T.; Bauman, Julie E.; Gibson, Michael K.; Branstetter, Barton F.; Heron, Dwight E.

    2015-01-01

    Purpose: Salvage options for unresectable locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN) are limited. Although the addition of reirradiation may improve outcomes compared to chemotherapy alone, significant toxicities limit salvage reirradiation strategies, leading to suboptimal outcomes. We therefore designed a phase 2 protocol to evaluate the efficacy of stereotactic body radiation therapy (SBRT) plus cetuximab for rSCCHN. Methods and Materials: From July 2007 to March 2013, 50 patients >18 years of age with inoperable locoregionally confined rSCCHN within a previously irradiated field receiving ≥60 Gy, with a Zubrod performance status of 0 to 2, and normal hepatic and renal function were enrolled. Patients received concurrent cetuximab (400 mg/m 2 on day −7 and then 250 mg/m 2 on days 0 and +8) plus SBRT (40-44 Gy in 5 fractions on alternating days over 1-2 weeks). Primary endpoints were 1-year locoregional progression-free survival and National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 graded toxicity. Results: Median follow-up for surviving patients was 18 months (range: 10-70). The 1-year local PFS rate was 60% (95% confidence interval [CI]: 44%-75%), locoregional PFS was 37% (95% CI: 23%-53%), distant PFS was 71% (95% CI: 54%-85%), and PFS was 33% (95% CI: 20%-49%). The median overall survival was 10 months (95% CI: 7-16), with a 1-year overall survival of 40% (95% CI: 26%-54%). At last follow-up, 69% died of disease, 4% died with disease, 15% died without progression, 10% were alive without progression, and 2% were alive with progression. Acute and late grade 3 toxicity was observed in 6% of patients respectively. Conclusions: SBRT with concurrent cetuximab appears to be a safe salvage treatment for rSCCHN of short overall treatment time

  19. 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

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

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    Stearns Duncan

    2011-02-01

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

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

    Science.gov (United States)

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

    2016-10-01

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

  2. 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.)

  3. 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

  4. 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

  5. Locoregional recurrence in patients suffering from a triple-negative breast cancer: interest of a systematic adjuvant ganglionary irradiation; Recidives locoregionales chez les patientes atteintes d'un cancer du sein triple-negatif: interet d'une irradiation ganglionnaire adjuvante systematique?

    Energy Technology Data Exchange (ETDEWEB)

    Clerc, J.; Sunyach, M.P.; Duruisseaux, M.; Mignotte, H.; Bajard, A.; Tredan, O.; Carrie, C.; Arnaud, A. [Centre Leon-Berard, Lyon (France)

    2011-10-15

    The authors report the assessment of locoregional recurrence percentage within women suffering from a triple-negative breast cancer without ganglionary attack, in order to examine the interest of a systematic adjuvant ganglionary irradiation. Nearly 250 women have been treated for a breast cancer between 1999 and 2009 in the Leon-Berard Centre in Lyons. All had surgery followed or not by a chemotherapy and/or a radiotherapy. The locoregional recurrence rate is not very high, but the authors cannot yet be sure to systematically propose this treatment. Short communication

  6. Recurrent varicocele

    Directory of Open Access Journals (Sweden)

    Katherine Rotker

    2016-01-01

    Full Text Available Varicocele recurrence is one of the most common complications associated with varicocele repair. A systematic review was performed to evaluate varicocele recurrence rates, anatomic causes of recurrence, and methods of management of recurrent varicoceles. The PubMed database was evaluated using keywords "recurrent" and "varicocele" as well as MESH criteria "recurrent" and "varicocele." Articles were not included that were not in English, represented single case reports, focused solely on subclinical varicocele, or focused solely on a pediatric population (age <18. Rates of recurrence vary with the technique of varicocele repair from 0% to 35%. Anatomy of recurrence can be defined by venography. Management of varicocele recurrence can be surgical or via embolization.

  7. 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.

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

    Science.gov (United States)

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

    2015-08-01

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

  10. 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.

  11. 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.

  12. 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.

  13. [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.

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

    Science.gov (United States)

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

    2018-05-15

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

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

    Directory of Open Access Journals (Sweden)

    Carolina Oliveira Rodini

    2010-12-01

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

  16. 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.

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

    NARCIS (Netherlands)

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

    2008-01-01

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

  18. 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.)

  19. 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...

  20. 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)

  1. Re-irradiation of metastatic spinal cord compression: A feasibility study by volumetric-modulated arc radiotherapy for in-field recurrence creating a dosimetric hole on the central canal

    International Nuclear Information System (INIS)

    Mancosu, Pietro; Navarria, Piera; Bignardi, Mario; Cozzi, Luca; Fogliata, Antonella; Lattuada, Paola; Santoro, Armando; Urso, Gaetano; Vigorito, Sabrina; Scorsetti, Marta

    2010-01-01

    When local recurrences arise within an irradiated region involving metastatic spinal cord compression, the dose limit to the spinal cord reduces the chance to re-treat the patient by 3D-conformational RT technique. The possibility of using volumetric modulated arc RT by RapidArc was evaluated for dose sparing at spinal cord level and preserving target coverage. A clinically satisfactory PTV coverage and dose sparing to the spinal cord were obtained. An upcoming trial on patients will provide clinical outcomes.

  2. 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.

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

    Science.gov (United States)

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

    2009-07-12

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

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

    Science.gov (United States)

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

    2017-10-01

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

  5. 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

  6. 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

  7. SU-E-J-274: Responses of Medulloblastoma Cells to Radiation Dosimetric Parameters in Intensity-Modulated Radiation Therapy

    International Nuclear Information System (INIS)

    Park, J; Park, J; Rogalla, S; Contag, C; Woo, D; Lee, D; Park, H; Suh, T

    2015-01-01

    Purpose: To evaluate radiation responses of the medulloblastoma cell line Daoy in intensity-modulated radiation therapy (IMRT), quantitative variations to variable radiation dosimetic parameters were tracked by bioluminescent images (BLIs). Methods: The luciferase and green fluorescent protein positive Daoy cells were cultured on dishes. The medulloblastoma cells irradiated to different dose rate, interval of fractionated doses, field margin and misalignment, and dose uniformity in IMRT were monitored using bioluminescent images. The cultured cells were placed into a dedicated acrylic phantom to deliver intensity-modulated fluences and calculate accurate predicted dose distribution. The radiation with dose rate from 0.5 Gy/min to 15 Gy/min was irradiated by adjusting monitor unit per minute and source-to-surface distances. The intervals of fractionated dose delivery were changed considering the repair time of double strand breaks (DSB) revealed by straining of gamma-H2AX.The effect of non-uniform doses on the cells were visualized by registering dose distributions and BLIs. The viability according to dosimetric parameters was correlated with bioluminescent intensities for cross-check of radiation responses. Results: The DSB and cell responses due to the first fractionated dose delivery significantly affected final tumor control rather than other parameters. The missing tumor volumes due to the smaller field margin than the tumor periphery or field misalignment caused relapse of cell responses on BLIs. The dose rate and gradient had effect on initial responses but could not bring out the distinguishable killing effect on cancer cells. Conclusion: Visualized and quantified bioluminescent images were useful to correlate the dose distributions with spatial radiation effects on cells. This would derive the effective combination of dose delivery parameters and fractionation. Radiation responses in particular IMRT configuration could be reflected to image based-dose re-optimization

  8. 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.

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Shah Keerti V

    2005-02-01

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

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

    Science.gov (United States)

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

    2005-01-01

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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. The whole-genome landscape of medulloblastoma subtypes

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  17. Re-irradiation after salvage mastectomy for local recurrence after a conservative treatment: a retrospective analysis of twenty patients (Nancy: 1988-2001); Re-irradiation parietale apres mastectomie de rattrapage pour recidive d'un cancer du sein apres traitement conservateur: etude retrospective sur 20 patientes (Nancy: 1988-2001)

    Energy Technology Data Exchange (ETDEWEB)

    Racadot, S.; Marchal, C.; Charra-Brunaud, C.; Peiffert, D.; Bey, P. [Centre Alexis-Vautrin, Service de Radiotherapie, 54 - Vandoeuvre-les-Nancy (France); Verhaeghe, J.L. [Centre Alexis-Vautrin, Service de Chirurgie, 54 - Vandoeuvre-les-Nancy (France)

    2003-12-01

    Purpose. - To retrospectively assess the efficacy of post-mastectomy re-irradiation for local relapse of breast cancer. Patients and methods. - Twenty patients, initially treated by conservative surgery and radiotherapy (50 Gy in 25 fractions over 5 weeks) were treated from 1998 to 2001 for a local relapse by salvage mastectomy and re-irradiation (either electron or photon beams). Mean age was 53 years (31-71). Reasons for re-irradiation were that the local relapses were inflammatory (4 pts), multifocal (5 pts), cutaneous (5 pts), involved the nipple (3 pts) or because the surgical margins (either muscle or skin) were involved (3 pts). The median dose of re-irradiation was 45 Gy (33-65) in 15 fractions over 33 days. Mean follow-up was 48 months (5-97). Results. - Fifteen patients remained free of a second local recurrence and 10 were still alive, without metastasis. Neither the dose of re-irradiation nor the irradiated surfaces were prognostic factors of local control (P = 0.877 and P = 0.424). Five patients developed radiation-induced pneumonitis without functional respiratory impairment. The incidence of pneumonitis seemed to be related to the biological dose of re-irradiation (P = 0.037). Other late complications occurred such as pigmentation changes (12 pts), telangiectasia (8 pts), chondritis (2 pts), parietal fibrosis (7 pts), rib fractures (4 pts), severe pain (11 pts) and lymphedema (2 pts). The increase in biological equivalent dose was highly statistically linked with the occurrence of disabling pain (P = 0.0123). Conclusion. - Parietal re-irradiation achieves good and lasting local control with an acceptable rate of acute complications but with a risk of disabling late sequelae such as severe pain. (author)

  18. 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.

  19. 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

    had clinically apparent radiation-induced esophagitis. The mean white blood count (WBC) nadir was 2.5/dl, and hematologic recovery occurred in all within 4 weeks of completing HFRT without the need of granulocyte-colony-stimulating factor. Two patients refused adjuvant chemotherapy, 3 patients experienced tumor progression during chemotherapy, and 2 of 18 remaining patients could not tolerate the full 9 months owing to hematologic toxicity. Of the 15 patients (93%) in Group 1, 14 remain in continuous remission for a median of 78 months, and none have died. Two of four patients in Group 2 are in continuous remission at 67 and 35 months, and two died at 18 and 30 months. One of the two patients in Group 2 who died refused adjuvant chemotherapy and developed tumor progression in the bone marrow. None of the three patients in Group 3 with evaluable disease (M3) had a complete response to therapy, and eventually all four died of progressive or recurrent disease. Conclusion: This multimodality protocol is feasible in the short term, and long-term monitoring of neurocognitive and neuroendocrine effects are in progress. Excellent long-term disease control has been achieved for medullo-blastoma patients with high T stages who were M0 at diagnosis (Group 1), the majority of whom had gross total resections. This group has a progression-free survival of 95% after a median period of follow-up of 6.5 years. Alternative treatment strategies must be developed for patients with high M stages, as five of seven patients died of progressive or recurrent disease

  20. Ototoxicity evaluation in medulloblastoma patients treated with involved field boost using intensity-modulated radiation therapy (IMRT): a retrospective review

    International Nuclear Information System (INIS)

    Vieira, Wilson Albieri; Nadalin, Wladimir; Odone Filho, Vicente; Petrilli, Antonio Sergio; Weltman, Eduardo; Chen, Michael Jenwei; Silva, Nasjla Saba da; Cappellano, Andrea Maria; Pereira, Liliane Desgualdo; Gonçalves, Maria Ines Rabelo; Ferrigno, Robson; Hanriot, Rodrigo Morais

    2014-01-01

    Ototoxicity is a known side effect of combined radiation therapy and cisplatin chemotherapy for the treatment of medulloblastoma. The delivery of an involved field boost by intensity modulated radiation therapy (IMRT) may reduce the dose to the inner ear when compared with conventional radiotherapy. The dose of cisplatin may also affect the risk of ototoxicity. A retrospective study was performed to evaluate the impact of involved field boost using IMRT and cisplatin dose on the rate of ototoxicity. Data from 41 medulloblastoma patients treated with IMRT were collected. Overall and disease-free survival rates were calculated by Kaplan-Meier method Hearing function was graded according to toxicity criteria of Pediatric Oncology Group (POG). Doses to inner ear and total cisplatin dose were correlated with hearing function by univariate and multivariate data analysis. After a mean follow-up of 44 months (range: 14 to 72 months), 37 patients remained alive, with two recurrences, both in spine with CSF involvement, resulting in a disease free-survival and overall survival of 85.2% and 90.2%, respectively. Seven patients (17%) experienced POG Grade 3 or 4 toxicity. Cisplatin dose was a significant factor for hearing loss in univariate analysis (p < 0.03). In multivariate analysis, median dose to inner ear was significantly associated with hearing loss (p < 0.01). POG grade 3 and 4 toxicity were uncommon with median doses to the inner ear bellow 42 Gy (p < 0.05) and total cisplatin dose of less than 375 mg/m 2 (p < 0.01). IMRT leads to a low rate of severe ototoxicity. Median radiation dose to auditory apparatus should be kept below 42 Gy. Cisplatin doses should not exceed 375 mg/m 2

  1. Recurrent Meningitis.

    Science.gov (United States)

    Rosenberg, Jon; Galen, Benjamin T

    2017-07-01

    Recurrent meningitis is a rare clinical scenario that can be self-limiting or life threatening depending on the underlying etiology. This review describes the causes, risk factors, treatment, and prognosis for recurrent meningitis. As a general overview of a broad topic, the aim of this review is to provide clinicians with a comprehensive differential diagnosis to aide in the evaluation and management of a patient with recurrent meningitis. New developments related to understanding the pathophysiology of recurrent meningitis are as scarce as studies evaluating the treatment and prevention of this rare disorder. A trial evaluating oral valacyclovir suppression after HSV-2 meningitis did not demonstrate a benefit in preventing recurrences. The data on prophylactic antibiotics after basilar skull fractures do not support their use. Intrathecal trastuzumab has shown promise in treating leptomeningeal carcinomatosis from HER-2 positive breast cancer. Monoclonal antibodies used to treat cancer and autoimmune diseases are new potential causes of drug-induced aseptic meningitis. Despite their potential for causing recurrent meningitis, the clinical entities reviewed herein are not frequently discussed together given that they are a heterogeneous collection of unrelated, rare diseases. Epidemiologic data on recurrent meningitis are lacking. The syndrome of recurrent benign lymphocytic meningitis described by Mollaret in 1944 was later found to be closely related to HSV-2 reactivation, but HSV-2 is by no means the only etiology of recurrent aseptic meningitis. While the mainstay of treatment for recurrent meningitis is supportive care, it is paramount to ensure that reversible and treatable causes have been addressed for further prevention.

  2. 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

  3. 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

  4. 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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2014-12-24

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

  7. 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.

  8. 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.

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

    Science.gov (United States)

    2015-10-01

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

  10. 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.)

  11. 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

  12. 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.

  13. 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.

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

    Directory of Open Access Journals (Sweden)

    Robert C Castellino

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

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. The effects of postoperative irradiation on loco-regional tumor control and survival in patients with head and neck carcinomas by tumor subsites and relative risk factors for recurrence

    International Nuclear Information System (INIS)

    Schmidt-Ullrich, Rupert K.; Johnson, Christopher R.; Payne, Cheryl; Lu Jiandong; Han, Daniel

    1997-01-01

    Purpose/Objective: This study reports on a unique experience in the management of patients with advanced head and neck squamous cell carcinomas (HNSCC) in which, between 1982 and 1990, patients with varied risk for recurrence were either referred for immediate postoperative irradiation by one surgical group or offered radiotherapy after surgical failure by the other. We have previously demonstrated in patients with high risk for recurrence that combined surgery and postoperative radiotherapy (S/RT) resulted in improved loco-regional tumor control (LRC) and overall patient survival (OS) for the entire patient cohort. This updated and expanded analysis describes the benefit of postoperative irradiation for patients with HNSCC depending upon relative risk factors for recurrence and different subsites of primary tumors. Materials and Methods: Of 219 patients, 190 were evaluable because of tumor locations in the major subsites analyzed, i.e. oral cavity (OC), oropharynx (OP), hypopharynx (HP), and larynx (L). Depending upon the philosophy of the two surgical groups, 79 patients were treated with combined S/RT and 111 with S alone with a >90% compliance. Minimum 2-year follow-up applies to all data reported. The two patient groups were well balanced with respect to tumor stages (AJCC 1983) and other patient characteristics. Histopathological review revealed 88 cases with one risk factor for recurrence, 49 patients with positive resection margin (PRM) and 39 with extracapsular extension (ECE); an additional 22 patients presented with both risk factors and 80 patients were found to have no risk factors. S, consisting of wide local excisions or radical resections including neck dissections, and postoperative RT with doses between 50 and 70 Gy were similar for both groups. Statistical evaluations consisted of Kaplan-Meier analyses to calculate LRC and OS rates and of multivariate Cox's proportional hazard models to estimate significance of treatment effects including S vs. S

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

    International Nuclear Information System (INIS)

    Aoki, Yoshiro

    1986-01-01

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

  1. Details of recurrence sites after elective nodal irradiation (ENI) using 3D-conformal radiotherapy (3D-CRT) combined with chemotherapy for thoracic esophageal squamous cell carcinoma--a retrospective analysis.

    Science.gov (United States)

    Yamashita, Hideomi; Okuma, Kae; Wakui, Reiko; Kobayashi-Shibata, Shino; Ohtomo, Kuni; Nakagawa, Keiichi

    2011-02-01

    To describe patterns of recurrence of elective nodal irradiation (ENI) in definitive chemoradiotherapy (CRT) for thoracic esophageal squamous cell carcinoma (SqCC) using 3D-conformal radiotherapy. One hundred and twenty-six consecutive patients with stages I-IVB thoracic esophageal SqCC newly diagnosed between June 2000 and July 2009 and treated with 3D-CRT in our institution were recruited from our database. Definitive CRT consisted of two cycles of nedaplatin/5FU repeated every 4 weeks, with concurrent radiation therapy of 50-50.4 Gy in 25-28 fractions. Until completion, radiotherapy was delivered to the N1 and M1a lymph nodes as ENI in addition to gross tumor volume. All 126 patients were included in this analysis, and their tumors were staged as follows: T1/T2/T3/T4, 28/18/54/26; N0/N1, 50/76; M0/M1a/M1b, 91/5/30. The mean follow-up period for the 63 surviving patients was 28.3 (±22.8) months. Eighty-seven patients (69%) achieved complete response (CR) without any residual tumor at least once after completion of CRT. After achieving CR, each of 40 patients experienced failures (local=20 and distant=20) and no patient experienced elective nodal failure without having any other site of recurrence. The upper thoracic esophageal carcinoma showed significantly more (34%) relapses at the local site than the middle (9%) or lower thoracic (11%) carcinomas. The 2-year and 3-year overall survival was 56% and 43%, respectively. The 1-year, 2-year and 3-year disease-free survival was 46%, 38% and 33%, respectively. In CRT for esophageal SqCC, ENI was effective for preventing regional nodal failure. The upper thoracic esophageal carcinomas had significantly more local recurrences than the middle or lower thoracic sites. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  2. 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).

  3. The whole-genome landscape of medulloblastoma subtypes

    Science.gov (United States)

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

    2018-01-01

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

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

    International Nuclear Information System (INIS)

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

    2004-01-01

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

  5. 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.

  6. OS7.7 Feasibility and toxicity of concomitant radiochemotherapy with vincristine in adult patients with medulloblastoma - results from the NOA-07 trial

    Science.gov (United States)

    Seidel, C.; Reimers, C.; Beier, D.; Pietsch, T.; Warmuth-Metz, M.; Bogdahn, U.; Kortmann, R.; Hau, P.

    2016-01-01

    Abstract Introduction: Medulloblastoma is a tumor of the cerebellum that is rare in adults with an incidence of about 0.6 cases per million per year. In children the introduction of chemotherapy with cisplatin, lomustine and vincristine in combination with craniospinal radiotherapy led to a significant improvement of overall survival. In adults, this regimen was never prospectively investigated in a clinical trial. Methods. The NOA-07 trial is a prospective single arm Phase II study to evaluate toxicity of craniospinal irradiation (1.6 Gy/35.2 Gy, posterior fossa boost 1.8 Gy/55.0 Gy) in combination with vincristine (1.5 mg/m2 weekly, ceiling dose 2.0 mg) followed by adjuvant chemotherapy with a maximum 8 of 6-weekly cycles of cisplatin (70 mg/m2, day 1), lomustine (75 mg/m2, day 1) and vincristine (1.5 g/m2, ceiling dose 2.0 mg, day 1, 8, 15) in adults with medulloblastoma. Here, we report on feasibility and toxicity of the concomitant radiochemotherapy. Results. 30 patients with medulloblastoma were recruited in 15 German centers. Radiotherapy was completed in all patients. Treatment interruptions occurred in 3/30 patients (toxicity related: 2, compliance: 1). Leukopenia was the major toxicity with grade 3 and 4 (CTC Version 3.0) occurring in 11 of 30 patients and 1 of 30 patients, respectively. Grade 3 to 4 thrombocytopenia occurred in 1 patient. Grade 3 to 4 infections occurred in 3 patients. Polyneuropathy due to vincristine was the most prevalent adverse event (Grade 1: 5, Grade 2: 4, Grade 3: 5 of 30 patients). Frequent but less severe toxicities involved sickness, dermatitis and alopecia. Conclusion. Concomitant radiochemotherapy with vincristine was feasible in adults with medulloblastoma. Leukopenia and polyneuropathy are major complications, pointing out that polyneuropathy occurs already early in treatment after application of only 1 to 6 doses in a substantial number of patients. Toxicity of the complete treatment protocol including

  7. RapidArc, intensity modulated photon and proton techniques for recurrent prostate cancer in previously irradiated patients: a treatment planning comparison study

    International Nuclear Information System (INIS)

    Weber, Damien C; Miralbell, Raymond; Wang, Hui; Cozzi, Luca; Dipasquale, Giovanna; Khan, Haleem G; Ratib, Osman; Rouzaud, Michel; Vees, Hansjoerg; Zaidi, Habib

    2009-01-01

    A study was performed comparing volumetric modulated arcs (RA) and intensity modulation (with photons, IMRT, or protons, IMPT) radiation therapy (RT) for patients with recurrent prostate cancer after RT. Plans for RA, IMRT and IMPT were optimized for 7 patients. Prescribed dose was 56 Gy in 14 fractions. The recurrent gross tumor volume (GTV) was defined on 18 F-fluorocholine PET/CT scans. Plans aimed to cover at least 95% of the planning target volume with a dose > 50.4 Gy. A maximum dose (D Max ) of 61.6 Gy was allowed to 5% of the GTV. For the urethra, D Max was constrained to 37 Gy. Rectal D Median was < 17 Gy. Results were analyzed using Dose-Volume Histogram and conformity index (CI 90 ) parameters. Tumor coverage (GTV and PTV) was improved with RA (V 95% 92.6 ± 7.9 and 83.7 ± 3.3%), when compared to IMRT (V 95% 88.6 ± 10.8 and 77.2 ± 2.2%). The corresponding values for IMPT were intermediate for the GTV (V 95% 88.9 ± 10.5%) and better for the PTV (V 95% 85.6 ± 5.0%). The percentages of rectal and urethral volumes receiving intermediate doses (35 Gy) were significantly decreased with RA (5.1 ± 3.0 and 38.0 ± 25.3%) and IMPT (3.9 ± 2.7 and 25.1 ± 21.1%), when compared to IMRT (9.8 ± 5.3 and 60.7 ± 41.7%). CI 90 was 1.3 ± 0.1 for photons and 1.6 ± 0.2 for protons. Integral Dose was 1.1 ± 0.5 Gy*cm 3 *10 5 for IMPT and about a factor three higher for all photon's techniques. RA and IMPT showed improvements in conformal avoidance relative to fixed beam IMRT for 7 patients with recurrent prostate cancer. IMPT showed further sparing of organs at risk

  8. 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.

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

    Science.gov (United States)

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

    2017-03-01

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

  10. Recurrent vulvovaginitis.

    Science.gov (United States)

    Powell, Anna M; Nyirjesy, Paul

    2014-10-01

    Vulvovaginitis (VV) is one of the most commonly encountered problems by a gynecologist. Many women frequently self-treat with over-the-counter medications, and may present to their health-care provider after a treatment failure. Vulvovaginal candidiasis, bacterial vaginosis, and trichomoniasis may occur as discreet or recurrent episodes, and have been associated with significant treatment cost and morbidity. We present an update on diagnostic capabilities and treatment modalities that address recurrent and refractory episodes of VV. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Absorbed dose distribution analyses in irradiation with adjacent fields

    International Nuclear Information System (INIS)

    Cudalbu, C.; Onuc, C.; Andrada, S.

    2002-01-01

    Because the special irradiation technique with adjacent fields is the most used in the case of medulloblastoma treatment, we consider very important to specify some general information about medulloblastoma. This malignant disease has a large incidence in children with age between 5-7 years. This tumor usually originates in the cerebellum and is referred to as primitive undifferentiated tumor. It may spread contiguously to the cerebellar peduncle, floor of the fourth ventricle, into the cervical spine. In addition, it may spread via the cerebrospinal fluid intracranially and/or to the spinal cord. For this purpose it is necessary to perform a treatment technique with cranial tangential fields combined with adjacent fields for the entire spinal cord to achieve a perfect coverage of the zones with malignant cells. The treatment in this case is an association between surgery-radio-chemotherapy, where the radiotherapy has a very important roll and a curative purpose. This is due to the fact that the migration of malignant cells in the body can't be controlled by surgery. Because of this special irradiation technique used in medulloblastoma treatment, we chase to describe in this paper this complex type of irradiation where the implications of the beams divergence in doses distribution are essentials

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

    Science.gov (United States)

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

    2016-03-01

    Adult medulloblastoma is a potentially curable malignant entity with an incidence of 0.5-1 per million. Valid data on prognosis, treatment, and demographics are lacking, as most current knowledge stems from retrospective studies. Surgical resection followed by radiotherapy are accepted parts of treatment regimes; however, established prognostic factors and data clarifying the role of chemotherapy are missing. We investigated 227 publications from 1969-2013, with 907 identifiable, individual patients being available for meta-analysis. Demographic data, risk stratification, and treatment of these patients were similar to previous cohorts. The median overall survival (mOS) was 65 months (95% CI: 54.6-75.3) , the 5-year overall survival was 50.9% with 16% of the patients dying more than 5 years after diagnosis. Incomplete resection, clinical and radiological signs for brainstem infiltration, and abstinence from radiotherapy were predictive of worse outcome. Metastatic disease at tumor recurrence was identified as a new prognostic factor, while neither metastasis at initial diagnosis nor desmoplastic/classic histology was correlated with survival. Patients receiving chemotherapy first-line survived significantly longer (mOS: 108 mo, 95% CI: 68.6-148.4) than patients treated with radiation alone (mOS: 57 mo, 95% CI: 39.6-74.4) or patients who received chemotherapy at tumor recurrence. This effect was not biased by tumor stage or decade of treatment. Importantly, (neo)adjuvant chemotherapy also significantly increased the chance for long-term survival (>5 y) compared with radiotherapy alone or chemotherapy at tumor recurrence. This meta-analysis clarifies relevant prognostic factors and suggests that chemotherapy as part of first-line therapy improves overall survival and increases the proportion of patients with long-term survival. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions

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

    DEFF Research Database (Denmark)

    Dagmar, Dagmar; Proescholdt, Martin; Reinert, Christiane

    2018-01-01

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

  14. 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.

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    Moatasem El-Ayadi

    2018-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Sara Badodi

    2017-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Gustavo A Barisone

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

  19. Severe encephalopathy after high-dose chemotherapy with autologous stem cell support for brain tumours

    NARCIS (Netherlands)

    van den Berkmortel, F.; Gidding, C.; de Kanter, M.; Punt, C. J. A.

    2006-01-01

    Recurrent medulloblastoma carries a poor prognosis. Long-term survival has been obtained with high-dose chemotherapy with autologous stem cell transplantation and secondary irradiation. A 21-year-old woman with recurrent medulloblastoma after previous chemotherapy and radiotherapy is presented. The

  20. 18F-FET PET prior to recurrent high-grade glioma re-irradiation-additional prognostic value of dynamic time-to-peak analysis and early static summation images?

    Science.gov (United States)

    Fleischmann, Daniel F; Unterrainer, Marcus; Bartenstein, Peter; Belka, Claus; Albert, Nathalie L; Niyazi, Maximilian

    2017-04-01

    Most high-grade gliomas (HGG) recur after initial multimodal therapy and re-irradiation (Re-RT) has been shown to be a valuable re-treatment option in selected patients. We evaluated the prognostic value of dynamic time-to-peak analysis and early static summation images in O-(2- 18 F-fluoroethyl)-l-tyrosine ( 18 F-FET) PET for patients treated with Re-RT ± concomitant bevacizumab. We retrospectively analyzed 72 patients suffering from recurrent HGG with 18 F-FET PET prior to Re-RT. PET analysis revealed the maximal tumor-to-background-ratio (TBR max ), the biological tumor volume, the number of PET-foci and pattern of time-activity-curves (TACs; increasing vs. decreasing). Furthermore, the novel PET parameters early TBR max (at 5-15 min post-injection) and minimal time-to-peak (TTP min ) were evaluated. Additional analysis was performed for gender, age, KPS, O6-methylguanine-DNA methyltransferase methylation status, isocitrate dehydrogenase 1 mutational status, WHO grade and concomitant bevacizumab therapy. The influence of PET and clinical parameters on post-recurrence survival (PRS) was investigated. Shorter TTP min was related to shorter PRS after Re-RT with 6 months for TTP min  25 min (p = 0.027). TTP min had a significant impact on PRS both on univariate (p = 0.027; continuous) and multivariate analysis (p = 0.011; continuous). Other factors significantly related to PRS on multivariate analysis were increasing vs. decreasing TACs (p = 0.008) and Karnofsky Performance Score (p = 0.015; PET parameters were not significantly related to PRS on univariate analysis. Dynamic 18 F-FET PET with TTP min provides a high prognostic value for recurrent HGG prior to Re-RT, whereas early TBR max does not. Dynamic 18 F-FET PET using TTP min might help to personalize Re-RT treatment regimens in future through voxelwise TTP min analysis for dose painting purposes and PET-guided dose escalation.

  1. 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.

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

    Directory of Open Access Journals (Sweden)

    D.P. Ivanov

    2016-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Frederique Zindy

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

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    Al-Otaibi Faisal

    2012-05-01

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

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

    Science.gov (United States)

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

    2016-11-01

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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

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

    Science.gov (United States)

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

    2013-08-01

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

  14. 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

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

    Science.gov (United States)

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

    2018-03-01

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

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  17. 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...

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

    Science.gov (United States)

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

    2005-10-01

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

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

    Science.gov (United States)

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

    2004-01-01

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

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

    Science.gov (United States)

    Elwood, J Mark; Aye, Phyu Sin

    2017-02-17

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

  1. 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.

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

    Science.gov (United States)

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

    2008-03-15

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

  3. 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)

  4. 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

  5. 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

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

    Directory of Open Access Journals (Sweden)

    Marcel Kool

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

  7. Postoperative beta irradiation in the treatment of pterygium

    International Nuclear Information System (INIS)

    Rahman, S.M.; Chung, C.K.; Constable, W.C.

    1979-01-01

    High recurrence rates are reported after surgical treatment of ptergyia. With the use of beta irradiation, the recurrence rate drops dramatically. This paper describes technic and dosage used in a group of patients receiving postoperative beta irradiation. Two thirds of these patients, however, had at least two surgical procedures. A recurrence rate of 3.5% was observed, with no apparent morbidity

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

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    Lowell Evan Michael

    2008-12-01

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

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

    Science.gov (United States)

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

    2017-03-01

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

  10. 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 

  11. 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.

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

    Science.gov (United States)

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

    2016-01-01

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

  13. 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.

  14. An evaluation of factors predicting breast recurrence and prognosis after recurrence, on distinguishing intramammary and extramammary recurrence, in breast-conserving surgery

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, Reiki; Nagao, Kazuharu; Miyayama, Haruhiko [Kumamoto City Hospital (Japan)] (and others)

    2001-06-01

    Recurrence of cancer in the breast is an important problem in breast-conserving therapy. We evaluated risk factors for recurrence from the viewpoint of recurrence type and outcome after recurrence. Of 533 cases of breast cancer treated with breast-conserving surgery from April 1989 through July 2000, disease in 66 recurred (12.4%) and were classified as 23 cases of breast recurrence only, 16 cases of both breast recurrence and distant metastasis, and 27 cases of distant metastasis only. The clinical factors examined included age, lymphatic invasion, nodal status, extensive intraductal component (EIC), proliferative activity, and estrogen receptor (ER) status. Of the 39 cases of breast recurrence, 19 had intramammary tumors and 20 had extramammary tumors of the skin, subcutaneous tissue, or muscle, including 8 cases with inflammatory breast recurrence. Multivariate analysis showed that factors correlated with breast recurrence were age, ER status, proliferative activity, and surgical margin. EIC-comedo was related to intramammary recurrence, whereas lymphatic invasion and nodal status were related to extramammary recurrence. Postoperative irradiation was an effective treatment for tumors in young women and tumors with positive margins or a comedo component. Outcome after breast recurrence depended on nodal status at primary operation, and survival rates were worst in patients with inflammatory breast recurrence. In conclusion, age, EIC-comedo status, the surgical margin, and negative ER status were correlated with breast recurrence. Countermeasures against these factors should be investigated. (author)

  15. An evaluation of factors predicting breast recurrence and prognosis after recurrence, on distinguishing intramammary and extramammary recurrence, in breast-conserving surgery

    International Nuclear Information System (INIS)

    Nishimura, Reiki; Nagao, Kazuharu; Miyayama, Haruhiko

    2001-01-01

    Recurrence of cancer in the breast is an important problem in breast-conserving therapy. We evaluated risk factors for recurrence from the viewpoint of recurrence type and outcome after recurrence. Of 533 cases of breast cancer treated with breast-conserving surgery from April 1989 through July 2000, disease in 66 recurred (12.4%) and were classified as 23 cases of breast recurrence only, 16 cases of both breast recurrence and distant metastasis, and 27 cases of distant metastasis only. The clinical factors examined included age, lymphatic invasion, nodal status, extensive intraductal component (EIC), proliferative activity, and estrogen receptor (ER) status. Of the 39 cases of breast recurrence, 19 had intramammary tumors and 20 had extramammary tumors of the skin, subcutaneous tissue, or muscle, including 8 cases with inflammatory breast recurrence. Multivariate analysis showed that factors correlated with breast recurrence were age, ER status, proliferative activity, and surgical margin. EIC-comedo was related to intramammary recurrence, whereas lymphatic invasion and nodal status were related to extramammary recurrence. Postoperative irradiation was an effective treatment for tumors in young women and tumors with positive margins or a comedo component. Outcome after breast recurrence depended on nodal status at primary operation, and survival rates were worst in patients with inflammatory breast recurrence. In conclusion, age, EIC-comedo status, the surgical margin, and negative ER status were correlated with breast recurrence. Countermeasures against these factors should be investigated. (author)

  16. 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

  17. 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

  18. 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

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

    Directory of Open Access Journals (Sweden)

    Hutzen Brian

    2012-11-01

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

  20. 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.

  1. Inhibition of SIRT1 Transcription inResveratrol-differentiated Medulloblastoma Cells

    Directory of Open Access Journals (Sweden)

    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

  2. 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

  3. 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.

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  5. 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

  6. 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.

  7. OS02.1 Multicenter pilot study of radio-chemotherapy as first-line treatment for adults with medulloblastoma - the NOA-07 trial

    Science.gov (United States)

    Beier, D.; Proescholdt, M.; Reinert, C.; Hattingen, E.; Seidel, C.; Dirven, L.; Lürding, R.; Pfister, S.; Pietsch, T.; Hau, P.

    2017-01-01

    Abstract Background: Medulloblastoma in adult patients has a low incidence, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. In contrast to children, no prospective data on the feasibility of radio-chemotherapy in adults exists. The German Neuro-Oncology Working Group (NOA) performed a prospective multicenter single-arm Phase II trial to evaluate the feasibility and toxicity of radio-chemotherapy in this population. Methods: The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by a maximum of eight cycles of cisplatin, lomustine and vincristine. Adverse events, imaging and progression patterns, combined histological and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated prospectively. The primary endpoints were the rate of toxicity-related treatment terminations after four cycles of chemotherapy, and the toxicity profile. Findings: Thirty patients were evaluable. Fifty percent of patients showed classic, and 50% desmoplastic-nodular histology. Sixty-eight percent of patients were genetically classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13.6% in wingless (WNT), and 17.7% in Non-WNT/Non-SHH (Group 4). Four cycles of chemotherapy were feasible in the majority of patients (n=21; 70.0%). Leukopenia was the major toxicity, with 79 events of CTC grade 3 and 4 in 17 patients. Polyneuropathy and ototoxicity were the only grade 3 or 4 non-haematological toxicities during the active treatment phase and occurred 12 times in eight patients and one time in one patient, respectively. Events were also calculated per cycle and showed an increase of toxicity over treatment time. Feasibility appeared to be age-dependent, leading to application of four cycles of chemotherapy in 72.7% of patients below age 45 and 62.5% of patients 45 or above. Testing for all eight adjuvant cycles revealed that 45.5% of all patients younger than 45 years completed

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

    Science.gov (United States)

    2015-12-01

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

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

    Science.gov (United States)

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

    2016-08-01

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

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    Ferrari Antonio Fernandes

    2003-01-01

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

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

    Science.gov (United States)

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

    2013-04-01

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

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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