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Sample records for hepatoblastoma medulloblastoma neuroblastoma

  1. Medulloblastoma.

    Science.gov (United States)

    von Hoff, Katja; Rutkowski, Stefan

    2012-08-01

    The mainstay of medulloblastoma treatment is high-quality interdisciplinary collaboration in diagnosis, treatment, and aftercare by all involved disciplines. The first step in treatment of medulloblastoma is a maximal safe surgery, followed by thorough staging. Surgery should only be performed in experienced neurosurgical centers, with age-appropriate postoperative care. As optimal risk stratification is based on histopathological and neuroradiological assessments, these should be performed or confirmed by experienced specialists. Central review of histopathological subtype, as well as review of staging evaluations is highly desirable. For young children with desmoplastic/nodular (DMB), or extensive nodular medulloblastoma, craniospinal or any radiotherapy should be avoided. For young children with classic medulloblastoma (CMB), large cell, or anaplastic medulloblastoma (LC/A MB) optimized strategies with high-dose chemotherapy and autologous stem cell rescue with or without local radiotherapy are under investigation. For older clinical standard risk patients (without metastases, without postoperative residual tumor >1.5 cm(2)) with CMB or DMB, craniospinal radiotherapy with 23.4 Gy and boost to the posterior fossa to 54 Gy, followed by maintenance chemotherapy can be regarded as a standard therapy besides other currently applied regimen, such as the use of intensified chemotherapy after irradiation. Older children with LC/A MB, metastatic medulloblastoma, and/or large residual tumor can be regarded as high-risk patients and should receive intensified treatment: intensified chemotherapeutic regimen before or after radiotherapy with increased dose (36-Gy CSI normofractionated, or 40-Gy hyperfractionated) is used. For treatment to be effective, quality control of radiotherapy is of high relevance. Information on long-term sequelae is essential and appropriate multidisciplinary follow-up and support, including rehabilitation and help for reintegration, is necessary

  2. Neuroblastoma

    OpenAIRE

    Davidoff, Andrew M.

    2012-01-01

    Neuroblastoma is a heterogeneous disease; tumors can spontaneously regress or mature, or display an aggressive, therapy-resistant phenotype. Increasing evidence indicates that the biologic and molecular features of neuroblastoma significantly influence and are highly predictive of clinical behavior. Because of this, neuroblastoma has served as a paradigm for biological risk assessment and treatment assignment. Most current clinical studies of neuroblastoma base therapy and its intensity on a ...

  3. Neuroblastoma

    Science.gov (United States)

    ... also may be at higher risk for other cancers. Caring for Your Child Being told your child has neuroblastoma can be ... Cancer Center Use Finn's Story to Talk About Cancer Preparing Your Child for Surgery Late Effects of Cancer and Cancer ...

  4. Hepatoblastoma in the nordic countries

    DEFF Research Database (Denmark)

    de Fine Licht, S; Schmidt, L S; Rod, Naja Hulvej

    2011-01-01

    Little is known about the aetiology of hepatoblastoma. Because of the young age at diagnosis, several studies have looked at various birth characteristics. The purpose of this study was to investigate the incidence of hepatoblastoma in the Nordic countries and the association between selected birth...

  5. Unresectable hepatoblastoma: current perspectives

    Directory of Open Access Journals (Sweden)

    Trobaugh-Lotrario AD

    2017-02-01

    Full Text Available Angela D Trobaugh-Lotrario,1 Rebecka L Meyers,2 Allison F O’Neill,3 James H Feusner4 1Department of Pediatric Hematology and Oncology, Providence Sacred Heart Children’s Hospital, Spokane, WA, 2Primary Children’s Hospital, University of Utah, Salt Lake City, UT, 3Dana-Farber Cancer Institute and Harvard University, Boston, MA, 4Children’s Hospital & Research Center Oakland, Oakland, CA, USA Abstract: Although rare, hepatoblastoma is the most common pediatric liver tumor. Complete resection is a critical component for cure; however, most patients will have tumors that are not resected at diagnosis. For these patients, administration of neoadjuvant chemotherapy renders tumors resectable in most patients. For patients whose tumors remain unresectable after chemotherapy, liver transplantation is indicated (in the absence of active unresectable metastatic disease. In patients whose tumors remain unresectable after conventional chemotherapy, interventional techniques may serve as a promising option to reduce tumor size, decrease systemic toxicity, decrease need for liver transplantation, and increase feasibility of tumor resection. Keywords: hepatoblastoma, unresectable, pediatric

  6. Neuroblastoma Screening

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    ... Neuroblastoma Treatment for more information about neuroblastoma. Most cases of neuroblastoma are diagnosed before 1 year of ... to Use This Summary PDQ is a registered trademark. The content of PDQ documents can be used ...

  7. Cerebellar neuroblastoma in an infant.

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    Nishio, S; Inamura, T; Morioka, T; Ishihara, S; Hirano, K; Murakami, N; Fukui, M

    2000-03-01

    A cerebellar neoplasm in an 8-month-old boy is reported. While this tumour was composed of small cells and had regions resembling desmoplastic medulloblastoma, it showed ultrastructural neuronal characteristics including bundles of microtubules in the cell processes, numerous synaptic vesicles, and occasional abortive or complete synapses. These characteristic features warranted the diagnosis of a neuroblastoma of the cerebellum. The nature of this rare intraparenchymal tumour in infants is also briefly discussed.

  8. DLK1, a serum marker for hepatoblastoma in young infants

    NARCIS (Netherlands)

    Falix, Farah A.; Aronson, Daniel C.; Lamers, Wouter H.; Hiralall, Johan K.; Seppen, Jurgen

    2012-01-01

    Hepatoblastoma is a malignant pediatric liver tumor. The currently used diagnostic serum marker for hepatoblastoma, a-fetoprotein (AFP), is not always reliable in infants with hepatoblastoma, due to the physiologically elevated levels of AFP in this age group. In this report, we show that Delta-like

  9. Hepatoblastomas in Oman: Unveiling success.

    Science.gov (United States)

    Rabah, Fatma; El-Banna, Nagwa; Bhuyan, Dipali; Al-Ghaithi, Ibrahim; Al-Hinai, Mohamed; Al-Sabahi, Amal; Al-Mashaikhi, Nawal; Beshlawi, Ismail

    2015-02-01

    Primary malignant liver tumours account for more than 1% of all paediatric malignancies, with the most common form being hepatoblastomas (HB). Such malignancies among Arab populations have rarely been addressed in the literature. Using data from Oman's sole national referral centre for childhood solid malignancies, this study aimed to present the nationwide Omani experience with HB over the past 21 years. This retrospective study reviewed the medical records of all children with HB who were managed in the Royal Hospital, Muscat, Oman, between January 1991 and April 2012. Clinical, radiological and laboratory characteristics were examined as well as treatments and outcomes. During the study period, 15 patients with HB were treated. Of these, 10 have survived to date. Nine of the survivors were no longer receiving treatment and one patient still had the disease but was in a stable condition. Of the remaining five patients, three did not survive and two were lost to follow-up. The survival rate among patients who completed therapy was 91%. HB has an excellent prognosis in Oman. The main obstacle to improving outcomes among Omani patients is non-compliance with therapy.

  10. Molecular subgroups of medulloblastoma

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

    2014-01-01

    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 understanding of the core medulloblastoma subgroups, focusing largely on clinically relevant discoveries that have already, and will continue to, shape research. PMID:22853794

  11. Diagnosis of neonatal neuroblastoma with postmortem magnetic resonance imaging

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    James Davis, MD

    2017-03-01

    Full Text Available Postmortem magnetic resonance imaging (MRI is emerging as a valuable tool to accompany traditional autopsy and has potential for use in cases when traditional autopsy is not possible. This case report will review the use of postmortem MRI with limited tissue sampling to differentiate between metastatic neuroblastoma and hepatoblastoma which could not be clearly differentiated with prenatal ultrasound, prenatal MRI, or emergent postnatal ultrasound. The mother presented to our institution at 27 weeks gestation after an obstetric ultrasound at her obstetrician's office identified a large abdominal mass. Fetal ultrasonography and MRI confirmed the mass but were unable to differentiate between neuroblastoma and multifocal hepatoblastoma. The baby was delivered by cesarean section after nonreassuring heart tones led to an emergent cesarean section. The baby underwent decompressive laparotomy to relieve an abdominal compartment syndrome; however, the family eventually decided to withdraw life support. At this time, we performed a whole body postmortem MRI which further characterized the mass as an adrenal neuroblastoma which was confirmed with limited tissue sampling. Postmortem MRI was especially helpful in this case, as the patient’s family declined traditional autopsy.

  12. Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma.

    Science.gov (United States)

    Koto, Karen S; Lescault, Pamela; Brard, Laurent; Kim, Kyukwang; Singh, Rakesh K; Bond, Jeff; Illenye, Sharon; Slavik, Marni A; Ashikaga, Takamaru; Saulnier Sholler, Giselle L

    2011-05-01

    Medulloblastoma, a neuroectodermal tumor arising in the cerebellum, is the most common brain tumor found in children. We recently showed that nifurtimox induces production of reactive oxygen species (ROS) and subsequent apoptosis in neuroblastoma cells both in vitro and in vivo. Tetrathiomolybdate (TM) has been shown to decrease cell proliferation by inhibition of superoxide dismutase-1 (SOD1). Since both nifurtimox and TM increase ROS levels in cells, we investigated whether the combination of nifurtimox and TM would act synergistically in medulloblastoma cell lines (D283, DAOY). Genome-wide transcriptional analysis, by hybridizing RNA isolated from nifurtimox and TM alone or in combination treated and control cells (D283) on Affymetrix exon array gene chips was carried out to further confirm synergy. We show that nifurtimox and TM alone and in combination decreased cell viability and increased ROS levels synergistically. Examination of cell morphology following drug treatment (nifurtimox + TM) and detection of caspase-3 activation via Western blotting indicated that cell death was primarily due to apoptosis. Microarray data from cells treated with nifurtimox and TM validated the induction of oxidative stress, as many Nrf2 target genes (HMOX1, GCLM, SLC7A11 and SRXN1) (pnifurtimox + TM. Taken together, our results suggest nifurtimox and TM act synergistically in medulloblastoma cells in vitro, and that this combination warrants further studies as a new treatment for medulloblastoma.

  13. The KDM1A histone demethylase is a promising new target for the epigenetic therapy of medulloblastoma

    Science.gov (United States)

    2013-01-01

    Background Medulloblastoma is a leading cause of childhood cancer-related deaths. Current aggressive treatments frequently lead to cognitive and neurological disabilities in survivors. Novel targeted therapies are required to improve outcome in high-risk medulloblastoma patients and quality of life of survivors. Targeting enzymes controlling epigenetic alterations is a promising approach recently bolstered by the identification of mutations in histone demethylating enzymes in medulloblastoma sequencing efforts. Hypomethylation of lysine 4 in histone 3 (H3K4) is also associated with a dismal prognosis for medulloblastoma patients. Functional characterization of important epigenetic key regulators is urgently needed. Results We examined the role of the H3K4 modifying enzyme, KDM1A, in medulloblastoma, an enzyme also associated with malignant progression in the closely related tumor, neuroblastoma. Re-analysis of gene expression data and immunohistochemistry of tissue microarrays of human medulloblastomas showed strong KDM1A overexpression in the majority of tumors throughout all molecular subgroups. Interestingly, KDM1A knockdown in medulloblastoma cell lines not only induced apoptosis and suppressed proliferation, but also impaired migratory capacity. Further analyses revealed bone morphogenetic protein 2 (BMP2) as a major KDM1A target gene. BMP2 is known to be involved in development and differentiation of granule neuron precursor cells (GNCPs), one potential cell of origin for medulloblastoma. Treating medulloblastoma cells with the specific KDM1A inhibitor, NCL-1, significantly inhibited growth in vitro. Conclusion We provide the first evidence that a histone demethylase is functionally involved in the regulation of the malignant phenotype of medulloblastoma cells, and lay a foundation for future evaluation of KDM1A-inihibiting therapies in combating medulloblastoma. PMID:24252778

  14. 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.

  15. Cerebellum: Development and Medulloblastoma

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    Roussel, Martine F.; Hatten, Mary E.

    2011-01-01

    In the last 20 years, it has become clear that developmental genes and their regulators, noncoding RNAs including microRNAs and long-noncoding RNAs, within signaling pathways play a critical role in the pathogenesis of cancer. Many of these pathways were first identified in genetic screens in Drosophila and other lower organisms. Mammalian orthologs were subsequently identified and genes within the pathways cloned and found to regulate cell growth. The GENES and pathways expressed during embryonic development, including the Notch, Wnt/β-Catenin, TGF-β/BMP, Shh/Patched, and Hippo pathways are mutated, lost, or aberrantly regulated in a wide variety of human cancers, including skin, breast, blood, and brain cancers, including medulloblastoma. These biochemical pathways affect cell fate determination, axis formation, and patterning during development and regulate tissue homeostasis and regeneration in adults. Medulloblastoma, the most common malignant nervous system tumor in childhood, are thought to arise from disruptions in cerebellar development [reviewed by Marino, S. (2005). Medulloblastoma: Developmental mechanisms out of control. Trends Mol. Med. 11, 17–22]. Defining the extracellular cues and intracellular signaling pathways that control cerebellar neurogenesis, especially granule cell progenitor (GCP) proliferation and differentiation has been useful for developing models to unravel the mechanisms underlying medulloblastoma formation and growth. In this chapter, we will review the development of the cerebellar cortex, highlighting signaling pathways of potential relevance to tumorigenesis. PMID:21295689

  16. Hirschsprung disease and hepatoblastoma: case report of a rare association

    Directory of Open Access Journals (Sweden)

    Raquel Borges Pinto

    Full Text Available ABSTRACT CONTEXT: Hirschsprung disease is a developmental disorder of the enteric nervous system that is characterized by absence of ganglion cells in the distal intestine, and it occurs in approximately 1 in every 500,000 live births. Hepatoblastoma is a malignant liver neoplasm that usually occurs in children aged 6 months to 3 years, with a prevalence of 0.54 cases per 100,000. CASE REPORT: A boy diagnosed with intestinal atresia in the first week of life progressed to a diagnosis of comorbid Hirschsprung disease. Congenital cataracts and sensorineural deafness were diagnosed. A liver mass developed and was subsequently confirmed to be a hepatoblastoma, which was treated by means of surgical resection of 70% of the liver volume and neoadjuvant chemotherapy (ifosfamide, cisplatin and doxorubicin. CONCLUSION: It is known that Hirschsprung disease may be associated with syndromes predisposing towards cancer, and that hepatoblastoma may also be associated with certain congenital syndromes. However, co-occurrence of hepatoblastoma and Hirschsprung disease has not been previously described. We have reported a case of a male patient born with ileal atresia, Hirschsprung disease and bilateral congenital cataract who was later diagnosed with hepatoblastoma.

  17. Hirschsprung disease and hepatoblastoma: case report of a rare association.

    Science.gov (United States)

    Pinto, Raquel Borges; Ramos, Ana Regina Lima; Backes, Ariane Nadia; Santos, Beatriz John Dos; Provenzi, Valentina Oliveira; Carbonera, Mário Rafael; Roenick, Maria Lúcia; Santos, Pedro Paulo Albino Dos; Falhauber, Fabrizia; Souza, Meriene Viquetti de; Bassols, João Vicente; Artigalás, Osvaldo

    2016-04-01

    Hirschsprung disease is a developmental disorder of the enteric nervous system that is characterized by absence of ganglion cells in the distal intestine, and it occurs in approximately 1 in every 500,000 live births. Hepatoblastoma is a malignant liver neoplasm that usually occurs in children aged 6 months to 3 years, with a prevalence of 0.54 cases per 100,000. A boy diagnosed with intestinal atresia in the first week of life progressed to a diagnosis of comorbid Hirschsprung disease. Congenital cataracts and sensorineural deafness were diagnosed. A liver mass developed and was subsequently confirmed to be a hepatoblastoma, which was treated by means of surgical resection of 70% of the liver volume and neoadjuvant chemotherapy (ifosfamide, cisplatin and doxorubicin). It is known that Hirschsprung disease may be associated with syndromes predisposing towards cancer, and that hepatoblastoma may also be associated with certain congenital syndromes. However, co-occurrence of hepatoblastoma and Hirschsprung disease has not been previously described. We have reported a case of a male patient born with ileal atresia, Hirschsprung disease and bilateral congenital cataract who was later diagnosed with hepatoblastoma.

  18. ALK Expression Is a Novel Marker for the WNT-activated Type of Pediatric Medulloblastoma and an Indicator of Good Prognosis for Patients.

    Science.gov (United States)

    Łastowska, Maria; Trubicka, Joanna; Niemira, Magdalena; Paczkowska-Abdulsalam, Magdalena; Karkucińska-Więckowska, Agnieszka; Kaleta, Magdalena; Drogosiewicz, Monika; Tarasińska, Magdalena; Perek-Polnik, Marta; Krętowski, Adam; Dembowska-Bagińska, Bożenna; Grajkowska, Wiesława; Pronicki, Maciej; Matyja, Ewa

    2017-06-01

    ALK gene rearrangements were identified in a variety of cancers, including neuroblastoma, where the presence of ALK expression is associated with adverse prognosis. ALK mutations have recently been found in the pediatric brain tumor medulloblastoma, and microarray data indicate that ALK is highly expressed in a subset of these tumors. Therefore, we investigated whether ALK expression correlates with transcriptional profiles and clinical features of medulloblastoma. Tumors from 116 medulloblastoma patients were studied at diagnosis for the detection of ALK expression at the RNA level by an application of NanoString technology and at the protein level by immunohistochemistry using antibody ALK clone D5F3. The results indicate that ALK expression, at both the RNA and the protein levels, is strongly associated with the WNT-activated type of tumors and therefore may serve as a useful marker for the detection of this type of medulloblastoma. Importantly, ALK protein expression alone is also an indicator of good prognosis for medulloblastoma patients.

  19. 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.

  20. Imaging Biomarkers for Adult Medulloblastomas

    DEFF Research Database (Denmark)

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

    2017-01-01

    BACKGROUND AND PURPOSE: The occurrence of medulloblastomas in adults is rare; nevertheless, these tumors can be subdivided into genetic and histologic entities each having distinct prognoses. This study aimed to identify MR imaging biomarkers to classify these entities and to uncover differences...... in MR imaging biomarkers identified in pediatric medulloblastomas. MATERIALS AND METHODS: Eligible preoperative MRIs from 28 patients (11 women; 22-53 years of age) of the Multicenter Pilot-study for the Therapy of Medulloblastoma of Adults (NOA-7) cohort were assessed by 3 experienced neuroradiologists......-WNT/non-SHH medulloblastomas (in adults, Group 4), and histologic entities were correlated with the imaging criteria. These MR imaging biomarkers were compared with corresponding data from a pediatric study. RESULTS: There were 19 SHH TP53 wild type (69%), 4 WNT-activated (14%), and 5 Group 4 (17%) medulloblastomas. Six...

  1. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma

    NARCIS (Netherlands)

    Perilongo, G.; Maibach, R.; Shafford, E.; Brugieres, L.; Brock, P.; Morland, B.; de Camargo, B.; Zsiros, J.; Roebuck, D.; Zimmermann, A.; Aronson, D.; Childs, M.; Widing, E.; Laithier, V.; Plaschkes, J.; Pritchard, J.; Scopinaro, M.; Czauderna, P.

    2009-01-01

    Background: Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). Methods: Children with standard-risk

  2. Cisplatin versus Cisplatin plus Doxorubicin for Standard-Risk Hepatoblastoma

    NARCIS (Netherlands)

    Perilongo, Giorgio; Maibach, Rudolf; Shafford, Elisabeth; Brugieres, Laurence; Brock, Penelope; Morland, Bruce; de Camargo, Beatriz; Zsiros, Jozsef; Roebuck, Derek; Zimmermann, Arthur; Aronson, Daniel; Childs, Margaret; Widing, Eva; Laithier, Veronique; Plaschkes, Jack; Pritchard, Jon; Scopinaro, Marcello; MacKinlay, Gordon; Czauderna, Piotr

    2009-01-01

    Background Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). Methods Children with standard-risk

  3. Mechanism of thrombocytosis in hepatoblastoma: a case report.

    Science.gov (United States)

    Yamaguchi, H; Ishii, E; Hayashida, Y; Hirata, Y; Sakai, R; Miyazaki, S

    1996-01-01

    Although thrombocytosis has long been recognized as a common finding in children with hepatoblastoma, its mechanism is still unknown. In this study, to confirm the role of thrombopoietin (Tpo) in the thrombocytosis in hepatoblastoma, the expression of Tpo mRNA in tumor cells was examined and the serum Tpo level was analyzed during the course of the disease. A 1-year, 6-month-old girl was diagnosed as having advanced hepatoblastoma. At diagnosis, she had marked thrombocytosis with 1220 x 10(9)/microL. After resection of the tumor and after four courses of chemotherapy, the level of alpha-fetoprotein normalized but the platelet count remained high. However, after the fifth course of chemotherapy, the platelet count decreased and normalized within 3 months. By enzyme-linked immunosorbent assay, the serum Tpo level was not high at diagnosis, whereas high Tpo levels were observed after chemotherapy. By polymerase chain reaction, Tpo mRNA was detected in both normal liver and tumor tissues, but the level of expression was not different between them. Therefore, in hepatoblastoma the serum Tpo level is not correlated with a high platelet count, and there is no difference in Tpo expression between normal liver and tumor tissues. Other unknown factors and their production sites to induce thrombocytosis should be examined in further studies.

  4. RESEARCH Lessons from the hepatoblastoma-familial polyposis ...

    African Journals Online (AJOL)

    Hepatoblastoma (HB) is the most common primary liver cancer of childhood, accounting for up to 1% of all paediatric malignancies, particularly in the younger child. HB is associated with congenital abnormalities in approximately one-third of patients, suggesting complex genetic and/or epigenetic factors in its ...

  5. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma.

    NARCIS (Netherlands)

    Perilongo, G.; Maibach, R.; Shafford, E.; Brugieres, L.; Brock, P.; Morland, B.; Camargo, B. de; Zsiros, J.; Roebuck, D.; Zimmermann, A.; Aronson, D.C.; Childs, M.; Widing, E.; Laithier, V.; Plaschkes, J.; Pritchard, J.; Scopinaro, M.; MacKinlay, G.; Czauderna, P.

    2009-01-01

    BACKGROUND: Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). METHODS: Children with standard-risk

  6. CITED1 Expression in Liver Development and Hepatoblastoma

    Directory of Open Access Journals (Sweden)

    Andrew J. Murphy

    2012-12-01

    Full Text Available Hepatoblastoma, the most common pediatric liver cancer, consists of epithelial mixed embryonal/fetal (EMEF and pure fetal histologic subtypes, with the latter exhibiting a more favorable prognosis. Few embryonal histology markers that yield insight into the biologic basis for this prognostic discrepancy exist. CBP/P-300 interacting transactivator 1 (CITED1, a transcriptional co-activator, is expressed in the self-renewing nephron progenitor population of the developing kidney and broadly in its malignant analog, Wilms tumor (WT. In this current study, CITED1 expression is detected in mouse embryonic liver initially on post-coitum day 10.5 (e10.5, begins to taper by e14.5, and is undetectable in e18.5 and adult livers. CITED1 expression is detected in regenerating murine hepatocytes following liver injury by partial hepatectomy and 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Importantly, while CITED1 is undetectable in normal human adult livers, 36 of 41 (87.8% hepatoblastoma specimens express CITED1, where it is enriched in EMEF specimens compared to specimens of pure fetal histology. CITED1 overexpression in Hep293TT human hepatoblastoma cells induces cellular proliferation and upregulates the Wnt inhibitors Kringle containing transmembrane protein 1 (KREMEN1 and CXXC finger protein 4 (CXXC4. CITED1 mRNA expression correlates with expression of CXXC4 and KREMEN1 in clinical hepatoblastoma specimens. These data show that CITED1 is expressed during a defined time course of liver development and is no longer expressed in the adult liver but is upregulated in regenerating hepatocytes following liver injury. Moreover, as in WT, this embryonic marker is reexpressed in hepatoblastoma and correlates with embryonal histology. These findings identify CITED1 as a novel marker of hepatic progenitor cells that is re-expressed following liver injury and in embryonic liver tumors.

  7. Medulloblastoma: From Myth to Molecular.

    Science.gov (United States)

    Ramaswamy, Vijay; Taylor, Michael D

    2017-07-20

    Current therapies for medulloblastoma were introduced primarily in the 1980s and consist of predominantly cytotoxic, nontargeted approaches. Mortality from medulloblastoma remains significant. In addition, many survivors suffer from severe treatment-related effects of radiation and cytotoxic chemotherapy. Further intensification of nonspecific therapy is unlikely to offer additional benefits, because survival rates have reached a plateau. Recent publications in medulloblastoma have revolved largely around the recognition that medulloblastoma per se does not exist, but rather, that there are a group of histologically similar but clinically and molecularly distinct entities that have been grouped under that rubric. Distinguishing the four molecular subgroups of medulloblastoma-wingless (WNT), sonic hedgehog (SHH), group 3, and group 4-in the daily treatment of patients, as well in the setting of clinical trials, is an important challenge in the near term for the pediatric neuro-oncology community. The preponderance of morbidity in treating patients with medulloblastoma is secondary to the treatment or prophylaxis of leptomeningeal metastases, and the cause of most deaths is leptomeningeal metastases. Recurrence of medulloblastoma is a nearly universally fatal event, with no significant salvage rate. The extent of spatial and temporal intratumoral heterogeneity as medulloblastoma metastasizes to leptomeninges and as it evolves in the face of radiation and cytotoxic chemotherapy is just beginning to be understood as a major barrier to therapeutic success. Pediatric neuro-oncology clinicians and scientists must now determine how best to incorporate rapid changes in our biologic understanding of medulloblastoma into the next generation of upfront clinical trials, with the goal of both improving survival for the highest-risk patients and improving quality of life for survivors.

  8. Genetics Home Reference: neuroblastoma

    Science.gov (United States)

    ... activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008 Oct 16;455(7215):967-70. doi: ... JM. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008 Oct 16;455(7215):930-5. doi: ...

  9. Hepatoblastoma in a neonate: a hypervascular presentation mimicking hemangioendothelioma

    Energy Technology Data Exchange (ETDEWEB)

    Ingram, J.D. [Department of Radiology, The Children' s Hospital, Denver (United States); Yerushalmi, B.; Sokol, R.J. [Department of Gastroenterology, Hepatology, and Nutrition, The Children' s Hospital, Denver, CO (United States); Connell, J. [Department of Medical Education, The Children' s Hospital, 1056 East 19th Avenue, Denver, CO (United States); Karrer, F.M. [Department of Pediatric Surgery, The Children' s Hospital, 1056 East 19th Avenue, Denver, CO (United States); Tyson, R.W. [Department of Pathology, The Children' s Hospital, Denver, CO (United States)

    2000-11-01

    Congenital heart failure in the neonate supported by classic imaging findings may allow the implementation of medical therapy for presumed hemangioendothelioma without obtaining a tissue diagnosis. This case report describes a neonate with these classic clinical and radiographic findings but who underwent surgery for failing medical treatment and was diagnosed as having a hepatoblastoma by pathology. This case supports the need to obtain tissue confirmation before beginning medical therapy. (orig.)

  10. Hepatoblastoma in childhood, long term survival achieved: 2 case reports and literature review

    Directory of Open Access Journals (Sweden)

    Antoine El Asmar

    2016-01-01

    Conclusion: Hepatoblastoma are rare tumors of the pediatric age group. Management depends highly on combined surgical and pediatric oncological knowledge. A complete disease remission can be achieved when both modalities are treatment are optimal. Therefore, hepatoblastoma cases should be referred to specialized centers for management.

  11. Olfactory Neuroblastoma: Diagnostic Difficulty

    Directory of Open Access Journals (Sweden)

    Vidya MN,

    2011-01-01

    Full Text Available Olfactory neuroblastoma is an uncommon malignant tumor of sinonasal tract arising from the olfactory neuro epithelium. The olfactory neuroblastomas presenting with divergent histomorphologies like, epithelial appearance of cells, lacking a neuro fibrillary background and absence of rosettes are difficult to diagnose. Such cases require immunohistochemistry to establish the diagnosis. We describe the clinical features, pathological and immunohistochemical findings of grade IV Olfactory neuroblastoma in a 57 year old man

  12. Cytogenetic Prognostication Within Medulloblastoma Subgroups

    Science.gov (United States)

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

    2014-01-01

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

  13. Survival After Relapse of Medulloblastoma.

    Science.gov (United States)

    Koschmann, Carl; Bloom, Karina; Upadhyaya, Santhosh; Geyer, J Russell; Leary, Sarah E S

    2016-05-01

    Survival after recurrence of medulloblastoma has not been reported in an unselected cohort of patients in the contemporary era. We reviewed 55 patients diagnosed with medulloblastoma between 2000 and 2010, and treated at Seattle Children's Hospital to evaluate patterns of relapse treatment and survival. Fourteen of 47 patients (30%) over the age of 3 experienced recurrent or progressive medulloblastoma after standard therapy. The median time from diagnosis to recurrence was 18.0 months (range, 3.6 to 62.6 mo), and site of recurrence was metastatic in 86%. The median survival after relapse was 10.3 months (range, 1.3 to 80.5 mo); 3-year survival after relapse was 18%. There were trend associations between longer survival and having received additional chemotherapy (median survival 12.8 vs. 1.3 mo, P=0.16) and radiation therapy (15.4 vs. 5.9 mo, P=0.20). Isolated local relapse was significantly associated with shorter survival (1.3 vs. 12.8 mo, P=0.009). Recurrence of medulloblastoma is more likely to be metastatic than reported in previous eras. Within the limits of our small sample, our data suggest a potential survival benefit from retreatment with cytotoxic chemotherapy and radiation even in heavily pretreated patients. This report serves as a baseline against which to evaluate novel therapy combinations.

  14. Chemotherapy for children with medulloblastoma

    NARCIS (Netherlands)

    Michiels, Erna M. C.; Schouten-van Meeteren, Antoinette Y. N.; Doz, François; Janssens, Geert O.; van Dalen, Elvira C.

    2015-01-01

    Background Post-surgical radiotherapy (RT) in combination with chemotherapy is considered as standard of care for medulloblastoma in children. Chemotherapy has been introduced to improve survival and to reduce RT-induced adverse effects. Reduction of RT-induced adverse effects was achieved by

  15. Chemotherapy for children with medulloblastoma

    NARCIS (Netherlands)

    Michiels, E.M.; Schouten-van Meeteren, A.Y.; Doz, F.; Janssens, G.O.R.J.; Dalen, E.C. van

    2015-01-01

    BACKGROUND: Post-surgical radiotherapy (RT) in combination with chemotherapy is considered as standard of care for medulloblastoma in children. Chemotherapy has been introduced to improve survival and to reduce RT-induced adverse effects. Reduction of RT-induced adverse effects was achieved by

  16. Hepatoblastoma: A Need for Cell Lines and Tissue Banks to Develop Targeted Drug Therapies

    Directory of Open Access Journals (Sweden)

    Rishi Raj Rikhi

    2016-03-01

    Full Text Available Limited research exists regarding the most aggressive forms of hepatoblastoma. Cell lines of the rare subtypes of hepatoblastoma with poor prognosis are not only difficult to attain, but are challenging to characterize histologically. A community approach to educating parents and families of the need for donated tissue is necessary for scientists to have access to resources for murine models and drug discovery. Herein we describe the currently available resources, the today’s existing gaps in research, and the path to move forward for uniform cure of hepatoblastoma.

  17. Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.

    Science.gov (United States)

    Phoenix, Timothy N; Patmore, Deanna M; Boop, Scott; Boulos, Nidal; Jacus, Megan O; Patel, Yogesh T; Roussel, Martine F; Finkelstein, David; Goumnerova, Liliana; Perreault, Sebastien; Wadhwa, Elizabeth; Cho, Yoon-Jae; Stewart, Clinton F; Gilbertson, Richard J

    2016-04-11

    The childhood brain tumor, medulloblastoma, includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant β-catenin in WNT-medulloblastoma, an essentially curable form of the disease, induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma, a less curable disease subtype, contains an intact blood brain barrier, rendering this tumor impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumor vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Identification of a novel inherited ALK variant M1199L in the WNT type of medulloblastoma.

    Science.gov (United States)

    Trubicka, J; Szperl, M; Grajkowska, W; Karkucińska-Więckowska, A; Tarasińska, M; Falana, K; Dembowska-Bagińska, B; Łastowska, M

    2016-01-01

    Rearrangements involving the ALK gene were identified in a variety of cancers, including paediatric tumour neuroblastoma where presence of ALK expression is also associated with adverse prognosis. Microarrays data indicate that ALK is expressed in another paediatric tumour - medulloblastoma. Therefore, we investigated if the ALK gene is mutated in medulloblastoma and performed simultaneously the molecular profiling of tumours. Tumours from sixty-four medulloblastoma patients were studied for detection of ALK alterations in exons 23 and 25 using Sanger method. The molecular subtypes of tumours were identified by detection of mutations in the CTNNB1 gene, monosomy 6 and by immunohistochemistry using a panel of representative antibodies. Among three ALK variants detected two resulted in intron variants (rs3738867, rs113866835) and the third one was a novel heterozygous variant c.3595A>T in exon 23 identified in the WNT type of tumour. It resulted in methionine to leucine substitution at codon position 1199 (M1199L) of the kinase domain of ALK protein. Results of analysis using three in silico algorithms confirmed the pathogenicity of this single nucleotide variation. The same gene alteration was detected in both patient and maternal peripheral blood leukocytes indicating an inherited type of the detected variant. Presence of ALK expression in tumour tissue was confirmed by immunohistochemistry. The tumour was diagnosed as classic medulloblastoma, however with visible areas of focal anaplastic features. The patient has been disease free for 6 years since diagnosis. This is the first evidence of an inherited ALK variant in the WNT type of medulloblastoma, what altogether with presence of ALK expression may point towards involvement of the ALK gene in this type of tumours.

  19. Evasion of cell senescence in SHH medulloblastoma.

    Science.gov (United States)

    Tamayo-Orrego, Lukas; Swikert, Shannon M; Charron, Frédéric

    2016-08-17

    The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1+/- mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia. Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma. These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations. Thus, cell senescence is an important characteristic of a subset of SHH medulloblastoma and might explain the acquisition of somatic TP53 mutations in human medulloblastoma. This mode of medulloblastoma formation contrasts with the one characterizing Li-Fraumeni patients with medulloblastoma, where TP53 germ-line mutations cause chromothriptic genomic instability and lead to mutations in Hedgehog signaling genes, which drive medulloblastoma growth. Here we discuss in detail these 2 alternative mechanisms leading to medulloblastoma tumorigenesis.

  20. Successfully Surgical Treatment of Lung Metastatic Hepatoblastoma: A Rare Case Report

    Directory of Open Access Journals (Sweden)

    Halim Bardi Taneh

    2017-08-01

    Full Text Available Background Hepatoblastoma is a common liver malignancy in children and commonly presents with primary tumors. In hepatoblastoma, lung is the most common place to metastasis. Chemotherapy have led to many improvements in the local control of hepatoblastoma. A main goal of treatment for hepatoblastoma is to achieve complete tumor resection. Case Presentation The patient was a 2.5 years old boy with abdominal distention and abdominal pain. Abdominal and pelvic ultrasound and thoracic and abdominal CT was performed for the patient and the results of them showed a large and hyperecho mass in the liver and several nodular lesions in lung segments. After doing some other tests, the diagnosis for the patient was hepatoblastoma. After chemothetapy the primary tumor was removed by surgery. Follow-up by CT scan after second chemotherapy showed that the lesions in the liver were removed, but lung masses were still unchanged and after second surgery, lung masses were removed too. The outcome has been favorable with no recurrence as of 20 months after the operation. Conclusion In our case, the patient did not respond to chemotherapy and as main treatment, surgery was carried out, that shows its importance in the treatment of hepatoblastoma.

  1. ASPM gene expression in medulloblastoma.

    Science.gov (United States)

    Vulcani-Freitas, Tânia M; Saba-Silva, Najsla; Cappellano, Andréa; Cavalheiro, Sérgio; Marie, Sueli K N; Oba-Shinjo, Sueli M; Malheiros, Suzana M F; de Toledo, Sílvia Regina Caminada

    2011-01-01

    Medulloblastomas are the most common malignant tumors of the central nervous system in childhood. The incidence is about 19-20% between children younger than 16 years old with peak incidence between 4 and 7 years. Despite its sensibility to no specific therapeutic means like chemotherapy and radiotherapy, the treatment is very aggressive and frequently results in regression, growth deficit, and endocrine dysfunction. From this point of view, new treatment approaches are needed such as molecular targeted therapies. Studies in glioblastoma demonstrated that ASPM gene was overexpressed when compared to normal brain and ASPM inhibition by siRNA-mediated inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM gene as a potential molecular target in glioblastoma. The aim of this work was to evaluate ASPM expression in medulloblastoma fragment samples, and to compare the results with the patient clinical features. Analysis of gene expression was performed by quantitative PCR real time using SYBR Green system in tumor samples from 37 children. The t test was used to analyze the gene expression, and Mann-Whitney test was performed to analyze the relationship between gene expressions and clinical characteristics. Kaplan-Meier test evaluated curve survival. All samples overexpressed ASPM gene more than 40-fold. However, we did not find any association between the overexpressed samples and the clinical parameters. ASPM overexpression may modify the ability of stem cells to differentiate during the development of the central nervous system, contributing to the development of medulloblastoma, a tumor of embryonic origin from cerebellar progenitor cells.

  2. Drugs Approved for Neuroblastoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for neuroblastoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  3. Immune Therapies for Neuroblastoma

    Science.gov (United States)

    Navid, Fariba; Armstrong, Michael; Barfield, Raymond C.

    2009-01-01

    Neuroblastoma, a solid tumor arising from developing cells of the sympathetic nervous system, is the most common extracranial tumor in children. The prognosis for high-risk neuroblastoma remains poor with conventional treatment, and new approaches are therefore being explored to treat this disease. One such alternative therapy that holds promise is immune therapy. We review here the recent advances in 4 types of immune therapy – cytokine, vaccine, antibody, and cellular therapy – to treat neuroblastoma. We present preclinical research and clinical trials on several promising candidates such as IL-12, dendritic cell vaccines, anti-GD2 antibodies, and allogeneic hematopoietic stem cell transplant. An optimal treatment plan for neuroblastoma will most likely involve multimodal approaches and combinations of immune therapies. PMID:19342881

  4. Immune Therapies for Neuroblastoma

    OpenAIRE

    Navid, Fariba; Armstrong, Michael; Barfield, Raymond C

    2009-01-01

    Neuroblastoma, a solid tumor arising from developing cells of the sympathetic nervous system, is the most common extracranial tumor in children. The prognosis for high-risk neuroblastoma remains poor with conventional treatment, and new approaches are therefore being explored to treat this disease. One such alternative therapy that holds promise is immune therapy. We review here the recent advances in 4 types of immune therapy – cytokine, vaccine, antibody, and cellular therapy – to treat neu...

  5. The cellular and molecular biology of medulloblastoma

    NARCIS (Netherlands)

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

    1995-01-01

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

  6. Adult medulloblastoma with myogenic differentiation

    Directory of Open Access Journals (Sweden)

    Xia-ling ZHANG

    2015-09-01

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

  7. Anaplastic large cell neuroblastoma.

    Science.gov (United States)

    Abramowsky, Carlos R; Katzenstein, Howard M; Alvarado, Carlos S; Shehata, Bahig M

    2009-01-01

    Anaplastic large cell neuroblastomas (ALCNB) are a subset of undifferentiated neuroblastomas with marked pleomorphic and anaplastic features that render them diagnostically challenging. We reviewed the records of all patients diagnosed with ALCNB at Children's Healthcare of Atlanta (Egleston Children's Hospital) for their clinical, biologic, and pathologic characteristics and their treatment outcomes. From 1998 to 2006, 7 patients were diagnosed with ALCNB. All patients presented with abdominal-pelvic masses, 3 of them of adrenal origin and 2 with thoracic extension, with clinical stages 3 or 4, and were considered to have high-risk disease. The N-MYC oncogene was amplified in 3 cases and catecholamines were elevated in 5 of 6 patients tested. All pretreatment tumors demonstrate pleomorphic, anaplastic morphology with bizarre mitoses admixed with undifferentiated but monomorphic cells with minimal if any neuropil or neuro-ganglionic differentiation. Immunohistochemical markers for neuron specific enolase (NSE) and synaptophysin were strongly positive in all specimens and chromogranin in 4 of 5. Interestingly, all tumors showed strong Fli-1 nuclear positivity despite a negative CD-99 stain. However, reverse transcription polymerase chain reaction or fluorescent in-situ hybridization testing for Ewing sarcoma transcripts was negative in 4 available specimens. This same Fli-1 antibody had tested negative on 30 conventional neuroblastomas, indicating a peculiar cross reactivity with this subset of ALCNB. Posttreatment biopsies showed maturation changes to more conventional neuroblastoma histology in 5 of the 7 cases. Follow-up ranged from 9 months to 4 years from diagnosis (median: 25 months). Five patients are still alive after treatment, 1 died 9 months after diagnosis, and another patient refused high-risk therapy and progressed and died 9 months from diagnosis. Anaplastic large cell neuroblastomas are a subset of undifferentiated neuroblastomas characterized by the

  8. Angiogenesis in neuroblastoma.

    Science.gov (United States)

    Ribatti, Domenico; Marimpietri, Danilo; Pastorino, Fabio; Brignole, Chiara; Nico, Beatrice; Vacca, Angelo; Ponzoni, Mirco

    2004-12-01

    Angiogenesis is a biological process by which new capillaries are formed from preexisting vessels. It occurs in physiological and pathological conditions, such as tumors, where a specific turning point is the transition from the avascular to the vascular phase. Tumor angiogenesis depends mainly on the release by neoplastic cells of growth factors specific for endothelial cells able to stimulate the growth of the host's blood vessels. In neuroblastoma, the most common extracranial solid tumor of infancy and childhood, angiogenesis also appears to play an important role in determining tumor phenotype. The nature of the angiogenic balance in neuroblastoma is complex, and a spectrum of angiogenesis stimulators, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), and inhibitors, such as tissue inhibitors of matrix metalloproteinases (MMPs), have been detected in neuroblastoma tumors. Moreover, an increased production of MMP-2 and -9 has been also observed in advanced stages of tumor, favoring degradation of extracellular matrix and enhancing tumor dissemination. High tumor vascularity is correlated with widely disseminated disease, MYCN amplification, unfavorable histology, and poor outcome. In contrast, low tumor vascularity is associated with prognostically favorable features, such as a localized disease and favorable histology. It is becoming increasingly evident that agents that interfere with blood vessel formation also block tumor progression. Preclinical studies suggest that antiangiogenic strategies may be effective in the treatment of neuroblastoma. A major goal is the determination of whether inhibition of angiogenesis is a realistic way of inhibiting tumor cell dissemination and formation of metastasis in neuroblastoma.

  9. Medulloblastoma stem cells: Promising targets in medulloblastoma therapy.

    Science.gov (United States)

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

    2016-05-01

    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. The CSCs are thought to be largely responsible for tumor initiation, maintenance, dissemination, and relapse; therefore, their pivotal roles have revealed them to be promising targets in MB therapy. Our growing understanding of the major medulloblastoma molecular subgroups and the derivation of some of these groups from specific stem or progenitor cells adds additional layers to the CSC knowledge base. Herein we review the current knowledge of MB stem cells, highlight the molecular mechanisms relating to MB relapse and leptomeningeal dissemination, and incorporate these with the need to develop more effective and accurate therapies for MB patients. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  10. Craniospinal radiotherapy in adult medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Selek, U.; Zorlu, F.; Hurmuz, P.; Cengiz, M.; Gurkaynak, M. [Hacettepe Univ., Ankara (Turkey). Dept. of Radiation Oncology; Turker, A. [Hacettepe Univ., Ankara (Turkey). Dept. of Internal Medicine; Soylemezoglu, F. [Hacettepe Univ., Ankara (Turkey). Dept. of Pathology

    2007-05-15

    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.)

  11. Patterns of antigen expression in hepatoblastoma and hepatocellular carcinoma in childhood.

    Science.gov (United States)

    O'Brien, W J; Finlay, J L; Gilbert-Barness, E F

    1989-01-01

    Two hepatocellular carcinomas and six hepatoblastomas were examined for the presence of 13 antigens using immunoperoxidase, avidin-biotin, staining techniques. Primary antibodies were directed against alpha-fetoprotein (AFP), alpha-1-antitrypsin (AAT), lysozyme (LYS), carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE), epithelial membrane antigen (EMA), hepatitis B surface antigen (HbSA), lactoferrin (LF), desmin (DES), vimentin (VIM), and keratin (KER). Except for HbSA, the antigen staining pattern was unable to differentiate between hepatoblastoma and hepatocellular carcinoma. Both neoplasms where positive for AFP, AAT, CEA, EMA, and KER; however, neither stained for GFAP, NSE, LYS, LF, HCG, or DES. Vimentin was weakly positive in those hepatoblastomas where mesenchymal tissue was present in the tumor. Only the tissue adjacent to hepatocellular carcinomas stained positively for HbSA and correlated with the elevated serum levels of HbSA.

  12. Delta-like protein (DLK) is a novel immunohistochemical marker for human hepatoblastomas

    DEFF Research Database (Denmark)

    Dezso, Katalin; Halász, Judit; Bisgaard, Hanne Cathrine

    2008-01-01

    Delta-like protein (DLK) is a membrane protein with mostly unknown function. It is expressed by several embryonic tissues among others by the hepatoblasts of rodent and human fetal livers. We have investigated in the present study if this protein is expressed in human hepatoblastomas. The presence...... of DLK has been studied by standard immunohistochemistry in 31 hepatoblastomas and in several differential diagnostically related tumours: hepatocellular carcinomas and in undifferentiated childhood neoplasms. All the hepatoblastomas were positive for DLK; the surrounding liver tissue remained negative....... The reaction was present in the epithelial component of the tumours. The staining pattern was mostly membranous, occasionally cytoplasmic. The other studied tumours were negative for DLK, except one hepatocellular carcinoma and the differentiating cells of two ganglioneuroblastomas. Therefore, DLK seems...

  13. Oncogenic role of cytomegalovirus in medulloblastoma?

    NARCIS (Netherlands)

    Hortal, Alejandro M.; Vermeulen, Jeroen F.; Van Hecke, Wim; Bovenschen, Niels

    2017-01-01

    Medulloblastoma is the most common solid tumor among children. Current therapeutic strategies for this malignancy include surgical resection, radiation therapy and chemotherapy. However, these treatments are accompanied with serious side effects such as neurological complications and psychosocial

  14. Oncogenic role of cytomegalovirus in medulloblastoma?

    Science.gov (United States)

    Hortal, Alejandro M; Vermeulen, Jeroen F; Van Hecke, Wim; Bovenschen, Niels

    2017-11-01

    Medulloblastoma is the most common solid tumor among children. Current therapeutic strategies for this malignancy include surgical resection, radiation therapy and chemotherapy. However, these treatments are accompanied with serious side effects such as neurological complications and psychosocial problems, due to the severity of treatment on the developing nervous system. To solve this problem, novel therapeutic approaches are currently being investigated. One of them is targeting human cytomegalovirus in medulloblastoma cancer cells. However, this approach is still under debate, since the presence of cytomegalovirus in medulloblastomas remains controversial. In this review, we discuss the current controversies on the role of cytomegalovirus in medulloblastoma oncogenesis and the potential of cytomegalovirus as a novel (immuno)therapeutic target. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  15. Genetic and molecular alterations across medulloblastoma subgroups.

    Science.gov (United States)

    Skowron, Patryk; Ramaswamy, Vijay; Taylor, Michael D

    2015-10-01

    Medulloblastoma is the most common malignant brain tumour diagnosed in children. Over the last few decades, advances in radiation and chemotherapy have significantly improved the odds of survival. Nevertheless, one third of all patients still succumb to their disease, and many long-term survivors are afflicted with neurocognitive sequelae. Large-scale multi-institutional efforts have provided insight into the transcriptional and genetic landscape of medulloblastoma. Four distinct subgroups of medulloblastoma have been identified, defined by distinct transcriptomes, genetics, demographics and outcomes. Integrated genomic profiling of each of these subgroups has revealed distinct genetic alterations, driving pathways and in some instances cells of origin. In this review, we highlight, in a subgroup-specific manner, our current knowledge of the genetic and molecular alterations in medulloblastoma and underscore the possible avenues for future therapeutic intervention.

  16. Relapse surveillance in AFP-positive hepatoblastoma: re-evaluating the role of imaging

    Energy Technology Data Exchange (ETDEWEB)

    Rojas, Yesenia; Vasudevan, Sanjeev A.; Nuchtern, Jed G. [Baylor College of Medicine, Pediatric Surgery Division, Michael E. DeBakey Department of Surgery, Texas Children' s Hospital, Houston, TX (United States); Guillerman, R.P. [Baylor College of Medicine, Department of Pediatric Radiology, Texas Children' s Hospital, Houston, TX (United States); Zhang, Wei [Texas Children' s Hospital, Surgical Outcomes Center, Houston, TX (United States); Thompson, Patrick A. [Baylor College of Medicine, Hematology-Oncology Division, Department of Pediatrics, Texas Children' s Cancer Center, Texas Children' s Hospital, Houston, TX (United States); University of North Carolina, Hematology-Oncology Division, Department of Pediatrics, North Carolina Children' s Hospital, Chapel Hill, NC (United States)

    2014-10-15

    Children with hepatoblastoma routinely undergo repetitive surveillance imaging, with CT scans for several years after therapy, increasing the risk of radiation-induced cancer. The purpose of this study was to determine the utility of surveillance CT scans compared to serum alpha-fetoprotein (AFP) levels for the detection of hepatoblastoma relapse. This was a retrospective study of all children diagnosed with AFP-positive hepatoblastoma from 2001 to 2011 at a single institution. Twenty-six children with hepatoblastoma were identified, with a mean age at diagnosis of 2 years 4 months (range 3 months to 11 years). Mean AFP level at diagnosis was 132,732 ng/ml (range 172.8-572,613 ng/ml). Five of the 26 children had hepatoblastoma relapse. A total of 105 imaging exams were performed following completion of therapy; 88 (84%) CT, 8 (8%) MRI, 5 (5%) US and 4 (4%) FDG PET/CT exams. A total of 288 alpha-fetoprotein levels were drawn, with a mean of 11 per child. The AFP level was elevated in all recurrences and no relapses were detected by imaging before AFP elevation. Two false-positive AFP levels and 15 false-positive imaging exams were detected. AFP elevation was found to be significantly more specific than PET/CT and CT imaging at detecting relapse. We recommend using serial serum AFP levels as the preferred method of surveillance in children with AFP-positive hepatoblastoma, reserving imaging for the early postoperative period, for children at high risk of relapse, and for determination of the anatomical site of clinically suspected recurrence. Given the small size of this preliminary study, validation in a larger patient population is warranted. (orig.)

  17. Relapse surveillance in AFP-positive hepatoblastoma: re-evaluating the role of imaging.

    Science.gov (United States)

    Rojas, Yesenia; Guillerman, R Paul; Zhang, Wei; Vasudevan, Sanjeev A; Nuchtern, Jed G; Thompson, Patrick A

    2014-10-01

    Children with hepatoblastoma routinely undergo repetitive surveillance imaging, with CT scans for several years after therapy, increasing the risk of radiation-induced cancer. The purpose of this study was to determine the utility of surveillance CT scans compared to serum alpha-fetoprotein (AFP) levels for the detection of hepatoblastoma relapse. This was a retrospective study of all children diagnosed with AFP-positive hepatoblastoma from 2001 to 2011 at a single institution. Twenty-six children with hepatoblastoma were identified, with a mean age at diagnosis of 2 years 4 months (range 3 months to 11 years). Mean AFP level at diagnosis was 132,732 ng/ml (range 172.8-572,613 ng/ml). Five of the 26 children had hepatoblastoma relapse. A total of 105 imaging exams were performed following completion of therapy; 88 (84%) CT, 8 (8%) MRI, 5 (5%) US and 4 (4%) FDG PET/CT exams. A total of 288 alpha-fetoprotein levels were drawn, with a mean of 11 per child. The AFP level was elevated in all recurrences and no relapses were detected by imaging before AFP elevation. Two false-positive AFP levels and 15 false-positive imaging exams were detected. AFP elevation was found to be significantly more specific than PET/CT and CT imaging at detecting relapse. We recommend using serial serum AFP levels as the preferred method of surveillance in children with AFP-positive hepatoblastoma, reserving imaging for the early postoperative period, for children at high risk of relapse, and for determination of the anatomical site of clinically suspected recurrence. Given the small size of this preliminary study, validation in a larger patient population is warranted.

  18. Hepatoblastoma in a 15-month-old female with trisomy 13.

    Science.gov (United States)

    Shah, Rachana; Tran, Hung Chi; Randolph, Linda; Mascarenhas, Leo; Venkatramani, Rajkumar

    2014-02-01

    Trisomy 13 (T13) is a rare autosomal aneuploidy. Greater than 90% of patients die during the first year of life. Malignancies reported in association with T13 include two cases of Wilms tumor and one case of pilocytic astrocytoma. There is no previous report of hepatoblastoma in patients with T13. We report a unique case of hepatoblastoma in a 15-month-old female with constitutional T13. Our patient was born at 38 weeks gestation and was noted to have phenotypic features consistent with T13. Genetic testing confirmed an abnormal karyotype of 47,XX,+13 in all cells. At fifteen months of age she was noted to have a right hepatic lobe mass on a routine follow-up renal ultrasound for hydronephrosis. Serum alpha-fetoprotein level was 55,300 ng/ml. Staging work-up revealed the absence of metastases. She underwent a complete surgical resection with right hepatic lobectomy. Histopathology was consistent with hepatoblastoma, mixed epithelial and mesenchymal type. She had a protracted postoperative course complicated by Enterobacter aerogenes urosepsis, a significant biloma, chronic pancreatitis, and apneic episodes of uncertain etiology. She received four courses of doxorubicin monotherapy without any severe or unexpected toxicity. She continues to be in remission 8 months following diagnosis. This is the first reported case of hepatoblastoma in a child with constitutional T13. This may represent a non-random association, as somatic trisomy of chromosome 13 in hepatoblastoma tumors has been previously described in the literature. Prolonged survival may have allowed for hepatoblastoma to present in our patient. © 2013 Wiley Periodicals, Inc.

  19. induced apoptosis of neuroblastoma

    African Journals Online (AJOL)

    Affiliated Hospital to Changchun Traditional Chinese Medicine University, 4Department of Pediatrics, The First Hospital of Jilin. University, Changchun ... treatment of cancer using a neuroblastoma (NB) cell model. Method: Cell viability assay ... long-term survival rate in the late-stage patients is less than 40 % even with ...

  20. 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.

  1. Paraneoplastic Recurrent Hypoglycaemic Seizures: An Initial Presentation of Hepatoblastoma in an Adolescent Male—A Rare Entity

    Directory of Open Access Journals (Sweden)

    Irappa Madabhavi

    2014-01-01

    Full Text Available Hepatoblastoma (HB is a rare malignant tumour of the liver and usually occurs in the first three years of life. Hepatoblastoma in adolescents and young adults is extremely rare; nevertheless the prognosis is much worse than in childhood, because these kinds of tumours are usually diagnosed late. Characteristic imaging and histopathological and AFP levels help in the diagnosis of hepatoblastoma. Paraneoplastic features of hepatoblastoma are not uncommon at presentation and include erythrocytosis, thrombocytosis, hypocalcaemia, isosexual precocious puberty, and rarely hypoglycaemia. Even though hypoglycaemia is commonly seen in hepatocellular carcinoma, its association with hepatoblastoma is very rare. We present a case of 15-year-old male patient presenting with complaints of recurrent hypoglycaemic seizures ultimately leading to diagnosis of hepatoblastoma. Managed successfully with neoadjuvant chemotherapy, surgery and adjuvant chemotherapy with adriamycin and cisplatin based regimens. An extensive review of literature in the PubMed and MEDLINE did not reveal much data on paraneoplastic recurrent hypoglycaemic seizures as an initial presentation of hepatoblastomas in adolescents and young adults.

  2. Hepatoblastoma Biology Using Isotope Ratio Mass Spectrometry: Utility of a Unique Technique for the Analysis of Oncological Specimens

    Directory of Open Access Journals (Sweden)

    Katarzyna Taran

    2016-07-01

    Full Text Available Introduction: Hepatoblastoma is the most common primary liver tumor in children. However, it occurs rarely, with an incidence of 0.5-1.5 cases per million children. There is no clear explanation of the relationship between clinicopathologic features, therapy, and outcome in hepatoblastoma cases, so far. One of the most widely accepted prognostic factors in hepatoblastoma is histology of the tumor. The aim of the study was to determine the potential differences in biology of hepatoblastoma histological subtypes at the atomic level using the unique method of isotope ratio mass spectrometry, which is especially valuable in examination of small groups of biological samples.Material/Methods: Twenty-four measurements of nitrogen stable isotope ratio, carbon stable isotope ratio and total carbon to nitrogen mass ratio in fetal and embryonal hepatoblastoma tissue were performed using a Sercon 20-22 Continuous Flow Isotope Ratio Mass Spectrometer (CF-IRMS coupled with a Sercon SL elemental analyzer for simultaneous carbon-nitrogen-sulfur (NCS analysis.Results: A difference of about 1.781‰ in stable nitrogen isotope 15N/14N ratio was found between examined hepatoblastoma histological subtypes.Conclusions: The prognosis in liver tumors cases in children may be challenging particularly because of the lack of versatile methods of its evaluation. Isotope ratio mass spectrometry allows one to determine the difference between hepatoblastoma histological subtypes and clearly indicates the cases with the best outcome.

  3. Role of MYC in Medulloblastoma

    Science.gov (United States)

    Roussel, Martine F.; Robinson, Giles W.

    2013-01-01

    Since its discovery as an oncogene carried by the avian acute leukemia virus MC29 in myelocytomatosis (Roussel et al. 1979) and its cloning (Vennstrom et al. 1982), c-MYC (MYC), as well as its paralogs MYCN and MYCL1, has been shown to play essential roles in cycling progenitor cells born from proliferating zones during embryonic development, and in all proliferating cells after birth. MYC deletion induces cell-cycle exit or cell death, depending on the cell type and milieu, whereas MYC and MYCN amplification or overexpression promotes cell proliferation and occurs in many cancers. Here, we review the relationship of MYC family proteins to the four molecularly distinct medulloblastoma subgroups, discuss the possible roles MYC plays in each of these subgroups and in the developing cells of the posterior fossa, and speculate on possible therapeutic strategies targeting MYC. PMID:24186490

  4. 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

  5. Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma

    NARCIS (Netherlands)

    Kalish, J.M.; Doros, L.; Helman, L.J.; Hennekam, R.C.; Kuiper, R.P.; Maas, S.M.; Maher, E.R.; Nichols, K.E.; Plon, S.E.; Porter, C.C.; Rednam, S.; Schultz, K.A.P.; States, L.J.; Tomlinson, G.E.; Zelley, K.; Druley, T.E.

    2017-01-01

    A number of genetic syndromes have been linked to increased risk for Wilms tumor (WT), hepatoblastoma (HB), and other embryonal tumors. Here, we outline these rare syndromes with at least a 1% risk to develop these tumors and recommend uniform tumor screening recommendations for North America.

  6. Using Acetaminophen's Toxicity Mechanism to Enhance Cisplatin Efficacy in Hepatocarcinoma and Hepatoblastoma Cell Lines

    Directory of Open Access Journals (Sweden)

    Alexander J. Neuwelt

    2009-10-01

    Conclusions: Our results suggest that a chemotherapeutic regimen containing both AAP and CDDP with delayed NAC rescue has the potential to enhance chemotherapeutic efficacy while decreasing adverse effects. This would be a promising approach particularly for hepatoblastomas regardless of cellular CYP2E1 protein level but could also be beneficial in other malignancies.

  7. Anti-angiogenesis in neuroblastoma.

    Science.gov (United States)

    Ribatti, Domenico

    2013-06-01

    The nature of the angiogenic balance in neuroblastoma is complex, and a spectrum of angiogenesis stimulators and inhibitors have been detected in neuroblastoma tumours. The complex relationships between angiogenic cascade and anti-angiogenic agents in the tumour vascular phase have indicated that anti-angiogenesis can be considered as a strategy for the adjuvant therapy of neuroblastoma. The major goal is to establish if inhibition of angiogenesis is a realistic therapeutic strategy for inhibiting tumour cell dissemination and the formation of metastasis in neuroblastoma. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  8. 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

  9. Mechanisms of neuroblastoma regression

    Science.gov (United States)

    Brodeur, Garrett M.; Bagatell, Rochelle

    2014-01-01

    Recent genomic and biological studies of neuroblastoma have shed light on the dramatic heterogeneity in the clinical behaviour of this disease, which spans from spontaneous regression or differentiation in some patients, to relentless disease progression in others, despite intensive multimodality therapy. This evidence also suggests several possible mechanisms to explain the phenomena of spontaneous regression in neuroblastomas, including neurotrophin deprivation, humoral or cellular immunity, loss of telomerase activity and alterations in epigenetic regulation. A better understanding of the mechanisms of spontaneous regression might help to identify optimal therapeutic approaches for patients with these tumours. Currently, the most druggable mechanism is the delayed activation of developmentally programmed cell death regulated by the tropomyosin receptor kinase A pathway. Indeed, targeted therapy aimed at inhibiting neurotrophin receptors might be used in lieu of conventional chemotherapy or radiation in infants with biologically favourable tumours that require treatment. Alternative approaches consist of breaking immune tolerance to tumour antigens or activating neurotrophin receptor pathways to induce neuronal differentiation. These approaches are likely to be most effective against biologically favourable tumours, but they might also provide insights into treatment of biologically unfavourable tumours. We describe the different mechanisms of spontaneous neuroblastoma regression and the consequent therapeutic approaches. PMID:25331179

  10. Imaging neuroblastoma in children.

    Science.gov (United States)

    Mehta, Kamini; Haller, Jack O; Legasto, Alan C

    2003-01-01

    Neuroblastoma is a common solid tumor of childhood that can involve the abdomen, thorax, pelvis, or the head and neck. The clinical manifestations are dependent on the widespread distribution of neural crest tissue and the length of the sympathetic chain involvement. Abdominal pain and hypertension may occur as a result of renal vasculature compression; respiratory distress may be evident in thoracic tumors; and Homer's syndrome or heterochromia of the iris may manifest from neuroblastoma of the head and neck. In addition, symptoms of cord compression and back pain may result from spinal cord compromise due to epidural invasion. Metastatic involvement of the liver, skin, periorbital regions, or bone may cause hepatomegaly, skin nodules, proptosis, or bone marrow failure, respectively. Clinical findings along with tumor metastasis may be studied by various imaging modalities to assess the nature and extent of the tumor. Diagnostic tests include plain radiography, ultrasonography, CT scanning, and MR imaging. Bone marrow studies, bone scans, and scintigraphy with 131I-metaiodobenzylmandelic may be utilized for metastatic evaluation. By using these imaging studies to detect the nature and behavior of neuroblastoma, early intervention may indeed improve patient survival.

  11. Medulloblastoma

    Science.gov (United States)

    ... of Tumors Astrocytoma Atypical Teratoid Rhaboid Tumor (ATRT) Chondrosarcoma Choroid Plexus Craniopharyngioma Cysts Ependymoma Germ Cell Tumor ... of Tumors Astrocytoma Atypical Teratoid Rhaboid Tumor (ATRT) Chondrosarcoma Choroid Plexus Craniopharyngioma Cysts Ependymoma Germ Cell Tumor ...

  12. 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

  13. 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.

  14. Dissecting the genomic complexity underlying medulloblastoma

    DEFF Research Database (Denmark)

    Jones, David T W; Jäger, Natalie; Kool, Marcel

    2012-01-01

    Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tum...

  15. Effect of estradiol and bisphenol A on human hepatoblastoma cell viability and telomerase activity.

    Science.gov (United States)

    Xu, B L; Zhao, Q Z; Gao, X Y; Hou, G J

    2015-11-01

    Sex hormones from environmental and physiological sources might play a major role in the pathogenesis of hepatoblastoma in children. This study investigated the effects of estradiol and bisphenol A on the proliferation and telomerase activity of human hepatoblastoma HepG2 cells. The cells were divided into 6 treatment groups: control, bisphenol A, estradiol, anti-estrogen ICI 182,780 (hereinafter ICI), bisphenol A+ICI, and estradiol+ICI. Cell proliferation was measured based on average absorbance using the Cell Counting-8 assay. The cell cycle distribution and apoptotic index were determined by flow cytometry. Telomerase activity was detected by polymerase chain reaction and a telomeric repeat amplification protocol assay. A higher cell density was observed in bisphenol A (Pbisphenol A+ICI (Pbisphenol A and estradiol promote HepG2 cell proliferation in vitro by inhibition of apoptosis and stimulation of telomerase activity via an estrogen receptor-dependent pathway.

  16. Chemotherapy for children with medulloblastoma.

    Science.gov (United States)

    Michiels, Erna M C; Schouten-Van Meeteren, Antoinette Y N; Doz, François; Janssens, Geert O; van Dalen, Elvira C

    2015-01-01

    Post-surgical radiotherapy (RT) in combination with chemotherapy is considered as standard of care for medulloblastoma in children. Chemotherapy has been introduced to improve survival and to reduce RT-induced adverse effects. Reduction of RT-induced adverse effects was achieved by deleting (craniospinal) RT in very young children and by diminishing the dose and field to the craniospinal axis and reducing the boost volume to the tumour bed in older children. 1. to determine the event-free survival/disease-free survival (EFS/DFS) and overall survival (OS) in children with medulloblastoma receiving chemotherapy as a part of their primary treatment, as compared with children not receiving chemotherapy as part of their primary treatment; 2. to determine EFS/DFS and OS in children with medulloblastoma receiving standard-dose RT without chemotherapy, as compared with children receiving reduced-dose RT with chemotherapy as their primary treatment. to determine possible adverse effects of chemotherapy and RT, including long-term adverse effects and effects on quality of life. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2013, Issue 7), MEDLINE/PubMed (1966 to August 2013) and EMBASE/Ovid (1980 to August 2013). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases (August 2013). Randomised controlled trials (RCTs) evaluating the above treatments in children (aged 0 to 21 years) with medulloblastoma. Two review authors independently performed study selection, data extraction and risk of bias assessment. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Where possible, we pooled results. The search identified seven RCTs, including 1080 children, evaluating treatment including chemotherapy and treatment not including chemotherapy. The meta-analysis of EFS/DFS not including disease progression during therapy as an event in the

  17. Hepatoblastoma: Transplant Versus Resection Experience in a Latin American Transplant Center.

    Science.gov (United States)

    Caicedo, Luis A; Sabogal, Angie; Serrano, Oscar; Villegas, Jorge I; Botero, Verónica; Agudelo, María T; Lotero, Viviana; Dávalos, Diana; Manzi, Eliana; Aristizabal, Ana M; Gomez, Catalina; Echeverri, Gabriel J

    2017-06-01

    Hepatoblastoma is the most common primary malignant liver tumor in children and is usually diagnosed during the first 3 years of life. Overall survival has increased 50% due to chemotherapeutic schemes, expertise surgery centers, and liver transplantation. A retrospective collection of data was performed from pediatric patients with diagnosis of hepatoblastoma. Variables included demographic, diagnostic tools and histological classification; chemotherapy and surgical treatment; and outcomes and patient survival. The PRETEXT classification was applied, which included the risk evaluation, and according to the medical criterion in an individualized way, underwent resection or transplant. The morbidity of patients was evaluated by the Clavien-Dindo classification. Statistical analysis was performed according to the distribution of data and the survival analysis was carried out using the Kaplan-Meier method. The patients (n = 16) were divided in a resection group (n = 8) and a transplant group (n = 8). The median age at the time of diagnosis was 13.5 months. The motive for the initial consultation was the discovery of a mass; all patients had high levels of α-fetoprotein and an imaging study. Ten of 16 patients required chemotherapy before the surgical procedure. In the resection group, 5 of 8 patients were classified as Clavien I and 4 of 8 patients of the transplant group were classified as Clavien II. Patient survival at 30 months was 100% in the resection group and 65% in the liver transplantation group. To our knowledge, this is the first case report of pediatric patients with hepatoblastoma and liver resection or transplant in Colombia and Latin America. Our results are comparable with the series worldwide, showing that resection and transplant increase the survival of the pediatric patients with hepatoblastoma. It is important to advocate for an increase of reporting in the scientific literature in Latin America.

  18. Resectable hepatoblastoma with tumor thrombus extending into the right atrium after chemotherapy: A case report

    Directory of Open Access Journals (Sweden)

    Kosuke Endo

    2016-04-01

    Full Text Available Hepatoblastoma with intraatrial tumor thrombus is relatively rare. We report a case of hepatoblastoma with tumor thrombus extending into the right atrium, which responded well to chemotherapy and was resected using extracorporeal circulation. A 4-year-old girl was referred to our hospital because of abdominal distention and tenderness. A computed tomography (CT scan showed a large tumor occupying the left 3 segments of the liver with tumor thrombus extending into the right atrium. There was also a small intrahepatic metastasis in the right lobe of the liver. She was diagnosed with hepatoblastoma on the basis of the results of open biopsy. Neoadjuvant chemotherapy with an intense CDDP-based regimen was performed. The tumor responded well to chemotherapy, and intrahepatic metastasis became undetectable on CT scan, although the tumor thrombus remained in the right atrium. After 7 courses of chemotherapy, we performed resection using extracorporeal circulation. The postoperative course was uneventful, and adjuvant chemotherapy was started 10 days after the operation. Her serum alpha-fetoprotein (AFP level decreased to the normal range, and she was free of disease for 1 year after the operation. Tumor resection using extracorporeal circulation can be performed safely and is justified in patients with intraatrial tumor thrombus.

  19. Neuroblastoma: Molecular Pathogenesis and Therapy

    OpenAIRE

    Louis, Chrystal U; Shohet, Jason M.

    2014-01-01

    Neuroblastoma is a developmental tumor of young children arising from the embryonic sympathoadrenal lineage of the neural crest. Currently neuroblastoma is the primary cause of death from pediatric cancer for children between the age of 1 and 5 years and accounts for approximately 13% of all pediatric cancer mortality. Its clinical impact and its unique biology have made this aggressive malignancy the focus of a large concerted translational research effort. New insights into tumor biology ar...

  20. The ATRA-induced differentiation of medulloblastoma cells is enhanced with LOX/COX inhibitors: an analysis of gene expression.

    Science.gov (United States)

    Chlapek, Petr; Neradil, Jakub; Redova, Martina; Zitterbart, Karel; Sterba, Jaroslav; Veselska, Renata

    2014-01-01

    A detailed analysis of the expression of 440 cancer-related genes was performed after the combined treatment of medulloblastoma cells with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). The combinations of retinoids and celecoxib as a COX-2 inhibitor were reported to be effective in some regimens of metronomic therapy of relapsed solid tumors with poor prognosis. Our previous findings on neuroblastoma cells using expression profiling showed that LOX/COX inhibitors have the capability of enhancing the differentiating action of ATRA. Presented study focused on the continuation of our previous work to confirm the possibility of enhancing ATRA-induced cell differentiation in these cell lines via the application of LOX/COX inhibitors. This study provides more detailed information concerning the mechanisms of the enhancement of the ATRA-induced differentiation of medulloblastoma cells. The Daoy and D283 Med medulloblastoma cell lines were chosen for this study. Caffeic acid (an inhibitor of 5-LOX) and celecoxib (an inhibitor on COX-2) were used in combined treatment with ATRA. The expression profiling was performed using Human Cancer Oligo GEArray membranes, and the most promising results were verified using RT-PCR. The expression profiling of the selected cancer-related genes clearly confirmed that the differentiating effects of ATRA should be enhanced via its combined administration with caffeic acid or celecoxib. This effect was detected in both cell lines. An increased expression of the genes that encoded the proteins participating in induced differentiation and cytoskeleton remodeling was detected in both cell lines in a concentration-dependent manner. This effect was also observed for the CDKN1A gene encoding the p21 protein, which is an important regulator of the cell cycle, and for the genes encoding proteins that are associated with proteasome activity. Furthermore, our results showed that D283 Med cells are

  1. HDM2 promotes WIP1-mediated medulloblastoma growth

    Science.gov (United States)

    Buss, Meghan C.; Read, Tracy-Ann; Schniederjan, Matthew J.; Gandhi, Khanjan; Castellino, Robert C.

    2012-01-01

    Medulloblastoma is the most common malignant childhood brain tumor. The protein phosphatase and oncogene WIP1 is over-expressed or amplified in a significant number of primary human medulloblastomas and cell lines. In the present study, we examine an important mechanism by which WIP1 promotes medulloblastoma growth using in vitro and in vivo models. Human cell lines and intracerebellar xenografted animal models were used to study the role of WIP1 and the major TP53 regulator, HDM2, in medulloblastoma growth. Stable expression of WIP1 enhances growth of TP53 wild-type medulloblastoma cells, compared with cells with stable expression of an empty-vector or mutant WIP1. In an animal model, WIP1 enhances proliferation and reduces the survival of immunodeficient mice bearing intracerebellar xenografted human medulloblastoma cells. Cells with increased WIP1 expression also exhibit increased expression of HDM2. HDM2 knockdown or treatment with the HDM2 inhibitor Nutlin-3a, the active enantomer of Nutlin-3, specifically inhibits the growth of medulloblastoma cells with increased WIP1 expression. Nutlin-3a does not affect growth of medulloblastoma cells with stable expression of an empty vector or of mutant WIP1. Knockdown of WIP1 or treatment with the WIP1 inhibitor CCT007093 results in increased phosphorylation of known WIP1 targets, reduced HDM2 expression, and reduced growth specifically in WIP1 wild-type and high-expressing medulloblastoma cells. Combined WIP1 and HDM2 inhibition is more effective than WIP1 inhibition alone in blocking growth of WIP1 high-expressing medulloblastoma cells. Our preclinical study supports a role for therapies that target WIP1 and HDM2 in the treatment of medulloblastoma. PMID:22379189

  2. 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.

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

    Science.gov (United States)

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

    2014-01-01

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

  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. 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

  6. 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

  7. Liver transplantation for hepatoblastoma in a child with congenital absence of the portal vein

    Energy Technology Data Exchange (ETDEWEB)

    Barton, J.W. III; Keller, M.S. (Yale Univ., New Haven, CT (USA). Dept. of Diagnostic Imaging)

    1989-11-01

    Congenital absence of the portal vein with systemic visceral venous return in a 8-year-old girl with oculoauriculovertebral dysplasia (Goldenhar Syndrome) had been previously reported following its discovery during preoperative evaluation of a liver mass which was diagnosed as focal nodular hyperplasia after open biopsy. Subsequently, an enlarging diffuse hepatic neoplasm developed with associated elevated alpha feto-protein levels. Repeat biopsy and imaging showed the tumor to be a hepatoblastoma involving both lobes of the liver. The patient was treated by hepatic resection and orthotopic liver transplantation and is doing well at 18 months follow-up. (orig.).

  8. Neuroblastoma: molecular pathogenesis and therapy.

    Science.gov (United States)

    Louis, Chrystal U; Shohet, Jason M

    2015-01-01

    Neuroblastoma is a developmental tumor of young children arising from the embryonic sympathoadrenal lineage of the neural crest. Neuroblastoma is the primary cause of death from pediatric cancer for children between the ages of one and five years and accounts for ∼13% of all pediatric cancer mortality. Its clinical impact and unique biology have made this aggressive malignancy the focus of a large concerted translational research effort. New insights into tumor biology are driving the development of new classification schemas. Novel targeted therapeutic approaches include small-molecule inhibitors as well as epigenetic, noncoding-RNA, and cell-based immunologic therapies. In this review, recent insights regarding the pathogenesis and biology of neuroblastoma are placed in context with the current understanding of tumor biology and tumor/host interactions. Systematic classification of patients coupled with therapeutic advances point to a future of improved clinical outcomes for this biologically distinct and highly aggressive pediatric malignancy.

  9. A patient with medulloblastoma in its early developmental stage.

    Science.gov (United States)

    Shinojima, Naoki; Nakamura, Hideo; Tasaki, Masayoshi; Kameno, Kouki; Anai, Shigeo; Iyama, Ken-ichi; Ando, Yukio; Seto, Hiroshi; Kuratsu, Jun-Ichi

    2014-12-01

    Medulloblastoma is the most frequent malignant brain tumor of the posterior fossa in children and is considered an embryonal tumor. It has been suggested that medulloblastomas be categorized into 4 distinct molecular subgroups- WNT (DKK1), SHH (SFRP1), Group 3 (NPR3), or Group 4 (KCNA1)-since each subgroup is distinct and there is no overlap. The authors report on a 13-year-old boy with medulloblastoma. He presented with sudden-onset nausea and vomiting due to intratumoral hemorrhage. The medulloblastoma was thought to be in an early developmental stage because the tumor volume was extremely small. Immunohistochemical analysis showed that the tumor was mainly composed of DKK1- and NPR3-positive areas. The individual areas of the tumor stained only for DKK1 or NPR3, with no overlap-that is, DKK1 and NPR3 expression were mutually exclusive. Samples obtained by laser microdissection of individual areas and subjected to mass spectrometry confirmed that the expression patterns of proteins were different. Fluorescence in situ hybridization for chromosome 6 showed there were 2 distinct types of cells that exhibited monosomy or disomy of chromosome 6. These results demonstrated that distinct subtypes of medulloblastoma may be present within a single tumor, an observation that has not been previously reported. Our findings in this case indicate that early-stage medulloblastoma may include more than 1 distinct subtype and hint at factors involved in the origin and development of medulloblastomas.

  10. BET bromodomain protein inhibition is a therapeutic option for medulloblastoma

    Science.gov (United States)

    Henssen, Anton; Thor, Theresa; Odersky, Andrea; Heukamp, Lukas; El-Hindy, Nicolai; Beckers, Anneleen; Speleman, Frank; Althoff, Kristina; Schäfers, Simon; Schramm, Alexander; Sure, Ulrich; Fleischhack, Gudrun; Eggert, Angelika; Schulte, Johannes H.

    2013-01-01

    Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications. PMID:24231268

  11. G-protein coupled receptor expression patterns delineate medulloblastoma subgroups

    Science.gov (United States)

    2013-01-01

    Background Medulloblastoma is the most common malignant brain tumor in children. Genetic profiling has identified four principle tumor subgroups; each subgroup is characterized by different initiating mutations, genetic and clinical profiles, and prognoses. The two most well-defined subgroups are caused by overactive signaling in the WNT and SHH mitogenic pathways; less is understood about Groups 3 and 4 medulloblastoma. Identification of tumor subgroup using molecular classification is set to become an important component of medulloblastoma diagnosis and staging, and will likely guide therapeutic options. However, thus far, few druggable targets have emerged. G-protein coupled receptors (GPCRs) possess characteristics that make them ideal targets for molecular imaging and therapeutics; drugs targeting GPCRs account for 30-40% of all current pharmaceuticals. While expression patterns of many proteins in human medulloblastoma subgroups have been discerned, the expression pattern of GPCRs in medulloblastoma has not been investigated. We hypothesized that analysis of GPCR expression would identify clear subsets of medulloblastoma and suggest distinct GPCRs that might serve as molecular targets for both imaging and therapy. Results Our study found that medulloblastoma tumors fall into distinct clusters based solely on GPCR expression patterns. Normal cerebellum clustered separately from the tumor samples. Further, two of the tumor clusters correspond with high fidelity to the WNT and SHH subgroups of medulloblastoma. Distinct over-expressed GPCRs emerge; for example, LGR5 and GPR64 are significantly and uniquely over-expressed in the WNT subgroup of tumors, while PTGER4 is over-expressed in the SHH subgroup. Uniquely under-expressed GPCRs were also observed. Our key findings were independently validated using a large international dataset. Conclusions Our results identify GPCRs with potential to act as imaging and therapeutic targets. Elucidating tumorigenic pathways

  12. 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.

  13. 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.

  14. 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.

  15. Cerebellar Medulloblastoma Metastasis to Sacrum: A Case Report

    Directory of Open Access Journals (Sweden)

    Erdal Kalkan

    2015-12-01

    Full Text Available Introduction: Medulloblastoma is a primitive-neuroectodermal (PNET tumor, mostly localized infratentorially and mostly seen in childhood . It can be seen rarely in adults . Medulloblastoma metastasis is generally seen at bone marrow and bone, such as pelvis, femur, vertebra and costal bones. Case Presentation: A 32-year-old male patient admitted to our clinic with complaints of headache, giddiness, and ataxia. Cystic tumoral lesion was seen in the cerebellum on magnetic resonance imaging (MRI scans. The tumor was excised totally by a paramedian suboccipital craniectomy. Pathological examination results were consistent with medulloblastoma. One year after the operation, the patient was admitted to our clinic with back pain, weakness in his legs and urinary incontinence. A sacral tumor was seen on lumbosacral MRI. Conclusion: This is the first report of a sacral medulloblastoma metastasis case successfully treated with a partial sacrectomy and total tumoral excision. [J Contemp Med 2015; 5(4.000: 261-264

  16. 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...... 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......-weighted sequences, only 41.1 % of all adult medulloblastomas appeared hypointense (vs. 89.3 %) and 69.6 % were hyperintense on T2 sequences (vs. 83 %). In contrast to pediatric patients only 53.3 % showed strong contrast enhancement (pediatric patients 77.1 %), while the contrast uptake of the remainder...

  17. 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,

  18. Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice

    National Research Council Canada - National Science Library

    Williams, Scott E; Garcia, Idoia; Crowther, Andrew J; Li, Shiyi; Stewart, Alyssa; Liu, Hedi; Lough, Kendall J; O'Neill, Sean; Veleta, Katherine; Oyarzabal, Esteban A; Merrill, Joseph R; Shih, Yen-Yu Ian; Gershon, Timothy R

    2015-01-01

    .... Here, we report that Aspm, a gene that is mutated in familial microcephaly, regulates postnatal neurogenesis in the cerebellum and supports the growth of medulloblastoma, the most common malignant pediatric brain tumor...

  19. Sakruma Metastaz Yapmış Medulloblastoma: Bir Olgu Sunumu

    OpenAIRE

    Kalkan, Erdal; İlik, Mustafa; Keskin, Fatih; Kaya, Bülent

    2018-01-01

    Introduction: Medulloblastoma is a primitive-neuroectodermal (PNET) tumor, mostly localized infratentorially and mostly seen in childhood . It can be seen rarely in adults . Medulloblastoma metastasis is generally seen at bone marrow and bone, such as pelvis, femur, vertebra and costal bones. Case Presentation: A 32-year-old male patient admitted to our clinic with complaints of headache, giddiness, and ataxia. Cystic tumoral lesion was seen in the cerebellum on magnetic resonance imagin...

  20. Cerebellar Medulloblastoma in Middle-to-Late Adulthood

    OpenAIRE

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

    2018-01-01

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

  1. Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis.

    Science.gov (United States)

    Xu, Tao; Zhang, Honglai; Park, Sung-Soo; Venneti, Sriram; Kuick, Rork; Ha, Kimberly; Michael, Lowell Evan; Santi, Mariarita; Uchida, Chiyoko; Uchida, Takafumi; Srinivasan, Ashok; Olson, James M; Dlugosz, Andrzej A; Camelo-Piragua, Sandra; Rual, Jean-François

    2017-03-01

    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. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Matching mice to malignancy: molecular subgroups and models of medulloblastoma

    Science.gov (United States)

    Lau, Jasmine; Schmidt, Christin; Markant, Shirley L.; Taylor, Michael D.; Wechsler-Reya, Robert J.

    2012-01-01

    Introduction Medulloblastoma, the largest group of embryonal brain tumors, has historically been classified into five variants based on histopathology. More recently, epigenetic and transcriptional analyses of primary tumors have sub-classified medulloblastoma into four to six subgroups, most of which are incongruous with histopathological classification. Discussion Improved stratification is required for prognosis and development of targeted treatment strategies, to maximize cure and minimize adverse effects. Several mouse models of medulloblastoma have contributed both to an improved understanding of progression and to developmental therapeutics. In this review, we summarize the classification of human medulloblastoma subtypes based on histopathology and molecular features. We describe existing genetically engineered mouse models, compare these to human disease, and discuss the utility of mouse models for developmental therapeutics. Just as accurate knowledge of the correct molecular subtype of medulloblastoma is critical to the development of targeted therapy in patients, we propose that accurate modeling of each subtype of medulloblastoma in mice will be necessary for preclinical evaluation and optimization of those targeted therapies. PMID:22315164

  3. Congenital neuroblastoma with placental involvement

    OpenAIRE

    Kume, Ayako; Morikawa, Teppei; Ogawa, Makiko; Yamashita, Aki; Yamaguchi, Shunichi; Fukayama, Masashi

    2014-01-01

    We describe an extremely rare case of congenital neuroblastoma with placental involvement. A fetus with a left abdominal mass detected during ultrasonography at 23 weeks’ gestation developed hydrops fetalis by 26 weeks’ gestation. The mother developed hypertension at 26 5/7 weeks’ gestation. Based on a clinical diagnosis of pregnancy-induced hypertension, labor was induced at 26 6/7 weeks. However, intrauterine fetal death was diagnosed during delivery. Postmortern examination revealed a soli...

  4. 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

  5. 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.

  6. OTX2 directly activates cell cycle genes and inhibits differentiation in medulloblastoma cells

    NARCIS (Netherlands)

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

    2012-01-01

    The transcription factor OTX2 has been implicated as an oncogene in medulloblastoma, which is the most common malignant brain tumor in children. It is highly expressed in most medulloblastomas and amplified in a subset of them. To study the role OTX2 has in medulloblastoma we investigated the

  7. File list: InP.Neu.05.AllAg.Medulloblastoma [Chip-atlas[Archive

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  1. Significance of pleural effusion in neuroblastoma.

    Science.gov (United States)

    Gupta, Himesh; Conrad, John; Khoury, Joseph D; McGregor, Lisa M; Krasin, Matthew J; Dome, Jeffrey S; Santana, Victor M; Davidoff, Andrew M

    2007-12-01

    Pleural effusion is uncommon at diagnosis of neuroblastoma in children. Because the presence of malignant cells in pleural fluid may significantly change the management and outcome of patients with neuroblastoma, we retrospectively analyzed a cohort of neuroblastoma patients who presented with pleural effusion at the time of diagnosis to determine the incidence, presentation, stage, treatment, and outcome of these patients. We reviewed the presenting features of 295 patients with the diagnosis of neuroblastoma who received treatment at St. Jude Children's Research Hospital between 1991 and 2005. Patients were chosen for further analysis if pleural effusion had been identified on chest radiographs or computed tomography (CT) scans at diagnosis Thirty-one out of 295(10.5%) patients with neuroblastoma had pleural effusion identified at time of presentation. International neuroblastoma staging system (INSS) risk stratification was high risk in 29 cases and intermediate risk and low risk in 1 case each. The primary site of disease was abdomen in 26 patients; mediastinum in 5. We conducted cytologic analysis of pleural fluid of nine patients; the specimen of seven contained malignant cells. Eighteen of 31 patients died of progressive or recurrent disease. In patients with neuroblastoma, pleural effusion is usually associated with unfavorable biologic features and high-risk disease. Pleural fluid should be examined cytologically and at a time when the results would change the risk stratification. There was no statistically significant difference in the survival rate of the patients with high-risk neuroblastoma with or without malignant pleural effusion. 2007 Wiley-Liss, Inc

  2. MiR-206, a Cerebellum Enriched miRNA Is Downregulated in All Medulloblastoma Subgroups and Its Overexpression Is Necessary for Growth Inhibition of Medulloblastoma Cells.

    Science.gov (United States)

    Panwalkar, Pooja; Moiyadi, Aliasgar; Goel, Atul; Shetty, Prakash; Goel, Naina; Sridhar, Epari; Shirsat, Neelam

    2015-07-01

    Medulloblastoma is the most common and a highly malignant pediatric brain tumor located in the cerebellar region of the brain. Medulloblastomas have recently been shown to consist of four distinct molecular subgroups, viz., WNT, SHH, group 3, and group 4. MiR-206, a miRNA first identified as a myomiR due to its enriched expression in skeletal muscle was found to be expressed specifically in the cerebellum, the site of medulloblastoma occurrence. MiR-206 expression was found to be downregulated in medulloblastomas belonging to all the four molecular subgroups as well as in established medulloblastoma cell lines. Further, the expression of murine homolog of miR-206 was also found to be downregulated in SHH subgroup medulloblastomas from the Smo (+/+) transgenic mice and the Ptch1 (+/-) knockout mice. MiR-206 downregulation in all the four medulloblastoma subgroups suggests tumor-suppressive role for miR-206 in medulloblastoma pathogenesis. The effect of miR-206 expression was analyzed in three established medulloblastoma cell lines, viz., Daoy, D425, and D283 belonging to distinct molecular subgroups. Restoration of miR-206 expression to the levels comparable to those in the normal cerebellum, however, was found to be insufficient to inhibit the growth of established medulloblastoma cell lines. OTX2, an oncogenic miR-206 target, overexpressed in all non-SHH medulloblastomas, is known to inhibit myogenic differentiation of medulloblastoma cells. Overexpression of miR-206 was necessary to downregulate OTX2 expression and inhibit growth of medulloblastoma cell lines.

  3. Antiarrhythmic Amiodarone Mediates Apoptotic Cell Death of HepG2 Hepatoblastoma Cells through the Mitochondrial Pathway

    OpenAIRE

    Isomoto, Shojiro; Kawakami, Atsushi; Ohtsuru, Akira; Yamashita, Shunichi; Yano, Katsusuke

    2004-01-01

    The antiarrhythmic amiodarone is known to cause hepatic toxicity. Recently, much attention has been devoted to the role of apoptosis in the pathogenesis of drug-induced cytotoxicity. The aim of this study is to investigate whether apoptosis contributes to hepatic toxicity caused by amiodarone and, if so, by which mechanism. HepG2 human hepatoblastoma cells were incubated for 48 hours with various concentration of amiodarone. To determine apoptotic cells, concentration of cytochrome c in the c...

  4. Diffuse postoperative cerebellar swelling in medulloblastoma: report of two cases.

    Science.gov (United States)

    Ogiwara, Hideki; Dipatri, Arthur J; Bowman, Robin M; Tomita, Tadanori; Alden, Tord D

    2011-05-01

    We report two cases of diffuse cerebellar swelling with upward transtentorial herniation following medulloblastoma resection. We present our insight for managing medulloblastoma with aggressive clinical behavior. Case 1 is a 32-month-old boy. Magnetic resonance imaging (MRI) revealed fourth ventricular mass with diffuse leptomeningeal metastasis. He underwent gross total resectioning of the tumor and histopathology revealed a large cell medulloblastoma. A ventriculoperitoneal shunt was placed on the 25th postoperative day. Ten days after he developed lethargy, and MRI showed diffuse cerebellar swelling with upward herniation. He underwent emergent posterior fossa decompression; however, he remained unresponsive since then. Case 2 is a 31-month-old boy. MRI revealed a fourth ventricular mass with diffuse leptomeningeal metastasis. He underwent gross total resection and histopathology was a large cell medulloblastoma. Due to developing ventriculomegaly, extraventricular drainage was reinserted on the 11th postoperative day. Four days after, he developed lethargy and decerebrate posturing. MRI showed diffuse cerebellar swelling with upward herniation. He underwent aggressive posterior fossa decompression. Chemotherapy was started postoperatively. Gradually, his movement of extremities improved. On the 79th postoperative day, he started to follow commands and talk some words. He was discharged to a rehabilitation institute and has continued to improve since then. Diffuse cerebellar swelling with upward herniation could occur in patients with aggressive medulloblastoma postoperatively. Our patients had diffuse leptomeningeal dissemination of the tumor at the initial presentation. Close monitoring and prompt diagnosis with earlier surgical posterior fossa decompression and administration of chemotherapy may prevent irreversible neurologic deterioration.

  5. TAp73 is a marker of glutamine addiction in medulloblastoma.

    Science.gov (United States)

    Niklison-Chirou, Maria Victoria; Erngren, Ida; Engskog, Mikael; Haglöf, Jakob; Picard, Daniel; Remke, Marc; McPolin, Phelim Hugh Redmond; Selby, Matthew; Williamson, Daniel; Clifford, Steven C; Michod, David; Hadjiandreou, Michalis; Arvidsson, Torbjörn; Pettersson, Curt; Melino, Gerry; Marino, Silvia

    2017-09-01

    Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma. © 2017 Niklison-Chirou et al.; Published by Cold Spring Harbor Laboratory Press.

  6. 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; 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

    2017-07-19

    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 molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered 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 therapeutic targets for the treatment of patients with medulloblastoma.

  7. High expression of DNA methyltransferases in primary human medulloblastoma.

    Science.gov (United States)

    Pócza, T; Krenács, T; Turányi, E; Csáthy, J; Jakab, Z; Hauser, P

    2016-01-01

    Epigenetic alterations have been implicated in cancer development. DNA methylation modulates gene expression, which is catalyzed by DNA methyltransferases (DNMTs). The objective of our study was to evaluate expression of DNMTs in medulloblastoma and analyze its correlation with clinical features. Nuclear expression of DNMT1, DNMT3A and DNMT3B was analyzed in human primary medulloblastoma of 44 patients using immunohistochemistry. Correlation of expression of DNMT levels with classical histological subtypes, novel molecular subgroups and survival of patients was analyzed. Elevated expression of DNMT1, DNMT3A and DNMT3B was observed in 63.64%, 68.18% and 72.73% of all cases, respectively. None of them showed a correlation with classical histology or survival. Concerning molecular subtypes, significantly higher expression of DNMT1 was observed in the SHH group compared to non-SHH samples (p = 0.02), but without significant difference in DNMT3A or DNMT3B levels between any subtypes. In conclusion, DNMT1, DNMT3A and DNMT3B are highly expressed in human medulloblastoma samples, suggesting that promoter hypermethylation may play a role in medulloblastoma development. Demethylation of tumor suppressor gene promoters may be considered as a possible future target in therapy of medulloblastoma.

  8. MPS1 kinase as a potential therapeutic target in medulloblastoma.

    Science.gov (United States)

    Alimova, Irina; Ng, June; Harris, Peter; Birks, Diane; Donson, Andrew; Taylor, Michael D; Foreman, Nicholas K; Venkataraman, Sujatha; Vibhakar, Rajeev

    2016-11-01

    Medulloblastoma is the most common type of malignant brain tumor that affects children. Although recent advances in chemotherapy and radiation have improved outcomes, high-risk patients perform poorly with significant morbidity. Gene expression profiling has revealed that monopolar spindle 1 (MPS1) (TTK1) is highly expressed in medulloblastoma patient samples compared to that noted in normal cerebellum. MPS1 is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. The SAC can be activated in aneuploid cancer cells and MPS1 is overexpressed in many types of cancers. A previous study has demonstrated the effectiveness of inhibiting MPS1 with small-molecule inhibitors, but the role of MPS1 in medulloblastoma is unknown. In the present study, we demonstrated that MPS1 inhibition by shRNA or with a small-molecule drug, NMS-P715, resulted in decreased cell growth, inhibition of clonogenic potential and induction of apoptosis in cells belonging to both the Shh and group 3 medulloblastoma genomic signature. These findings highlight MPS1 as a rational therapeutic target for medulloblastoma.

  9. Ganglioglioma Arising From Desmoplastic Medulloblastoma: A Case Report and Review of Literature.

    Science.gov (United States)

    Valvi, Santosh; Ziegler, David S

    2017-03-01

    We describe a case of medulloblastoma maturating into ganglioglioma during therapy. A 10-month-old boy was diagnosed with a desmoplastic medulloblastoma and was treated with gross total resection followed by induction chemotherapy. A recurrence in the tumor bed during therapy was managed with focal radiation therapy and consolidation chemotherapy. After further progression, the recurrent tumor was resected completely. The histopathology revealed a benign ganglioglioma with no residual medulloblastoma. This case raises the possibility that a malignant medulloblastoma can differentiate into a benign tumor and suggests that differentiation therapy may have value in the treatment of medulloblastoma. Copyright © 2017 by the American Academy of Pediatrics.

  10. Olfactory neuroblastoma in a horse.

    Science.gov (United States)

    Yamate, Jyoji; Izawa, Takeshi; Ogata, Keiko; Kobayashi, Osamu; Okajima, Ryoko; Kuwamura, Mitsuru; Kotani, Takao; Aoki, Mika

    2006-05-01

    An 11-year-old thoroughbred gelding was euthanatized because of right nasal cavity tumor. The tumor consisted of round to oval cells with a scanty cytoplasm and hyperchromatic nuclei. Homer-Wright rosettes and pseudorosettes, as well as microcysts were seen. Neoplastic cells were immunoreactive to vimentin, S-100 protein, and neuron-specific enolase, glial fibrillary acidic protein and microtube-associated protein in varying degrees, indicating neurogenic nature. Based on these findings, this tumor was diagnosed as an olfactory neuroblastoma. Since this type is an uncommon tumor showing histological variety, the nature is discussed.

  11. Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma.

    Science.gov (United States)

    Faria, Claudia C; Agnihotri, Sameer; Mack, Stephen C; Golbourn, Brian J; Diaz, Roberto J; Olsen, Samantha; Bryant, Melissa; Bebenek, Matthew; Wang, Xin; Bertrand, Kelsey C; Kushida, Michelle; Head, Renee; Clark, Ian; Dirks, Peter; Smith, Christian A; Taylor, Michael D; Rutka, James T

    2015-08-28

    Advances in the molecular biology of medulloblastoma revealed four genetically and clinically distinct subgroups. Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy. We investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen. The Connectivity Map (C-MAP) analysis identified piperlongumine as the top candidate drug for non-WNT medulloblastomas and the cyclin-dependent kinase (CDK) inhibitor alsterpaullone as the compound predicted to have specific antitumor activity against Group 3 medulloblastomas. To validate our findings we used these inhibitors against established Group 3 medulloblastoma cell lines. The C-MAP predicted drugs reduced cell proliferation in vitro and increased survival in Group 3 medulloblastoma xenografts. Alsterpaullone had the highest efficacy in Group 3 medulloblastoma cells. Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC. Our results demonstrate the preclinical efficacy of using a targeted therapy approach for Group 3 medulloblastomas. Specifically, we provide rationale for advancing alsterpaullone as a targeted therapy in Group 3 medulloblastoma.

  12. 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.

  13. 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)

  14. 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.

  15. Akt2 regulates metastatic potential in neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Jingbo Qiao

    Full Text Available Activation of PI3K/AKT pathway correlates with poor prognosis in patients with neuroblastoma. Our previous studies have demonstrated that PI3K/AKT signaling is critical for the oncogenic transformations induced by gastrin-releasing peptide (GRP and its receptor, GRP-R, in neuroblastoma. Moreover, PI3K/AKT-dependent oncogenic transformations require N-myc, an extensively studied oncogene in neuroblastoma. Whether AKT directly regulates the expression of N-myc oncogene is yet to be determined. Here, we report a novel finding that of the three AKT isoforms, AKT2 specifically regulated N-myc expression in neuroblastoma cells. We also confirmed that GRP-R is upstream of AKT2 and in turn, regulated N-myc expression via AKT2 in neuroblastoma cells. Functional assays demonstrated that attenuation of AKT2 impaired cell proliferation and anchorage-independent cell growth, and decreased the secretion of angiogenic factor VEGF in vitro. Furthermore, silencing AKT2 inhibited migration and invasion of neuroblastoma cells in vitro. Xenografts established by injecting AKT2 silenced human neuroblastoma cells into murine spleen expressed decreased levels of AKT2 and resulted in fewer liver metastases compared to controls in vivo. Hence, our study highlights the potential molecular mechanism(s mediating the oncogenic role of GRP/GRP-R and demonstrates a novel role for AKT2 in neuroblastoma tumorigenesis, indicating that targeting the GRP/GRP-R/AKT2 axis may be important for developing novel therapeutics in the treatment of clinically aggressive neuroblastoma.

  16. Oncogenic mutations of ALK kinase in neuroblastoma.

    Science.gov (United States)

    Chen, Yuyan; Takita, Junko; Choi, Young Lim; Kato, Motohiro; Ohira, Miki; Sanada, Masashi; Wang, Lili; Soda, Manabu; Kikuchi, Akira; Igarashi, Takashi; Nakagawara, Akira; Hayashi, Yasuhide; Mano, Hiroyuki; Ogawa, Seishi

    2008-10-16

    Neuroblastoma in advanced stages is one of the most intractable paediatric cancers, even with recent therapeutic advances. Neuroblastoma harbours a variety of genetic changes, including a high frequency of MYCN amplification, loss of heterozygosity at 1p36 and 11q, and gain of genetic material from 17q, all of which have been implicated in the pathogenesis of neuroblastoma. However, the scarcity of reliable molecular targets has hampered the development of effective therapeutic agents targeting neuroblastoma. Here we show that the anaplastic lymphoma kinase (ALK), originally identified as a fusion kinase in a subtype of non-Hodgkin's lymphoma (NPM-ALK) and more recently in adenocarcinoma of lung (EML4-ALK), is also a frequent target of genetic alteration in advanced neuroblastoma. According to our genome-wide scans of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, the ALK locus, centromeric to the MYCN locus, was identified as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed eight novel missense mutations in 13 out of 215 (6.1%) fresh tumours and 8 out of 24 (33%) neuroblastoma-derived cell lines. All but one mutation in the primary samples (12 out of 13) were found in stages 3-4 of the disease and were harboured in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wild-type kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumours in nude mice. Furthermore, we demonstrate that downregulation of ALK through RNA interference suppresses proliferation of neuroblastoma cells harbouring mutated ALK. We anticipate that our findings will provide new insights into the pathogenesis of advanced neuroblastoma and that ALK-specific kinase inhibitors might improve its clinical outcome.

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

    Science.gov (United States)

    Chen, Y S; Li, S P; Xiao, H; Xie, Z Y; Tan, M X; Liu, B; Zhang, W M

    2016-06-17

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

  18. Gene signatures associated with mouse postnatal hindbrain neural stem cells and medulloblastoma cancer stem cells identify novel molecular mediators and predict human medulloblastoma molecular classification.

    Science.gov (United States)

    Corno, Daniela; Daniela, Corno; Pala, Mauro; Cominelli, Manuela; Cipelletti, Barbara; Leto, Ketty; Croci, Laura; Barili, Valeria; Brandalise, Federico; Melzi, Raffaella; Di Gregorio, Alessandra; Sergi, Lucia Sergi; Politi, Letterio Salvatore; Piemonti, Lorenzo; Bulfone, Alessandro; Rossi, Paola; Rossi, Ferdinando; Consalez, Gian Giacomo; Poliani, Pietro Luigi; Galli, Rossella

    2012-06-01

    Medulloblastoma arises from mutations occurring in stem/progenitor cells located in restricted hindbrain territories. Here we report that the mouse postnatal ventricular zone lining the IV ventricle also harbors bona fide stem cells that, remarkably, share the same molecular profile with cerebellar white matter-derived neural stem cells (NSC). To identify novel molecular mediators involved in medulloblastomagenesis, we compared these distinct postnatal hindbrain-derived NSC populations, which are potentially tumor initiating, with murine compound Ptch/p53 mutant medulloblastoma cancer stem cells (CSC) that faithfully phenocopy the different variants of human medulloblastoma in vivo. Transcriptome analysis of both hindbrain NSCs and medulloblastoma CSCs resulted in the generation of well-defined gene signatures, each reminiscent of a specific human medulloblastoma molecular subclass. Most interestingly, medulloblastoma CSCs upregulated developmentally related genes, such as Ebfs, that were shown to be highly expressed in human medulloblastomas and play a pivotal role in experimental medullo-blastomagenesis. These data indicate that gene expression analysis of medulloblastoma CSCs holds great promise not only for understanding functional differences between distinct CSC populations but also for identifying meaningful signatures that might stratify medulloblastoma patients beyond histopathologic staging.

  19. 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.

  20. Medulloblastoma in adulthood: prognostic factors influencing survival and recurrence.

    Science.gov (United States)

    Aragonés, M P; Magallón, R; Piqueras, C; Ley, L; Vaquero, J; Bravo, G

    1994-01-01

    Thirty adult patients presenting with medulloblastoma between 1974 and 1991 were studied and treated at Puerta de Hierro Clinic. After diagnosis, all patients were treated by surgery followed by radiotherapy and eight of them received adjuvant chemotherapy. We have studied the influence of some factors such as age, sex, location of tumour in the cerebellum, amount of surgical resection and histological variants on survival and recurrence of the disease. Only the histological type has a statistically significant influence on survival and recurrence: we have found that patients presenting classic medulloblastoma have a long survival and a long relapse-free interval.

  1. 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.

  2. Chemotherapeutic approaches for newly diagnosed hepatoblastoma: past, present, and future strategies.

    Science.gov (United States)

    Trobaugh-Lotrario, Angela D; Katzenstein, Howard M

    2012-11-01

    Surgical resection is the foundation of therapy in hepatoblastoma (HB), yet most patients have unresectable tumors at diagnosis. Patients with resectable tumors have event-free survival (EFS) of 80-90% and can be cured with cisplatin, 5-fluorouracil, and vincristine. Patients whose tumors are unresectable but without overt metastases at diagnosis have EFS of 60-70%, and many can be rendered resectable without doxorubicin. Children with metastatic disease have fared poorly with 20-50% EFS, and new approaches for these patients remain desperately needed. Dose intensification of cisplatin and doxorubicin appears beneficial in high-risk patients. Future treatment strategies, which may be useful, include increasing intensity and/or duration of therapy, developing a maintenance regimen (oral irinotecan), using liver transplantation more often for patients to undergo complete resection, and identifying and incorporating novel agents. A better understanding of the biologic and pathologic factors is critical for predicting tumor behavior and developing more logical risk-based treatments. Copyright © 2012 Wiley Periodicals, Inc.

  3. Parental infertility, infertility treatment and hepatoblastoma: a report from the Children's Oncology Group.

    Science.gov (United States)

    Puumala, Susan E; Ross, Julie A; Feusner, James H; Tomlinson, Gail E; Malogolowkin, Marcio H; Krailo, Mark D; Spector, Logan G

    2012-06-01

    A recent study suggested a markedly increased risk of hepatoblastoma (HB) among children conceived with treatment for infertility. However, it is not clear whether this finding is confounded by the association between HB and low birthweight (LBW). Associations between parental infertility and its treatment and HB were examined using data from a case-control study conducted through the Children's Oncology Group (COG). Telephone interviews were completed for 383 mothers of cases diagnosed with HB at US COG institutions between January 2000 and December 2008 and for 387 mothers of controls recruited through state birth registries. Logistic regression was used to examine possible associations. After adjusting for birthweight and other potential confounders, no significant association was found for any of the measures of parental infertility or its treatment. In HB cases conceived through assisted reproductive technology (ART), 4 of 16 also had Beckwith-Wiedemann syndrome (BWS) compared with 9 of 365 in HB cases without ART. Little evidence of an association between parental infertility or its treatment and HB was found. The relationship found in a previous study could be due to LBW and BWS which are risk factors for HB and also associated with parental infertility and its treatment.

  4. Narcolepsy/Cataplexy and Occult Neuroblastoma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-11-01

    Full Text Available Investigators at the University of Chicago and Northwestern University, Chicago, IL; University Hospital Southampton, UK; and Kiev Paediatric Hospital, Ukraine, report three children with narcolepsy and cataplexy subsequently diagnosed with neuroblastoma.

  5. The regulation of angiogenesis in neuroblastoma.

    Science.gov (United States)

    Chlenski, Alexandre; Liu, Shuqing; Cohn, Susan L

    2003-07-18

    Angiogenesis is required for the growth and metastasis of malignant tumors, and high vascular density has been correlated with aggressive tumor growth in many types of cancer. This process is regulated by the local balance of stimulatory and inhibitory molecules produced by tumor cells, stromal cells, and the organ-specific environment. In neuroblastoma, a pediatric malignancy that is characterized by a broad spectrum of clinical behavior, angiogenesis also appears to play an important role in determining tumor phenotype. The nature of the angiogenic balance in neuroblastoma is complex, and a spectrum of angiogenesis stimulators and inhibitors has been detected in neuroblastoma tumors. This review summarizes our current understanding of the regulation of angiogenesis in neuroblastoma.

  6. Histone deacetylase 8 in neuroblastoma tumorigenesis.

    Science.gov (United States)

    Oehme, Ina; Deubzer, Hedwig E; Wegener, Dennis; Pickert, Diana; Linke, Jan-Peter; Hero, Barbara; Kopp-Schneider, Annette; Westermann, Frank; Ulrich, Scott M; von Deimling, Andreas; Fischer, Matthias; Witt, Olaf

    2009-01-01

    The effects of pan-histone deacetylase (HDAC) inhibitors on cancer cells have shown that HDACs are involved in fundamental tumor biological processes such as cell cycle control, differentiation, and apoptosis. However, because of the unselective nature of these compounds, little is known about the contribution of individual HDAC family members to tumorigenesis and progression. The purpose of this study was to evaluate the role of individual HDACs in neuroblastoma tumorigenesis. We have investigated the mRNA expression of all HDAC1-11 family members in a large cohort of primary neuroblastoma samples covering the full spectrum of the disease. HDACs associated with disease stage and survival were subsequently functionally evaluated in cell culture models. Only HDAC8 expression was significantly correlated with advanced disease and metastasis and down-regulated in stage 4S neuroblastoma associated with spontaneous regression. High HDAC8 expression was associated with poor prognostic markers and poor overall and event-free survival. The knockdown of HDAC8 resulted in the inhibition of proliferation, reduced clonogenic growth, cell cycle arrest, and differentiation in cultured neuroblastoma cells. The treatment of neuroblastoma cell lines as well as short-term-culture neuroblastoma cells with an HDAC8-selective small-molecule inhibitor inhibited cell proliferation and clone formation, induced differentiation, and thus reproduced the HDAC8 knockdown phenotype. Global histone 4 acetylation was not affected by HDAC8 knockdown or by selective inhibitor treatment. Our data point toward an important role of HDAC8 in neuroblastoma pathogenesis and identify this HDAC family member as a specific drug target for the differentiation therapy of neuroblastoma.

  7. Neuroblastoma: Developmental Biology, Cancer Genomics, and Immunotherapy

    Science.gov (United States)

    Cheung, Nai-Kong V.; Dyer, Michael A.

    2015-01-01

    Neuroblastoma is a solid tumor that arises from the developing sympathetic nervous system. Over the past decade, our understanding of this disease has advanced tremendously. The future challenge is to apply the knowledge gained toward developing risk-based therapies and ultimately improving outcome. Here we review the key discoveries in the developmental biology, molecular genetics, and immunology of neuroblastoma, as well as new translational tools to bring these promising scientific advances into the clinic. PMID:23702928

  8. 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.

  9. Comprehensive high-resolution genomic profiling and cytogenetics of two pediatric and one adult medulloblastoma.

    Science.gov (United States)

    Holland, Heidrun; Xu, Li-Xin; Ahnert, Peter; Kirsten, Holger; Koschny, Ronald; Bauer, Manfred; Schober, Ralf; Meixensberger, Jürgen; Krupp, Wolfgang

    2013-09-01

    Medulloblastoma (WHO grade IV) is a rare, malignant, invasive, embryonal tumor which mainly occurs in children and represents less than 1% of all adult brain tumors. Systematic comprehensive genetic analyses on medulloblastomas are rare but necessary to provide more detailed information. Therefore, we performed comprehensive cytogenetic analyses (blood and tissue) of two pediatric and one adult medulloblastoma, using trypsin-Giemsa staining, spectral karyotyping (tissues only), SNP-arrays, and gene expression analyses. We confirmed frequently detected chromosomal aberrations in medulloblastoma, such as +7q, -8p/q, -9q, -11q, -12q, and +17q and identified novel genetic events. Applying SNP-array, we identified constitutional de novo losses 5q21.1, 15q11.2, 17q21.31, 19p12 (pediatric medulloblastoma), 9p21.1, 19p12, 19q13.3, 21q11.2 (adult medulloblastoma) and gains 16p11.1-16p11.2, 18p11.32, Yq11.223-Yq11.23 (pediatric medulloblastoma), Xp22.31 (adult medulloblastoma) possibly representing inherited causal events for medulloblastoma formation. We show evidence for somatic segmental uniparental disomy in regions 1p36, 6q16.3, 6q24.1, 14q21.2, 17p13.3, and 17q22 not previously described for primary medulloblastoma. Gene expression analysis supported classification of the adult medulloblastoma to the WNT-subgroup and classification of pediatric medulloblastomas to group 3 tumors. Analyses of tumors and matched normal tissues (blood) with a combination of complementary techniques will help to further elucidate potentially causal genetic events for medulloblastomas. Copyright © 2013 Elsevier GmbH. All rights reserved.

  10. Antitumor activity of nifurtimox observed in a patient with neuroblastoma.

    Science.gov (United States)

    Saulnier Sholler, Giselle L; Kalkunte, Satyan; Greenlaw, Carla; McCarten, Kathleen; Forman, Edwin

    2006-10-01

    Chemotherapy-resistant neuroblastoma is a difficult disease to treat with poor survival. We treated a patient with neuroblastoma who had progressed on conventional chemotherapy. This 5-year-old girl with chemotherapy-resistant neuroblastoma developed Chagas disease at the start of salvage chemotherapy for which she was also started on nifurtimox. The neuroblastoma response to these treatments resulted in clinical remission. In vitro, treatment of a neuroblastoma cell line with nifurtimox resulted in decreased cell viability whereas no effect was seen on an endothelial cell line. Nifurtimox shows promise as a potential new treatment for neuroblastoma and warrants further testing.

  11. Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    DuBois, Steven G. [Department of Pediatrics, UCSF School of Medicine, Box 0106, San Francisco, CA 94143-0106 (United States); Matthay, Katherine K. [Department of Pediatrics, UCSF School of Medicine, Box 0106, San Francisco, CA 94143-0106 (United States)], E-mail: matthayk@peds.ucsf.edu

    2008-08-15

    Introduction: Neuroblastoma is the most common pediatric extracranial solid cancer. This tumor is characterized by metaiodobenzylguanidine (MIBG) avidity in 90% of cases, prompting the use of radiolabeled MIBG for targeted radiotherapy in these tumors. Methods: The available English language literature was reviewed for original research investigating in vitro, in vivo and clinical applications of radiolabeled MIBG for neuroblastoma. Results: MIBG is actively transported into neuroblastoma cells by the norepinephrine transporter. Preclinical studies demonstrate substantial activity of radiolabeled MIBG in neuroblastoma models, with {sup 131}I-MIBG showing enhanced activity in larger tumors compared to {sup 125}I-MIBG. Clinical studies of {sup 131}I-MIBG in patients with relapsed or refractory neuroblastoma have identified myelosuppression as the main dose-limiting toxicity, necessitating stem cell reinfusion at higher doses. Most studies report a response rate of 30-40% with {sup 131}I-MIBG in this population. More recent studies have focused on the use of {sup 131}I-MIBG in combination with chemotherapy or myeloablative regimens. Conclusions: {sup 131}I-MIBG is an active agent for the treatment of patients with neuroblastoma. Future studies will need to define the optimal role of this targeted radiopharmaceutical in the therapy of this disease.

  12. 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

  13. The whole-genome landscape of medulloblastoma subtypes

    DEFF Research Database (Denmark)

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

    2017-01-01

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

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

    African Journals Online (AJOL)

    East and Central African Journal of Surgery. Journal Home · ABOUT · 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, A Agrawal, DN ...

  15. Clonal selection drives genetic divergence of metastatic medulloblastoma

    NARCIS (Netherlands)

    Wu, Xiaochong; Northcott, Paul A.; Dubuc, Adrian; Dupuy, Adam J.; Shih, David J. H.; Witt, Hendrik; Croul, Sidney; Bouffet, Eric; Fults, Daniel W.; Eberhart, Charles G.; Garzia, Livia; van Meter, Timothy; Zagzag, David; Jabado, Nada; Schwartzentruber, Jeremy; Majewski, Jacek; Scheetz, Todd E.; Pfister, Stefan M.; Korshunov, Andrey; Li, Xiao-Nan; Scherer, Stephen W.; Cho, Yoon-Jae; Akagi, Keiko; MacDonald, Tobey J.; Koster, Jan; McCabe, Martin G.; Sarver, Aaron L.; Collins, V. Peter; Weiss, William A.; Largaespada, David A.; Collier, Lara S.; Taylor, Michael D.

    2012-01-01

    Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord(1). Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis

  16. Active medulloblastoma enhancers reveal subgroup-specific cellular origins

    Science.gov (United States)

    Lin, Charles Y.; Erkek, Serap; Tong, Yiai; Yin, Linlin; Federation, Alexander J.; Zapatka, Marc; Haldipur, Parthiv; Kawauchi, Daisuke; Risch, Thomas; Warnatz, Hans-Jörg; Worst, Barbara C.; Ju, Bensheng; Orr, Brent A.; Zeid, Rhamy; Polaski, Donald R.; Segura-Wang, Maia; Waszak, Sebastian M.; Jones, David T.W.; Kool, Marcel; Hovestadt, Volker; Buchhalter, Ivo; Sieber, Laura; Johann, Pascal; Chavez, Lukas; Gröschel, Stefan; Ryzhova, Marina; Korshunov, Andrey; Chen, Wenbiao; Chizhikov, Victor V.; Millen, Kathleen J.; Amstislavskiy, Vyacheslav; Lehrach, Hans; Yaspo, Marie-Laure; Eils, Roland; Lichter, Peter; Korbel, Jan O.; Pfister, Stefan M.; Bradner, James E.; Northcott, Paul A.

    2016-01-01

    Summary Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Using H3K27ac and BRD4 ChIP-Seq, coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-Seq, that are responsible for subgroup divergence and implicate candidate cells-of-origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins. PMID:26814967

  17. Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice.

    Science.gov (United States)

    Williams, Scott E; Garcia, Idoia; Crowther, Andrew J; Li, Shiyi; Stewart, Alyssa; Liu, Hedi; Lough, Kendall J; O'Neill, Sean; Veleta, Katherine; Oyarzabal, Esteban A; Merrill, Joseph R; Shih, Yen-Yu Ian; Gershon, Timothy R

    2015-11-15

    Alterations in genes that regulate brain size may contribute to both microcephaly and brain tumor formation. Here, we report that Aspm, a gene that is mutated in familial microcephaly, regulates postnatal neurogenesis in the cerebellum and supports the growth of medulloblastoma, the most common malignant pediatric brain tumor. Cerebellar granule neuron progenitors (CGNPs) express Aspm when maintained in a proliferative state by sonic hedgehog (Shh) signaling, and Aspm is expressed in Shh-driven medulloblastoma in mice. Genetic deletion of Aspm reduces cerebellar growth, while paradoxically increasing the mitotic rate of CGNPs. Aspm-deficient CGNPs show impaired mitotic progression, altered patterns of division orientation and differentiation, and increased DNA damage, which causes progenitor attrition through apoptosis. Deletion of Aspm in mice with Smo-induced medulloblastoma reduces tumor growth and increases DNA damage. Co-deletion of Aspm and either of the apoptosis regulators Bax or Trp53 (also known as p53) rescues the survival of neural progenitors and reduces the growth restriction imposed by Aspm deletion. Our data show that Aspm functions to regulate mitosis and to mitigate DNA damage during CGNP cell division, causes microcephaly through progenitor apoptosis when mutated, and sustains tumor growth in medulloblastoma. © 2015. Published by The Company of Biologists Ltd.

  18. 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…

  19. Paediatric medulloblastoma cells are susceptible to Viscum album (Mistletoe) preparations.

    Science.gov (United States)

    Zuzak, T J; Rist, L; Eggenschwiler, J; Grotzer, M A; Viviani, A

    2006-01-01

    Medulloblastoma constitute more than 20% of all paediatric brain tumours and are the most common malignant brain tumours in children. Adjuvant chemotherapy has seen a strong increase in the use of complementary medicine for cancer treatment. Evidence for cytotoxic and apoptotic effects of Viscum album (Mistletoe) in vitro is available, however, no data concerning paediatric tumours, especially paediatric brain tumours, has been provided so far. In order to compare the receptiveness of medulloblastoma cells to different Viscum album preparations, in vitro cytotoxic effects of eight Viscum album extracts on four different paediatric medulloblastoma cell lines were analysed by MTT-Tests. Lectin contents of the extracts were determined to correlate them with the mitochondrial activity of mistletoe-treated cells. Flowcytometric analyses with Annexin V-FITC staining were carried out to quantify the amount of apoptotic cells compared to necrotic and viable cells. Data obtained with the medulloblastoma cell lines, Daoy, D342, D425 and UW-288-2, treated with Viscum album preparations from eight dissimilar host trees (Iscucin Abietis, Pini, Populi, Mali, Salicis, Crataegi, Quercus and Tiliae), indicated a significant growth-inhibition of all cell lines, yet the cell susceptibility was dissimilar against the different extracts. The decrease in mitochondrial activity and increase in apoptosis correlated with the lectin content of the used preparation in a dose-dependent manner. These in vitro results show that paediatric medulloblastoma cells respond to Viscum album preparations, by undergoing cell death through apoptosis and that this growth-inhibition correlates with the lectin content of the used preparation.

  20. 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

  1. Cholinergic regulation of VIP gene expression in human neuroblastoma cells

    DEFF Research Database (Denmark)

    Kristensen, Bo; Georg, Birgitte; Fahrenkrug, Jan

    1997-01-01

    Vasoactive intestinal polypeptide, muscarinic receptor, neuroblastoma cell, mRNA, gene expression, peptide processing......Vasoactive intestinal polypeptide, muscarinic receptor, neuroblastoma cell, mRNA, gene expression, peptide processing...

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

    OpenAIRE

    Pöschl, J; Lorenz, A; Hartmann, W.; Von Bueren, AO; Kool, M; S. Li; Peraud, A.; Tonn, J-C; Herms, J; Xiang, M.; Rutkowski, S; Kretzschmar, HA; 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 precursors. The homeodomain transcription factor Barhl1 is known to regulate migration and survival of granule cell precursors, but its functional role in medulloblastoma is unknown. We show here that the e...

  3. 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.

  4. Dilated cardiomyopathy in a child with abdominal neuroblastoma ...

    African Journals Online (AJOL)

    Neuroblastoma is the most common extracranial solid tumour of childhood. Dilated cardiomyopathy as an initial presentation of neuroblastoma is rare. We report the case of a three-year-old child with giant abdominal neuroblastoma encasing the abdominal aorta who presented with dilated cardiomyopathy in heart failure ...

  5. 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

  6. Icariside II-induced mitochondrion and lysosome mediated apoptosis is counterbalanced by an autophagic salvage response in hepatoblastoma.

    Science.gov (United States)

    Geng, Ya-di; Zhang, Chao; Shi, Ya-Min; Xia, Yuan-Zheng; Guo, Chao; Yang, Lei; Kong, Ling-Yi

    2015-09-28

    In this study, the anti-cancer effect of Icariside II (IS), a natural plant flavonoid, against hepatoblastoma cells and the underlying mechanisms were investigated. The in vitro and in vivo studies show that IS decreased the viability of human hepatoblastoma HepG2 cells in a concentration- and time-dependent manner and inhibited tumor growth in mice transplanted with H22 liver carcinomas. IS impaired mitochondria and lysosomes as evidenced by signs of induced mitochondrial and lysosomal membrane permeabilization, resulting in caspase activation and apoptosis. SQSTM1 up-regulation and autophagic flux measurements demonstrated that IS exposure also impaired autophagosome degradation which resulted in autophagosome accumulation, which plays a pro-survival role as the genetic knockdown of LC3B further sensitized the IS-treated cells. Electron microscopy images showed that autophagosome engulfs IS-impaired mitochondria and lysosomes, thus blocking cytotoxicity induced by further leakage of the hydrolases from lysosomes and pro-apoptosis members from mitochondria. In conclusion, these data suggest that IS plays multiple roles as a promising chemotherapeutic agent that induces cell apoptosis involving both mitochondrial and lysosomal damage. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Neuroblastoma management in Chinese children.

    Science.gov (United States)

    Li, Kai; Dong, Kuiran; Gao, Jiechun; Yao, Wei; Xiao, Xianmin; Zheng, Shan

    2012-04-01

    This study assesses the clinical features of neuroblastoma and survival. Data for 98 patients between January 2000 and December 2006 at Children's Hospital of Fudan University, Shanghai, China, were retrospectively analyzed. Diagnostic methods included imaging, 24-hr urine catecholamines, bone marrow biopsies, and histopathology analyses. Treatment followed the modified Japanese Study Group Protocol. Clinical characteristics, treatment, and outcome were depicted, and difficulties encountered were analyzed. The median age of patients was 48 months. There were 3, 13, 31, 49, and 2 patients in stages 1, 2, 3, 4, and 4s disease, respectively. Positive urinary vanillylmandelic acid (VMA) prevalence was low in localized disease (51.1%) and high in disseminated disease (70.6%, p = .03). Gross total resection rate was 60.8%. The five-year overall survival (OS) rate was 80% for stages 1 and 2, 48.3% for stage 3, and 20% for stage 4. The five-year OS rates significantly decreased in children older than 18 months (p indigence were the main causes for poorer outcome in late stages.

  8. Epigenetic regulation of neuroblastoma development.

    Science.gov (United States)

    Durinck, Kaat; Speleman, Frank

    2018-01-19

    In recent years, technological advances have enabled a detailed landscaping of the epigenome and the mechanisms of epigenetic regulation that drive normal cell function, development and cancer. Rather than merely a structural entity to support genome compaction, we now look at chromatin as a very dynamic and essential constellation that is actively participating in the tight orchestration of transcriptional regulation as well as DNA replication and repair. The unique feature of chromatin flexibility enabling fast switches towards more or less restricted epigenetic cellular states is, not surprisingly, intimately connected to cancer development and treatment resistance, and the central role of epigenetic alterations in cancer is illustrated by the finding that up to 50% of all mutations across cancer entities affect proteins controlling the chromatin status. We summarize recent insights into epigenetic rewiring underlying neuroblastoma (NB) tumor formation ranging from changes in DNA methylation patterns and mutations in epigenetic regulators to global effects on transcriptional regulatory circuits that involve key players in NB oncogenesis. Insights into the disruption of the homeostatic epigenetic balance contributing to developmental arrest of sympathetic progenitor cells and subsequent NB oncogenesis are rapidly growing and will be exploited towards the development of novel therapeutic strategies to increase current survival rates of patients with high-risk NB.

  9. Fertility in male medulloblastoma survivors: closing the gaps in counseling

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    Nahata L

    2013-12-01

    Full Text Available Leena Nahata,1 Richard N Yu,2 Ian P Dumont,3,4 Peter E Manley,3,4 Laurie E Cohen1,3,4 1Division of Endocrinology, 2Department of Urology, Department of Medicine, Boston Children's Hospital, 3Division of Hematology/Oncology, Department of Medicine, Boston Children's Hospital, 4Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Background: Pediatric medulloblastoma patients have high survival rates and are at risk for treatment-related sequelae, including infertility, emphasizing the need for fertility counseling. This cohort is less likely to pursue higher education, marry, and live independently, which may impact fertility counseling. Our goal was to explore fertility-related concerns in medulloblastoma survivors and counseling practices among providers. Methods: This study was performed at the Dana-Farber/Children's Hospital Cancer Center in Boston, Massachusetts. Surveys were administered to male pediatric medulloblastoma survivors aged 18 years and older and pediatric neuro-oncology practitioners. Medical records were reviewed to determine treatment protocols and documentation of fertility counseling. Data analysis was descriptive. Results: Fourteen male medulloblastoma survivors and six neuro-oncology practitioners completed the study. All patients had received central nervous system irradiation and adjuvant chemotherapy with at least one alkylating agent. Five (83% practitioners stated that they discussed fertility with all survivors at most visits. Eight (57% medulloblastoma survivors stated that they had received fertility counseling at initial diagnosis. Six (43% stated that fertility had been discussed since treatment had ended. The majority (>70% of survivors reported a desire to have children and were open to learning more about their fertility status. Fertility counseling was documented in survivorship visits in only 46% of subjects. Conclusion: Most of our subjects had no documented fertility

  10. Immune Thrombocytopenia in a Child with Neuroblastoma

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    Hasan Tarkan Ikizoglu

    2017-01-01

    Full Text Available Thrombocytopenia is a frequent finding in patients with solid tumors. It is usually caused by bone marrow infiltration or by myelosuppression due to anticancer therapy; however immune thrombocytopenia (ITP associated with solid tumors is rare. Neuroblastoma is the most common extracranial solid tumor in children. Here we report the case of a two-year-nine-month-old patient with adrenal neuroblastoma who presented with ITP. Paraneoplastic ITP was considered in the differential diagnosis. Bone marrow infiltration and other causes of thrombocytopenia were excluded and the patient was treated with intravenous immunoglobulin and tumor resection. Platelet count increased rapidly after surgery and complete remission of ITP was achieved.

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

    Science.gov (United States)

    2017-09-01

    chose to make new medulloblastoma models with oncogenic PIK3CA (PIK3CAH1047R). However, this change caused major delay in our progress since we have not...these tumors. 15. SUBJECT TERMS cancer stem cells, medulloblastoma, targeted therapy, therapy resistance , pediatric cancer, brain tumor, Notch1...Keywords……………………………………………………………. 4 3. Accomplishments………..………………………………………….. 4 4. Impact…………………………...…………………………………… 8 5. Changes /Problems

  12. [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.

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

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    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.

  14. 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.

  15. Intracerebellar haematoma simulating congenital medulloblastoma during neonatal period.

    Science.gov (United States)

    Babakhouya, Abdeladim; Abourazzak, Sana; Aggouri, Mohamed; Chakour, Khalid; Chaoui, Faiz Mohamed; Hida, Moustapha; Bouharrou, Abdelhak

    2011-04-09

    The authors report a case of intracerebellar haematoma occurring during the neonatal period. A 5-day-old baby girl was admitted because of poor feeding and the anterior fontanelle was tense. CT scan of the brain revealed a round mass at the cerebellar vermis; the lesion simulated a cerebellar tumour such as a medulloblastoma. The mass was surgically removed and found to be an intracerebellar haematoma. The clinical and radiologic characteristics are discussed.

  16. Co-localization of the oncogenic transcription factor MYCN and the DNA methyl binding protein MeCP2 at genomic sites in neuroblastoma.

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    Derek M Murphy

    Full Text Available MYCN is a transcription factor that is expressed during the development of the neural crest and its dysregulation plays a major role in the pathogenesis of pediatric cancers such as neuroblastoma, medulloblastoma and rhabdomyosarcoma. MeCP2 is a CpG methyl binding protein which has been associated with a number of cancers and developmental disorders, particularly Rett syndrome.Using an integrative global genomics approach involving chromatin immunoprecipitation applied to microarrays, we have determined that MYCN and MeCP2 co-localize to gene promoter regions, as well as inter/intragenic sites, within the neuroblastoma genome (MYCN amplified Kelly cells at high frequency (70.2% of MYCN sites were also positive for MeCP2. Intriguingly, the frequency of co-localization was significantly less at promoter regions exhibiting substantial hypermethylation (8.7%, as determined by methylated DNA immunoprecipitation (MeDIP applied to the same microarrays. Co-immunoprecipitation of MYCN using an anti-MeCP2 antibody indicated that a MYCN/MeCP2 interaction occurs at protein level. mRNA expression profiling revealed that the median expression of genes with promoters bound by MYCN was significantly higher than for genes bound by MeCP2, and that genes bound by both proteins had intermediate expression. Pathway analysis was carried out for genes bound by MYCN, MeCP2 or MYCN/MeCP2, revealing higher order functions.Our results indicate that MYCN and MeCP2 protein interact and co-localize to similar genomic sites at very high frequency, and that the patterns of binding of these proteins can be associated with significant differences in transcriptional activity. Although it is not yet known if this interaction contributes to neuroblastoma disease pathogenesis, it is intriguing that the interaction occurs at the promoter regions of several genes important for the development of neuroblastoma, including ALK, AURKA and BDNF.

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

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    Carolina Oliveira Rodini

    2010-12-01

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

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

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    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.

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

    Science.gov (United States)

    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

    2011-11-24

    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 precursors. The homeodomain transcription factor Barhl1 is known to regulate migration and survival of granule cell precursors, but its functional role in medulloblastoma is unknown. We show here that the expression of BARHL1 is significantly upregulated during human cerebellar development and in human medulloblastoma samples as compared with the normal adult cerebellum. We also detected high levels of Barhl1 expression in medulloblastomas of Math1-cre:SmoM2 mice, a mouse model for Sonic hedgehog-associated medulloblastomas that we developed previously. To investigate Barhl1 function in vivo during tumor development, we generated Barhl1(-/-)Math1-cre:SmoM2 mice. Interestingly, tumors that developed in these mice displayed increased mitotic activity and decreased neuronal differentiation. Moreover, survival of these mice was significantly decreased. Similarly, low expression of BARHL1 in human medulloblastoma cases was associated with a less favorable prognosis for patients. These results suggest that the expression of Barhl1 decelerates tumor growth both in human and in murine medulloblastomas and should be further investigated with respect to potential implications for individualized therapeutic strategies.

  20. Medulloblastomas of the Cerebellum in Children: Clinicopathologic Comparison

    Directory of Open Access Journals (Sweden)

    V. V. Morgun

    2017-04-01

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

  1. Immunocombination therapy for high-risk neuroblastoma.

    NARCIS (Netherlands)

    Kroesen, M.; Lindau, D.; Hoogerbrugge, P.; Adema, G.J.

    2012-01-01

    Neuroblastoma (NBL) is an aggressive malignancy of the sympathetic nervous system. Advanced-stage NBLs prove fatal in approximately 50% of patients within 5 years. Therefore, new treatment modalities are urgently needed. Immunotherapy is a treatment modality that can be combined with established

  2. Monoclonal Antibody Therapy for Advanced Neuroblastoma

    Science.gov (United States)

    NCI is sponsoring two clinical trials of a monoclonal antibody called ch14.18, in combination with other drugs, to see if the antibody may be helpful for children or young adults (up to age 21) with relapsed or refractory neuroblastoma.

  3. Cervical neonatal neuroblastoma with recurrent SVT.

    Science.gov (United States)

    Al-Shammari, N F; Redha, E; Al Hajeri, M H

    2009-07-01

    Neuroblastoma is the most common extracranial solid tumor of childhood and the third most common paediatric malignancy after leukemia and central nervous system (CNS) tumors. It constitutes 10% of all paediatric malignancies and 75% of them present in children below 4 years of age. Seventy five percent of neuroblastoma arise in the abdomen and pelvis, 20% in the thorax and 5% in the neck. The median age at diagnosis is 22 months. Up to 95% of cases are diagnosed by the age of ten years. Neuroblastomas have been diagnosed in utero as early as 19 weeks of gestational age. They can arise anywhere along the sympathetic chain. They occur most commonly in the adrenal medulla (35%). Neuroblastomas also occur as primary tumors in the extra-adrenal retroperitoneum in 30% of cases, in the posterior mediastinum in 20% of cases , in the neck up to 5% of cases and in the pelvis in 5% of cases. Approximately 50% of patients will have metastasis at presentation.

  4. Peripheral neuroblastomas in dogs: a case series.

    Science.gov (United States)

    Arenas-Gamboa, A M; Tanabe, M; Edwards, J; Storts, R

    2014-05-01

    The peripheral neuroblastic tumours (PNTs) include neuroblastoma, ganglioneuroblastoma and ganglioneuromas. These subtypes reflect a spectrum of differentiation of progenitor cells of the sympathetic nervous system from tumours with predominant undifferentiated neuroblasts to those consisting of neuronal cell bodies that are well differentiated. Peripheral neuroblastoma is a tumour composed of neuroblastic cells with no or limited neuronal differentiation. In dogs, peripheral neuroblastoma is rare. The present report documents nine cases of canine peripheral neuroblastoma, the majority occurring as large masses in the craniodorsal abdominal cavity of young dogs (mean age of 3 years at diagnosis). Microscopically, all of the masses consisted of round to oval cells with a scant cytoplasm and hyperchromatic nuclei. Homer-Wright rosettes and pseudorosettes were evident in three of the nine cases. Neoplastic cells were immunoreactive in varying degrees to S100, neuron-specific enolase, synaptophysin, chromogranin A, tyrosine hydroxylase (one case) and were negative for vimentin, cytokeratin, CD3 and CD79a, indicating a neurogenic nature. Four of the nine cases occurred in Labrador retrievers (44%) and two (22%) in boxers, suggesting a possible breed predisposition. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Molecular events during tumor progression in neuroblastoma

    NARCIS (Netherlands)

    Bernards, R.A.; Lenardo, M.

    1990-01-01

    The N-myc oncogene was first identified as an amplified DNA element with homology to c-myc in human neuroblastoma. Since this initial observation, amplification of N-myc has also been observed in other types of human cancer, predominantly in retinoblastoma and small cell lung cancer. The

  6. Utility of PAS and β-catenin staining in histological categorisation and prediction of prognosis of hepatoblastomas.

    Science.gov (United States)

    Bera, Goutam; Das, Ram Narayan; Roy, Paromita; Ghosh, Ranajoy; Islam, Nelofar; Mishra, Prafulla Kumar; Chatterjee, Uttara

    2017-06-19

    The aim of this study was to assess the usefulness of PAS, β-catenin and Ki-67 in categorising hepatoblastomas (HBs) and their significance in predicting prognosis. In addition, we have also documented the various chemotherapy induced histologic changes in HBs. In this retrospective observational study of 29 cases of hepatoblastomas, 27 cases were considered for statistical analysis, excluding two cases of diagnostic core biopsies. All clinicopathological parameters and follow up data were collected. All HB cases including the mixed epithelial and mesenchymal HBs were classified into two groups: fetal predominant and embryonal predominant type according to the predominant epithelial component. PAS, β-catenin and Ki-67 staining were done and their correlation with histologic subtypes was assessed. Kaplan-Meier survival analysis was performed in relation to histology, PAS, β-catenin and Ki-67 staining characteristics. Diffuse nuclear staining of β-catenin was significantly more common in embryonal predominant type (p = 0.036), whereas strong PAS positivity was significantly associated with fetal predominant type (p = 0.002). But no significant correlation was seen between histologic type and Ki-67 staining (p = 0.42). Survival analysis showed cases with diffuse PAS positivity, focal nuclear β-catenin staining and low Ki-67 LI had better survival. PAS is a simple stain and can be utilised in histological categorisation of HB and also predicting its outcome. Nuclear β-catenin staining which is significantly common in embryonal elements in HB predicts shorter survival.

  7. YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells.

    Science.gov (United States)

    Dey, A; Robitaille, M; Remke, M; Maier, C; Malhotra, A; Gregorieff, A; Wrana, J L; Taylor, M D; Angers, S; Kenney, A M

    2016-08-11

    Postnatal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells of origin for the SHH-associated subgroup of medulloblastoma, is driven by Sonic hedgehog (Shh) and insulin-like growth factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is upregulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh subgroup of medulloblastoma in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and MBCs and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.

  8. More than the genes, the tumor microenvironment in neuroblastoma

    Science.gov (United States)

    Borriello, Lucia; Seeger, Robert C.; Asgharzadeh, Shahab; DeClerck, Yves A.

    2017-01-01

    Neuroblastoma is the second most common solid tumor in children. Since the seminal discovery of the role of amplification of the MYCN oncogene in the pathogenesis of neuroblastoma in the 1980s, much focus has been on the contribution of genetic alterations in the progression of this cancer. However it is now clear that not only genetic events play a role but that the tumor microenvironment (TME) substantially contributes to the biology of neuroblastoma. In this article, we present a comprehensive review of the literature on the contribution of the TME to the ten hallmarks of cancer in neuroblastoma and discuss the mechanisms of communication between neuroblastoma cells and the TME that underlie the influence of the TME on neuroblastoma progression. We end our review by discussing how the knowledge acquired over the last two decades in this field is now leading to new clinical trials targeting the TME. PMID:26597947

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

    Science.gov (United States)

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

    2007-01-25

    With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to correlate with anaplasia and unfavorable prognosis. In neuroblastoma--an embryonal tumor with biological similarities to MB--the quassinoid NBT-272 has been demonstrated to inhibit cellular proliferation and to down-regulate c-MYC protein expression. To study MB cell responses to NBT-272 and their dependence on the level of c-MYC expression, DAOY (wild-type, empty vector transfected or c-MYC transfected), D341 (c-MYC amplification) and D425 (c-MYC amplification) human MB cells were used. The cells were treated with different concentrations of NBT-272 and the impact on cell proliferation, apoptosis and c-MYC expression was analyzed. NBT-272 treatment resulted in a dose-dependent inhibition of cellular proliferation (IC50 in the range of 1.7-9.6 ng/ml) and in a dose-dependent increase in apoptotic cell death in all human MB cell lines tested. Treatment with NBT-272 resulted in up to 90% down-regulation of c-MYC protein, as demonstrated by Western blot analysis, and in a significant inhibition of c-MYC binding activity. Anti-proliferative effects were slightly more prominent in D341 and D425 human MB cells with c-MYC amplification and slightly more pronounced in c-MYC over-expressing DAOY cells compared to DAOY wild-type cells. Moreover, treatment of synchronized cells by NBT-272 induced a marked cell arrest at the G1/S boundary. In human MB cells, NBT-272 treatment inhibits cellular proliferation at nanomolar concentrations, blocks cell cycle progression, induces apoptosis, and down-regulates the expression of the oncogene c-MYC. Thus, NBT-272 may represent a novel drug candidate to inhibit proliferation of human MB cells in vivo.

  10. Inhibition of GPR137 suppresses proliferation of medulloblastoma cells in vitro.

    Science.gov (United States)

    Wang, Chengfeng; Liang, Qinchuan; Chen, Guangming; Jing, Junjie; Wang, Shousen

    2015-01-01

    Medulloblastoma is the most common malignant pediatric brain tumor in children. GPR137 is a ubiquitously expressed gene in the central nervous system. It has been reported that GPR137 modulates malignant proliferation of glioma cells. However, the relationship between GPR137 and medulloblastoma is still unknown. In this study, we knocked down GPR137 in the medulloblastoma cell line Daoy via a lentivirus-based RNA interference system to explore its role in medulloblastoma. Functional analyses showed that cell proliferation and colony formation were obviously restrained in Daoy cells after GPR137 knockdown. Furthermore, knockdown of GPR137 in Daoy cells led to a significant increase in cell percentage in the G0/G1 phase but a decrease in the S phase. Additionally, the cell population in the sub-G1 phase, which represents apoptotic cells, was remarkably increased in GPR137 knockdown cells. GPR137 inhibition induced a strong proapoptotic effect in Daoy cells, as confirmed by annexin V-APC/7-AAD double staining. In conclusion, GPR137 knockdown inhibited growth of Daoy medulloblastoma cells via disturbing cell cycle progression and inducing apoptosis. Our investigation suggested that GPR137 could be a potential oncogene in medulloblastoma cells and might serve as a target for the treatment of medulloblastoma. © 2014 International Union of Biochemistry and Molecular Biology, Inc.

  11. Medulloblastoma with Atypical Dynamic Imaging Changes: Case Report with Literature Review.

    Science.gov (United States)

    Song, Shuang-Shuang; Wang, Jian-Hong; Fu, Wei-Wei; Li, Ying; Sui, Qing-Lan; Liu, Xue-Jun

    2017-09-01

    We analyzed a case of medulloblastoma with atypical dynamic imaging changes retrospectively to summarize the atypical magnetic resonance imaging (MRI) features of medulloblastoma by reviewing the literature. An atypical case of medulloblastoma in the cerebellar hemisphere confirmed by pathology was analyzed retrospectively, and the literature about it was reviewed. The radiologic findings of the patient were based on 3 examinations. The first examination showed that the cortex of the bilateral cerebellar hemisphere had diffuse nodular thickening, with a high signal on diffusion-weighted imaging and significant enhancement. Contrast enhancement MRI 1 year later showed the signal of cerebellar hemisphere returned to normal but revealed an enhanced nodule. A reexamination 6 months later showed an irregular mass with a high-density shadow in the cerebellar vermis on CT scan. The T2-weighted image revealed multiple degenerative cysts, and the mass had significant enhancement. The radiologic characteristics of atypical medulloblastomas vary in adults and children. Understanding the radiologic characteristics of medulloblastomas, such as MRI features, age of onset, and location of atypical medulloblastomas, can help improve the diagnosis of medulloblastomas. Copyright © 2017. Published by Elsevier Inc.

  12. 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.

  13. 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.

  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. MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation.

    Science.gov (United States)

    Liu, Hailong; Sun, Qianwen; Sun, Youliang; Zhang, Junping; Yuan, Hongyu; Pang, Shuhuan; Qi, Xueling; Wang, Haoran; Zhang, Mingshan; Zhang, Hongwei; Yu, Chunjiang; Gu, Chunyu

    2017-09-01

    Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stem-like cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large-cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK- or EZH2-positive staining status could be considered as a potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2, and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stem-like cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients.Implications: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma. Mol Cancer Res; 15(9); 1275-86. ©2017 AACR. ©2017 American Association for Cancer Research.

  16. Neuroblastoma treatment in the post-genomic era.

    Science.gov (United States)

    Esposito, Maria Rosaria; Aveic, Sanja; Seydel, Anke; Tonini, Gian Paolo

    2017-02-08

    Neuroblastoma is an embryonic malignancy of early childhood originating from neural crest cells and showing heterogeneous biological, morphological, genetic and clinical characteristics. The correct stratification of neuroblastoma patients within risk groups (low, intermediate, high and ultra-high) is critical for the adequate treatment of the patients.High-throughput technologies in the Omics disciplines are leading to significant insights into the molecular pathogenesis of neuroblastoma. Nonetheless, further study of Omics data is necessary to better characterise neuroblastoma tumour biology. In the present review, we report an update of compounds that are used in preclinical tests and/or in Phase I-II trials for neuroblastoma. Furthermore, we recapitulate a number of compounds targeting proteins associated to neuroblastoma: MYCN (direct and indirect inhibitors) and downstream targets, Trk, ALK and its downstream signalling pathways. In particular, for the latter, given the frequency of ALK gene deregulation in neuroblastoma patients, we discuss on second-generation ALK inhibitors in preclinical or clinical phases developed for the treatment of neuroblastoma patients resistant to crizotinib.We summarise how Omics drive clinical trials for neuroblastoma treatment and how much the research of biological targets is useful for personalised medicine. Finally, we give an overview of the most recent druggable targets selected by Omics investigation and discuss how the Omics results can provide us additional advantages for overcoming tumour drug resistance.

  17. The genetic landscape of the childhood cancer medulloblastoma

    OpenAIRE

    Parsons, D. Williams; Li, Meng; Zhang, Xiaosong; Jones, Siân; Leary, Rebecca J.; Lin, Jimmy Cheng-Ho; Boca, Simina M.; Carter, Hannah; Samayoa, Josue; Bettegowda, Chetan; Gallia, Gary L.; Jallo, George I.; Binder, Zev A.; Nikolsky, Yuri; Hartigan, James

    2010-01-01

    Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high density microarrays and sequenced all known protein-coding genes and miRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, 5 to 10-fold fewer than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog ...

  18. Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma

    Science.gov (United States)

    Balakrishnan, Ilango; Harris, Peter; Birks, Diane K; Griesinger, Andrea; Amani, Vladimir; Cristiano, Brian; Remke, Marc; Taylor, Michael D; Handler, Michael; Foreman, Nicholas K; Vibhakar, Rajeev

    2014-01-01

    Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo. PMID:24796395

  19. Combined in situ hypothermic liver preservation and cardioplegia for resection of hepatoblastoma with intra-atrial extension in a 3 year old child

    Directory of Open Access Journals (Sweden)

    Julian Thalhammer

    2016-09-01

    Full Text Available Cure of hepatoblastoma requires complete macro- and microscopic resection of the tumor, without tumor rupture. In case of hepatoblastoma with intra-atrial tumor extension (ITE, “en bloc” resection of the hepatic tumor and ITE, with minimal risk of postoperative liver failure, constitutes a surgical challenge. We report on a 3 year old child with hepatoblastoma of the right liver lobe, and ITE through the upper Inferior Vena Cava. Initial chemotherapy (SIOPEL IV HR induced good response, but tumor persisted inside the right atrium with tight adhesions to the cardiac wall. “En bloc” right extended hepatectomy and removal of the ITE with reconstruction of the atrial and caval wall with autologous pericardial patch was performed under normothermic extracorporeal circulation and cardioplegia, combined with in situ hypothermic liver preservation of the remaining left liver. Complete tumor resection was achieved without tumor rupture. Postoperative liver function was immediately good and adjuvant chemotherapy was resumed per protocol. Eleven months after the end of treatment the child is in complete tumor remission. In children with hepatic tumor and ITE, combination of normothermic extracorporeal circulation with cardioplegia and in situ hypothermic liver preservation allows “en bloc” extended hepatectomy and removal of ITE, with limited risk of postoperative liver failure.

  20. Tailoring Medulloblastoma Treatment Through Genomics: Making a Change, One Subgroup at a Time.

    Science.gov (United States)

    Holgado, Borja L; Guerreiro Stucklin, Ana; Garzia, Livia; Daniels, Craig; Taylor, Michael D

    2017-08-31

    After more than a decade of genomic studies in medulloblastoma, the time has come to capitalize on the knowledge gained and use it to directly improve patient care. Although metastatic and relapsed disease remain poorly understood, much has changed in how we define medulloblastoma, and it has become evident that with conventional therapies, specific groups of patients are currently under- or overtreated. In this review, we summarize the latest insights into medulloblastoma biology, focusing on how genomics is affecting patient stratification, informing preclinical studies of targeted therapies, and shaping the new generation of clinical trials.

  1. Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells

    Directory of Open Access Journals (Sweden)

    Mengling Liu

    2016-10-01

    Full Text Available High-risk neuroblastoma remains one of the deadliest childhood cancers. Identification of metabolic pathways that drive or maintain high-risk neuroblastoma may open new avenues of therapeutic interventions. Here, we report the isolation and propagation of neuroblastoma sphere-forming cells with self-renewal and differentiation potential from tumors of the TH-MYCN mouse, an animal model of high-risk neuroblastoma with MYCN amplification. Transcriptional profiling reveals that mouse neuroblastoma sphere-forming cells acquire a metabolic program characterized by transcriptional activation of the cholesterol and serine-glycine synthesis pathways, primarily as a result of increased expression of sterol regulatory element binding factors and Atf4, respectively. This metabolic reprogramming is recapitulated in high-risk human neuroblastomas and is prognostic for poor clinical outcome. Genetic and pharmacological inhibition of the metabolic program markedly decreases the growth and tumorigenicity of both mouse neuroblastoma sphere-forming cells and human neuroblastoma cell lines. These findings suggest a therapeutic strategy for targeting the metabolic program of high-risk neuroblastoma.

  2. 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

  3. CASE REPORT Proptosis as a manifestation of neuroblastoma ...

    African Journals Online (AJOL)

    The most common cause was orbital cellulitis, followed by thyroid eye disease and optic nerve/chiasm glioma.3. Ophthalmic involvement by neuroblastoma is defined by the. International Neuroblastoma Staging System (INSS)2 as stage 4 disease. Treatment of the primary disease is based on the Children's Oncology.

  4. Rho-associated kinase is a therapeutic target in neuroblastoma.

    Science.gov (United States)

    Dyberg, Cecilia; Fransson, Susanne; Andonova, Teodora; Sveinbjörnsson, Baldur; Lännerholm-Palm, Jessika; Olsen, Thale K; Forsberg, David; Herlenius, Eric; Martinsson, Tommy; Brodin, Bertha; Kogner, Per; Johnsen, John Inge; Wickström, Malin

    2017-08-08

    Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK)2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3β-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.

  5. MMSET is highly expressed and associated with aggressiveness in neuroblastoma.

    Science.gov (United States)

    Hudlebusch, Heidi Rye; Skotte, Julie; Santoni-Rugiu, Eric; Zimling, Zarah Glad; Lees, Michael James; Simon, Ronald; Sauter, Guido; Rota, Rossella; De Ioris, Maria Antonietta; Quarto, Micaela; Johansen, Jens Vilstrup; Jørgensen, Mette; Rechnitzer, Catherine; Maroun, Lisa Leth; Schrøder, Henrik; Petersen, Bodil Laub; Helin, Kristian

    2011-06-15

    MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis.

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

    Science.gov (United States)

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

    2014-03-19

    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

  7. Sonic Hedgehog-Induced Histone Deacetylase Activation Is Required for Cerebellar Granule Precursor Hyperplasia in Medulloblastoma

    Science.gov (United States)

    Lee, Seung Joon; Lindsey, Stephan; Graves, Bruce; Yoo, Soonmoon; Olson, James M.; Langhans, Sigrid A.

    2013-01-01

    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. PMID:23951168

  8. The Molecular Classification of Medulloblastoma: Driving the next generation clinical trials

    Science.gov (United States)

    Leary, Sarah E. S.; Olson, James M.

    2012-01-01

    Purpose of Review Most children diagnosed with cancer today are expected to be cured. Medulloblastoma, the most common pediatric malignant brain tumor, is an example of a disease that has benefitted from advances in diagnostic imaging, surgical techniques, radiation therapy and combination chemotherapy over the past decades. An incurable disease 50 years ago, approximately 70% of children with medulloblastoma are now cured of their disease. However, the pace of increasing the cure rate has slowed over the past two decades, and we have likely reached the maximal benefit that can be achieved with cytotoxic therapy and clinical risk stratification. Long-term toxicity of therapy also remains significant. To increase cure rates and decrease long-term toxicity, there is great interest in incorporating biologic “targeted” therapy into treatment of medulloblastoma, but this will require a paradigm shift in how we classify and study disease. Recent Findings Using genome-based high-throughput analytic techniques, several groups have independently reported methods of molecular classification of medulloblastoma within the past year. This has resulted in a working consensus to view medulloblastoma as four molecular subtypes including WNT pathway subtype, SHH pathway subtype, and two less well-defined subtypes, Group C and Group D. Summary Novel classification and risk stratification based on biologic subtypes of disease will form the basis of further study in medulloblastoma, and identify specific subtypes which warrant greater research focus. PMID:22189395

  9. 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.

  10. 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

  11. Gene Expression Analyses of the Spatio-Temporal Relationships of Human Medulloblastoma Subgroups during Early Human Neurogenesis

    Science.gov (United States)

    Hooper, Cornelia M.; Hawes, Susan M.; Kees, Ursula R.; Gottardo, Nicholas G.; Dallas, Peter B.

    2014-01-01

    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. PMID:25412507

  12. A cross comparison of technologies for the detection of microRNAs in clinical FFPE samples of hepatoblastoma patients.

    Science.gov (United States)

    Chatterjee, Aniruddha; Leichter, Anna L; Fan, Vicky; Tsai, Peter; Purcell, Rachel V; Sullivan, Michael J; Eccles, Michael R

    2015-06-03

    Although formalin fixed paraffin embedded (FFPE) tissue is a major biological source in cancer research, it is challenging to work with due to macromolecular fragmentation and nucleic acid crosslinking. Therefore, it is important to characterise the quality of data that can be obtained from FFPE samples. We have compared three independent platforms (next generation sequencing, microarray and NanoString) for profiling microRNAs (miRNAs) using clinical FFPE samples from hepatoblastoma (HB) patients. The number of detected miRNAs ranged from 228 to 345 (median = 294) using the next generation sequencing platform, whereas 79 to 125 (median = 112) miRNAs were identified using microarrays in three HB samples, including technical replicates. NanoString identified 299 to 372 miRNAs in two samples. Between the platforms, we observed high reproducibility and significant levels of shared detection. However, for commonly detected miRNAs, a strong correlation between platforms was not observed. Analysis of 10 additional HB samples with NanoString identified significantly overlapping miRNA expression profiles, and an alternative pattern was identified in a poorly differentiated HB with an aggressive phenotype. This investigation serves as a roadmap for future studies investigating miRNA expression in clinical FFPE samples, and as a guideline for the selection of an appropriate platform.

  13. Spinal deformity in children treated for neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Mayfield, J.K.; Riseborough, E.J.; Jaffe, N.; Nehme, M.E.

    1981-02-01

    Of seventy-four children who were treated at a mean age of seventeen months for neuroblastoma and survived more than five years, fifty-six had spinal deformity due either to the disease or to the treatment after a mean follow-up of 12.9 years. Of these fifty-six, 50 per cent had post-radiation scoliosis, and 16 per cent had post-radiation kyphosis, most frequently at the thoracolumbar junction, at the time of follow-up. Two kyphotic thoracolumbar curve patterns were identified: an angular kyphosis with a short radius of curvature and its apex at the twelfth thoracic and first lumbar vertebrae, and a thoracic kyphosis with a long radius of curvature that extended into the lumbar spine. The post-radiation deformity - both the scoliosis and the kyphosis - progressed with growth, the scoliosis at a rate of 1 degree per year and the kyphosis at a rate of 3 degrees per year. Epidural spread of the neuroblastoma was associated with most of the cases of severe scoliosis and kyphosis. The deformity was due either to the laminectomy or to the paraplegia acting in conjunction with the radiation. Eighteen per cent of 419 children with this malignant disease survived more than five years, and of the survivors, 20 per cent had spinal deformity severe enough to warrant treatment. The factors associated with the development of spinal deformity in patient treated for neuroblastoma were: orthovoltage radiation exceeding 3000 rads, asymmetrical radiation of the spine, thoracolumbar kyphosis, and epidural spread of the tumor.

  14. Incidence of late endocrine dysfunction following irradiation for childhood medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Abayomi, O.K.; Sadeghi-Nejad, A.

    1986-06-01

    A retrospective analysis of treatment in 20 patients who had received post-operative radiotherapy for medulloblastoma between 1969 and 1977 was completed. The patients were followed for a minimum of 60 months. Eleven patients survived for 5 or more years after treatment. The patients received 3600 cGy to the whole brain. The posterior fossa received 5600 cGY and the spinal axis 3600 cGY. Eight of eleven patients developed growth impairment; 6 of 7 patients had growth hormone deficiency. Since all endocrine gland failures are amenable to therapy, early attention to patients' growth rate and detection of hypothalamic-pituitary failure, would be of benefit to longterm survivors.

  15. [Therapeutic outcomes of medulloblastoma in Casablanca from 2000 to 2012].

    Science.gov (United States)

    Elbachiri, M; Dao, A; Jabir, H; Sahraoui, S; Taleb, A; Bouchbika, Z; Benchakroun, N; Jouhadi, H; Tawfiq, N; Benider, A

    2015-12-01

    To describe the therapeutic results, with the aim to contribute to improving the care of patients with medulloblastoma. A retrospective study of 69 cases of medulloblastoma collected in the university hospital Ibn Rochd of Casablanca between 2000 and 2012. Fifty-three children with an average age of 9 years and 16 adults with an average age of 32.4 years were included in the study. Thirty-seven children and eight adults suffered from a high-risk tumour. The radiotherapy was received by all patients with a mean dose of 36 Gy to the whole brain and 54 Gy in the posterior fossa. All patients in the paediatric group and 10 patients in the adult group received concomitant chemotherapy, 44 children and four adults received adjuvant chemotherapy. Tumour recurrence was observed in 17 children after a mean follow-up period of 38 months. These recurrences were observed in five adults after a mean follow-up period of 42 months. The posterior fossa was the main site of relapses. Overall survival was 77.7% for the children and 61% for the adults. Overall survival was better (70% versus 25%) when the interval between radiotherapy and surgery was less than 40 days in the paediatric group. The recurrence rate was significantly higher for the high-risk group: 41% versus 13% for the standard risk. In the adult group, overall survival differences according to the risk group were significant (100% for the standard risk versus 37.5% for the high risk). The overall survival and recurrences rate obtained are encouraging. The risk group and time between surgery and radiotherapy were prognostic factors with significant impact on survival depending on the age group. We recommend reducing these times to improve therapeutic results. Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  16. In vitro Natural Killer cell immunotherapy for medulloblastoma

    Directory of Open Access Journals (Sweden)

    Lucia eFernandez

    2013-04-01

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

  17. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples.

    Science.gov (United States)

    Northcott, Paul A; Shih, David J H; Remke, Marc; Cho, Yoon-Jae; Kool, Marcel; Hawkins, Cynthia; Eberhart, Charles G; Dubuc, Adrian; Guettouche, Toumy; Cardentey, Yoslayma; Bouffet, Eric; Pomeroy, Scott L; Marra, Marco; Malkin, David; Rutka, James T; Korshunov, Andrey; Pfister, Stefan; Taylor, Michael D

    2012-04-01

    The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials.

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

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

    2017-03-01

    Medulloblastoma is the most common form of brain malignancy of childhood. The mainstay of epidemiological data regarding childhood medulloblastoma is derived from case series, hence population-based studies are warranted to improve the accuracy of survival estimates. To utilize a big-data approach to update survival estimates in a contemporary cohort of children with medulloblastoma. We performed a population-based retrospective observational cohort study utilizing the Surveillance, Epidemiology, and End Results Program database that captures all children, less than 20 years of age, between 1973 and 2012 in 18 geographical regions representing 28% of the US population. We included all participants with a presumed or histologically diagnosis of medulloblastoma. The main outcome of interest is survivors at 1, 5 and 10 years following diagnosis. A cohort of 1735 children with a median (interquartile range) age at diagnosis of 7 (4-11) years, with a diagnosis of medulloblastoma were identified. The incidence and prevalence of pediatric medulloblastoma has remained stable over the past 4 decades. There is a critical time point at 1990 when the overall survival has drastically improved. In the contemporary cohort (1990 onwards), the percentage of participants alive was 86, 70 and 63% at 1, 5 and 10 years, respectively. Multivariate Cox-Regression model demonstrated Radiation (HR 0.37; 95% CI 0.30-0.46, p 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 the likelihood of long-term survival.

  19. Intermittent Hypoxia Effect on Osteoclastogenesis Stimulated by Neuroblastoma Cells

    Science.gov (United States)

    Bhaskara, Vasantha Kumar; Mohanam, Indra; Gujrati, Meena; Mohanam, Sanjeeva

    2014-01-01

    Background Neuroblastoma is the most common extracranial pediatric solid tumor. Intermittent hypoxia, which is characterized by cyclic periods of hypoxia and reoxygenation, has been shown to positively modulate tumor development and thereby induce tumor growth, angiogenic processes, and metastasis. Bone is one of the target organs of metastasis in advanced neuroblastoma Neuroblastoma cells produce osteoclast-activating factors that increase bone resorption by the osteoclasts. The present study focuses on how intermittent hypoxia preconditioned SH-SY5Y neuroblastoma cells modulate osteoclastogenesis in RAW 264.7 cells compared with neuroblastoma cells grown at normoxic conditions. Methods We inhibited HIF-1α and HIF-2α in neuroblastoma SH-SY5Y cells by siRNA/shRNA approaches. Protein expression of HIF-1α, HIF-2α and MAPKs were investigated by western blotting. Expression of osteoclastogenic factors were determined by real-time RT-PCR. The influence of intermittent hypoxia and HIF-1α siRNA on migration of neuroblastoma cells and in vitro differentiation of RAW 264.7 cells were assessed. Intratibial injection was performed with SH-SY5Y stable luciferase-expressing cells and in vivo bioluminescence imaging was used in the analysis of tumor growth in bone. Results Upregulation of mRNAs of osteoclastogenic factors VEGF and RANKL was observed in intermittent hypoxia-exposed neuroblastoma cells. Conditioned medium from the intermittent hypoxia-exposed neuroblastoma cells was found to enhance osteoclastogenesis, up-regulate the mRNAs of osteoclast marker genes including TRAP, CaSR and cathepsin K and induce the activation of ERK, JNK, and p38 in RAW 264.7 cells. Intermittent hypoxia-exposed neuroblastoma cells showed an increased migratory pattern compared with the parental cells. A significant increase of tumor volume was found in animals that received the intermittent hypoxia-exposed cells intratibially compared with parental cells. Conclusions Intermittent hypoxic

  20. Primary cerebral neuroblastoma: a case report and review.

    Science.gov (United States)

    Etuş, Volkan; Kurtkaya, Ozlem; Sav, Aydin; Ilbay, Konuralp; Ceylan, Savaş

    2002-05-01

    Primitive neuroepithelial tumors are the least common among supratentorial tumors in children. They pose great diagnostic difficulty, preoperatively as well as pathologically. Being quite rare, cerebral neuroblastomas are accepted as a distinct pathological entity, which differs from other neuroectodermal tumors, although clinically, radiologically, and morphologically at operation they are indistinguishable. Also differentiation between primary cerebral neuroblastoma and the other primitive neuroectodermal tumors may be difficult on light microscopy and be misleading. A 9-year-old girl with primary cerebral neuroblastoma who was initially misdiagnosed is reported. The other cases from the literature are reviewed and the nature of this rare tumor and its differential diagnosis is discussed.

  1. Intrarenal neuroblastoma mimics Wilms' tumor; Neuroblastoma intrarenal mimetizando tumor de Wilms

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    Muniz, Maria T. Cartaxo; Soares, Andrezza B.; Freitas, Elizabete M. [Pernambuco Univ., Recife, PE (Brazil). Hospital Universitario Oswaldo Cruz. Inst. de Ciencias Biologicas]. E-mail: tcartaxo@icb.upe.br; Araujo, Marcela [Centro Infantil Boldrini, Campinas, SP (Brazil). Lab. de Biologia Molecular; Pureza, Leda M.M.; Morais, Adriana; Antunes, Consuelo; Salles, Terezinha de J. Marques; Borges, Josenilda C.; Morais, Vera L.L. de [Pernambuco Univ., Recife, PE (Brazil). Hospital Universitario Oswaldo Cruz; Romualdo Filho, Jose [Pernambuco Univ., Recife, PE (Brazil). Hospital Universitario Oswaldo Cruz. Centro Integrado de Anatomia Patologica; Magalhaes, Mario H. [Instituto Nacional de Cancer, Rio de Janeiro, RJ (Brazil). Dept. de Patologia

    2005-07-01

    This work reports the case history of a child with intrarenal neuroblastoma, initially diagnosed as Wilms' tumor. The patient, a one year and three months old girl, presented a hard abdominal mass on the left flank that extended to the meso gastric region, plus fever and paleness. The ultrasound of the entire abdomen revealed an intrarenal mass. Biopsy with fine needle in many points of the tumor revealed Wilms' tumor. The scarcely of the material, however, made immunohistoquemistry impossible at that moment. Because of the child's severe condition the SIOP protocol was started. As no clinical response was observed, an exploratory laparotomy was indicated with partial resection of the tumor and bone marrow aspiration (MO). The histopathologic study revealed a malignant neoplasia of small cells, poorly differentiated. IHQ was negative for WT-1 and positive for NB-84, synaptofisin, cromogranine. N-myc amplification was observed by molecular biology. The bone marrow aspiration identified metastatic small round cells infiltration. Intrarenal neuroblastoma is a rare entity that clinically and radiographically resembles Wilms' tumor. The objective of this case report is to show the importance of immunohistochemical and molecular analysis in the diagnosis of intrarenal neuroblastoma. (author)

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

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    Abhimanyu Ghose MD

    2014-04-01

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

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

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    Sara Badodi

    2017-12-01

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

  4. Update on the integrated histopathological and genetic classification of medulloblastoma - a practical diagnostic guideline.

    Science.gov (United States)

    Pietsch, Torsten; Haberler, Christine

    The revised WHO classification of tumors of the CNS 2016 has introduced the concept of the integrated diagnosis. The definition of medulloblastoma entities now requires a combination of the traditional histological information with additional molecular/genetic features. For definition of the histopathological component of the medulloblastoma diagnosis, the tumors should be assigned to one of the four entities classic, desmoplastic/nodular (DNMB), extensive nodular (MBEN), or large cell/anaplastic (LC/A) medulloblastoma. The genetically defined component comprises the four entities WNT-activated, SHH-activated and TP53 wildtype, SHH-activated and TP53 mutant, or non-WNT/non-SHH medulloblastoma. Robust and validated methods are available to allow a precise diagnosis of these medulloblastoma entities according to the updated WHO classification, and for differential diagnostic purposes. A combination of immunohistochemical markers including β-catenin, Yap1, p75-NGFR, Otx2, and p53, in combination with targeted sequencing and copy number assessment such as FISH analysis for MYC genes allows a precise assignment of patients for risk-adapted stratification. It also allows comparison to results of study cohorts in the past and provides a robust basis for further treatment refinement.
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  5. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

    Science.gov (United States)

    da Silva, Patrícia Benites Gonçalves; Teixeira Dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Pereira, Márcia Cristina Leite; Furukawa, Gabriela; da Cruz, Daniel Sanzio Gimenes; Goldfeder, Mauricio Barbugiani; Rocha, Clarissa Ribeiro Reily; Rosenberg, Carla; Okamoto, Oswaldo Keith

    2017-03-21

    Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.

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

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    Gustavo A Barisone

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

  7. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma

    Science.gov (United States)

    Snuderl, Matija; Batista, Ana; Kirkpatrick, Nathaniel D.; de Almodovar, Carmen Ruiz; Riedemann, Lars; Walsh, Elisa C.; Anolik, Rachel; Huang, Yuhui; Martin, John D.; Kamoun, Walid; Knevels, Ellen; Schmidt, Thomas; Farrar, Christian T.; Vakoc, Benjamin J.; Mohan, Nishant; Chung, Euiheon; Roberge, Sylvie; Peterson, Teresa; Bais, Carlos; Zhelyazkova, Boryana H.; Yip, Stephen; Hasselblatt, Martin; Rossig, Claudia; Niemeyer, Elisabeth; Ferrara, Napoleone; Klagsbrun, Michael; Duda, Dan G.; Fukumura, Dai; Xu, Lei; Carmeliet, Peter; Jain, Rakesh K.

    2013-01-01

    SUMMARY Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastases, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1—and not vascular endothelial growth factor receptor 1 (VEGFR1)—to promote tumor cell survival. This critical tumor-stroma interaction—mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes—supports the development of therapies targeting PlGF/Nrp1 pathway. PMID:23452854

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

    Science.gov (United States)

    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

    2016-06-14

    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 medulloblastoma, we set out to identify novel drugs that could potentiate the effect of ionizing radiation.Thereto, a small molecule library, consisting of 960 chemical compounds, was screened for its ability to sensitize towards irradiation. This small molecule screen identified the flavonoid quercetin as a novel radiosensitizer for the medulloblastoma cell lines DAOY, D283-med, and, to a lesser extent, D458-med at low micromolar concentrations and irradiation doses used in fractionated radiation schemes. Quercetin did not affect the proliferation of neural precursor cells or normal human fibroblasts. Importantly, in vivo experiments confirmed the radiosensitizing properties of quercetin. Administration of this flavonoid at the time of irradiation significantly prolonged survival in orthotopically xenografted mice. Together, these findings indicate that quercetin is a potent radiosensitizer for medulloblastoma cells that may be a promising lead for the treatment of medulloblastoma in patients.

  9. Immune response to racotumomab in a child with relapsed neuroblastoma

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    CLAUDIA VANESA SAMPOR

    2012-12-01

    Full Text Available Immunotherapy targeting ganglioside antigens is a powerful tool for the treatment of high risk neuroblastoma. However, only treatment with anti-GD2 antibodies has been used in clinical practice and other options may be pursued. We report the use of racotumomab, an anti-idiotype vaccine against N-glycolyl neuraminic acid (NeuGc- containing gangliosides, eliciting an immune response in a child with relapsed neuroblastoma expressing the NeuGcGM3 ganglioside.

  10. Neuroblastoma: morphological pattern, molecular genetic features, and prognostic factors

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    A. M. Stroganova

    2016-01-01

    Full Text Available Neuroblastoma, the most common extracranial tumor of childhood, arises from the developing neurons of the sympathetic nervous system (neural cress stem cells and has various biological and clinical characteristics. The mean age at disease onset is 18 months. Neuroblastoma has a number of unique characteristics: a capacity for spontaneous regression in babies younger than 12 months even in the presence of distant metastases, for differentiation (maturation into ganglioneuroma in infants after the first year of life, and for swift aggressive development and rapid metastasis. There are 2 clinical classifications of neuroblastoma: the International neuroblastoma staging system that is based on surgical results and the International Neuroblastoma Risk Group Staging System. One of the fundamentally important problems for the clinical picture of neuroblastoma is difficulties making its prognosis. Along with clinical parameters (a patient’s age, tumor extent and site, some histological, molecular biochemical (ploidy and genetic (chromosomal aberrations, MYCN gene status, deletion of the locus 1p36 and 11q, the longer arm of chromosome 17, etc. characteristics of tumor cells are of considerable promise. MYCN gene amplification is observed in 20–30 % of primary neuroblastomas and it is one of the major indicators of disease aggressiveness, early chemotherapy resistance, and a poor prognosis. There are 2 types of MYCN gene amplification: extrachromosomal (double acentric chromosomes and intrachromosomal (homogenically painted regions. Examination of double acentric chromosomes revealed an interesting fact that it may be eliminated (removed from the nucleus through the formation of micronuclei. MYCN oncogene amplification is accompanied frequently by 1p36 locus deletion and longer 17q arm and less frequently by 11q23 deletion; these are poor prognostic factors for the disease. The paper considers in detail the specific, unique characteristics of the

  11. Activating mutations in ALK provide a therapeutic target in neuroblastoma.

    Science.gov (United States)

    George, Rani E; Sanda, Takaomi; Hanna, Megan; Fröhling, Stefan; Luther, William; Zhang, Jianming; Ahn, Yebin; Zhou, Wenjun; London, Wendy B; McGrady, Patrick; Xue, Liquan; Zozulya, Sergey; Gregor, Vlad E; Webb, Thomas R; Gray, Nathanael S; Gilliland, D Gary; Diller, Lisa; Greulich, Heidi; Morris, Stephan W; Meyerson, Matthew; Look, A Thomas

    2008-10-16

    Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.

  12. Ku70 Acetylation in Neuroblastoma Pathogenesis and Therapy

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    Castle, Valerie; Kwok, Roland; Opipari, Anthony; Subramanian, Chitra

    2010-01-01

    Neuroblastoma is a cancer that occurs in children. It develops from stem cells that normally give rise to parts of the peripheral nervous system and adrenal glands. Although most children with localized neuroblastoma are cured, children with wide-spread disease have a small chance of survival even after surgery, chemotherapy, radiation and bone marrow transplantation. Ten to fifteen percent of patients die from treatment complications, and long-term survival is less than 30%. Although contemp...

  13. Restoration of miR-30a expression inhibits growth, tumorigenicity of medulloblastoma cells accompanied by autophagy inhibition.

    Science.gov (United States)

    Singh, Satishkumar Vishram; Dakhole, Aditi Nigam; Deogharkar, Akash; Kazi, Sadaf; Kshirsagar, Rohan; Goel, Atul; Moiyadi, Aliasgar; Jalali, Rakesh; Sridhar, Epari; Gupta, Tejpal; Shetty, Prakash; Gadewal, Nikhil; Shirsat, Neelam Vishwanath

    2017-09-30

    Medulloblastoma is a highly malignant pediatric brain tumor. About 30% patients have metastasis at diagnosis and respond poorly to treatment. Those that survive, suffer long term neurocognitive, endocrine and developmental defects due to the cytotoxic treatment to developing child brain. It is therefore necessary to develop targeted treatment strategies based on underlying biology for effective treatment of medulloblastoma with minimal side effects. Medulloblastomas are believed to be the result of deregulated nervous system development as evident from the role of WNT and SHH developmental signaling pathways in pathogenesis of medulloblastomas. MicroRNAs are known to play vital roles in nervous system development as well as in cancer. MicroRNA profiling of medulloblastomas identified miR-30 family members' expression to be downregulated in medulloblastomas belonging to the four known molecular subgroups viz. WNT, SHH, Group 3 and Group 4 as compared to that in normal brain tissues. Furthermore, established medulloblastoma cell lines Daoy, D283 and D425 were also found to underexpress miR-30a. Restoration of miR-30a expression using inducible lentiviral vector inhibited proliferation, clonogenic potential and tumorigenicity of medulloblastoma cells. MiR-30a is known to target Beclin1, a mediator of autophagy. MiR-30a expression was found to downregulate Beclin1 expression and inhibit autophagy in the medulloblastoma cell lines as judged by downregulation of LC3B expression and its turnover upon chloroquine treatment and starvation induced autophagy induction. MiR-30a therefore could serve as a novel therapeutic agent for the effective treatment of medulloblastoma by inhibiting autophagy that is known to play important role in cancer cell growth, survival and malignant behavior. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Integrated genomic analysis identifies the mitotic checkpoint kinase WEE1 as a novel therapeutic target in medulloblastoma

    Science.gov (United States)

    2014-01-01

    Background Medulloblastoma is the most common type of malignant brain tumor that afflicts children. Although recent advances in chemotherapy and radiation have improved outcomes, high-risk patients do poorly with significant morbidity. Methods To identify new molecular targets, we performed an integrated genomic analysis using structural and functional methods. Gene expression profiling in 16 medulloblastoma patient samples and subsequent gene set enrichment analysis indicated that cell cycle-related kinases were associated with disease development. In addition a kinome-wide small interfering RNA (siRNA) screen was performed to identify kinases that, when inhibited, could prevent cell proliferation. The two genome-scale analyses were combined to identify key vulnerabilities in medulloblastoma. The inhibition of one of the identified targets was further investigated using RNAi and a small molecule inhibitor. Results Combining the two analyses revealed that mitosis-related kinases were critical determinants of medulloblastoma cell proliferation. RNA interference (RNAi)-mediated knockdown of WEE1 kinase and other mitotic kinases was sufficient to reduce medulloblastoma cell proliferation. These data prompted us to examine the effects of inhibiting WEE1 by RNAi and by a small molecule inhibitor of WEE1, MK-1775, in medulloblastoma cell lines. MK-1775 inhibited the growth of medulloblastoma cell lines, induced apoptosis and increased DNA damage at nanomolar concentrations. Further, MK-1775 was synergistic with cisplatin in reducing medulloblastoma cell proliferation and resulted in an associated increase in cell death. In vivo MK-1775 suppressed medulloblastoma tumor growth as a single agent. Conclusions Taken together, these findings highlight mitotic kinases and, in particular, WEE1 as a rational therapeutic target for medulloblastoma. PMID:24661910

  15. Mesenchymal change and drug resistance in neuroblastoma.

    Science.gov (United States)

    Naiditch, Jessica A; Jie, Chunfa; Lautz, Timothy B; Yu, Songtao; Clark, Sandra; Voronov, Dimitry; Chu, Fei; Madonna, Mary Beth

    2015-01-01

    Metastatic initiation has many phenotypic similarities to epithelial-to-mesenchymal transition, including loss of cell-cell adhesion, increased invasiveness, and increased cell mobility. We have previously demonstrated that drug resistance is associated with a metastatic phenotype in neuroblastoma (NB). The purpose of this project was to determine if the development of doxorubicin resistance is associated with characteristics of mesenchymal change in human NB cells. Total RNA was isolated from wild type (WT) and doxorubicin-resistant (DoxR) human NB cell lines (SK-N-SH and SK-N-BE(2)C) and analyzed using the Illumina Human HT-12 version 4 Expression BeadChip. Differentially expressed genes (DEGs) were identified. Volcano plots and heat maps were generated. Genes of interest with a fold change in expression >1.5 and an adjusted P change via multiple pathways in the transition to a drug-resistant state. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Potentiation of neuroblastoma metastasis by loss of caspase-8.

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    Stupack, Dwayne G; Teitz, Tal; Potter, Matthew D; Mikolon, David; Houghton, Peter J; Kidd, Vincent J; Lahti, Jill M; Cheresh, David A

    2006-01-05

    Neuroblastoma, the most common paediatric solid tumour, arises from defective neural crest cells. Genetic alterations occur frequently in the most aggressive neuroblastomas. In particular, deletion or suppression of the proapoptotic enzyme caspase-8 is common in malignant, disseminated disease, although the effect of this loss on disease progression is unclear. Here we show that suppression of caspase-8 expression occurs during the establishment of neuroblastoma metastases in vivo, and that reconstitution of caspase-8 expression in deficient neuroblastoma cells suppressed their metastases. Caspase-8 status was not a predictor of primary tumour growth; rather, caspase-8 selectively potentiated apoptosis in neuroblastoma cells invading the collagenous stroma at the tumour margin. Apoptosis was initiated by unligated integrins by means of a process known as integrin-mediated death. Loss of caspase-8 or integrin rendered these cells refractory to integrin-mediated death, allowed cellular survival in the stromal microenvironment, and promoted metastases. These findings define caspase-8 as a metastasis suppressor gene that, together with integrins, regulates the survival and invasive capacity of neuroblastoma cells.

  17. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.

    Science.gov (United States)

    Molenaar, Jan J; Koster, Jan; Zwijnenburg, Danny A; van Sluis, Peter; Valentijn, Linda J; van der Ploeg, Ida; Hamdi, Mohamed; van Nes, Johan; Westerman, Bart A; van Arkel, Jennemiek; Ebus, Marli E; Haneveld, Franciska; Lakeman, Arjan; Schild, Linda; Molenaar, Piet; Stroeken, Peter; van Noesel, Max M; Ora, Ingrid; Santo, Evan E; Caron, Huib N; Westerhout, Ellen M; Versteeg, Rogier

    2012-02-22

    Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.

  18. 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.

  19. 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].

  20. 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.

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    of the clinical specimens also showed expression of HCMV immediate early and late proteins, in comparative analyses using three immunohistochemical protocols. Cell culture experiments validated the chronic endogenous replication stress in medulloblastoma cell lines and showed sharply differential, intriguing...... 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...... responses of normal cells and medulloblastoma cells to HCMV infection, including differential subcellular mislocalization and enhancement of replication stress-related 53BP1 body formation, the latter in cell-non-autonomous manner. Overall, our results strongly indicate that in human medulloblastomas...

  2. Serpine2/PN-1 Is Required for Proliferative Expansion of Pre-Neoplastic Lesions and Malignant Progression to Medulloblastoma

    Science.gov (United States)

    Vaillant, Catherine; Kool, Marcel; Schwarzentruber-Schauerte, Alexandra; Méreau, Hélène; Cabuy, Erik; Lobrinus, Johannes A.; Pfister, Stefan; Zuniga, Aimée; Frank, Stephan; Zeller, Rolf

    2015-01-01

    Background Medulloblastomas are malignant childhood brain tumors that arise due to the aberrant activity of developmental pathways during postnatal cerebellar development and in adult humans. Transcriptome analysis has identified four major medulloblastoma subgroups. One of them, the Sonic hedgehog (SHH) subgroup, is caused by aberrant Hedgehog signal transduction due to mutations in the Patched1 (PTCH1) receptor or downstream effectors. Mice carrying a Patched-1 null allele (Ptch1∆/+) are a good model to study the alterations underlying medulloblastoma development as a consequence of aberrant Hedgehog pathway activity. Results Transcriptome analysis of human medulloblastomas shows that SERPINE2, also called Protease Nexin-1 (PN-1) is overexpressed in most medulloblastomas, in particular in the SHH and WNT subgroups. As siRNA-mediated lowering of SERPINE2/PN-1 in human medulloblastoma DAOY cells reduces cell proliferation, we analyzed its potential involvement in medulloblastoma development using the Ptch1∆/+ mouse model. In Ptch1∆/+ mice, medulloblastomas arise as a consequence of aberrant Hedgehog pathway activity. Genetic reduction of Serpine2/Pn-1 interferes with medulloblastoma development in Ptch1∆/+ mice, as ~60% of the pre-neoplastic lesions (PNLs) fail to develop into medulloblastomas and remain as small cerebellar nodules. In particular the transcription factor Atoh1, whose expression is essential for development of SHH subgroup medulloblastomas is lost. Comparative molecular analysis reveals the distinct nature of the PNLs in young Ptch1∆/+Pn-1Δ/+ mice. The remaining wild-type Ptch1 allele escapes transcriptional silencing in most cases and the aberrant Hedgehog pathway activity is normalized. Furthermore, cell proliferation and the expression of the cell-cycle regulators Mycn and Cdk6 are significantly reduced in PNLs of Ptch1∆/+Pn-1Δ/+ mice. Conclusions Our analysis provides genetic evidence that aberrant Serpine2/Pn-1 is required for

  3. Role of Na+/Ca2+ Exchangers in Therapy Resistance of Medulloblastoma Cells.

    Science.gov (United States)

    Pelzl, Lisann; Hosseinzadeh, Zohreh; Al-Maghout, Tamer; Singh, Yogesh; Sahu, Itishri; Bissinger, Rosi; Schmidt, Sebastian; Alkahtani, Saad; Stournaras, Christos; Toulany, Mahmoud; Lang, Florian

    2017-01-01

    Alterations of cytosolic Ca2+-activity ([Ca2+]i) are decisive in the regulation of tumor cell proliferation, migration and survival. Transport processes participating in the regulation of [Ca2+]i include Ca2+ extrusion through K+-independent (NCX) and/or K+-dependent (NCKX) Na+/Ca2+-exchangers. The present study thus explored whether medulloblastoma cells express Na+/Ca2+-exchangers, whether expression differs between therapy sensitive D283 and therapy resistant UW228-3 medulloblastoma cells, and whether Na+/Ca2+-exchangers participate in the regulation of cell survival. In therapy sensitive D283 and therapy resistant UW228-3 medulloblastoma cells transcript levels were estimated by RT-PCR, protein abundance by Western blotting, cytosolic Ca2+-activity ([Ca2+]i) from Fura-2-fluorescence, Na+/ Ca2+-exchanger activity from the increase of [Ca2+]i (Δ[Ca2+]i) and from whole cell current (Ica) following abrupt replacement of Na+ containing (130 mM) and Ca2+ free by Na+ free and Ca2+ containing (2 mM) extracellular perfusate as well as cell death from PI -staining and annexin-V binding in flow cytometry. The transcript levels of NCX3, NCKX2, and NCKX5, protein abundance of NCX3, slope and peak of Δ[Ca2+]i as well as Ica were significantly lower in therapy sensitive D283 than in therapy resistant UW228-3 medulloblastoma cells. The Na+/Ca2+-exchanger inhibitor KB-R7943 (10 µM) significantly blunted Δ[Ca2+]i, and augmented the ionizing radiation-induced apoptosis but did not significantly modify clonogenicity of medulloblastoma cells. Apoptosis was further enhanced by NCX3 silencing. Na+/Ca2+-exchanger activity significantly counteracts apoptosis but does not significantly affect clonogenicity after radiation of medulloblastoma cells. © 2017 The Author(s). Published by S. Karger AG, Basel.

  4. Long non-coding RNA CRNDE promotes tumor growth in medulloblastoma.

    Science.gov (United States)

    Song, H; Han, L-M; Gao, Q; Sun, Y

    2016-06-01

    Medulloblastoma is the most common malignant brain tumor in children. Despite remarkable advances over the past decades, a novel therapeutic strategy is urgently required to increase long-term survival. This study aimed to understand the role of a long non-coding RNA (lncRNA), colorectal neoplasia differentially expressed (CRNDE), in medulloblastoma tumor growth. The transcript level of CRNDE was initially examined in dissected clinical tissues and cultured cancerous cells. Effects of CRNDE knockdown on cell viability and colony formation in vitro were assessed using the CCK-8 and colony formation assays, respectively. Cell cycle progression and survival were also determined after CRNDE knockdown. A xenograft mouse model of human medulloblastoma was established by injecting nude mice with medulloblastoma cells stably depleted of CRNDE expression. Our data suggest that transcript levels of CRNDE are elevated in clinical medulloblastoma tissues instead of in adjacent non-cancerous tissues. Knockdown of CRNDE significantly slowed cell proliferation rates and inhibited colony formation in Daoy and D341 cells. Tumor growth in vivo was also inhibited after CRNDE knockdown. Moreover, after knockdown of CRNDE, cell cycle progression was arrested in S phase and apoptosis was promoted by 15-20% in Daoy and D341 cells. In vivo data further showed that proliferating cell nuclei antigen (PCNA) was decreased, whereas the apoptosis initiator cleaved-caspase-3 was increased upon CRNDE knockdown in cancerous tissues from the mouse model. All these data suggest that CRNDE promotes tumor growth both in vitro and in vivo. This growth-promotion effect might be achieved via arresting cell cycle progression and inhibiting apoptosis. Therapeutics against CRNDE may be a novel strategy for the treatment of medulloblastoma.

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

    Science.gov (United States)

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

    2016-01-01

    OBJECT The purpose of this study was to explore the clinical features and outcome of medulloblastoma in Chinese children. The authors analyze the reasons that treatment is abandoned and attempt to provide evidence-based recommendations for improving the prognosis of medulloblastoma in this population. METHODS A total of 67 pediatric cases of newly diagnosed medulloblastoma were included in this study. All of the children were treated at Xinhua Hospital between January 2007 and June 2013. The authors retrospectively analyzed the clinical data, treatment modalities, and outcome. The male-to-female ratio was 2:1, and the patients' median age at diagnosis was 51.96 months (range 3.96-168.24 months). The median duration of follow-up was 32 months (range 3-70 months). RESULTS At the most recent follow-up date, 31 patients (46%) were alive, 30 (45%) had died, and 6 (9%) had been lost to follow-up. The estimated 3-year overall survival and progression-free survival, based on Kaplan-Meier analysis, were 55.1% ± 6.4% and 45.6% ± 6.7%, respectively. Univariate analysis showed that standard-risk group (p = 0.009), postoperative radiotherapy (RT) combined with chemotherapy (p 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 treatment teams could improve the prognosis of medulloblastoma in Chinese children.

  6. An Unusual Combination of Mirror-Image Dextrocardia with Familial Medulloblastoma: Is There a Histogenetic Relationship?

    Science.gov (United States)

    Ke, Chao; Wang, Jing; Xi, Shaoyan; Li, Kay Ka-Wai; Luo, Junran; Chen, Zhenghe; Wang, Jian; Chen, Zhong-Ping

    2017-11-01

    The occurrence of medulloblastoma in the absence of hereditary syndromes is rare. Dextrocardia with situs inversus is also called mirror-image dextrocardia. A combination of mirror-image dextrocardia with medulloblastoma has not been reported previously. To the best of our knowledge, this is the first report of this rare combination in a family with medulloblastoma. The clinical manifestation, radiographic characteristics, treatment, and outcomes of 3 medulloblastoma cases in 2 cousins and their maternal uncle was described. Tumor samples of the 2 cousins were first examined for histologic subtypes. Total RNA of their tumors was extracted from formalin-fixed and paraffin-embedded samples. Then, expression of 22 subgroup-specific genes and 3 housekeeping genes was analyzed by the NanoString nCounter Analysis System. The posttest data were normalized by NanoStringNorm package for molecular subgroup prediction. The proband remains tumor free and alive up to the latest follow-up. His cousin, who had combined mirror-image dextrocardia with situs inversus, died of anoxia after surgery and his uncle died of tumor 2.5 years after surgery. Medulloblastoma of the 2 cousins was classified as classic and molecular group 4 subtype. The same classic and molecular group 4 subtype of the 2 cousins may suggest a similar genetic predisposition. Involvement of the Otx2 gene dysfunction in both group 4 subtype medulloblastoma and mirror-image dextrocardia with situs inversus points to a possible mechanism that dysfunction of a shared signaling pathway such as Otx2 might be the underlying cause of these 2 conditions in this family. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    Sun, Lue; Moritake, Takashi; Ito, Kazuya; Matsumoto, Yoshitaka; Yasui, Hironobu; Nakagawa, Hidehiko; Hirayama, Aki; Inanami, Osamu; Tsuboi, Koji

    2017-01-01

    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.

  8. 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.

  9. 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.

  10. The genetic landscape of the childhood cancer medulloblastoma

    Science.gov (United States)

    Parsons, D. Williams; Li, Meng; Zhang, Xiaosong; Jones, Siân; Leary, Rebecca J.; Lin, Jimmy Cheng-Ho; Boca, Simina M.; Carter, Hannah; Samayoa, Josue; Bettegowda, Chetan; Gallia, Gary L.; Jallo, George I.; Binder, Zev A.; Nikolsky, Yuri; Hartigan, James; Smith, Doug R.; Gerhard, Daniela S.; Fults, Daniel W.; VandenBerg, Scott; Berger, Mitchel S.; Marie, Suely Kazue Nagahashi; Shinjo, Sueli Mieko Oba; Clara, Carlos; Phillips, Peter C.; Minturn, Jane E.; Biegel, Jaclyn A.; Judkins, Alexander R.; Resnick, Adam C.; Storm, Phillip B.; Curran, Tom; He, Yiping; Rasheed, B. Ahmed; Friedman, Henry S.; Keir, Stephen T.; McLendon, Roger; Northcott, Paul A.; Taylor, Michael D.; Burger, Peter C.; Riggins, Gregory J.; Karchin, Rachel; Parmigiani, Giovanni; Bigner, Darell D.; Yan, Hai; Papadopoulos, Nick; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.

    2011-01-01

    Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high density microarrays and sequenced all known protein-coding genes and miRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, 5 to 10-fold fewer than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis. PMID:21163964

  11. Targeted treatment for sonic hedgehog-dependent medulloblastoma

    Science.gov (United States)

    Kieran, Mark W.

    2014-01-01

    Novel treatment options, including targeted therapies, are needed for patients with medulloblastoma (MB), especially for those with high-risk or recurrent/relapsed disease. Four major molecular subgroups of MB have been identified, one of which is characterized by activation of the sonic hedgehog (SHH) pathway. Preclinical data suggest that inhibitors of the hedgehog (Hh) pathway could become valuable treatment options for patients with this subgroup of MB. Indeed, agents targeting the positive regulator of the pathway, smoothened (SMO), have demonstrated efficacy in a subset of patients with SHH MB. However, because of resistance and the presence of mutations downstream of SMO, not all patients with SHH MB respond to SMO inhibitors. The development of agents that target these resistance mechanisms and the potential for their combination with traditional chemotherapy and SHH inhibitors will be discussed. Due to its extensive molecular heterogeneity, the future of MB treatment is in personalized therapy, which may lead to improved efficacy and reduced toxicity. This will include the development of clinically available tests that can efficiently discern the SHH subgroup. The preliminary use of these tests in clinical trials is also discussed herein. PMID:24951114

  12. Identification of ALK as the Major Familial Neuroblastoma Predisposition Gene

    Science.gov (United States)

    Mossë, Yalë P; Laudenslager, Marci; Longo, Luca; Cole, Kristina A; Wood, Andrew; Attiyeh, Edward F; Laquaglia, Michael J; Sennett, Rachel; Lynch, Jill E; Perri, Patrizia; Laureys, Geneviève; Speleman, Frank; Hakonarson, Hakon; Torkamani, Ali; Schork, Nicholas J; Brodeur, Garrett M; Tonini, Gian Paolo; Rappaport, Eric; Devoto, Marcella; Maris, John M

    2009-01-01

    SUMMARY Survival rates for the childhood cancer neuroblastoma have not substantively improved despite dramatic escalation in chemotherapy intensity. Like most human cancers, this embryonal malignancy can be inherited, but the genetic etiology of familial and sporadically occurring neuroblastoma was largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase gene (ALK) explain the majority of hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at the short arm of chromosome 2 (maximum nonparametric LOD=4.23 at rs1344063) using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate missense mutations in the tyrosine kinase domain of ALK (G1128A, R1192P and R1275Q) that segregated with the disease in eight separate families. Examination of 491 sporadically occurring human neuroblastoma samples showed that the ALK locus was gained in 22.8%, and highly amplified in an additional 3.3%, and that these aberrations were highly associated with death from disease (P=0.0003). Resequencing of 194 high-risk neuroblastoma samples showed somatically acquired mutations within the tyrosine kinase domain in 12.4%. Nine of the ten mutations map to critical regions of the kinase domain and were predicted to be oncogenic drivers with high probability. Mutations resulted in constitutive phosphorylation consistent with activation, and targeted knockdown of ALK mRNA resulted in profound growth inhibition of 4 of 4 cell lines harboring mutant or amplified ALK, as well as 2 of 6 wild type for ALK. Our results demonstrate that heritable mutations of ALK are the major cause of familial neuroblastoma, and that germline or acquired activation of this cell surface kinase is a tractable therapeutic target for this lethal pediatric malignancy. PMID:18724359

  13. Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

    Science.gov (United States)

    Peifer, Martin; Hertwig, Falk; Roels, Frederik; Dreidax, Daniel; Gartlgruber, Moritz; Menon, Roopika; Krämer, Andrea; Roncaioli, Justin L; Sand, Frederik; Heuckmann, Johannes M; Ikram, Fakhera; Schmidt, Rene; Ackermann, Sandra; Engesser, Anne; Kahlert, Yvonne; Vogel, Wenzel; Altmüller, Janine; Nürnberg, Peter; Thierry-Mieg, Jean; Thierry-Mieg, Danielle; Mariappan, Aruljothi; Heynck, Stefanie; Mariotti, Erika; Henrich, Kai-Oliver; Gloeckner, Christian; Bosco, Graziella; Leuschner, Ivo; Schweiger, Michal R; Savelyeva, Larissa; Watkins, Simon C; Shao, Chunxuan; Bell, Emma; Höfer, Thomas; Achter, Viktor; Lang, Ulrich; Theissen, Jessica; Volland, Ruth; Saadati, Maral; Eggert, Angelika; de Wilde, Bram; Berthold, Frank; Peng, Zhiyu; Zhao, Chen; Shi, Leming; Ortmann, Monika; Büttner, Reinhard; Perner, Sven; Hero, Barbara; Schramm, Alexander; Schulte, Johannes H; Herrmann, Carl; O'Sullivan, Roderick J; Westermann, Frank; Thomas, Roman K; Fischer, Matthias

    2015-10-29

    Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

  14. 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.

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

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    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.

  16. The PI3K inhibitor GDC-0941 displays promising in vitro and in vivo efficacy for targeted medulloblastoma therapy

    Science.gov (United States)

    Holst, Martin I.; Pietsch, Torsten; Dilloo, Dagmar

    2015-01-01

    Deregulation of the Phosphoinositide 3-kinase (PI3K)/AKT signalling network is a hallmark of oncogenesis. Also medulloblastoma, the most common malignant brain tumor in children, is characterized by high levels of AKT phosphorylation and activated PI3K signalling in medulloblastoma is associated with enhanced cellular motility, survival and chemoresistency underscoring its role of as a potential therapeutic target. Here we demonstrate that GDC-0941, a highly specific PI3K inhibitor with good clinical tolerability and promising anti-neoplastic activity in adult cancer, also displays anti-proliferative and pro-apoptotic effects in pediatric human medulloblastoma cell lines. Loss in cell viability is accompanied by reduced phosphorylation of AKT, a downstream target of PI3K. Furthermore, we show that GDC-0941 attenuates the migratory capacity of medulloblastoma cells and targets subpopulations expressing the stem cell marker CD133. GDC-0941 also synergizes with the standard medulloblastoma chemotherapeutic etoposide. In an orthotopic xenograft model of the most aggressive human medulloblastoma variant we document that oral adminstration of GDC-0941 impairs tumor growth and significantly prolongs survival. These findings provide a rational to further investigate GDC-0941 alone and in combination with standard chemotherapeutics for medulloblastoma treatment. PMID:25596739

  17. Inhibition of CDK4/6 by Palbociclib Significantly Extends Survival in Medulloblastoma Patient-Derived Xenograft Mouse Models.

    Science.gov (United States)

    Cook Sangar, Michelle L; Genovesi, Laura A; Nakamoto, Madison W; Davis, Melissa J; Knobluagh, Sue E; Ji, Pengxiang; Millar, Amanda; Wainwright, Brandon J; Olson, James M

    2017-10-01

    Purpose: Bioinformatics analysis followed by in vivo studies in patient-derived xenograft (PDX) models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly group 3 MYC-amplified tumors that have the worst clinical prognosis.Experimental Design: A protein interaction network derived from a Sleeping Beauty mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets. The top hit from this analysis was validated in vivo using PDX models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice.Results: Informatics analysis identified the CDK4/6/CYCLIN D/RB pathway as a novel "druggable" pathway for multiple subgroups of medulloblastoma. Palbociclib, a highly specific inhibitor of CDK4/6, was found to inhibit RB phosphorylation and cause G1 arrest in PDX models of medulloblastoma. The drug caused rapid regression of Sonic hedgehog (SHH) and MYC-amplified group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing MYC-amplified intracranial tumors.Conclusions: Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and MYC-amplified group 3 medulloblastoma. Clin Cancer Res; 23(19); 5802-13. ©2017 AACR. ©2017 American Association for Cancer Research.

  18. Risk of unfavorable character among neuroblastomas detected through mass screening. The Japanese Infantile Neuroblastoma Cooperative Study.

    Science.gov (United States)

    Tanaka, T; Matsumura, T; Iehara, T; Sawada, T

    2000-12-01

    Current study shows that about 50% of neuroblastomas (NBs) detected through mass screening had factor(s) indicating an unfavorable biological nature and that early intervention after the screening might improve clinical outcome of the patients. On the other hand, favorable properties were detected in the remaining half of the mass-screening NBs. Some of them might have the ability to regress spontaneously. Therapeutic modality should be determined according to their biological nature. Further investigation for their biologic properties is necessary to evaluate the benefits of the mass screening. Copyright 2000 Wiley-Liss, Inc.

  19. Uniformity under in vitro conditions: Changes in the phenotype of cancer cell lines derived from different medulloblastoma subgroups.

    Science.gov (United States)

    Chlapek, Petr; Zitterbart, Karel; Kren, Leos; Filipova, Lenka; Sterba, Jaroslav; Veselska, Renata

    2017-01-01

    Medulloblastoma comprises four main subgroups (WNT, SHH, Group 3 and Group 4) originally defined by transcriptional profiling. In primary medulloblastoma tissues, these groups are thought to be distinguishable using the immunohistochemical detection of β-catenin, filamin A, GAB1 and YAP1 protein markers. To investigate the utility of these markers for in vitro studies using medulloblastoma cell lines, immunoblotting and indirect immunofluorescence were employed for the detection of β-catenin, filamin A, GAB1 and YAP1 in both DAOY and D283 Med reference cell lines and the panel of six medulloblastoma cell lines derived in our laboratory from the primary tumor tissues of known molecular subgroups. Immunohistochemical detection of these markers was performed on formalin-fixed paraffin-embedded tissue of the matching primary tumors. The results revealed substantial divergences between the primary tumor tissues and matching cell lines in the immunoreactivity pattern of medulloblastoma-subgroup-specific protein markers. Regardless of the molecular subgroup of the primary tumor, all six patient-derived medulloblastoma cell lines exhibited a uniform phenotype: immunofluorescence showed the nuclear localization of YAP1, accompanied by strong cytoplasmic positivity for β-catenin and filamin A, as well as weak positivity for GAB1. The same immunoreactivity pattern was also found in both DAOY and D283 Med reference medulloblastoma cell lines. Therefore, we can conclude that various medulloblastoma cell lines tend to exhibit the same characteristics of protein marker expression under standard in vitro conditions. Such a finding emphasizes the importance of the analyses of primary tumors in clinically oriented medulloblastoma research and the urgent need to develop in vitro models of improved clinical relevance, such as 3D cultures and organotypic slice cultures.

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

    Science.gov (United States)

    2012-01-01

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

  1. The emerging molecular pathogenesis of neuroblastoma: implications for improved risk assessment and targeted therapy

    OpenAIRE

    Van Roy, Nadine; De Preter, Katleen; Hoebeeck, Jasmien; Van Maerken, Tom; Pattyn, Filip; Mestdagh, Pieter; Vermeulen, Joëlle; Vandesompele, Jo; Speleman, Franki

    2009-01-01

    Neuroblastoma is one of the most common solid tumors of childhood, arising from immature sympathetic nervous system cells. The clinical course of patients with neuroblastoma is highly variable, ranging from spontaneous regression to widespread metastatic disease. Although the outcome for children with cancer has improved considerably during the past decades, the prognosis of children with aggressive neuroblastoma remains dismal. The clinical heterogeneity of neuroblastoma mirrors the biologic...

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  14. A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma

    Science.gov (United States)

    Pignataro, Piero; Lasorsa, Vito Alessandro; Hogarty, Michael D.; Castellano, Aurora; Conte, Massimo; Tonini, Gian Paolo; Iolascon, Achille; Gasparre, Giuseppe; Capasso, Mario

    2016-01-01

    Background Neuroblastoma, a tumor of the developing sympathetic nervous system, is a common childhood neoplasm that is often lethal. Mitochondrial DNA (mtDNA) mutations have been found in most tumors including neuroblastoma. We extracted mtDNA data from a cohort of neuroblastoma samples that had undergone Whole Exome Sequencing (WES) and also used snap-frozen samples in which mtDNA was entirely sequenced by Sanger technology. We next undertook the challenge of determining those mutations that are relevant to, or arisen during tumor development. The bioinformatics pipeline used to extract mitochondrial variants from matched tumor/blood samples was enriched by a set of filters inclusive of heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. Results Our in silico multistep workflow applied both on WES and Sanger-sequenced neuroblastoma samples, allowed us to identify a limited burden of somatic and germline mitochondrial mutations with a potential pathogenic impact. Conclusions The few singleton germline and somatic mitochondrial mutations emerged, according to our in silico analysis, do not appear to impact on the development of neuroblastoma. Our findings are consistent with the hypothesis that most mitochondrial somatic mutations can be considered as ‘passengers’ and consequently have no discernible effect in this type of cancer. PMID:27351283

  15. A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma.

    Science.gov (United States)

    Calabrese, Francesco Maria; Clima, Rosanna; Pignataro, Piero; Lasorsa, Vito Alessandro; Hogarty, Michael D; Castellano, Aurora; Conte, Massimo; Tonini, Gian Paolo; Iolascon, Achille; Gasparre, Giuseppe; Capasso, Mario

    2016-08-02

    Neuroblastoma, a tumor of the developing sympathetic nervous system, is a common childhood neoplasm that is often lethal. Mitochondrial DNA (mtDNA) mutations have been found in most tumors including neuroblastoma. We extracted mtDNA data from a cohort of neuroblastoma samples that had undergone Whole Exome Sequencing (WES) and also used snap-frozen samples in which mtDNA was entirely sequenced by Sanger technology. We next undertook the challenge of determining those mutations that are relevant to, or arisen during tumor development. The bioinformatics pipeline used to extract mitochondrial variants from matched tumor/blood samples was enriched by a set of filters inclusive of heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. Our in silico multistep workflow applied both on WES and Sanger-sequenced neuroblastoma samples, allowed us to identify a limited burden of somatic and germline mitochondrial mutations with a potential pathogenic impact. The few singleton germline and somatic mitochondrial mutations emerged, according to our in silico analysis, do not appear to impact on the development of neuroblastoma. Our findings are consistent with the hypothesis that most mitochondrial somatic mutations can be considered as 'passengers' and consequently have no discernible effect in this type of cancer.

  16. Identification of ALK as a major familial neuroblastoma predisposition gene.

    Science.gov (United States)

    Mossé, Yaël P; Laudenslager, Marci; Longo, Luca; Cole, Kristina A; Wood, Andrew; Attiyeh, Edward F; Laquaglia, Michael J; Sennett, Rachel; Lynch, Jill E; Perri, Patrizia; Laureys, Geneviève; Speleman, Frank; Kim, Cecilia; Hou, Cuiping; Hakonarson, Hakon; Torkamani, Ali; Schork, Nicholas J; Brodeur, Garrett M; Tonini, Gian P; Rappaport, Eric; Devoto, Marcella; Maris, John M

    2008-10-16

    Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.

  17. Genomic Profiles of Neuroblastoma Associated With Opsoclonus Myoclonus Syndrome.

    Science.gov (United States)

    Hero, Barbara; Clement, Nathalie; Øra, Ingrid; Pierron, Gaelle; Lapouble, Eve; Theissen, Jessica; Pasqualini, Claudia; Valteau-Couanet, Dominique; Plantaz, Dominique; Michon, Jean; Delattre, Olivier; Tardieu, Marc; Schleiermacher, Gudrun

    2017-11-13

    Opsoclonus myoclonus syndrome (OMS), often called "dancing eyed syndrome," is a rare neurological condition associated with neuroblastoma in the majority of all childhood cases. Genomic copy number profiles have shown to be of prognostic significance for neuroblastoma patients. The aim of this retrospective multicenter study was to analyze the genomic copy number profiles of tumors from children with neuroblastoma presenting with OMS at diagnosis. In 44 cases of neuroblastoma associated with OMS, overall genomic profiling by either array-comparative genomic hybridization or single nucleotide polymorphism array proved successful in 91% of the cases, distinguishing tumors harboring segmental chromosome alterations from those with numerical chromosome alterations only. A total of 23/44 (52%) tumors showed an segmental chromosome alterations genomic profile, 16/44 (36%) an numerical chromosome alterations genomic profile, and 1 case displayed an atypical profile (12q amplicon). No recurrently small interstitial copy number alterations were identified. With no tumor relapse nor disease-related deaths, the overall genomic profile was not of prognostic impact with regard to the oncological outcome in this series of patients. Thus, the observation of an excellent oncological outcome, even for those with an unfavorable genomic profile of neuroblastoma, supports the hypothesis that an immune response might be involved in tumor control in these patients with OMS.

  18. Cytopathogenicity of Naegleria for cultured neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Fulford, D.E.

    1985-01-01

    The cytopathic activity of live Naegleria amoebae and cell-free lysates of Naegleria for B-103 rat neuroblastoma cells was investigated using a /sup 51/Cr release assay. Live amoebae and cell-free lysates of N. fowleri, N. australiensis, N. lovaniensis, and N. gruberi all induced sufficient damage to radiolabeled B-103 cells to cause a significant release of chromium. The cytotoxic activity present in the cell-free lysates of N. fowleri can be recovered in the supernatant fluid following centrifugation at 100,000xg and precipitation of the 100,000xg supernatant fluid with ammonium sulfate. Initial characterization of the cytotoxic factor indicates that it is a heat labile, pH sensitive, soluble protein. The cytotoxic activity is abolished by either extraction, unaffected by repeated freeze-thawing, and is not sensitive to inhibitors of proteolytic enzymes. Phospholipase A activity was detected in the cytotoxic ammonium sulfate precipitable material, suggesting that this enzyme activity may have a role in the cytotoxic activity of the cell-free lysates.

  19. 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.

  20. Neurocognitive Function and Health-Related Quality of Life in Pediatric Korean Survivors of Medulloblastoma.

    Science.gov (United States)

    Yoo, Hee Jung; Kim, Hyery; Park, Hyeon Jin; Kim, Dong Seok; Ra, Young Shin; Shin, Hee Young

    2016-11-01

    The neurocognitive function and quality of life of 58 Korean survivors of childhood medulloblastoma were assessed after surgery, cranial radiation and chemotherapy. All patients were evaluated with a battery of neurocognitive function tests and the Pediatric Functional Assessment of Cancer Therapy-Brain Tumor Survivors, which consists of self-report questionnaires on quality of life. The mean full-scale intelligence quotient (IQ), verbal IQ, and performance IQ scores were 90.2, 97.1, and 84.16, respectively. The mean memory quotient (MQ) score was 86.78, which was within 1 standard deviation of the average score of 100. Processing speed, attention, and executive function showed mild to moderate deficits. Intelligence, memory, executive function, visuospatial function, and simple motor function were significantly lower in the patients diagnosed before 8 years of age compared with those diagnosed after 8. The cognitive deficits in the patients diagnosed at younger ages might be related to earlier exposure to craniospinal irradiation and chemotherapy. The patient and parent proxy evaluations of attention, fine motor function, and quality of life did not differ. We found significant neurocognitive changes in a wide range of neurocognitive functional domains in Korean survivors of childhood medulloblastoma. Long-term follow-up studies of survivors of childhood medulloblastoma beginning at the time of their first diagnosis are required to better understand the deficits exhibited by survivors of childhood medulloblastoma, so that intervention strategies and treatment refinements that reduce the long-term neurocognitive decline can be developed.

  1. FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma.

    Science.gov (United States)

    Suryo Rahmanto, Aldwin; Savov, Vasil; Brunner, Andrä; Bolin, Sara; Weishaupt, Holger; Malyukova, Alena; Rosén, Gabriela; Čančer, Matko; Hutter, Sonja; Sundström, Anders; Kawauchi, Daisuke; Jones, David Tw; Spruck, Charles; Taylor, Michael D; Cho, Yoon-Jae; Pfister, Stefan M; Kool, Marcel; Korshunov, Andrey; Swartling, Fredrik J; Sangfelt, Olle

    2016-10-17

    SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here, we show that SOX9 is a substrate of FBW7, a tumor suppressor, and a SCF (SKP1/CUL1/F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase and consequently degraded by SCFFBW7α Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. FBW7 is either mutated or downregulated in medulloblastoma, and in cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Transcriptional profiling of medulloblastoma cells expressing a degradation-resistant SOX9 mutant reveals activation of pro-metastatic genes and genes linked to cisplatin resistance. Finally, we show that pharmacological inhibition of PI3K/AKT/mTOR pathway activity destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

  2. Characterization of novel biomarkers in selecting for subtype specific medulloblastoma phenotypes.

    Science.gov (United States)

    Liang, Lisa; Aiken, Christopher; McClelland, Robyn; Morrison, Ludivine Coudière; Tatari, Nazanin; Remke, Marc; Ramaswamy, Vijay; Issaivanan, Magimairajan; Ryken, Timothy; Del Bigio, Marc R; Taylor, Michael D; Werbowetski-Ogilvie, Tamra E

    2015-11-17

    Major research efforts have focused on defining cell surface marker profiles for characterization and selection of brain tumor stem/progenitor cells. Medulloblastoma is the most common primary malignant pediatric brain cancer and consists of 4 molecular subgroups: WNT, SHH, Group 3 and Group 4. Given the heterogeneity within and between medulloblastoma variants, surface marker profiles may be subtype-specific. Here, we employed a high throughput flow cytometry screen to identify differentially expressed cell surface markers in self-renewing vs. non-self-renewing SHH medulloblastoma cells. The top 25 markers were reduced to 4, CD271/p75NTR/NGFR, CD106/VCAM1, EGFR and CD171/NCAM-L1, by evaluating transcript levels in SHH tumors relative to samples representing the other variants. However, only CD271/p75NTR/NGFR and CD171/NCAM-L1 maintain differential expression between variants at the protein level. Functional characterization of CD271, a low affinity neurotrophin receptor, in cell lines and primary cultures suggested that CD271 selects for lower self-renewing progenitors or stem cells. Moreover, CD271 levels were negatively correlated with expression of SHH pathway genes. Our study reveals a novel role for CD271 in SHH medulloblastoma and suggests that targeting CD271 pathways could lead to the design of more selective therapies that lessen the broad impact of current treatments on developing nervous systems.

  3. Risk factors for the prognosis of pediatric medulloblastoma: a retrospective analysis of 40 cases.

    Science.gov (United States)

    Yu, Jianzhong; Zhao, Rui; Shi, Wei; Li, Hao

    2017-05-01

    In this study, we evaluated the association of molecular subtypes, clinical characteristics and pathological types with the prognosis of patients with medulloblastoma. We analyzed forty patients with medulloblastoma who underwent surgical resection at our center between January 2004 and June 2014. Risk factors associated with survival, disease progression and recurrence were analyzed with a univariate Cox regression analysis, and the identified significant risk factors were further analyzed by Kaplan-Meier survival curves. Factors associated with overall survival included M stage (p=0.014), calcification (p=0.012), postoperative treatment, postoperative Karnofsky Performance Scale (KPS) score (p=0.015), and molecular subtype (p=0.005 for WNT and p=0.008 for SHH). Number of symptoms (p=0.029), M stage (p2 and ≥M1 stage without postoperative radiotherapy. The risk of recurrence increased with advanced M stage. Protective factors for recurrence included M0 stage and a combination of chemotherapy and radiotherapy. We identified the risk factors associated with survival, disease progression and recurrence of medulloblastoma patients. This information is helpful for understanding the prognostic factors related to medulloblastoma.

  4. ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy.

    Science.gov (United States)

    Morfouace, Marie; Cheepala, Satish; Jackson, Sadhana; Fukuda, Yu; Patel, Yogesh T; Fatima, Soghra; Kawauchi, Daisuke; Shelat, Anang A; Stewart, Clinton F; Sorrentino, Brian P; Schuetz, John D; Roussel, Martine F

    2015-09-15

    While a small number of plasma membrane ABC transporters can export chemotherapeutic drugs and confer drug resistance, it is unknown whether these transporters are expressed or functional in less therapeutically tractable cancers such as Group 3 (G3) medulloblastoma. Herein we show that among this class of drug transporters, only ABCG2 was expressed at highly increased levels in human G3 medulloblastoma and a mouse model of this disease. In the mouse model, Abcg2 protein was expressed at the plasma membrane where it functioned as expected on the basis of export of prototypical substrates. By screening ABC substrates against mouse G3 medulloblastoma tumorspheres in vitro, we found that Abcg2 inhibition could potentiate responses to the clinically used drug topotecan, producing a more than 9-fold suppression of cell proliferation. Extended studies in vivo in this model confirmed that Abcg2 inhibition was sufficient to enhance antiproliferative responses to topotecan, producing a significant survival advantage compared with subjects treated with topotecan alone. Our findings offer a preclinical proof of concept for blockade of ABCG2 transporter activity as a strategy to empower chemotherapeutic responses in G3 medulloblastoma. ©2015 American Association for Cancer Research.

  5. RNA Binding Protein-Mediated Post-Transcriptional Gene Regulation in Medulloblastoma

    Science.gov (United States)

    Bish, Rebecca; Vogel, Christine

    2014-01-01

    Medulloblastoma, the most common malignant brain tumor in children, is a disease whose mechanisms are now beginning to be uncovered by high-throughput studies of somatic mutations, mRNA expression patterns, and epigenetic profiles of patient tumors. One emerging theme from studies that sequenced the tumor genomes of large cohorts of medulloblastoma patients is frequent mutation of RNA binding proteins. Proteins which bind multiple RNA targets can act as master regulators of gene expression at the post-transcriptional level to co-ordinate cellular processes and alter the phenotype of the cell. Identification of the target genes of RNA binding proteins may highlight essential pathways of medulloblastomagenesis that cannot be detected by study of transcriptomics alone. Furthermore, a subset of RNA binding proteins are attractive drug targets. For example, compounds that are under development as anti-viral targets due to their ability to inhibit RNA helicases could also be tested in novel approaches to medulloblastoma therapy by targeting key RNA binding proteins. In this review, we discuss a number of RNA binding proteins, including Musashi1 (MSI1), DEAD (Asp-Glu-Ala-Asp) box helicase 3 X-linked (DDX3X), DDX31, and cell division cycle and apoptosis regulator 1 (CCAR1), which play potentially critical roles in the growth and/or maintenance of medulloblastoma. PMID:24608801

  6. 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

  7. Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin.

    Science.gov (United States)

    Lun, Xue Qing; Zhou, Hongyuan; Alain, Tommy; Sun, Beichen; Wang, Limei; Barrett, John W; Stanford, Marianne M; McFadden, Grant; Bell, John; Senger, Donna L; Forsyth, Peter A

    2007-09-15

    We have shown previously the oncolytic potential of myxoma virus in a murine xenograft model of human glioma. Here, we show that myxoma virus used alone or in combination with rapamycin is effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection, and pretreatment of cells with rapamycin increased the extent of in vitro oncolysis. Intratumoral injection of live myxoma virus when compared with control inactivated virus prolonged survival in D341 and Daoy orthotopic human medulloblastoma xenograft mouse models [D341 median survival: 21 versus 12.5 days; P = 0.0008; Daoy median survival: not reached (three of five mice apparently "cured" after 223 days) versus 75 days; P = 0.0021]. Rapamycin increased the extent of viral oncolysis, "curing" most Daoy tumor-bearing mice and reducing or eliminating spinal cord and ventricle metastases. Rapamycin enhanced tumor-specific myxoma virus replication in vivo and prolonged survival of D341 tumor-bearing mice (median survival of mice treated with live virus (LV) and rapamycin, versus LV alone, versus rapamycin alone, versus inactivated virus: 25 days versus 19, 13, and 11 days, respectively; P myxoma virus oncolysis. These observations suggest that myxoma virus may be an effective oncolytic agent against medulloblastoma and that combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus.

  8. 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

  9. 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...

  10. Adjuvant chemotherapy and overall survival in adult medulloblastoma.

    Science.gov (United States)

    Kann, Benjamin H; Lester-Coll, Nataniel H; Park, Henry S; Yeboa, Debra N; Kelly, Jacqueline R; Baehring, Joachim M; Becker, Kevin P; Yu, James B; Bindra, Ranjit S; Roberts, Kenneth B

    2017-02-01

    Although chemotherapy is used routinely in pediatric medulloblastoma (MB) patients, its benefit for adult MB is unclear. We evaluated the survival impact of adjuvant chemotherapy in adult MB. Using the National Cancer Data Base, we identified patients aged 18 years and older who were diagnosed with MB in 2004-2012 and underwent surgical resection and adjuvant craniospinal irradiation (CSI). Patients were divided into those who received adjuvant CSI and chemotherapy (CRT) or CSI alone (RT). Predictors of CRT compared with RT were evaluated with univariable and multivariable logistic regression. Survival analysis was limited to patients receiving CSI doses between 23 and 36 Gy. Overall survival (OS) was evaluated using the Kaplan-Meier estimator, log-rank test, multivariable Cox proportional hazards modeling, and propensity score matching. Of the 751 patients included, 520 (69.2%) received CRT, and 231 (30.8%) received RT. With median follow-up of 5.0 years, estimated 5-year OS was superior in patients receiving CRT versus RT (86.1% vs 71.6%, P < .0001). On multivariable analysis, after controlling for risk factors, CRT was associated with superior OS compared with RT (HR: 0.53; 95%CI: 0.32-0.88, P = .01). On planned subgroup analyses, the 5 year OS of patients receiving CRT versus RT was improved for M0 patients (P < .0001), for patients receiving 36 Gy CSI (P = .0007), and for M0 patients receiving 36 Gy CSI (P = .0008). This national database analysis demonstrates that combined postoperative chemotherapy and radiotherapy are associated with superior survival for adult MB compared with radiotherapy alone, even for M0 patients who receive high-dose CSI.

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

    Science.gov (United States)

    Pal, Rekha; Greene, Stephanie

    2015-01-01

    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. PMID:26394044

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

    Directory of Open Access Journals (Sweden)

    Rekha Pal

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

  13. Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders

    Science.gov (United States)

    2017-11-20

    Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma; Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma; Childhood Langerhans Cell Histiocytosis; Histiocytic Sarcoma; Juvenile Xanthogranuloma; Malignant Glioma; Recurrent Central Nervous System Neoplasm; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Solid Neoplasm; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Peripheral Primitive Neuroectodermal Tumor; Refractory Central Nervous System Neoplasm; Refractory Childhood Malignant Germ Cell Tumor; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Solid Neoplasm; Refractory Neuroblastoma; Rhabdoid Tumor; Stage III Osteosarcoma AJCC v7; Stage III Soft Tissue Sarcoma AJCC v7; Stage IV Osteosarcoma AJCC v7; Stage IV Soft Tissue Sarcoma AJCC v7; Stage IVA Osteosarcoma AJCC v7; Stage IVB Osteosarcoma AJCC v7; Wilms Tumor

  14. Pediatric MATCH: Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations

    Science.gov (United States)

    2017-10-30

    Advanced Malignant Solid Neoplasm; Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; EZH2 Gene Mutation; Histiocytosis; Loss of BRG1 Protein Expression; Loss of INI 1 Protein Expression; Low Grade Glioma; Malignant Glioma; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Childhood Ependymoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma; Recurrent Germ Cell Tumor; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Hodgkin Lymphoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Solid Neoplasm; Recurrent Medulloblastoma; Recurrent Neuroblastoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma; Recurrent Peripheral Primitive Neuroectodermal Tumor; Recurrent Rhabdomyosarcoma; Refractory Central Nervous System Neoplasm; Refractory Hodgkin Lymphoma; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Germ Cell Tumor; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Rhabdoid Tumor; Stage III Childhood Hodgkin Lymphoma; Stage III Childhood Non-Hodgkin Lymphoma; Stage III Soft Tissue Sarcoma AJCC v7; Stage IV Childhood Hodgkin Lymphoma; Stage IV Childhood Non-Hodgkin Lymphoma; Stage IV Soft Tissue Sarcoma AJCC v7; Wilms Tumor

  15. Pediatric MATCH: PI3K/mTOR Inhibitor LY3023414 in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations

    Science.gov (United States)

    2018-01-26

    Advanced Malignant Solid Neoplasm; Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma; Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma; Malignant Glioma; Recurrent Central Nervous System Neoplasm; Recurrent Childhood Ependymoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma; Recurrent Glioma; Recurrent Hepatoblastoma; Recurrent Langerhans Cell Histiocytosis; Recurrent Malignant Solid Neoplasm; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Peripheral Primitive Neuroectodermal Tumor; Refractory Central Nervous System Neoplasm; Refractory Childhood Malignant Germ Cell Tumor; Refractory Langerhans Cell Histiocytosis; Refractory Malignant Solid Neoplasm; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Rhabdoid Tumor; Stage III Osteosarcoma AJCC v7; Stage III Soft Tissue Sarcoma AJCC v7; Stage IV Osteosarcoma AJCC v7; Stage IV Soft Tissue Sarcoma AJCC v7; Stage IVA Osteosarcoma AJCC v7; Stage IVB Osteosarcoma AJCC v7; TSC1 Gene Mutation; TSC2 Gene Mutation; Wilms Tumor

  16. A Hybrid Robotic Control System Using Neuroblastoma Cultures

    Science.gov (United States)

    Ferrández, J. M.; Lorente, V.; Cuadra, J. M.; Delapaz, F.; Álvarez-Sánchez, José Ramón; Fernández, E.

    The main objective of this work is to analyze the computing capabilities of human neuroblastoma cultured cells and to define connection schemes for controlling a robot behavior. Multielectrode Array (MEA) setups have been designed for direct culturing neural cells over silicon or glass substrates, providing the capability to stimulate and record simultaneously populations of neural cells. This paper describes the process of growing human neuroblastoma cells over MEA substrates and tries to modulate the natural physiologic responses of these cells by tetanic stimulation of the culture. We show that the large neuroblastoma networks developed in cultured MEAs are capable of learning: establishing numerous and dynamic connections, with modifiability induced by external stimuli and we propose an hybrid system for controlling a robot to avoid obstacles.

  17. 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.

  18. Survival of children with medulloblastoma in Canada diagnosed between 1990 and 2009 inclusive.

    Science.gov (United States)

    Johnston, Donna L; Keene, Daniel; Kostova, Maria; Lafay-Cousin, Lucie; Fryer, Chris; Scheinemann, Katrin; Carret, Anne-Sophie; Fleming, Adam; Percy, Vanessa; Afzal, Samina; Wilson, Beverly; Bowes, Lynette; Zelcer, Shayna; Mpofu, Chris; Silva, Mariana; Larouche, Valerie; Brossard, Josee; Strother, Douglas; Bouffet, Eric

    2015-09-01

    The treatment of medulloblastoma, the most common malignant brain tumor in children, has evolved over the last few decades. The objectives of this paper were to determine the survival of pediatric medulloblastoma in Canada, to determine if there has been an improvement in the survival rates between the years of 1990 and 2009, inclusive, and to determine prognostic factors for survival. All patients under the age of 18 years diagnosed with medulloblastoma from 1990 to 2009, inclusive, in Canada were included. Data collected included date of diagnosis, age at diagnosis, gender, stage, pathology, treatment, recurrence and current status. From these, survival rates were determined. Data were obtained on 628 eligible patients. The overall 5-year survival rate for the study time period was 69.2 ± 3.3 %. The survival rate increased during the interval of 1996-2000, then remained stable; 1990-1994: 60.2 ± 4.3 %; 1995-1999: 73.2 ± 3.5 %; 2000-2004: 68.8 ± 3.7 %; and 2005-2009: 72.1 ± 4.9 %, p = 0.05. Children over 14 years of age had a significantly better overall survival than those age 5-14 and those under 5 (85.7 ± 5.5 % vs 76.1 ± 2.7 % and 60.8 ± 3 % respectively, p = 0.001). Histologic medulloblastoma subtype and M stage of disease did not result in significant differences in survival. Despite changes in approaches to therapy, we demonstrate a steady survival rate for children with medulloblastoma after 1996. In our analyses, age over 14 years was associated with a higher survival rate.

  19. Resolution of precocious puberty following resection of fourth ventricular medulloblastoma: case report.

    Science.gov (United States)

    Medina, Renata G; Dempsher, David P; Gauvain, Karen M; Geller, Thomas J; Elbabaa, Samer K

    2015-09-01

    Medulloblastoma is a malignant embryonal tumor that arises in the cerebellum and invades the fourth ventricle, often resulting in obstructive hydrocephalus. Patients typically present with symptoms related to increased intracranial pressure and cerebellar dysfunction. The authors report a rare case of classic medulloblastoma with central precocious puberty (CPP) as its only presenting symptom. A 7-year-old boy with no prior history of medulloblastoma presented with Tanner Stage IV testicular enlargement and a 4-month history of acne and pubic hair. Laboratory tests of blood samples demonstrated highly elevated luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Admission MRI of the brain revealed a mass in the posterior fossa, which bordered and compressed the fourth ventricle. The patient also exhibited mild lateral and third ventriculomegaly. Surgical options were discussed with the neurosurgical department. A suboccipital craniotomy and C-1 laminectomy were performed. A large mass was seen arising from the inferior surface of the vermis, and lying within the fourth ventricle. Gross-total microsurgical resection of the mass was performed. Histopathological investigation characterized the tumor as classic medulloblastoma. Follow-up laboratory tests of blood samples demonstrated a reduction of LH, FSH, and testosterone back to prepubertal levels. The patient then began radiation and chemotherapy. This report demonstrates that mild obstructive hydrocephalus due to a posterior fossa tumor may present with unexpected symptoms, such as CPP. To the authors' knowledge, precocious puberty has not yet been associated with medulloblastoma, although it has been found with other posterior fossa tumors. Extensive imaging of the CNS for patients presenting with CPP is recommended.

  20. 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

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

    Directory of Open Access Journals (Sweden)

    Lowell Evan Michael

    2008-12-01

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

  2. Metastatic medulloblastoma in adults: outcome of patients treated according to the HIT2000 protocol.

    Science.gov (United States)

    von Bueren, André O; Friedrich, Carsten; von Hoff, Katja; Kwiecien, Robert; Müller, Klaus; Pietsch, Torsten; Warmuth-Metz, Monika; Hau, Peter; Benesch, Martin; Kuehl, Joachim; Kortmann, Rolf D; Rutkowski, Stefan

    2015-11-01

    Due to the rarity of metastatic medulloblastoma in adults, knowledge about the efficacy and toxicity of intensified chemotherapy and radiotherapy is limited. Adults with disseminated medulloblastoma registered in the HIT2000 trial as observational patients and treated according to one of two different treatment regimens were analysed. The sandwich strategy MET-HIT2000AB4 consists of postoperative chemotherapy, hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy; while the HIT'91 maintenance strategy consists of postoperative craniospinal radiotherapy, and maintenance chemotherapy. Twenty-three patients (median age: 30.7years), diagnosed from November 2001 to July 2009, and treated in 18 institutions in Germany and Austria, were eligible. The median follow-up of surviving patients was 3.99years. The 4-year event-free survival (EFS) and overall survival (OS)±standard error (SE) were 52%±12% and 91%±6%, respectively. The survival was similar in both treatment groups (HIT'91 maintenance strategy, n=9; MET-HIT2000AB4 sandwich strategy, n=14). Patients with large cell/anaplastic medulloblastoma relapsed and died (n=2; 4-year EFS/OS: 0%) and OS differed compared to patients with classic (n=11; 4-year EFS/OS: 71%/91%) and desmoplastic medulloblastoma (n=10; 4-year EFS/OS: 48%/100%), respectively (p=0.161 for EFS and p=0.033 for OS). Treatment-induced toxicities consisted mainly of neurotoxicity (50% of patients, ⩾ °II), followed by haematotoxicity and nephrotoxicity/ototoxicity. The professional outcome appeared to be negatively affected in the majority of evaluable patients (9/10). Treatment of adults with metastatic medulloblastoma according to the intensified paediatric HIT2000 protocol was feasible with acceptable toxicities. EFS rates achieved by both chemotherapeutic protocols were favourable and appear to be inferior to those obtained in older children/adolescents with metastatic disease. Copyright © 2015 Elsevier Ltd. All rights

  3. Medulloblastoma and Brucellosis - Molecular Evidence of Brucella sp in Association with Central Nervous System Cancer

    Directory of Open Access Journals (Sweden)

    Binxue Zhang, Mina Izadjoo, Iren Horkayne-Szakaly, Alan Morrison, Douglas J. Wear

    2011-01-01

    Full Text Available Neurobrucellosis has been reported to cause lesions in a number of different locations in the central nervous system. Histologically or radiologically, these lesions were consistent with an infection. In response to parents who believed their child's brain tumor, histologically typical of medulloblastoma, was in reality neurobrucellosis, formalin-fixed paraffin-embedded tumor tissue from the medulloblastoma was sectioned, DNA extracted, and tested by polymerase chain reaction (PCR. Specific primer/probe sets, designed in our laboratory to target Brucella species, B. melitensis, B. abortus and B. suis, and designated OMP31, B-m, B-a and B-s, respectively, were used in TaqMan real-time PCR to amplify those gene targets in two separate blocks of the child's tumor. Sections from two blocks were positive only for Brucella species. Although the patient grew up in a European country known to harbor brucella in foods, such as unpasturized milk and cheese, the patient was seronegative for B. mellitensis, B. suis, and B. abortus. In an effort to test whether a relationship existed between the presence of brucella and medulloblastoma, 20 medulloblastomas were retrieved from the tissue repository of the AFIP. The above four primer/probe sets were again used to amplify brucella DNA. Five of 20 tumors (25% contained Brucella species DNA by the OMP31 primer/probe set. None of the 20 medulloblastomas had specific sequences for B. mellitensis, B. suis, or B. abortus. Is chronic brucellosis similar to other infectious agents such as helicobacter that is associated with tumor formation?

  4. Preclinical models for neuroblastoma: establishing a baseline for treatment.

    Directory of Open Access Journals (Sweden)

    Tal Teitz

    2011-04-01

    Full Text Available Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system.Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents.The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal

  5. Integrative genomics identifies LMO1 as a neuroblastoma oncogene.

    Science.gov (United States)

    Wang, Kai; Diskin, Sharon J; Zhang, Haitao; Attiyeh, Edward F; Winter, Cynthia; Hou, Cuiping; Schnepp, Robert W; Diamond, Maura; Bosse, Kristopher; Mayes, Patrick A; Glessner, Joseph; Kim, Cecilia; Frackelton, Edward; Garris, Maria; Wang, Qun; Glaberson, Wendy; Chiavacci, Rosetta; Nguyen, Le; Jagannathan, Jayanti; Saeki, Norihisa; Sasaki, Hiroki; Grant, Struan F A; Iolascon, Achille; Mosse, Yael P; Cole, Kristina A; Li, Hongzhe; Devoto, Marcella; McGrady, Patrick W; London, Wendy B; Capasso, Mario; Rahman, Nazneen; Hakonarson, Hakon; Maris, John M

    2011-01-13

    Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2 × 10(-16), odds ratio of risk allele = 1.34 (95% confidence interval 1.25-1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.

  6. CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma.

    Science.gov (United States)

    Dahlin, Anna M; Hollegaard, Mads V; Wibom, Carl; Andersson, Ulrika; Hougaard, David M; Deltour, Isabelle; Hjalmars, Ulf; Melin, Beatrice

    2015-10-01

    Recent studies have described a number of genes that are frequently altered in medulloblastoma tumors and that have putative key roles in the development of the disease. We hypothesized that common germline genetic variations in these genes may be associated with medulloblastoma development. Based on recent publications, we selected 10 genes that were frequently altered in medulloblastoma: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 (now renamed as KMT2D). Common genetic variants (single nucleotide polymorphisms) annotating these genes (n = 221) were genotyped in germline DNA (neonatal dried blood spot samples) from 243 childhood medulloblastoma cases and 247 control subjects from Sweden and Denmark. Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P(combined) medulloblastoma.

  7. JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma.

    Science.gov (United States)

    Chan, Tiffany Sin Yu; Hawkins, Cynthia; Krieger, Jonathan R; McGlade, C Jane; Huang, Annie

    2016-05-01

    Substantial evidence links Myc-PI3K/AKT signaling to the most aggressive subtype of medulloblastoma and this axis in medulloblastoma therapy. In this study, we advance understanding of how Myc-PI3K/AKT signaling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this setting. Overall, our findings highlight two novel prometastatic loci in medulloblastoma and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of PI3K/AKT signaling in medulloblastoma. Cancer Res; 76(9); 2802-12. ©2016 AACR. ©2016 American Association for Cancer Research.

  8. 20(S)-Protopanaxadiol induces apoptosis in human hepatoblastoma HepG2 cells by downregulating the protein kinase B signaling pathway.

    Science.gov (United States)

    Lu, Zeyuan; Xu, Huali; Yu, Xiaofeng; Wang, Yuchen; Huang, Long; Jin, Xin; Sui, Dayun

    2018-02-01

    Hepatoblastoma is the most common primary liver tumor for children aged S)-Protopanaxadiol (PPD) is a ginsenoside extracted from Pananx quinquefolium L ., which inhibits tumor growth in several cancer cell lines. The purpose of the present study was to assess the anticancer activities of 20(S)-PPD in human hepatoblastoma HepG2 cells. The cytotoxicity of 20(S)-PPD on HepG2 cells was evaluated using an MTT assay. Apoptosis was detected using DAPI staining and flow cytometry. The expression of apoptosis-associated proteins was identified by western blotting. The results demonstrated that 20(S)-PPD inhibited the viability of HepG2 cell in a dose and time-dependent manner. The IC 50 values were 81.35, 73.5, 48.79 µM at 24, 48 and 72 h, respectively. Topical morphological changes of apoptotic body formation following 20(S)-PPD treatment were detected by DAPI staining. The percentage of Annexin V-fluoroscein isothyiocyanate positive cells were 3.73, 17.61, 23.44 and 65.43% in HepG2 cells treated with 0, 40, 50 and 60 µM of 20(S)-PPD, respectively. Furthermore, 20(S)-PPD upregulated the expression of Bax and downregulated the expression of Bcl-2 and also activated caspases-3 and -9, and Poly [ADP-ribose] polymerase cleavage. In addition, 20(S)-PPD inhibited the phosphorylation of protein kinase B (Akt; Ser473). The results indicate that 20(S)-PPD inhibits the viability of HepG2 cells and induces apoptosis in HepG2 cells by inhibiting the phosphoinositide-3-kinase/Akt pathway.

  9. Prolonged Isotretinoin in Ultra High-Risk Neuroblastoma.

    Science.gov (United States)

    Cash, Thomas; Alazraki, Adina; Qayed, Muna; Katzenstein, Howard M

    2017-01-01

    Patients with high-risk neuroblastoma remain a therapeutic challenge with significant numbers of patients failing to respond sufficiently to initial therapy. These patients with poor response to induction are considered as ultra high-risk and are in need of novel treatment strategies. Isotretinoin is part of the standard of care treatment for patients with high-risk disease who undergo high-dose chemotherapy with autologous stem cell rescue although some have questioned the optimal administration schedule. Prolonged use of isotretinoin was well tolerated and may have contributed to long-term survival in a group of patients with ultra high-risk neuroblastoma.

  10. Probenecid Sensitizes Neuroblastoma Cancer Stem Cells to Cisplatin.

    Science.gov (United States)

    Campos-Arroyo, Denise; Maldonado, Vilma; Bahena, Ivan; Quintanar, Valeria; Patiño, Nelly; Carlos Martinez-Lazcano, Juan; Melendez-Zajgla, Jorge

    2016-01-01

    We used both in vitro cultures of neuroblastoma cell lines and nude-mice xenotransplants to explore the effects of co-administration of cisplatin and probenecid. Probenecid sensitized neuroblastoma cells, including tumor cells with stem features, to the effects of cisplatin, both in vitro and in vivo. This effect was mediated by an increase in the apoptotic cell death and a concomitant decrease in cell proliferation. This effect is accompanied by modulation of the mRNA and protein of the drug efflux transporters MDR1, MRP2, and BCRP. The co-administration of probenecid with cisplatin should be explored as a possible therapeutic strategy.

  11. Identifying microRNAs that Regulate Neuroblastoma Cell Differentiation

    Science.gov (United States)

    2014-09-01

    prognostic marker in neuroblastoma, Cancer Res 71, 4314-4324. 6. Le, M. T., Xie, H., Zhou, B., Chia , P. H., Rizk, P., Um, M., Udolph, G., Yang, H...matter,   or   any   new   and   useful   improvement   thereof,   which,  taken  together,  include   practically  everything...is  an   important   therapeutic   strategy   for  neuroblastoma.  We  developed  a  direct   functional  high-­‐content

  12. 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

  13. Simultaneous Measurement of Neural Spike Recordings and Multi-Photon Calcium Imaging in Neuroblastoma Cells

    Directory of Open Access Journals (Sweden)

    Jeehyun Kim

    2012-11-01

    Full Text Available This paper proposes the design and implementation of a micro-electrode array (MEA for neuroblastoma cell culturing. It also explains the implementation of a multi-photon microscope (MPM customized for neuroblastoma cell excitation and imaging under ambient light. Electrical signal and fluorescence images were simultaneously acquired from the neuroblastoma cells on the MEA. MPM calcium images of the cultured neuroblastoma cell on the MEA are presented and also the neural activity was acquired through the MEA recording. A calcium green-1 (CG-1 dextran conjugate of 10,000 D molecular weight was used in this experiment for calcium imaging. This study also evaluated the calcium oscillations and neural spike recording of neuroblastoma cells in an epileptic condition. Based on our observation of neural spikes in neuroblastoma cells with our proposed imaging modality, we report that neuroblastoma cells can be an important model for epileptic activity studies.

  14. SHP2, SOCS3 and PIAS3 Expression Patterns in Medulloblastomas: Relevance to STAT3 Activation and Resveratrol-Suppressed STAT3 Signaling.

    Science.gov (United States)

    Li, Cong; Li, Hong; Zhang, Peng; Yu, Li-Jun; Huang, Tian-Miao; Song, Xue; Kong, Qing-You; Dong, Jian-Li; Li, Pei-Nan; Liu, Jia

    2016-12-27

    Activated STAT3 signaling is critical for human medulloblastoma cells. SHP2, SOCS3 and PIAS3 are known as the negative regulators of STAT3 signaling, while their relevance to frequent STAT3 activation in medulloblastomas remains unknown. Tissue microarrays were constructed with 17 tumor-surrounding noncancerous brain tissues and 61 cases of the classic medulloblastomas, 44 the large-cell medulloblastomas, and 15 nodular medulloblastomas, which were used for immunohistochemical profiling of STAT3, SHP2, SOCS3 and PIAS3 expression patterns and the frequencies of STAT3 nuclear translocation. Three human medulloblastoma cell lines (Daoy, UW228-2 and UW228-3) were cultured with and without 100 μM resveratrol supplementation. The influences of resveratrol in SHP2, SOCS3 and PIAS3 expression and SOCS3 knockdown in STAT3 activation were analyzed using multiple experimental approaches. SHP2, SOCS3 and PIAS3 levels are reduced in medulloblastomas in vivo and in vitro, of which PIAS3 downregulation is more reversely correlated with STAT3 activation. In resveratrol-suppressed medulloblastoma cells with STAT3 downregulation and decreased incidence of STAT3 nuclear translocation, PIAS3 is upregulated, the SHP2 level remains unchanged and SOCS3 is downregulated. SOCS3 proteins are accumulated in the distal ends of axon-like processes of resveratrol-differentiated medulloblastoma cells. Knockdown of SOCS3 expression by siRNA neither influences cell proliferation nor STAT3 activation or resveratrol sensitivity but inhibits resveratrol-induced axon-like process formation. Our results suggest that (1) the overall reduction of SHP2, SOCS3 and PIAS3 in medulloblastoma tissues and cell lines; (2) the more inverse relevance of PIAS3 expression with STAT3 activation; (3) the favorable prognostic values of PIAS3 for medulloblastomas and (4) the involvement of SOCS3 in resveratrol-promoted axon regeneration of medulloblastoma cells.

  15. Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization.

    Science.gov (United States)

    Bhatia, Shilpa; Baig, Nimrah A; Timofeeva, Olga; Pasquale, Elena B; Hirsch, Kellen; MacDonald, Tobey J; Dritschilo, Anatoly; Lee, Yi Chien; Henkemeyer, Mark; Rood, Brian; Jung, Mira; Wang, Xiao-Jing; Kool, Marcel; Rodriguez, Olga; Albanese, Chris; Karam, Sana D

    2015-04-20

    The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased β1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Pancreatic Endoplasmic Reticulum Kinase Activation Promotes Medulloblastoma Cell Migration and Invasion through Induction of Vascular Endothelial Growth Factor A

    Science.gov (United States)

    Jamison, Stephanie; Lin, Yifeng; Lin, Wensheng

    2015-01-01

    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. PMID:25794107

  18. Inhibition of SIRT1 Transcription inResveratrol-differentiated Medulloblastoma Cells

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    Jing-Xin Ma

    2013-05-01

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

  19. Sphingolipids in neuroblastoma : Their role in drug resistance mechanisms

    NARCIS (Netherlands)

    Sietsma, H; Dijkhuis, AJ; Kamps, W; Kok, JW

    Disseminated neuroblastoma usually calls for chemotherapy as the primary approach for treatment. Treatment failure is often attributable to drug resistance. This involves a variety of cellular mechanisms, including increased drug efflux through expression of ATP-binding cassette transporters (e.g.,

  20. Thymic Neuroblastoma within a Thymic Cyst in an Adult

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    Yuichiro Ueda

    2012-08-01

    Full Text Available Case Presentation: A 65-year-old female patient with no clinical manifestations was hospitalized for examination and treatment of an anterior mediastinal tumor found at the time of a regular health checkup. Enhanced computed tomography (CT and magnetic resonance imaging revealed a cystic lesion containing a solid tumor. Positron emission tomography-CT demonstrated increased uptake in the solid lesion. Tumor resection with total thymectomy was performed. A pathological diagnosis of thymic neuroblastoma within a thymic cyst was made. Micorscopic examination revealed that tumor cells of the solid component were lined with thymic epithelial cells of the inner cyst wall. Furthermore, some tumor cells of the solid component had melanin granules. These findings suggest that this tumor arose from progenitors of the thymic epithelial cells with the potential to differentiate along neural lines. Conclusions: Neuroblastoma commonly occurs in children. However, the diagnosis of neuroblastoma in adults has been reported in several case reports. We report an adult case of histogenetically informative thymic neuroblastoma within a thymic cyst. There are no standard treatment strategies and chemotherapy protocols. Complete surgical resection might be important for a better outcome.

  1. Neuroblastoma: a challenge for pediatric oncology of the third millennium.

    Science.gov (United States)

    Massimo, Luisa

    2002-06-01

    Neuroblastoma is the only cancer of childhood considered in this conference on hormone-related tumors, because the percentage of deaths in children with this rare type of cancer is still very high. Pediatricians feel the need for help from basic researchers to better understand the biological nature of this disease and to improve protocols and the challenge of cure.

  2. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

    NARCIS (Netherlands)

    J. Molenaar (Jan); J. Koster (Jan); D. Zwijnenburg (Danny); P. van Sluis (Peter); L.J. Valentijn (Linda); I. van der Ploeg (Ida); M. Hamdi (Mohamed); J. van Nes (Johan); B.A. Westerman (Bart); J. van Arkel (Jennemiek); M.E. Ebus; F. Haneveld (Franciska); A. Lakeman (Arjan); L. Schild (Linda); P. Molenaar (Piet); P. Stroeken (Peter); M.M. van Noesel (Max); I. Øra (Ingrid); J.P. di Santo (James); H.N. Caron (Huib); E.M. Westerhout (Ellen); R. Versteeg (Rogier)

    2012-01-01

    textabstractNeuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification

  3. Cytokines Synergize to Combat Metastatic Neuroblastoma | Center for Cancer Research

    Science.gov (United States)

    Neuroblastoma is the most common extracranial solid tumor in children, and clinical outcomes of patients with this disease are quite variable. Prognosis is particularly poor for patients with high-risk tumors (classification based on patients’ age, extent of disease spread, and other biological features).

  4. Mucopolysaccharide in the blood of a patient with neuroblastoma

    Science.gov (United States)

    Broughton, P. M. G.; Dykes, J. R. W.; Holt, Shirley; Ridley, J. W.; Steel, A. E.

    1970-01-01

    In a case of neuroblastoma the presence of an abnormal blood constituent was suspected from the raised erythrocyte sedimentation rate, sludging of the red cells, marked rouleaux formation, an atypical Leishman stain, increased plasma viscosity, and a distorted protein electrophoresis pattern. The abnormal constituent was shown to be a mucopolysaccharide which was either hyaluronic acid or chondroitin sulphate. Images PMID:4192677

  5. Microdontia after chemotherapy in a child treated for neuroblastoma.

    NARCIS (Netherlands)

    Remmers, D.; Bokkerink, J.P.M.; Katsaros, C.

    2006-01-01

    OBJECTIVE: Chemotherapy used on paediatric oncology patients often causes disturbances in dental development. Aim of this case report is to present the late effects of chemotherapy on dental development in a patient treated for neuroblastoma at early age. DESIGN: Case report. RESULTS: This paper

  6. A medulloblastoma showing an unusually long doubling time: reflection of its singular nature.

    Science.gov (United States)

    Doron, Omer; Zauberman, Jacob; Feldman, Ze'ev

    2016-06-01

    In this paper, we present a case of a 4-year-old male diagnosed with a desmoplastic, SHH-type medulloblastoma. Retrospectively, we discovered that the patient underwent an MRI scan at 21 months for reasons unrelated, revealing a T1-enhanced lesion at the vermis, later recognized as the source of the tumor. This unique case provides us with a glimpse into the natural history of this tumor. Our ability to measure tumor volume at two defined time points, 31 months apart, enabled us to deduce the tumor's doubling time. This is defined as the time of one cell cycle divided by the amount of cycling cells, multiplied by cell loss factor. Potential doubling time (Tpot) and actual doubling time (Td), calculated using the Gompertzian model, are the most clinically relevant with regard to a tumor's response to radiotherapy. Here, we show an actual doubling-time (Td) of 78 days, and an extrapolated tumor diameter at the time of birth of 0.25 mm. These results both support the medulloblastoma's embryonic origin, and indicating a threefold longer actual doubling time when compared to previous studies. Taking into account the reported range of medulloblastoma potential doubling time, we deduced a cell loss factor of between 48.9 and 95.5 %. These percentages fall in line with other malignant tumors. Although limited due to the obvious reliance on only two points in time and using the Gompertzian model to complete the remainder, to the best of our knowledge, this is the longest follow-up period reported for medulloblastoma. We have described how a unique turn of events enabled us to get a glimpse into the in situ development of a medulloblastoma over a 31-month period. Regarded sometimes as an idiosyncratic tumor comprised of an array of molecular changes, the complexity of medulloblastoma is displayed here, by revealing for the first time an actual doubling time three- to fourfold the previously known length.

  7. Graphene Oxide Nanoribbons Induce Autophagic Vacuoles in Neuroblastoma Cell Lines

    Directory of Open Access Journals (Sweden)

    Emanuela Mari

    2016-11-01

    Full Text Available Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs and analyzed their toxicity in two human neuroblastoma cell lines. Neuroblastoma is the most common solid neoplasia in children. The hallmark of these tumors is the high number of different clinical variables, ranging from highly metastatic, rapid progression and resistance to therapy to spontaneous regression or change into benign ganglioneuromas. Patients with neuroblastoma are grouped into different risk groups that are characterized by different prognosis and different clinical behavior. Relapse and mortality in high risk patients is very high in spite of new advances in chemotherapy. Cell lines, obtained from neuroblastomas have different genotypic and phenotypic features. The cell lines SK-N-BE(2 and SH-SY5Y have different genetic mutations and tumorigenicity. Cells were exposed to low doses of GO for different times in order to investigate whether GO was a good vehicle for biological molecules delivering individualized therapy. Cytotoxicity in both cell lines was studied by measuring cellular oxidative stress (ROS, mitochondria membrane potential, expression of lysosomial proteins and cell growth. GO uptake and cytoplasmic distribution of particles were studied by Transmission Electron Microscopy (TEM for up to 72 h. The results show that GO at low concentrations increased ROS production and induced autophagy in both neuroblastoma cell lines within a few hours of exposure, events that, however, are not followed by growth arrest or death. For this reason, we suggest that the GO nanoparticle can be used for therapeutic delivery to the brain tissue with minimal effects on healthy cells.

  8. The emerging molecular pathogenesis of neuroblastoma: implications for improved risk assessment and targeted therapy.

    Science.gov (United States)

    Van Roy, Nadine; De Preter, Katleen; Hoebeeck, Jasmien; Van Maerken, Tom; Pattyn, Filip; Mestdagh, Pieter; Vermeulen, Joëlle; Vandesompele, Jo; Speleman, Frank

    2009-07-27

    Neuroblastoma is one of the most common solid tumors of childhood, arising from immature sympathetic nervous system cells. The clinical course of patients with neuroblastoma is highly variable, ranging from spontaneous regression to widespread metastatic disease. Although the outcome for children with cancer has improved considerably during the past decades, the prognosis of children with aggressive neuroblastoma remains dismal. The clinical heterogeneity of neuroblastoma mirrors the biological and genetic heterogeneity of these tumors. Ploidy and MYCN amplification have been used as genetic markers for risk stratification and therapeutic decision making, and, more recently, gene expression profiling and genome-wide DNA copy number analysis have come into the picture as sensitive and specific tools for assessing prognosis. The applica tion of new genetic tools also led to the discovery of an important familial neuroblastoma cancer gene, ALK, which is mutated in approximately 8% of sporadic tumors, and genome-wide association studies have unveiled loci with risk alleles for neuroblastoma development. For some of the genomic regions that are deleted in some neuroblastomas, on 1p, 3p and 11q, candidate tumor suppressor genes have been identified. In addition, evidence has emerged for the contribution of epigenetic disturbances in neuroblastoma oncogenesis. As in other cancer entities, altered microRNA expression is also being recognized as an important player in neuroblastoma. The recent successes in unraveling the genetic basis of neuroblastoma are now opening opportunities for development of targeted therapies.

  9. 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...... patients to represent the variability in tumor location relative to the hippocampal region. Treatment plans were generated using 3D conformal radiotherapy, hippocampal sparing intensity-modulated radiotherapy, and spot-scanned proton therapy, using 3 different treatment margins for the conformal tumor...... boost. Neurocognitive impairment risk was estimated based on dose-response models from pediatric CNS malignancy survivors and compared among different margins and treatment techniques.ResultsMean hippocampal dose and corresponding risk of cognitive impairment were decreased with decreasing treatment...

  10. A case of Cushing ulcer in an 8-month-old patient with medulloblastoma.

    Science.gov (United States)

    Sivakumar, Walavan; Spader, Heather S; Scaife, Eric; Bollo, Robert J

    2016-04-01

    The authors present the first case of a Cushing ulcer in an infant with medulloblastoma who, despite being administered stress ulcer prophylaxis, worsened after corticosteroids were initiated. An 8-month-old boy presented with progressive vomiting, lethargy, and decreased oral intake. Imaging revealed a heterogeneous fourth ventricular mass. Preoperatively, the patient was started on dexamethasone. The patient underwent an uncomplicated external ventricular drain placement and suboccipital craniotomy for resection of the lesion. The results of the pathological analysis were consistent with medulloblastoma. Postoperatively, the patient had melanotic stools, which were reported to be occurring for months prior to presentation. Two proximal duodenal bulb ulcers were found and required definitive surgical repair. The patient recovered from the acute postsurgical course after continued stress ulcer prophylaxis and is currently undergoing chemotherapy.

  11. Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study.

    Science.gov (United States)

    Minturn, Jane E; Evans, Audrey E; Villablanca, Judith G; Yanik, Gregory A; Park, Julie R; Shusterman, Suzanne; Groshen, Susan; Hellriegel, Edward T; Bensen-Kennedy, Debra; Matthay, Katherine K; Brodeur, Garrett M; Maris, John M

    2011-10-01

    TrkB acts as an oncogenic kinase in a subset of human neuroblastomas. Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated activity in preclinical models of neuroblastoma. Patients with refractory high-risk neuroblastoma received lestaurtinib twice daily for 5 days out of seven in 28-day cycles, starting at 70% of the adult recommended Phase 2 dose. Lestaurtinib dose was escalated using a 3 + 3 design. Pharmacokinetics and plasma phospho-TrkB inhibitory activity were evaluated in the first cycle. Forty-seven subjects were enrolled, and 10 dose levels explored starting at 25 mg/M(2)/dose BID. Forty-six subjects were evaluable for response, and 42 subjects were fully evaluable for determination of dose escalation. Asymptomatic and reversible grade 3-4 transaminase elevation was dose limiting in 4 subjects. Reversible pancreatitis (grade 2) was observed in 3 subjects after prolonged treatment at higher dose levels. Other toxicities were mild and reversible. Pharmacokinetic analyses revealed rapid drug absorption, however inter-patient variability was large. Plasma inhibition of phospho-TrkB activity was observed 1 h post-dosing at 85 mg/M(2) with uniform inhibition at 120 mg/M(2). There were two partial responses and nine subjects had prolonged stable disease at dose levels ≥ 5, (median: 6 cycles). A biologically effective and recommended phase 2 dose of 120 mg/M(2)/dose BID was established. Lestaurtinib was well tolerated in patients with refractory neuroblastoma, and a dose level sufficient to inhibit TrkB activity was established. Safety and signs of activity at the higher dose levels warrant further evaluation in neuroblastoma.

  12. Na,K-ATPase β1-subunit is a target of sonic hedgehog signaling and enhances medulloblastoma tumorigenicity.

    Science.gov (United States)

    Lee, Seung Joon; Litan, Alisa; Li, Zhiqin; Graves, Bruce; Lindsey, Stephan; Barwe, Sonali P; Langhans, Sigrid A

    2015-08-19

    The Sonic hedgehog (Shh) signaling pathway plays an important role in cerebellar development, and mutations leading to hyperactive Shh signaling have been associated with certain forms of medulloblastoma, a common form of pediatric brain cancer. While the fundamentals of this pathway are known, the molecular targets contributing to Shh-mediated proliferation and transformation are still poorly understood. Na,K-ATPase is a ubiquitous enzyme that maintains intracellular ion homeostasis and functions as a signaling scaffold and a cell adhesion molecule. Changes in Na,K-ATPase function and subunit expression have been reported in several cancers and loss of the β1-subunit has been associated with a poorly differentiated phenotype in carcinoma but its role in medulloblastoma progression is not known. Human medulloblastoma cell lines and primary cultures of cerebellar granule cell precursors (CGP) were used to determine whether Shh regulates Na,K-ATPase expression. Smo/Smo medulloblastoma were used to assess the Na,K-ATPase levels in vivo. Na,K-ATPase β1-subunit was knocked down in DAOY cells to test its role in medulloblastoma cell proliferation and tumorigenicity. Na,K-ATPase β1-subunit levels increased with differentiation in normal CGP cells. Activation of Shh signaling resulted in reduced β1-subunit mRNA and protein levels and was mimicked by overexpression of Gli1and Bmi1, both members of the Shh signaling cascade; overexpression of Bmi1 reduced β1-subunit promoter activity. In human medulloblastoma cells, low β1-subunit levels were associated with increased cell proliferation and in vivo tumorigenesis. Na,K-ATPase β1-subunit is a target of the Shh signaling pathway and loss of β1-subunit expression may contribute to tumor development and progression not only in carcinoma but also in medulloblastoma, a tumor of neuronal origin.

  13. Exploratory analysis of ERCC2 DNA methylation in survival among pediatric medulloblastoma patients.

    Science.gov (United States)

    Banfield, Emilyn; Brown, Austin L; Peckham, Erin C; Rednam, Surya P; Murray, Jeffrey; Okcu, M Fatih; Mitchell, Laura E; Chintagumpala, Murali M; Lau, Ching C; Scheurer, Michael E; Lupo, Philip J

    2016-10-01

    Medulloblastoma is the most frequent malignant pediatric brain tumor. While survival rates have improved due to multimodal treatment including cisplatin-based chemotherapy, there are few prognostic factors for adverse treatment outcomes. Notably, genes involved in the nucleotide excision repair pathway, including ERCC2, have been implicated in cisplatin sensitivity in other cancers. Therefore, this study evaluated the role of ERCC2 DNA methylation profiles on pediatric medulloblastoma survival. The study population included 71 medulloblastoma patients (age DNA methylation profiles were generated from peripheral blood samples using the Illumina Infinium Human Methylation 450 Beadchip. Sixteen ERCC2-associated CpG sites were evaluated in this analysis. Multivariable regression models were used to determine the adjusted association between DNA methylation and survival. Cox regression and Kaplan-Meier curves were used to compare 5-year overall survival between hyper- and hypo-methylation at each CpG site. In total, 12.7% (n=9) of the patient population died within five years of diagnosis. In our population, methylation of the cg02257300 probe (Hazard Ratio=9.33; 95% Confidence Interval: 1.17-74.64) was associated with death (log-rank p=0.01). This association remained suggestive after correcting for multiple comparisons (FDR pDNA methylation within the promoter region of the ERCC2 gene may be associated with survival in pediatric medulloblastoma. If confirmed in future studies, this information may lead to improved risk stratification or promote the development of novel, targeted therapeutics. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    OpenAIRE

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

    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...

  15. Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

    OpenAIRE

    Castro-Gamero, Angel Mauricio; Borges, Kleiton Silva; Lira, Regia Caroline; Andrade, Augusto Faria; Fedatto, Paola Fernanda; Cruzeiro, Gustavo Alencastro Veiga; Silva, Ricardo Bonfim; Fontes,Aparecida Maria; Valera, Elvis Terci; Bobola, Michael; Scrideli,Carlos Alberto; Tone,Luiz Gonzaga

    2013-01-01

    Chromosomal heterogeneity is a hallmark of most tumors and it can drive critical events as growth advantages, survival advantages, progression and karyotypic evolution. Medulloblastoma (MB) is the most common malignant central nervous system tumor in children. This work attempted to investigate chromosomal heterogeneity and instability profiles of two MB pediatric cell lines and their relationship with cell phenotype. We performed GTG-banding and cytokinesis-block micronucleus cytome assays, ...

  16. miR-367 promotes proliferation and stem-like traits in medulloblastoma cells.

    Science.gov (United States)

    Kaid, Carolini; Silva, Patrícia B G; Cortez, Beatriz A; Rodini, Carolina O; Semedo-Kuriki, Patricia; Okamoto, Oswaldo K

    2015-09-01

    In medulloblastoma, abnormal expression of pluripotency factors such as LIN28 and OCT4 has been correlated with poor patient survival. The miR-302/367 cluster has also been shown to control self-renewal and pluripotency in human embryonic stem cells and induced pluripotent stem cells, but there is limited, mostly correlational, information about these pluripotency-related miRNA in cancer. We evaluated whether aberrant expression of such miRNA could affect tumor cell behavior and stem-like traits, thereby contributing to the aggressiveness of medulloblastoma cells. Basal expression of primary and mature forms of miR-367 were detected in four human medulloblastoma cell lines and expression of the latter was found to be upregulated upon enforced expression of OCT4A. Transient overexpression of miR-367 significantly enhanced tumor features typically correlated with poor prognosis; namely, cell proliferation, 3-D tumor spheroid cell invasion and the ability to generate neurosphere-like structures enriched in CD133 expressing cells. A concurrent downregulation of the miR-367 cancer-related targets RYR3, ITGAV and RAB23, was also detected in miR-367-overexpressing cells. Overall, these findings support the pro-oncogenic activity of miR-367 in medulloblastoma and reveal a possible mechanism contributing to tumor aggressiveness, which could be further explored to improve patient stratification and treatment of this important type of pediatric brain cancer. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  17. 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.

  18. 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.

  19. 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

  20. Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study.

    Science.gov (United States)

    Zsiros, József; Brugieres, Laurence; Brock, Penelope; Roebuck, Derek; Maibach, Rudolf; Zimmermann, Arthur; Childs, Margaret; Pariente, Daniele; Laithier, Veronique; Otte, Jean-Bernard; Branchereau, Sophie; Aronson, Daniel; Rangaswami, Arun; Ronghe, Milind; Casanova, Michela; Sullivan, Michael; Morland, Bruce; Czauderna, Piotr; Perilongo, Giorgio

    2013-08-01

    The objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma. SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with either metastatic disease, tumour in all liver segments, abdominal extrahepatic disease, major vascular invasion, low α fetoprotein, or tumour rupture were eligible. Treatment consisted of preoperative chemotherapy (cycles A1-A3: cisplatin 80 mg/m(2) per day intravenous in 24 h on day 1; cisplatin 70 mg/m(2) per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m(2) per day intravenous in 24 h on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumour lesions if feasible (including liver transplantation and metastasectomy, if needed). Patients whose tumour remained unresectable received additional preoperative chemotherapy (cycle B: doxorubicin 25 mg/m(2) per day in 24 h on days 1-3 and 22-24, and carboplatin area under the curve [AUC] 10·6 mg/mL per min per day intravenous in 1 h on days 1 and 22) before surgery was attempted. After surgery, postoperative chemotherapy was given (cycle C: doxorubicin 20 mg/m(2) per day in 24 h on days 1, 2, 22, 23, 43, and 44, and carboplatin AUC 6·6 mg/mL per min per day in 1 h on days 1, 22, and 43) to patients who did not receive cycle B. The primary endpoint was the proportion of patients with complete remission at the end of treatment. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00077389. We report the final analysis of the trial. 62 eligible patients (39 with lung metastases) were included and analysed. 60 (98%, 95% CI 91-100) of 61 evaluable patients (one child underwent primary hepatectomy) had a partial response to preoperative chemotherapy. Complete resection of all tumour

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

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

    Directory of Open Access Journals (Sweden)

    Gidley Paul W

    2011-06-01

    Full Text Available Abstract Background 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. Methods 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. Results The predicted mean cochlear radiation dose was 30 60Co-Gy Equivalents (range 19-43, and the mean cumulative cisplatin dose was 303 mg/m2 (range 298-330. Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (P Conclusions 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.

  7. 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

  8. Adult medulloblastoma: clinical characters, prognostic factors, outcomes and patterns of relapse.

    Science.gov (United States)

    Zhang, Na; Ouyang, Taohui; Kang, Huicong; Long, Wang; Thomas, Benjamin; Zhu, Suiqiang

    2015-09-01

    To analyze the clinical characters, prognostic factors, patterns of relapse and treatment outcomes for medulloblastoma in adults. The clinical materials of 73 consecutive adult patients (age, ≥16 years) with medulloblastoma were analyzed retrospectively. Follow-up data were available in 62 patients, ranging from 10 to 142 months (median, 78.4 months). Outcome in survival was assessed by the progression-free survival (PFS) and overall survival (OS). Univariate and multivariate analysis were performed to determine the prognostic factors. Total or near-total tumor resection was achieved in 37 cases (59.7 %), subtotal in 19 cases (30.6 %), and partial resection in 6 cases (9.7 %).Twenty-two patients experienced recurrences, and 45 % percent of all recurrences occurred more than 4 years after initial surgery. The PFS rates at 5 and 8 years were 60.1 and 37.0 %, respectively. The OS rates at 5 and 8 years were 82.6 and 57.3 %, respectively. In univariate analysis, less tumor resection, non-desmoplastic pathology, and brainstem involvement were risk factors for worse PFS and OS (P medulloblastoma, late relapse is common and therefore long-term follow-up is important for evaluating the real impact of treatments. Risk category had prognostic value just for PFS, but not for OS. Complete resection and desmoplastic histology are independently predictive factors for favorable outcomes.

  9. 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.

  10. 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.

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

    Science.gov (United States)

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

    2016-10-19

    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.

  12. Working memory abilities among children treated for medulloblastoma: parent report and child performance.

    Science.gov (United States)

    Knight, Sarah J; Conklin, Heather M; Palmer, Shawna L; Schreiber, Jane E; Armstrong, Carol L; Wallace, Dana; Bonner, Melanie; Swain, Michelle A; Evankovich, Karen D; Mabbott, Donald J; Boyle, Robyn; Huang, Qinlei; Zhang, Hui; Anderson, Vicki A; Gajjar, Amar

    2014-06-01

    We investigated the 5-year postsurgical developmental trajectory of working memory (WM) in children with medulloblastoma using parent and performance-based measures. This study included 167 patients treated for medulloblastoma. Serial assessments of WM occurred at predetermined time points for 5 years. There was a subtle, statistically significant increase in parental concern about WM, coupled with a statistically significant decrease in age-standardized scores on performance-based measures. However, whole-group mean scores on both parent and performance-based measures remained in the age-expected range. Posterior fossa syndrome was consistently associated with poorer WM. Younger age at treatment and higher treatment intensity were associated with greater negative change in WM performance only. Most children treated for medulloblastoma display WM within the age-appropriate range according to parent report and performance. However, the subtle negative changes over time and identified subgroups at increased risk highlight the need for ongoing monitoring of this population. © The Author 2014. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  13. MicroRNA-184-mediated inhibition of tumour growth in an orthotopic murine model of neuroblastoma.

    Science.gov (United States)

    Tivnan, Amanda; Foley, Niamh H; Tracey, Lorraine; Davidoff, Andrew M; Stallings, Raymond L

    2010-11-01

    Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system. Previous studies have shown that miR-184 expression has anti-proliferative effects in neuroblastoma cells grown in culture. Therefore, it was of interest to evaluate this effect in vivo. Neuroblastoma cells overexpressing miR-184 were injected retroperitoneally into CB17-SCID mice and tumour burden was assessed by measuring bioluminescence. Overall survival was also evaluated. Ectopic overexpression of miR-184 in neuroblastoma cell lines is anti-proliferative. In addition, overexpression of miR-184 led to a significant reduction in tumour growth relative to negative control-treated cohorts in a xenograft model of neuroblastoma. This study demonstrated for the first time that miR-184 significantly reduces tumour growth and increases overall survival in an orthotopic murine model of neuroblastoma through assessment of tumour growth and moribundity relative to control miRNA-treated cohorts.

  14. Sesquiterpene lactones derived from Saussurea lappa induce apoptosis and inhibit invasion and migration in neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Keiichi Tabata

    2015-04-01

    Full Text Available Neuroblastoma is among the most fatal of solid tumors in the pediatric age group, even when treated aggressively. Therefore, a new effective therapeutic drug(s for neuroblastoma is urgently needed. To clarify the anticancer effects of the sesquiterpene lactones dehydrocostus lactone and costunolide, derived from Saussurea lappa, we examined the cytotoxic and migration/invasion-inhibitory effects of these compounds against neuroblastoma cell lines. Both the compounds exerted significant cytotoxicity against the neuroblastoma cell lines IMR-32, NB-39, SK-N-SH, and LA-N-1. Evidence of cellular apoptosis, such as nuclear condensation and membrane inversion, were observed after treatment with these compounds. Both compounds induced caspase-7 activation and PARP cleavage as confirmed by Western blotting. Furthermore, the sesquiterpene lactones also suppressed invasion and migration of the neuroblastoma cells. These results suggest that dehydrocostus lactone and costunolide are promising candidates for being developed into novel anticancer drugs effective against neuroblastoma.

  15. Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma.

    Science.gov (United States)

    Powers, John T; Tsanov, Kaloyan M; Pearson, Daniel S; Roels, Frederik; Spina, Catherine S; Ebright, Richard; Seligson, Marc; de Soysa, Yvanka; Cahan, Patrick; Theißen, Jessica; Tu, Ho-Chou; Han, Areum; Kurek, Kyle C; LaPier, Grace S; Osborne, Jihan K; Ross, Samantha J; Cesana, Marcella; Collins, James J; Berthold, Frank; Daley, George Q

    2016-07-14

    Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.

  16. miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring through the regulation of DHFR, integrins, and CD47.

    Science.gov (United States)

    Yang, Seung Yeob; Choi, Seung Ah; Lee, Ji Yeoun; Park, Ae-Kyung; Wang, Kyu-Chang; Phi, Ji Hoon; Koh, Eun Jung; Park, Woong-Yang; Park, Sung-Hye; Hwang, Do Won; Jung, Hee Won; Kim, Seung-Ki

    2015-12-22

    The main cause of death in medulloblastoma is recurrence associated with leptomeningeal dissemination. During this process, the role of microRNAs (miRs) in the acquisition of metastatic phenotype remains poorly understood. This study aimed to identify the miR involved in leptomeningeal dissemination and to elucidate its biological functional mechanisms. We analyzed the miR expression profiles of 29 medulloblastomas according to the presence of cerebrospinal fluid (CSF) seeding. Differentially expressed miRs (DEmiRs) were validated in 29 medulloblastoma tissues and three medulloblastoma cell lines. The biological functions of the selected miRs were evaluated using in vitro and in vivo studies. A total of 12 DEmiRs were identified in medulloblastoma with seeding, including miR-192. The reduced expression of miR-192 was confirmed in the tumor seeding group and in the medulloblastoma cells. Overexpression of miR-192 inhibited cellular proliferation by binding DHFR. miR-192 decreased cellular anchoring via the repression of ITGAV, ITGB1, ITGB3, and CD47. Animals in the miR-192-treated group demonstrated a reduction of spinal seeding (P Medulloblastoma with seeding showed specific DEmiRs compared with those without. miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring ability.

  17. MicroRNA 128a Increases Intracellular ROS Level by Targeting Bmi-1 and Inhibits Medulloblastoma Cancer Cell Growth by Promoting Senescence

    Science.gov (United States)

    Venkataraman, Sujatha; Alimova, Irina; Fan, Rong; Harris, Peter; Foreman, Nicholas; Vibhakar, Rajeev

    2010-01-01

    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. PMID:20574517

  18. PI3K/AKT and ERK regulate retinoic acid-induced neuroblastoma cellular differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Qiao, Jingbo [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Paul, Pritha; Lee, Sora [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Qiao, Lan; Josifi, Erlena; Tiao, Joshua R. [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Chung, Dai H., E-mail: dai.chung@vanderbilt.edu [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer Retinoic acid (RA) induces neuroblastoma cells differentiation, which is accompanied by G0/G1 cell cycle arrest. Black-Right-Pointing-Pointer RA resulted in neuroblastoma cell survival and inhibition of DNA fragmentation; this is regulated by PI3K pathway. Black-Right-Pointing-Pointer RA activates PI3K and ERK1/2 pathway; PI3K pathway mediates RA-induced neuroblastoma cell differentiation. Black-Right-Pointing-Pointer Upregulation of p21 is necessary for RA-induced neuroblastoma cell differentiation. -- Abstract: Neuroblastoma, the most common extra-cranial solid tumor in infants and children, is characterized by a high rate of spontaneous remissions in infancy. Retinoic acid (RA) has been known to induce neuroblastoma differentiation; however, the molecular mechanisms and signaling pathways that are responsible for RA-mediated neuroblastoma cell differentiation remain unclear. Here, we sought to determine the cell signaling processes involved in RA-induced cellular differentiation. Upon RA administration, human neuroblastoma cell lines, SK-N-SH and BE(2)-C, demonstrated neurite extensions, which is an indicator of neuronal cell differentiation. Moreover, cell cycle arrest occurred in G1/G0 phase. The protein levels of cyclin-dependent kinase inhibitors, p21 and p27{sup Kip}, which inhibit cell proliferation by blocking cell cycle progression at G1/S phase, increased after RA treatment. Interestingly, RA promoted cell survival during the differentiation process, hence suggesting a potential mechanism for neuroblastoma resistance to RA therapy. Importantly, we found that the PI3K/AKT pathway is required for RA-induced neuroblastoma cell differentiation. Our results elucidated the molecular mechanism of RA-induced neuroblastoma cellular differentiation, which may be important for developing novel therapeutic strategy against poorly differentiated neuroblastoma.

  19. Adult Neuroblastoma Complicated by Increased Intracranial Pressure: A Case Report and Review of the Literature

    OpenAIRE

    Stevens, Patrick L.; Johnson, Douglas B.; Thompson, Mary Ann; Keedy, Vicki L.; Frangoul, Haydar A.; Snyder, Kristen M.

    2014-01-01

    Neuroblastoma is the third most commonly occurring malignancy of the pediatric population, although it is extremely rare in the adult population. In adults, neuroblastoma is often metastatic and portends an extremely poor overall survival. Our case report documents metastatic neuroblastoma occurring in a healthy 29-year-old woman whose course was complicated by an unusual presentation of elevated intracranial pressures. The patient was treated with systemic chemotherapy, I131 metaiodobenzylgu...

  20. Association of congenital neuroblastoma and congenital heart disease. Is there a common embryologic basis

    Energy Technology Data Exchange (ETDEWEB)

    Bellah, R.; D' Andrea, A.; Darillis, E.; Fellows, K.E.

    1989-01-01

    Several authors have reported an association between neuroblastoma and congenital heart disease; others contend that, unlike specific wellknown associations between malignancy and congenital defects (Wilm's tumor and aniridia, leukemia and Down's syndrome), no real relationship exists. We present three cases of cyanotic congenital heart disease in which subclinical neuroblastoma was found. We speculate that abnormal neural crest cell migration and development may be a common link between cardiac malformations and congenital neuroblastoma.

  1. Nifurtimox Induces Apoptosis of Neuroblastoma Cells in vitro and in vivo

    OpenAIRE

    Sholler, Giselle L Saulnier; Brard, Laurent; Straub, Jennifer A; Dorf, Lee; Illyene, Sharon; Koto, Karen; Kalkunte, Satyan; Bosenberg, Marcus; Ashikaga, Taka; Nishi, Rae

    2009-01-01

    Neuroblastoma is the most common extracranial solid tumor in children and, when disseminated, carries a poor prognosis. Even with aggressive combinations of chemotherapy, surgery, autologous bone marrow transplant and radiation, long-term survival remains at 30% and new therapies are needed. Recently, a patient with neuroblastoma who acquired Chagas disease was treated with nifurtimox with subsequent reduction in tumor size. The effect of nifurtimox on the neuroblastoma cell lines CHLA-90, LA...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2008-11-15

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

  3. Head injury, diagnostic X-rays, and risk of medulloblastoma and primitive neuroectodermal tumor: a Children's Oncology Group study.

    Science.gov (United States)

    Khan, Saira; Evans, Alison A; Rorke-Adams, Lucy; Orjuela, Manuela A; Shiminski-Maher, Tania; Bunin, Greta R

    2010-07-01

    A comprehensive case-control study was conducted to determine potential risk factors for medulloblastoma/primitive neuroectodermal tumor (PNET), a common brain tumor in children. This analysis evaluated possible associations between previous head injury and ionizing radiation exposure through diagnostic X-rays and medulloblastoma/PNET. Mothers of 318 cases head injury (OR: 0.78, 95% CI: 0.40-1.5) or head X-ray for any reason including head injury with medulloblastoma/PNET. A statistically non-significant excess of cases reported having an X-ray for reason other than head injury (OR 2.3, 95% CI 0.91-5.7). When cases that received an X-ray for a common symptom of medulloblastoma/PNET were considered unexposed this association weakened (OR: 1.3, 95% CI: 0.49-3.7). No dose-response relationship was observed. Head injury and exposure to diagnostic head X-rays were not associated with medulloblastoma/PNET in this study. Future studies should investigate all imaging procedures with ionizing radiation exposure including computed tomography scans and utilize radiation dose estimations.

  4. Sodium valproate does not augment Prpsc in murine neuroblastoma cells.

    Science.gov (United States)

    Legendre, C; Casagrande, F; Andrieu, T; Dormont, D; Clayette, P

    2007-10-01

    Sodium valproate (VPA) has been reported to increase the accumulation of the pathologic isoform of prion protein (PrPsc) in scrapie-infected murine neuroblastoma cells. In this study, the effect of VPA on PrPsc accumulation was investigated in murine N2a neuroblastoma cells chronically infected with scrapie strain 22L (N2a-22L). No accumulation of PrPsc was detected after short-term (3 days) or long-term (21 days) treatment of N2a-22L cells with 4.8, 12, 18 or 24 microM VPA. Higher VPA concentrations (240 and 600 microM) also failed to augment PrPsc expression. In conclusion, in our experimental conditions, no deleterious effect was induced by VPA on prions replication.

  5. Of mice and men: olfactory neuroblastoma among animals and humans.

    Science.gov (United States)

    Lubojemska, A; Borejko, M; Czapiewski, P; Dziadziuszko, R; Biernat, W

    2016-09-01

    Olfactory neuroblastoma (ONB) is a rare tumour of nasal cavity and paranasal sinuses that arises from the olfactory neuroepithelium and has unpredictable clinical course. As the sense of smell is phylogenetically one of the first senses and olfactory neuroepithelium is evolutionary conserved with striking similarities among different species, we performed an extensive analysis of the literature in order to evaluate the similarities and differences between animals and humans on the clinical, morphological, immunohistochemical, ultrastructural and molecular level. Our analysis revealed that ONB was reported mainly in mammals and showed striking similarities to human ONB. These observations provide rationale for introduction of therapy modalities used in humans into the veterinary medicine. Animal models of neuroblastoma should be considered for the preclinical studies evaluating novel therapies for ONB. © 2014 John Wiley & Sons Ltd.

  6. Adrenocorticotropic hormone in the aetiology and regression of neuroblastoma.

    Science.gov (United States)

    Tucker, Graeme R

    2002-08-01

    Neuroblastoma is predominantly a paediatric neoplasm of the sympathetic nervous system. Despite the aggressive nature of the disease, spontaneous regression is frequently observed in infants diagnosed under the age of 12 months; especially with a specific stage referred to as stage 4s. Discovering the conditions, the elements, the mechanism and the indices behind this regression phenomenon could have therapeutic potential for prevention and cure. A review of the literature has implicated adrenocorticotropin hormone in both the aetiology and spontaneous regression of neuroblastoma. Manipulation of adrenocorticotropin hormone may offer hope for prevention and cure. Ingestible products such as retinoic acid, glycyrrhizic acid, salsolinol and ketoconazole acting in concert, could represent instrumental tools in a therapeutic manipulation process.

  7. Immunoproteomic studies on paediatric opsoclonus-myoclonus associated with neuroblastoma.

    Science.gov (United States)

    Torres-Vega, Estefanía; Durán-Moreno, María; Sánchez Del Pino, Manuel; Yáñez, Yania; Cañete, Adela; Castel, Victoria; López-Cuevas, Rogelio; Vílchez, Juan Jesús; Dalmau, Josep; Graus, Francesc; García Verdugo, José Manuel; Bataller, Luis

    2016-08-15

    We aimed to identify new cell-membrane antigens implicated in opsoclonus-myoclonus with neuroblastoma. The sera of 3 out of 14 patients showed IgG electron-microscopy immunogold reactivity on SH-SY5Y neuroblastoma cells. Immunoprecipitation experiments using rat brain synaptosomes and SH-SY5Y cells led to the identification of: (1) thirty-one nuclear/cytoplasmic proteins (including antigens HuB, HuC); (2) seven neuronal membrane proteins, including the Shaw-potassium channel Kv3.3 (KCNC3), whose genetic disruption in mice causes ataxia and generalized muscle twitching. Although cell-based assays did not demonstrate direct antigenicity, our findings point to Shaw-related subfamily of the potassium voltage-gated channels complexed proteins as hypothetical antigenic targets. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor.

    Directory of Open Access Journals (Sweden)

    Barbara Hämmerle

    Full Text Available Neuroblastma cell lines contain a side-population of cells which express stemness markers. These stem-like cells may represent the potential underlying mechanism for resistance to conventional therapy and recurrence of neuroblastoma in patients.To develop novel strategies for targeting the side-population of neurobastomas, we analyzed the effects of 13-cis-retinoic acid (RA combined with the proteasome inhibitor MG132. The short-term action of the treatment was compared with effects after a 5-day recovery period during which both chemicals were withdrawn. RA induced growth arrest and differentiation of SH-SY5Y and SK-N-BE(2 neuroblastoma cell lines. Inhibition of the proteasome caused apoptosis in both cell lines, thus, revealing the critical role of this pathway in the regulated degradation of proteins involved in neuroblastoma proliferation and survival. The combination of RA with MG132 induced apoptosis in a dose-dependent manner, in addition to promoting G2/M arrest in treated cultures. Interestingly, expression of stem cell markers such as Nestin, Sox2, and Oct4 were reduced after the recovery period of combined treatment as compared with untreated cells or treated cells with either compound alone. Consistent with this, neurosphere formation was significantly impaired by the combined treatment of RA and MG132.Given that stem-like cells are associated with resistant to conventional therapy and are thought to be responsible for relapse, our results suggest that dual therapy of RA and proteasome inhibitor might be beneficial for targeting the side-population of cells associated residual disease in high-risk neuroblastoma.

  9. Disseminated peripheral neuroblastoma in a Rhodesian Ridgeback dog.

    Science.gov (United States)

    Cook, R W; Abraham, L A; McCowan, C I

    2017-04-01

    A 4-year-old neutered male Rhodesian Ridgeback dog with right-sided Horner's syndrome, bilateral laryngeal paralysis, neck pain and bilateral hindlimb ataxia was euthanased following deterioration of its neurological status. Necropsy examination revealed an off-white retropharyngeal neoplastic mass (100 × 30 × 30 mm) attached to the base of the skull on the right side and macroscopic nodular metastases in the spleen and three vertebral bodies (C6, C7 and T6), including a nodule attached to the dura at C7. Histological evidence of neuroblastic tumour was detected in these macroscopic lesions, a regional lymph node, bone marrow of a femur and all 15 vertebral bodies (C1-T8) examined, including the three with macroscopic metastases, and in the lumens of small blood vessels in the lungs and liver. Ganglion cell differentiation was detected only in the primary retropharyngeal mass, one splenic nodule and the C7 dural nodule. Neoplastic cells were immunoreactive to neurofilament protein (ganglion cells only), vimentin and synaptophysin, and were negative for S100 protein, GFAP, CD3 and Pax5. The diagnosis was disseminated peripheral neuroblastoma, differentiating subtype (International Neuroblastoma Pathology Classification), with likely primary involvement of the right cranial cervical ganglion. This appears to be the first report of neuroblastoma in a dog with widespread occult haematogenous metastasis to bone marrow. © 2017 Australian Veterinary Association.

  10. Intrarenal neuroblastoma - a diagnostic dilemma: A report of three cases

    Directory of Open Access Journals (Sweden)

    Anupam Lall

    2001-01-01

    Full Text Available Differentiation between the Wilms′ tumor (WT and the intrarenal neuroblastoma (IRNB is imperative, as the prognosis and the treatment are different for these condi-tions. It may pose a diagnostic challenge to distinguish them pre-operatively. Over the period of last 10 years (1990-1999, 3 children aged 2 months to 4 years were diagnosed to have IRNB. 2 cases were operated with a provisional diagnosis of WT, but on histology were found to have neuroblastoma. Taking benefit from our previous experience, the third case we encountered with a renal lump and bony metastasis with clinical features not con-sistent with the diagnosis of Wilms′ tumor was further investigated. Urinary catecholamines were significantly elevated and there was bone marrow involvement and positive bone scan for multiple bony metastasis. 2 pa-tients are on chemotherapy and follow-up for last 6 months, while 1 died 6 years back after a follow-up of 2 years. Patients who have a renal mass on imaging, with clinical features of rapid deterioration in general condi-tion and evidence of bony secondaries, should undergo work-up for neuroblastoma pre-operatively to confirm the diagnosis.

  11. Nuclear medicine and multimodality imaging of pediatric neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Wolfgang Peter; Pfluger, Thomas [Ludwig-Maximilians-University of Munich, Department of Nuclear Medicine, Munich (Germany); Coppenrath, Eva [Ludwig-Maximilians-University of Munich, Department of Radiology, Munich (Germany)

    2013-04-15

    Neuroblastoma is an embryonic tumor of the peripheral sympathetic nervous system and is metastatic or high risk for relapse in nearly 50% of cases. Therefore, exact staging with radiological and nuclear medicine imaging methods is crucial for defining the adequate therapeutic choice. Tumor cells express the norepinephrine transporter, which makes metaiodobenzylguanidine (MIBG), an analogue of norepinephrine, an ideal tumor specific agent for imaging. MIBG imaging has several disadvantages, such as limited spatial resolution, limited sensitivity in small lesions and the need for two or even more acquisition sessions. Most of these limitations can be overcome with positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose [FDG]. Furthermore, new tracers, such as fluorodopa or somatostatin receptor agonists, have been tested for imaging neuroblastoma recently. However, MIBG scintigraphy and PET alone are not sufficient for operative or biopsy planning. In this regard, a combination with morphological imaging is indispensable. This article will discuss strategies for primary and follow-up diagnosis in neuroblastoma using different nuclear medicine and radiological imaging methods as well as multimodality imaging. (orig.)

  12. BIRICODAR (VX-710; Incel): an effective chemosensitizer in neuroblastoma.

    Science.gov (United States)

    Yanagisawa, T; Newman, A; Coley, H; Renshaw, J; Pinkerton, C R; Pritchard-Jones, K

    1999-06-01

    Clinical studies have suggested that both MDR1 and MRP may play a significant role in the chemosensitivity and outcome of neuroblastoma. To clarify the nature of multidrug resistance (MDR) in this tumour a series of six neuroblastoma cell lines have been characterized with regard to P-glycoprotein, MRP and LRP expression using immunocytochemistry and expression of MDR1, MRP, LRP and topoisomerase II genes using reverse transcription polymerase chain reaction (RT-PCR). By RT-PCR, all lines expressed MRP, five expressed LRP and four expressed MDR1, but protein levels of each of these were variable. Chemosensitization to a range of MDR-associated drugs (vincristine, doxorubicin, etoposide, taxotere, topotecan) and non-MDR-associated drugs (cisplatin, melphalan) by three modulating agents, cyclosporin A, PSC 833 and the novel Biricodar (VX-710; Incel), was evaluated using a colourimetric cytotoxicity assay (MTS). Alteration of daunorubicin efflux by these agents was evaluated using FACS analysis. Clonogenic assay was used to study the influence of these chemosensitizers on vincristine cytotoxicity. Marked sensitization to vincristine was observed in MDR1-positive lines, and a similar but less consistent effect was seen with taxotere, doxorubicin and etoposide. With MRP-positive, MDR-negative lines, only VX-710 caused consistent sensitization. These data confirm MDR1 and MRP expression as contributory factors in chemoresistance in neuroblastoma and indicate that VX-710 may be a useful modulator of both mechanisms and worthy of clinical evaluation in this tumour.

  13. The comparison of grey-scale ultrasonic and clinical features of hepatoblastoma and hepatocellular carcinoma in children: a retrospective study for ten years

    Directory of Open Access Journals (Sweden)

    Luo Yan

    2011-06-01

    Full Text Available Abstract Background Hepatoblastoma (HBL and hepatocellular carcinoma (HCC are respectively the first and the second most common pediatric malignant liver tumors. The purpose of this study was to evaluate the combined use of the ultrasound examination and the assessment of the patients' clinical features for differentiating HBL from HCC in children. Methods Thirty cases of the confirmed HBL and 12 cases of the confirmed HCC in children under the age of 15 years were enrolled into our study. They were divided into the HBL group and the HCC group according to the histological types of the tumors. The ultrasonic features and the clinical manifestations of the two groups were retrospectively analyzed, with an emphasis on the following parameters: onset age, gender (male/female ratio, positive epatitis-B-surface-antigen (HBV, alpha-fetoprotein increase, and echo features including septa, calcification and liquefaction within the tumors. Results Compared with the children with HCC, the children with HBL had a significantly younger onset age (8.2 years vs. 3.9 years, P Conclusion Ultrasonic features combined with clinical manifestations are valuable for differentiating HBL from HCC in children.

  14. Effective Strategy of the Combination of High-Intensity Focused Ultrasound and Transarterial Chemoembolization for Improving Outcome of Unresectable and Metastatic Hepatoblastoma: a Retrospective Cohort Study

    Directory of Open Access Journals (Sweden)

    Bailin Chen

    2014-12-01

    Full Text Available The combination of high-intensity focused ultrasound (HIFU and transarterial chemoembolization (TACE has been experimentally performed in a variety of malignant tumors, and its validity has not yet been evaluated for hepatoblastoma (HB. We evaluated the disease-response rate, resection rate, and toxicity in children with unresectable or metastatic HB (stage III and stage IV HB after sequential treatment with TACE plus HIFU in a controlled clinical trial. The 35 patients with unresectable or metastatic HB were nonrandomly assigned to HIFU ablation (n = 12 or C5V chemotherapy (n = 23. The rates of complete resection, tumor response, and treatment toxicity were evaluated for both regimens. Nine patients who received C5V and 10 patients who received TACE plus HIFU became operable (P = .02. The 3-year event-free survival and overall survival rates were 43.03% and 56.68% in the C5V group and 38.57% and 57.86% in the TACE plus HIFU group, respectively. Acute grade 3 or 4 adverse events, including neutropenia, thrombocytopenia, and anemia, were more frequent in patients treated with C5V therapy than in patients receiving TACE plus HIFU. HIFU ablation achieved a higher rate of complete resection and a lower rate of severe complications compared with C5V treatment in children with advanced HB (Chinese Clinical Trials Registry No. ChiCTR-PRCH-08000182.

  15. Patterns of hepatoblastoma and hepatocellular carcinoma in children after universal hepatitis B vaccination in taiwan: a report from a single institution in southern Taiwan.

    Science.gov (United States)

    Hsiao, Chih-Cheng; Chuang, Jiin-Haur; Tiao, Mao-Ming; Sheen, Jiunn-Ming; Shieh, Chie-Song

    2009-02-01

    To retrospectively evaluate clinical features, treatment, and outcome of patients with hepatoblastoma (HB) and hepatocellular carcinoma (HCC). From January 1994 to December 2007, 16 patients of HB and 13 cases of HCC were reviewed. The mean age of HB patients was much younger than HCC patients (1.2 vs. 11.5 y). There was an 84.6% positive rate for hepatitis B surface antigen in HCC, but none for HB. Mean serum alpha-fetoprotein level was higher with HCC (654,158 ng/mL) than the HB patients (352,843 ng/mL), especially higher in HCC with lung metastasis. Among the HB patients, 12 (75%) had thrombocytosis and 6 (37.5%) had microcytic anemia with high or normal ferritin, whereas only 3 of 13 with HCC (23.1%) had thrombocytosis and none had microcytic anemia. All HBs were resectable either before or after chemotherapy, but only 4 (30.8%) HCCs were resectable. Five-year disease-free survival rate was significantly higher in HB (87%) than in HCC (30%, Pthrombocytosis, anemia, alpha-fetoprotein levels are important factors associated with difference in long-term outcomes in children with HB and HCC.

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

    Directory of Open Access Journals (Sweden)

    Giuseppe Privitera

    2009-01-01

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

  17. Identification of membrane-type 1 matrix metalloproteinase tyrosine phosphorylation in association with neuroblastoma progression

    Directory of Open Access Journals (Sweden)

    Gingras Denis

    2009-12-01

    Full Text Available Abstract Background Neuroblastoma is a pediatric tumor of neural crest cells that is clinically characterized by its variable evolution, from spontaneous regression to malignancy. Despite many advances in neuroblastoma research, 60% of neuroblastoma, which are essentially metastatic cases, are associated with poor clinical outcome due to the lack of effectiveness of current therapeutic strategies. Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14, an enzyme involved in several steps in tumor progression, has previously been shown to be associated with poor clinical outcome for neuroblastoma. Based on our recent demonstration that MT1-MMP phosphorylation is involved in the growth of fibrosarcoma tumors, we examined the potential role of phosphorylated MT1-MMP in neuroblastoma progression. Methods Tyrosine phosphorylated MT1-MMP was immunostained on tissue microarray samples from 55 patients with neuroblastoma detected by mass screening (known to be predominantly associated with favourable outcome, and from 234 patients with standard diagnosed neuroblastoma. In addition, the effects of a non phosphorylable version of MT1-MMP on neuroblastoma cell migration and proliferation were investigated within three-dimensional collagen matrices. Results Although there is no correlation between the extent of tyrosine phosphorylation of MT1-MMP (pMT1-MMP and MYCN amplification or clinical stage, we observed greater phosphorylation of pMT1-MMP in standard neuroblastoma, while it is less evident in neuroblastoma from mass screening samples (P = 0.0006 or in neuroblastoma samples from patients younger than one year (P = 0.0002. In vitro experiments showed that overexpression of a non-phosphorylable version of MT1-MMP reduced MT1-MMP-mediated neuroblastoma cell migration and proliferation within a three-dimensional type I collagen matrix, suggesting a role for the phosphorylated enzyme in the invasive properties of neuroblastoma cells. Conclusion Overall

  18. Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas.

    Science.gov (United States)

    Ikegaki, Naohiko; Shimada, Hiroyuki; Fox, Autumn M; Regan, Paul L; Jacobs, Joshua R; Hicks, Sakeenah L; Rappaport, Eric F; Tang, Xao X

    2013-04-09

    Cancer stem cells (CSCs) are plastic in nature, a characteristic that hampers cancer therapeutics. Neuroblastoma (NB) is a pediatric tumor of neural crest origin, and half of the cases are highly aggressive. By treating NB cell lines [SKNAS, SKNBE(2)C, CHP134, and SY5Y] with epigenetic modifiers for a short time, followed by sphere-forming culture conditions, we have established stem cell-like NB cells that are phenotypically stable for more than a year. These cells are characterized by their high expression of stemness factors, stem cell markers, and open chromatin structure. We referred to these cells as induced CSCs (iCSCs). SKNAS iCSC and SKNBE(2)C iCSC clones (as few as 100 cells) injected s.c. into SCID/Beige mice formed tumors, and in one case, SKNBE(2)C iCSCs metastasized to the adrenal gland, suggesting their increased metastatic potential. SKNAS iCSC xenografts showed the histologic appearance of totally undifferentiated large-cell NBs (LCNs), the most aggressive and deadly form of NB in humans. Immunohistochemical analyses showed that SKNAS iCSC xenografts expressed high levels of the stem cell marker CXCR4, whereas the SKNAS monolayer cell xenografts did not. The patterns of CXCR4 and MYC expression in SKNAS iCSC xenografts resembled those in the LCNs. The xenografts established from the NB iCSCs shared two common features: the LCN phenotype and high-level MYC/MYCN expression. These observations suggest both that NB cells with large and vesicular nuclei, representing their open chromatin structure, are indicative of stem cell-like tumor cells and that epigenetic changes may have contributed to the development of these most malignant NB cells.

  19. Synthesis of New Quinoxalines Containing an Oxirane Ring by the TDAE Strategy and in Vitro Evaluation in Neuroblastoma Cell Lines

    Directory of Open Access Journals (Sweden)

    Marc Montana

    2014-09-01

    Full Text Available Neuroblastoma is an aggressive pediatric malignancy with significant chemotherapeutic resistance. In order to obtain new compounds active on neuroblastoma cell lines, we investigated the reactivity of carbanion formed via TDAE in quinoxaline series. The new synthesized compounds were tested for their anti-proliferative activity on two neuroblastoma cell lines, and seven oxirane derivatives obtained interesting activities.

  20. Targeting gastrin-releasing peptide suppresses neuroblastoma progression via upregulation of PTEN signaling.

    Directory of Open Access Journals (Sweden)

    Pritha Paul

    Full Text Available We have previously demonstrated the role of gastrin-releasing peptide (GRP as an autocrine growth factor for neuroblastoma. Here, we report that GRP silencing regulates cell signaling involved in the invasion-metastasis cascade. Using a doxycycline inducible system, we demonstrate that GRP silencing decreased anchorage-independent growth, inhibited migration and neuroblastoma cell-mediated angiogenesis in vitro, and suppressed metastasis in vivo. Targeted inhibition of GRP decreased the mRNA levels of oncogenes responsible for neuroblastoma progression. We also identified PTEN/AKT signaling as a key mediator of the tumorigenic properties of GRP in neuroblastoma cells. Interestingly, PTEN overexpression decreased GRP-mediated migration and angiogenesis; a novel role for this, otherwise, understated tumor suppressor in neuroblastoma. Furthermore, activation of AKT (pAKT positively correlated with neuroblastoma progression in an in vivo tumor-metastasis model. PTEN expression was slightly decreased in metastatic lesions. A similar phenomenon was observed in human neuroblastoma sections, where, early-stage localized tumors had a higher PTEN expression relative to pAKT; however, an inverse expression pattern was observed in liver lesions. Taken together, our results argue for a dual purpose of targeting GRP in neuroblastoma--1 decreasing expression of critical oncogenes involved in tumor progression, and 2 enhancing activation of tumor suppressor genes to treat aggressive, advanced-stage disease.

  1. TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells

    NARCIS (Netherlands)

    Boes, Marianne; Meyer-Wentrup, Friederike

    2015-01-01

    Neuroblastoma is the most common extracranial solid tumor in children, causing 12% of all pediatric cancer mortality. Neuroblastoma specific T-cells have been detected in patients, but usually fail to attack and eradicate the tumors. Tumor immune evasion may thus play an important role in

  2. LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis

    NARCIS (Netherlands)

    Zhu, S.; Zhang, X.; Weichert-Leahey, N.; Dong, Z.; Zhang, C.; Lopez, G.; Tao, T.; He, S.; Wood, A.C.; Oldridge, D.; Ung, C.Y.; Ree, J.H. van; Khan, A.; Salazar, B.M.; Rocha, E.L. da; Zimmerman, M.W.; Guo, F.; Cao, H.; Hou, X.; Weroha, S.J.; Perez-Atayde, A.R.; Neuberg, D.S.; Meves, A.; McNiven, M.A.; Deursen, J.M.A. van; Li, H.; Maris, J.M.; Look, A.T.

    2017-01-01

    A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dbetah promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN

  3. Synergistic interaction between cisplatin and gemcitabine in neuroblastoma cell lines and multicellular tumor spheroids

    NARCIS (Netherlands)

    Besançon, Odette G.; Tytgat, Godelieve A. M.; Meinsma, Rutger; Leen, René; Hoebink, Jerry; Kalayda, Ganna V.; Jaehde, Ulrich; Caron, Huib N.; van Kuilenburg, André B. P.

    2012-01-01

    The efficacy and mechanism of action of cisplatin and gemcitabine were investigated in a panel of neuroblastoma cell lines and multicellular tumor spheroids. In neuroblastoma spheroids, the combination of cisplatin and gemcitabine induced a complete cytostasis at clinical relevant concentrations. A

  4. Neuroblastoma in a boy with MCA/MR syndrome, deletion 11q, and duplication 12q.

    Science.gov (United States)

    Koiffmann, C P; Gonzalez, C H; Vianna-Morgante, A M; Kim, C A; Odone-Filho, V; Wajntal, A

    1995-07-31

    Deletion 11q23-->qter and duplication 12q23-->qter are described in a boy with neuroblastoma, multiple congenital anomalies, and mental retardation. The patient has clinical manifestations of 11q deletion and 12q duplication syndromes. The possible involvement of the segment 11q23-->24 in the cause of the neuroblastoma is discussed.

  5. Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines

    NARCIS (Netherlands)

    Michaelis, Martin; Kleinschmidt, Malte C.; Barth, Susanne; Rothweiler, Florian; Geiler, Janina; Breitling, Rainer; Mayer, Bernd; Deubzer, Hedwig; Witte, Olaf; Kreuter, Joerg; Doerr, Hans Wilhelm; Cinatl, Jaroslav; Cinatl, Jindrich; Witt, Olaf; Cinatl Jr., Jindrich

    2010-01-01

    Artemisinin derivatives are well-tolerated anti-malaria drugs that also exert anti-cancer activity. Here, we investigated artemisinin and its derivatives dihydroartemisinin and artesunate in a panel of chemosensitive and chemoresistant human neuroblastoma cells as well as in primary neuroblastoma

  6. Scrotal hematoma, anemia, and jaundice as manifestations of adrenal neuroblastoma in a newborn

    NARCIS (Netherlands)

    Kreeftenberg, HG; Zeebregts, CJAM; Tamminga, RYJ; de Langen, ZJ; Zijlstra, RJ

    1999-01-01

    Clinically, a neuroblastoma presents mostly as an abdominal mass. Within the tumor, bleeding can be present, sometimes extending in to its surroundings. This case report describes a neuroblastoma, presenting as scrotal hematoma in a newborn boy, which initially raised the suspicion of a torsio

  7. Birth and parental characteristics and risk of neuroblastoma in a population-based Norwegian cohort study

    OpenAIRE

    Bj?rge, T; Engeland, A; S. Tretli; Heuch, I.

    2008-01-01

    In this population-based Norwegian cohort study (2.1 million children), the impact of birth and parental characteristics on the risk of neuroblastoma (178 cases) was evaluated. In children below the age of 18 months, there was an increased neuroblastoma risk among those with congenital malformations and suggestion of increased risk when the mother had pre-eclampsia.

  8. N-myc down regulates neural cell adhesion molecule expression in rat neuroblastoma

    NARCIS (Netherlands)

    Akeson, R.; Bernards, R.A.

    1990-01-01

    In human neuroblastoma, amplification of the N-myc oncogene is correlated with increased metastatic ability. We recently showed that transfection of the rat neuroblastoma cell line B104 with an N-myc expression vector resulted in an increase in metastatic ability and a significant reduction in the

  9. Olfactory Neuroblastoma (ONB) in a 2 year old child: A case Report ...

    African Journals Online (AJOL)

    A case of olfactory neuroblastoma (ONB) presenting in a 2 year old girl as a nasal mass is presented. Although olfactory neuroblastomas have been reported from various parts of the world, this, to our knowledge is the first report from Midwestern Nigeria. We wish to emphasize the importance of histological examination of ...

  10. In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy

    Science.gov (United States)

    Holst, Martin I.; Pietsch, Thorsten; Dilloo, Dagmar

    2014-01-01

    Regardless of the recent advances in cytotoxic therapies, 30% of children diagnosed with medulloblastoma. succumb to the disease. Therefore, novel therapeutic approaches are warranted. Here we demonstrate that Pazopanib a clinically approved multi-kinase angiogenesis inhibitor (MKI) inhibits proliferation and apoptosis in medulloblastoma cell lines. Moreover, Pazopanib profoundly attenuates medulloblastoma cell migration, a prerequisite for tumor invasion and metastasis. In keeping with the observed anti-neoplastic activity of Pazopanib, we also delineate reduced phosphorylation of the STAT3 protein, a key regulator of medulloblastoma proliferation and cell survival. Finally, we document profound in vivo activity of Pazopanib in an orthotopic mouse model of the most aggressive c-myc amplified human medulloblastoma variant. Pazopanib reduced the growth rate of intracranial growing medulloblastoma and significantly prolonged the survival. Furthermore, to put these results into a broader perspective we analysed Pazopanib side by side with the MKI Sorafenib. Both compounds share a similar target profile but display different pharmacodynamics and pharmacokinetics with distinct cytotoxic activity in different tumor entities. Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy. PMID:25216529

  11. Functional MRI in medulloblastoma survivors supports prophylactic reading intervention during tumor treatment.

    Science.gov (United States)

    Zou, Ping; Conklin, Heather M; Scoggins, Matthew A; Li, Yimei; Li, Xingyu; Jones, Melissa M; Palmer, Shawna L; Gajjar, Amar; Ogg, Robert J

    2016-03-01

    Development of reading skills is vulnerable to disruption in children treated for brain tumors. Interventions, remedial and prophylactic, are needed to mitigate reading and other learning difficulties faced by survivors. A functional magnetic resonance imaging (fMRI) study was conducted to investigate long-term effects of a prophylactic reading intervention administered during radiation therapy in children treated for medulloblastoma. The fMRI study included 19 reading-intervention (age 11.7 ± 0.6 years) and 21 standard-of-care (age 12.1 ± 0.6 years) medulloblastoma survivors, and 21 typically developing children (age 12.3 ± 0.6 years). The survivors were 2.5 [1.2, 5.4] years after completion of tumor therapies and reading-intervention survivors were 2.9 [1.6, 5.9] years after intervention. Five fMRI tasks (Rapid Automatized Naming, Continuous Performance Test using faces and letters, orthographic and phonological processing of letter pairs, implicit word reading, and story reading) were used to probe reading-related neural activation. Woodcock-Johnson Reading Fluency, Word Attack, and Sound Awareness subtests were used to evaluate reading abilities. At the time of fMRI, Sound Awareness scores were significantly higher in the reading-intervention group than in the standard-of-care group (p = 0.046). Brain activation during the fMRI tasks was detected in left inferior frontal, temporal, ventral occipitotemporal, and subcortical regions, and differed among the groups (p reading-intervention group. Standardized reading scores and patterns of brain activation provide evidence of long-term effects of prophylactic reading intervention in children treated for medulloblastoma.

  12. PI-3K Inhibitors Preferentially Target CD15+ Cancer Stem Cell Population in SHH Driven Medulloblastoma.

    Directory of Open Access Journals (Sweden)

    Alok R Singh

    Full Text Available Sonic hedgehog (SHH medulloblastoma (MB subtype is driven by a proliferative CD15+ tumor propagating cell (TPC, also considered in the literature as a putative cancer stem cell (CSC. Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN and phosphoinositide 3-kinase (PI-3K play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs, we demonstrate that the CD15+TPCs are 1 obligately required for SmoA1Tg-driven tumorigenicity 2 regulated by PTEN and PI-3K signaling 3 selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4 in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.

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

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Aaron P. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Barney, Christian L. [Baylor College of Medicine, Houston, Texas (United States); Grosshans, David R.; McAleer, Mary Frances [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Groot, John F. de; Puduvalli, Vinay K. [Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Tucker, Susan L. [Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Crawford, Cody N.; Khan, Meena [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Khatua, Soumen [Department of Pediatric Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Gilbert, Mark R. [Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Brown, Paul D. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mahajan, Anita, E-mail: amahajan@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-06-01

    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.

  14. Vulnerability of white matter to insult during childhood: evidence from patients treated for medulloblastoma.

    Science.gov (United States)

    Moxon-Emre, Iska; Bouffet, Eric; Taylor, Michael D; Laperriere, Normand; Sharpe, Michael B; Laughlin, Suzanne; Bartels, Ute; Scantlebury, Nadia; Law, Nicole; Malkin, David; Skocic, Jovanka; Richard, Logan; Mabbott, Donald J

    2016-07-01

    OBJECTIVE Craniospinal irradiation damages the white matter in children treated for medulloblastoma, but the treatment-intensity effects are unclear. In a cross-sectional retrospective study, the effects of treatment with the least intensive radiation protocol versus protocols that delivered more radiation to the brain, in addition to the effects of continuous radiation dose, on white matter architecture were evaluated. METHODS Diffusion tensor imaging was used to assess fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. First, regional white matter analyses and tract-based spatial statistics were conducted in 34 medulloblastoma patients and 38 healthy controls. Patients were stratified according to those treated with 1) the least intensive radiation protocol, specifically reduced-dose craniospinal irradiation plus a boost to the tumor bed only (n = 17), or 2) any other dose and boost combination that delivered more radiation to the brain, which was also termed the "all-other-treatments" group (n = 17), and comprised patients treated with standard-dose craniospinal irradiation plus a posterior fossa boost, standard-dose craniospinal irradiation plus a tumor bed boost, or reduced-dose craniospinal irradiation plus a posterior fossa boost. Second, voxel-wise dose-distribution analyses were conducted on a separate cohort of medulloblastoma patients (n = 15). RESULTS The all-other-treatments group, but not the reduced-dose craniospinal irradiation plus tumor bed group, had lower fractional anisotropy and higher radial diffusivity than controls in all brain regions (all p 0.05). CONCLUSIONS Together, the results show that white matter damage has a clear association with increasing radiation dose, and that treatment with reduced-dose craniospinal irradiation plus tumor bed boost appears to preserve white matter in some brain regions.

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

    Science.gov (United States)

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

    2016-02-01

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

  16. PI-3K Inhibitors Preferentially Target CD15+ Cancer Stem Cell Population in SHH Driven Medulloblastoma.

    Science.gov (United States)

    Singh, Alok R; Joshi, Shweta; Zulcic, Muamera; Alcaraz, Michael; Garlich, Joseph R; Morales, Guillermo A; Cho, Yoon J; Bao, Lei; Levy, Michael L; Newbury, Robert; Malicki, Denise; Messer, Karen; Crawford, John; Durden, Donald L

    2016-01-01

    Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.

  17. Involvement of Wnt signaling pathway in murine medulloblastoma induced by human neurotropic JC virus.

    Science.gov (United States)

    Gan, D D; Reiss, K; Carrill, T; Del Valle, L; Croul, S; Giordano, A; Fishman, P; Khalili, K

    2001-08-09

    By using the early genome of the human neurotropic polyomavirus, JCV, we have created transgenic animals that develop cerebellar primitive neuroectodermal tumors which model human medulloblastoma. Expression of T-antigen was found in some, but not all, tumor cells, and examination of the clonal cell lines derived from the tumor population showed enhanced tumorigenicity of cells expressing T-antigen in comparison to T-antigen negative cells. Considering the earlier notion on the potential involvement of beta-catenin with human medulloblastoma, we investigated various components of the Wnt signaling pathway including beta-catenin, its partner transcription factor, LEF-1, and their downstream target gene c-myc in these two cell populations. Immunohistochemical staining of the cells revealed enhanced nuclear appearance of beta-catenin in T-antigen positive cells. Results from Western blot showed higher levels of beta-catenin and LEF-1 in T-antigen positive cells in comparison to those in T-antigen negative cells. The enhanced level of LEF-1 expression correlated with the increase in DNA binding activity of this protein in nuclear extracts of T-antigen positive cells. Results from Northern and Western blot analyses revealed that the level of c-myc expression is augmented both at the RNA and protein levels in T-antigen positive cells. These observations corroborated results from transfection studies indicating the ability of JCV T-antigen to stimulate c-myc promoter activity. Further, co-transfection experiments revealed that the amount of c-myc and T-antigen protein in tumor cells may dictate the activity of JCV early promoter in these cells. These observations are interesting in light of recent discoveries on the association of JCV with human medulloblastoma and suggest that communication between JCV and the Wnt pathway may be an important event in the genesis of these tumors.

  18. Ectopic olfactory neuroblastoma: report of four cases and a review of the literature.

    LENUS (Irish Health Repository)

    Wormald, R

    2011-04-01

    Our objective is to present a short series of four rare cases of ectopic olfactory neuroblastoma. Our methods present four case reports of ectopic olfactory neuroblastoma and a review of the literature for management and treatment of this disease. The results indicate short case series reports of ectopic olfactory neuroblastoma arising from the anterior ethmoidal sinuses, the nasopharynx, the lateral nasal wall and the floor of the nose. The discussion focuses on likely origins of ectopic olfactory neuroblastoma, its clinical features and management. We conclude that ectopic olfactory neuroblastoma is a rare disease. Treatment principles are the same for non-ectopic disease and guided by extension into adjacent structures such as the orbit or anterior cranial fossa and usually involves surgery with or without adjuvant radiotherapy.

  19. Adult Neuroblastoma Complicated by Increased Intracranial Pressure: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Patrick L. Stevens

    2014-01-01

    Full Text Available Neuroblastoma is the third most commonly occurring malignancy of the pediatric population, although it is extremely rare in the adult population. In adults, neuroblastoma is often metastatic and portends an extremely poor overall survival. Our case report documents metastatic neuroblastoma occurring in a healthy 29-year-old woman whose course was complicated by an unusual presentation of elevated intracranial pressures. The patient was treated with systemic chemotherapy, I131 metaiodobenzylguanidine (MIBG radiotherapy, and autologous stem cell transplant (SCT. Unfortunately the patient’s response to therapy was limited and she subsequently died. We aim to review neuroblastoma in the context of increased intracranial pressure and the limited data of neuroblastoma occurring in the adult population, along with proposed treatment options.

  20. Medulloblastoma arising from an immature teratoma of the posterior fossa. Case report.

    Science.gov (United States)

    Das, Sunit; Muro, Kenji; Goldman, Stewart; Rajaram, Veena; DiPatri, Arthur J

    2007-01-01

    Teratomas, a group of nongerminomatous germ cell tumors, account for 3% of all childhood tumors. These unusual lesions reproduce the cellular and structural phenotypic traits associated with the three classic germ layers in inappropriate places in the body and often retain an embryonal character. These immature cells can differentiate into more malignant neoplasms. An intracranial location for this lesion type is rare. The authors describe the case of a 2-year-old boy with a teratoma of the posterior fossa that had partially differentiated into a medulloblastoma.

  1. Postoperative Radiotherapy Patterns of Care and Survival Implications for Medulloblastoma in Young Children.

    Science.gov (United States)

    Kann, Benjamin H; Park, Henry S; Lester-Coll, Nataniel H; Yeboa, Debra N; Benitez, Viviana; Khan, Atif J; Bindra, Ranjit S; Marks, Asher M; Roberts, Kenneth B

    2016-12-01

    Postoperative radiotherapy to the craniospinal axis is standard-of-care for pediatric medulloblastoma but is associated with long-term morbidity, particularly in young children. With the advent of modern adjuvant chemotherapy strategies, postoperative radiotherapy deferral has gained acceptance in children younger than 3 years, although it remains controversial in older children. To analyze recent postoperative radiotherapy national treatment patterns and implications for overall survival in patients with medulloblastoma ages 3 to 8 years. Using the National Cancer Data Base, patients ages 3 to 8 years diagnosed as having histologically confirmed medulloblastoma in 2004 to 2012, without distant metastases, who underwent surgery and adjuvant chemotherapy with or without postoperative radiotherapy at facilities nationwide accredited by the Commission on Cancer were identified. Patients were designated as having "postoperative radiotherapy upfront" if they received radiotherapy within 90 days of surgery or "postoperative radiotherapy deferred" otherwise. Factors associated with postoperative radiotherapy deferral were identified using multivariable logistic regression. Overall survival (OS) was compared using Kaplan-Meier analysis with log-rank tests and multivariable Cox regression. Statistical tests were 2-sided. Postoperative radiotherapy utilization and overall survival. Among 816 patients, 123 (15.1%) had postoperative radiotherapy deferred, and 693 (84.9%) had postoperative radiotherapy upfront; 36.8% of 3-year-olds and 4.1% of 8-year-olds had postoperative radiotherapy deferred (P radiotherapy deferral were age (odds ratio [OR], 0.57 per year; 95% CI, 0.49-0.67 per year) and year of diagnosis (OR, 1.18 per year; 95% CI, 1.08-1.29 per year). On survival analysis, with median follow-up of 4.8 years, OS was improved for those receiving postoperative radiotherapy upfront vs postoperative radiotherapy deferred (5-year OS: 82.0% vs 63.4%; P radiotherapy deferral

  2. trans-4,4’-Dihydroxystilbene (DHS) inhibits human neuroblastoma tumor growth and induces mitochondrial and lysosomal damages in neuroblastoma cell lines

    Science.gov (United States)

    Saha, Bhaskar; Patro, Birija Sankar; Koli, Mrunesh; Pai, Ganesh; Ray, Jharna; Bandyopadhyay, Sandip K.; Chattopadhyay, Subrata

    2017-01-01

    In view of the inadequacy of neuroblastoma treatment, five hydroxystilbenes and resveratrol (Resv) were screened for their cytotoxic property against human neuroblastoma cell lines. The mechanism of cytotoxic action of the most potent compound, trans-4,4’-dihydroxystilbene (DHS) was investigated in vitro using human neuroblastoma cell lines. DHS was also tested in a mouse xenograft model of human neuroblastoma tumor. The MTT, sub-G1, annexin V and clonogenic assays as well as microscopy established higher cytotoxicity of DHS than Resv to the IMR32 cell line. DHS (20 μM) induced mitochondrial membrane permeabilization (MMP) in the cells, as revealed from JC-1 staining, cytochrome c and ApaF1 release and caspases-9/3 activation. DHS also induced lysosomal membrane permeabilization (LMP) to release cathepsins B, L and D, and the cathepsins inhibitors partially reduced MMP/caspase-3 activation. The ROS, produced by DHS activated the p38 and JNK MAPKs to augment the BAX activity and BID-cleavage, and induce LMP and MMP in the cells. DHS (100 mg/kg) also inhibited human neuroblastoma tumor growth in SCID mice by 51%. Hence, DHS may be a potential chemotherapeutic option against neuroblastoma. The involvement of an independent LMP as well as a partially LMP-dependent MMP by DHS is attractive as it provides options to target both mitochondria and lysosome. PMID:29088756

  3. trans-4,4'-Dihydroxystilbene (DHS) inhibits human neuroblastoma tumor growth and induces mitochondrial and lysosomal damages in neuroblastoma cell lines.

    Science.gov (United States)

    Saha, Bhaskar; Patro, Birija Sankar; Koli, Mrunesh; Pai, Ganesh; Ray, Jharna; Bandyopadhyay, Sandip K; Chattopadhyay, Subrata

    2017-09-26

    In view of the inadequacy of neuroblastoma treatment, five hydroxystilbenes and resveratrol (Resv) were screened for their cytotoxic property against human neuroblastoma cell lines. The mechanism of cytotoxic action of the most potent compound, trans-4,4'-dihydroxystilbene (DHS) was investigated in vitro using human neuroblastoma cell lines. DHS was also tested in a mouse xenograft model of human neuroblastoma tumor. The MTT, sub-G1, annexin V and clonogenic assays as well as microscopy established higher cytotoxicity of DHS than Resv to the IMR32 cell line. DHS (20 μM) induced mitochondrial membrane permeabilization (MMP) in the cells, as revealed from JC-1 staining, cytochrome c and ApaF1 release and caspases-9/3 activation. DHS also induced lysosomal membrane permeabilization (LMP) to release cathepsins B, L and D, and the cathepsins inhibitors partially reduced MMP/caspase-3 activation. The ROS, produced by DHS activated the p38 and JNK MAPKs to augment the BAX activity and BID-cleavage, and induce LMP and MMP in the cells. DHS (100 mg/kg) also inhibited human neuroblastoma tumor growth in SCID mice by 51%. Hence, DHS may be a potential chemotherapeutic option against neuroblastoma. The involvement of an independent LMP as well as a partially LMP-dependent MMP by DHS is attractive as it provides options to target both mitochondria and lysosome.

  4. [Neurosurgical aspects of the treatment of neuroblastoma patients].

    Science.gov (United States)

    Ozerov, S S; Samarin, A E; Andreev, E S; Tereshchenko, G V; Kachanov, D Yu; Shamanskaya, T V; Varfolomeeva, S R

    Neuroblastoma (NB) is the most common extracranial solid tumor in children. The neoplasm grows from progenitor cells of the sympathetic nervous system and can be detected anywhere along the sympathetic neurological circuit: retroperitoneally, mediastinally, cervically, and pelvically. Examination of children with suspected neuroblastoma is comprehensive and performed in strict compliance with a therapeutic protocol. A decision on the treatment regimen is made based on the tumor staging and the risk group of the patient. The diagnosis and treatment of NB patients are comprehensive and can be fully carried out only at the pediatric oncology department. In 10-15% of cases, an hourglass tumor spreads to the intervertebral foramina or spinal canal at one or more levels. A tumor node is always located extradurally with respect to the spinal cord. Symptoms of spinal cord compression of various severity are observed in 5-7% of patients. We present several cases of patients with neuroblastoma with intraspinal extension. Despite apparent benefits of primary surgical decompression of the spinal cord, modern experience of treatment of children with intraspinal tumor extension does not reveal advantages of surgery over chemotherapy. Neurological disorders of various nature and severity persist in the majority of patients in the long-term period, regardless of primary treatment. A higher level of spinal deformities after surgical tumor resection is observed. The issue of spinal cord decompression should be discussed by the neurosurgeon and pediatric oncologist, and the most common method of choice may be chemotherapy. The article discusses the indications and contraindications for neurosurgical interventions in NB patients and addresses the issues of NB metastasis to the brain and cranial bones as well as the opsoclonus-myoclonus syndrome.

  5. The role of local irradiation for advanced neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Masunaga, Ken; Mugishima, Hideo; Harada, Kensuke [Nihon Univ., Tokyo (Japan). School of Medicine

    1995-06-01

    Since 1985, 30 patients with advanced neuroblastoma were treated with a comprehensive therapy including chemotherapy, radiotherapy, operation, and autologous bone marrow transplant (A-BMT). After surgery, many patients received local irradiation at the primary tumor site. We investigated the role of local irradiation for advanced neuroblastoma. Of the 30 patients, 22 received local irradiation. These patients included 2 with stage III, 17 with stage IV{sub A}, and 3 with stage IV{sub B}. Most patients were 1 year of age or older at the time of diagnosis. Adrenal tumors were present in 13, retroperitoneal in 5, thoracic in 3, and both retroperitoneal and thoracic in 1. N-myc amplification was present in 8 patients. In terms of patient characteristics, there were no difference between local irradiation group and non-local irradiation group. All patients received induction chemotherapy, as described by Sawaguchi and others. After surgery, 22 patients received local irradiation of 10 to 26 Gy in 1 to 16 fractions at the primary tumor site. Intraoperative irradiation in a dose of 10 to 15 Gy in single fraction had been administered to 15 patients. Most patients received purged marrow using immunomagnetic beads. All patients received preconditioning regimen (VAMP, modified VAMP with or without TBI) and then transplanted. Following A-BMT, 13-cis-retinoic acid was administered for the purpose of tumor differentiation. Of the 22 patients with local irradiation, 6 relapsed and 5 died. Of the 8 patients without local irradiation, 2 relapsed and 1 died. Patients who completely received local irradiation showed no evidence of primary tumor recurrence. Patients who did not receive or incompletely received local irradiation showed primary tumor recurrence. Local irradiation for advanced neuroblastoma is very useful treatment to prevent primary tumor recurrence. (author).

  6. Tumor Growth Model with PK Input for Neuroblastoma Drug Development

    Science.gov (United States)

    2015-09-01

    the predicted effect maps against IHC using spatial analysis. We will orient the tumor tissue (before IHC processing) to the corresponding ultrasound ...neuroblastoma (NB5) xenograft tumors (n=3 CD1 nude mice/time point) using nonlinear contrast enhanced  ultrasound   technique  (CEUS). Tumor tissue and...The output from the individualized tumor compartment from the PBPK model will be used to predict individual tumor concentration-time data that could

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

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  9. Chromatin Accessibility Mapping Identifies Mediators of Basal Transcription and Retinoid-Induced Repression of OTX2 in Medulloblastoma

    Science.gov (United States)

    Zhang, Monica; Song, Lingyun; Lee, Bum-Kyu; Iyer, Vishwanath R.; Furey, Terrence S.; Crawford, Gregory E.; Yan, Hai; He, Yiping

    2014-01-01

    Despite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes. PMID:25198066

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

    NARCIS (Netherlands)

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

    2008-01-01

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

  11. High levels of PROM1 (CD133) transcript are a potential predictor of poor prognosis in medulloblastoma

    NARCIS (Netherlands)

    Raso, Alessandro; Mascelli, Samantha; Biassoni, Roberto; Nozza, Paolo; Kool, Marcel; Pistorio, Angela; Ugolotti, Elisabetta; Milanaccio, Claudia; Pignatelli, Sara; Ferraro, Manuela; Pavanello, Marco; Ravegnani, Marcello; Cama, Armando; Garrè, Maria Luisa; Capra, Valeria

    2011-01-01

    The surface marker PROM1 is considered one of the most important markers of tumor-initiating cells, and its expression is believed to be an adverse prognostic factor in gliomas and in other malignancies. To date, to our knowledge, no specific studies of its expression in medulloblastoma series have

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2017-03-01

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

  15. Joint Binding of OTX2 and MYC in Promotor Regions Is Associated with High Gene Expression in Medulloblastoma

    NARCIS (Netherlands)

    Bunt, J.; Hasselt, N.E.; Zwijnenburg, D.A.; Koster, J.; Versteeg, R.; Kool, M.

    2011-01-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Gregory M Shackleford

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

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

    Science.gov (United States)

    Shackleford, Gregory M; Shi, Xiang-He; Swanson, Kimberly S; Mahdi, Min Y; Gonzalez-Gomez, Ignacio; Asgharzadeh, Shahab; D'Apuzzo, Massimo; Erdreich-Epstein, Anat; Moats, Rex A

    2016-01-01

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

  19. Evaluating the effect of therapeutic stem cells on TRAIL resistant and sensitive medulloblastomas.

    Directory of Open Access Journals (Sweden)

    Irina Nesterenko

    Full Text Available Mesenchymal stem cells (MSC are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential in medulloblastomas (MB has not been explored to date. In this study, we engineered human MSC to express a potent and secretable variant of a tumor specific agent, tumor necrosis factor-apoptosis-inducing ligand (S-TRAIL and assessed the ability of MSC-S-TRAIL mediated MB killing alone or in combination with a small molecule inhibitor of histone-deacetylase, MS-275, in TRAIL-sensitive and -resistant MB in vitro and in vivo. We show that TRAIL sensitivity/resistance correlates with the expression of its cognate death receptor (DR5 and MSC-S-TRAIL induces caspase-3 mediated apoptosis in TRAIL-sensitive MB lines. In TRAIL-resistant MB, we show upregulation of DR4/5 levels when pre-treated with MS-275 and a subsequent sensitization to MSC-S-TRAIL mediated apoptosis. Using intracranially implanted MB and MSC lines engineered with different combinations of fluorescent and bioluminescent proteins, we show that MSC-S-TRAIL has significant anti-tumor effects in mice bearing TRAIL-sensitive and MS-275 pre-treated TRAIL-resistant MBs. To our knowledge, this is the first study that explores the use of human MSC as MB-targeting therapeutic-vehicles in vivo in TRAIL-sensitive and resistant tumors, and has implications for developing effective therapies for patients with medulloblastomas.

  20. 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.

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

    Science.gov (United States)

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

    2008-12-01

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

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

    Science.gov (United States)

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

    2017-07-01

    International consensus recognises four medulloblastoma molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGrp3), and group 4 (MBGrp4), each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0-16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3-16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MBWNT remained unchanged and each remaining consensus subgroup was split in two. MBSHH was split into age-dependent subgroups corresponding to infant (<4·3 years; MBSHH-Infant; n=65) and

  3. Intermittent Hypoxia Regulates Stem-like Characteristics and Differentiation of Neuroblastoma Cells

    Science.gov (United States)

    Bhaskara, Vasantha Kumar; Mohanam, Indra; Rao, Jasti S.; Mohanam, Sanjeeva

    2012-01-01

    Background Neuroblastomas are the most common extracranial solid tumors in children. Neuroblastomas are derived from immature cells of the sympathetic nervous system and are characterized by clinical and biological heterogeneity. Hypoxia has been linked to tumor progression and increased malignancy. Intermittent hypoxia or repeated episodes of hypoxia followed by re-oxygenation is a common phenomenon in solid tumors including neuroblastoma and it has a significant influence on the outcome of therapies. The present study focuses on how intermittent hypoxia modulates the stem-like properties and differentiation in neuroblastoma cells. Methods and Findings Cell survival was assessed by clonogenic assay and cell differentiation was determined by morphological characterization. Hypoxia-inducible genes were analyzed by real-time PCR and Western blotting. Immunofluorescence, real-time PCR and Western blotting were utilized to study stem cell markers. Analysis of neural crest / sympathetic nervous system (SNS) markers and neuronal differentiation markers were done by real-time PCR and Western blotting, respectively. Intermittent hypoxia stimulated the levels of HIF-1α and HIF-2 α proteins and enhanced stem-like properties of neuroblastoma cells. In intermittent hypoxia-conditioned cells, downregulation of SNS marker genes and upregulation of genes expressed in the neural crest were observed. Intermittent hypoxia suppressed the retinoic acid-induced differentiation of neuroblastoma cells. Conclusions Our results suggest that intermittent hypoxia enhances stem-like characteristics and suppresses differentiation propensities in neuroblastoma cells. PMID:22363512

  4. Neuroblastoma in a Case with Congenital Horner’s Syndrome

    Directory of Open Access Journals (Sweden)

    Hüseyin Mayalı

    2014-08-01

    Full Text Available Miosis, ptosis, and ipsilateral facial anhidrosis are normally present in Horner’s syndrome. Pathologies which show central, preganglionic and postganglionic residence in sympathetic chain are present in its etiology. A 3-month-old girl baby was admitted to our clinic for ptosis in the left eye. Heterochromia, ptosis in the left eye, myosis and, ipsilateral anhidrosis were detected in her examination. In view of these findings, it seemed possible that her disease could be congenital Horner’s syndrome. Brachial plexus injury due to birth trauma plays a major role in the etiology of congenital Horner’s syndrome. There was not any birth trauma history in our patient. The patient was diagnosed to have neuroblastoma as a result of etiologic tests. In conclusion, Horner’s syndrome can be the presenting sign of childhood neuroblastoma. Therefore, it is advisable to examine the oculosympathetic system in detail in order to leave out any underlying serious disorder. (Turk J Ophthalmol 2014; 44: 325-6

  5. 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

  6. Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients

    Science.gov (United States)

    Kao, Clara; Hernandez, Kyle M.; DeWane, Gillian; Salwen, Helen R.; Chlenski, Alexandre; Dobratic, Marija; Mariani, Christopher J.; Godley, Lucy A.; Prabhakar, Nanduri; White, Kevin; Stranger, Barbara E.; Cohn, Susan L.

    2016-01-01

    Neuroblastoma is notable for its broad spectrum of clinical behavior ranging from spontaneous regression to rapidly progressive disease. Hypoxia is well known to confer a more aggressive phenotype in neuroblastoma. We analyzed transcriptome data from diagnostic neuroblastoma tumors and hypoxic neuroblastoma cell lines to identify genes whose expression levels correlate with poor patient outcome and are involved in the hypoxia response. By integrating a diverse set of transcriptome datasets, including those from neuroblastoma patients and neuroblastoma derived cell lines, we identified nine genes (SLCO4A1, ENO1, HK2, PGK1, MTFP1, HILPDA, VKORC1, TPI1, and HIST1H1C) that are up-regulated in hypoxia and whose expression levels are correlated with poor patient outcome in three independent neuroblastoma cohorts. Analysis of 5-hydroxymethylcytosine and ENCODE data indicate that at least five of these nine genes have an increase in 5-hydroxymethylcytosine and a more open chromatin structure in hypoxia versus normoxia and are putative targets of hypoxia inducible factor (HIF) as they contain HIF binding sites in their regulatory regions. Four of these genes are key components of the glycolytic pathway and another three are directly involved in cellular metabolism. We experimentally validated our computational findings demonstrating that seven of the nine genes are significantly up-regulated in response to hypoxia in the four neuroblastoma cell lines tested. This compact and robustly validated group of genes, is associated with the hypoxia response in aggressive neuroblastoma and may represent a novel target for biomarker and therapeutic development. PMID:27765905

  7. Establishing a high-risk neuroblastoma cohort using the Pediatric Health Information System Database.

    Science.gov (United States)

    Desai, Ami V; Kavcic, Marko; Huang, Yuan-Shung; Herbst, Nicole; Fisher, Brian T; Seif, Alix E; Li, Yimei; Hennessy, Sean; Aplenc, Richard; Bagatell, Rochelle

    2014-06-01

    International Classification of Diseases, 9th Revision (ICD-9) code(s) for neuroblastoma do not exist, preventing identification of these patients in administrative databases. To overcome this challenge, a three-step algorithm, using ICD-9 codes, exclusion criteria, and manual review of chemotherapy billing data, was utilized to assemble a high-risk neuroblastoma cohort (n = 952) from the Pediatric Health Information System (PHIS) Database and validated at a single institution [sensitivity 89.1%; positive predictive value (PPV) 96.1%]. This cohort provides a data source for future comparative effectiveness and clinical epidemiology studies in high-risk neuroblastoma patients. © 2014 Wiley Periodicals, Inc.

  8. Estridor inspiratorio en neonato por neuroblastoma cervical. Descripción de un caso

    Directory of Open Access Journals (Sweden)

    María Rosario GÓMEZ-GONZÁLEZ

    2016-11-01

    Full Text Available Introduction: Neuroblastoma is the solid tumor more frequent in the infancy, although, his cervical location is rare. It may present as a asymptomatic mass or produce stridor, dyspnea o difficulty in swallowing. Description: Patient of a one month old, male reporting inspiratory stridor. RM showed a mass compatible with an unilocular cystic lymphatic malformation in right carotid and prevertebral spaces with airway compromise. The definitive diagnosis was of neuroblastoma after surgical excision. Discussion: In RM neuroblastoma and lymphatic malformations present similar patterns. This case shows the importance of a correct differential diagnosis and approach of cervical masses in newborns.

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    Quintero Eliana A

    2008-04-01

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

  11. Lack of association between MDM2 promoter SNP309 and clinical outcome in patients with neuroblastoma.

    Science.gov (United States)

    Rihani, Ali; Van Maerken, Tom; De Wilde, Bram; Zeka, Fjoralba; Laureys, Geneviève; Norga, Koen; Tonini, Gian Paolo; Coco, Simona; Versteeg, Rogier; Noguera, Rosa; Schulte, Johannes H; Eggert, Angelika; Stallings, Raymond L; Speleman, Frank; Vandesompele, Jo

    2014-10-01

    While a polymorphism located within the promoter region of the MDM2 proto-oncogene, SNP309 (T > G), has previously been associated with increased risk and aggressiveness of neuroblastoma and other tumor entities, a protective effect has also been reported in certain other cancers. In this study, we evaluated the association of MDM2 SNP309 with outcome in 496 patients with neuroblastoma and its effect on MDM2 expression. No significant difference in overall or event-free survival was observed among patients with neuroblastoma with or without MDM2 SNP309. The presence of SNP309 does not affect MDM2 expression in neuroblastoma. © 2014 Wiley Periodicals, Inc.

  12. Gene therapy as a potential tool for treating neuroblastoma-a focused review.

    Science.gov (United States)

    Kumar, M D; Dravid, A; Kumar, A; Sen, D

    2016-05-01

    Neuroblastoma, a solid tumor caused by rapid division of undifferentiated neuroblasts, is the most common childhood malignancy affecting children aged genes is restored to normalcy. Gene therapy is a powerful tool with the potential to inhibit the deleterious effects of oncogenes by inserting corrected/normal genes into the genome. Both viral and non-viral vector-based gene therapies have been developed and adopted to deliver the target genes into neuroblastoma cells. These attempts have given hope to bringing in a new regime of treatment against neuroblastoma. A few gene-therapy-based treatment strategies have been tested in limited clinical trials yielding some positive results. This mini review is an attempt to provide an overview of the available options of gene therapy to treat neuroblastoma.

  13. CDDO and ATRA Instigate Differentiation of IMR32 Human Neuroblastoma Cells

    National Research Council Canada - National Science Library

    Namrata Chaudhari; Priti Talwar; Christian Lefebvre D'hellencourt; Palaniyandi Ravanan

    2017-01-01

    ...(11)-dien-28-oic acid (CDDO) on human neuroblastoma IMR32 cells. Our results demonstrate that treatment with low concentration of CDDO and particularly in combination with all trans retinoic acid (ATRA...

  14. Genetic instability and intratumoral heterogeneity in neuroblastoma with MYCN amplification plus 11q deletion.

    Directory of Open Access Journals (Sweden)

    Eva Villamón

    Full Text Available Genetic analysis in neuroblastoma has identified the profound influence of MYCN amplification and 11q deletion in patients' prognosis. These two features of high-risk neuroblastoma usually occur as mutually exclusive genetic markers, although in rare cases both are present in the same tumor. The purpose of this study was to characterize the genetic profile of these uncommon neuroblastomas harboring both these high-risk features.We selected 18 neuroblastomas with MNA plus 11q loss detected by FISH. Chromosomal aberrations were analyzed using Multiplex Ligation-dependent Probe Amplification and Single Nucleotide Polymorphism array techniques.This group of tumors has approximately the same high frequency of aberrations as found earlier for 11q deleted tumors. In some cases, DNA instability generates genetic heterogeneity, and must be taken into account in routine genetic diagnosis.

  15. Urinary catecholamine metabolites: Capillary gas chromatography method and experience with 12 cases of neuroblastoma.

    Science.gov (United States)

    Grkovic, Sanja; Nikolic, Rajko; Dordevic, Maja; Stojanov, Ljubomir

    2005-07-01

    We propose a rapid, simple metodology for routine analysis of human urine to detect vanillylmandelic and homovanillic acid related to neuroblastoma. The assay were specific capillary gas chromatography with flame ionization detection. In this methodology an internal standard is used and the procedure involves ethyl ester formation without isolation of the compounds of interest. The run time is 36 minutes. We also report quantitative results for urinary vanillylmandelic and homovanillic acid in neuroblastoma patients, demonstrating the diagnostic value of this method.

  16. MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma.

    LENUS (Irish Health Repository)

    Tivnan, Amanda

    2011-01-01

    Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system and accounts for 15% of childhood cancer mortalities. With regards to the role of miRNAs in neuroblastoma, miR-34a, mapping to a chromosome 1p36 region that is commonly deleted, has been found to act as a tumor suppressor through targeting of numerous genes associated with cell proliferation and apoptosis.

  17. The genetic landscape of high-risk neuroblastoma | Office of Cancer Genomics

    Science.gov (United States)

    Abstract: Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative.

  18. Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Akter, Jesmin [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Takatori, Atsushi, E-mail: atakatori@chiba-cc.jp [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Islam, Md. Sazzadul [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakazawa, Atsuko [Department of Pathology, National Center for Child Health and Development, Tokyo (Japan); Ozaki, Toshinori, E-mail: tozaki@chiba-cc.jp [Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nagase, Hiroki [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakagawara, Akira [Saga Medical Centre, 840-8571 (Japan)

    2014-10-10

    Highlights: • NLRR3 is a membrane protein highly expressed in favorable neuroblastoma. • NLRR3-ICD was produced through proteolytic processing by secretases. • NLRR3-ICD was induced to be translocated into cell nucleus following ATRA exposure. • NLRR3-ICD plays a pivotal role in ATRA-mediated neuroblastoma differentiation. - Abstract: We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas.

  19. A high-content morphological screen identifies novel microRNAs that regulate neuroblastoma cell differentiation.

    Science.gov (United States)

    Zhao, Zhenze; Ma, Xiuye; Hsiao, Tzu-Hung; Lin, Gregory; Kosti, Adam; Yu, Xiaojie; Suresh, Uthra; Chen, Yidong; Tomlinson, Gail E; Pertsemlidis, Alexander; Du, Liqin

    2014-05-15

    Neuroblastoma, the most common extracranial solid tumor of childhood, arises from neural crest cell precursors that fail to differentiate. Inducing cell differentiation is an important therapeutic strategy for neuroblastoma. We developed a direct functional high-content screen to identify differentiation-inducing microRNAs, in order to develop microRNA-based differentiation therapy for neuroblastoma. We discovered novel microRNAs, and more strikingly, three microRNA seed families that induce neuroblastoma cell differentiation. In addition, we showed that microRNA seed families were overrepresented in the identified group of fourteen differentiation-inducing microRNAs, suggesting that microRNA seed families are functionally more important in neuroblastoma differentiation than microRNAs with unique sequences. We further investigated the differentiation-inducing function of the microRNA-506-3p/microRNA-124-3p seed family, which was the most potent inducer of differentiation. We showed that the differentiation-inducing function of microRNA-506-3p/microRNA-124-3p is mediated, at least partially, by down-regulating expression of their targets CDK4 and STAT3. We further showed that expression of miR-506-3p, but not miR-124-3p, is dramatically upregulated in differentiated neuroblastoma cells, suggesting the important role of endogenous miR-506-3p in differentiation and tumorigenesis. Overall, our functional screen on microRNAs provided the first comprehensive analysis on the involvements of microRNA species in neuroblastoma cell differentiation and identified novel differentiation-inducing microRNAs. Further investigations are certainly warranted to fully characterize the function of the identified microRNAs in order to eventually benefit neuroblastoma therapy.

  20. Neuroblastoma in a boy with MCA/MR syndrome, deletion 11q, and duplication 12q

    Energy Technology Data Exchange (ETDEWEB)

    Koiffmann, C.P.; Vianna-Morgante, A.M.; Wajntal, A. [Univ. of Sao Paulo (Brazil)] [and others

    1995-07-31

    Deletion 11q23{r_arrow}qter and duplication 12q23{r_arrow}qter are described in a boy with neuroblastoma, multiple congenital anomalies, and mental retardation. The patient has clinical manifestations of 11q deletion and 12q duplication syndromes. The possible involvement of the segment 11q23{r_arrow}24 in the cause of the neuroblastoma is discussed. 18 refs., 2 figs., 1 tab.

  1. [Establishment of subcutaneously transplanted and metastatic neuroblastoma models in nude mice].

    Science.gov (United States)

    Lu, Hong-ting; Dong, Qian; Gao, Qiang; Hao, Xi-wei; Song, Hua; Zhao, Nan

    2010-04-01

    To establish a tumor-bearing nude mouse model of human neuroblastoma in order to study the mechanisms of neuroblastoma invasion and metastasis, and to investigate potential therapeutic modalities in the experimental animal models. A human neuroblastoma cell line was cultured in vitro. 1 x 10(7) cells undergoing exponential growth were collected in 0.1 ml of suspension and subcutaneously inoculated into the right flank next to the forelimb in nude mice. The biological characteristics of the developed tumors were observed, and histopathological and DNA microarray analyses were performed. The expressions of NSE in the subcutaneous tumor, metastatic tumor and the primary neuroblastoma tumor tissues from a pediatric patient were analyzed by immunohistochemistry. Tumors successfully grew in 36 out of 48 injected mice, with a total tumor-formation rate of 75.0%. Metastasis occurred in 10 cases, and the metastatic rate was 20.8%. Tumors in five injected mice grew locally without metastasis. These tumors had large volume and the tumor weight reached up to half of the body weight of the host animal. Four mice exhibited systemic metastasis without tumor growth at the primary inoculation site. There were six mice with locally growing tumor accompanied by metastasis. We have successfully established a human neuroblastoma xenograft model in nude mice with high tumor growth and metastatic rates. This model depicting the natural cell growth, local infiltration and distant metastasis characteristics of human neuroblastoma, providing an ideal animal model for in vivo studies of neuroblastoma. In addition, the results of this study indicate the heterogeneous nature of neuroblastoma, it may play an important role in metastasis of this tumor.

  2. Polysulfide promotes neuroblastoma cell differentiation by accelerating calcium influx.

    Science.gov (United States)

    Koike, Shin; Shibuya, Norihiro; Kimura, Hideo; Ishii, Kazuyuki; Ogasawara, Yuki

    2015-04-10

    Polysulfides are a typical type of bound sulfur, which is physiologically stable form of sulfur species, derived from the hydrogen sulfide (H2S) that is generated endogenously in cells. We previously reported that bound sulfur protects neuronal cells from oxidative injury. In the present study, we demonstrated that polysulfides inhibited cell growth and promoted neurite outgrowth in mouse neuroblastoma Neuro2A (N2A) cells. However, Na2S showed no effect on neurite outgrowth in N2A cells. Furthermore, 2-APB and SKF96365, which are typical transient receptor potential (TRP) channel inhibitors, suppressed the neurite outgrowth induced by Na2S4. These new findings suggest that bound sulfur could induce neurite outgrowth and cell differentiation of N2A cells by accelerating calcium influx. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Management of VIP Associated Diarrhea in a Case with Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Begul Yagci-Kupeli

    2013-06-01

    Full Text Available Watery diarrhea associated with hypokalemia and achlorhydria (WDHA syndrome is commonly caused by vasoactive intestinal peptide (VIP secreting tumors in adults and generally associated with neural crest tumors in pediatric population. VIP secretion is associated with neuroblastic cell differentiation. Octreotide treatment can be a choice for diarrhea in such cases. However, its benefit is controversial and surgery is usually needed. A 14-month-old female with diagnosis of inoperable undifferantiated intraabdominal neuroblastoma who developed chronic diarrhea at first year of chemotherapy is reported. Octreotide treatment was used to control diarrhea. Because of the failure of octreotide treatment, debulking surgery was performed and diarrhea subsided after the surgery. [Cukurova Med J 2013; 38(3.000: 528-530

  4. Dancing eye syndrome as first symptom of neuroblastoma.

    Science.gov (United States)

    Venturelli, Cristina; Guerra, Azzurra; Paolucci, Paolo; Iughetti, Lorenzo

    2013-09-01

    "Dancing eye syndrome", also called Kinsbourne syndrome or Opsoclonus-Myoclonus-Ataxia Syndrome (OMS) is a rare neurological disorder that in children is frequently associated to occult, low-grade neuroblastoma (NB) (>50% of the cases). OMS may also be triggered by infections and it is often associated to developmental impairment and disability. We discuss the case of a 16 months old female with acutely onset of OMS associated to occult stage III NB. OMS represents a diagnostic challenge for pediatric clinicians. The suspect of OMS imposes the search for an occult NB in order to promptly treat a life-threatening event like tumor and to prevent the neurological sequels linked to OMS.

  5. The connections between neural crest development and neuroblastoma.

    Science.gov (United States)

    Jiang, Manrong; Stanke, Jennifer; Lahti, Jill M

    2011-01-01

    Neuroblastoma (NB), the most common extracranial solid tumor in childhood, is an extremely heterogeneous disease both biologically and clinically. Although significant progress has been made in identifying molecular and genetic markers for NB, this disease remains an enigmatic challenge. Since NB is thought to be an embryonal tumor that is derived from precursor cells of the peripheral (sympathetic) nervous system, understanding the development of normal sympathetic nervous system may highlight abnormal events that contribute to NB initiation. Therefore, this review focuses on the development of the peripheral trunk neural crest, the current understanding of how developmental factors may contribute to NB and on recent advances in the identification of important genetic lesions and signaling pathways involved in NB tumorigenesis and metastasis. Finally, we discuss how future advances in identification of molecular alterations in NB may lead to more effective, less toxic therapies, and improve the prognosis for NB patients. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. A granulomatous reaction to Avitene mimicking recurrence of a medulloblastoma. Case report.

    Science.gov (United States)

    O'Shaughnessy, Brian A; Schafernak, Kristian T; DiPatri, Arthur J; Goldman, Stewart; Tomita, Tadanori

    2006-01-01

    Microfibrillar collagen hemostat (MCH), also known by its trade name Avitene, is commonly used to control hemorrhage during neurosurgery. Among the documented complications associated with this agent, a granulomatous foreign body reaction is rare, having been described in the central nervous system in only one previous clinical report. In the present study, the authors report the case of a 3-year-old boy who presented with a lesion which appeared to be the recurrence of a tumor 2 months after he had undergone gross-total resection for a medulloblastoma. The patient underwent resection of the presumed recurrent tumor, but histopathological analysis of the specimen revealed a granulomatous foreign body reaction to MCH and no tumor recurrence. In addition to describing the case, the authors review the surgical literature on foreign body reactions to MCH.

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

    DEFF Research Database (Denmark)

    Brodin, Nils Patrik

    this results in irradiating a large volume of healthy tissue in these young patients. The general aim of this thesis is reducing the risk of late treatment toxicity through risk-based advanced radiotherapy optimization. We specifically investigated the use of radiobiological models to estimate late......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 aggressive anti-cancer therapy. Some of the most important late complications for these patients include secondary malignancies, cardiac events and neurocognitive decline. Much of the late complication risk can be attributed the craniospinal irradiation which is part of standard management, since...

  8. Dielectrophoretic capture and genetic analysis of single neuroblastoma tumor cells

    Directory of Open Access Journals (Sweden)

    Erica L Carpenter

    2014-07-01

    Full Text Available Our understanding of the diversity of cells that escape the primary tumor and seed micrometastases remains rudimentary, and approaches for studying circulating and disseminated tumor cells have been limited by low throughput and sensitivity, reliance on single parameter sorting, and a focus on enumeration rather than phenotypic and genetic characterization. Here we utilize a highly sensitive microfluidic and dielectrophoretic approach for the isolation and genetic analysis of individual tumor cells. We employed fluorescence labeling to isolate 208 single cells from spiking experiments conducted with 11 cell lines, including 8 neuroblastoma cell lines, and achieved a capture sensitivity of 1 tumor cell per 106 white blood cells. Sample fixation or freezing had no detectable effect on cell capture. Point mutations were accurately detected in the whole genome amplification product of captured single tumor cells but not in negative control white blood cells. We applied this approach to capture 144 single tumor cells from 10 bone marrow samples from patients suffering from neuroblastoma. In this pediatric malignancy, high-risk patients often exhibit wide-spread hematogenous metastasis, but access to primary tumor can be difficult or impossible. Here we used flow-based sorting to pre-enrich samples with tumor involvement below 0.02%. For all patients for whom a mutation in the Anaplastic Lymphoma Kinase gene had already been detected in their primary tumor, the same mutation was detected in single cells from their marrow. These findings demonstrate a novel, non-invasive, and adaptable method for the capture and genetic analysis of single tumor cells from cancer patients.

  9. An Integrated Cross-Platform Prognosis Study on Neuroblastoma Patients

    Science.gov (United States)

    Chen, Qing-Rong; Song, Young K.; Wei, Jun S.; Bilke, Sven; Asgharzadeh, Shahab; Seeger, Robert C.; Khan, Javed

    2008-01-01

    There have been several reports about the potential for predicting prognosis of neuroblastoma patients using microarray gene expression profiling of the tumors. However these studies have revealed an apparent diversity in the identity of the genes in their predictive signatures. In order to test the contribution of the platform to this discrepancy we applied z-scoring method to minimize the impact of platform and combine gene expression profiles of neuroblastoma (NB) tumors from two different platforms, cDNA and Affymetrix. A total of 12442 genes were common to both cDNA and Affymetrix arrays in our dataset. Two-way ANOVA analysis was applied to the combined dataset for assessing the relative effect of prognosis and platform on gene expression. We found 26.6% (3307) of the genes had significant impact on survival. There was no significant impact of microarray platform on expression after application of z-scoring standardization procedure. Artificial neural network (ANN) analysis of the combined data set in a leave-one-out prediction strategy correctly predicted the outcome for 90% of the samples. Hierarchical clustering analysis using the top-ranked 160 genes showed the great separation of two clusters, and the majority of matched samples from the different platforms were clustered next to each other. The ANN classifier trained with our combined cross-platform data for these 160 genes could predict the prognosis of 102 independent test samples with 71% accuracy. Furthermore it correctly predicted the outcome for 85/102 (83%) NB patients through the leave-one-out cross validation approach. Our study showed that gene expression studies performed in different platforms could be integrated for prognosis analysis after removing variation resulting from different platforms. PMID:18598751

  10. An integrated cross-platform prognosis study on neuroblastoma patients.

    Science.gov (United States)

    Chen, Qing-Rong; Song, Young K; Wei, Jun S; Bilke, Sven; Asgharzadeh, Shahab; Seeger, Robert C; Khan, Javed

    2008-10-01

    There have been several reports about the potential for predicting prognosis of neuroblastoma patients using microarray gene expression profiling of the tumors. However these studies have revealed an apparent diversity in the identity of the genes in their predictive signatures. To test the contribution of the platform to this discrepancy we applied the z-scoring method to minimize the impact of platform and combine gene expression profiles of neuroblastoma (NB) tumors from two different platforms, cDNA and Affymetrix. A total of 12442 genes were common to both cDNA and Affymetrix arrays in our data set. Two-way ANOVA analysis was applied to the combined data set for assessing the relative effect of prognosis and platform on gene expression. We found that 26.6% (3307) of the genes had significant impact on survival. There was no significant impact of microarray platform on expression after application of z-scoring standardization procedure. Artificial neural network (ANN) analysis of the combined data set in a leave-one-out prediction strategy correctly predicted the outcome for 90% of the samples. Hierarchical clustering analysis using the top-ranked 160 genes showed the great separation of two clusters, and the majority of matched samples from the different platforms were clustered next to each other. The ANN classifier trained with our combined cross-platform data for these 160 genes could predict the prognosis of 102 independent test samples with 71% accuracy. Furthermore it correctly predicted the outcome for 85/102 (83%) NB patients through the leave-one-out cross-validation approach. Our study showed that gene expression studies performed in different platforms could be integrated for prognosis analysis after removing variation resulting from different platforms.

  11. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    LENUS (Irish Health Repository)

    Abel, Frida

    2011-04-14

    Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p < 0.05, one-way ANOVA test). PCA clusters p1, p2, and p3 were found to correspond well to the postulated subtypes 1, 2A, and 2B, respectively. Remarkably, a fourth novel cluster was detected in all three independent data sets. This cluster comprised mainly 11q-deleted MNA-negative tumours with low expression of ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and\\/or dead of disease, p < 0.05, Fisher\\'s exact test). Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group\\'s specific characteristics.

  12. [Surgical approach of retroperitoneal neuroblastoma in infancy (author's transl)].

    Science.gov (United States)

    Utrilla, J G; Monereo, J; Domínguez, J; Benchi, F

    1976-11-01

    Rarely retroperitoneal neuroblastoma is a well localized, encapsulated tumor, like it my appear somewhere else, as in the pelvic floor or mediastinum. Even with the same histological findings they are different from de point of view of invasion. Therefore the surgical approach should be different in each case. This is our main conclusion after de study performed in 48 cases operated upon in the last 8 years. We have tried three kinds of operations. 1. The so called curative, total resections. Performing a surgical ablation of the tumor and the organs macroscopically involved, either prior or after radiotherapy or quimiotherapy. At any risk, even of life in the early postoperative period. This kind of surgery has been undertaken in 34 cases with an early mortality of 9. The main aim of this technique is to divide the tumor in two across the supraaortic line well below the renal vessels and up to the diaphragm. In 18 cases the homolateral kidney was resected with the suprarrenal gland. Spleen and pancreas in 5 cases, colon in 4, and the inferior vena cava in 3. The survivors over 2 years are 19 cases. 2. Paliative resection, taking out the main tumor only, has been achieved in 4 cases, with the highest mortality because postoperative hemorrhage. We believed is a dangerous procedure. None of these children survived more than one year. 3. Biopsy and surgical macroscopic diagnosis of invasion plus placing clips at their margin has been carried out in 12 occasions. This had naturally the best early postoperative but not in the long run, none survived more than 2 years. A second look up with resection was undertaken in 3 cases with mortality of one. Most surgeons are puzzled when dealing with retroperitoneal neuroblastoma and some how disappointed before undertaking a long, difficult and highly risk operation, but in many instances still is about the only hope they may have.

  13. Iodine-131 Metaiodobenzylguanidine Therapy for Neuroblastoma: Reports So Far and Future Perspective

    Directory of Open Access Journals (Sweden)

    Daiki Kayano

    2015-01-01

    Full Text Available Neuroblastoma, which derives from neural crest, is the most common extracranial solid cancer in childhood. The tumors express the norepinephrine (NE transporters on their cell membrane and take in metaiodobenzylguanidine (MIBG via a NE transporter. Since iodine-131 (I-131 MIBG therapy was firstly reported, many trails of MIBG therapy in patients with neuroblastoma were performed. Though monotherapy with a low dose of I-131 MIBG could achieve high-probability pain reduction, the objective response was poor. In contrast, more than 12 mCi/kg I-131 MIBG administrations with or without hematopoietic cell transplantation (HCT obtain relatively good responses in patients with refractory or relapsed neuroblastoma. The combination therapy with I-131 MIBG and other modalities such as nonmyeloablative chemotherapy and myeloablative chemotherapy with HCT improved the therapeutic response in patients with refractory or relapsed neuroblastoma. In addition, I-131 MIBG therapy incorporated in the induction therapy was proved to be feasible in patients with newly diagnosed neuroblastoma. To expand more the use of MIBG therapy for neuroblastoma, further studies will be needed especially in the use at an earlier stage from diagnosis, in the use with other radionuclide formations of MIBG, and in combined use with other therapeutic agents.

  14. T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma.

    Science.gov (United States)

    Singh, Nathan; Kulikovskaya, Irina; Barrett, David M; Binder-Scholl, Gwendolyn; Jakobsen, Bent; Martinez, Daniel; Pawel, Bruce; June, Carl H; Kalos, Michael D; Grupp, Stephan A

    The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY-ESO-1. After confirming antigen-specific activity of T cells genetically engineered to express an NY-ESO-1 directed high-affinity transgenic T cell receptor in vitro , we performed xenograft mouse studies assessing the efficacy of NY-ESO-1-targeted T cells in both localized and disseminated models of neuroblastoma. Disease responses were monitored by tumor volume measurement and in vivo bioluminescence. After delivery of NY-ESO-1 transgenic TCR T cells, we observed significant delay of tumor progression in mice bearing localized and disseminated neuroblastoma, as well as enhanced animal survival. These data demonstrate that NY-ESO-1 is an antigen target in neuroblastoma and that targeted T cells represent a potential therapeutic option for patients with neuroblastoma.

  15. Main caregivers' experiences of managing pain for children with neuroblastoma in Taiwan.

    Science.gov (United States)

    Lu, Ching-Hui; Huang, Chu-Yu; Park, Jeong-Hwan; Lin, Hung-Ru; Lee, Ya-Ling; Cheng, Su-Fen

    2011-01-01

    Neuroblastoma is a common malignant tumor among children. Seventy percent of children with neuroblastoma have metastatic disease when the diagnosis is established. The aim of this study was to understand the main caregivers' lived experiences in managing pain for children with neuroblastoma. A descriptive qualitative design was used. Twelve main caregivers of children with neuroblastoma were interviewed. Two themes evolved: experiences of pain and coping with pain. Three subthemes were found under the theme "experience of pain": pain assessment based on language expressions and behavioral observations, tendency of misdiagnosing tumor metastasis-related pain, and unique manifestations of pain at various phases. Four subthemes evolved under the theme "coping with pain": utilization of pharmacological and nonpharmacological modalities for pain management, learning to confront pain, seeking mental and emotional support, and adjustment of family lifestyle. The results provide a description regarding the expression of pain in children with neuroblastoma and the pain management modalities used by the main caregivers. The findings serve as a reference for health care providers in Taiwan as they manage pain for children with neuroblastoma and seek to understand the needs of the main caregivers.

  16. Sesquiterpene lactones derived from Saussurea lappa induce apoptosis and inhibit invasion and migration in neuroblastoma cells.

    Science.gov (United States)

    Tabata, Keiichi; Nishimura, Yuki; Takeda, Taiji; Kurita, Masahiro; Uchiyama, Taketo; Suzuki, Takashi

    2015-04-01

    Neuroblastoma is among the most fatal of solid tumors in the pediatric age group, even when treated aggressively. Therefore, a new effective therapeutic drug(s) for neuroblastoma is urgently needed. To clarify the anticancer effects of the sesquiterpene lactones dehydrocostus lactone and costunolide, derived from Saussurea lappa, we examined the cytotoxic and migration/invasion-inhibitory effects of these compounds against neuroblastoma cell lines. Both the compounds exerted significant cytotoxicity against the neuroblastoma cell lines IMR-32, NB-39, SK-N-SH, and LA-N-1. Evidence of cellular apoptosis, such as nuclear condensation and membrane inversion, were observed after treatment with these compounds. Both compounds induced caspase-7 activation and PARP cleavage as confirmed by Western blotting. Furthermore, the sesquiterpene lactones also suppressed invasion and migration of the neuroblastoma cells. These results suggest that dehydrocostus lactone and costunolide are promising candidates for being developed into novel anticancer drugs effective against neuroblastoma. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  17. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.

    Science.gov (United States)

    Janoueix-Lerosey, Isabelle; Lequin, Delphine; Brugières, Laurence; Ribeiro, Agnès; de Pontual, Loïc; Combaret, Valérie; Raynal, Virginie; Puisieux, Alain; Schleiermacher, Gudrun; Pierron, Gaëlle; Valteau-Couanet, Dominique; Frebourg, Thierry; Michon, Jean; Lyonnet, Stanislas; Amiel, Jeanne; Delattre, Olivier

    2008-10-16

    Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.

  18. P73 expression in neuroblastoma: a role in the biology of advanced tumors?

    Science.gov (United States)

    Matos, P; Isidro, G; Vieira, E; Lacerda, A F; Martins, A G; Boavida, M G

    2001-01-01

    p73, a recently identified gene showing high homology to p53 and mapping to 1p36.33, was presented as a candidate gene for neuroblastoma. In this study the authors evaluate the levels and allelic nature of p73 expression in primary neuroblastomas using reverse transcription-polymerase chain reaction-restriction fragment length polymorphism strategies based on intragenic polymorphisms. From 32 neuroblastoma patients, 11 were heterozygous for the p73 polymorphisms analyzed. p73 expression was found to be low in the correspondent tumors and while all 6 stages 1 and 2 tumors presented biallelic expression, 4 out of the 5 stage 4 tumors showed only one active p73 allele. Analysis of blood samples from 8 healthy donors and 4 neuroblastoma patients revealed much higher levels of p73 expression, and exclusively of biallelic nature. These results are supportive of a role for p73 in the biology of neuroblastoma, particularly in some advanced tumors. Nevertheless, the G81A/C91T polymorphism, previously implicated in regulating the expression of p73, did not show any significant association with neuroblastoma development.

  19. Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation.

    Science.gov (United States)

    Akter, Jesmin; Takatori, Atsushi; Islam, Md Sazzadul; Nakazawa, Atsuko; Ozaki, Toshinori; Nagase, Hiroki; Nakagawara, Akira

    2014-10-10

    We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Regression of orthotopic neuroblastoma in mice by targeting the endothelial and tumor cell compartments

    Directory of Open Access Journals (Sweden)

    Stridsberg Mats

    2009-03-01

    Full Text Available Abstract Background High-risk neuroblastoma has an overall five-year survival of less than 40%, indicating a need for new treatment strategies such as angiogenesis inhibition. Recent studies have shown that chemotherapeutic drugs can inhibit angiogenesis if administered in a continuous schedule. The aim of this study was primarily to characterize tumor spread in an orthotopic, metastatic model for aggressive, MYCN-amplified neuroblastoma and secondarily to study the effects of daily administration of the chemotherapeutic agent CHS 828 on tumor angiogenesis, tumor growth, and spread. Methods MYCN-amplified human neuroblastoma cells (IMR-32, 2 × 106 were injected into the left adrenal gland in SCID mice through a flank incision. Nine weeks later, a new laparotomy was performed to confirm tumor establishment and to estimate tumor volume. Animals were randomized to either treatment with CHS 828 (20 mg/kg/day; p.o. or vehicle control. Differences between groups in tumor volume were analyzed by Mann-Whitney U test and in metastatic spread using Fisher's exact test. Differences with p Results The orthotopic model resembled clinical neuroblastoma in respect to tumor site, growth and spread. Treatment with CHS 828 resulted in tumor regression (p Conclusion The metastatic animal model in this study resembled clinical neuroblastoma and is therefore clinically relevant for examining new treatment strategies for this malignancy. Our results indicate that daily scheduling of CHS 828 may be beneficial in treating patients with high-risk neuroblastoma.

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

    DEFF Research Database (Denmark)

    Dagmar, Dagmar; Proescholdt, Martin; Reinert, Christiane

    2018-01-01

    Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radio-chemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive...... and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after four chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles...... of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% percent showed classic and desmoplastic-nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in Non-WNT/Non-SHH. Four cycles...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    PURPOSE: Medulloblastoma is the most common malignant brain tumor in childhood. Radical surgery in the non-metastatic stage is an important factor with respect to overall survival. In this case, 5-aminolevulinic acid (5-ALA) was used at second-look surgery in order to improve surgical results....... METHODS: The child was pretreated with 3 × 4 mg dexamethasone for 4 days prior to the second surgery. At 5 a.m. on the day of surgery, a freshly prepared solution of 5-ALA (20 mg/kg body weight; Medac, Germany) was given orally. RESULTS: At surgery, through the original opening, the vague red fluorescence...... changed from the high-risk medulloblastoma regimen to the standard-risk regimen. CONCLUSIONS: In this particular difficult case of non-contrast-enhancing tumor, 5-ALA was of vital importance to improve rate of resection and change the aggressiveness needed in postsurgery radiation therapy....

  3. 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

  4. 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 cases were confirmed as DNMB including three cases of medulloblastoma with extensive nodularity. Median age at diagnosis was 26 months. Radiology showed five cases with a vermis location and one with T2 hyperintensity. All cases showed a SHH immunoprofile. A 9q deletion was found in 6 cases, a MYCN-MYCL amplification in 1 case, and a SUFU germline mutation in 1 case (/9). The presence of SUFU and PTCH1 germline mutations agreed with previous reports. At 3 years, progression-free survival and overallsurvival rates were 72 ± 15% and 85 ± 10%, respectively. The rate of recurrence was relatively high (4 patients). This may have been because chemotherapy was delayed in two cases. Age > 3 years, and residual tumor may also have been an explanation for recurrence.

  5. Unusual chromaffin cell differentiation of a neuroblastoma after chemotherapy and radiotherapy: report of an autopsy case with immunohistochemical evaluations.

    Science.gov (United States)

    Miyauchi, Jun; Kiyotani, Chikako; Shioda, Yoko; Kumagai, Masaaki; Honna, Toshiro; Matsuoka, Kentaro; Masaki, Hidekazu; Aiba, Motohiko; Hata, Jun-ichi; Tsunematsu, Yukiko

    2004-04-01

    Neuroblastomas are derived from neural crest cells that are capable of multilineage differentiation. Ganglionic neuronal differentiation of childhood neuroblastoma is seen with increasing age, leading to more differentiated tumors called ganglioneuroblastomas or ganglioneuromas. Despite the fact that neuroblastomas most often arise from the adrenal medulla, chromaffin-cell differentiation in neuroblastomas is not widely recognized. Tumor cells with a chromaffin-cell nature have only been detected using histochemical techniques in neuroblastoma cell lines or focal areas of certain in vivo tumors. We describe a neuroblastoma that exhibited an unusual differentiation toward chromaffin cells in a patient that had been treated with surgery, intensive chemotherapy, and radiotherapy. Although a biopsy specimen of the retroperitoneal primary tumor was extensively necrotic, possibly because of a previous chemotherapy regimen, surgically resected metastatic tumors of bilateral ovaries were viable and diagnosed as poorly differentiated neuroblastomas according to the International Neuroblastoma Pathology Classification system. However, metastatic tumors of bilateral lungs examined at the time of autopsy exhibited histologic features similar to those of a pheochromocytoma/paraganglioma, and immunohistochemical examinations demonstrated that these tumors were composed of extra-adrenal chromaffin cells. This case confirms that neuroblastomas in childhood can transform into pheochromocytoma/paraganglioma-like tumors under special conditions.

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

    Science.gov (United States)

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

    2016-02-01

    Childhood medulloblastoma is associated with significant morbidity and mortality that is compounded by neurotoxicity for the developing brain caused by current therapies, including surgery, craniospinal radiation, and chemotherapy. Innate therapeutic resistance of some aggressive pediatric medulloblastoma has been attributed to a subpopulation of cells, termed cancer-initiating cells or cancer stemlike cells (CSCs), marked by the surface protein CD133 or CD15. Brain tumors characteristically contain areas of pathophysiologic hypoxia, which has been shown to drive the CSC phenotype leading to heightened invasiveness, angiogenesis, and metastasis. Novel therapies that target medulloblastoma CSCs are needed to improve outcomes and decrease toxicity. We hypothesized that oncolytic engineered herpes simplex virus (oHSV) therapy could effectively infect and kill pediatric medulloblastoma cells, including CSCs marked by CD133 or CD15. Using 4 human pediatric medulloblastoma xenografts, including 3 molecular subgroup 3 tumors, which portend worse patient outcomes, we determined the expression of CD133, CD15, and the primary HSV-1 entry molecule nectin-1 (CD111) by fluorescence activated cell sorting (FACS) analysis. Infectability and cytotoxicity of clinically relevant oHSVs (G207 and M002) were determined in vitro and in vivo by FACS, immunofluorescent staining, cytotoxicity assays, and murine survival studies. We demonstrate that hypoxia increased the CD133+ cell fraction, while having the opposite effect on CD15 expression. We established that all 4 xenografts, including the CSCs, expressed CD111 and were highly sensitive to killing by G207 or M002. Pediatric medulloblastoma, including Group 3 tumors, may be an excellent target for oHSV virotherapy, and a clinical trial in medulloblastoma is warranted. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. 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.

  8. Estrogen and soy isoflavonoids decrease sensitivity of medulloblastoma and central nervous system primitive neuroectodermal tumor cells to chemotherapeutic cytotoxicity

    OpenAIRE

    Belcher, Scott M.; Burton, Caleb C.; Cookman, Clifford J.; Kirby, Michelle; Miranda, Gabriel L.; Saeed, Fatima O.; Wray, Kathleen E.

    2017-01-01

    Background Our previous studies demonstrated that growth and migration of medulloblastoma (MB), the most common malignant brain tumor in children, are stimulated by 17?-estradiol. The growth stimulating effects of estrogens are mediated through ER? and insulin-like growth factor 1 signaling to inhibit caspase 3 activity and reduce tumor cell apoptosis. The objective of this study was to determine whether estrogens decreased sensitivity of MB cells to cytotoxic actions of chemotherapeutic drug...

  9. The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Sarah Ball

    Full Text Available Tumors of the central nervous system represent a major source of cancer-related deaths, with medulloblastoma and glioblastoma being the most common malignant brain tumors in children and adults respectively. While significant advances in treatment have been made, with the 5-year survival rate for medulloblastoma at 70-80%, treating patients under 3 years of age still poses a problem due to the deleterious effects of radiation on the developing brain, and the median survival for patients with glioblastoma is only 15 months. The transcription factor, STAT3, has been found constitutively activated in a wide variety of cancers and in recent years it has become an attractive therapeutic target. We designed a non-peptide small molecule STAT3 inhibitor, LLL12, using structure-based design. LLL12 was able to inhibit STAT3 phosphorylation, decrease cell viability and induce apoptosis in medulloblastoma and glioblastoma cell lines with elevated levels of p-STAT3 (Y705. IC(50 values for LLL12 were found to be between 1.07 µM and 5.98 µM in the five cell lines expressing phosphorylated STAT3. STAT3 target genes were found to be downregulated and a decrease in STAT3 DNA binding was observed following LLL12 treatment, indicating that LLL12 is an effective STAT3 inhibitor. LLL12 was also able to inhibit colony formation, wound healing and decreased IL-6 and LIF secretion. Our results suggest that LLL12 is a potent STAT3 inhibitor and that it may be a potential therapeutic treatment for medulloblastoma and glioblastoma.

  10. Targeted immunotherapy for high-risk neuroblastoma--the role of monoclonal antibodies.

    Science.gov (United States)

    Parsons, Kerry; Bernhardt, Brooke; Strickland, Brandy

    2013-02-01

    To systematically review clinical trials evaluating anti-disialoganglioside (GD2) antibodies in treating high-risk neuroblastoma in children. A literature search was conducted in PubMed/MEDLINE, International Pharmaceutical Abstracts, and Cumulative Index of Nursing and Allied Health Literature (all searches 1990-August 2012) using the terms neuroblastoma, immunotherapy, 3F8, ch14.18, and hu14.18. Meeting abstracts presented between 1990 and 2012 from the American Society of Clinical Oncology, European Society for Medical Oncology, the American Society of Pediatric Hematology Oncology, Society of Surgical Oncology, and the American Society of Hematology were also evaluated. All completed and ongoing clinical trials of anti-GD2 antibodies in neuroblastoma were included. References from selected articles were also reviewed to identify additional citations. In 1999, the results of a Children's Cancer Group trial established that consolidation therapy after induction, surgery, and radiation should include purged autologous stem cell rescue followed by maintenance with isotretinoin. Overall survival at 7 years with this regimen remains below 30%. Over the following decade, antibodies targeting GD2, a surface antigen found on the surface of neuroblastoma cells, have emerged as a major therapeutic development for high-risk neuroblastoma. Anti-GD2 antibodies incite immune-mediated cytotoxicity toward neuroblastoma cells when given as monotherapy or in combination with cytokines such as sargramostim (granulocyte-macrophage colony-stimulating factor) or aldesleukin (interleukin-2). Responses to anti-GD2 agents appear most notable in patients with minimal residual disease following standard therapy. A chimeric preparation, ch14.18, is the only anti-GD2 antibody to be evaluated in a large controlled clinical trial, in which it demonstrated overall survival of 86% at 2 years in patients with high-risk neuroblastoma. Older nonrandomized studies of ch14.18 monotherapy and 3F8, a

  11. Functional polymorphisms in FAS/FASL system increase the risk of neuroblastoma in Chinese population.

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    Wei Han

    Full Text Available The FAS and FASL system plays a substantial role in apoptosis and immune escape of cells. Three polymorphisms located in the promoter regions of FAS (-1377G/A and -670A/G and FASL (-844T/C have been shown to alter the transcriptional activity of the genes, respectively. This study was conducted to evaluate the effects of these polymorphisms on the susceptibility of neuroblastoma in the Chinese population. A total of 203 patients with neuroblastoma and 411 controls were recruited in this case-control study. Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP was applied for genotyping. Unconditional logistic regression was used to estimate cancer risk by calculating odds ratios (ORs and their 95% confidence intervals (95% CIs. It was observed that significantly increased risks of neuroblastoma associated with FAS -1377G/A and FASL -844T/C polymorphisms, with ORs equal to 1.55 (95% CI, 1.10-2.20 for FAS -1377 A allele and 2.90 (95% CI, 2.04-4.12 for FASL -844CC genotype carriers compared with non-carriers, respectively. However, no association was found between the polymorphisms of FAS -670A/G and risk of neuroblastoma. In addition, the cumulative effect of FAS and FASL polymorphisms on risk of neuroblastoma was observed (P for trend = 2.502×10(-10, with OR for the carriers of both FAS -1377A allele and FASL -844CC genotypes equaled to 3.95 (95% CI, 2.40-6.51. This work reveals that polymorphisms of FAS -1377G/A and FASL -844T/C but not FAS -670A/G are associated with risk of neuroblastoma in Chinese. These findings support the hypothesis that genetic polymorphism in FAS/FASL death system may influence individual susceptibility to neuroblastoma.

  12. Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma.

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    Mao, Yumeng; Eissler, Nina; Blanc, Katarina Le; Johnsen, John Inge; Kogner, Per; Kiessling, Rolf

    2016-08-01

    Neuroblastoma is the most common extracranial solid cancer type in childhood, and high-risk patients have poor prognosis despite aggressive multimodal treatment. Neuroblastoma-driven inflammation contributes to the induction of suppressive myeloid cells that hamper efficient antitumor immune responses. Therefore, we sought to enhance antitumor immunity by removing immunosuppression mediated by myeloid cells. The prognostic values of myeloid cells are demonstrated by analyzing genomic datasets of neuroblastoma patients. The impact of tumor-derived factors on myelopoiesis and local induction of suppressive myeloid cells is dissected by in vitro culture models using freshly isolated human CD34(+) hematopoietic stem cells, primary human monocytes, and murine bone marrow cells. To test the therapeutic efficacy of BLZ945 as a monotherapy or in combination with checkpoint inhibitors, we used a transgenic murine model (TH-MYCN) that develops aggressive spontaneous neuroblastoma. We report that infiltrating CSF-1R(+) myeloid cells predict poor clinical outcome in patients with neuroblastoma. In vitro, neuroblastoma-derived factors interfere with early development of myeloid cells and enable suppressive functions on human monocytes through M-CSF/CSF-1R interaction. In a transgenic mouse model (TH-MYCN) resembling high-risk human neuroblastoma, antagonizing CSF-1R with a selective inhibitor (BLZ945) modulates the induction of human and murine suppressive myeloid cells and efficiently limit tumor progression. While checkpoint inhibitors are insufficient in controlling tumor growth, combining BLZ945 with PD-1/PD-L1 blocking antibodies results in superior tumor control. Our results demonstrate the essential role of CSF-1R signaling during the induction of suppressive myeloid cells and emphasize its clinical potential as an immunotherapy for human cancers. Clin Cancer Res; 22(15); 3849-59. ©2016 AACR. ©2016 American Association for Cancer Research.

  13. Identification of epigenetically regulated genes that predict patient outcome in neuroblastoma

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    Enström Camilla

    2011-02-01

    Full Text Available Abstract Background Epigenetic mechanisms such as DNA methylation and histone modifications are important regulators of gene expression and are frequently involved in silencing tumor suppressor genes. Methods In order to identify genes that are epigenetically regulated in neuroblastoma tumors, we treated four neuroblastoma cell lines with the demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC either separately or in conjunction with the histone deacetylase inhibitor trichostatin A (TSA. Expression was analyzed using whole-genome expression arrays to identify genes activated by the treatment. These data were then combined with data from genome-wide DNA methylation arrays to identify candidate genes silenced in neuroblastoma due to DNA methylation. Results We present eight genes (KRT19, PRKCDBP, SCNN1A, POU2F2, TGFBI, COL1A2, DHRS3 and DUSP23 that are methylated in neuroblastoma, most of them not previously reported as such, some of which also distinguish between biological subsets of neuroblastoma tumors. Differential methylation was observed for the genes SCNN1A (p PRKCDBP (p KRT19 (p KRT19 and PRKCDBP was significantly lower in patients that have died from the disease compared with patients with no evidence of disease (fold change -8.3, p = 0.01 for KRT19 and fold change -2.4, p = 0.04 for PRKCDBP. Conclusions In our study, a low methylation frequency of SCNN1A, PRKCDBP and KRT19 is significantly associated with favorable outcome in neuroblastoma. It is likely that analysis of specific DNA methylation will be one of several methods in future patient therapy stratification protocols for treatment of childhood neuroblastomas.

  14. MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma.

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    Fabian, Johannes; Opitz, Desirée; Althoff, Kristina; Lodrini, Marco; Hero, Barbara; Volland, Ruth; Beckers, Anneleen; de Preter, Katleen; Decock, Anneleen; Patil, Nitin; Abba, Mohammed; Kopp-Schneider, Annette; Astrahantseff, Kathy; Wünschel, Jasmin; Pfeil, Sebastian; Ercu, Maria; Künkele, Annette; Hu, Jamie; Thole, Theresa; Schweizer, Leonille; Mechtersheimer, Gunhild; Carter, Daniel; Cheung, Belamy B; Popanda, Odilia; von Deimling, Andreas; Koster, Jan; Versteeg, Rogier; Schwab, Manfred; Marshall, Glenn M; Speleman, Frank; Erb, Ulrike; Zoeller, Margot; Allgayer, Heike; Simon, Thorsten; Fischer, Matthias; Kulozik, Andreas E; Eggert, Angelika; Witt, Olaf; Schulte, Johannes H; Deubzer, Hedwig E

    2016-10-11

    The systemic and resistant nature of metastatic neuroblastoma renders it largely incurable with current multimodal treatment. Clinical progression stems mainly from the increasing burden of metastatic colonization. Therapeutically inhibiting the migration-invasion-metastasis cascade would be of great benefit, but the mechanisms driving this cycle are as yet poorly understood. In-depth transcriptome analyses and ChIP-qPCR identified the cell surface glycoprotein, CD9, as a major downstream player and direct target of the recently described GRHL1 tumor suppressor. CD9 is known to block or facilitate cancer cell motility and metastasis dependent upon entity. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome. MYCN and HDAC5 colocalized to the CD9 promoter and repressed transcription. CD9 expression diminished with progressive tumor development in the TH-MYCN transgenic mouse model for neuroblastoma, and CD9 expression in neuroblastic tumors was far below that in ganglia from wildtype mice. Primary neuroblastomas lacking MYCN amplifications displayed differential CD9 promoter methylation in methyl-CpG-binding domain sequencing analyses, and high-level methylation was associated with advanced stage disease, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to embryonic bone marrow. Combined treatment of neuroblastoma cells with HDAC/DNA methyltransferase inhibitors synergistically induced CD9 expression despite hypoxic, metabolic or cytotoxic stress. Our results show CD9 is a critical and indirectly druggable suppressor of the invasion-metastasis cycle in neuroblastoma.

  15. Copy number variation at 1q21.1 associated with neuroblastoma.

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    Diskin, Sharon J; Hou, Cuiping; Glessner, Joseph T; Attiyeh, Edward F; Laudenslager, Marci; Bosse, Kristopher; Cole, Kristina; Mossé, Yaël P; Wood, Andrew; Lynch, Jill E; Pecor, Katlyn; Diamond, Maura; Winter, Cynthia; Wang, Kai; Kim, Cecilia; Geiger, Elizabeth A; McGrady, Patrick W; Blakemore, Alexandra I F; London, Wendy B; Shaikh, Tamim H; Bradfield, Jonathan; Grant, Struan F A; Li, Hongzhe; Devoto, Marcella; Rappaport, Eric R; Hakonarson, Hakon; Maris, John M

    2009-06-18

    Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at approximately 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent-offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.

  16. High programmed cell death 1 ligand-1 expression: association with CD8+ T-cell infiltration and poor prognosis in human medulloblastoma.

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    Murata, Daiki; Mineharu, Yohei; Arakawa, Yoshiki; Liu, Bin; Tanji, Masahiro; Yamaguchi, Makoto; Fujimoto, Ko-Ichi; Fukui, Nobuyuki; Terada, Yukinori; Yokogawa, Ryuta; Yamaguchi, Maki; Minamiguchi, Sachiko; Miyamoto, Susumu

    2017-05-05

    OBJECTIVE Medulloblastoma is a type of malignant tumor arising in the cerebellum. The clinical importance of programmed cell death 1 ligand-1 (PD-L1) expression in medulloblastoma remains unknown. The aim of the present study was to examine the expression of PD-L1 and tumor-infiltrating T cells, and to evaluate their relationships to the prognosis of patients with medulloblastoma. METHODS The authors immunohistochemically analyzed PD-L1 expression and CD3+ and CD8+ lymphocyte infiltrations in tumor specimens from 16 patients with medulloblastoma. RESULTS High expression of PD-L1 was observed in 9 (56.3%) of 16 samples studied. High expression of PD-L1 was associated with low infiltrations of CD3+ or CD8+ lymphocytes. Patients with high expression of PD-L1 had shorter progression-free survival and overall survival times than those with low expression (p = 0.076 and p = 0.099, respectively). In addition, patients with high expression of PD-L1 and with low infiltration of CD8+ lymphocytes had a significantly worse outcome, with a 5-year survival rate of 15%, as compared with the other patients, who had a 5-year survival rate of nearly 90% (p = 0.0048 for progression-free survival and p = 0.010 for overall survival). CONCLUSIONS These findings indicate that PD-L1 expression was associated with a reduced infiltration of CD8+ T cells and poor prognosis in human medulloblastoma.

  17. Extracellular matrix rigidity modulates neuroblastoma cell differentiation and N-myc expression.

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    Lam, Wilbur A; Cao, Lizhi; Umesh, Vaibhavi; Keung, Albert J; Sen, Shamik; Kumar, Sanjay

    2010-02-10

    Neuroblastoma is a pediatric malignancy characterized by tremendous clinical heterogeneity, in which some tumors are extremely aggressive while others spontaneously differentiate into benign forms. Because the degree of differentiation correlates with prognosis, and because differentiating agents such as retinoic acid (RA) have proven to decrease mortality, much effort has been devoted to identifying critical regulators of neuroblastoma differentiation in the cellular microenvironment, including cues encoded in the extracellular matrix (ECM). While signaling between tumor cells and the ECM is classically regarded to be based purely on biochemical recognition of ECM ligands by specific cellular receptors, a number of recent studies have made it increasingly clear that the biophysical properties of the ECM may also play an important role in this cross-talk. Given that RA-mediated neuroblastoma differentiation is accompanied by profound changes in cell morphology and neurite extension, both of which presumably rely upon mechanotransductive signaling systems, it occurred to us that mechanical cues from the ECM might also influence RA-mediated differentiation, which in turn might regulate clinically-relevant aspects of neuroblastoma biology. In this study, we tested this hypothesis by subjecting a series of neuroblastoma culture models to ECM microenvironments of varying mechanical stiffness and examined the regulatory role of ECM stiffness in proliferation, differentiation, and expression of tumor markers. We find that increasing ECM stiffness enhances neuritogenesis and suppresses cell proliferation. Remarkably, increasing ECM stiffness also reduces expression of N-Myc, a transcription factor involved in multiple aspects of oncogenic proliferation that is used for evaluating prognosis and clinical grading of neuroblastoma. Furthermore, the addition of RA enhances all of these effects for all ECM stiffnesses tested. Together, our data strongly support the notion that

  18. Common variations within HACE1 gene and neuroblastoma susceptibility in a Southern Chinese population

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    Zhang Z

    2017-02-01

    Full Text Available Zhuorong Zhang,1,2,* Ruizhong Zhang,1,* Jinhong Zhu,3 Fenghua Wang,1 Tianyou Yang,1 Yan Zou,1 Jing He,1 Huimin Xia1,2 1Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 2Southern Medical University, Guangzhou, Guangdong, 3Molecular Epidemiology Laboratory and Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China *These authors contributed equally to this work Abstract: Neuroblastoma is a common fatal pediatric cancer of the developing sympathetic nervous system, which accounts for ~10% of all pediatric cancer deaths. To investigate genetic risk factors related to neuroblastoma, many genome-wide association studies have been performed, and single nucleotide polymorphisms (SNPs within HACE1 gene have been identified to associate with neuroblastoma risk. However, the association of the HACE1 SNPs with neuroblastoma needs to be validated in Southern Chinese children. We genotyped five SNPs located in the HACE1 gene (rs4336470 C>T, rs9404576 T>G, rs4079063 A>G, rs2499663 T>C, and rs2499667 A>G in 256 Southern Chinese patients in comparison with 531 ethnically matched healthy controls. Single locus analysis showed no significant association between any of HACE1 SNPs and neuroblastoma risk in Southern Chinese children. However, when all the risk genotypes were combined, we found a borderline significant trend toward an increased neuroblastoma risk with 4–5 risk genotypes (adjusted odds ratio =1.36, 95% confidence interval =0.98–1.89, P=0.065. Moreover, stratified analysis found that carriers of 4–5 risk genotypes tended to develop neuroblastoma in the retroperitoneal region and have more aggressive tumors, progressing to advanced clinical stages III/IV, when compared with those of 0–3 risk genotypes. In conclusion, HACE1 gene may have weak effect on neuroblastoma risk in

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

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    Wei ZHENG

    2011-06-01

    Full Text Available Objective To retrospectively review the clinical characteristics of medulloblastoma,discuss the optimized treatment regimen,and analyze the prognostic influential factors.Methods Thirty-three children with pathologically certified medulloblastoma(aged 3-14 years with average of 6.5 years,admitted from Aug.2004 to Dec.2007,received radiotherapy within 3 weeks post surgery.Ratiotherapy consisted of 28~36Gy whole craniospinal radiation and a supplementary radiation aimed at tumors by three-dimensional conformal radiotherapy(3D-CRT for a total dose of 50~54Gy(conventional fraction dose of 1.8-2.0Gy.A part of patients received hyperfractionation radiotherapy(1.0Gy/f,2f/d for alleviating the tardive adverse events.Meanwhile,a synchronized chemotherapy,consisting of lomustine + vincristine + cisplatin,or isophosphamide + carboplatin + etoposide,was administered after the completion of whole craniospinal radiation,and 3-5 courses of sequential chemotherapy were given after the overall radiotherapy was finished.According to the metastasis,and the residual tumor and its size,the 33 patients were divided into 2 groups as follows: low-risk group(n=24: no metastases,total or sub-total excision of tumors(residual tumors ≤1.5cm3;high-risk group(n=9: either metastases or residual tumor > 1.5cm3.The 3-year survival rates of two groups were then compared.Results The combined radiotherapy and chemotherapy was effective to 10 of the 11 patients(90.9% with residual tumors.Out of the 33 patients,31 obtained complete remission(93.9%,and 2 patients showed partial remission or stable status(3.0%,respectively.The median survival time of 33 patients was 51 months,3-year disease free survival(DFS was 75.8%,and 3-year overall survival(OS was 78.8%,including 33.3% in high-risk group and 95.8% in low-risk group(P < 0.01.The major side effects occurred in haematological system and digestive system,such as an incidence of 21.2%(7/33 with grade Ⅲ-Ⅳ bone marrow suppression

  20. Risk factors for development of postoperative cerebellar mutism syndrome in children after medulloblastoma surgery.

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    Pols, San Y C V; van Veelen, Marie Lise C; Aarsen, Femke K; Gonzalez Candel, Antonia; Catsman-Berrevoets, Coriene E

    2017-07-01

    OBJECTIVE Postoperative cerebellar mutism syndrome (pCMS) occurs in 7%-50% of children after cerebellar tumor surgery. Typical features include a latent onset of 1-2 days after surgery, transient mutism, emotional lability, and a wide variety of motor and neurobehavioral abnormalities. Sequelae of this syndrome usually persist long term. The principal causal factor is bilateral surgical damage (regardless of tumor location) to any component of the proximal efferent cerebellar pathway, which leads to temporary dysfunction of cerebral cortical regions as a result of diaschisis. Tumor type, cerebellar midline location, and brainstem involvement are risk factors for pCMS that have been identified repeatedly, but they do not explain its latent onset. Ambiguous or negative results for other factors, such as hydrocephalus, postoperative meningitis, length of vermian incision, and tumor size, have been reached. The aim of this study was to identify perioperative clinical, radiological, and laboratory factors that also increase risk for the development of pCMS. The focus was on factors that might explain the delayed onset of pCMS and thus might provide a time window for taking precautionary measures to prevent pCMS or reduce its severity. The study was focused specifically on children who had undergone surgery for medulloblastoma. METHODS In this single-center retrospective cohort study, the authors included 71 children with medulloblastoma, 28 of whom developed pCMS after primary resection. Clinical and laboratory data were collected prospectively and analyzed systematically. Variables were included for univariate and multivariate analysis. RESULTS Univariate regression analysis revealed 7 variables that had a significant influence on pCMS onset, namely, tumor size, maximum tumor diameter > 5 cm, tumor infiltration or compression of the brainstem, significantly larger decreases in hemoglobin (p = 0.010) and hematocrit (p = 0.003) in the pCMS group after surgery than in the

  1. The value of anterior displacement of the abdominal aorta in diagnosing neuroblastoma in children

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    Schiavon, Jose Luiz de Oliveira; Caran, Eliana Maria Monteiro; Lederman, Henrique Manoel, E-mail: schiavon00@gmail.com [Universidade Federal de Sao Paulo (EPM/UNIFESP), Sao Paulo, SP (Brazil). Escola Paulista de Medicina; Odone Filho, Vicente [Universidade de Sao Paulo (FM/USP), Sao Paulo, SP (Brazil). Faculdade de Medicina

    2016-11-15

    Objective: To determine the value of anterior displacement of the abdominal aorta, when present at any level or only at the level of the adrenal gland, contralateral to the mass, in diagnosing neuroblastoma on computed tomography or magnetic resonance imaging in children up to 7 years of age. Materials and Methods: Imaging examinations of 66 patients were classified by consensus as for the presence of anterior aorta displacement and were compared with the pathology report. Results: We found anterior abdominal aorta displacement in 26 (39.39%) of the 66 patients evaluated. Among those 26 patients, we identified neuroblastoma in 22 (84.62%), nephroblastoma in 3 (11.54%), and Burkitt lymphoma in 1 (3.85%). The positive predictive value was 84.62%, and the specificity was 88.24%. The displacement of the aorta was at the adrenal level, contralateral to the mass, in 14 cases, all of which were attributed to neuroblastoma. Conclusion: When the abdominal aorta is displaced at the level of the adrenal gland, contralateral to the mass, it can be said that the diagnosis is neuroblastoma, whereas abdominal aorta displacement occurring at other abdominal levels has a positive predictive value for neuroblastoma of approximately 85%. (author)

  2. The value of anterior displacement of the abdominal aorta in diagnosing neuroblastoma in children

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    Jose Luiz de Oliveira Schiavon

    Full Text Available Abstract Objective: To determine the value of anterior displacement of the abdominal aorta, when present at any level or only at the level of the adrenal gland, contralateral to the mass, in diagnosing neuroblastoma on computed tomography or magnetic resonance imaging in children up to 7 years of age. Materials and Methods: Imaging examinations of 66 patients were classified by consensus as for the presence of anterior aorta displacement and were compared with the pathology report. Results: We found anterior abdominal aorta displacement in 26 (39.39% of the 66 patients evaluated. Among those 26 patients, we identified neuroblastoma in 22 (84.62%, nephroblastoma in 3 (11.54%, and Burkitt lymphoma in 1 (3.85%. The positive predictive value was 84.62%, and the specificity was 88.24%. The displacement of the aorta was at the adrenal level, contralateral to the mass, in 14 cases, all of which were attributed to neuroblastoma. Conclusion: When the abdominal aorta is displaced at the level of the adrenal gland, contralateral to the mass, it can be said that the diagnosis is neuroblastoma, whereas abdominal aorta displacement occurring at other abdominal levels has a positive predictive value for neuroblastoma of approximately 85%.

  3. Prediction of Clinical Outcome Using Gene Expression Profiling and Artificial Neural Networks for Patients with Neuroblastoma

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    Wei, Jun S.; Greer, Braden T.; Westermann, Frank; Steinberg, Seth M.; Son, Chang-Gue; Chen, Qing-Rong; Whiteford, Craig C.; Bilke, Sven; Krasnoselsky, Alexei L.; Cenacchi, Nicola; Catchpoole, Daniel; Berthold, Frank; Schwab, Manfred; Khan, Javed

    2005-01-01

    Currently, patients with neuroblastoma are classified into risk groups (e.g., according to the Children’s Oncology Group risk-stratification) to guide physicians in the choice of the most appropriate therapy. Despite this careful stratification, the survival rate for patients with high-risk neuroblastoma remains artificial neural networks to develop an accurate predictor of survival for each individual patient with neuroblastoma. Using principal component analysis we found that neuroblastoma tumors exhibited inherent prognostic specific gene expression profiles. Subsequent artificial neural network-based prognosis prediction using expression levels of all 37,920 good-quality clones achieved 88% accuracy. Moreover, using an artificial neural network-based gene minimization strategy in a separate analysis we identified 19 genes, including 2 prognostic markers reported previously, MYCN and CD44, which correctly predicted outcome for 98% of these patients. In addition, these 19 predictor genes were able to additionally partition Children’s Oncology Group-stratified high-risk patients into two subgroups according to their survival status (P = 0.0005). Our findings provide evidence of a gene expression signature that can predict prognosis independent of currently known risk factors and could assist physicians in the individual management of patients with high-risk neuroblastoma. PMID:15466177

  4. Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas.

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    Castino, Roberta; Pace, Deborah; Démoz, Marina; Gargiulo, Marco; Ariatta, Chiara; Raiteri, Elisabetta; Isidoro, Ciro

    2002-02-20

    Neuroblastoma is the most common type of cancer in infants. In children this tumor is particularly aggressive; despite various new therapeutic approaches, it is associated with poor prognosis. Given the importance of endosomal-lysosomal proteolysis in cellular metabolism, we hypothesized that inhibition of lysosomal protease would impact negatively on neuroblastoma cell survival. Treatment with E-64 or CA074Me (2 specific inhibitors of cathepsin B) or with pepstatin A (a specific inhibitor of cathepsin D) was cytotoxic for 2 neuroblastoma cell lines having different degrees of malignancy. Cell death was associated with condensation and fragmentation of chromatin and externalization of plasma membrane phosphatidylserine, 2 hallmarks of apoptosis. Concomitant inhibition of the caspase cascade protected neuroblastoma cells from cathepsin inhibitor-induced cytotoxicity. These data indicate that prolonged inhibition of the lysosomal proteolytic pathway is incompatible with cell survival, leading to apoptosis of neuroblastoma cells, and that the cathepsin-mediated and caspase-mediated proteolytic systems are connected and cooperate in the regulation of such an event. Since modern antitumor chemotherapy is aimed at restoring the normal rate of apoptosis in neoplastic tissues, the demonstration that endosomal-lysosomal cathepsins are involved in this process may constitute a basis for novel strategies that include cathepsin inhibitors in the therapeutic regimen. Copyright 2001 Wiley-Liss, Inc.

  5. Transcribed-ultra conserved region expression is associated with outcome in high-risk neuroblastoma

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    Garaventa Alberto

    2009-12-01

    Full Text Available Abstract Background Neuroblastoma is the most common, pediatric, extra-cranial, malignant solid tumor. Despite multimodal therapeutic protocols, outcome for children with a high-risk clinical phenotype remains poor, with long-term survival still less than 40%. Hereby, we evaluated the potential of non-coding RNA expression to predict outcome in high-risk, stage 4 neuroblastoma. Methods We analyzed expression of 481 Ultra Conserved Regions (UCRs by reverse transcription-quantitative real-time PCR and of 723 microRNAs by microarrays in 34 high-risk, stage 4 neuroblastoma patients. Results First, the comparison of 8 short- versus 12 long-term survivors showed that 54 UCRs were significantly (P P P P Conclusions Our pilot study suggests that a deregulation of the microRNA/T-UCR network may play an important role in the pathogenesis of neuroblastoma. After further validation on a larger independent set of samples, such findings may be applied as the first T-UCR prognostic signature for high-risk neuroblastoma patients.

  6. Nifurtimox induces apoptosis of neuroblastoma cells in vitro and in vivo.

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    Saulnier Sholler, Giselle L; Brard, Laurent; Straub, Jennifer A; Dorf, Lee; Illeyne, Sharon; Koto, Karen; Kalkunte, Satyan; Bosenberg, Marcus; Ashikaga, Taka; Nishi, Rae

    2009-03-01

    Neuroblastoma is the most common extracranial solid tumor in children and, when disseminated, carries a poor prognosis. Even with aggressive combinations of chemotherapy, surgery, autologous bone marrow transplant, and radiation, long-term survival remains at 30% and new therapies are needed. Recently, a patient with neuroblastoma who acquired Chagas disease was treated with nifurtimox with subsequent reduction in tumor size. The effect of nifurtimox on the neuroblastoma cell lines CHLA-90, LA1-55n, LA-N2, SMS-KCNR, and SY5Y was examined. Nifurtimox decreased cell viability in a concentration-dependent manner. Cell morphology, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay, and caspase-3 activation indicate that cell death was primarily due to apoptosis. Nifurtimox also suppressed basal and TrkB-mediated Akt phosphorylation, and the cytotoxicity of nifurtimox was attenuated by a tyrosine hydroxylase inhibitor (alpha-methyl-tyrosine). Nifurtimox killed catecholaminergic, but not cholinergic, autonomic neurons in culture. In vivo xenograft models showed inhibition of tumor growth with a histologic decrease in proliferation and increase in apoptosis. These results suggest that nifurtimox induces cell death in neuroblastoma. Therefore, further studies are warranted to develop nifurtimox as a promising new treatment for neuroblastoma.

  7. Iodine-123-MIBG scintigraphy in neuroblastoma. Relationship between the intensity of uptake and tumor characteristics

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    Okuyama, Chio; Ushijima, Yo; Watanabe, Kaori; Sugihara, Hiroki; Nishimura, Tsunehiko [Kyoto Prefectural Univ. of Medicine (Japan)

    1999-10-01

    Iodine-123-MlBG ({sup 123}I-MIBG) scintigraphy were performed for 23 patients with neuroblastoma at diagnosis. The intensity of MIBG activity in the primary tumor was evaluated visually (grade 3; intense uptake-grade 0; no definite uptake), and its relationship to the size, degree of tumor spread, urinary catecholamine metabolites (VMA, HVA), and histological types were investigated. The results of {sup 123}I-MIBG uptake grade were as follows: grade 3; 44% (10/23), grade 2; 30% (7/23), grade 1; 17% (4/23), grade 0; 9% (2/23). The grade was not associated with the tumor size, or the degree of tumor extension to the distant lesion, either. The more catecholamine metabolites were excreted in the urine, the tumor tended to have more intense uptake. The tumors of neuroblastoma rosette fibrillary type, and ganglioneuroblastoma poorly differentiated type had more intense uptake than neuroblastoma round cell type and ganglioneuroblastoma well differentiated type. The case of ganglioneuroma did not have definite MIBG uptake. The intensity of MIBG uptake is not relevant to the pathological grade of neuroblastoma, but considering the electromicroscopical features of neuroblastoma reported previously, it is thought to reflect the histological type. (author)

  8. Improved antitumour immunity in murine neuroblastoma using a combination of IL-2 and IL-12.

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    Siapati, K E; Barker, S; Kinnon, C; Michalski, A; Anderson, R; Brickell, P; Thrasher, A J; Hart, S L

    2003-05-19

    Neuroblastoma immunotherapy using cytokine-modified tumour cells has been tested in clinical trials. However, because of the complex nature of antitumour immune responses, a number of therapies may be required for complete tumour eradication and generation of systemic immunity. We report here the improved antitumour effect of two cytokines, interleukin-2 (IL-2) and interleukin-12 (IL-12), when coexpressed by neuroblastoma cell lines. Initially, transfection of human and mouse neuroblastoma cell lines resulted in high expression levels of biologically active IL-2 and IL-12 in vitro. These cytokines when expressed by transfected Neuro-2A cells completely abolished their in vivo tumorigenicity in a syngeneic neuroblastoma model. Vaccination of established tumours with IL-12-producing cells exhibited a clear effect with reduced tumour growth in the presence of IL-2. In vivo depletion studies showed that CD4(+) and CD8(+) T cells mediate the response against cytokine-producing cells. These results suggest that IL-2 and IL-12, when cotransfected in tumour cells, are effective against established disease and provide a promising immunotherapeutic approach for the treatment of neuroblastoma.

  9. Molecular mechanisms of anti-cancer action of garlic compounds in neuroblastoma.

    Science.gov (United States)

    Karmakar, Surajit; Choudhury, Subhasree Roy; Banik, Naren L; Ray, Swapan K

    2011-05-01

    The medicinal properties of garlic (Allium sativum) have been well known and widely used since historical times. Garlic compounds have received increasing attention during the last few years due to their cancer chemopreventive properties. The anti-cancer activity of garlic-derived organosulfur compounds (OSCs) are extensively reported in many cancers but only a few in the pediatric tumor neuroblastoma, which warrants exploration of new therapy for its management. There are some recent reports suggesting that garlic-derived OSCs cause cell cycle arrest, generate reactive oxygen species (ROS), activate stress kinases, and also stimulate the mitochondrial pathway for apoptosis in malignant neuroblastoma. The comprehensive mechanisms of anti-cancer action of OSCs still remain unclear and require more studies in neuroblastoma. This review is designed to highlight the molecular mechanisms of anti-cancer actions of garlic-derived OSCs in neuroblastoma and as well as in several other cancers. Further studies should be conducted to establish the clinical expediency of garlic-derived OSCs for treatment of malignant neuroblastoma in humans.

  10. A multidisciplinary team care approach improves outcomes in high-risk pediatric neuroblastoma patients.

    Science.gov (United States)

    Chang, Hsiu-Hao; Liu, Yen-Lin; Lu, Meng-Yao; Jou, Shiann-Tarng; Yang, Yung-Li; Lin, Dong-Tsamn; Lin, Kai-Hsin; Tzen, Kai-Yuan; Yen, Ruoh-Fang; Lu, Ching-Chu; Liu, Chia-Ju; Peng, Steven Shinn-Forng; Jeng, Yung-Ming; Huang, Shiu-Feng; Lee, Hsinyu; Juan, Hsueh-Fen; Huang, Min-Chuan; Liao, Yung-Feng; Lee, Ya-Ling; Hsu, Wen-Ming

    2017-01-17

    We assessed the impact of a multidisciplinary team care program on treatment outcomes in neuroblastoma patients. Newly diagnosed neuroblastoma patients received treatment under the Taiwan Pediatric Oncology Group (TPOG) N2002 protocol at the National Taiwan University Hospital beginning in 2002. A multidisciplinary team care approach that included nurse-led case management for patients treated under this protocol began in January 2010. Fifty-eight neuroblastoma patients, including 29 treated between 2002 and 2009 (Group 1) and 29 treated between 2010 and 2014 (Group 2), were enrolled in the study. The 5-year overall survival (OS) and event-free survival (EFS) rates for all 58 patients were 59% and 54.7%, respectively. Group 2 patients, who were treated after implementation of the multidisciplinary team care program, had better 3-year EFS (P = 0.046), but not OS (P = 0.16), rates than Group 1 patients. In a multivariate analysis, implementation of the multidisciplinary team approach was the only significant independent prognostic factor for neuroblastoma patients. In further subgroup analyses, the multidisciplinary team approach improved EFS, but not OS, in patients with stage 4 disease, those in the high-risk group, and those with non-MYCN amplified tumors. These data indicate a multidisciplinary team care approach improved survival outcomes in high-risk neuroblastoma patients. However, further investigation will be required to evaluate the long-term effects of this approach over longer follow-up periods.

  11. Phenolic diterpenes derived from Hyptis incana induce apoptosis and G(2)/M arrest of neuroblastoma cells.

    Science.gov (United States)

    Tabata, Keiichi; Kim, Myongjun; Makino, Mitsuko; Satoh, Mitsuru; Satoh, Yoshio; Suzuki, Takashi

    2012-11-01

    Neuroblastoma is one of the most commonly encountered solid tumors in the pediatric age group, and the prognosis of patients with advanced neuroblastoma is very poor. In this study, the antitumor effects of five phenolic diterpenes derived from Hyptis incana (Lamiaceae), a Brazilian medicinal plant, were examined on neuroblastoma cells. Cytotoxicity was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptotic nuclear shrinkage was monitored by Hoechst 33342 staining. The cell-cycle status was evaluated by flow cytometry and protein alterations were monitored by western blotting. Differentiated cells were photographed and counted in a randomized fashion. All of the examined compounds exhibited significant cytotoxicity towards the neuroblastoma cells. In particular, 7-ethoxyrosmanol had a high degree of efficacy. Nuclear condensation and degradation of procaspase-3 and -9 were observed after treatment of the cells with these compounds. Moreover, phenolic diterpenes induced cell-cycle arrest in the G(2)/M phase. Rosmanol and epirosmanol tended to induce differentiation. Phenolic diterpenes isolated from H. incana have multiple antitumor effects on neuroblastoma cells.

  12. Adult versus Pediatric Neuroblastoma: The M.D. Anderson Cancer Center Experience

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    Henry J. Conter

    2014-01-01

    Full Text Available Background. Staging and treatment of adult neuroblastoma has yet to be formalized. We sought to determine the utility of the pediatric classification system in adults and determine the efficacy of different treatment modalities. Methods. Medical records of 118 adults (patients >17 years old and 112 pediatric patients (ages 2–17, who were treated for neuroblastoma at M.D. Anderson Cancer Center from January 1994 to September 2012, were reviewed. International neuroblastoma risk group (INRG variables were abstracted. The primary outcome of interest was actuarial progression-free survival. Results. Median age of pediatric patients was 5 years (range 3–16 and 47 years (range 18–82 for adult patients. There were no differences in PFS or OS between stage-matched risk categories between pediatric and adult patients (L1-P=0.40, L2-P=0.54, and M-P=0.73. In the treatment of L1 disease, median PFS for adults treated with surgery and radiation was 11.1 months compared with single modality local treatment ± chemotherapy (6.4 and 5.1 months, resp.; P=0.07. Median PFS in L2 adult patients was 5.2 months with local therapy and 4 months with the addition of chemotherapy (P=0.23. Conclusions. Adult and pediatric patients with neuroblastoma achieve similar survival outcomes. INRG classification should be employed to stratify adult neuroblastoma patients and help select treatment.

  13. LMNA knock-down affects differentiation and progression of human neuroblastoma cells.

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    Giovanna Maresca

    Full Text Available BACKGROUND: Neuroblastoma (NB is one of the most aggressive tumors that occur in childhood. Although genes, such as MYCN, have been shown to be involved in the aggressiveness of the disease, the identification of new biological markers is still desirable. The induction of differentiation is one of the strategies used in the treatment of neuroblastoma. A-type lamins are components of the nuclear lamina and are involved in differentiation. We studied the role of Lamin A/C in the differentiation and progression of neuroblastoma. METHODOLOGY/PRINCIPAL FINDINGS: Knock-down of Lamin A/C (LMNA-KD in neuroblastoma cells blocked retinoic acid-induced differentiation, preventing neurites outgrowth and the expression of neural markers. The genome-wide gene-expression profile and the proteomic analysis of LMNA-KD cells confirmed the inhibition of differentiation and demonstrated an increase of aggressiveness-related genes and molecules resulting in augmented migration/invasion, and increasing the drug resistance of the cells. The more aggressive phenotype acquired by LMNA-KD cells was also maintained in vivo after injection into nude mice. A preliminary immunohistochemistry analysis of Lamin A/C expression in nine primary stages human NB indicated that this protein is poorly expressed in most of these cases. CONCLUSIONS/SIGNIFICANCE: We demonstrated for the first time in neuroblastoma cells that Lamin A/C plays a central role in the differentiation, and that the loss of this protein gave rise to a more aggressive tumor phenotype.

  14. Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene

    LENUS (Irish Health Repository)

    Meehan, Maria

    2012-02-05

    Abstract Background Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. Results As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA\\'s primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. Conclusions PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.

  15. CASP8 SNP D302H (rs1045485) is associated with worse survival in MYCN-amplified neuroblastoma patients

    NARCIS (Netherlands)

    Rihani, Ali; de Wilde, Bram; Zeka, Fjoralba; Laureys, Geneviève; Francotte, Nadine; Tonini, Gian Paolo; Coco, Simona; Versteeg, Rogier; Noguera, Rosa; Schulte, Johannes H.; Eggert, Angelika; Stallings, Raymond L.; Speleman, Frank; Vandesompele, Jo; van Maerken, Tom

    2014-01-01

    Neuroblastoma is a pediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to fatal disease in high-risk patients. The identification of single nucleotide polymorphisms (SNPs) may help explain the heterogeneity of neuroblastoma and assist in

  16. p53 Nongenotoxic Activation and mTORC1 Inhibition Lead to Effective Combination for Neuroblastoma Therapy

    NARCIS (Netherlands)

    Moreno-Smith, Myrthala; Lakoma, Anna; Chen, Zaowen; Tao, Ling; Scorsone, Kathleen A.; Schild, Linda; Aviles-Padilla, Kevin; Nikzad, Rana; Zhang, Yankai; Chakraborty, Rikhia; Molenaar, Jan J.; Vasudevan, Sanjeev A.; Sheehan, Vivien; Kim, Eugene S.; Paust, Silke; Shohet, Jason M.; Barbieri, Eveline

    2017-01-01

    Purpose: mTORC1 inhibitors are promising agents for neuroblastoma therapy; however, they have shown limited clinical activity as monotherapy, thus rational drug combinations need to be explored to improve efficacy. Importantly, neuroblastoma maintains both an active p53 and an aberrant mTOR

  17. Galectin-3 impairment of MYCN-dependent apoptosis-sensitive phenotype is antagonized by nutlin-3 in neuroblastoma cells.

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    Veronica Veschi

    Full Text Available MYCN amplification occurs in about 20-25% of human neuroblastomas and characterizes the majority of the high-risk cases, which display less than 50% prolonged survival rate despite intense multimodal treatment. Somehow paradoxically, MYCN also sensitizes neuroblastoma cells to apoptosis, understanding the molecular mechanisms of which might be relevant for the therapy of MYCN amplified neuroblastoma. We recently reported that the apoptosis-sensitive phenotype induced by MYCN is linked to stabilization of p53 and its proapoptotic kinase HIPK2. In MYCN primed neuroblastoma cells, further activation of both HIPK2 and p53 by Nutlin-3 leads to massive apoptosis in vitro and to tumor shrinkage and impairment of metastasis in xenograft models. Here we report that Galectin-3 impairs MYCN-primed and HIPK2-p53-dependent apoptosis in neuroblastoma cells. Galectin-3 is broadly expressed in human neuroblastoma cell lines and tumors and is repressed by MYCN to induce the apoptosis-sensitive phenotype. Despite its reduced levels, Galectin-3 can still exert residual antiapoptotic effects in MYCN amplified neuroblastoma cells, possibly due to its specific subcellular localization. Importantly, Nutlin-3 represses Galectin-3 expression, and this is required for its potent cell killing effect on MYCN amplified cell lines. Our data further characterize the apoptosis-sensitive phenotype induced by MYCN, expand our understanding of the activity of MDM2-p53 antagonists and highlight Galectin-3 as a potential biomarker for the tailored p53 reactivation therapy in patients with high-risk neuroblastomas.

  18. Molecular mechanism of action of opioids in human neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Yu, V.C.K.

    1987-01-01

    A series of human neuroblastoma cell lines was screened for the presence of opioid receptor sites. Of these cell lines, SK-N-SH was found to express approximately 50,000 ..mu.. and 10,000 delta opioid receptor sites/cell. In vitro characterization revealed that the binding properties of these receptor sites closely resembled those of human and rodent brain. Phosphatidylinositol turnover as a potential second messenger system for the ..mu.. receptor was examined in SK-N-SH cells. Neurotransmitter receptor systems were determined in the three sub-clones of SK-N-SH cells. Cells of the SH-SY5Y line, a phenotypically stable subclone of SK-N-SH cells, were induced to differentiate by treatment with various inducing agents, and changes of several neurotransmitter receptor systems were determined. Nerve growth factor (NGF) and retinoic acid (RA) up-regulated, while dBcAMP down-regulated opioid receptor sites. (/sup 3/H)Dopamine uptake was slightly enhanced only in RA-treated cells. Strikingly, the efficacy of PGE/sub 1/-stimulated accumulation of cAMP was enhanced by 15- to 30-fold upon RA treatment.

  19. PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs

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    Serena Vella

    2016-01-01

    Full Text Available Neuroblastoma (NB is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcomes of high-risk NB patients. Among neuroepithelial cancers, NB is the most studied tumor as far as PPAR ligands are concerned. PPAR ligands are endowed with antitumoral effects, mainly acting on cancer stem cells, and constitute a possible add-on therapy to antiblastic drugs, in particular for NB with unfavourable prognosis. While discussing clinical background, this review will provide a synopsis of the major studies about PPAR expression in NB, focusing on the potential beneficial effects of hypoglycemic drugs, thiazolidinediones and metformin, to reduce the occurrence of relapses as well as tumor regrowth in NB patients.

  20. Neuroblastoma GOTO cells are hypersensitive to disruption of lipid rafts.

    Science.gov (United States)

    Tomioka, Ryosaku; Minami, Natsumi; Kushida, Ai; Horibe, Shiho; Izumi, Ippei; Kato, Akira; Fukushima, Keiko; Ideo, Hiroko; Yamashita, Katsuko; Hirose, Shigehisa; Saito, Yuji

    2009-11-06

    GOTO cells, a neuroblastoma cell line retaining the ability to differentiate into neuronal or Schwann cells, were found to be rich in membrane rafts containing ganglioside GM2 and hypersensitive to lipid raft-disrupting methyl-beta-cyclodextrin (MbetaCD); the GM2-rich rafts and sensitivity to MbetaCD were markedly diminished upon their differentiation into Schwann cells. We first raised a monoclonal antibody that specifically binds to GOTO cells but not to differentiated Schwann cells and determined its target antigen as ganglioside GM2, which was shown to be highly concentrated in lipid rafts by its colocalization with flotillin, a marker protein of rafts. Disturbance of normal structure of the lipid raft by depleting its major constituent, cholesterol, with MbetaCD resulted in acute apoptotic cell death of GOTO cells, but little effects were seen on differentiated Schwann cells. Until this study, GM2-rich rafts are poorly characterized and MbetaCD hypersensitivity, which may have clinical implications, has not been reported.