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Sample records for high risk medulloblastoma

  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. High expression of DNA methyltransferases in primary human medulloblastoma.

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    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.

  3. 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

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

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    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.

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

    Science.gov (United States)

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

    2017-06-01

    Children with high-risk medulloblastoma historically have had a poor prognosis. The Children's Oncology Group completed a Phase II study using oral etoposide given with radiotherapy followed by intensive chemotherapy. Patients enrolled in the study had high-risk disease defined as ≥1.5 cm2 of residual disease postsurgery or definite evidence of central nervous metastasis. All patients underwent surgery followed by radiotherapy. During radiation, the patients received oral etoposide (21 days on, 7 off) at an initial dose of 50 mg/m2 per day (treatment 1), which was reduced to 35 mg/m2 per day (treatment 2) due to toxicity. After radiotherapy, the patients received chemotherapy with three cycles of cisplatin and oral etoposide, followed by eight courses of cyclophosphamide and vincristine. Between November 1998 and October 2002, 53 patients were accrued; 15 received treatment 1 and 38 treatment 2. Forty-seven patients (89%) were eligible. Response to radiation was excellent, with 19 (40.4%) showing complete response, 24 (51.1%) partial response, and four (8.5%) no recorded response. The overall 2- and 5-year progression-free survival (PFS) was 76.6 ± 6% and 70.2 ± 7%, respectively. The 2- and 5-year overall survival (OS) was 80.9 ± 6% and 76.6 ± 6%, respectively. Clinical response postradiation and PFS/OS were not significantly different between the treatment groups. There was a trend toward a difference in 5-year PFS between those without and with metastatic disease (P = 0.072). Oral etoposide was tolerable at 35 mg/m2 (21 days on and 7 days off) when given during full-dose irradiation in patients with high-risk medulloblastoma with encouraging survival data. © 2016 Wiley Periodicals, Inc.

  6. 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.

  7. 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...

  8. 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

  9. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

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    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.

  10. Risk factors for development of postoperative cerebellar mutism syndrome in children after medulloblastoma surgery.

    Science.gov (United States)

    Pols, San Y C V; van Veelen, Marie Lise C; Aarsen, Femke K; Gonzalez Candel, Antonia; Catsman-Berrevoets, Coriene E

    2017-07-01

    no-pCMS group, significantly more reported incidents of severe bleeding in the tumor bed during surgery in the pCMS group, preoperative hydrocephalus, and a mean body temperature rise of 0.5°C in the first 4 days after surgery in the pCMS group. Multiple regression analysis revealed that tumor size, tumor infiltration into or compression of the brainstem, and higher mean body temperature in the first 4 postoperative days were independent and highly significant predictors for pCMS. CONCLUSIONS The authors confirmed earlier findings that tumor-associated preoperative conditions, such as a maximum tumor diameter ≥ 5 cm and infiltration into or compression of the brainstem, are associated with a higher risk for the development of pCMS. Most importantly, the authors found that a 0.5°C higher mean body temperature in the first 4 postoperative days increased the odds ratio for the development of pCMS almost 5-fold. These data suggest that an important focus for the prevention of pCMS in children who have undergone medulloblastoma surgery might be rigorous maintenance of normothermia as standard care after surgery.

  11. 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.

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

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

    2017-06-01

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

  13. 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.

  14. 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

  15. 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...

  16. 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...

  17. 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...

  18. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Brodin, N. Patrik (Radiation Medicine Research Center, Dept. of Radiation Oncology, Rigshospitalet, Univ. of Copenhagen (Denmark); Niels Bohr Inst., Faculty of Sciences, Univ. of Copenhagen (Denmark)), e-mail: brodin.patrik@gmail.com; Munck af Rosenschoeld, Per; Aznar, Marianne C.; Vogelius, Ivan R. (Radiation Medicine Research Center, Dept. of Radiation Oncology, Rigshospitalet, Univ. of Copenhagen (Denmark)); Kiil-Berthelsen, Anne (Radiation Medicine Research Center, Dept. of Radiation Oncology, Rigshospitalet, Univ. of Copenhagen (Denmark); Dept. of Clinical Physiology and Nuclear Medicine, Centre of Diagnostic Investigations, Rigshospitalet, Univ. of Copenhagen (Denmark)); Nilsson, Per; Bjoerk-Eriksson, Thomas (Dept. of Oncology, Skaane Univ. Hospital and Lund Univ., Lund (Sweden)); Lannering, Birgitta (Dept. of Paediatric Oncology, The Queen Silvia Children' s Hospital, Gothenburg (Sweden))

    2011-08-15

    Introduction. The aim of this model study was to estimate and compare the risk of radiation-induced adverse late effects in pediatric patients with medulloblastoma (MB) treated with either three-dimensional conformal radiotherapy (3D CRT), inversely-optimized arc therapy (RapidArc (RA)) or spot-scanned intensity-modulated proton therapy (IMPT). The aim was also to find dose-volume toxicity parameters relevant to children undergoing RT to be used in the inverse planning of RA and IMPT, and to use in the risk estimations. Material and methods. Treatment plans were created for all three techniques on 10 pediatric patients that have been treated with craniospinal irradiation (CSI) at our institution in 2007-2009. Plans were generated for two prescription CSI doses, 23.4 Gy and 36 Gy. Risk estimates were based on childhood cancer survivor data when available and secondary cancer (SC) risks were estimated as a function of age at exposure and attained age according to the organ-equivalent dose (OED) concept. Results. Estimates of SC risk was higher for the RA plans and differentiable from the estimates for 3D CRT at attained ages above 40 years. The risk of developing heart failure, hearing loss, hypothyroidism and xerostomia was highest for the 3D CRT plans. The risks of all adverse effects were estimated as lowest for the IMPT plans, even when including secondary neutron (SN) irradiation with high values of the neutron radiation weighting factors (WR{sub neutron}). Conclusions. When comparing RA and 3D CRT treatment for pediatric MB it is a matter of comparing higher SC risk against higher risks of non-cancer adverse events. Considering time until onset of the different complications is necessary to fully assess patient benefit in such a comparison. The IMPT plans, including SN dose contribution, compared favorably to the photon techniques in terms of all radiobiological risk estimates

  20. 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

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

    Science.gov (United States)

    Zhang, Rui; Howell, Rebecca M.; Giebeler, Annelise; Taddei, Phillip J.; Mahajan, Anita; Newhauser, Wayne D.

    2013-02-01

    Pediatric patients who received radiation therapy are at risk of developing side effects such as radiogenic second cancer. We compared proton and photon therapies in terms of the predicted risk of second cancers for a 4 year old medulloblastoma patient receiving craniospinal irradiation (CSI). Two CSI treatment plans with 23.4 Gy or Gy (RBE) prescribed dose were computed: a three-field 6 MV photon therapy plan and a four-field proton therapy plan. The primary doses for both plans were determined using a commercial treatment planning system. Stray radiation doses for proton therapy were determined from Monte Carlo simulations, and stray radiation doses for photon therapy were determined from measured data. Dose-risk models based on the Biological Effects of Ionization Radiation VII report were used to estimate the risk of second cancer in eight tissues/organs. Baseline predictions of the relative risk for each organ were always less for proton CSI than for photon CSI at all attained ages. The total lifetime attributable risk of the incidence of second cancer considered after proton CSI was much lower than that after photon CSI, and the ratio of lifetime risk was 0.18. Uncertainty analysis revealed that the qualitative findings of this study were insensitive to any plausible changes of dose-risk models and mean radiation weighting factor for neutrons. Proton therapy confers lower predicted risk of second cancer than photon therapy for the pediatric medulloblastoma patient.

  2. Extraneural metastases in medulloblastoma

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    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.

  3. 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.

  4. Early Clinical Outcomes Demonstrate Preserved Cognitive Function in Children With Average-Risk Medulloblastoma When Treated With Hyperfractionated Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Gupta, Tejpal, E-mail: tejpalgupta@rediffmail.com [Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Jalali, Rakesh [Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Goswami, Savita [Department of Clinical Psychology and Psychiatry Unit, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Nair, Vimoj [Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Moiyadi, Aliasgar [Division of Neuro-Surgery, Department of Surgical Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Epari, Sridhar [Department of Pathology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India); Sarin, Rajiv [Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer and Tata Memorial Hospital, Mumbai (India)

    2012-08-01

    Purpose: To report on acute toxicity, longitudinal cognitive function, and early clinical outcomes in children with average-risk medulloblastoma. Methods and Materials: Twenty children {>=}5 years of age classified as having average-risk medulloblastoma were accrued on a prospective protocol of hyperfractionated radiation therapy (HFRT) alone. Radiotherapy was delivered with two daily fractions (1 Gy/fraction, 6 to 8 hours apart, 5 days/week), initially to the neuraxis (36 Gy/36 fractions), followed by conformal tumor bed boost (32 Gy/32 fractions) for a total tumor bed dose of 68 Gy/68 fractions over 6 to 7 weeks. Cognitive function was prospectively assessed longitudinally (pretreatment and at specified posttreatment follow-up visits) with the Wechsler Intelligence Scale for Children to give verbal quotient, performance quotient, and full-scale intelligence quotient (FSIQ). Results: The median age of the study cohort was 8 years (range, 5-14 years), representing a slightly older cohort. Acute hematologic toxicity was mild and self-limiting. Eight (40%) children had subnormal intelligence (FSIQ <85), including 3 (15%) with mild mental retardation (FSIQ 56-70) even before radiotherapy. Cognitive functioning for all tested domains was preserved in children evaluable at 3 months, 1 year, and 2 years after completion of HFRT, with no significant decline over time. Age at diagnosis or baseline FSIQ did not have a significant impact on longitudinal cognitive function. At a median follow-up time of 33 months (range, 16-58 months), 3 patients had died (2 of relapse and 1 of accidental burns), resulting in 3-year relapse-free survival and overall survival of 83.5% and 83.2%, respectively. Conclusion: HFRT without upfront chemotherapy has an acceptable acute toxicity profile, without an unduly increased risk of relapse, with preserved cognitive functioning in children with average-risk medulloblastoma.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. High programmed cell death 1 ligand-1 expression: association with CD8+ T-cell infiltration and poor prognosis in human medulloblastoma.

    Science.gov (United States)

    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.

  10. 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

  11. 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

  12. [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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Xiangkui Mu; Zackrisson, Bjoern [Umeaa Univ. (Sweden). Dept. of Radiation Sciences; Bjoerk-Eriksson, Thomas; Johansson, Lennart; Karlsson, Mikael [Sahlgrenska Univ. Hospital, Goeteborg (Sweden). Dept. of Oncology; Nill, Simeon; Oelfke, Uwe [DKFZ-Heidelberg, (Germany). Dept. of Medical Physics; Johansson, Karl-Axel [Sahlgrenska Univ. Hospital, Goeteborg (Sweden). Dept. of Therapeutic Radiation Physics; Gagliardi, Giovanna [Radiumhemmet, Stockholm (Sweden). Dept. of Hospital Physics

    2005-09-01

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

  14. [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.

  15. 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

  16. 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

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

    Directory of Open Access Journals (Sweden)

    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

  18. 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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    Background. A mathematical framework is presented for simultaneously quantifying and evaluating the trade-off between tumor control and late complications for risk-based radiation therapy (RT) decision-support. To demonstrate this, we estimate life years lost (LYL) attributable to tumor recurrence......, late cardiac toxicity and secondary cancers for standard-risk pediatric medulloblastoma (MB) patients and compare the effect of dose re-distribution on a common scale. Methods. Total LYL were derived, based on the LYL attributable to radiation-induced late complications and the LYL from not controlling...... the primary disease. We compared the estimated LYL for three different treatments in 10 patients: 1) standard 3D conformal RT; 2) proton therapy; 3) risk-adaptive photon treatment lowering the dose to part of the craniospinal (CS) target volume situated close to critical risk organs. Results. Late toxicity...

  20. Molecular subgroups of medulloblastoma

    Science.gov (United States)

    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

  1. 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

  2. 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

  3. 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

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

    Science.gov (United States)

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

    2012-09-15

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

  5. 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

  6. 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.

  7. PRAME gene expression profile in medulloblastoma

    Directory of Open Access Journals (Sweden)

    Tânia Maria Vulcani-Freitas

    2011-02-01

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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  9. 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.

  10. 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

  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. Cerebellum: Development and Medulloblastoma

    Science.gov (United States)

    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

  13. 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.)

  14. 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.

  15. 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.

  16. 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...

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

    Energy Technology Data Exchange (ETDEWEB)

    Eaton, Bree R.; Esiashvili, Natia [Departments of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia (United States); Kim, Sungjin [Department of Biostatistics and Bioinformatics, Cedars-Sinai Medical Center, Los Angeles, California (United States); Weyman, Elizabeth A.; Thornton, Lauren T. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Mazewski, Claire; MacDonald, Tobey [Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, Georgia (United States); Ebb, David [Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts (United States); MacDonald, Shannon M.; Tarbell, Nancy J. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Yock, Torunn I., E-mail: tyock@partners.org [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2016-01-01

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

  18. 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.

  19. 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...

  20. [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.

  1. 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

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    Yukiko Nakahara

    2010-01-01

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

  4. 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....

  5. 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.

  6. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-08-01

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

  8. 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.

  9. 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.

  10. 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

  11. 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 ...

  12. 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.

  13. 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

  14. 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

  15. 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

  16. 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

    childhood patients (≥4·3 years; MBSHH-Child; n=38). MBGrp3 and MBGrp4 were each split into high-risk (MBGrp3-HR [n=65] and MBGrp4-HR [n=85]) and low-risk (MBGrp3-LR [n=50] and MBGrp4-LR [n=73]) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroup-dependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 [25%] of 215 patients; 91% survival [95% CI 82-100]); standard risk (50 [23%] patients; 81% survival [70-94]); high-risk (82 [38%] patients; 42% survival [31-56]); and very high-risk (29 [13%] patients; 28% survival [14-56]). The discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations. Cancer Research UK, The Tom Grahame Trust, Star for Harris, Action Medical Research, SPARKS, The JGW Patterson Foundation, The INSTINCT network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK). Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. Successful Use of Dose Dense Neoadjuvant Chemotherapy and Sodium Valproate with Minimal Toxicity in an Infant with Medulloblastoma in Extremely Poor General Condition.

    Science.gov (United States)

    Gupta, Ajay; Kumar, Amit; Abrari, Andaleeb; Patir, Rana; Vaishya, Sandeep

    2016-09-01

    Medulloblastoma is the most common malignant brain tumor in children. Infants are in the high-risk category. Complete surgical resection is the single most important determinant of prognosis and survival in nonmetastatic disease. Infants with large primaries after incomplete resection/biopsy and poor general condition have bad prognosis. They are considered poor candidates for intensive chemotherapy involving high dose methotrexate/autologous stem cell transplantation as they are often unable to tolerate these aggressive regimens. The patient, withinfantile medulloblastoma, was supposed to have complete resection but only a biopsy could be attempted because of increased tumor vascularity. He was in very poor general condition after surgery and his parents declined aggressive chemotherapy and shunt surgery. He was given dose dense neo-adjuvant chemotherapy along with the histone deactylase inhibitor valproate for 5 cycles, with minimal toxicity, after which the tumor was resected. The examination of the resected specimen revealed a complete pathologic response. He then received a total of 18 cycles of chemotherapy and valproate to complete 1 year of systemic treatment. The child is now 6.5 years of age, disease-free, without evidence of any neurocognitive or developmental abnormalities. We suggest that the role of neoadjuvant chemotherapy should be explored in patients with infantile medulloblastoma in whom upfront complete resection is not possible, considering the gratifying results obtained in our case. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Carolina Oliveira Rodini

    2010-12-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-06-15

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-02-01

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

  13. 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

  14. 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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  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    Abhimanyu Ghose MD

    2014-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Sara Badodi

    2017-12-01

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

  3. Role of 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. 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. 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

  7. 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 ...

  8. 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

  9. [Detecting high risk pregnancy].

    Science.gov (United States)

    Doret, Muriel; Gaucherand, Pascal

    2009-12-20

    Antenatal care is aiming to reduce maternal land foetal mortality and morbidity. Maternal and foetal mortality can be due to different causes. Their knowledge allows identifying pregnancy (high risk pregnancy) with factors associated with an increased risk for maternal and/or foetal mortality and serious morbidity. Identification of high risk pregnancies and initiation of appropriate treatment and/or surveillance should improve maternal and/or foetal outcome. New risk factors are continuously described thanks to improvement in antenatal care and development in biology and cytopathology, increasing complexity in identifying high risk pregnancies. Level of risk can change all over the pregnancy. Ideally, it should be evaluated prior to the pregnancy and at each antenatal visit. Clinical examination is able to screen for intra-uterin growth restriction, pre-eclampsia, threatened for preterm labour; ultrasounds help in the diagnosis of foetal morphological anomalies, foetal chromosomal anomalies, placenta praevia and abnormal foetal growth; biological exams are used to screen for pre-eclampsia, gestational diabetes, trisomy 21 (for which screening method just changed), rhesus immunisation, seroconversion for toxoplasmosis or rubeola, unknown infectious disease (syphilis, hepatitis B, VIH). During pregnancy, most of the preventive strategies have to be initiated during the first trimester or even before conception. Prevention for neural-tube defects, neonatal hypocalcemia and listeriosis should be performed for all women. On the opposite, some measures are concerning only women with risk factors such as prevention for toxoplasmosis, rhesus immunization (which recently changed), tobacco complications and pre-eclampsia and intra-uterine growth factor restriction.

  10. 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 ...

  11. 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.

  12. 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

  13. 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...

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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...

  19. Application of probabilistic fiber-tracking method of MR imaging to measure impact of cranial irradiation on structural brain connectivity in children treated for medulloblastoma

    Science.gov (United States)

    Duncan, Elizabeth C.; Reddick, Wilburn E.; Glass, John O.; Hyun, Jung Won; Ji, Qing; Li, Yimei; Gajjar, Amar

    2016-03-01

    We applied a modified probabilistic fiber-tracking method for the extraction of fiber pathways to quantify decreased white matter integrity as a surrogate of structural loss in connectivity due to cranial radiation therapy (CRT) as treatment for pediatric medulloblastoma. Thirty subjects were examined (n=8 average-risk, n=22 high-risk) and the groups did not differ significantly in age at examination. The pathway analysis created a structural connectome focused on sub-networks within the central executive network (CEN) for comparison between baseline and post-CRT scans and for comparison between standard and high dose CRT. A paired-wise comparison of the connectivity between baseline and post-CRT scans showed the irradiation did have a significant detrimental impact on white matter integrity (decreased fractional anisotropy (FA) and decreased axial diffusivity (AX)) in most of the CEN sub-networks. Group comparisons of the change in the connectivity revealed that patients receiving high dose CRT experienced significant AX decreases in all sub-networks while the patients receiving standard dose CRT had relatively stable AX measures across time. This study on pediatric patients with medulloblastoma demonstrated the utility of this method to identify specific sub-networks within the developing brain affected by CRT.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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.

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

    Directory of Open Access Journals (Sweden)

    Wei ZHENG

    2011-06-01

    Full Text Available Objective To retrospectively review the clinical characteristics of medulloblastoma,discuss the optimized treatment regimen,and analyze the prognostic influential factors.Methods Thirty-three children with pathologically certified medulloblastoma(aged 3-14 years with average of 6.5 years,admitted from Aug.2004 to Dec.2007,received radiotherapy within 3 weeks post surgery.Ratiotherapy consisted of 28~36Gy whole craniospinal radiation and a supplementary radiation aimed at tumors by three-dimensional conformal radiotherapy(3D-CRT for a total dose of 50~54Gy(conventional fraction dose of 1.8-2.0Gy.A part of patients received hyperfractionation radiotherapy(1.0Gy/f,2f/d for alleviating the tardive adverse events.Meanwhile,a synchronized chemotherapy,consisting of lomustine + vincristine + cisplatin,or isophosphamide + carboplatin + etoposide,was administered after the completion of whole craniospinal radiation,and 3-5 courses of sequential chemotherapy were given after the overall radiotherapy was finished.According to the metastasis,and the residual tumor and its size,the 33 patients were divided into 2 groups as follows: low-risk group(n=24: no metastases,total or sub-total excision of tumors(residual tumors ≤1.5cm3;high-risk group(n=9: either metastases or residual tumor > 1.5cm3.The 3-year survival rates of two groups were then compared.Results The combined radiotherapy and chemotherapy was effective to 10 of the 11 patients(90.9% with residual tumors.Out of the 33 patients,31 obtained complete remission(93.9%,and 2 patients showed partial remission or stable status(3.0%,respectively.The median survival time of 33 patients was 51 months,3-year disease free survival(DFS was 75.8%,and 3-year overall survival(OS was 78.8%,including 33.3% in high-risk group and 95.8% in low-risk group(P < 0.01.The major side effects occurred in haematological system and digestive system,such as an incidence of 21.2%(7/33 with grade Ⅲ-Ⅳ bone marrow suppression

  7. [High dynamic risk cystoceles].

    Science.gov (United States)

    Salinas Casado, Jesús; Méndez Rubio, Santiago; Virseda Chamorro, Miguel; Pelaquim, Humberto; Silmi Moyano, Angel

    2010-06-01

    To assess the bladder compliance in a series of cystoceles referred for urodynamic study. Retrospective study of a series of patients with cystocele undergoing medical history, videurodynamic study, pelvic MRI and lower urinary tract, urological ultrasound and cystoscopy. We Excluded cases with neurogenic dysfunction and urinary infection. The terminology followed the criteria of the ICS, if not specified otherwise. The series includes 3333 cases of cystocele 616 of which are grade III cystocele. There were 3 cases with low bladder compliance; this is 0.0009% of total (1:1000) and 0.5% of grade III cystocele (1:200) All cases of cystocele whith low compliance were associated with feeling of a bulk in the vagina and functional symptoms of lower urinary tract(LUTS). No urinary incontinence was related to cough. These patients also showed urodynamic alterations in the voiding phase, type hypo / acontractile detrusor and postvoid residual. The patients were subjected to various techniques of abdominal and transvaginal cystocele repair (with preventive anti-incontinence surgery), getting a vagina bulk disappearance, improvement of symptoms of lower urinary tract function, normalization of bladder compliance and detrusor contractility, with elimination of the postvoid residual. Although they are not frequent, high-risk cystoceles should be discarded in high-grade cystocele that apart from low bladder accommodation, have a hipo/acontractile detrusor and postvoid residual. Surgical correction of cystocele not only reduces the bulk and LUTS, but normalizes urodynamic alterations.

  8. 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.

  9. [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.

  10. 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

  11. Perceptions of high risk sports.

    Science.gov (United States)

    Pedersen, D M

    1997-10-01

    High risk sports were rated as to risk, appeal, and likelihood of participation by 282 men and 162 women. Ascending order of perceived risk was skiing, scuba diving, bungee jumping, rock climbing, motorcycle racing, hang gliding, cliff jumping, and skydiving. Profile analysis showed stated likelihood of participation to be directly related to appeal and inversely related to perceived risk.

  12. 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.

  13. 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.

  14. High-Risk Pregnancy

    Science.gov (United States)

    ... risk? » Related A-Z Topics Diabetes Pregnancy Loss Preeclampsia and Eclampsia NICHD News Spotlights Podcast: NICHD launches PregSource to learn more about pregnancy News Release: NIH Begins Large HIV Treatment Study in Pregnant Women Spotlight: Zika Research after ...

  15. 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.

  16. 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.

  17. 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...

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Cerebellar Medulloblastoma in Middle-to-Late Adulthood

    Directory of Open Access Journals (Sweden)

    Majid Aljoghaiman

    2018-01-01

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

  3. 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.

  4. Analysis of the causes of subfrontal recurrence in medulloblastoma and its salvage treatment

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Jae Ho; Koom, Woong Sub; Lee, Chang Geol [Yonsei University College of Medicine, Seoul (Korea, Republic of)] (and others)

    2004-09-15

    Firstly, to analyze factors in terms of radiation treatment that might potentially cause subfrontal replace in two patients who had been treated by craniospinal irradiation (CSI) for medulloblastoma. Secondly, to explore an effective salvage treatment for these relapses. Two patients who had high-risk disease (T3bM1, T3bM3) were treated with combined chemoradiotherapy. CT-simulation based radiation-treatment planning (RTP) was performed. One patient who experienced relapse at 16 months after CSI was treated with salvage surgery followed by a 30.6 Gy IMRT (intensity modulated radiotherapy). The other patient whose tumor relapsed at 12 months after CSI was treated by surgery alone for the recurrence. To investigate factors that might potentially cause subfrontal relapse, we evaluated thoroughly the charts and treatment planning process including portal films, and tried to find out a method to give help for placing blocks appropriately between subfrotal-cribrifrom plate region and both eyes. To salvage subfrontal relapse in a patient, re-irradiation was planned after subtotal tumor removal. We have decided to treat this patient with IMRT because of the proximity of critical normal tissues and large burden of re-irradiation. With seven beam directions, the prescribed mean dose to PTV was 30.6 Gy (1.8 Gy fraction) and the doses to the optic nerves and eyes were limited to 25 Gy and 10 Gy, respectively. Review of radiotherapy portals clearly indicated that the subfrontal-cribriform plate region was excluded from the therapy beam by eye blocks in both cases, resulting in cold spot within the target volume. When the whole brain was rendered in 3-D after organ drawing in each slice, it was easier to judge appropriateness of the blocks in port film. IMRT planning showed excellent dose distributions (Mean doses to PTV, right and left optic nerves, right and left eyes: 31.1 Gy, 14.7 Gy, 13.9 Gy, 6.9 Gy, and 5.5 Gy, respectively. Maximum dose to PTV: 36 Gy). The patient who

  5. 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.

  6. 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.

  7. 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

  8. 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...

  9. 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,

  10. 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...

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

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

    Science.gov (United States)

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

    2014-11-01

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

  18. 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...

  19. 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...

  20. 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

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

    Directory of Open Access Journals (Sweden)

    Golubičić Ivana V.

    2003-01-01

    , with no patient living longer than two years (p=0.0134 (Graph 3. By analysis of OS and DFS in relation to presence of the malignant cells in liquor, statistically significant difference, i. e. positive CSF cytology was not obtained, which was of statistical importance for survival (p=0.8207. Neither shunt placement nor shunt type showed any impact on survival (p=0.5307 and 0.7119, respectively. Children younger than three years had significantly poorer survival compared to those older than 16 years (p=0.0473. Although there was a better survival rate in females than in males this was not statistically significant (p=0.2386.The analysis results of treatment showed that significantly better survival occurred in patients in whom total or subtotal tumor removal was possible (p=0.0022 (Graph 4. Patients who started radiotherapy within two months after surgery have better survival, but again this was not statistically significant, probably due to the small number of patients receiving delayed radiotherapy (p=0.2231(Graph5. CONCLUSION Based on this factors standard and high risk group could be defined. Combined chemotherapy should to be investigated particularly for high risk subgroup. Future research should be done to define new therapeutic modalities (gene therapy, compounds active in tumor antiangiogenesis etc.

  2. 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.

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  17. Mir-449a, a potential diagnostic biomarker for WNT group of medulloblastoma.

    Science.gov (United States)

    Li, Yongxiao; Jiang, Tao; Shao, Liwei; Liu, Yan; Zheng, Chen; Zhong, Yanfeng; Zhang, Jing; Chang, Qing

    2016-09-01

    Medulloblastoma (MB) is the most common malignant brain tumor in childhood. The 5 year disease-free survival rate is rather low. There is a consensus that MB can be divided into at least four clinically, transcriptionally, and genetically distinct molecular variants, being designated as wingless (WNT), sonic hedgehog (SHH), Group 3 and Group 4. It poses a great challenge to the design of therapeutic strategy for MB patients. Intensive clinical intervention, including high dose radiotherapy, is commonly used in treatment of high risk MB, most of which are considered to be Group 3 patients. But such intensive therapy should be avoided to protect neurologic function of patients in the lower risk WNT group. In present study, MB subgroup assignment in formalin-fixed paraffin embedded (FFPE) specimens from 45 Chinese patients were performed by Nanostring platform using 22 well-known signature genes. Based on comparative expression profiles of miRNA real-time PCR microarray in MB cells with and without treatment of demethylation reagent, as well as MSP assay, miR-449a was demonstrated to be significantly silenced by aberrant DNA methylation in tumor cells. Real-time PCR showed that expression level of miR-449a in WNT group was significantly different from other subgroups, although it was down-regulated in most of the MB samples. In conclusion, current study demonstrates for the first time the feasibility of using the Nanostring assay for subgrouping of MBs in Chinese patients. In addition, MiR-449a, a candidate tumor suppressor regulated by hypermethylation, is a novel potential diagnostic marker for WNT group of MBs.

  18. 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.

  19. 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.

  20. 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.

  1. 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)

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. A phase II study of radioimmunotherapy with intraventricular 131 I-3F8 for medulloblastoma.

    Science.gov (United States)

    Kramer, Kim; Pandit-Taskar, Neeta; Humm, John L; Zanzonico, Pat B; Haque, Sofia; Dunkel, Ira J; Wolden, Suzanne L; Donzelli, Maria; Goldman, Debra A; Lewis, Jason S; Lyashchenko, Serge K; Khakoo, Yasmin; Carrasquillo, Jorge A; Souweidane, Mark M; Greenfield, Jeffrey P; Lyden, David; De Braganca, Kevin D; Gilheeney, Stephen W; Larson, Steven M; Cheung, Nai-Kong V

    2018-01-01

    High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131 I-labeled 3F8 in patients with MB on a phase II clinical trial. Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) 124 I-3F8 or 131 I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) 131 I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6-12 months thereafter. Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0-2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3-55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18-0.88, P = 0.024). cRIT with 131 I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB. © 2017 Wiley Periodicals, Inc.

  9. 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.

  10. 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.

  11. 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 ...

  12. 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

  13. 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.

  14. 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…

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. Critical Combinations of Radiation Dose and Volume Predict Intelligence Quotient and Academic Achievement Scores After Craniospinal Irradiation in Children With Medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Merchant, Thomas E., E-mail: thomas.merchant@stjude.org [Division of Radiation Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Schreiber, Jane E. [Department of Psychology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Wu, Shengjie [Department of Biostatistcs, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Lukose, Renin [Division of Radiation Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Xiong, Xiaoping [Department of Biostatistcs, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Gajjar, Amar [Department of Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States)

    2014-11-01

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

  1. 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

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

    Directory of Open Access Journals (Sweden)

    Živković Nenad

    2014-01-01

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

  3. MEDULLOBLASTOMA 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.

  4. 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.

  5. Oncolytic effects of parvovirus H-1 in medulloblastoma are associated with repression of master regulators of early neurogenesis

    Science.gov (United States)

    Lacroix, Jeannine; Schlund, Franziska; Leuchs, Barbara; Adolph, Kathrin; Sturm, Dominik; Bender, Sebastian; Hielscher, Thomas; Pfister, Stefan M; Witt, Olaf; Rommelaere, Jean; Schlehofer, Jörg R; Witt, Hendrik

    2014-01-01

    Based on extensive pre-clinical studies, the oncolytic parvovirus H-1 (H-1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high-risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H-1PV on MB cells in vitro and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non-transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H-1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H-1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H-1PV. H-1PV induced down-regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H-1PV infection. H-1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. PMID:23852775

  6. Childhood and adult medulloblastoma: What difference?; Le medulloblastome de l'enfant et de l'adulte: quelle difference?

    Energy Technology Data Exchange (ETDEWEB)

    Padovani, L.; Muracciole, X. [CHU de la Timone-Enfant, Dept. de Radiotherapie, 13 - Marseille (France); Andre, N. [CHU de la Timone-Enfant, Dept. de Oncologie Pediatrique, 13 - Marseille (France); Carrie, C. [Centre Leon-Berard, Dept. de Radiotherapie, 69 - Lyon (France)

    2009-10-15

    Medulloblastoma is the most frequent childhood brain tumor (30%) but account only for less than 1% of adult brain tumor. The overall survival increased significantly during the last two decades with 80% of long survivors at five years whatever the stage. Most children who survive have significant neuro cognitive sequelae. All children are included in national and international prospective studies which propose risk-adapted radiation therapy and chemotherapy after surgery. Quality control of radiotherapy leads to reduce significantly the risk of recurrence and has an impact on survival. Risks of late toxicity should be taken into account at the time of the treatment. Due to the rarity in adult population, no prospective studies and few data about late effects are available. Adult medulloblastoma is a therapeutic challenge and their therapeutic strategies are similar to pediatric protocols. In order to improve the understanding of adult disease and to homogenize the treatment, National Cancer Institute (I.N.C.a.) stimulated the creation of web conference to discuss each case prospectively and to propose a protocol of treatment. A better comprehension of biological processes and abnormal cellular signalling pathways involved in medulloblastoma pathogenesis had led toward a new prognostic classification to adapt the therapeutic strategy and gives hope of new therapeutic tools. (authors)

  7. Early Detection of High Risk Pregnancy

    OpenAIRE

    Kurniawan, Arif; Sistiarani, Colti; Hariyadi, Bambang

    2017-01-01

    There are 30.939 pregnant women in Banyumas, with 6.206 cases referred due to high-risk pregnancies. Petahunan village in Pekuncen has the the highest incidence of high-risk pregnancies compared with other villages. The purpose of this study is to describe the implementation of early detection of high-risk pregnancies in Petahunan village, Pekuncen. This study used qualitative research methods with case study approach. Research instruments used in-depth interviews and focus group disscussion ...

  8. [Socioeconomic factors in high risk pregnancy].

    Science.gov (United States)

    Armas Domínguez, J; Shor Pinsker, V; Mac Gregor, C; Karchmer, S

    1977-05-01

    The study of high risk during pregnancy was undertaken to show the most viable ways for solving those problems affecting maternal-fetal morbidity and mortality. The authors are hopeful that in the future, the 2 branches of medicine, perinatology and obstetrics, will no longer differentiate between high risk for mother and fetus or neonate but will direct attention to what is high risk for 1 society in particular. These professionals will undertake an interdisciplinary approach of the problem to benefit society. (author's)

  9. 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

  10. Low risk and high risk human papillomaviruses (HPVs) and cervical ...

    African Journals Online (AJOL)

    Low risk and high risk human papillomaviruses (HPVs) and cervical cancer in Zimbabwe: epidemiological evidence. M Chirara, G A Stanczuk, S A Tswana, L Nystrom, S Bergstrom, S R Moyo, M J Nzara. Abstract. No Abstract. Central African Journal of Medicine Vol. 47 (2) 2001: pp. 32-34.

  11. 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.

  12. High risk of permafrost thaw

    Science.gov (United States)

    E.A.G. Schuur; B.W. Abbott; W.B. Bowden; V. Brovkin; P. Camill; J.P. Canadell; F.S. Chapin; T.R. Christensen; J.P. Chanton; P. Ciais; P.M. Crill; B.T. Crosby; C.I. Czimczik; G. Grosse; D.J. Hayes; G. Hugelius; J.D. Jastrow; T. Kleinen; C.D. Koven; G. Krinner; P. Kuhry; D.M. Lawrence; S.M. Natali; C.L. Ping; A. Rinke; W.J. Riley; V.E. Romanovsky; A.B.K. Sannel; C. Schadel; K. Schaefer; Z.M. Subin; C. Tarnocai; M. Turetsky; K. M. Walter-Anthony; C.J. Wilson; S.A. Zimov

    2011-01-01

    Arctic temperatures are rising fast, and permafrost is thawing. Carbon released into the atmosphere from permafrost soils will accelerate climate change, but the magnitude of this effect remains highly uncertain. Our collective estimate is that carbon will be released more quickly than models suggest, and at levels that are cause for serious concern. We calculate that...

  13. 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.

  14. 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.

  15. Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1⁺/⁻ mice after paternal irradiation.

    Science.gov (United States)

    Paris, Lorena; Giardullo, Paola; Leonardi, Simona; Tanno, Barbara; Meschini, Roberta; Cordelli, Eugenia; Benassi, Barbara; Longobardi, Maria Grazia; Izzotti, Alberto; Pulliero, Alessandra; Mancuso, Mariateresa; Pacchierotti, Francesca

    2015-11-03

    The hypothesis of transgenerational induction of increased cancer susceptibility after paternal radiation exposure has long been controversial because of inconsistent results and the lack of a mechanistic interpretation. Here, exploiting Ptch1 heterozygous knockout mice, susceptible to spontaneous and radiation-induced medulloblastoma, we show that exposure of paternal germ cells to 1 Gy X-rays, at the spermatogonial stage, increased by a considerable 1.4-fold the offspring susceptibility to medulloblastoma induced by neonatal irradiation. This effect gained further biological significance thanks to a number of supporting data on the immunohistochemical characterization of the target tissue and preneoplastic lesions (PNLs). These results altogether pointed to increased proliferation of cerebellar granule cell precursors and PNLs cells, which favoured the development of frank tumours. The LOH analysis of tumor DNA showed Ptch1 biallelic loss in all tumor samples, suggesting that mechanisms other than interstitial deletions, typical of radiation-induced medulloblastoma, did not account for the observed increased cancer risk. This data was supported by comet analysis showing no differences in DNA damage induction and repair in cerebellar cells as a function of paternal irradiation. Finally, we provide biological plausibility to our results offering evidence of a possible epigenetic mechanism of inheritance based on radiation-induced changes of the microRNA profile of paternal sperm.

  16. 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.

  17. 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.

  18. Improving antenatal risk assessment in women exposed to high risks.

    Science.gov (United States)

    Perry, Natasha; Newman, Louise K; Hunter, Mick; Dunlop, Adrian

    2015-01-01

    Antenatal substance use and related psychosocial risk factors are known to increase the likelihood of child protection involvement; less is known about the predictive nature of maternal reflective functioning (RF) in this population. This preliminary study assessed psychosocial and psychological risk factors for a group of substance dependent women exposed to high risks in pregnancy, and their impact on child protection involvement. Pregnant women on opiate substitution treatment (n = 11) and a comparison group (n = 15) were recruited during their third trimester to complete measures of RF (Pregnancy Interview), childhood trauma, mental health and psychosocial assessments. At postnatal follow-up, RF was reassessed (Parent Development Interview - Revised Short Version) and mother-infant dyads were videotaped to assess emotional availability (EA). Child protection services were contacted to determine if any concerns had been raised for infant safety. Significant between-group differences were observed for demographics, psychosocial factors, trauma and mental health symptoms. Unexpectedly, no significant differences were found for RF or EA between groups. Eight women in the 'exposed to high risks' group became involved with child protection services. Reflective functioning was not significantly associated with psychosocial risk factors, and therefore did not mediate the outcome of child protection involvement. Women 'exposed to high risks' were equally able to generate a model of their own and their infants' mental states and should not be seen within a deficit perspective. Further research is required to better understand the range of risk factors that predict child protection involvement in high risk groups. © The Author(s) 2013.

  19. The high-risk plaque initiative

    DEFF Research Database (Denmark)

    Falk, Erling; Sillesen, Henrik; Muntendam, Pieter

    2011-01-01

    The High-Risk Plaque (HRP) Initiative is a research and development effort to advance the understanding, recognition, and management of asymptomatic individuals at risk for a near-term atherothrombotic event such as myocardial infarction or stroke. Clinical studies using the newest technologies...

  20. High risk of permafrost thaw

    Energy Technology Data Exchange (ETDEWEB)

    Schuur, E.A.G.; Abbott, B.; Koven, C.D,; Riley, W.J.; Subin, Z.M.; al, et

    2011-11-01

    In the Arctic, temperatures are rising fast, and permafrost is thawing. Carbon released to the atmosphere from permafrost soils could accelerate climate change, but the likely magnitude of this effect is still highly uncertain. A collective estimate made by a group of permafrost experts, including myself, is that carbon could be released more quickly than models currently suggest, and at levels that are cause for serious concern. While our models of carbon emission from permafrost thaw are lacking, experts intimately familiar with these landscapes and processes have accumulated knowledge about what they expect to happen, based on both quantitative data and qualitative understanding of these systems. We (the authors of this piece) attempted to quantify this expertise through a survey developed over several years, starting in 2009. Our survey asked experts what percentage of surface permafrost they thought was likely to thaw, how much carbon would be released, and how much of that would be methane, for three time periods and under four warming scenarios that are part of the new IPCC Fifth Assessment Report.

  1. Proton radiation therapy for pediatric medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for very young children treated with upfront chemotherapy.

    Science.gov (United States)

    Jimenez, Rachel B; Sethi, Roshan; Depauw, Nicolas; Pulsifer, Margaret B; Adams, Judith; McBride, Sean M; Ebb, David; Fullerton, Barbara C; Tarbell, Nancy J; Yock, Torunn I; Macdonald, Shannon M

    2013-09-01

    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). All patients aged 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. 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. 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. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. The postirradiation incidence of cavernous angioma is higher in patients with childhood pineoblastoma or primitive neuroectodermal tumors than medulloblastoma.

    Science.gov (United States)

    Yamasaki, Fumiyuki; Takayasu, Takeshi; Nosaka, Ryo; Kenjo, Masahiro; Akiyama, Yuji; Tominaga, Atsushi; Sugiyama, Kazuhiko; Kobayashi, Masao; Kurisu, Kaoru

    2015-06-01

    The purpose of this study is to investigate the incidence of cavernous angioma (CVA) in long-term survivors of childhood embryonal tumors treated by cranial irradiation. Between 1990 and 2012, we treated 25 patients (13 males, 12 females) with embryonal tumors (17 medulloblastomas, 5 primitive neuroectodermal tumors (PNET), 3 pineoblastomas) with craniospinal irradiation. Follow-up ranged from 15.5 to 289.9 months, the irradiation dose to the whole neural axis from 18 to 36 Gy, and the total local dose from 49.6 to 60 Gy. All patients underwent follow-up magnetic resonance imaging (MRI) studies at least once a year, and the diagnosis of posttreatment CVA was based solely on MRI findings. At the time of this writing, 18 were alive and free of the recurrence of the original disease or the development of secondary neoplasms other than CVA; another 2 were alive with medulloblastoma or diffuse astrocytoma. Posttreatment, 14 patients developed CVAs in the course of a median of 56.7 months; 13 of these presented with multiple CVAs. Patients who underwent radiation therapy (RT) at an age younger than 6 years developed multiple CVAs significantly earlier than those treated at a later age (p = 0.0110). Patients with PNET or pineoblastoma developed Zabramski type 1 and 2 CVA significantly earlier than did medulloblastoma patients (p = 0.0042). We attribute the high rate of post-RT CVA in our long-term follow-up study of pediatric patients to the delivery of cranial irradiation for embryonal tumors, especially PNET and pineoblastoma, and recommend the regular, long-term follow-up of patients whose embryonal tumors were treated by cranial irradiation.

  3. 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.

  4. High risk pregnancy monitored antenatally at home

    NARCIS (Netherlands)

    Monincx, W. M.; Zondervan, H. A.; Birnie, E.; Ris, M.; Bossuyt, P. M.

    1997-01-01

    OBJECTIVE: Is domiciliary antenatal fetal surveillance for selected high risk pregnancies, a feasible alternative for hospital admission? DESIGN: A randomized controlled trial conducted at the Academical Medical Centre, Amsterdam, The Netherlands. SUBJECTS: Between September 1992 and June 1994, 76

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

    Directory of Open Access Journals (Sweden)

    Biassoni Veronica

    2009-01-01

    Full Text Available Abstract Introduction The improved survival of children with brain tumors has increased concerns about treatment-related sequelae. Growth hormone deficiency is frequently observed after craniospinal irradiation for medulloblastoma. It has been widely reported that growth hormone replacement therapy does not increase the risk of second tumors, but there are reports in the literature of growth hormone, and its downstream mediator insulin-like Growth Factor 1, having an important proinflammatory action. There are few reports, however, on the "in-vivo" induction of edema and symptomatic inflammatory lesions during replacement therapy. Case presentation We report the case of a 7-year-old girl treated for metastatic medulloblastoma who developed growth hormone deficiency 2 years after oncological treatment. Three months after replacement therapy, magnetic resonance imaging showed exacerbation of her brain edema, which was already present after oncological treatment. We consequently suspended the growth hormone until a new magnetic resonance image obtained 3 months later documented a reduction of the inflammatory areas. We then re-introduced somatotropin at lower doses with no further increase in brain edema in subsequent radiological controls. Conclusion This case and its iconography suggest a strong association between growth hormone administration and the exacerbation of inflammatory reactions within the tumor bed. Replacement therapy should be carefully monitored in this particular subset of patients.

  6. Management of high-risk pregnancy.

    Science.gov (United States)

    Coco, L; Giannone, T T; Zarbo, G

    2014-08-01

    Today, 88% of pregnancies has a physiological course during which just basic care, while in 12% of cases there is a high-risk pregnancy that requires additional assistance and specific. The approach that should be used is that of supervision in all pregnant women considering their potential to have a normal pregnancy until there is no clear evidence to the contrary. Pregnancy is considered at risk if there are medical conditions that may affect maternal or fetal health or life of the mother, fetus or both. Among the risk factors for pregnancy there is first the woman's age, in fact the increase in high-risk pregnancies in the last 20 years is attributable to the increase in the average age of women who face pregnancy. In addition, the diet is very important during pregnancy and diabetes or autoimmune diseases often lead to the failure of a pregnancy. Risk factors for pregnancy, also, are the complications that occur during its course as hypertension during pregnancy, and infectious diseases. Fears and anxieties typical of a high-risk pregnancy prevent the couple to live happily in the months of gestation. Effective communication, control and early detection are important tools that doctors must be able to ensure that women in order to plan the best treatment strategies and to minimize the risks of maternal and / or fetal.

  7. Impact of radiation technique, radiation fraction dose, and total cisplatin dose on hearing : Retrospective analysis of 29 medulloblastoma patients.

    Science.gov (United States)

    Scobioala, Sergiu; Parfitt, Ross; Matulat, Peter; Kittel, Christopher; Ebrahimi, Fatemeh; Wolters, Heidi; Am Zehnhoff-Dinnesen, Antoinette; Eich, Hans Theodor

    2017-11-01

    To analyze the incidence and degree of sensorineural hearing loss (SNHL) resulting from different radiation techniques, fractionation dose, mean cochlear radiation dose (Dmean), and total cisplatin dose. In all, 29 children with medulloblastoma (58 ears) with subclinical pretreatment hearing thresholds participated. Radiotherapy (RT) and cisplatin had been applied sequentially according to the HIT MED Guidance. Audiological outcomes up to the latest follow-up (median 2.6 years) were compared. Bilateral high-frequency SNHL was observed in 26 patients (90%). No significant differences were found in mean hearing threshold between left and right ears at any frequency. A significantly better audiological outcome (p cisplatin dose reached above 210 mg/m2, with the highest abnormal level found 8-12 months after RT regardless of radiation technique or fraction dose. The cochlear radiation dose should be kept as low as possible in patients who receive simultaneous cisplatin-based chemotherapy. The risk of clinically relevant HL was shown when Dmean exceeds 45 Gy independent of radiation technique or radiation regime. Cisplatin ototoxicity was shown to have a dose-dependent effect on bilateral SNHL, which was more pronounced in higher frequencies.

  8. 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

  9. Electroconvulsive therapy during high-risk pregnancy.

    Science.gov (United States)

    Walker, R; Swartz, C M

    1994-09-01

    Pregnancy increases the risk of injury associated with mental illness. The varieties of malnutrition, substance abuse, and aggression that may accompany mental illness can injure the unborn child in more severe ways than the patient herself. Dangers associated with illness-related behavior can outweight the risks of pharmacotherapy, but no psychotropic drug is approved for use during pregnancy. Failure to produce a prompt or lasting remission of psychiatric symptoms also is a significant possibility with medication. The morbidity from continued illness and the incompletely described adverse effects of psychotropic drugs increases the attractiveness of ECT for severely depressed pregnant patients, especially with associated high-risk conditions. This paper discusses physiologic changes occurring during pregnancy and ECT and reviews contemporary monitors of maternal and fetal well-being. Guidelines are suggested for ECT during regular and high-risk pregnancies. The authors conclude that using additional precautions with high-risk pregnant patients permits ECT to be given with relative safety; medical and obstetric risk factors need not prevent its use.

  10. 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

  11. 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.

  12. 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

  13. 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

  14. High risk process control system assessment methodology

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Venetia [Pontificia Universidade Catolica do Rio de Janeiro (PUC-Rio), RJ (Brazil); Zamberlan, Maria Cristina [National Institute of Tehnology (INT), Rio de Janeiro, RJ (Brazil). Human Reliability and Ergonomics Research Group for the Oil, Gas and Energy Sector

    2009-07-01

    The evolution of ergonomics methodology has become necessary due to the dynamics imposed by the work environment, by the increase of the need of human cooperation and by the high interaction between various sections within a company. In the last 25 years, as of studies made in the high risk process control, we have developed a methodology to evaluate these situations that focus on the assessment of activities and human cooperation, the assessment of context, the assessment of the impact of work of other sectors in the final activity of the operator, as well as the modeling of existing risks. (author)

  15. Treatment of high-risk smoldering myeloma.

    Science.gov (United States)

    Korde, Neha

    2016-12-01

    Multiple myeloma (MM) is a hematologic malignancy of the plasma cell that causes symptoms of bone pain, renal failure, and anemia. It is usually preceded by a precursor disease state, such as smoldering multiple myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS), and traditional dogma dictates that treatment should be initiated on frank MM symptom development. Emerging evidence suggests that a defined group of "high-risk SMM" may benefit from early treatment, before organ damage and symptoms actually occur. The following article frames the evidence for treatment of high-risk SMM by defining risk categories, reviewing existing therapeutic trial data, and exploring the long-term biologic implications of early treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Not all risks are equal: the risk taking inventory for high-risk sports.

    Science.gov (United States)

    Woodman, Tim; Barlow, Matt; Bandura, Comille; Hill, Miles; Kupciw, Dominika; Macgregor, Alexandra

    2013-10-01

    Although high-risk sport participants are typically considered a homogenous risk-taking population, attitudes to risk within the high-risk domain can vary considerably. As no validated measure allows researchers to assess risk taking within this domain, we validated the Risk Taking Inventory (RTI) for high-risk sport across four studies. The RTI comprises seven items across two factors: deliberate risk taking and precautionary behaviors. In Study 1 (n = 341), the inventory was refined and tested via a confirmatory factor analysis used in an exploratory fashion. The subsequent three studies confirmed the RTI's good model-data fit via three further separate confirmatory factor analyses. In Study 2 (n = 518) and in Study 3 (n = 290), concurrent validity was also confirmed via associations with other related traits (sensation seeking, behavioral activation, behavioral inhibition, impulsivity, self-esteem, extraversion, and conscientiousness). In Study 4 (n = 365), predictive validity was confirmed via associations with mean accidents and mean close calls in the high-risk domain. Finally, in Study 4, the self-report version of the inventory was significantly associated with an informant version of the inventory. The measure will allow researchers and practitioners to investigate risk taking as a variable that is conceptually distinct from participation in a high-risk sport.

  17. Breast MRI in high risk patients

    NARCIS (Netherlands)

    A.I.M. Obdeijn (Inge-Marie)

    2015-01-01

    markdownabstractAbstract In this thesis we address various indications of breast MRI, with the emphasis on the value of MRI in screening of women with high genetic risk for breast cancer, and especially in BRCA1 mutation carriers. We showed that in the era of up-to-date MRI expertise and

  18. Trends in emerging and high risk activities

    Science.gov (United States)

    Robert C. White; Richard Schreyer; Kent Downing

    1980-01-01

    Newly emerging and high risk activities have increased markedly in the last generation, yet little is known about trends in participation. Factors such as technological innovation and creative experimentation with traditional activities appear to play a major role in the development of new activities. Christy's criteria for mass demand in recreation are used to...

  19. 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.

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

    Science.gov (United States)

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

    2017-03-01

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

  1. High-risk neighborhoods and high-risk families: the human ecology of child maltreatment.

    Science.gov (United States)

    Garbarino, J; Sherman, D

    1980-03-01

    Based on multiple regression analysis to identify the socioeconomic, demographic, and attitudinal correlates of neighborhood differences in the rate of child abuse and neglect, a pair of neighborhoods matched for socioeconomic level was selected, one high risk, the other low risk. Interviews with expert informants ranging from elementary school principals to mailmen were used to develop neighborhood profiles. Samples of families were drawn from each neighborhood and interviews conducted to identify stresses and supports, with special emphasis on sources of help, social networks, evaluation of the neighborhood, and use of formal family support systems. The results lend support to the concept of neighborhood "risk." Families in the high-risk neighborhood, though socioeconomically similar to families in the low-risk neighborhood, report less positive evaluation of the neighborhood as a context for child and family development. Furthermore, they reveal a general pattern of "social impoverishment" in comparison with families in the low-risk neighborhood.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    -modulated proton therapy (IMPT). RESULTS: Lung cancer contributed most to the estimated LYL, followed by myocardial infarction, and stomach cancer. The estimates of breast or thyroid cancer incidence were higher than those for lung and stomach cancer incidence, but LYL were lower because of the relatively good......The authors developed a framework for estimating and comparing the risks of various long-term complications on a common scale and applied it to 3 different techniques for craniospinal irradiation in patients with pediatric medulloblastoma. METHODS: Radiation dose-response parameters related...... to excess hazard ratios for secondary breast, lung, stomach, and thyroid cancer; heart failure, and myocardial infarction were derived from large published clinical series. Combined with age-specific and sex-specific hazards in the US general population, the dose-response analysis yielded excess hazards...

  3. Major Risk Factors for Heart Disease: High Blood Cholesterol

    Science.gov (United States)

    ... Major Risk Factors for Heart Disease High Blood Cholesterol High blood cholesterol is another major risk factor for heart disease ... can do something about. The higher your blood cholesterol level, the greater your risk for developing heart ...

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

    Directory of Open Access Journals (Sweden)

    Gustavo A Barisone

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

  5. 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.

  6. Receiver operating characteristic curve analysis of SEER medulloblastoma and primitive neuroectodermal tumor (PNET) outcome data: identification and optimization of predictive models.

    Science.gov (United States)

    Cheung, Min Rex

    2014-01-01

    This study used receiver operating characteristic curves to analyze Surveillance, Epidemiology and End RESULTS (SEER) medulloblastoma (MB) and primitive neuroectodermal tumor (PNET) outcome data. The aim of this study was to identify and optimize predictive outcome models. Patients diagnosed from 1973 to 2009 were selected for analysis of socio-economic, staging and treatment factors available in the SEER database for MB and PNET. For the risk modeling, each factor was fitted by a generalized linear model to predict the outcome (brain cancer specific death, yes/no). The area under the receiver operating characteristic curve (ROC) was computed. Similar strata were combined to construct the most parsimonious models. A Monte Carlo algorithm was used to estimate the modeling errors. There were 3,702 patients included in this study. The mean follow up time (S.D.) was 73.7 (86.2) months. Some 40% of the patients were female and the mean (S.D.) age was 16.5 (16.6) years. There were more adult MB/PNET patients listed from SEER data than pediatric and young adult patients. Only 12% of patients were staged. The SEER staging has the highest ROC (S.D.) area of 0.55 (0.05) among the factors tested. We simplified the 3-layered risk levels (local, regional, distant) to a simpler non-metastatic (I and II) versus metastatic (III) model. The ROC area (S.D.) of the 2-tiered model was 0.57 (0.04). ROC analysis optimized the most predictive SEER staging model. The high under staging rate may have prevented patients from selecting definitive radiotherapy after surgery.

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

    Science.gov (United States)

    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

    2013-10-01

    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, as well as morphological characterization, cell population doubling time, colony-forming efficiency, and chemo-sensitivity assays in two pediatric MB cell lines (UW402 and UW473). Both MB cells showed a high chromosomal heterogeneity. UW473 cells showed ~2 fold higher both clonal- and non-clonal chromosomal alterations than UW402 cells. Besides, UW473 showed two clonal-groups well-differentiated by ploidy level ( and ) and also presented a significantly higher number of chromosomal instability biomarkers. These results were associated with high morphological heterogeneity and survival advantages for UW473 and proliferation advantages for UW402 cells. Moreover, UW473 was significantly more sensitive to methotrexate, temozolomide and cisplatin while UW402 cells were more sensitive to doxorubicin. These data suggest that distinct different degrees of karyotypic heterogeneity and instability may affect neoplasic phenotype of MB cells. These findings bring new insights into cell and tumor biology.

  8. Cavernous angioma after chemotherapy for desmoplastic/nodular medulloblastoma associated with anhidrotic ectodermal dysplasia.

    Science.gov (United States)

    Yamasaki, Fumiyuki; Takayasu, Takeshi; Nosaka, Ryo; Kawaguchi, Hiroshi; Sugiyama, Kazuhiko; Kobayashi, Masao; Kurisu, Kaoru

    2016-02-01

    While cavernous angioma (CVA) after cranial irradiation has been documented, its development after high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) has not. We present a patient with desmoplastic/nodular medulloblastoma (DNMB) associated with anhidrotic ectodermal dysplasia (AED) who developed CVA 2 years after high-dose chemotherapy and PBSCT. A 1-year-old boy with ingravescent vomiting was admitted to our institute. He presented with a large head, a depressed nasal bridge, low-set ears, thick lips with peg-shaped teeth, hypohidrosis, sparse hair, thin atrophic skin, scaly dermatitis with frontal bossing, and a bulging anterior fontanel. Neuroradiological examination revealed multiple cerebellar masses with heterogeneous enhancement and speckled calcifications and severe obstructive hydrocephalus. The histological diagnosis of surgical specimens was DNMB, and he underwent postoperative multiple-drug chemotherapy with autologous PBSCT. The outcome was favorable and he did not undergo radiotherapy. After 2 years, intracranial hemorrhage was detected at his regular radiological check-up and he again underwent surgery. The histological diagnosis was CVA. To our knowledge, this is the first report of AED-associated DNMB and CVA.

  9. 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.

  10. 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].

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

    Science.gov (United States)

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

    2014-07-01

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

  12. 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...

  13. Defining high risk in endovascular aneurysm repair.

    Science.gov (United States)

    Mastracci, Tara M; Greenberg, Roy K; Hernandez, Adrian V; Morales, Catherine

    2010-05-01

    Long-term survival benefit contrasted with rupture risk should determine which patients are suitable for abdominal aortic aneurysm (AAA) intervention. Our aim was to develop a model capable of predicting long-term survival based on preoperative characteristics. A prospective cohort study using Cox regression modeling. We aimed to associate preoperative characteristics with long-term mortality, and create a predictive nomogram, which was then externally validated on an independent cohort (697 patients) who underwent endovascular abdominal aortic aneurysm (AAA) repair. We pooled the results of 412 patients undergoing endovascular repair of infrarenal and juxtarenal aneurysm who were high risk (average Glasgow aneurysm scores of 72.8 [SD 10.4]). Despite anatomic differences, there were no statistically significant differences in perioperative or long-term outcomes between infrarenal and juxtarenal aneurysms (log rank test, P = .5). Data from this group (64% infrarenal aneurysms and 36% juxtarenal aneurysms) were randomly and evenly split into a model development and test group. Independent predictors of mortality included in the model are age, aneurysm diameter, history of peripheral artery disease, chronic obstructive pulmonary disease (COPD), or congestive heart failure, requirement for supplemental home oxygen, and use of salicylates. Internal validation reveals good calibration and discriminative ability (c-statistic 0.68 [95% confidence interval 0.65-0.71]). External validation confirms good calibration. In the context of acceptable perioperative results, long-term mortality risk can be predicted in endovascular AAA repair and must be balanced against risk of rupture to determine which patients should be offered treatment. Copyright (c) 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  14. A comparative evaluation of supervised and unsupervised representation learning approaches for anaplastic medulloblastoma differentiation

    Science.gov (United States)

    Cruz-Roa, Angel; Arevalo, John; Basavanhally, Ajay; Madabhushi, Anant; González, Fabio

    2015-01-01

    Learning data representations directly from the data itself is an approach that has shown great success in different pattern recognition problems, outperforming state-of-the-art feature extraction schemes for different tasks in computer vision, speech recognition and natural language processing. Representation learning applies unsupervised and supervised machine learning methods to large amounts of data to find building-blocks that better represent the information in it. Digitized histopathology images represents a very good testbed for representation learning since it involves large amounts of high complex, visual data. This paper presents a comparative evaluation of different supervised and unsupervised representation learning architectures to specifically address open questions on what type of learning architectures (deep or shallow), type of learning (unsupervised or supervised) is optimal. In this paper we limit ourselves to addressing these questions in the context of distinguishing between anaplastic and non-anaplastic medulloblastomas from routine haematoxylin and eosin stained images. The unsupervised approaches evaluated were sparse autoencoders and topographic reconstruct independent component analysis, and the supervised approach was convolutional neural networks. Experimental results show that shallow architectures with more neurons are better than deeper architectures without taking into account local space invariances and that topographic constraints provide useful invariant features in scale and rotations for efficient tumor differentiation.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. Highly Enhanced Risk Management Emergency Satellite

    DEFF Research Database (Denmark)

    Dalmeir, Michael; Gataullin, Yunir; Indrajit, Agung

    HERMES (Highly Enhanced Risk Management Emergency Satellite) is potential European satellite mission for global flood management, being implemented by Technical University Munich and European Space Agency. With its main instrument - a reliable and precise Synthetic Aperture Radar (SAR) antenna...... - and its orbit characteristics (covering the whole earth surface in 3 days, low altitude), HERMES will provide stand-alone-data for: flood disaster monitoring, flood forecasting and flood prevention. Data obtained by HERMES can be used for commercial soil type maps (e.g. for optimized land use). As only...... highly effective and orbit proven hardware is used, HERMES is designed to be reliable, precise and of low cost. The project can be extended for use on other space bodies (planets) for rapid observation of the planetary surface....

  1. 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.

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

    Science.gov (United States)

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

    2017-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Ganesh Rao

    2003-05-01

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

  4. [Antiphospholipid antibodies in high-risk pregnancy].

    Science.gov (United States)

    Nestorowicz, B; Ostanek, L; Ronin-Walknowska, E; Fiedorowicz-Fabrycy, I; Skoczowska, M; Czajkowska, E; Fischer, K

    2000-06-01

    Recently the connection of antiphospholipid antibodies (aPLs) presence with pregnancy loss and complications in pregnancy has been observed APLs related obstetric complications include: miscarriages after 10 weeks, IUGR, intrauterine foetal death, preeclampsia and severe preeclampsia. Our objective was to determine the aPLs prevalence in patients with recurrent pregnancy loss and/or complicated pregnancy. We examined 154 pregnant women aged 19-42 (average of 29.1) with recurrent pregnancy loss, current pregnancy complicated by preeclampsia and severe preeclampsia and/or IUGR, thrombotic episodes, thrombocytopenia or autoimmune disease. In all the patients anticardiolipin antibodies (aCL) were determined at least twice using ELISA and their coagulation system was tested including lupus anticoagulant (LA) test. In justified cases immunological examinations detecting connective tissue systemic diseases were conducted. Increased aCL titre was detected in 54 (34.4%) women. Statistically significant risk of increased aCL titre was observed in patients with autoimmunological diseases (RR = 4.3). Increased, but Statistically insignificant, risk of high aCL titre was observed in patients with venous thrombosis (RR = 2.45) as well as in patients with thrombocytopenia (RR = 2.45). LA prevailed significantly more often in patients with venous thrombosis episodes (RR = 6.33) and with autoimmunological diseases (RR = 17.4). Preterm deliveries were significantly more frequent in pregnant women with increased aCL titre and/or LA. Moreover, in this group foetal death and preterm stillbirth more often occurred. The above mentioned risks increased when aCL and LA coexisted. No relation between increased aPLs and miscarriage frequency was observed. 1) Increased aPLs titre prevail in multiparas with bad obstetrical anamnesis and with pathological course in present pregnancy, 2) increased aPLs titre prevail in patients with autoimmunological diseases, 3) increased aPLs titre are

  5. Prenatal screening with evaluated high risk scores.

    Science.gov (United States)

    Papiernik, E; Grangé, G

    1999-01-01

    This paper reviews data that support the effectiveness of the French approach of using risk scoring for evaluating the risk of preterm delivery. This approach, which was developed in 1969 and spread to obstetricians and midwives throughout France in the early 1970s, includes systematic information about the recognition of uterine contractions, advice about reduction of physical exercise, and the prescription of work-leave for women with heavy or physically demanding work loads. The effectiveness of this prevention strategy is assessed using three different data sets: an evaluation of a preterm prevention program in the Alsace Region of France, five successive French national sample surveys which collected data on pregnant women, and a study of the effectiveness of a prevention program for twins in the district of Haut de Seine near Paris. The authors show that the rate of preterm birth in France declined substantially, but that the decline was concentrated among singleton spontaneous births. Since the 1970s induced preterm births have increased, and, interventions have not reduced the high rates of preterm birth among twins.

  6. High-risk obstetrics, medicolegal problems.

    Science.gov (United States)

    Herczeg, J

    1997-02-01

    The perinatal period is one of the most dangerous time of life. The responsibilities of the obstetricians are multifold. It is very difficult to draw a line between good and substandard care, therefore in perinatology and especially in high-risk obstetrical cases there are no absolute rules of management. The lay public is convinced through media channels, that modern reproductive research eliminated all the risks and hazards associated with childbirths, therefore only 100% healthy babies are accepted. Pregnancy is regarded as a 'success story' and if the baby is born with neurological defects (cerebral palsy) the parents and their advisors feel, that someone responsible for the defect should be found in the chain of management. This attitude starts a legal battle focusing on the events of labor and delivery. But in most cases it is very difficult to determine if a peripartal neonatal encephalopathy originated from the time period of labor and delivery, or started weeks earlier during pregnancy as an unnoticed event. Perinatal morbidity indicators are best based on neonatal clinical signs, which are predictive of later morbidity of the child. Neonatal seizures within 48 h of delivery of the baby could be a good index of later morbidity.

  7. 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.

  8. Suicide risk assessment in high-risk adolescents.

    Science.gov (United States)

    Gray, Barbara P; Dihigo, Sharolyn K

    2015-09-13

    A significant number of adolescents experience depression and other mental health disorders that may put them at risk for suicide. Mental health assessment is an important component of primary healthcare. Depression and suicide risk screening can assist healthcare providers in preventing suicides.

  9. High body mass index and cancer risk

    DEFF Research Database (Denmark)

    Benn, Marianne; Tybjærg-Hansen, Anne; Smith, George Davey

    2016-01-01

    alleles was associated with a 3 % higher BMI (P cancer. In instrumental variable analysis for a 10 kg/m(2) higher genetically determined BMI the odds ratio for any non-skin cancer was 1.16 (0.64-2.09), with a corresponding observational estimate of 0.94 (0.88-1.01). Using......High body mass index (BMI) has been associated with increased risk of some cancer. Whether these reflect causal associations is unknown. We examined this issue. Using a Mendelian randomisation approach, we studied 108,812 individuals from the general population. During a median of 4.7 years...... of follow-up (range 0-37), 8002 developed non-skin cancer, 3347 non-melanoma skin cancer, 1396 lung cancer, 637 other smoking related cancers, 1203 colon cancer, 159 kidney cancer, 1402 breast cancer, 1062 prostate cancer, and 2804 other cancers. Participants were genotyped for five genetic variants...

  10. Safety culture in high-risk industries.

    Science.gov (United States)

    Martyka, Joanna; Lebecki, Kazimierz

    2014-01-01

    This paper addresses the question of whether adopting safety culture improves hazard prevention in enterprises characterized by high primary risk. To answer this question, sample underground coal mines were examined to investigate the basic elements of the safety culture of employees. This paper presents the results of a diagnosis of the basic elements of the safety culture of supervisors (midlevel managers) and blue-collar workers in 3 underground coal mines. The study used 2 techniques: a Likert-type scale and a questionnaire. The results indicate the need to introduce changes in the safety culture of underground coal mine employees. This study also presents the conditions for improvement. Special attention was paid to (a) the conditions for improving safety culture and (b) a programme for modifying risky behaviours.

  11. Prescription of the High Risk Narcotics and Trading or Illicit Purchasing of High Risk Narcotics

    Directory of Open Access Journals (Sweden)

    Nicoleta-Elena Buzatu

    2012-05-01

    Full Text Available The present essay will analyze the offence of prescribing high risk narcotics and trading or illicit purchasing of high risk narcotics, as it was regulated - together with other offences - by Law no 143 of July 26, 2000 on preventing and fighting against the traffic and illicit consumption of narcotics. The same law defines the meaning of such a phrase “substances which are under national control” by mentioning the fact that they are the narcotics and their precursors listed in Annexes I-IV of the law. The analysis of the offence of prescribing the high risk narcotics and trading or illicit purchasing of high risk narcotics is following the already known structure mentioned in the doctrine and which consists of: object and subjects of the offence, its constituent content: the objective side with its material element, the immediate consequence and causality connections; the subjective side of the offence, as well as forms and modalities of these offences, and the applicable sanctions, of course.

  12. Challenging Propofol Sedation in Gastrointestinal Endoscopy: High Risk Patients and High Risk Procedures

    Directory of Open Access Journals (Sweden)

    Eduardo Redondo-Cerezo

    2012-12-01

    Full Text Available Sedation is increasingly becoming a must for most endoscopic procedures. Non-anesthesiologist administration of propofol is the standard of practice in many European countries. Nevertheless, despite anesthesiology societies concerns about sedation guided by endoscopist, practitioners find some limits to propofol administration, related to high risk patients or high risk and complex procedures, which can be long lasting and technically challenging. The main patient related risk factors for sedation are elderly patients, obesity, ASA≥3 patients, individuals with craniofacial abnormalities or with pharyngolaringeal tumors, patients with an acute gastrointestinal bleeding, under pain medications, sedatives, antidepressants, or who consume significant amounts of alcohol or drugs. Procedure related risk factors have more to do with the duration and complexity of the procedure than with other factors, in which considering a general anesthesia allows the endoscopist to concentrate on a difficult task. Published papers addressing the most challenging sedation groups in endoscopy are exploring and even trespassing previously assumed frontiers, and new scenarios are opening to the endoscopist, increasing his/her autonomy, reducing costs and giving patients levels of comfort previously unknown. In this review we analyse each risk group determining the ones in which a sedation protocol could be widely applied, and other in which the published evidence does not guarantee a safe endoscopist guided propofol sedation.

  13. Modeling HIV Risk in Highly Vulnerable Youth

    Science.gov (United States)

    Huba, G. J.; Panter, A. T.; Melchior, Lisa A.; Trevithick, Lee; Woods, Elizabeth R.; Wright, Eric; Feudo, Rudy; Tierney, Steven; Schneir, Arlene; Tenner, Adam; Remafedi, Gary; Greenberg, Brian; Sturdevant, Marsha; Goodman, Elizabeth; Hodgins, Antigone; Wallace, Michael; Brady, Russell E.; Singer, Barney; Marconi, Katherine

    2003-01-01

    This article examines the structure of several HIV risk behaviors in an ethnically and geographically diverse sample of 8,251 clients from 10 innovative demonstration projects intended for adolescents living with, or at risk for, HIV. Exploratory and confirmatory factor analyses identified 2 risk factors for men (sexual intercourse with men and a…

  14. Modeling HIV risk in highly vulnerable youth

    NARCIS (Netherlands)

    Huba, GJ; Panter, AT; Melchior, LA; Trevithick, L; Woods, ER; Wright, E; Feudo, R; Tierney, S; Schneir, A; Tenner, A; Remafedi, G; Greenberg, B; Sturdevant, M; Goodman, E; Hodgins, A; Wallace, M; Brady, RE; Singer, B; Marconi, K

    2003-01-01

    This article examines the structure of several HIV risk behaviors in an ethnically and geographically diverse sample of 8,251 clients from 10 innovative demonstration projects intended for adolescents living with, or at risk for, HIV. Exploratory and confirmatory factor analyses identified 2 risk

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. Long-term life expectancy for children with ependymoma and medulloblastoma.

    Science.gov (United States)

    Frandsen, Jonathan E; Wagner, Aaron; Bollo, Robert J; Shrieve, Dennis C; Poppe, Matthew M

    2015-11-01

    There is a paucity of long-term follow-up data for children with intracranial ependymoma (IE) and medulloblastoma (MB). What happens to these children 20, 30, or 40 years after diagnosis? Do they have potential for a normal lifespan? The purpose of this study was to ascertain the long-term survival potential in children with MB or IE who have survived 5 years from diagnosis. A retrospective analysis was conducted using the SEER Program. Children (ages 0-19 years) from 1973 to 2011 with a diagnosis of MB or IE were identified. A cohort was created of potentially cured patients who survived 5 years from diagnosis. Cox proportional hazards models and Kaplan-Meier estimates were utilized to analyze long-term survival. We identified 876 patients with MB and 474 patients with IE who were alive 5 years from diagnosis. Patients with MB had a 30-year overall survival (OS) and cancer-specific survival (CSS) of 70.2% and 80.1%, respectively. Patients with IE had a 30-year OS and CSS of 57.3% and 68.8%, respectively. When comparing MB with IE, MB had improved CSS (P = 0.04) and trended toward increased OS (P = 0.10). A significant number of deaths due to disease occur for several decades after treatment for both IE and MB. Despite this, the potential for long-term survival exists in 5-year survivors of both histologies. If alive at 5 years from diagnosis, patients with MB tend to have a lower risk of death from disease compared to those with IE. © 2015 Wiley Periodicals, Inc.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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?

  5. Prevalence and Risk Factors of High Risk Human Papillomavirus ...

    African Journals Online (AJOL)

    Cervical cancer is the most common female cancer in northern Nigeria, yet the pattern of infection with human papillomavirus, the principal aetiologic agent is unknown. This was a preliminary study conducted in two referral hospitals in order to establish base-line data on the prevalence and risk factors for the infection in ...

  6. 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.

  7. Proteomic analysis of human Sonic Hedgehog (SHH) medulloblastoma stem-like cells.

    Science.gov (United States)

    Ronci, Maurizio; Catanzaro, Giuseppina; Pieroni, Luisa; Po, Agnese; Besharat, Zein Mersini; Greco, Viviana; Levi Mortera, Stefano; Screpanti, Isabella; Ferretti, Elisabetta; Urbani, Andrea

    2015-06-01

    Human medulloblastoma (MB) is a malignant brain tumor that comprises four distinct molecular subgroups including the Sonic Hedgehog (SHH)-MB group. A leading cause of the SHH subgroup is an aberrant activation of the SHH pathway, a developmental signaling that regulates postnatal development of the cerebellum by promoting the mitotic expansion of granule neural precursors (GNPs) in the external granule layer (EGL). The abnormal SHH signaling pathway drives not only SHH-MB but also its cancer stem-like cells (SLCs), which represent a fraction of the tumor cell population that maintain cancer growth and have been associated with high grade tumors. Here, we report the first proteomic analysis of human SHH-MB SLCs before and after Retinoic Acid (RA)-induced differentiation. A total of 994 nLC-MS buckets were statistically analysed returning 68 modulated proteins between SLCs and their differentiated counterparts. Heat Shock Protein 70 (Hsp70) was one of the proteins that characterized the protein profile of SLCs. By means of Ingenuity Pathway Analysis (IPA), Genomatix analysis and extending the network obtained using the differentially expressed proteins we found a correlation between Hsp70 and the NF-κB complex. A key driver of the SHH-MB group is cMET whose downstream proliferation/survival signalling is indeed via PI3K/Akt/NF-κB. We confirmed the results of the proteomic analysis by western blot, underlining that a P-p65/NF-κB activatory complex is highly expressed in SLCs. Taking together these results we define a new protein feature of SHH-MB SLCs.

  8. 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

  9. 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.

  10. Communicating about risk: strategies for situations where public concern is high but the risk is low

    OpenAIRE

    Claire Hooker; Adam Capon; Julie Leask

    2017-01-01

    In this article, we summarise research that identifies best practice for communicating about hazards where the risk is low but public concern is high. We apply Peter Sandman’s ‘risk = hazard + outrage’ formulation to these risks, and review factors associated with the amplification of risk signals. We discuss the structures that determine the success of risk communication strategies, such as the capacity for early communication to ‘capture’ the dominant representation of risk issues, the impo...

  11. 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.

  12. 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.

  13. 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

  14. [Anesthesiological management of the high-risk surgical patient].

    Science.gov (United States)

    Bertoldi, G; Avalle, M

    1980-03-01

    Evaluation of the anaesthesiological risk in surgical patients is described and an account is given of results obtained with an association of ketamin and NLA II in 57 high-risk patients subjected to general surgical management.

  15. Advanced Risk Analysis for High-Performing Organizations

    National Research Council Canada - National Science Library

    Alberts, Christopher; Dorofee, Audrey

    2006-01-01

    ...) are not readily identified using traditional risk analysis techniques. High-performing organizations have the basic skills needed to identify and manage these new types of risk, but lack sufficient techniques...

  16. Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization.

    Science.gov (United States)

    Yokota, Naoki; Mainprize, Todd G; Taylor, Michael D; Kohata, Tomohiko; Loreto, Michael; Ueda, Shigeo; Dura, Wieslaw; Grajkowska, Wiesia; Kuo, John S; Rutka, James T

    2004-04-22

    To increase our understanding of the molecular pathogenesis of medulloblastoma (MB), we utilized the technique of suppression subtractive hybridization (SSH) to identify genes that are dysregulated in MB when compared to cerebellum. SSH-enriched cDNA libraries from both human and Ptch+/- heterozygous murine MBs were generated by subtracting common cDNAs from corresponding non-neoplastic cerebellum. For the human classic MB library, total human cerebellar RNA was used as control tissue; for the Ptch+/- heterozygous MB, non-neoplastic cerebellum from an unaffected Ptch+/- littermate was used as the control. Through differential screening of these libraries, over 100 upregulated tumor cDNA fragments were isolated, sequenced and identified with the NCBI BLAST program. From these, we selected genes involved in cellular proliferation, antiapoptosis, and cerebellar differentiation for further analysis. Upregulated genes identified in the human MB library included Unc33-like protein (ULIP), SOX4, Neuronatin (NNAT), the mammalian homologue of Drosophila BarH-like 1(BARHL1), the nuclear matix protein NRP/B (ENC1), and the homeobox OTX2 gene. Genes found to be upregulated in the murine MB library included cyclin D2 (Ccnd2), thymopoietin (Tmpo), Musashi-1 (Msh1), protein phosphatase 2A inhibitor-2 (I-2pp2a), and Unc5h4(D). Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), the mRNA expression levels for these genes were markedly higher in human MBs than in cerebellum. Western blot analysis was used to further confirm the overexpression of a subset of these genes at the protein level. Notch pathway overactivity was demonstrated in the TE671 MB cell line expressing high levels of MSH1 through HES1-Luciferase transfections. This study has revealed a panel of developmentally regulated genes that may be involved in the pathogenesis of MB. Copyright 2004 Nature Publishing Group

  17. Inhibition of SIRT1 Transcription inResveratrol-differentiated Medulloblastoma Cells

    Directory of Open Access Journals (Sweden)

    Jing-Xin Ma

    2013-05-01

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

  18. Systemic immunomodulatory strategies in high-risk corneal transplantation

    Directory of Open Access Journals (Sweden)

    Tulio B Abud

    2017-01-01

    Full Text Available The cornea is the most commonly transplanted tissue in the body. Although corneal grafts generally have high success rates, transplantation onto inflamed and vascularized host beds, or so-called high-risk corneal transplantation, has a high rate of graft rejection. The management of this high-risk corneal transplantation is challenging and involves numerous measures. One of the key measures to prevent graft rejection in these cases is the use of systemic immunosuppressive agents. In this article, we will review the systemic immunosuppressive agents most commonly used for high-risk corneal transplantation, which include corticosteroids, cysclosporine A, tacrolimus, mycophenolate mofetil, and rapamycin. Benefits, risks, and published data on the use of these medications for high-risk corneal transplantation will be detailed. We will also summarize novel immunoregulatory approaches that may be used to prevent graft rejection in high-risk corneal transplantation.

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    Revathi Rajagopal

    2017-04-01

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

  1. 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.

  2. Heterogeneity of Psychosis Risk Within Individuals at Clinical High Risk: A Meta-analytical Stratification

    NARCIS (Netherlands)

    Fusar-Poli, Paolo; Cappucciati, Marco; Borgwardt, Stefan; Woods, Scott W.; Addington, Jean; Nelson, Barnaby; Nieman, Dorien H.; Stahl, Daniel R.; Rutigliano, Grazia; Riecher-Rössler, Anita; Simon, Andor E.; Mizuno, Masafumi; Lee, Tae Young; Kwon, Jun Soo; Lam, May M. L.; Perez, Jesus; Keri, Szabolcs; Amminger, Paul; Metzler, Sibylle; Kawohl, Wolfram; Rössler, Wulf; Lee, Jimmy; Labad, Javier; Ziermans, Tim; An, Suk Kyoon; Liu, Chen-Chung; Woodberry, Kristen A.; Braham, Amel; Corcoran, Cheryl; McGorry, Patrick; Yung, Alison R.; McGuire, Philip K.

    2016-01-01

    Individuals can be classified as being at clinical high risk (CHR) for psychosis if they meet at least one of the ultra-high-risk (UHR) inclusion criteria (brief limited intermittent psychotic symptoms [BLIPS] and/or attenuated psychotic symptoms [APS] and/or genetic risk and deterioration syndrome

  3. Evaluation of Risk Management Strategies for a Low-Cost, High-Risk Project

    Science.gov (United States)

    Shishko, Robert; Jorgensen, Edward J.

    1996-01-01

    This paper summarizes work in progress to define and implement a risk management process tailored to a low-cost, high-risk, NASA mission -the Microrover Flight Experiment (MFEX, commonly called the Mars microrover).

  4. Standardizing care for high-risk patients in spine surgery: the Northwestern high-risk spine protocol.

    Science.gov (United States)

    Halpin, Ryan J; Sugrue, Patrick A; Gould, Robert W; Kallas, Peter G; Schafer, Michael F; Ondra, Stephen L; Koski, Tyler R

    2010-12-01

    Review article of current literature on the preoperative evaluation and postoperative management of patients undergoing high-risk spine operations and a presentation of a multidisciplinary protocol for patients undergoing high-risk spine operation. To provide evidence-based outline of modifiable risk factors and give an example of a multidisciplinary protocol with the goal of improving outcomes. Protocol-based care has been shown to improve outcomes in many areas of medicine. A protocol to evaluate patients undergoing high-risk procedures may ultimately improve patient outcomes. The English language literature to date was reviewed on modifiable risk factors for spine surgery. A multidisciplinary team including hospitalists, critical care physicians, anesthesiologists, and spine surgeons from neurosurgery and orthopedics established an institutional protocol to provide comprehensive care in the pre-, peri-, and postoperative periods for patients undergoing high-risk spine operations. An example of a comprehensive pre-, peri-, and postoperative high-risk spine protocol is provided, with focus on the preoperative assessment of patients undergoing high-risk spine operations and modifiable risk factors. Standardizing preoperative risk assessment may lead to better outcomes after major spine operations. A high-risk spine protocol may help patients by having dedicated physicians in multiple specialties focusing on all aspects of a patients care in the pre-, intra-, and postoperative phases.

  5. High-Risk and Low-Risk Human Papillomavirus and the Absolute Risk of Cervical Intraepithelial Neoplasia or Cancer

    DEFF Research Database (Denmark)

    Thomsen, Louise T; Frederiksen, Kirsten; Munk, Christian

    2014-01-01

    OBJECTIVE: To determine the absolute risk of cervical intraepithelial neoplasia (CIN) grade 3 or cervical cancer (CIN 3 or worse) after detection of low-risk human papillomavirus (HPV) and after a negative high-risk HPV test. METHODS: In this prospective cohort study, consecutive liquid-based cer......OBJECTIVE: To determine the absolute risk of cervical intraepithelial neoplasia (CIN) grade 3 or cervical cancer (CIN 3 or worse) after detection of low-risk human papillomavirus (HPV) and after a negative high-risk HPV test. METHODS: In this prospective cohort study, consecutive liquid...

  6. 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.

  7. 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.

  8. 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, ...

  9. 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.

  10. 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.

  11. High Blood Pressure, Afib and Your Risk of Stroke

    Science.gov (United States)

    ... Peripheral Artery Disease Venous Thromboembolism Aortic Aneurysm More High Blood Pressure, AFib and Your Risk of Stroke Updated:Aug ... have a stroke for the first time have high blood pressure . And an irregular atrial heart rhythm — a condition ...

  12. Elite High Schools Breed Higher Risk of Addiction

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_166144.html Elite High Schools Breed Higher Risk of Addiction: Study ... from drug addiction, new research suggests. Teens at elite U.S. high schools seem to face a higher ...

  13. Sexual risk behaviours of high school female learners in Mbonge ...

    African Journals Online (AJOL)

    Introduction: since female learners in high schools in Cameroon fall within the age group hardest hit by HIV/AIDS, it is assumed that these learners might be exposed to sexual risk behaviours. However, little has been explored on the sexual risk behaviours of high school female learners in Cameroon. This study aimed at ...

  14. Alcohol consumption and high risk sexual behaviour among female ...

    African Journals Online (AJOL)

    Alcohol consumption has been associated with high risk sexual behaviour among key populations such as female sex workers. We explored the drivers of alcohol consumption and its relationship to high risk sexual behaviour. Participants were drawn from a cohort of 1 027 women selected from 'hot spots' in the suburbs of ...

  15. Correlation between high-risk pregnancy and developmental delay ...

    African Journals Online (AJOL)

    Background: The future development of children is considered more than ever now due to the advances in medical knowledge and thus the increase in survival rates of high-risk infants. This study investigated the correlation between high-risk pregnancy and developmental delay in children aged 4- 60 months. Methods: ...

  16. High Risk Behavior among Adolescent Mothers: The Problem in Context.

    Science.gov (United States)

    Kissman, Kris

    1998-01-01

    Discusses the particular consequences of high-risk behavior for adolescent women, including unintended pregnancies, sexually transmitted diseases, school dropout and poverty, developmental disabilities, and poor school performance. Considers the role of male partners in teenage women's high risk behavior. Describes prevention efforts such as…

  17. Elevated level of serum triglyceride among high risk stress bank ...

    African Journals Online (AJOL)

    The objective of this study was to estimate lipid profile among high risk stress bank employees' correlated with heart disorders in Riyadh, Saudi Arabia. A total of 129 patients with high risk stress employees were involved in this study, which were divided into 69 males and 60 females between the age of 25 to 55 years.

  18. Prevalence and risk factors of obesity and high blood pressure ...

    African Journals Online (AJOL)

    Risk factors for these diseases have been well studied in high income countries but less studied in developing countries. Objective: The study was to document the prevalence and risk factors of Obesity and high blood pressure among healthy adults in a military settlement in Ibagwa, Southern Nigeria. The study also sought ...

  19. 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.

  20. 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.

  1. Early Molecular Stratification of High-risk Primary Biliary Cholangitis.

    Science.gov (United States)

    Hardie, Claire; Green, Kile; Jopson, Laura; Millar, Ben; Innes, Barbara; Pagan, Sarah; Tiniakos, Dina; Dyson, Jessica; Haniffa, Muzlifah; Bigley, Venetia; Jones, David E; Brain, John; Walker, Lucy J

    2016-12-01

    High-risk primary biliary cholangitis (PBC), defined by inadequate response at one year to Ursodeoxycholic acid (UDCA), is associated with disease progression and liver transplantation. Stratifying high-risk patients early would facilitate improved approaches to care. Using long-term follow-up data to define risk at presentation, 6 high-risk PBC patients and 8 low-risk patients were identified from biopsy, transplant and biochemical archival records. Formalin-fixed paraffin-embedded (FFPE) liver biopsies taken at presentation were graded (Scheuer and Nakanuma scoring) and gene expression analysed using the NanoString® nCounter PanCancer Immunity 770-gene panel. Principle component analysis (PCA) demonstrated discrete gene expression clustering between controls and high- and low-risk PBC. High-risk PBC was characterised by up-regulation of genes linked to T-cell activation and apoptosis, INF-γ signalling and leukocyte migration and down-regulation of those linked to the complement pathway. CDKN1a, up-regulated in high-risk PBC, correlated with significantly increased expression of its gene product, the senescence marker p21 WAF1/Cip , by biliary epithelial cells. Our findings suggest high- and low-risk PBC are biologically different from disease outset and senescence an early feature in high-risk disease. Identification of a high-risk 'signal' early from standard FFPE tissue sections has clear clinical utility allowing for patient stratification and second-line therapeutic intervention. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

  2. High Center Volume Does Not Mitigate Risk Associated with Using High Donor Risk Organs in Liver Transplantation.

    Science.gov (United States)

    Beal, Eliza W; Black, Sylvester M; Mumtaz, Khalid; Hayes, Don; El-Hinnawi, Ashraf; Washburn, Kenneth; Tumin, Dmitry

    2017-09-01

    High-risk donor allografts increase access to liver transplant, but potentially reduce patient and graft survival. It is unclear whether the risk associated with using marginal donor livers is mitigated by increasing center experience. The United Network for Organ Sharing registry was queried for adult first-time liver transplant recipients between 2/2002 and 12/2015. High donor risk was defined as donor risk index >1.9, and 1-year patient and graft survival were compared according to donor risk index in small and large centers. Multivariable Cox regression estimated the hazard ratio (HR) associated with using high-risk donor organs, according to a continuous measure of annual center volume. The analysis included 51,770 patients. In 67 small and 67 large centers, high donor risk index predicted increased mortality (p = 0.001). In multivariable analysis, high-donor risk index allografts predicted greater mortality hazard at centers performing 20 liver transplants per year (HR 1.35; 95% CI 1.22, 1.49; p transplant. Specific strategies to mitigate the risk of liver transplant involving high-risk donors are needed, in addition to accumulation of center expertise.

  3. 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.

  4. 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

  5. Prognosis of Carotid Endarterectomy in High Risk Patients

    Directory of Open Access Journals (Sweden)

    MH Modaghegh

    2016-04-01

    Full Text Available Introduction: Carotid Endarterectomy (CE can be mentioned as a valuable theraputic method for primary and secondary prevention of stroke, provided it can be performed in vascular surgery centers with a low surgical risk. Thus, the present study aimed to assess prognosis of CE in high risk patients of an Iranian vascular surgery center. Methods: This prospective observational study consisted of 50 high risk CE patients during 2011-14 in Mashhad University of Medical Sciences. All the high risk CE were performed by a vascular surgeon and a surgical carotid shunt was placed in each CE. Neurologic evaluation was performed before CE and serial neurologic axamination was done after CE by a neurologist. Surgical complications including stroke, death and lower cranial nerve palsy were recorded for 30 days after operation. Results: The study results revealed that 80% of high risk CE patients had symptomatic carotid stenosis on the operation side and 80% had carotid stenosis contralateral to the operation side. Thirteen high risk CE were performed simultaneously with coronary artery by pass graft and 24 patients were demonstrated to have diabetes. Post surgical death and stroke in the high risk CE patients were reported 2% and 4%, respectively. Lower cranial nerve palsy appeared in 2% of patients. Conclusion: The 6% post operative stroke and death rate in the high risk CE patients are comparable to best vascular surgery centers in Europe and North America.

  6. Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury

    Energy Technology Data Exchange (ETDEWEB)

    Giantsoudi, Drosoula; Sethi, Roshan V. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Yeap, Beow Y. [Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts (United States); Eaton, Bree R. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Ebb, David H. [Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts (United States); Caruso, Paul A.; Rapalino, Otto [Department of Radiology (O.R.) at the Massachusetts General Hospital, Boston, Massachusetts (United States); Chen, Yen-Lin E.; Adams, Judith A.; Yock, Torunn I.; Tarbell, Nancy J.; Paganetti, Harald [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); MacDonald, Shannon M., E-mail: smacdonald@mgh.harvard.edu [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2016-05-01

    Background: Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. Methods and Materials: We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. Results: At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). Conclusions: Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

  7. 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)

  8. High Framingham risk score decreases quality of life in adults

    Directory of Open Access Journals (Sweden)

    Christian Yosaputra

    2010-04-01

    Full Text Available Cardiovascular disease (CVD risk factors, such as diabetes, hypertension, hypercholesterolemia, smoking, and obesity tend to occur together in the general population. Increasing prevalence of multiple CVD risk factors has been related to increased risk of death from coronary heart disease and stroke. Studies have suggested that people with several risk factors of CVD may have impaired health-related quality of life. The objective of this study was to assess the association of CVD risk factors with quality of life (QOL among adults aged 40 to 65 years. A cross-sectional study was conducted involving 220 subjects 40 - 65 years of age at a health center. The CVD risk factors were assessed using the Framingham risk score that is the standard instrument for assessment of the risk of a first cardiac event. The risk factors assessed were age, smoking, blood pressure, total cholesterol and high density lipoprotein cholesterol concentrations. QOL was assessed by means of the WHOQOL-BREF instrument that had been prevalidated. The results of the study showed that 28.2% of subjects were smokers, 56.4% had stage 1 hypertension, 42.8% high total cholesterol and 13.6% low HDL cholesterol. The high risk group amounted to 45.5% and 42.3% constitued an intermediate risk group. High CVD risk scores were significantly associated with a low QOL for all domains (physical, psychological, social and environment (p=0.000. Preventing or reducing the multiple CVD risk factors to improve QOL is necessary among adults.

  9. 'High-risk' pregnancy after perinatal loss: understanding the label.

    Science.gov (United States)

    Simmons, Heather A; Goldberg, Lisa S

    2011-08-01

    to explore women's experience of living with a 'high-risk' pregnancy following a perinatal loss. a feminist phenomenological methodology provided the framework for the research study. the experience of 'high-risk' pregnancy following perinatal loss of seven women receiving care at a tertiary health centre in Atlantic Canada was explored by way of conversational interviews and reflective journaling. four themes emerged through thematic analysis and researcher interpretation: (1) understanding the meaning in the label of 'high-risk' pregnancy, (2) relational engagement with the unborn infant, (3) insight and acceptance of the influence of previous loss, and (4) essentiality of information. Taken together, these four themes represent the storied text embedded in the research study. The focus of attention in this article is based solely on the first theme, understanding the meaning in the label of 'high-risk' pregnancy, in so far as this fosters an ability to attend to the interpretive text in the methodological manner appropriate to phenomenological inquiry. although previous research indicates that the label of 'high-risk' in pregnancy is often associated with increased anxiety and fear, findings from this study suggest that a 'high-risk' pregnancy following perinatal loss results in women embracing the 'high-risk' label. By recognising the possibility that women experiencing 'high-risk' pregnancy following perinatal loss may perceive the label of 'high-risk' pregnancy in a positive way, nurses, midwives and other health-care providers may begin to alter their practices when caring for these women in current health-care environments. Copyright © 2010 Elsevier Ltd. All rights reserved.

  10. Radical prostatectomy in clinically localized high-risk prostate cancer

    DEFF Research Database (Denmark)

    Røder, Martin Andreas; Berg, Kasper Drimer; Christensen, Ib Jarle

    2013-01-01

    Abstract Objective. The optimal therapeutic strategy for high-risk localized prostate cancer (PCa) is controversial. Supported by randomized trials, the combination of external beam radiation therapy (EBRT) and endocrine therapy (ET) is advocated by many, while radical prostatectomy (RP......) is regarded as primary therapy by others. This study examined the outcome for high-risk localized PCa patients treated with RP. Material and methods. Of 1300 patients who underwent RP, 231 were identified as high-risk. Patients were followed for biochemical recurrence (BCR) (defined as prostate...

  11. A social work study high-risk behavior among teenagers

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Iravani

    2012-01-01

    Full Text Available Teenagers are believed the people who are supposed to build the world's future. High-risk behaviors such as addiction to drugs, smoking cigarettes, sex, etc. could significantly hurts teenagers and there must be some supporting programs to reduce these issues as much as possible. This paper performs an empirical investigation to study the different factors influencing high- risk behavior among teenagers who live in a city of Esfahan, Iran. The proposed study designs a questionnaire and distribute between two groups of female and male teenagers. The results indicate that while there is a meaningful relationship between high-risk behaviors and average high school marks among male students there is no meaningful relationship between high-risk behaviors and high school grades among female students. The results also indicate that there is a meaningful difference between gender and high-risk behavior. The season of birth for female and male students is another important factor for having high-risk behaviors. While the order of birth plays an important role among male students, the order of birth is not an important factor among female teenagers. Finally, the results indicate that teenagers' parental financial affordability plays a vital role on both female and male teenagers.

  12. Awareness and prevalence of metabolic syndrome among high-risk ...

    African Journals Online (AJOL)

    MetS) in high-risk individuals attending 30 internal medicine clinics in Amman, Jordan, and also to evaluate the various factors associated with increased risk of MetS among them. Methods: This retrospective cross-sectional study was carried out ...

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

    Science.gov (United States)

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

    2013-11-01

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

  14. 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.

  15. Brachytherapy boost and cancer-specific mortality in favorable high-risk versus other high-risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Vinayak Muralidhar

    2016-02-01

    Full Text Available Purpose : Recent retrospective data suggest that brachytherapy (BT boost may confer a cancer-specific survival benefit in radiation-managed high-risk prostate cancer. We sought to determine whether this survival benefit would extend to the recently defined favorable high-risk subgroup of prostate cancer patients (T1c, Gleason 4 + 4 = 8, PSA 20 ng/ml. Material and methods: We identified 45,078 patients in the Surveillance, Epidemiology, and End Results database with cT1c-T3aN0M0 intermediate- to high-risk prostate cancer diagnosed 2004-2011 treated with external beam radiation therapy (EBRT only or EBRT plus BT. We used multivariable competing risks regression to determine differences in the rate of prostate cancer-specific mortality (PCSM after EBRT + BT or EBRT alone in patients with intermediate-risk, favorable high-risk, or other high-risk disease after adjusting for demographic and clinical factors. Results : EBRT + BT was not associated with an improvement in 5-year PCSM compared to EBRT alone among patients with favorable high-risk disease (1.6% vs. 1.8%; adjusted hazard ratio [AHR]: 0.56; 95% confidence interval [CI]: 0.21-1.52, p = 0.258, and intermediate-risk disease (0.8% vs. 1.0%, AHR: 0.83, 95% CI: 0.59-1.16, p = 0.270. Others with high-risk disease had significantly lower 5-year PCSM when treated with EBRT + BT compared with EBRT alone (3.9% vs. 5.3%; AHR: 0.73; 95% CI: 0.55-0.95; p = 0.022. Conclusions : Brachytherapy boost is associated with a decreased rate of PCSM in some men with high-risk prostate cancer but not among patients with favorable high-risk disease. Our results suggest that the recently-defined “favorable high-risk” category may be used to personalize therapy for men with high-risk disease.

  16. Physical activity barriers and motivators among high-risk employees.

    Science.gov (United States)

    Paguntalan, John C; Gregoski, Mathew

    2016-11-22

    Worksite wellness programs offer an ideal setting to target high-risk sedentary workers to improve health status. Lack of physical activity is associated with increased risk for coronary heart disease and mortality. Despite the risks, the number of sedentary workers is increasing. This study examined the perceived barriers and motivators for physical activity among employees at high-risk for coronary heart disease. A purposive sample of 24 high-risk workers participating in a wellness program in rural South Carolina were enrolled in the study. Qualitative data was obtained through semi-structured face-to-face interviews. Grounded theory was used to analyze qualitative data, and identify overarching themes. Physical limitations due to pain and weakness, lack of motivation, and lack of time emerged as the main barriers to physical activity. Family relationships were reported as the strongest motivator along with social support and potential health benefits. Findings highlight the unique experience of high-risk workers with physical activity. The findingsunderscore the need to design and implement effective interventions specifically designed to meet the needs of high-risk employees.

  17. DASH - Youth Risk Behavior Surveillance System (YRBSS): High School

    Data.gov (United States)

    U.S. Department of Health & Human Services — 1991-2015. High School Dataset. The Youth Risk Behavior Surveillance System (YRBSS) monitors six categories of priority health behaviors among youth and young...

  18. Suicide Risk Especially High for U.S. Farmers

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_166800.html Suicide Risk Especially High for U.S. Farmers Other occupations ... Two decades after the U.S. farm crisis, the suicide rate among American farmers remains much higher than ...

  19. Sensation seeking in males involved in recreational high risk sports

    National Research Council Canada - National Science Library

    Guszkowska, M; Bołdak, A

    2010-01-01

    ...) of Zuckerman was applied.Results show, that high risk sports males are featured by stronger need of sensations in comparison to control group and this concerned all but one aspect of sensation seeking variable...

  20. High prevalence of cardiovascular risk factors in Durban South ...

    African Journals Online (AJOL)

    High prevalence of cardiovascular risk factors in Durban South African Indians: The Phoenix Lifestyle Project. ... All participants had demographic, anthropometric and biochemical measurements using the modified World Health Organization (WHO) STEPwise survey methods. Hypertension, obesity, lipid abnormalities and ...

  1. Psychological characteristics in high-risk MSM in China

    National Research Council Canada - National Science Library

    Chen, Guanzhi; Li, Yang; Zhang, Beichuan; Yu, Zengzhao; Li, Xiufang; Wang, Lixin; Yu, Ziming

    2012-01-01

    .... To date, little is known regarding the behavioral, social and psychological characteristics in Chinese MSM, which makes the implementation of preventive and therapeutic strategies for this high-risk...

  2. Treating Patients with High-Risk Smoldering Myeloma

    Science.gov (United States)

    In this phase III clinical trial, patients with smoldering myeloma classified as high risk for progression will be randomly assigned to undergo standard observation or six 4-week courses of treatment with the drug lenalidomide.

  3. High alcohol consumption causes high IgE levels but not high risk of allergic disease

    DEFF Research Database (Denmark)

    Lomholt, Frederikke K; Nielsen, Sune F; Nordestgaard, Børge G

    2016-01-01

    .2-2.5) for 1 allergic disease, 3.9 (95% CI, 3.5-4.4) for 2 allergic diseases, and 7.5 (95% CI, 6.2-9.0) for 3 allergic diseases. High alcohol consumption was associated with high IgE levels but not with high risk of allergic disease. The odds ratio for high versus low IgE levels per 1 alcoholic drink per week......BACKGROUND: High alcohol consumption is associated with high IgE levels in observational studies; however, whether high alcohol consumption leads to high IgE levels and allergic disease is unclear. OBJECTIVE: We tested the hypothesis that high alcohol consumption is associated with high IgE levels...... for the alcohol-metabolizing enzymes alcohol dehydrogenase 1B (ADH-1B; rs1229984) and alcohol dehydrogenase 1c (ADH-1C; rs698). Observationally, we investigated associations between IgE levels and allergic disease (allergic asthma, rhinitis, and eczema) and between alcohol consumption and IgE levels and allergic...

  4. Vaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies

    DEFF Research Database (Denmark)

    Klein, K; Rode, L; Nicolaides, K H

    2011-01-01

    OBJECTIVES: Progesterone treatment reduces the risk of preterm delivery in high-risk singleton pregnancies. Our aim was to evaluate the preventive effect of vaginal progesterone in high-risk twins. METHODS: This was a subanalysis of a Danish-Austrian, double-blind, placebo-controlled, randomized...... trial (PREDICT study), in which women with twin pregnancies were randomized to daily treatment with progesterone or placebo pessaries from 20-24 weeks until 34 weeks' gestation. This subpopulation consisted of high-risk pregnancies, defined by the finding of cervical length ≤ 10th centile at 20-24 weeks...... (10.6%) of the 677 women participating in the PREDICT study, the pregnancy was considered to be high-risk, including 47 with cervical length ≤ 10th centile, 28 with a history of preterm delivery or late miscarriage and three fulfilling both criteria. Baseline characteristics for progesterone...

  5. High-Risk Human Papillomavirus Targets Crossroads in Immune Signaling

    OpenAIRE

    Bart Tummers; van der Burg, Sjoerd H

    2015-01-01

    Persistent infections with a high-risk type human papillomavirus (hrHPV) can progress to cancer. High-risk HPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses to invading pathogens. Viral persistence is achieved by active interference with KCs innate and adaptive immune mechanisms. To this end hrHPV utilizes proteins encoded by its viral genome, as well as exploits cellu...

  6. Outcomes of parental investment in high-risk children.

    Science.gov (United States)

    Bugental, Daphne Blunt; Corpuz, Randy; Samec, Rachel

    2013-09-01

    This study assesses the combined effects of children's early medical risk (e.g., preterm status) and parental investment levels (time spent in provision of care to target children as opposed to other family members) on children's response to novel, potentially distressing stimuli. While engaged in play activities, children were exposed to stimuli that were either neutral (a speaker on television with a calm voice) or threatening (a speaker with an angry voice). A significant interaction between children's risk status and parental investment was found only for threatening stimuli. High-risk children with high-investing parents showed high visual engagement with potentially threatening responses, whereas high-risk children with low-investing parents were more likely to show visual avoidance. No comparable effects were found for low-risk children. Findings were interpreted as showing that high-risk children with a history of high parental investment are more likely to attend to potentially threatening events, an adaptive response in the presence of reliable support. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. High-risk smoldering myeloma: Perspective on watchful monitoring.

    Science.gov (United States)

    Leng, Siyang; Lentzsch, Suzanne

    2016-12-01

    In a 2008 paper, Dispenzieri and colleagues at the Mayo Clinic proposed a risk stratification system for patients with smoldering multiple myeloma (SMM) based on the presence of three risk factors: serum M-protein ≥3 g/dL, bone marrow plasma cell percentage ≥10%, and a free light chain (FLC) ratio (κ to λ) of either ≤0.125 or ≥8. The patient in this vignette has all three risk factors, classifying him as high-risk, with an associated median time to progression (TTP) of 1.9 years. This is significantly worse than a patient with intermediate-risk (median TTP 5.1 years) or low-risk (10 years) disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Predicting reattendance at a high-risk breast cancer clinic.

    Science.gov (United States)

    Ormseth, Sarah R; Wellisch, David K; Aréchiga, Adam E; Draper, Taylor L

    2015-10-01

    The research about follow-up patterns of women attending high-risk breast-cancer clinics is sparse. This study sought to profile daughters of breast-cancer patients who are likely to return versus those unlikely to return for follow-up care in a high-risk clinic. Our investigation included 131 patients attending the UCLA Revlon Breast Center High Risk Clinic. Predictor variables included age, computed breast-cancer risk, participants' perceived personal risk, clinically significant depressive symptomatology (CES-D score ≥ 16), current level of anxiety (State-Trait Anxiety Inventory), and survival status of participants' mothers (survived or passed away from breast cancer). A greater likelihood of reattendance was associated with older age (adjusted odds ratio [AOR] = 1.07, p = 0.004), computed breast-cancer risk (AOR = 1.10, p = 0.017), absence of depressive symptomatology (AOR = 0.25, p = 0.009), past psychiatric diagnosis (AOR = 3.14, p = 0.029), and maternal loss to breast cancer (AOR = 2.59, p = 0.034). Also, an interaction was found between mother's survival and perceived risk (p = 0.019), such that reattendance was associated with higher perceived risk among participants whose mothers survived (AOR = 1.04, p = 0.002), but not those whose mothers died (AOR = 0.99, p = 0.685). Furthermore, a nonlinear inverted "U" relationship was observed between state anxiety and reattendance (p = 0.037); participants with moderate anxiety were more likely to reattend than those with low or high anxiety levels. Demographic, medical, and psychosocial factors were found to be independently associated with reattendance to a high-risk breast-cancer clinic. Explication of the profiles of women who may or may not reattend may serve to inform the development and implementation of interventions to increase the likelihood of follow-up care.

  9. Communicating about risk: strategies for situations where public concern is high but the risk is low.

    Science.gov (United States)

    Hooker, Claire; Capon, Adam; Leask, Julie

    2017-01-15

    In this article, we summarise research that identifies best practice for communicating about hazards where the risk is low but public concern is high. We apply Peter Sandman's 'risk = hazard + outrage' formulation to these risks, and review factors associated with the amplification of risk signals. We discuss the structures that determine the success of risk communication strategies, such as the capacity for early communication to 'capture' the dominant representation of risk issues, the importance of communicating uncertainty, and the usefulness of engaging with communities. We argue that, when facing trade-offs in probable outcomes from communication, it is always best to choose strategies that maintain or build trust, even at the cost of initial overreactions. We discuss these features of successful risk communication in relation to a range of specific examples, particularly opposition to community water fluoridation, Ebola, and routine childhood immunisation.

  10. Communicating about risk: strategies for situations where public concern is high but the risk is low

    Directory of Open Access Journals (Sweden)

    Claire Hooker

    2017-02-01

    Full Text Available In this article, we summarise research that identifies best practice for communicating about hazards where the risk is low but public concern is high. We apply Peter Sandman’s ‘risk = hazard + outrage’ formulation to these risks, and review factors associated with the amplification of risk signals. We discuss the structures that determine the success of risk communication strategies, such as the capacity for early communication to ‘capture’ the dominant representation of risk issues, the importance of communicating uncertainty, and the usefulness of engaging with communities. We argue that, when facing trade-offs in probable outcomes from communication, it is always best to choose strategies that maintain or build trust, even at the cost of initial overreactions. We discuss these features of successful risk communication in relation to a range of specific examples, particularly opposition to community water fluoridation, Ebola, and routine childhood immunisation.

  11. Genomic analysis of high-risk smoldering multiple myeloma.

    Science.gov (United States)

    López-Corral, Lucía; Mateos, María Victoria; Corchete, Luis A; Sarasquete, María Eugenia; de la Rubia, Javier; de Arriba, Felipe; Lahuerta, Juan-José; García-Sanz, Ramón; San Miguel, Jesús F; Gutiérrez, Norma C

    2012-09-01

    Smoldering myeloma is an asymptomatic plasma cell dyscrasia with a heterogeneous propensity to progress to active myeloma. In order to investigate the biology of smoldering myeloma patients with high risk of progression, we analyzed the genomic characteristics by FISH, SNP-arrays and gene expression profile of a group of patients with high-risk smoldering myeloma included in a multicenter randomized trial. Chromosomal abnormalities detected by FISH and SNP-arrays at diagnosis were not associated to risk of progression to symptomatic myeloma. However, the overexpression of four SNORD genes (SNORD25, SNORD27, SNORD30 and SNORD31) was correlated with shorter time to progression (Psmoldering patients who progressed to symptomatic myeloma were sequentially analyzed, newly acquired lesions together with an increase in the proportion of plasma cells carrying a given abnormality were observed. These findings suggest that gene expression profiling is a valuable technique to identify smoldering myeloma patients with high risk of progression. (Clinical Trials NCT00443235).

  12. High alcohol consumption causes high IgE levels but not high risk of allergic disease.

    Science.gov (United States)

    Lomholt, Frederikke K; Nielsen, Sune F; Nordestgaard, Børge G

    2016-11-01

    High alcohol consumption is associated with high IgE levels in observational studies; however, whether high alcohol consumption leads to high IgE levels and allergic disease is unclear. We tested the hypothesis that high alcohol consumption is associated with high IgE levels and allergic disease both observationally and genetically using a Mendelian randomization design free of reverse causation and largely free of confounding. Among 111,408 subjects aged 20 to 100 years from the general population, 50,019 had plasma IgE measurements, and 102,270 were genotyped for the alcohol-metabolizing enzymes alcohol dehydrogenase 1B (ADH-1B; rs1229984) and alcohol dehydrogenase 1c (ADH-1C; rs698). Observationally, we investigated associations between IgE levels and allergic disease (allergic asthma, rhinitis, and eczema) and between alcohol consumption and IgE levels and allergic disease. Genetically, we explored potential causal relationships between alcohol consumption and IgE levels and allergic disease. The multivariable adjusted odds ratio for IgE levels greater than versus less than 150 kU/L and compared with subjects without allergic disease was 2.3 (95% CI, 2.2-2.5) for 1 allergic disease, 3.9 (95% CI, 3.5-4.4) for 2 allergic diseases, and 7.5 (95% CI, 6.2-9.0) for 3 allergic diseases. High alcohol consumption was associated with high IgE levels but not with high risk of allergic disease. The odds ratio for high versus low IgE levels per 1 alcoholic drink per week higher consumption was 1.12 (95% CI, 1.02-1.23) genetically and 1.01 (95% CI, 1.01-1.02) observationally; for allergic disease, the corresponding odds ratios were 0.96 (95% CI, 0.92-1.00) genetically and 1.00 (95% CI, 1.00-1.00) observationally. High alcohol consumption is associated observationally and genetically with high IgE levels but not with high risk of allergic disease. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  13. 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

  14. The risk ogf high-risk jobs : psychological health consequences in forensic physicians and ambulance workers

    NARCIS (Netherlands)

    Ploeg, E. van der

    2003-01-01

    The risk of high-risk jobs: Psychological health consequences in forensic doctors and ambulance workers This thesis has shown that forensic physicians and ambulance personnel frequently suffer from psychological complaints as a result of dramatic events and sources of chronic work stress. A

  15. Risk factors for congenital anomalies in high risk pregnant women: A ...

    African Journals Online (AJOL)

    Tella Sunitha

    2016-05-14

    May 14, 2016 ... Abstract Background: High Risk Pregnancy (HRP) is a condition where mother or developing fetus or both are at increased risk of complications during or after pregnancy and birth. There are no studies so far which have characterized congenital anomalies (CAs) in HRP women with dif- ferent previous ...

  16. Risk factors for congenital anomalies in high risk pregnant women: A ...

    African Journals Online (AJOL)

    Tella Sunitha

    2016-05-14

    May 14, 2016 ... Rubella;. CMV and HSV. Abstract Background: High Risk Pregnancy (HRP) is a condition where mother or developing fetus or both are at increased risk of complications during or after pregnancy and birth. There are no studies so far which have characterized congenital anomalies (CAs) in HRP women ...

  17. On risk, leverage and banks: do highly leveraged banks take on excessive risk?

    NARCIS (Netherlands)

    Koudstaal, M.; van Wijnbergen, S.

    2012-01-01

    This paper deals with the relation between excessive risk taking and capital structure in banks. Examining a quarterly dataset of U.S. banks between 1993 and 2010, we find that equity is valued higher when more risky portfolios are chosen when leverage is high, and that more risk taking has a

  18. Clinical risk factors for gestational hypertensive disorders in pregnant women at high risk for developing preeclampsia

    NARCIS (Netherlands)

    Wong, Tsz Y.; Groen, Henk; Faas, Marijke M.; van Pampus, Maria G.

    2013-01-01

    Objectives: To evaluate clinical risk factors for the development of gestational hypertensive disorders in a group of pregnant women at high risk for developing preeclampsia. Secondly we evaluated the incidence and recurrence rate of preeclampsia and pregnancy-induced hypertension. Study design: A

  19. Who Takes Risks in High-Risk Sports? A Typological Personality Approach

    Science.gov (United States)

    Castanier, Carole; Le Scanff, Christine; Woodman, Tim

    2010-01-01

    We investigated the risk-taking behaviors of 302 men involved in high-risk sports (downhill skiing, mountaineering, rock climbing, paragliding, or skydiving). The sportsmen were classified using a typological approach to personality based on eight personality types, which were constructed from combinations of neuroticism, extraversion, and…

  20. Risk behaviors for the health of adolescents from High School

    Directory of Open Access Journals (Sweden)

    José Henrique Ramos

    2009-09-01

    Full Text Available Objective: To investigate the risk behaviors (smoking addiction, alcoholism, drug use and sexual risk behavior of adolescents from High School. Methods: It was an analytical and cross-sectional study. The sample consisted of 720 scholars (252 boys and 468 girls from the age group of 16 to 17 years-old, from three public schools in Florianopolis/SC. The data was collected through two types of self administrated questionnaires; one for the parents and another one for the students, from March to December, 2005. The studied variables were legal and illegal drug use and sexual risk behavior. The descriptive statistics and the chi- squared test were used to carry out the data analysis Results: The beginning of risk behaviors occurred between 14 and 15 years old, for both genders. It was observed that 26 (3.6% scholars drank alcohol regularly; 38 (5.3% smoked daily; 66 (9.2 % were drug users or had used drugs several times and 14 (2% were drug dependents. Concerning to sexual risk behavior, 318 (44.5% scholars had sexual risk behavior and from those, 97 (13.6% did not always use condom. From the studied sample, 545 (76.5% scholars did not present any risk behavior. Among risk behaviors, sexual risk prevailed (42.5%. Conclusion: The number of adolescents with risk behavior was not high. Nevertheless, there is a small proportion of adolescents that smoke, drink and do drugs and have sexual risk behavior. This points out to the need of a bigger supervision and guidance for these students.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Early Parental Adaptation, Prenatal Distress, and High-Risk Pregnancy.

    Science.gov (United States)

    Dollberg, Daphna G; Rozenfeld, Tamir; Kupfermincz, Michael

    2016-09-01

    To examine the examined the effects of high risk pregnancy and prenatal distress on parental postnatal adaptation. A sample of 111 expecting parents, consisting of 32 high risk pregnancy (HRP) mothers and 21 spouses and 36 matched low risk pregnancy (LRP) mothers and 22 spouses completed reports of depression symptoms (BDI) and pregnancy related concerns prenatally. At three months postpartum, parent-infant direct observations and reports of parenting alliance (PAI), stress (PSI-SF), satisfaction and efficacy (PSOC) were gathered. Data was analyzed with GLM multivariate analyses and the actor-partner interdependence model. Parents' prenatal BDI predicted postnatal parental stress. BDI and concerns predicted postnatal satisfaction, but only for mothers. Mother's concerns predicted low maternal and high paternal parenting alliance. Partner effect was found so that high concerns predicted high reports of parenting alliance by spouse. Mean-group differences were found between HRP and LRP during parent-infant observations, so that HRP parents displayed lower sensitivity and reciprocity. Prenatal distress, and to some degree high risk pregnancy, are risk factors that may interfere with the early formation of parent-infant relationship. Clinical implications of these findings are presented. © The Author 2016. 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.

  9. The risk of hydrogen explosion in a submarine p. IV The implementation of high risk projects

    Directory of Open Access Journals (Sweden)

    Kłos Ryszard

    2017-06-01

    Full Text Available This series of articles on high risk projects looks at the example of the modernisation of hydrogen incinerators on a submarine. The article describes problems connected with the management of such a project.

  10. Cumulative Experiences of Violence among High-Risk Urban Youth

    Science.gov (United States)

    Taylor, Catherine A.; Boris, Neil W.; Heller, Sherryl Scott; Clum, Gretchen A.; Rice, Janet C.; Zeanah, Charles H.

    2008-01-01

    This study examines type-specific and cumulative experiences of violence among a vulnerable population of youth. Sixty high-risk, shelter-dwelling, urban youth were interviewed regarding their history of childhood maltreatment, exposure to community violence (ECV), and experience with intimate partner violence (IPV). Results show a high prevalence…

  11. An assessment of high risk sexual behaviour and HIV transmission ...

    African Journals Online (AJOL)

    Method: A total of 300 randomly selected migrant oil workers were assessed using structured questionnaires to evaluate key highrisk sexual behavioral parameters such as multiplicity of sexual partners, bisexuality (closet homosexuality), high grade sexual behaviour and lesbianism. Sampling period was two months with ...

  12. 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.

  13. 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

  14. High risk drinking and college students' self-perceptions.

    Science.gov (United States)

    Araujo, Gabriel C; Wong, Eugene H

    2005-12-01

    The present study examined the relationship between high risk drinking and college students' self-perceptions. High risk drinking was defined as the consumption of four or more drinks in a row for women and five or more drinks in a row for men during a single sitting (within the last year). Historical trends regarding college-age drinking indicate that 44% of college students fit the criteria for high risk drinking at least once over the past year. A survey was administered to 210 college students (52 men and 158 women) between 18 and 22 years of age (M = 20.9, SD = 1.3) to assess their use of alcohol and their self-perceptions. Students' self-perceptions were measured with four subscales from the Neemann-Harter Self-perception Profile for College Students. Students either volunteered to participate in this study outside of class or were solicited during class. It was predicted that students' self-perceptions would differ significantly depending upon their alcohol consumption, i.e., 17.1% were Abstainers, 25.2% were Nonproblem Drinkers, and 57.6% were High Risk Drinkers. Analysis gave significant difference on Global Self-worth between students who abstained and those who were High Risk Drinkers. However, students' perceptions of Scholastic Competence, Intellectual Ability, and Social Acceptance did not differ significantly for the alcohol consumption groups. In addition to high risk drinking, a number of other variables were associated with self-perceptions, such as high school alcohol use, low high school GPA, and students' reported academic involvement. These relations are discussed.

  15. Psychological characteristics in high-risk MSM in China.

    Science.gov (United States)

    Chen, Guanzhi; Li, Yang; Zhang, Beichuan; Yu, Zengzhao; Li, Xiufang; Wang, Lixin; Yu, Ziming

    2012-01-20

    Men who have sex with men (MSM) have become a high-risk group of HIV infection in China. To date, little is known regarding the behavioral, social and psychological characteristics in Chinese MSM, which makes the implementation of preventive and therapeutic strategies for this high-risk subpopulation of people extremely difficult. A total of 714 questionnaires were retrieved from the database of a Chinese government-sponsored National Key Research Project titled "Risk Analysis and Strategic Prevention of HIV Transmission from MSM to the General Population in China". The respondents were categorized into a high-risk group and a control group. Their behavioral, social and psychological characteristics were comparatively analyzed. Of the 714 MSM analyzed, 59 (8.26%) had high-risk homosexual behaviors. This sub-group of MSM had a higher in-marriage rate, a higher monthly income, heavier alcohol consumption and more serious problems with sexual abuse in childhood, intentional suicide attempts and mistaken assumption on condom's role in protecting HIV infection, as compared with the control group (P discrimination (P > 0.05). A vast majority of the individuals in both behavior categories expressed support of legally protected gay clubs as well as gay marriage legislation in China. There was a strong correlation between high-risk behaviors and sexual abuse in childhood, alcohol drinking, income level and a mistaken belief in perfect HIV protection through the use of condoms. MSM with and without high-risk homosexual behaviors have different social and psychological characteristics, which should be taken into account when implementing behavioral and therapeutic interventions aimed at preventing HIV/AIDS transmission among MSM as well as from MSM to the general population in China.

  16. 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.

  17. Psychological characteristics in high-risk MSM in China

    Directory of Open Access Journals (Sweden)

    Chen Guanzhi

    2012-01-01

    Full Text Available Abstract Background Men who have sex with men (MSM have become a high-risk group of HIV infection in China. To date, little is known regarding the behavioral, social and psychological characteristics in Chinese MSM, which makes the implementation of preventive and therapeutic strategies for this high-risk subpopulation of people extremely difficult. Methods A total of 714 questionnaires were retrieved from the database of a Chinese government-sponsored National Key Research Project titled "Risk Analysis and Strategic Prevention of HIV Transmission from MSM to the General Population in China". The respondents were categorized into a high-risk group and a control group. Their behavioral, social and psychological characteristics were comparatively analyzed. Results Of the 714 MSM analyzed, 59 (8.26% had high-risk homosexual behaviors. This sub-group of MSM had a higher in-marriage rate, a higher monthly income, heavier alcohol consumption and more serious problems with sexual abuse in childhood, intentional suicide attempts and mistaken assumption on condom's role in protecting HIV infection, as compared with the control group (P P > 0.05. A vast majority of the individuals in both behavior categories expressed support of legally protected gay clubs as well as gay marriage legislation in China. There was a strong correlation between high-risk behaviors and sexual abuse in childhood, alcohol drinking, income level and a mistaken belief in perfect HIV protection through the use of condoms. Conclusions MSM with and without high-risk homosexual behaviors have different social and psychological characteristics, which should be taken into account when implementing behavioral and therapeutic interventions aimed at preventing HIV/AIDS transmission among MSM as well as from MSM to the general population in China.

  18. Factors Influencing Cancer Risk Perception in High Risk Populations: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Tilburt Jon C

    2011-05-01

    Full Text Available Abstract Background Patients at higher than average risk of heritable cancer may process risk information differently than the general population. However, little is known about clinical, demographic, or psychosocial predictors that may impact risk perception in these groups. The objective of this study was to characterize factors associated with perceived risk of developing cancer in groups at high risk for cancer based on genetics or family history. Methods We searched Ovid MEDLINE, Ovid Embase, Ovid PsycInfo, and Scopus from inception through April 2009 for English-language, original investigations in humans using core concepts of "risk" and "cancer." We abstracted key information and then further restricted articles dealing with perceived risk of developing cancer due to inherited risk. Results Of 1028 titles identified, 53 articles met our criteria. Most (92% used an observational design and focused on women (70% with a family history of or contemplating genetic testing for breast cancer. Of the 53 studies, 36 focused on patients who had not had genetic testing for cancer risk, 17 included studies of patients who had undergone genetic testing for cancer risk. Family history of cancer, previous prophylactic tests and treatments, and younger age were associated with cancer risk perception. In addition, beliefs about the preventability and severity of cancer, personality factors such as "monitoring" personality, the ability to process numerical information, as well as distress/worry also were associated with cancer risk perception. Few studies addressed non-breast cancer or risk perception in specific demographic groups (e.g. elderly or minority groups and few employed theory-driven analytic strategies to decipher interrelationships of factors. Conclusions Several factors influence cancer risk perception in patients at elevated risk for cancer. The science of characterizing and improving risk perception in cancer for high risk groups, although

  19. HIFU therapy for patients with high risk prostate cancer

    Science.gov (United States)

    Solovov, V. A.; Vozdvizhenskiy, M. O.; Matysh, Y. S.

    2017-03-01

    Objectives. Patients with high-risk prostate cancer undergoing radical prostatectomy, external beam radiation therapy (EBRT) combined with androgen deprivation therapy (ADT) or ADT alone. The widely accepted definition of high-risk prostate was first proposed by D'Amico based on a pretreatment Gleason score of ≥8, clinical stage T3, PSA level ≥20 ng/mL. There is no trial that compares traditional methods of treatment of such patients with HIFU therapy. Here we explored the effectiveness of the HIFU in multimodal treatment for patients with high risk prostate cancer. Materials & Methods. 701 patients with high risk prostate cancer were treated in our center between September 2007 and December 2013. Gleason score were 8-10, stage T3N0M0, age 69 (58-86) years, mean PSA before treatment 43.3 (22.1-92.9) ng/ml, mean prostate volume - 59.3 (38-123) cc. 248 patients were treated by HIFU. We compare this group of patients with patients who undertook EBRT: number 196, and ADT: number 257. Mean follow-up time 58 months (6-72). Results. The 5-year overall survival rates in patients after HIFU were 73.8 %, after EBRT - 63.0 % and after ADT - 18.1%. Conclusions. Our experience showed that HIFU therapy in combined treatment were successful for high risk prostate cancer.

  20. Detection of high risk campylobacteriosis clusters at three geographic levels

    Directory of Open Access Journals (Sweden)

    Jennifer Weisent

    2011-11-01

    Full Text Available Campylobacteriosis is a leading cause of bacterial gastroenteritis in the United States and many other developed countries. Understanding the spatial distribution of this disease and identifying high-risk areas is vital to focus resources for prevention and control measures. In addition, determining the appropriate scale for geographical analysis of surveillance data is an area of concern to epidemiologists and public health officials. The purpose of this study was to (i compare standardized risk estimates for campylobacteriosis in Tennessee over three distinct geographical scales (census tract, zip code and county subdivision, and (ii identify and investigate high-risk spatial clustering of campylobacteriosis at the three geographical scales to determine if clustering is scale dependent. Significant high risk clusters (P <0.05 were detected at all three spatial scales. There were overlaps in regions of high-risk and clusters at all three geographic levels. At the census tract level, spatial analysis identified smaller clusters of finer resolution and detected more clusters than the other two levels. However, data aggregation at zip code or county subdivision yielded similar findings. The importance of this line of research is to create a framework whereby economically efficient disease control strategies become more attainable through improved geographical precision and risk detection. Accurate identification of disease clusters for campylobacteriosis can enable public health personnel to focus scarce resources towards prevention and control programmes on the most at-risk populations. Consistent results at multiple spatial levels highlight the robustness of the geospatial techniques utilized in this study. Furthermore, analyses at the zip code and county subdivision levels can be useful when address level information (finer resolution data are not available. These procedures may also be used to help identify regionally specific risk factors for

  1. Personality and sensation seeking in high-risk sports

    OpenAIRE

    Polona Klinar; Stojan Burnik; Tanja Kajtna

    2017-01-01

    Background: Personality represents a relatively consistent and unique sum of psychological, cognitive and physical characteristics of an individual. Sensation seeking is defined as an action, characterized by the search for different, new, complex and intensive emotions and experiences and preparedness to take physical, social, legal and financial risks in order to achieve these experiences.Objective: We were looking for differences in personality and sensation seeking between high-risk sport...

  2. Correlates of hopelessness in the high suicide risk police occupation

    OpenAIRE

    Violanti, John M.; Andrew, Michael E.; Mnatsakanova, Anna; Hartley, Tara A.; Fekedulegn, Desta; Burchfiel, Cecil M.

    2015-01-01

    Police officers are chronically exposed to work stress. We examined specific stressors that may be associated with hopelessness, a possible risk factor for suicide in this high suicide risk population. The study included 378 officers (276 men and 102 women) with complete data. Analysis of variance was used to estimate mean levels of hopelessness scores as associated with stress, adjusted for age, gender, and race/ ethnicity. Posttraumatic symptoms were tested as a modifier of the association ...

  3. A novel risk classification paradigm for patients with impaired glucose tolerance and high cardiovascular risk.

    Science.gov (United States)

    Bethel, M Angelyn; Chacra, Antonio R; Deedwania, Prakash; Fulcher, Gregory R; Holman, Rury R; Jenssen, Trond; Kahn, Steven E; Levitt, Naomi S; McMurray, John J V; Califf, Robert M; Raptis, Sotirios A; Thomas, Laine; Sun, Jie-Lena; Haffner, Steven M

    2013-07-15

    We used baseline data from the NAVIGATOR trial to (1) identify risk factors for diabetes progression in those with impaired glucose tolerance and high cardiovascular risk, (2) create models predicting 5-year incident diabetes, and (3) provide risk classification tools to guide clinical interventions. Multivariate Cox proportional hazards models estimated 5-year incident diabetes risk and simplified models examined the relative importance of measures of glycemia in assessing diabetes risk. The C-statistic was used to compare models; reclassification analyses compare the models' ability to identify risk groups defined by potential therapies (routine or intensive lifestyle advice or pharmacologic therapy). Diabetes developed in 3,254 (35%) participants over 5 years median follow-up. The full prediction model included fasting and 2-hour glucose and hemoglobin A1c (HbA1c) values but demonstrated only moderate discrimination for diabetes (C = 0.70). Simplified models with only fasting glucose (C = 0.67) or oral glucose tolerance test values (C = 0.68) had higher C statistics than models with HbA1c alone (C = 0.63). The models were unlikely to inappropriately reclassify participants to risk groups that might receive pharmacologic therapy. Our results confirm that in a population with dysglycemia and high cardiovascular risk, traditional risk factors are appropriate predictors and glucose values are better predictors than HbA1c, but discrimination is moderate at best, illustrating the challenges of predicting diabetes in a high-risk population. In conclusion, our novel risk classification paradigm based on potential treatment could be used to guide clinical practice based on cost and availability of screening tests. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. High-Risk Stress Fractures: Diagnosis and Management.

    Science.gov (United States)

    McInnis, Kelly C; Ramey, Lindsay N

    2016-03-01

    Stress fractures are common overuse injuries in athletes. They occur during periods of increased training without adequate rest, disrupting normal bone reparative mechanisms. There are a host of intrinsic and extrinsic factors, including biochemical and biomechanical, that put athletes at risk. In most stress fractures, the diagnosis is primarily clinical, with imaging indicated at times, and management focused on symptom-free relative rest with advancement of activity as tolerated. Overall, stress fractures in athletes have an excellent prognosis for return to sport, with little risk of complication. There is a subset of injuries that have a greater risk of fracture progression, delayed healing, and nonunion and are generally more challenging to treat with nonoperative care. Specific locations of high-risk stress fracture include the femoral neck (tension side), patella, anterior tibia, medial malleolus, talus, tarsal navicular, proximal fifth metatarsal, and great toe sesamoids. These sites share a characteristic region of high tensile load and low blood flow. High-risk stress fractures require a more aggressive approach to evaluation, with imaging often necessary, to confirm early and accurate diagnosis and initiate immediate treatment. Treatment consists of nonweight-bearing immobilization, often with a prolonged period away from sport, and a more methodic and careful reintroduction to athletic activity. These stress fractures may require surgical intervention. A high index of suspicion is essential to avoid delayed diagnosis and optimize outcomes in this subset of stress fractures. Copyright © 2016 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

  5. Assessment of Primitive Reflexes in High-risk Newborns.

    Science.gov (United States)

    Sohn, Min; Ahn, Youngmee; Lee, Sangmi

    2011-12-01

    Assessment of primitive reflexes is one of the earliest, simplest, and most frequently used assessment tools among health care providers for newborns and young infants. However, very few data exist for high-risk infants in this topic. Among the various primitive reflexes, this study was undertaken particularly to describe the sucking, Babinski and Moro reflexes in high-risk newborns and to explore their relationships with clinical variables. This study is a cross-sectional descriptive study. Sixty seven high-risk newborns including full-term infants required intensive care as well as premature infants were recruited in a neonatal intensive care unit using convenient sampling method. The sucking, Babinski and Moro reflexes were assessed and classified by normal, abnormal and absence. To explore their relationships with clinical variables, birth-related variables, brain sonogram results, and behavioral state (the Anderson Behavioral State Scale, ABSS) and mental status (the Infant Coma Scale, ICS) were assessed. The sucking reflex presented a normal response most frequently (63.5%), followed by Babinski reflex (58.7%) and Moro reflex (42.9%). Newborns who presented normal sucking and Babinski reflex responses were more likely to have older gestational age, heavier birth and current weight, higher Apgar scores, shorter length of hospitalization, better respiratory conditions, and better mental status assessed by ICS, but not with Moro reflex. High risk newborns presented more frequent abnormal and absence responses of primitive reflex and the proportions of the responses varied by reflex. Further researches are necessary in exploring diverse aspects of primitive reflexes and revealing their clinical implication in the high-risk newborns that are unique and different to normal healthy newborns. Primitive reflex; High risk infants; Korean; Moro reflex; Sucking reflex; Babinski reflex; The Anderson Behavioral State Scale; Infant Coma Scale.

  6. 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

  7. 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

  8. Quantifying the risk of respiratory infection in healthcare workers performing high-risk procedures.

    Science.gov (United States)

    Macintyre, C R; Seale, H; Yang, P; Zhang, Y; Shi, W; Almatroudi, A; Moa, A; Wang, X; Li, X; Pang, X; Wang, Q

    2014-09-01

    This study determined the risk of respiratory infection associated with high-risk procedures (HRPs) performed by healthcare workers (HCWs) in high-risk settings. We prospectively studied 481 hospital HCWs in China, documented risk factors for infection, including performing HRPs, measured new infections, and analysed whether HRPs predicted infection. Infection outcomes were clinical respiratory infection (CRI), laboratory-confirmed viral or bacterial infection, and an influenza infection. About 12% (56/481) of the study participants performed at least one HRP, the most common being airway suctioning (7·7%, 37/481). HCWs who performed a HRP were at significantly higher risk of developing CRI and laboratory-confirmed infection [adjusted relative risk 2·9, 95% confidence interval (CI) 1·42-5·87 and 2·9, 95% CI 1·37-6·22, respectively]. Performing a HRP resulted in a threefold increase in the risk of respiratory infections. This is the first time the risk has been prospectively quantified in HCWs, providing data to inform occupational health and safety policies.

  9. Humanized birth in high risk pregnancy: barriers and facilitating factors.

    Science.gov (United States)

    Behruzi, Roxana; Hatem, Marie; Goulet, Lise; Fraser, William; Leduc, Nicole; Misago, Chizuru

    2010-02-01

    The medical model of childbearing assumes that a pregnancy always has the potential to turn into a risky procedure. In order to advocate humanized birth in high risk pregnancy, an important step involves the enlightenment of the professional's preconceptions on humanized birth in such a situation. The goal of this paper is to identify the professionals' perception of the potential obstacles and facilitating factors for the implementation of humanized care in high risk pregnancies. Twenty-one midwives, obstetricians, and health administrator professionals from the clinical and academic fields were interviewed in nine different sites in Japan from June through August 2008. The interviews were audio taped, and transcribed with the participants' consent. Data was subsequently analyzed using content analysis qualitative methods. Professionals concurred with the concept that humanized birth is a changing and promising process, and can often bring normality to the midst of a high obstetric risk situation. No practice guidelines can be theoretically defined for humanized birth in a high risk pregnancy, as there is no conflict between humanized birth and medical intervention in such a situation. Barriers encountered in providing humanized birth in a high risk pregnancy include factors such as: the pressure of being responsible for the safety of the mother and the fetus, lack of the women's active involvement in the decision making process and the heavy burden of responsibility on the physician's shoulders, potential legal issues, and finally, the lack of midwifery authority in providing care at high risk pregnancy. The factors that facilitate humanized birth in a high risk include: the sharing of decision making and other various responsibilities between the physicians and the women; being caring; stress management, and the fact that the evolution of a better relationship and communication between the health professional and the patient will lead to a stress

  10. 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

  11. 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

  12. Personality and sensation seeking in high-risk sports

    Directory of Open Access Journals (Sweden)

    Polona Klinar

    2017-03-01

    Full Text Available Background: Personality represents a relatively consistent and unique sum of psychological, cognitive and physical characteristics of an individual. Sensation seeking is defined as an action, characterized by the search for different, new, complex and intensive emotions and experiences and preparedness to take physical, social, legal and financial risks in order to achieve these experiences.Objective: We were looking for differences in personality and sensation seeking between high-risk sports athletes and recreational athletes and the correlation between one's purpose to participate in high-risk sports and actual participation.Method: The data was acquired using three different questionnaires: Sensation Seeking Scale (forms SSS - V and SSS - VI and the Big Five Questionnaire. The sample consisted of 76 high-risk sports athletes and 51 recreational athletes. Data was analyzed using the SPSS statistical program.Results: The results were unexpected because we noticed differences between the two groups in which recreational athletes received higher results, especially in openness. Mostly results from such research show the converse - athletes of high-risk sports are more open. We did not find any difference between the two groups in sensation seeking. We found some correlations between personality traits and factors of Sensation Seeking Scale (SSS - V and SSS - VI. Openness and the Thrill and adventure seeking factor correlated in both versions of SSS.Conclusions: We conclude that high-risk sports athletes differ from recreational athletes, especially in openness. Also, we can confirm that both used versions of SSS are equally effective for analyzing sensation seeking.

  13. 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.

  14. 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.

  15. 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.

  16. Multiple causes of high extinction risk in large mammal species.

    Science.gov (United States)

    Cardillo, Marcel; Mace, Georgina M; Jones, Kate E; Bielby, Jon; Bininda-Emonds, Olaf R P; Sechrest, Wes; Orme, C David L; Purvis, Andy

    2005-08-19

    Many large animal species have a high risk of extinction. This is usually thought to result simply from the way that species traits associated with vulnerability, such as low reproductive rates, scale with body size. In a broad-scale analysis of extinction risk in mammals, we find two additional patterns in the size selectivity of extinction risk. First, impacts of both intrinsic and environmental factors increase sharply above a threshold body mass around 3 kilograms. Second, whereas extinction risk in smaller species is driven by environmental factors, in larger species it is driven by a combination of environmental factors and intrinsic traits. Thus, the disadvantages of large size are greater than generally recognized, and future loss of large mammal biodiversity could be far more rapid than expected.

  17. Identification of high risk metropolitan intersection sites in Perth, Australia.

    Science.gov (United States)

    Hobday, Michelle; Chow, Kyle; Meuleners, Lynn; Argus, Fritha

    2017-09-01

    As convergence points for road users approaching from multiple directions, intersections have more opportunities for conflicts, thus higher crash risk than other parts of the road network. Given the limited resources available for road safety, it is important to identify high risk intersections so that they can be prioritised for infrastructure improvement. This study used a three-stage approach to identify intersections in Perth, Western Australia: using Road Trauma Risk Analysis, then Comparative Safety Performance Analysis and finally ranking the intersections by the KSI (Killed and Serious Injury) metric. These methodologies were developed by Main Roads Western Australia. Crash data from 2011 to 2015 were used in the analyses. The results identify the top high risk intersections for each intersection type (by speed environment and control type). Recommendations are made for extensions to this process to improve identification of high risk intersections, and the use of a taxonomy to identify candidate treatments. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  18. Recording of risk-factors and lifestyle counselling in patients at high risk for cardiovascular diseases in European primary care.

    NARCIS (Netherlands)

    Ludt, S.; Petek, D.; Laux, G.; Lieshout, J. van; Campbell, S.M.; Kunzi, B.; Glehr, M.; Wensing, M.J.

    2012-01-01

    BACKGROUND: Detection and registration of high risk for cardiovascular diseases (CVD) by assessing individual's absolute cardiovascular risk is recommended in clinical guidelines. Effective interventions to reduce cardiovascular risk are available, but not optimally implemented. The aim of this

  19. High wall shear stress and high-risk plaque: an emerging concept.

    Science.gov (United States)

    Eshtehardi, Parham; Brown, Adam J; Bhargava, Ankit; Costopoulos, Charis; Hung, Olivia Y; Corban, Michel T; Hosseini, Hossein; Gogas, Bill D; Giddens, Don P; Samady, Habib

    2017-07-01

    In recent years, there has been a significant effort to identify high-risk plaques in vivo prior to acute events. While number of imaging modalities have been developed to identify morphologic characteristics of high-risk plaques, prospective natural-history observational studies suggest that vulnerability is not solely dependent on plaque morphology and likely involves additional contributing mechanisms. High wall shear stress (WSS) has recently been proposed as one possible causative factor, promoting the development of high-risk plaques. High WSS has been shown to induce specific changes in endothelial cell behavior, exacerbating inflammation and stimulating progression of the atherosclerotic lipid core. In line with experimental and autopsy studies, several human studies have shown associations between high WSS and known morphological features of high-risk plaques. However, despite increasing evidence, there is still no longitudinal data linking high WSS to clinical events. As the interplay between atherosclerotic plaque, artery, and WSS is highly dynamic, large natural history studies of atherosclerosis that include WSS measurements are now warranted. This review will summarize the available clinical evidence on high WSS as a possible etiological mechanism underlying high-risk plaque development.

  20. Characterization of patients at high risk of melanoma in Austria.

    Science.gov (United States)

    Müller, C; Wendt, J; Rauscher, S; Burgstaller-Muehlbacher, S; Sunder-Plassmann, R; Scheurecker, C; Richtig, E; Fae, I; Fischer, G; Pehamberger, H; Okamoto, I

    2016-06-01

    Risk of melanoma is determined by genetic and exogenous factors. Only a few studies have included both characteristics in a comprehensive multivariable analysis. To find determinants of patients at high risk of melanoma in Austria, including phenotype, genotype and lifestyle characteristics in comprehensive analyses. In total, 1668 patients with melanoma from the M3 case-control study were studied. Overall, 567 participants were sequenced for CDKN2A, 232 for CDK4, 123 for MITF encoding the variant E318K and 964 for MC1R. Patients with melanoma with a positive family history (n = 190, 11·6%), multiple primary melanomas (n = 261, 15·7%) and younger age (risk. All other patients with melanoma were defined as the reference group. We found significant differences between those two groups and between the high-risk subgroups (positive family history, multiple primary melanomas and younger age). Pigmentation phenotype was associated with the high-risk group in general (childhood freckling, odds ratio 1·46, P = 0·007; blond/reddish hair colour, odds ratio 1·43, P = 0·011). Patients with a positive family history and patients with early-onset disease were similar regarding both their phenotypic characteristics and external factors. Established high-risk mutations in CDKN2A were found in cases with a positive family history (n = 12) or multiple melanomas (n = 2). Moreover, we found three patients carrying the MITF p.E318K variant, two with a CDK4 variant and seven with nonsynonymous MC1R variants with undescribed biological significance, of which four were predicted as damaging. Austrian patients could represent a reservoir for novel genetic variants. Further investigation of populations in Central and Eastern Europe might reveal more novel and disease-relevant variants. © 2016 British Association of Dermatologists.

  1. Risk factors for the occurrence and spread of Highly Pathogenic ...

    African Journals Online (AJOL)

    Outbreaks of Highly Pathogenic Avian Influenza (HPAI) subtype H5N1 occurred previously for three consecutive years, 2006, 2007 and 2008 in Kano State, Nigeria, causing heavy economic losses to farmers and the government. It was against this background that risk factors for the occurrence and spread of HPAI H5N1 ...

  2. Health risk behaviours of high school learners and their perceptions ...

    African Journals Online (AJOL)

    Learners reported a high prevalence of health risk behaviours: 65% for alcohol use, 57% for sexual activity, 39% for tobacco use and 15% for drug use. 2. The predominant pattern of substance use ..... are predominantly from the lower and middle socio-economic groups. Learners generally do not know the family income.

  3. an assessment of high risk sexual behaviour and hiv transmission ...

    African Journals Online (AJOL)

    We did not also encounter any lesbian sexual orientation in this study. The distribution of. HRSB amongst the migrant oil wOrkers showed that the commonest variety was bisexuality (closet homosexuality) with 10(43.5%) followed by high-risk sexual behaviour 7(30.4%), while the least common was multiplicity of sexual ...

  4. High risk bladder cancer : current management and survival

    NARCIS (Netherlands)

    Leliveld-Kors, Anna; Bastiaannet, Esther; Doornweerd, Benjamin H J; Schaapveld, Michael; de Jong, Igle J

    2011-01-01

    Purpose: To evaluate the pattern of care in patients with high risk non muscle invasive bladder cancer (NMIBC) in the Comprehensive Cancer Center North-Netherlands (CCCN) and to assess factors associated with the choice of treatment, recurrence and progression free survival rates. Materials and

  5. Cyberbullying and Its Risk Factors among Chinese High School Students

    Science.gov (United States)

    Zhou, Zongkui; Tang, Hanying; Tian, Yuan; Wei, Hua; Zhang, Fengjuan; Morrison, Chelsey M.

    2013-01-01

    Cyberbullying has become a common occurrence among adolescents worldwide; however, it has yet to receive adequate scholarly attention in China, especially in the mainland. The present study investigated the epidemiological characteristics and risk factors of cyberbullying, utilizing a sample of 1,438 high school students from central China.…

  6. Sensation seeking in males involved in recreational high risk sports

    Directory of Open Access Journals (Sweden)

    M Guszkowska

    2010-09-01

    Full Text Available The study examined sensation seeking intensity level in males involved in recreational high risk sports and investigated whether its level depends on type of sport practised. Additionally, in case of parachutists, sport experience of study participants were scrutinised with regard to its possible impact on the level of sensation seeking.The research involved 217 males aged 17 to 45, practising recreational high risk sports, namely: parachuting (n=98; wakeboarding (n=30; snowboarding (n=30; scuba diving (n=22; alpinism (n=20; paragliding (n=17. The control group included 54 men not involved in sports. Polish version of Sensation Seeking Scale (SSS-IV of Zuckerman was applied.Results show, that high risk sports males are featured by stronger need of sensations in comparison to control group and this concerned all but one aspect of sensation seeking variable. The only exception was the need of intellectual stimulation. Except from the thrill and adventure seeking dimension, type of sport may also be an important determinant of sensation seeking. Men practising snowboard and wakeboard presented stronger need for sensations, especially in the dimension of experience seeking, disinhibition and boredom susceptibility. Sport experience (number of jumps in parachuting did not differentiate the level of sensation seeking among investigated parachutists. Population of sport high risk male takers was not homogeneous, and therefore in future research one should analyse specific sports (or events in a certain sport separately.

  7. Chorangioma of Placenta with High Risk Pregnancy: A Case Series

    African Journals Online (AJOL)

    Chorangioma of Placenta with High Risk Pregnancy: A Case Series. Uma S Andola, Shabnam Karangadan1, Sainath K Andola1, Rajashekhar Jewargikar1. Department of Obstetrics and Gynecology, 1Resident, Professor and Head of Department, Professor, Department of Pathology, Mahadevappa. Rampure Medical ...

  8. Monitoring paneer for Listeria monocytogenes - A high risk food ...

    African Journals Online (AJOL)

    A multiplex polymerase chain reaction (PCR) assay was developed and applied to spiked and natural paneer samples to detect Listeria monocytogenes, a high risk food pathogen. The sensitivity of the assay on L. monocytogenes spiked paneer samples was 104 cells prior to enrichment, was improved to 103 cells after 4 h ...

  9. anaesthetic challenges in a high risk parturient with myasthenia ...

    African Journals Online (AJOL)

    10 October 2013. ANAESTHETIC CHALLENGES IN A HIGH RISK PARTURIENT WITH MYASTHENIA GRAVIS UNDERGOING ... to highlight some of the challenges, the management and the lessons learnt during the management of this patient. .... be more appropriate if there is bulbar involvement, or severe respiratory ...

  10. High Risk Drinking among Non-Affiliated College Students

    Science.gov (United States)

    Smith, Margaret; Finneran, John; Droppa, Marj

    2014-01-01

    This study investigated the high risk drinking practices of unaffiliated college students who are not involved in formal athletics, fraternities, or sororities. Using a qualitative research design, the investigators interviewed students at a northeast public college in fall 2010 to learn about unaffiliated students' drinking experiences and their…

  11. Hypertensive patients and diabetes : A high-risk population

    NARCIS (Netherlands)

    Bilo, HJG; Gans, ROB

    1998-01-01

    Rising worldwide rates of diabetes mellitus heighten the need to maintain adequate metabolic control in diabetic patients and to control for other cardiovascular risk factors, such as lipid profile disturbances, high blood pressure, and smoking habits. This is especially the case in diabetic

  12. Risk management practices of high school principals regarding ...

    African Journals Online (AJOL)

    This study was undertaken to identify what the key safety concerns at schools in PE are, and to establish what the risk management practices implemented by principals at high schools in selected provinces are. This paper follows the approach that school principals are staff with the highest authority and legal liability for the ...

  13. Risk management practices of high school sport coaches and ...

    African Journals Online (AJOL)

    The purpose of this study was to identify the key safety dimensions of school sport, and to assess the risk management practices implemented by coaches and administrators at high schools. The aim was also to highlight the chief problems associated with safety in sport and to develop strategies to protect learners.

  14. Drug response prediction in high-risk multiple myeloma

    DEFF Research Database (Denmark)

    Vangsted, A J; Helm-Petersen, S; Cowland, J B

    2018-01-01

    A Drug Response Prediction (DRP) score was developed based on gene expression profiling (GEP) from cell lines and tumor samples. Twenty percent of high-risk patients by GEP70 treated in Total Therapy 2 and 3A have a progression-free survival (PFS) of more than 10years. We used available GEP data ...

  15. Detection of Patients at High Risk of Medication Errors

    DEFF Research Database (Denmark)

    Sædder, Eva Aggerholm; Lisby, Marianne; Nielsen, Lars Peter

    2016-01-01

    Medication errors (MEs) are preventable and can result in patient harm and increased expenses in the healthcare system in terms of hospitalization, prolonged hospitalizations and even death. We aimed to develop a screening tool to detect acutely admitted patients at low or high risk of MEs...

  16. Identifying patients at high risk for obstructive sleep apnoea ...

    African Journals Online (AJOL)

    Background: Obstructive sleep apnoea is associated with significant health consequences. A significant proportion of hospitalized patients at risk for obstructive sleep apnoea were never identified and referred for polysomnography for diagnosis. The objective of this study was to determine the factors associated with high ...

  17. The National Cross-Site Evaluation of High-Risk Youth Programs: Understanding Risk, Protection, and Substance Use among High-Risk Youth. Monograph Series.

    Science.gov (United States)

    Springer, J. Fred; Sambrano, Soledad; Sale, Elizabeth; Kasim, Rafa; Hermann, Jack

    This document summarizes findings from the Center for Substance Abuse Prevention's National Cross-Site Evaluation of High-Risk Youth Programs, which identified characteristics associated with strong substance abuse prevention outcomes in 48 prevention programs. Major findings include: as youth age, levels of risk and protection shift considerably,…

  18. Antiplatelet therapy in populations at high risk of atherothrombosis.

    Science.gov (United States)

    Faxon, David P; Nesto, Richard W

    2006-05-01

    Atherothrombosis is the most common cause of an acute ischemic event. Antiplatelet agents form the cornerstone of atherothrombosis prevention. The purpose of this article is to review the use of antiplatelet agents in patients that are at particularly high risk of atherothrombotic events. To undertake this review, we searched the literature to identify key studies on the use of antiplatelet agents in this group of patients. Antiplatelet agents, such as aspirin and clopidogrel, play a fundamental role in the treatment and management of secondary thrombotic events. The routine use of aspirin is recommended, as it has been shown to reduce the risk of thrombotic events by approximately 25%. Additional benefit has been demonstrated with clopidogrel, both as a monotherapy and in combination with aspirin. In the CAPRIE trial, 19,185 patients with atherosclerotic vascular disease were randomized to receive clopidogrel (75 mg/day) or aspirin (325 mg/day) for a mean duration of follow-up of 1.91 years. Clopidogrel provided an additional 8.7% relative risk reduction in the primary composite endpoint of ischemic stroke, myocardial infraction or vascular death compared with aspirin. In the CURE trial, the addition of clopidogrel to background aspirin was associated with a 20% relative risk reduction in a composite of death from cardiovascular causes, nonfatal myocardial infarction or stroke compared with aspirin alone. In patients undergoing PCI as part of the PCI-CURE substudy, clopidogrel was associated with a 30% relative reduction in the incidence of cardiovascular events in the first 30 days after intervention compared with aspirin. The benefits of antiplatelet therapy continue to be investigated. Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk primary prevention is unknown. The ongoing CHARISMA trial aims to determine the relative efficacies of aspirin monotherapy and aspirin/clopidogrel combination therapy in a broad range of high-risk

  19. Increased Cardiometabolic Risk and Worsening Hypoxemia at High Altitude.

    Science.gov (United States)

    Miele, Catherine H; Schwartz, Alan R; Gilman, Robert H; Pham, Luu; Wise, Robert A; Davila-Roman, Victor G; Jun, Jonathan C; Polotsky, Vsevolod Y; Miranda, J Jaime; Leon-Velarde, Fabiola; Checkley, William

    2016-06-01

    Miele, Catherine H., Alan R. Schwartz, Robert H. Gilman, Luu Pham, Robert A. Wise, Victor G. Davila-Roman, Jonathan C. Jun, Vsevolod Y. Polotsky, J. Jaime Miranda, Fabiola Leon-Velarde, and William Checkley. Increased cardiometabolic risk and worsening hypoxemia at high altitude. High Alt Med Biol. 17:93-100, 2016.-Metabolic syndrome, insulin resistance, diabetes, and dyslipidemia are associated with an increased risk of cardiovascular disease. While excessive erythrocytosis is associated with cardiovascular complications, it is unclear how worsening hypoxemia of any degree affects cardiometabolic risk factors in high-altitude populations. We studied the relationship between daytime resting oxyhemoglobin saturation and cardiometabolic risk factors in adult participants living in Puno, Peru (3825 m above sea level). We used multivariable logistic regression models to study the relationship between having a lower oxyhemoglobin saturation and markers of cardiometabolic risk. Nine hundred and fifty-four participants (mean age 55 years, 52% male) had information available on pulse oximetry and markers of cardiometabolic risk. Average oxyhemoglobin saturation was 90% (interquartile range 88%-92%) and 43 (4.5%) had excessive erythrocytosis. Older age, decreased height-adjusted lung function, and higher body mass index (BMI) were associated with having an oxyhemoglobin saturation ≤85%. When adjusting for age, sex, socioeconomic status, having excessive erythrocytosis, and site, we found that each 5% decrease in oxyhemoglobin saturation was associated with a higher adjusted odds of metabolic syndrome (OR = 1.35, 95% CI: 1.07-1.72, p 2 mass units (OR = 1.29, 95% CI: 1.00-1.67, p < 0.05), hemoglobin A1c ≥6.5% (OR = 1.66, 95% CI: 1.09-2.51, p < 0.04), and high sensitivity C-reactive protein (hs-CRP) ≥3 mg/L (OR = 1.46, 95% CI: 1.09-1.96, p < 0.01). In high-altitude populations in Puno, Peru, a higher BMI and lower pulmonary function were

  20. Beyond sensation seeking: affect regulation as a framework for predicting risk-taking behaviors in high-risk sport.

    Science.gov (United States)

    Castanier, Carole; Le Scanff, Christine; Woodman, Tim

    2010-10-01

    Sensation seeking has been widely studied when investigating individual differences in the propensity for taking risks. However, risk taking can serve many different goals beyond the simple management of physiological arousal. The present study is an investigation of affect self-regulation as a predictor of risk-taking behaviors in high-risk sport. Risk-taking behaviors, negative affectivity, escape self-awareness strategy, and sensation seeking data were obtained from 265 high-risk sportsmen. Moderated hierarchical regression analysis revealed significant main and interaction effects of negative affectivity and escape self-awareness strategy in predicting risk-taking behaviors: high-risk sportsmen's negative affectivity leads them to adopt risk-taking behaviors only if they also use escape self-awareness strategy. Furthermore, the affective model remained significant when controlling for sensation seeking. The present study contributes to an in-depth understanding of risk taking in high-risk sport.

  1. Wandering spleen: 'presentation in adolescent with high thrombotic risk'.

    Science.gov (United States)

    Tchidjou, Hyppolite K; Castelluzzo, Maria A; Messia, Virginia; Luciani, Matteo; Monti, Lidia; Grimaldi, Chiara; Bernardi, Stefania; D'Argenio, Patrizia

    2014-07-01

    The term 'wandering spleen' refers to an abnormal hypermobility of the spleen, which may be congenital or acquired. The absence or abnormal laxity of splenic ligaments combined with an abnormally long and mobile vascular pedicle predispose to complications such as torsion of the splenic pedicle, infarction and splenic vein thrombosis. The clinical presentation of such disease is highly variable. In this case, we describe an asymptomatic case of wandering spleen in high thrombotic risk patients with cavernoma of splenic vein and infarction of the spleen. Physical examination was normal except the enlarged and no tender consistency spleen palpable at left iliac fossa. Ultrasonography revealed enlarged spleniform mass below its normal position suggesting vascular impairment and subsequently has been confirmed by colour Doppler ultrasound and computed tomography. The family history was positive for ischemic thrombotic vascular diseases and the screening for thrombotic risk has revealed hyperhomocysteinemia, thrombophilic homozygous gene mutations for factor V (H1299R) and MTHFR (C677T). For high thrombotic risk, prophylaxis postsplenectomy was suggested according to the international recommendations with subcutaneous low molecular weight heparin, associated with a preventive treatment with acetyl salicylic acid and folic acid along with B-vitamin. This case report may be helpful for clinicians involved in the care of splenectomized patients, because it has shown the importance of an appropriate pre and postoperative antithrombotic management to reduce as soon as possible the risk of thrombotic events in such patients after splenectomy.

  2. Case Management Reduces Drinking During Pregnancy among High Risk Women.

    Science.gov (United States)

    May, Philip A; Marais, Anna-Susan; Gossage, J Phillip; Barnard, Ronel; Joubert, Belinda; Cloete, Marise; Hendricks, Natalie; Roux, Sumien; Blom, Annalien; Steenekamp, Jeanetta; Alexander, Theresa; Andreas, Romena; Human, Suzanne; Snell, Cudore; Seedat, Soraya; Parry, Charles C; Kalberg, Wendy O; Buckley, David; Blankenship, Jason

    2013-05-01

    Estimate the efficacy of Case Management (CM) for women at high risk for bearing a child with Fetal Alcohol Spectrum Disorders (FASD). Women were recruited from antenatal clinics and engaged in 18 months of CM. A South African community with a subculture of heavy, regular, weekend, recreational drinking and high documented rates of FASD. Forty-one women who were high risk for bearing a child with FASD. Statistical analysis of trends in drinking and other risk factors. At intake 87.8% were pregnant, most had previous alcohol-exposed pregnancies, most/all of their friends drink alcohol (67.5%), and 50.0% had stressful lives. CM was particularly valuable for pregnant women, as statistically significant reductions in alcohol risk were obtained for them in multiple variables: total drinks on weekends after six months of CM (p = .026) and estimated peak blood alcohol concentration (BAC) at six (p managers reduced maternal drinking at critical times, and therefore, alcohol exposure levels to the fetus.

  3. Youth risk behavior surveillance. National Alternative High School Youth Risk Behavior Survey, United States, 1998.

    Science.gov (United States)

    Grunbaum, J A; Kann, L; Kinchen, S A; Ross, J G; Gowda, V R; Collins, J L; Kolbe, L J

    2000-01-01

    Alternative high schools serve approximately 280,000 students nationwide who are at high risk for failing or dropping out of regular high school or who have been expelled from regular high school because of illegal activity or behavioral problems. Such settings provide important opportunities for delivering health promotion education and services to these youth and young adults. However, before this survey, the prevalence of health-risk behaviors among students attending alternative high schools nationwide was unknown. The Youth Risk Behavior Surveillance System (YRBSS) monitors the following six categories of priority health-risk behaviors among youth and young adults: behaviors that contribute to unintentional and intentional injuries; tobacco use; alcohol and other drug use; sexual behaviors that contribute to unintended pregnancy and sexually transmitted diseases (STDs) (including human immunodeficiency virus [HIV] infection); unhealthy dietary behaviors; and physical inactivity. The national Alternative High School Youth Risk Behavior Survey (ALT-YRBS) is one component of the YRBSS; it was conducted in 1998 to measure priority health-risk behaviors among students at alternative high schools. The 1998 ALT-YRBS used a three-stage cluster sample design to produce a nationally representative sample of students in grades 9-12 in the United States who attend alternative high schools. The school response rate was 81.0%, and the student response rate was 81.9%, resulting in an overall response rate of 66.3%. This report summarizes results from the 1998 ALT-YRBS. The reporting period is February-May 1998. In the United States, 73.6% of all deaths among youth and young adults aged 10-24 years results from only four causes--motor vehicle crashes, other unintentional injuries, homicide, and suicide. Results from the 1998 ALT-YRBS demonstrate that many students at alternative high schools engage in behaviors that increase their likelihood of death from these four causes

  4. Youth Risk Behavior Surveillance--National Alternative High School Youth Risk Behavior Survey, United States, 1998.

    Science.gov (United States)

    Grunbaum, J A; Kann, L; Kinchen, S A; Ross, J G; Gowda, V R; Collins, J L; Kolbe, L J

    1999-10-29

    Alternative high schools serve approximately 280,000 students nationwide who are at high risk for failing or dropping out of regular high school or who have been expelled from regular high school because of illegal activity or behavioral problems. Such settings provide important opportunities for delivering health promotion education and services to these youth and young adults. However, before this survey, the prevalence of health-risk behaviors among students attending alternative high schools nationwide was unknown. February-May 1998. The Youth Risk Behavior Surveillance System (YRBSS) monitors the following six categories of priority health-risk behaviors among youth and young adults: behaviors that contribute to unintentional and intentional injuries; tobacco use; alcohol and other drug use; sexual behaviors that contribute to unintended pregnancy and sexually transmitted diseases (STDs) (including human immunodeficiency virus [HIV] infection); unhealthy dietary behaviors; and physical inactivity. The national Alternative High School Youth Risk Behavior Survey (ALT-YRBS) is one component of the YRBSS; it was conducted in 1998 to measure priority health-risk behaviors among students at alternative high schools. The 1998 ALT-YRBS used a three-stage cluster sample design to produce a nationally representative sample of students in grades 9-12 in the United States who attend alternative high schools. The school response rate was 81.0%, and the student response rate was 81.9%, resulting in an overall response rate of 66.3%. This report summarizes results from the 1998 ALT-YRBS. In the United States, 73.6% of all deaths among youth and young adults aged 10-24 years results from only four causes--motor vehicle crashes, other unintentional injuries, homicide, and suicide. Results from the 1998 ALT-YRBS demonstrate that many students at alternative high schools engage in behaviors that increase their likelihood of death from these four causes. During the 30 days

  5. ASPHYXIA AND DEVELOPMENTAL OUTCOME IN HIGH RISK INFANTS

    Directory of Open Access Journals (Sweden)

    Valentina DUKOVSKA

    2010-04-01

    Full Text Available Asphyxia is a risk factor that is very often related to neuro-developmental issues in high risk infants and equally affects preterm and term infants, however its outcome on the developed brain differs from the outcome on the preterm brain.In preterm infants, asphyxia usually exerts a hemorrhagic or ischaemic event and periventricular leukomalacia.In term infants, asphyxia leads to cerebral edema and atrophy of the brain, which may later lead to hypoxic ischaemic encephalopathy (HIE.The number of term infants with HIE who have survived is lower than those of preterm infants, while the percentage of term infants with HIE who have neuro-developmental issues is higher. Preemies face more problems in their motor development as a result of the brain damage, while term infants suffer from encephalopathy and their cognitive abilities are more affected.We have conducted a study about the effects that asphyxia has on the developmental outcomes in high risk infants. In our study, we did a longitudinal developmental follow-up of 30 high risk infants and an evaluation of their developmental outcome using the Griffiths Mental Development Scales, from the 4th month of life until the end of the 36th month. First, we found that high risk infants had a much lower developmental outcome than the control group during the trial. Finally, we found that asphyxia makes a difference in the developmental outcome of preterm infants without asphyxia who have a very low birth weight, the preterm infants with asphyxia, and the term infants with HIE-II.

  6. Validation of the High-Risk Pregnancy Stress Scale in a sample of hospitalized Greek high-risk pregnant women.

    Science.gov (United States)

    Gourounti, Kleanthi; Karpathiotaki, Natassa; Karapanou, Vassiliki; Antzaklis, Panos; Daskalakis, Georgios

    2016-01-01

    The aim of the authors in this study was to determine the psychometric properties of the Greek adaptation of the High-Risk Pregnancy Stress Scale (HRPSS) in a sample of high-risk hospitalized pregnant women. The sample consisted of 133 high-risk pregnant women with gestational age from 9 to 37 weeks. Data were collected between February and June of 2014. HRPSS was "forward-backward" translated from English to Greek. Principal axis factoring with promax rotation was used to test the factor structure of the HRPSS. Measures of state anxiety (STAI) and depressive symptoms (EPDS) were used to assess the convergent validity of the HRPSS. Exploratory factor analysis suggested three factors: concerns of pregnancy, movement restriction, and isolation and restriction of external activities. Construct validity was confirmed by computing correlations between the HRPSS and constructions of anxiety and depressive symptoms. Internal consistency reliability was satisfactory (α = 0.813). The original factor structure of the HRPSS was only partly replicated. The results of the exploratory factor analysis suggested that a three-factor solution instead of a two-factor solution would be the most adequate. The HRPSS is an appropriate measure for assessing the levels of concerns regarding pregnancy outcome, movement restriction, isolation, and external activity restrictions in Greek high-risk pregnant women.

  7. Antenatal Care Utilisation and Content between Low-Risk and High-Risk Pregnant Women

    Science.gov (United States)

    Yeoh, Ping Ling; Hornetz, Klaus; Dahlui, Maznah

    2016-01-01

    Background The purpose of antenatal care is to monitor and improve the wellbeing of the mother and foetus. The World Health Organization recommends risk-oriented strategy that includes: (i) routine care to all women, (ii) additional care for women with moderately severe diseases and complications, (iii) specialised obstetrical and neonatal care for women with severe diseases and complications. Antenatal care is concerned with adequate care in order to be effective. Measurement for adequacy of antenatal care often applies indexes that assess initiation of care and number of visits. In addition, adequacy of care content should also be assessed. Results of studies in developed settings demonstrate that women without risk factors use antenatal services more frequently than recommended. Such over-utilisation is problematic for low-resourced settings. Moreover, studies show that a substantial proportion of high-risk women had utilisation or content of care below the recommended standard. Yet studies in developing countries have seldom included a comparison between low-risk and high-risk women. The purpose of the study was therefore to assess adequacy of care and pregnancy outcomes for the different risk groups. Methods A retrospective study using a multistage sampling technique, at public-funded primary health care clinics was conducted. Antenatal utilisation level was assessed using a modified Adequacy of Prenatal Care Utilisation index that measures the timing for initiation of care and observed-to-expected visits ratio. Adequacy of antenatal care content assessed compliance to routine care based on the local guidelines. Results Intensive or “adequate-plus” antenatal care utilisation as defined by the modified index was noted in over half of the low-risk women. On the other hand, there were 26% of the high-risk women without the expected intensive utilisation. Primary- or non-educated high-risk women were less likely to have a higher antenatal care utilisation

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

    Science.gov (United States)

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

    2014-01-01

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

  9. Who takes risks in high-risk sport?: the role of alexithymia.

    Science.gov (United States)

    Barlow, Matthew; Woodman, Tim; Chapman, Caradog; Milton, Matthew; Stone, Daniel; Dodds, Tom; Allen, Ben

    2015-02-01

    People who have difficulty identifying and describing their emotions are more likely to seek out the experience of emotions in the high-risk domain. This is because the high-risk domain provides the experience of more easily identifiable emotions (e.g., fear). However, the continued search for intense emotion may lead such individuals to take further risks within this domain, which, in turn, would lead to a greater likelihood of experiencing accidents. Across three studies, we provide the first evidence in support of this view. In Study 1 (n = 762), alexithymia was associated with greater risk taking and a greater propensity to experience accidents and close calls. In Study 2 (n = 332) and Study 3 (n = 356), additional bootstrapped mediation models confirmed these relationships. The predictive role of alexithymia remained significant when controlling for sensation seeking (Study 1) and anhedonia (Study 2 and Study 3). We discuss the practical implications of the present model as they pertain to minimizing accidents and close calls in the high-risk domain.

  10. Chronic kidney disease and bleeding risk in patients at high cardiovascular risk: a cohort study.

    Science.gov (United States)

    Ocak, G; Rookmaaker, M B; Algra, A; de Borst, G J; Doevendans, P A; Kappelle, L J; Verhaar, M C; Visseren, F L

    2018-01-01

    Essentials The association between chronic kidney disease and bleeding is unknown. We followed 10 347 subjects at high cardiovascular risk for bleeding events. Chronic kidney disease was associated with a 1.5-fold increased bleeding risk. Especially albuminuria rather than decreased kidney function was associated with bleeding events. Background There are indications that patients with chronic kidney disease have an increased bleeding risk. Objectives To investigate the association between chronic kidney disease and bleeding in patients at high cardiovascular risk. Methods We included 10 347 subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2015 for an outpatient visit with classic risk factors for arterial disease or with symptomatic arterial disease (Second Manifestation of Arterial disease [SMART] cohort). Patients were staged according to the KDIGO guidelines, on the basis of estimated glomerular filtration rate (eGFR) and albuminuria, and were followed for the occurrence of major hemorrhagic events until March 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) for bleeding were calculated with Cox proportional hazards analyses. Results The incidence rate for bleeding in subjects with chronic kidney disease was 8.0 per 1000 person-years and that for subjects without chronic kidney disease was 3.5 per 1000 person-years. Patients with chronic kidney disease (n = 2443) had a 1.5-fold (95% CI 1.2-1.9) increased risk of bleeding as compared with subjects without chronic kidney disease (n = 7904) after adjustment. Subjects with an eGFR of Chronic kidney disease is a risk factor for bleeding in patients with classic risk factors for arterial disease or with symptomatic arterial disease, especially in the presence of albuminuria. © 2017 University Medical Center Utrecht. Journal of Thrombosis and Haemostasis © 2017 International Society on Thrombosis and Haemostasis.

  11. Gang masculinity and high-risk sexual behaviours.

    Science.gov (United States)

    Dickson-Gomez, Julia; Quinn, Katherine; Broaddus, Michelle; Pacella, Maria

    2017-02-01

    High-risk sexual behaviours include practices such as relationship violence and substance use, which often cluster together among young people in high-risk settings. Youth gang members often show high rates of such behaviours, substance use and relationship violence. This paper draws on data from in-depth interviews with male and female gang members from six different gangs to explore the role of powerful socialising peer groups that set gender, sexual and relationship roles and expectations for their male and female members. High-risk sexual behaviours among gang members included sex with multiple partners and group sex. Gang norms included the belief that male members were sexually insatiable with multiple sexual partners and that female gang members should be sexually available to male members. Alcohol and drugs were seen to have a large influence on sexual desire and the inability to use condoms. Much sexual behaviour with gangs, such as group sex, was viewed with ambivalence and seen as somewhat coercive. Finally, gendered sexual expectations (boys as sexually insatiable and girls as sexually available) made forming long-term romantic relationships problematic for gang members. The influence of gang norms such as these must be addressed in future programmes and interventions with gang members.

  12. Environmental risk factors associated with bovine tuberculosis among cattle in high-risk areas.

    Science.gov (United States)

    Winkler, B; Mathews, F

    2015-11-01

    Our research shows that environmental features are important predictors of bovine tuberculosis (bTB) in British cattle herds in high-prevalence regions. Data from 503 case and 808 control farms included in the randomized badger culling trial (RBCT) were analysed. bTB risk increased in larger herds and on farms with greater areas of maize, deciduous woodland and marsh, whereas a higher percentage of boundaries composed of hedgerows decreased the risk. The model was tested on another case-control study outside RBCT areas, and here it had a much smaller predictive power. This suggests that different infection dynamics operate outside high-risk areas, although it is possible that unknown confounding factors may also have played a role. © 2015 The Author(s).

  13. Venous Thromboembolism Risk and Adequacy of Prophylaxis in High Risk Pregnancy in the Arabian Gulf.

    Science.gov (United States)

    Alsayegh, Faisal; Al-Jassar, Waleed; Wani, Salima; Tahlak, Muna; Albahar, Awatef; Al Kharusi, Lamya; Al-Tamimi, Halima; El-Taher, Faten; Mahmood, Naeema; Al-Zakwani, Ibrahim

    2016-01-01

    To estimate the prevalence of venous thromboembolism (VTE) risk factors in pregnancy and the proportion of pregnancies at risk of VTE that received the recommended prophylaxis according to the American College of Chest Physicians (ACCP) 2012 published guidelines in antenatal clinics in the Arabian Gulf. The evaluation of venous thromboembolism (EVE)-Risk project was a non-interventional, cross-sectional, multi-centre, multi-national study of all eligible pregnant women (≥17 years) screened during antenatal clinics from 7 centres in the Arabian Gulf countries (United Arab Emirates, Kuwait, Bahrain, Qatar and Oman). Pregnant women were recruited during a 3-month period between September and December 2012. Of 4,131 screened pregnant women, 32% (n=1,337) had ≥1 risk factors for VTE. Common VTE risk factors included obesity (76%), multiparity (33%), recurrent miscarriages (9.1%), varicose veins (6.9%), thrombophilia (2.6%), immobilization (2.0%), sickle cell disease (2.8%) and previous VTE (1.6%). Only 8.3% (n=111) of the high risk patients were on the recommended VTE prophylaxis. Enoxaparin was used in 80% (n=89) of the cases followed by tinzaparin (4%; n=4). Antiplatelet agents were prescribed in 11% (n=149) of pregnant women. Of those on anticoagulants (n=111), 59% (n=66) were also co-prescribed antiplatelet agents. Side effects (mainly local bruising at the injection site) were reported in 12% (n=13) of the cases. A large proportion of pregnant women in the Arabian Gulf countries have ≥1 VTE risk factor with even a smaller fraction on prophylaxis. VTE risk assessment must be adopted to identify those at risk who would need VTE prophylaxis.

  14. 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

  15. Multislice computed tomography in an asymptomatic high-risk population.

    Science.gov (United States)

    Romeo, Francesco; Leo, Roberto; Clementi, Fabrizio; Razzini, Cinzia; Borzi, Mauro; Martuscelli, Eugenio; Pizzuto, Francesco; Chiricolo, Gaetano; Mehta, Jawahar L

    2007-02-01

    Approximately 50% of all acute coronary syndromes occur in previously asymptomatic patients. This study evaluated the value of multislice computed tomography for early detection of significant coronary artery disease (CAD) in high-risk asymptomatic subjects. One hundred sixty-eight asymptomatic subjects with >or=1 major risk factor (hypertension, diabetes, hypercholesterolemia, family history, or smoking) and an inconclusive or unfeasible noninvasive stress test result (stress electrocardiography, echocardiography, or nuclear scintigraphy) were evaluated in an outpatient setting. After clinical examination and laboratory risk analysis, all patients underwent multislice computed tomographic (MSCT) coronary angiography within 1 week. In all subjects, conventional coronary angiography was also carried out. Multislice computed tomography displayed single-vessel CAD in 16% of patients, 2-vessel CAD in 7%, and 3-vessel CAD in 4%. Selective coronary angiography confirmed the results of multislice computed tomography in 99% of all patients. Sensitivity and specificity of MSCT coronary angiography were 100% and 98%, respectively, with a positive predictive value of 95% and a negative predictive value of 100%. In conclusion, MSCT coronary angiography is an excellent noninvasive technique for early identification of significant CAD in high-risk asymptomatic patients with inconclusive or unfeasible noninvasive stress test results.

  16. Atopic dermatitis in a high-risk cohort: natural history, associated allergic outcomes, and risk factors.

    Science.gov (United States)

    Carlsten, Chris; Dimich-Ward, Helen; Ferguson, Alexander; Watson, Wade; Rousseau, Roxanne; Dybuncio, Anne; Becker, Allan; Chan-Yeung, Moira

    2013-01-01

    Atopic dermatitis (AD) is commonly associated with asthma and other atopic disorders in childhood. To evaluate the natural history of AD and its association with other allergic outcomes in a high-risk cohort through the age of 7 years. A total of 373 high-risk infants, who had undergone a randomized controlled trial with intervention measures for primary prevention of asthma applied during the first year of life, were assessed for asthma, AD, and allergic sensitization at 1, 2, and 7 years. The multifaceted intervention program did not reduce AD despite reducing the prevalence of asthma significantly. Sixty-two children (16.6%) had AD during the first 2 years (early-onset AD); of these, 26 continue to have AD at the age of 7 years (persistent), whereas 36 no longer had the disease (nonpersistent) at the age of 7 years. Twenty-three children (6.2%) developed AD only after the age of 2 years (late-onset AD). Early-onset AD, persistent or nonpersistent, was associated with increased risk of allergic sensitization to food allergens within the first 2 years of life and asthma diagnosis at year 7. However, only persistent AD was associated with an increased risk of other atopic diseases and allergic sensitization to food and aeroallergens at year 7. Late-onset AD was not associated with atopic diseases or allergic sensitization at year 7 with the exception of Alternaria alternans. In this cohort of infants at high risk of asthma, early-onset persistent AD, which was highly associated with atopic sensitization, increased the risk of atopic diseases in later childhood and thus appears to be part of the atopic march. Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  17. Plaque At RISK (PARISK): prospective multicenter study to improve diagnosis of high-risk carotid plaques

    NARCIS (Netherlands)

    Truijman, M.T.; Kooi, M.E.; Dijk, A.; de Rotte, A.A.J.; van der Kolk, A.G.; Liem, M.; Schreuder, F.H.; Boersma, M.; Mess, W.H.; van Oostenbrugge, R.J.; Koudstaal, P.J.; Kappelle, L.J.; Nederkoorn, P.J.; Nederveen, A.J.; Hendrikse, J.; van der Steen, A.F.; Daemen, M.J.; van der Lugt, A.

    2014-01-01

    BACKGROUND: Patients with symptomatic carotid artery stenosis are at high risk for recurrent stroke. To date, the decision to perform carotid endarterectomy in patients with a recent cerebrovascular event is mainly based on degree of stenosis of the ipsilateral carotid artery. However, additional

  18. Risk factors for congenital anomalies in high risk pregnant women: A large study from South India

    Directory of Open Access Journals (Sweden)

    Tella Sunitha

    2017-01-01

    Conclusion: High prevalence of CAs was found in HRP women compared to general population. Low parental age contributed toward CAs in primi gravida women while consanguinity was found to be a predisposing factor for CAs in HRP with previous BOH. Toxoplasmosis conferred risk for CAs in HRP women with previous normal pregnancies.

  19. Papillary thyroid microcarcinoma: the significance of high risk features.

    Science.gov (United States)

    Bradley, Nori L; Wiseman, Sam M

    2017-02-16

    Papillary carcinomas that measure 1.0cm or less are diagnosed as papillary thyroid microcarcinomas (PTMs). The clinical significance and recommendations for management of these PTMs is still evolving. The objective of the study was to compare the characteristics of small (PTM. We performed a retrospective analysis of these cases using Fisher's Exact Test. The statistical significance was set at p PTM and high risk features was observed only for extra-thyroidal cancer extension (ETE). Six of 57 large PTM (11%) but none of the 75 small PTM had ETE (p PTM (5/9 cases) and large PTM (4/9 cases). A distant metastases was diagnosed in association with a small PTM. For PTM, neither small cancer size, nor the absence of high-risk features, excluded the possibility of synchronous lymph node metastases.

  20. The Violence Risk Scale: Predictive Validity and Linking Changes in Risk with Violent Recidivism in a Sample of High-Risk Offenders with Psychopathic Traits

    Science.gov (United States)

    Lewis, Kathy; Olver, Mark E.; Wong, Stephen C. P.

    2013-01-01

    The Violence Risk Scale (VRS) uses ratings of static and dynamic risk predictors to assess violence risk, identify targets for treatment, and assess changes in risk following treatment. The VRS was rated pre- and posttreatment on a sample of 150 males, mostly high-risk violent offenders many with psychopathic personality traits. These individuals…

  1. High risk bladder cancer: current management and survival

    Directory of Open Access Journals (Sweden)

    Anna M. Leliveld

    2011-04-01

    Full Text Available PURPOSE: To evaluate the pattern of care in patients with high risk non muscle invasive bladder cancer (NMIBC in the Comprehensive Cancer Center North-Netherlands (CCCN and to assess factors associated with the choice of treatment, recurrence and progression free survival rates. MATERIALS AND METHODS: Retrospective analysis of 412 patients with newly diagnosed high risk NMIBC. Clinical, demographic and follow-up data were obtained from the CCCN Cancer Registry and a detailed medical record review. Uni and multivariate analysis was performed to identify factors related to choice of treatment and 5 year recurrence and progression free survival. RESULTS: 74/412 (18% patients with high risk NMIBC underwent a transurethral resection (TUR as single treatment. Adjuvant treatment after TUR was performed in 90.7% of the patients treated in teaching hospitals versus 71.8 % in non-teaching hospitals (p 80 years OR 0.1 p = 0.001 and treatment in non-teaching hospitals (OR 0.25; p < 0.001 were associated with less adjuvant treatment after TUR. Tumor recurrence occurred in 191/392 (49% and progression in 84 /392 (21.4% patients. The mean 5-years progression free survival was 71.6% (95% CI 65.5-76.8. CONCLUSION: In this pattern of care study in high risk NMIBC, 18% of the patients were treated with TUR as single treatment. Age and treatment in non-teaching hospitals were associated with less adjuvant treatment after TUR. None of the variables sex, age, comorbidity, hospital type, stage and year of treatment was associated with 5 year recurrence or progression rates.

  2. Cryosurgical ablation of the prostate: high risk patient outcomes.

    Science.gov (United States)

    Prepelica, Kristofer L; Okeke, Zephaniah; Murphy, Alana; Katz, Aaron E

    2005-04-15

    The authors report their experience with cryosurgical ablation of the prostate in men with high-risk features for prostate carcinoma who were unwilling to undergo radical surgery or radiation therapy. Between January 1998 and April 2002, 65 men underwent primary cryosurgery for prostate carcinoma with high-risk features. All patients had biopsy-proven prostate carcinoma without evidence for metastatic disease on magnetic resonance images, computed tomography scans, or radionuclide images of bones. High-risk parameters were defined as either a prostate-specific antigen (PSA) level >/= 10 ng/mL, or a Gleason sum score >/= 8, or both. Patients who had undergone prior surgery, radiation therapy, or cryoablation for prostate carcinoma were excluded from the study. Patients were monitored with physical examination and PSA screening every 3 months and with radiologic imaging when indicated. The median patient age was 72 years (range, 41-86 years), and t he median follow-up was 35 months (range, 4-77 months). There were 2 patients (3.1%) with rectal pain and incontinence. Durable PSA biochemical disease-free survival was noted in 83.3% of patients according to the American Society for Therapeutic Radiology and Oncology (ASTRO) criteria. A 6-year Kaplan-Meier analysis revealed an 81.7% ASTRO survival probability as well as PSA nadir < 4.0 ng/mL and PSA nadir < 1.0 ng/mL projections of 50% and 35%, respectively. One of 8 postcryosurgery biopsies (12.5%) were positive. No patient had progressed at last follow-up, and the overall survival rate was 100%. Cryoablation was a feasible treatment option in patients with organ-confined prostate carcinoma who had high-risk features. Longer follow-up will be necessary to determine the effectiveness of this approach. (c) 2005 American Cancer Society.

  3. Comprehensive brain MRI segmentation in high risk preterm newborns.

    OpenAIRE

    Xintian Yu; Yanjie Zhang; Robert E Lasky; Sushmita Datta; Nehal A Parikh; Ponnada A Narayana

    2010-01-01

    Most extremely preterm newborns exhibit cerebral atrophy/growth disturbances and white matter signal abnormalities on MRI at term-equivalent age. MRI brain volumes could serve as biomarkers for evaluating the effects of neonatal intensive care and predicting neurodevelopmental outcomes. This requires detailed, accurate, and reliable brain MRI segmentation methods. We describe our efforts to develop such methods in high risk newborns using a combination of manual and automated segmentation too...

  4. Rosuvastatin: Role in Cardiovascular High-risk Patient

    Directory of Open Access Journals (Sweden)

    John E Feliciano-Alfonso

    2013-01-01

    Full Text Available Statins are the lipid-lowering drug family of first choice in situations of hypercholesterolemia or mixed dyslipidemia with predominant increase in cholesterol. The evidence shows conclusively that each one of the commercially available statins have proven benefits on outcomes of cardiovascular morbidity and mortality. However, rosuvastatin has certain pharmacokinetic efficacy and cost-effectiveness characteristics that make it an attractive molecule to be the statin of choice in patients at high cardiovascular risk.

  5. Postoperative chemoradiotherapy in high risk locally advanced gastric cancer

    Energy Technology Data Exchange (ETDEWEB)

    Song, Sang Hyuk; Chie, Eui Kyu; Kim, Kyu Bo; Lee, Hyuk Joon; Yang, Han Kwang; Han, Sae Won; Oh, Do Youn; Im, Seok Ah; Bang, Yung Jue; Ha, Sung W. [Seoul National University College of Medicine, Seoul(Korea, Republic of)

    2012-12-15

    To evaluate treatment outcome of patients with high risk locally advanced gastric cancer after postoperative chemoradiotherapy. Between May 2003 and May 2012, thirteen patients who underwent postoperative chemoradiotherapy for gastric cancer with resection margin involvement or adjacent structure invasion were retrospectively analyzed. Concurrent chemotherapy was administered in 10 patients. Median dose of radiation was 50.4 Gy (range, 45 to 55.8 Gy). The median follow-up duration for surviving patients was 48 months (range, 5 to 108 months). The 5-year overall survival rate was 42% and the 5-year disease-free survival rate was 28%. Major pattern of failure was peritoneal seeding with 46%. Loco-regional recurrence was reported in only one patient. Grade 2 or higher gastrointestinal toxicity occurred in 54% of the patients. However, there was only one patient with higher than grade 3 toxicity. Despite reported suggested role of adjuvant radiotherapy with combination chemotherapy in gastric cancer, only very small portion of the patients underwent the treatment. Results from this study show that postoperative chemoradiotherapy provided excellent locoregional control with acceptable and manageable treatment related toxicity in patients with high risk locally advanced gastric cancer. Thus, postoperative chemoradiotherapy may improve treatment result in terms of locoregional control in these high risk patients. However, as these findings are based on small series, validation with larger cohort is suggested.

  6. TOB-G: Tobacco Cessation Guidelines for High risk Populations

    Directory of Open Access Journals (Sweden)

    Panagiotis Behrakis

    2016-03-01

    Full Text Available The TOB-G project is funded under the EU 3rd Health Programme which is the main instrument that the Commission uses to implement the EU Health Strategy. The project started in June 2014 and will be completed in September 2017. The project consortium consists of 5 partners from 4 European countries (Belgium, Greece, Ireland and Romania. The TOB-G project aims to develop and implement an innovative and cost effective approach to prevent chronic diseases related to tobacco dependence by focusing on creating specialized tobacco cessation guidelines for populations of high risk including adolescents, pregnant women, adults with COPD, Cardiovascular disease and diabetes. The specialized guidelines for high risks groups will be developed according to ENSP’s evidence based and good practices in tobacco cessation. The smoking cessation guidelines contain strategies and recommendations designed to assist clinicians/ doctors in delivering and supporting effective treatments for tobacco use and dependence and will also be available within the context of an e-learning platform for European clinicians. Overall, the TOB-G project will enhance the overall European capacity in the treatment of tobacco dependence, through offering smoking cessation tools, appropriately assessed and fitted to the specific needs of high risk groups.

  7. Development of Financial Support Program for High Risk Pregnant Women.

    Science.gov (United States)

    Jeong, Ihnsook; Kim, Jiyun; Im, Sook Bin

    2016-06-01

    The purpose of this study was to develop a financial support program for high-risk pregnant women based on opinions obtained using a questionnaire survey. The program development involved two steps: (1) developing a questionnaire through reviewing previous financial support programs for maternal care and then validating it via professional consultation; and (2) drafting a financial support program. Sixty professionals, 26 high-risk pregnant women, and 100 program implementers completed the questionnaire between August 2014 and October 2014. Based on the obtained professional consultation and survey investigation, the framework of the financial support program was constructed. The suggested recipients were mothers with early labor pains, mothers who have been hospitalized for > 3 weeks, and mothers who used uterine stimulant Pitocin during hospitalization. All hospitalization, medication, and examination costs needed to be supported considering the income level of the recipient. A basic policy for financially supporting high-risk pregnant women has been developed. The efficacy and feasibility of the policy needs to be carefully examined in future studies.

  8. Learning rate and temperament in a high predation risk environment

    Science.gov (United States)

    DePasquale, C.; Wagner, Tyler; Archard, G.A.; Ferguson, B.; Braithwaite, V.A.

    2014-01-01

    Living in challenging environments can influence the behavior of animals in a number of ways. For instance, populations of prey fish that experience frequent, nonlethal interactions with predators have a high proportion of individuals that express greater reaction to risk and increased activity and exploration—collectively known as temperament traits. Temperament traits are often correlated, such that individuals that are risk-prone also tend to be active and explore more. Spatial learning, which requires the integration of many sensory cues, has also been shown to vary in fish exposed to different levels of predation threat. Fish from areas of low predation risk learn to solve spatial tasks faster than fish from high predation areas. However, it is not yet known whether simpler forms of learning, such as learning associations between two events, are similarly influenced. Simple forms of associative learning are likely to be affected by temperament because a willingness to approach and explore novel situations could provide animals with a learning advantage. However, it is possible that routine-forming and inflexible traits associated with risk-prone and increased exploratory behavior may act in the opposite way and make risk-prone individuals poorer at learning associations. To investigate this, we measured temperament in Panamanian bishop fish (Brachyrhaphis episcopi) sampled from a site known to contain many predators. The B. episcopi were then tested with an associative learning task. Within this population, fish that explored more were faster at learning a cue that predicted access to food, indicating a link between temperament and basic learning abilities.

  9. Learning rate and temperament in a high predation risk environment.

    Science.gov (United States)

    DePasquale, C; Wagner, T; Archard, G A; Ferguson, B; Braithwaite, V A

    2014-11-01

    Living in challenging environments can influence the behavior of animals in a number of ways. For instance, populations of prey fish that experience frequent, nonlethal interactions with predators have a high proportion of individuals that express greater reaction to risk and increased activity and exploration-collectively known as temperament traits. Temperament traits are often correlated, such that individuals that are risk-prone also tend to be active and explore more. Spatial learning, which requires the integration of many sensory cues, has also been shown to vary in fish exposed to different levels of predation threat. Fish from areas of low predation risk learn to solve spatial tasks faster than fish from high predation areas. However, it is not yet known whether simpler forms of learning, such as learning associations between two events, are similarly influenced. Simple forms of associative learning are likely to be affected by temperament because a willingness to approach and explore novel situations could provide animals with a learning advantage. However, it is possible that routine-forming and inflexible traits associated with risk-prone and increased exploratory behavior may act in the opposite way and make risk-prone individuals poorer at learning associations. To investigate this, we measured temperament in Panamanian bishop fish (Brachyrhaphis episcopi) sampled from a site known to contain many predators. The B. episcopi were then tested with an associative learning task. Within this population, fish that explored more were faster at learning a cue that predicted access to food, indicating a link between temperament and basic learning abilities.

  10. 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.

  11. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer

    NARCIS (Netherlands)

    Rodenhuis, S; Bontenbal, M; Beex, LVAM; Wagstaff, J; Richel, DJ; Nooij, MA; Voest, EE; Hupperets, P; van Tinteren, H; Peterse, HL; TenVergert, EM; de Vries, EGE

    2003-01-01

    BACKGROUND: The use of high-dose adjuvant chemotherapy for high-risk primary breast cancer is controversial. We studied its efficacy in patients with 4 to 9 or 10 or more tumor-positive axillary lymph nodes. METHODS: Patients younger than 56 years of age who had undergone surgery for breast cancer

  12. Efficacy of smartphone applications in high-risk pigmented lesions.

    Science.gov (United States)

    Ngoo, Alexander; Finnane, Anna; McMeniman, Erin; Tan, Jean-Marie; Janda, Monika; Soyer, H Peter

    2017-02-27

    Melanoma apps are smartphone applications that assess risk of pigmented lesions using a smartphone camera and underlying algorithm. We aimed to assess the capability of melanoma smartphone applications (apps) in making clinical decisions about risk, compared with lesion assessment by specialist trained dermatologists. A prospective study of 3 melanoma apps was conducted between 2015 and 2016, recruiting 30 patients with 57 pigmented lesions. Risk categories assigned by the apps were compared with the clinical decisions of two consultant dermatologists classifying lesions as 'suspicious' or 'benign'. Of the 42 lesions deemed clinically suspicious to a dermatologist, from 9 to 26 were classified as suspicious by the apps; of the 15 clinically benign lesions 3 to 15 were correctly classified as benign by the apps. The apps' sensitivity and specificity ranged from 21 to 72% and 27 to 100.0%, respectively, when compared with the specialists' decisions. Two apps were unable to analyse 14 and 18% of lesions submitted, respectively. Interrater agreement between dermatologists and apps was poor (κ = -0.01 SE = 0.16; P = 0.97) to slight (κ = 0.16 SE = 0.09; P = 0.12). None of the melanoma apps tested had high enough agreement with the dermatologist's clinical opinion to be considered to provide additional benefit to patients in assessing their skin for high-risk pigmented lesions. The low sensitivity in detecting lesions that are suspicious to a trained specialist may mean false reassurance is being given to patients. Development of highly sensitive and specific melanoma apps remains a work in progress. © 2017 The Australasian College of Dermatologists.

  13. Preterm birth risk at high altitude in Peru.

    Science.gov (United States)

    Levine, Lisa D; Gonzales, Gustavo F; Tapia, Vilma L; Gasco, Manuel; Sammel, Mary D; Srinivas, Sindhu K; Ludmir, Jack

    2015-02-01

    High altitude has been implicated in a variety of adverse pregnancy outcomes including preeclampsia and stillbirth. Smaller studies show conflicting data on the association between high altitude and preterm birth (PTB). The objective of this study was to assess the association between altitude and PTB. A retrospective cohort study was performed using data from the Perinatal Information System, which includes deliveries from 43 hospitals in Peru from 2000 through 2010. Altitude was classified into the following categories: low (0-1999 m), moderate (2000-2900 m), and high (3000-4340 m). The primary outcome was PTB (delivery <37 weeks). Secondary outcomes were cesarean delivery and small for gestational age (SGA). Deliveries less than 23 weeks are not included in the database. χ(2) analyses were performed to compare categorical variables, and a logistic regression was used to calculate the odds ratios and control for confounders. Clustering by hospital was accounted for using generalized estimating equations. A total of 550,166 women were included (68% low, 15% moderate, 17% high altitude). The overall PTB rate was 5.9%, with no difference in the PTB rate among the 3 altitudes (5.6%, 6.2%, 6.8%, P = .13). There was a significant difference in cesarean rates (28.0%, 26.6%, 20.6%, P < .001) with a 34% decreased risk at high vs low altitude adjusted for confounders (adjusted odds ratio, 0.66; 95% confidence interval, 0.51-0.85). There was a difference in SGA (3.3%, 3.6%, 5.0%, P = .02) with a 51% increased risk at high vs low altitude adjusted for confounders (adjusted odds ratio, 1.49; 95% confidence interval, 1.14-1.93). High altitude is not associated with PTB. At high altitude, the cesarean rate was reduced and the SGA rate was increased. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. INSTRUMENTS OF HIGH RISK SEXUAL BEHAVIOR ASSESSMENT: A SYSTEMATIC REVIEW.

    Science.gov (United States)

    Mirzaei, Mojtaba; Ahmadi, Khodabakhsh; Saadat, Seyed-Hassan; Ramezani, Mohammad Arash

    2016-02-01

    Sexual behavior is a complex activity affecting all aspects of human's life. Risky sexual behaviors impose negative outcomes on family, relationships and health. Unsafe sex is the second most leading cause of disability adjusted life years worldwide. Valid and reliable tools for assessment of risky sexual behaviors are necessary for implementing preventive measures. we searched Medline and the Cochrane Library of Systematic Reviews, with the keywords of "risky sexual behavior assessment", "sexual risk assessment", "high risk sexual behavior", "sexual risk taking". By reviewing references of the articles, some complementary studies were added. Assessment can be performed by questionnaire or non-questionnaire instruments. Questionnaires vary depending on their target population, evaluation of risky sexual behavior as a whole or focusing on an associated risk factor. In order to avoid usual biases in self reports, objective biomarker assessment of unprotected sex are employed. These markers include prostate specific antigen, chromosome Y DNA and Seminogelin. Risky sexual behavior can be assessed by various subjective and objective methods. While self-reports are more feasible, objective methods offer a higher degree of reliability. Further studies for finding more feasible methods of using biomarkers are recommended.

  15. Psychosocial differences in high risk versus low risk acute low-back pain patients.

    Science.gov (United States)

    Pulliam, C B; Gatchel, R J; Gardea, M A

    2001-03-01

    The current study built upon previous research that predicted with 90.7% accuracy which patients presenting with acute low-back pain go on to develop chronic disability problems. Fifty-seven patients were classified as high risk (HR) or low risk (LR) according to a predictive algorithm, and were evaluated with a variety of psychosocial measures. Overall, HR patients had more Axis I pathology than LR patients, and used poorer coping styles. Logistic regression analyses identified variables that differentiated, with 80% accuracy, between the HR and LR patients. The results highlight the importance of identifying patients who are at risk for developing chronic pain following acute injury so that prophylactic intervention can be offered before chronic pain disability status becomes entrenched.

  16. [Home care for the high-risk newborn infant].

    Science.gov (United States)

    Puddu, M

    2010-06-01

    With increased survival of extremely low birth weigh (ELBW) and very ill infants, a lot of them are discharged with unresolved medical issues that complicate their subsequent care. Infants born preterm with low birth weight who require neonatal intensive care experience a much higher rate of hospital readmission and death during the first year after birth compared with healthy term infants. Despite initial hospital care which is one of the most expensive of all kind of hospitalization, home care services are sometimes still sparse though the high risk of this group for failure to thrive, respiratory problems, developmental delays, parenting problems. In addition, societal and economic forces have come to bear on the timing and process of discharge and home care. Moreover it takes time for the family of a high-risk infant to prepare to care for their infant in a home setting and to obtain the necessary support services and mobilize community resources. Careful preparation for discharge, good follow-up and medical home after discharge may reduce these risks.

  17. 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...

  18. Correlates of hopelessness in the high suicide risk police occupation.

    Science.gov (United States)

    Violanti, John M; Andrew, Michael E; Mnatsakanova, Anna; Hartley, Tara A; Fekedulegn, Desta; Burchfiel, Cecil M

    Police officers are chronically exposed to work stress. We examined specific stressors that may be associated with hopelessness, a possible risk factor for suicide in this high suicide risk population. The study included 378 officers (276 men and 102 women) with complete data. Analysis of variance was used to estimate mean levels of hopelessness scores as associated with stress, adjusted for age, gender, and race/ ethnicity. Posttraumatic symptoms were tested as a modifier of the association between stress and hopelessness. Increasing stress of administrative practices and lack of support were significantly associated with increasing hopelessness among officers (p hopelessness range: 1.64-2.65; and p hopelessness range 1.60-2.80, respectively). Posttraumatic stress disorder (PTSD) symptoms significantly modified the association between lack of organizational support and hopelessness (p hopelessness is associated with specific stressors in police work, and this is modified by posttraumatic symptomatology.

  19. Risk Factors Associated with Incident Syphilis in a Cohort of High-Risk Men in Peru.

    Directory of Open Access Journals (Sweden)

    Hayoung Park

    Full Text Available Syphilis is concentrated among high-risk groups, but the epidemiology of syphilis reinfection is poorly understood. We characterized factors associated with syphilis incidence, including reinfection, in a high-risk cohort in Peru.Participants in the NIMH CPOL trial were assessed at baseline and 2 annual visits with HIV/STI testing and behavioral surveys. Participants diagnosed with syphilis also attended 4- and 9-month visits. All participants underwent syphilis testing with RPR screening and TPPA confirmation. Antibiotic treatment was provided according to CDC guidelines. Reinfection was defined as a 4-fold titer increase or recurrence of seroreactivity after successful treatment with subsequent negative RPR titers. The longitudinal analysis used a Possion generalized estimating equations model with backward selection of variables in the final model (criteria P <0.02.Of 2,709 participants, 191 (7.05% were RPR-reactive (median 1:8, range 1:1-1:1024 with TPPA confirmation. There were 119 total cases of incident syphilis, which included both reinfection and first-time incident cases. In the bivariate analysis, the oldest 2 quartiles of age (incidence ratio (IR 3.84; P <0.001 and IR 8.15; P <0.001 and being MSM/TW (IR 6.48; P <0.001 were associated with higher risk of incident syphilis infection. Of the sexual risk behaviors, older age of sexual debut (IR 12.53; P <0.001, not being in a stable partnership (IR 1.56, P = 0.035, higher number of sex partners (IR 3.01; P <0.001, unprotected sex in the past 3 months (IR 0.56; P = 0.003, HIV infection at baseline (IR 3.98; P <0.001 and incident HIV infection during the study period (IR 6.26; P = 0.003 were all associated with incident syphilis. In the multivariable analysis, older age group (adjusted incidence ratio (aIR 6.18; P <0.001, men reporting having sex with a man (aIR 4.63; P <0.001, and incident HIV infection (aIR 4.48; P = 0.008 were significantly associated.We report a high rate of syphilis

  20. Risk Factors Associated with Incident Syphilis in a Cohort of High-Risk Men in Peru

    Science.gov (United States)

    Konda, Kelika A.; Roberts, Chelsea P.; Maguiña, Jorge L.; Leon, Segundo R.; Clark, Jesse L.; Coates, Thomas J.; Caceres, Carlos F.; Klausner, Jeffrey D.

    2016-01-01

    Background Syphilis is concentrated among high-risk groups, but the epidemiology of syphilis reinfection is poorly understood. We characterized factors associated with syphilis incidence, including reinfection, in a high-risk cohort in Peru. Methods Participants in the NIMH CPOL trial were assessed at baseline and 2 annual visits with HIV/STI testing and behavioral surveys. Participants diagnosed with syphilis also attended 4- and 9-month visits. All participants underwent syphilis testing with RPR screening and TPPA confirmation. Antibiotic treatment was provided according to CDC guidelines. Reinfection was defined as a 4-fold titer increase or recurrence of seroreactivity after successful treatment with subsequent negative RPR titers. The longitudinal analysis used a Possion generalized estimating equations model with backward selection of variables in the final model (criteria P <0.02). Results Of 2,709 participants, 191 (7.05%) were RPR-reactive (median 1:8, range 1:1–1:1024) with TPPA confirmation. There were 119 total cases of incident syphilis, which included both reinfection and first-time incident cases. In the bivariate analysis, the oldest 2 quartiles of age (incidence ratio (IR) 3.84; P <0.001 and IR 8.15; P <0.001) and being MSM/TW (IR 6.48; P <0.001) were associated with higher risk of incident syphilis infection. Of the sexual risk behaviors, older age of sexual debut (IR 12.53; P <0.001), not being in a stable partnership (IR 1.56, P = 0.035), higher number of sex partners (IR 3.01; P <0.001), unprotected sex in the past 3 months (IR 0.56; P = 0.003), HIV infection at baseline (IR 3.98; P <0.001) and incident HIV infection during the study period (IR 6.26; P = 0.003) were all associated with incident syphilis. In the multivariable analysis, older age group (adjusted incidence ratio (aIR) 6.18; P <0.001), men reporting having sex with a man (aIR 4.63; P <0.001), and incident HIV infection (aIR 4.48; P = 0.008) were significantly associated

  1. Entropy measure of credit risk in highly correlated markets

    Science.gov (United States)

    Gottschalk, Sylvia

    2017-07-01

    We compare the single and multi-factor structural models of corporate default by calculating the Jeffreys-Kullback-Leibler divergence between their predicted default probabilities when asset correlations are either high or low. Single-factor structural models assume that the stochastic process driving the value of a firm is independent of that of other companies. A multi-factor structural model, on the contrary, is built on the assumption that a single firm's value follows a stochastic process correlated with that of other companies. Our main results show that the divergence between the two models increases in highly correlated, volatile, and large markets, but that it is closer to zero in small markets, when asset correlations are low and firms are highly leveraged. These findings suggest that during periods of financial instability, when asset volatility and correlations increase, one of the models misreports actual default risk.

  2. 2017 Taiwan lipid guidelines for high risk patients

    Directory of Open Access Journals (Sweden)

    Yi-Heng Li

    2017-04-01

    Full Text Available In Taiwan, the prevalence of hyperlipidemia increased due to lifestyle and dietary habit changes. Low density lipoprotein cholesterol (LDL-C and non-high density lipoprotein cholesterol (non-HDL-C are all significant predicting factors of coronary artery disease in Taiwan. We recognized that lipid control is especially important in patients with existed atherosclerotic cardiovascular diseases (ASCVD, including coronary artery disease (CAD, ischemic stroke and peripheral arterial disease (PAD. Because the risk of ASCVD is high in patients with diabetes mellitus (DM, chronic kidney disease (CKD and familial hypercholesterolemia (FH, lipid control is also necessary in these patients. Lifestyle modification is the first step to control lipid. Weight reduction, regular physical exercise and limitation of alcohol intake all reduce triglyceride (TG levels. Lipid-lowering drugs include HMG-CoA reductase inhibitors (statins, cholesterol absorption inhibitors (ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9 inhibitors, nicotinic acids (niacin, fibric acids derivatives (fibrates, and long-chain omega-3 fatty acids. Statin is usually the first line therapy. Combination therapy with statin and other lipid-lowering agents may be considered in some clinical settings. For patients with acute coronary syndrome (ACS and stable CAD, LDL-C 40 in men and >50 mg/dL in women in DM. LDL-C increased CV risk in patients with CKD. In adults with glomerular filtration rate (GFR < 60 mL/min/1.73m2 without chronic dialysis (CKD stage 3–5, statin therapy should be initiated if LDL-C ≥ 100 mg/dL. Ezetimibe can be added to statin to consolidate the CV protection in CKD patients. Mutations in LDL receptor, apolipoprotein B and PCSK9 genes are the common causes of FH. Diagnosis of FH usually depends on family history, clinical history of premature CAD, physical findings of xanthoma or corneal arcus and high levels of LDL-C. In addition to conventional lipid

  3. Operational Collision Risk Management - Evaluating and Mitigating High-Risk Conjunction Events

    Science.gov (United States)

    Duncan, M.; Wysack, J.

    2011-09-01

    Operational collision threat characterization is now an essential component of space mission operations. Most spacecraft operators have some semblance of a process to evaluate and mitigate high-risk conjunction events. As the size of the space object catalog increases, satellite operators will be faced with more conjunction events to evaluate. Thus more sophisticated collision threat characterization and collision avoidance strategies must be implemented. This paper presents an overview of SpaceNav’s Collision Risk Management software. The software suite enables mission stakeholders to qualify high interest conjunction events. The tools produce various figures and graphs, which aid in analyzing event data. Optimal avoidance maneuver solutions are generated for a user defined set of goals and constraints.

  4. 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...

  5. 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.

  6. Old age, high risk medication, polypharmacy: a trilogy of risks in older patients with atrial fibrillation

    Directory of Open Access Journals (Sweden)

    Wang Y

    2016-06-01

    Full Text Available Background: The safety of pharmacotherapy in atrial fibrillation (AF is compounded by a trilogy of risks old age, high-risk medications (e.g., antithrombotics, antiarrhythmics, polypharmacy due to multiple patient comorbidities. However, to date, scarce study has investigated the use of polypharmacy (including potentially inappropriate medication (PIM in AF patients, and how this may contribute to their overall risk of medication misadventure. Objectives: To review the extent of polypharmacy and PIM use in older patients (65 years or older with AF. Methods: Information was extracted from a database characterising a cohort of older AF patients treated in general practice in New South Wales, Australia. Patient characteristics, number and types of drugs, the degree of PIM use were recorded. The predictors for the use of polypharmacy in older AF patients were identified. Results: Overall, 367 patients (mean age 77.8 years were reviewed, among which 94.8% used 5 medications or more and over half used 10 medications or more. Cardiovascular agents were most commonly used (98.9%, followed by antithrombotics (90.7%. Among agents deemed PIMs, digoxin (30.2% was the most frequently used, followed by benzodiazepines (19.6%, and sotalol (9.8%. AF patients using polypharmacy were more likely to have low bleeding risk (OR=10.97, representing those patients in whom high-risk antithrombotics are mostly indicated. Patients with major-polypharmacy (5-9 medications are more likely to have obstructive pulmonary diseases (OR=2.32, upper gastrointestinal diseases (OR=2.02 and poor physical function (OR=1.04, but less likely to have cognitive impairment (OR=0.27. Conclusion: Polypharmacy affects oldest AF patients, comprising medications that are indicated for AF, yet regarded as PIMs. Patients with lower risk of bleeding, obstructive pulmonary diseases, upper gastrointestinal diseases and poor physical function are also at higher risk of using higher number of

  7. Fetal and umbilical Doppler ultrasound in high-risk pregnancies.

    Science.gov (United States)

    Alfirevic, Zarko; Stampalija, Tamara; Dowswell, Therese

    2017-06-13

    Abnormal blood flow patterns in fetal circulation detected by Doppler ultrasound may indicate poor fetal prognosis. It is also possible that false positive Doppler ultrasound findings could lead to adverse outcomes from unnecessary interventions, including preterm delivery. The objective of this review was to assess the effects of Doppler ultrasound used to assess fetal well-being in high-risk pregnancies on obstetric care and fetal outcomes. We updated the search of Cochrane Pregnancy and Childbirth's Trials Register on 31 March 2017 and checked reference lists of retrieved studies. Randomised and quasi-randomised controlled trials of Doppler ultrasound for the investigation of umbilical and fetal vessels waveforms in high-risk pregnancies compared with no Doppler ultrasound. Cluster-randomised trials were eligible for inclusion but none were identified. Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. Data entry was checked. We assessed the quality of evidence using the GRADE approach. Nineteen trials involving 10,667 women were included. Risk of bias in trials was difficult to assess accurately due to incomplete reporting. None of the evidence relating to our main outcomes was graded as high quality. The quality of evidence was downgraded due to missing information on trial methods, imprecision in risk estimates and heterogeneity. Eighteen of these studies compared the use of Doppler ultrasound of the umbilical artery of the unborn baby with no Doppler or with cardiotocography (CTG). One more recent trial compared Doppler examination of other fetal blood vessels (ductus venosus) with computerised CTG.The use of Doppler ultrasound of the umbilical artery in high-risk pregnancy was associated with fewer perinatal deaths (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.52 to 0.98, 16 studies, 10,225 babies, 1.2% versus 1.7 %, number needed to treat (NNT) = 203; 95% CI 103 to 4352

  8. [Residual risk: The roles of triglycerides and high density lipoproteins].

    Science.gov (United States)

    Grammer, Tanja; Kleber, Marcus; Silbernagel, Günther; Scharnagl, Hubert; März, Winfried

    2016-06-01

    In clinical trials, the reduction of LDL-cholesterol (LDL-C) with statins reduces the incidence rate of cardiovascular events by approximately one third. This means, that a sizeable "residual risk" remains. Besides high lipoprotein (a), disorders in the metabolism of triglyceride-rich lipoproteins and high density liproteins have been implicated as effectors of the residual risk. Both lipoprotein parameters correlate inversely with each other. Therefore, the etiological contributions of triglycerides and / or of HDL for developing cardiovascular disease can hardly be estimated from either observational studies or from intervention studies. The largely disappointing results of intervention studies with inhibitors of the cholesteryl ester transfer protein and in particular the available set of genetically-epidemiological studies suggest that in the last decade, the importance of HDL cholesterol has been overvalued, while the importance of triglycerides has been underestimated. High triglycerides not always atherogenic, but only if they are associated with the accumulation relatively cholesterol-enriched, incompletely catabolized remnants of chylomicrons and very low density lipoproteins (familial type III hyperlipidemia, metabolic syndrome, diabetes mellitus). The normalization of the concentration of triglycerides and remnants by inhibiting the expression of apolipoprotein C3 is hence a new, promising therapeutic target. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Quantitative breast MRI radiomics for cancer risk assessment and the monitoring of high-risk populations

    Science.gov (United States)

    Mendel, Kayla R.; Li, Hui; Giger, Maryellen L.

    2016-03-01

    Breast density is routinely assessed qualitatively in screening mammography. However, it is challenging to quantitatively determine a 3D density from a 2D image such as a mammogram. Furthermore, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is used more frequently in the screening of high-risk populations. The purpose of our study is to segment parenchyma and to quantitatively determine volumetric breast density on pre-contrast axial DCE-MRI images (i.e., non-contrast) using a semi-automated quantitative approach. In this study, we retroactively examined 3D DCE-MRI images taken for breast cancer screening of a high-risk population. We analyzed 66 cases with ages between 28 and 76 (mean 48.8, standard deviation 10.8). DCE-MRIs were obtained on a Philips 3.0 T scanner. Our semi-automated DCE-MRI algorithm includes: (a) segmentation of breast tissue from non-breast tissue using fuzzy cmeans clustering (b) separation of dense and fatty tissues using Otsu's method, and (c) calculation of volumetric density as the ratio of dense voxels to total breast voxels. We examined the relationship between pre-contrast DCE-MRI density and clinical BI-RADS density obtained from radiology reports, and obtained a statistically significant correlation [Spearman ρ-value of 0.66 (p < 0.0001)]. Our method within precision medicine may be useful for monitoring high-risk populations.

  10. Teamwork in high-risk environments analogous to space

    Science.gov (United States)

    Kanki, Barbara G.

    1990-01-01

    Mountaineering expeditions combine a number of factors which make them potentially good analogs to the planetary exploration facet of long-duration space missions. A study of mountain climbing teams was conducted in order to evaluate the usefulness of the environment as a space analog and to specifically identify the factors and issues surrounding teamwork and 'successful' team performance in two mountaineering environments. This paper focuses on social/organizational factors, including team size and structure, leadership styles and authority structure which were found in the sample of 22 climb teams (122 individuals). The second major issue discussed is the construction of a valid performance measure in this high-risk environment.

  11. High-Risk Cardiac Disease in Pregnancy: Part I.

    Science.gov (United States)

    Elkayam, Uri; Goland, Sorel; Pieper, Petronella G; Silverside, Candice K

    2016-07-26

    The incidence of pregnancy in women with cardiovascular disease is rising, primarily due to the increased number of women with congenital heart disease reaching childbearing age and the changing demographics associated with advancing maternal age. Although most cardiac conditions are well tolerated during pregnancy and women can deliver safely with favorable outcomes, there are some cardiac conditions that have significant maternal and fetal morbidity and mortality. The purpose of this paper is to review the available published reports and provide recommendations on the management of women with high-risk cardiovascular conditions during pregnancy. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  12. Against the tide: climate change and high-risk cities

    Energy Technology Data Exchange (ETDEWEB)

    Dodman, David

    2008-11-15

    In the world's poorest and most vulnerable nations, most cities and towns face a distinct dual pressure: rapidly growing population and high vulnerability to the impacts of climate change. Drought, storms, flooding and sea level rise are likely to hit hardest here. These in turn put water supplies, infrastructure, health and livelihoods at risk in the very cities already struggling to provide or safeguard such key needs. An effective response demands capable local and national government and support from strong international networks in building capacity to cope. Most of the Least Developed Countries lack both.

  13. Epidural Anesthesia in a Patient with High Cardiac Risk

    Directory of Open Access Journals (Sweden)

    Tuğba Doğu

    2014-03-01

    Full Text Available Cardiac morbidity is the most common cause postoperative of mortality furthermore anesthesia technics are associated with cardiac morbidity and mortality. A 48-year-old male, 90 kg, ASA physical status IV patient underwent femoropopliteal bypass under epidural anesthesia. Comorbidities included atrial fibrillation, dilated cardiomyopathy and 20%  left ventricular ejection fraction. Epidural anesthesia was established with bupivacaine and fentanyl at L3-L4 intervertebral space. Hemodynamic stability and pain relief were established during and after the surgery. We consider that epidural anesthesia is preferable as an alternative regarding the risks of spinal anesthesia and general anesthesia for high cardiac risky patients.

  14. Mechanical Circulatory Support for High-Risk Pulmonary Embolism.

    Science.gov (United States)

    Elder, Mahir; Blank, Nimrod; Shemesh, Adi; Pahuja, Mohit; Kaki, Amir; Mohamad, Tamam; Schreiber, Theodore; Giri, Jay

    2018-01-01

    Temporary mechanical circulatory support (MCS) devices have a role in treating high-risk patients with pulmonary embolism with cardiogenic shock. Mechanical circulatory device selection should be made based on center experience and device-specific features. All current devices are effective in decreasing right arterial pressure and providing circulatory support of 4 to 5 L/min. The pulmonary artery pulsatility index may prove to be an unreliable method to assess right ventricular function. Careful clinical evaluation on an individual patient basis should determine the need for MCS. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Recommendations of activity restriction in high-risk pregnancy scenarios

    DEFF Research Database (Denmark)

    Bendix, Jane; Hegaard, Hanne Kristine; Bergholt, Thomas

    2015-01-01

    and the Danish Association of Midwives were asked to complete a tested, structured questionnaire. Results: We sent 1815 invitations; the overall response rate was 54%. A majority of clinicians recommended some form of activity restriction in the nine scenarios. The midwives recommended strict or moderate...... obstetricians and midwives prescribe activity restriction in most high-risk pregnancies. The degree of activity restriction and the presumed effect vary between clinicians. This may reflect different attitudes and lack of guidelines based on clinical studies of a possible benefit of activity restriction....

  16. Vaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis

    DEFF Research Database (Denmark)

    Klein, K; Rode, L; Nicolaides, K H

    2011-01-01

    Progesterone treatment reduces the risk of preterm delivery in high-risk singleton pregnancies. Our aim was to evaluate the preventive effect of vaginal progesterone in high-risk twins.......Progesterone treatment reduces the risk of preterm delivery in high-risk singleton pregnancies. Our aim was to evaluate the preventive effect of vaginal progesterone in high-risk twins....

  17. At-risk high school seniors: Science remediation for Georgia's High School Graduation Test

    Science.gov (United States)

    Carroll, Carolyn M.

    State departments of education have created a system of accountability for the academic achievement of students under the mandate of the No Child Left Behind Act of 2001. The Georgia Department of Education established the Georgia High School Graduation Test (GHSGT) as their method of evaluating the academic achievement of high school students. The GHSGT consist of five sections and students must pass all five sections before students they are eligible to receive a diploma. The purpose of the study was to examine the effects of teacher-lead and computer based remediation for a group of high school seniors who have been unsuccessful in passing the science portion of the GHSGT. The objectives of this study include (a) Identify the most effective method of remediation for at-risk students on the science section of the GHSGT, and (b) evaluate the methods of remediation for at-risk students on the science section of GHSGT available to high school students. The participants of this study were at-risk seniors enrolled in one high school during the 2007-2008 school year. The findings of this research study indicated that at-risk students who participated in both types of remediation, teacher-led and computer-based, scored significantly higher than the computer-based remediation group alone. There was no significant relationship between the test scores and the number of times the students were tested.

  18. High-risk behaviors in teenage male athletes.

    Science.gov (United States)

    Forman, E S; Dekker, A H; Javors, J R; Davison, D T

    1995-01-01

    This project studied high-risk activities in adolescent male athletes (ages 13-19) compared with a control group of adolescent male and female nonathletes. All athletes surveyed participated in one or more interscholastic sports. The prevalence of drug use by athletes compared to nonathletes was determined. Of the 19 drugs observed in this study, all were shown to have a lower prevalence of use among athletes in their senior year of high school, compared to the comparison group. Among the more commonly abused substances by the athlete population, beer, wine and whiskey, cigarettes, and marijuana were shown to have a lower use rate, by 25.5, 39.9, 57.5, and 57.7%, respectively. The prevalence of drug use by adolescent male athletes compared to adolescent nonathletes was also studied. Of the 19 individual drugs surveyed, all demonstrated a lower prevalence of use among athletes in their senior year of high school compared to the national data. The second high-risk activity measured was sexual activity. Of the athletes, 45.5% stated that they had never had sexual intercourse, compared to 50.0% of the nonathletes. Of the sexually active athletes, 81.9% had their first intercourse at between 13 and 15 years of age, whereas only 67.8% of the nonathlete control group had done so. This difference diminished significantly at age 16 and above. The results of this study suggest that participation in athletics by male athletes may lead to a significant decrease in drug and alcohol use and abuse but, also may increase early sexual contact. These trends were seen throughout all 4 years of high school in the athletes studied.

  19. Protecting military personnel from high risk dietary supplements.

    Science.gov (United States)

    Deuster, Patricia A; Lieberman, Harris R

    2016-01-01

    It is legal tomarketmost naturally occurring substances as dietary supplements in the USA without manufacturers demonstrating they are safe or effective, and an endless variety of ingredients, from esoteric botanicals to unapproved pharmaceuticals, can be found in dietary supplements. Use of certain supplements can pose a risk, but since a robust reporting systemdoes not exist in the USA it is difficult to know which are problematic and the number of adverse events (AE) resulting from their use. Certain populations, includingmilitary personnel, aremore likely to use dietary supplements than the general population. Approximately 70% of military personnel take dietary supplements while about 50% of civilians do. Service members prefer supplements purported to enhance physical performance such as supposedly natural stimulants, protein and amino acids, and combination products. Since some of thesemay be problematic, Servicemembers are probably at higher risk of injury than the general population. Ten percent of military populations appear to be taking potentially risky supplements, and the US Department of Defense (DoD) has taken variousmeasures to protect uniformed personnel including education, policy changes, and restricting sales. Actions taken include launching Operation Supplement Safety (OPSS), introducing a High Risk Supplement list, educating health care professionals on reporting AE thatmight be associated with dietary supplements, recommending policy for reporting AE, and developing an online AE reporting system. OPSS is a DoD-wide effort to educate service members, leaders, health care providers, military families, and retirees on how to safely select supplements

  20. Carotid stenosis: what is the high-risk population?

    Directory of Open Access Journals (Sweden)

    Jong Hun Park

    Full Text Available OBJECTIVE: Prevention is the best treatment for cerebrovascular disease, which is why early diagnosis and the immediate treatment of carotid stenosis contribute significantly to reducing the incidence of stroke. Given its silent nature, 80% of stroke cases occur in asymptomatic individuals, emphasizing the importance of screening individuals with carotid stenosis and identifying high-risk groups for the disease. The aim of this study was to determine the prevalence and the most frequent risk factors for carotid stenosis. METHODS: A transversal study was conducted in the form of a stroke prevention campaign held on three nonconsecutive Saturdays. During the sessions, carotid stenosis diagnostic procedures were performed for 500 individuals aged 60 years or older who had systemic arterial hypertension and/or diabetes mellitus and/or coronary heart disease and/or a family history of stroke. RESULTS: The prevalence of carotid stenosis in the population studied was 7.4%, and the most frequent risk factors identified were mean age of 70 years, carotid bruit, peripheral obstructive arterial disease, coronary insufficiency and smoking. Independent predictive factors of carotid stenosis include the presence of carotid bruit or peripheral obstructive heart disease and/or coronary insufficiency. CONCLUSIONS: The population with peripheral obstructive heart disease and carotid bruit should undergo routine screening for carotid stenosis.

  1. [Relevance of diabetes in high cardiovascular risk hypertensive patients].

    Science.gov (United States)

    Segura, Julián; de la Sierra, Alejandro; Fernández, Sandra; Ruilope, Luis M

    2013-10-05

    The aim of this cross-sectional study was to compare the prevalence of target organ damage (TOD) and established cardiovascular disease (CVD) in a cohort of nondiabetic hypertensive patients with 3 or more cardiovascular risk factors (CVRF) against a group of hypertensives with type 2 diabetes. We included 4,725 hypertensive patients, 62% male, mean age 64 (SD 12) years, with type 2 diabetes mellitus, independently of the number of associated CVRF (N=2,608), or non-diabetics, in which case we required the presence of 3 CVRF (N=2,117). The prevalence of established CVD (clinical interview) and TOD (left ventricular hypertrophy by electrocardiogram, microalbuminuria and estimated glomerular filtration rate) were estimated. Hypertensive patients with type 2 diabetes had an older age and more marked obesity. Furthermore, these patients showed a higher prevalence of micro- and macroalbuminuria, renal failure, left ventricular hypertrophy, atherosclerotic plaques in carotid arteries and CVD compared with nondiabetic hypertensive patients with 3 or more CVRF. Multivariate analysis showed that the risk of TOD or established CVD were associated independently with the presence of diabetes. Hypertensive patients with type 2 diabetes have a higher prevalence of LOD and CVD compared to nondiabetic hypertensive patients with 3 or more CVRF. Although both situations are included in the high cardiovascular risk stratum, it would be expected an increased incidence of cardiovascular complications in hypertensive diabetic patients. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  2. Pharmacological management of dyslipidemia in high and very high cardiovascular risk patients

    Directory of Open Access Journals (Sweden)

    V. Pascual Fuster

    Full Text Available Dyslipaemia is one of the main risk factors in the development of cardiovascular diseases. Currently, there are different alternatives available (amongst which statins occupy a pre-eminent place, to optimise the treatment of patients at high or very high cardiovascular risk. Despite this, the percentage of patients that achieve good lipid control is low. The causes of the mismatch with proposed objectives include lack of patient adherence and therapeutic inertia. This review uses available evidence and the latest clinical guides as a basis to assess the pharmacological treatment of dyslipaemia in patients with a background of arteriosclerotic vascular disease, diabetes, chronic kidney disease, cardiovascular risk at ≥5% calculated by SCORE and familial hypercholesterolaemia. The treatment of hypertriglyceridemia is also reviewed along with the special consideration that poly-pharmacy deserves in patients treated with statins, making mention of the treatment of dyslipaemia with HIV infection. The global assessment of cardiovascular risk is of high priority to adapt treatment to the specific objectives of the c-LDL for each risk category.

  3. Reducing sexual risk behavior among high-risk couples in Northern India.

    Science.gov (United States)

    Jones, Deborah; Bagga, Rashmi; Nehra, Ritu; Deepika; Sethi, Sunil; Walia, Kamini; Kumar, Mahendra; Villar-Loubet, Olga; Lopez, Maria; Weiss, Stephen M

    2013-09-01

    With a population of 1.1 billion, India is considered to be a country in which effective prevention interventions could contain the development of a human immunodeficiency virus (HIV) epidemic. Heterosexual transmission accounts for 85 % of the extant HIV infections. This study sought to assess the feasibility of conducting a group, culturally tailored behavioral intervention and its impact on sexual barrier use, self-efficacy, knowledge, conflict resolution, and coping among high-risk heterosexual couples in Northern India. This pilot study was conducted at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India from February 2008 to January 2009. Thirty sexually active high-risk couples were drawn from a convenience sample of PGIMER patients attending infectious disease and family planning clinics. Couples participated in 1 month of three weekly gender-concordant behavioral intervention groups and were individually administered assessments preintervention and post-intervention. The intervention was tailored to the Northern Indian context and addressed sexual barrier use, human immunodeficiency virus (HIV)/sexually transmitted infection transmission, and cognitive behavioral skill building focusing on sexual negotiation and communication. The participants had a mean age of 32 years (men) and 29 years (women), and the majority had at least 10 years of education. At baseline, the majority reported inconsistent condom use (coping tactics. The results highlight the potential to successfully utilize a group intervention to discuss sensitive issues such as sexual risk behavior among both men and women. Strategies to improve condom use and communication without increasing intimate partner violence in high-risk couples may be an important adjunct to preventing the development of a generalized epidemic in India.

  4. High dislocation cumulative risk in THA versus hemiarthroplasty for fractures.

    Science.gov (United States)

    Poignard, Alexandre; Bouhou, Mohamed; Pidet, Olivier; Flouzat-Lachaniette, Charles-Henri; Hernigou, Philippe

    2011-11-01

    Although not all elderly patients with femoral neck fractures are candidates for THA, active, mentally competent, independent patients achieve the most durable functional scores with THA compared with hemiarthroplasty. However, a relatively high frequency of early or late dislocation could reduce the potential benefits with THA. We asked whether the incidence of first-time, recurrent dislocation, and revision differed in patients with hip fractures having THA or hemiarthroplasty. We retrospectively reviewed 380 patients with hip fractures (380 hips) who underwent THAs between 1995 and 1999, and compared them with 412 patients with hip fractures (412 hips) who underwent hemiarthroplasties between 1990 and 1994. The mean followup was 8 years (range, 1-20 years). THA had a higher early risk of first-time dislocation and a higher late risk: 19 (4.5%) of the 412 hips treated with hemiarthroplasty had at least one dislocation whereas 30 (8.1%) of the 380 hips treated with THA had at least one dislocation. The cumulative number of dislocations at the most recent followup (first time and recurrent dislocations) was 58 (13%) for the 380 THAs and 22 (5%) for the 412 hemiarthroplasties. At the 10-year followup, eight THAs (2%) had revision (six recurrent dislocations, two loosenings), and 42 hemiarthroplasties (10%) had revision (40 acetabular protrusions, one recurrent dislocation). The risk of revision for recurrent dislocation increases with THA, but it remains lower than the risk of revision for wear of cartilage and acetabular protrusion in hemiarthroplasty. Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

  5. Risk factors associated with developmental abnormalities among high-risk children attended at a multidisciplinary clinic.

    Science.gov (United States)

    Resegue, Rosa; Puccini, Rosana Fiorini; Silva, Edina Mariko Koga da

    2008-01-02

    Knowledge of risk factors associated with child development disorders is essential for delivering high-quality childcare. The objective here was to evaluate the relationships between risk factors and occurrences of developmental abnormalities among children attended at a reference clinic for children at risk of developmental abnormalities. Retrospective study at a multidisciplinary reference center, Embu, São Paulo. All cases followed up for more than three months between 1995 and 2003 were reviewed. The risk factors assessed were low birth weight, gestational age, length of stay in neonatal ward, perinatal asphyxia, mothers age 5 days, prematurity and mothers age 18 years and older. Low birth weight, history of perinatal asphyxia and mothers age continued to be significant in multivariate analysis. Special attention must be paid to the development of low birth weight infants and/or infants with histories of neonatal complications. Low birth weight is easily assessed and should be considered to be an important marker when defining guidelines for following up child development.

  6. Risk factors associated with developmental abnormalities among high-risk children attended at a multidisciplinary clinic

    Directory of Open Access Journals (Sweden)

    Rosa Resegue

    Full Text Available CONTEXT AND OBJECTIVE: Knowledge of risk factors associated with child development disorders is essential for delivering high-quality childcare. The objective here was to evaluate the relationships between risk factors and occurrences of developmental abnormalities among children attended at a reference clinic for children at risk of developmental abnormalities. DESIGN AND SETTING: Retrospective study at a multidisciplinary reference center, Embu, São Paulo. METHODS: All cases followed up for more than three months between 1995 and 2003 were reviewed. The risk factors assessed were low birth weight, gestational age, length of stay in neonatal ward, perinatal asphyxia, mother’s age 5 days, prematurity and mother’s age 18 years and older. Low birth weight, history of perinatal asphyxia and mother’s age continued to be significant in multivariate analysis. CONCLUSIONS: Special attention must be paid to the development of low birth weight infants and/or infants with histories of neonatal complications. Low birth weight is easily assessed and should be considered to be an important marker when defining guidelines for following up child development.

  7. Characterizing and reaching high-risk drinkers using audience segmentation.

    Science.gov (United States)

    Moss, Howard B; Kirby, Susan D; Donodeo, Fred