Science.gov

Sample records for glioblastoma multiforme confirmatory

  1. Lactate levels with glioblastoma multiforme

    PubMed Central

    Kahlon, Arunpreet Singh; Alexander, Mariam; Kahlon, Arundeep

    2016-01-01

    A 37-year-old woman with known glioblastoma multiforme was admitted for treatment of new deep vein thrombosis. Anion gap and plasma lactate levels were found to be elevated. Magnetic resonance imaging of the brain showed a stable, advanced glioblastoma multiforme. All causes of lactic acidosis, including infections and medications, were ruled out. Aggressive tumors have been shown to produce lactate levels in minute quantities in their microenvironment, which helps them metastasize and evade immune response and even radiation. PMID:27365883

  2. [Glioblastoma multiforme... with multifocal presentation].

    PubMed

    Sousa, Gabriela; Rocha, Armando; Alfaiate, Teresa; Carvalho, Teresa; Veiga e Moura, António; Ferreira, Mário Rui

    2002-01-01

    Glioblastoma multiforme is the most common malignant primary brain tumor in adults (+/- 40% of the Central Nervous System primary tumors). Representing only 2% of all oncologic processes, they are associated with a great deterioration of cerebral functions and a poor prognosis, facts that contribute to their great individual and social impact. The authors report a case of glioblastoma multiforme, with multifocal lesions "ab initio" and show the difficulty to make a correct diagnosis, even with the most modern imagiologic techniques. They also make a brief review of the literature. PMID:12525027

  3. Extraneural Glioblastoma Multiforme Vertebral Metastasis

    PubMed Central

    Goodwin, C. Rory; Liang, Lydia; Abu-Bonsrah, Nancy; Hdeib, Alia; Elder, Benjamin D.; Kosztowski, Thomas; Bettegowda, Chetan; Laterra, John; Burger, Peter; Sciubba, Daniel M.

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor; however, extraneural metastasis is uncommon. Of those that metastasize extraneurally, metastases to the vertebral bodies represent a significant proportion. We present a review of 28 cases from the published literature of GBM metastasis to the vertebra. The mean age at presentation was 38.4 years with an average overall survival of 26 months. Patients were either asymptomatic with metastasis discovered at autopsy or presented with varying degrees of pain, weakness of the extremities, or other neurologic deficits. Of the cases that included the time to spinal metastasis, the average time was 26.4 months with a reported survival of 10 months after diagnosis of vertebral metastasis. A significant number of patients had no treatments for their spinal metastasis, although the intracranial lesions were treated extensively with surgery and/or adjuvant therapy. With increasing incremental gains in the survival of patients with GBM, clinicians will encounter patients with extracranial metastasis. As such, this review presents timely information concerning the presentation and outcomes of patients with vertebral metastasis. PMID:26704201

  4. Extraneural Glioblastoma Multiforme Vertebral Metastasis.

    PubMed

    Goodwin, C Rory; Liang, Lydia; Abu-Bonsrah, Nancy; Hdeib, Alia; Elder, Benjamin D; Kosztowski, Thomas; Bettegowda, Chetan; Laterra, John; Burger, Peter; Sciubba, Daniel M

    2016-05-01

    Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor; however, extraneural metastasis is uncommon. Of those that metastasize extraneurally, metastases to the vertebral bodies represent a significant proportion. We present a review of 28 cases from the published literature of GBM metastasis to the vertebra. The mean age at presentation was 38.4 years with an average overall survival of 26 months. Patients were either asymptomatic with metastasis discovered at autopsy or presented with varying degrees of pain, weakness of the extremities, or other neurologic deficits. Of the cases that included the time to spinal metastasis, the average time was 26.4 months with a reported survival of 10 months after diagnosis of vertebral metastasis. A significant number of patients had no treatments for their spinal metastasis, although the intracranial lesions were treated extensively with surgery and/or adjuvant therapy. With increasing incremental gains in the survival of patients with GBM, clinicians will encounter patients with extracranial metastasis. As such, this review presents timely information concerning the presentation and outcomes of patients with vertebral metastasis. PMID:26704201

  5. Current data and strategy in glioblastoma multiforme

    PubMed Central

    Dinca, EB

    2009-01-01

    Glioblastoma multiforme (GBM) or astrocytoma grade Ⅳ on WHO classification is the most aggressive and the most frequent of all primary brain tumors. Glioblastoma is multiforme , resistant to therapeutic interventions illustrating the heterogeneity exhibited by this tumor in its every aspect, including clinical presentation, pathology, genetic signature. Current data and treatment strategy in GBM are presented focusing on basic science data and key clinical aspects like surgery, including personal experience; adjuvant modalities: radiotherapy, chemotherapy, but also for experimental approaches. Therapeutic attitude in recurrent GBM is also widely discussed. PMID:20108752

  6. Current data and strategy in glioblastoma multiforme.

    PubMed

    Iacob, Gabriel; Dinca, Eduard B

    2009-01-01

    Glioblastoma multiforme (GBM) or astrocytoma grade IV on WHO classification is the most aggressive and the most frequent of all primary brain tumors. Glioblastoma is multiforme, resistant to therapeutic interventions illustrating the heterogeneity exhibited by this tumor in its every aspect, including clinical presentation, pathology, genetic signature. Current data and treatment strategy in GBM are presented focusing on basic science data and key clinical aspects like surgery, including personal experience; adjuvant modalities: radiotherapy, chemotherapy, but also for experimental approaches. Therapeutic attitude in recurrent GBM is also widely discussed.

  7. Advanced case of glioblastoma multiforme and pregnancy

    PubMed Central

    Al-Rasheedy, Intisar M.; Al-Hameed, Fahad M.

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant form of the glial tumors. Advanced and treated GBM is rarely associated with pregnancy for many reasons. Glioblastoma multiforme presenting during pregnancy carries unique challenges to the patient, baby, family, and health care providers. We describe an unusual case of advanced GBM that was treated with maximum doses of chemotherapy and radiations, and she became pregnant and presented at eighteenth weeks of gestation. Her medical management was associated with a significant ethical dilemma. We managed to deliver the baby safely through cesarean section at week 28 despite the critical condition of the mother. Unfortunately, the mother died 2 weeks post delivery. We concluded that although recurrent and treated GBM is rarely associated with pregnancy and carries dismal prognosis, but if it occurs, it can still be carried, and a multidisciplinary team work is the key for successful outcome. PMID:26492122

  8. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme

    PubMed Central

    Bradshaw, Amy; Wickremsekera, Agadha; Tan, Swee T.; Peng, Lifeng; Davis, Paul F.; Itinteang, Tinte

    2016-01-01

    Glioblastoma multiforme (GBM), an aggressive tumor that typically exhibits treatment failure with high mortality rates, is associated with the presence of cancer stem cells (CSCs) within the tumor. CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells that drive tumor growth. Studies of many cancer types have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple GBM and glioblastoma cancer stem cell subtypes, making investigation and establishment of a universal treatment difficult. This review examines the current knowledge on the CSC markers SALL4, OCT-4, SOX2, STAT3, NANOG, c-Myc, KLF4, CD133, CD44, nestin, and glial fibrillary acidic protein, specifically focusing on their use and validity in GBM research and how they may be utilized for investigations into GBM’s cancer biology. PMID:27148537

  9. Extracranial oral cavity metastasis from glioblastoma multiforme: A case report

    PubMed Central

    Kup, Philipp Günther; Nieder, Carsten; Winnekendonk, Guido; Adamietz, Irenäus Anton; Fakhrian, Khashayar

    2016-01-01

    Glioblastoma multiforme is the most common primary malignant brain tumor. The clinical outcome following diagnosis remains extremely poor. The treatment of choice is wide surgical resection of the visible tumor, frequently followed by adjuvant combined radiochemotherapy (RCTx) with temozolomide as the chemotherapeutic agent. Extracranial metastases are extremely rare, with <200 cases of extracranial metastases from glioblastoma multiforme reported in the literature to date. We herein present a case of a patient suffering from a fast-growing metastasis to the oral cavity, completely filling the buccal cavity within 2 weeks, as the only manifestation of recurrent glioblastoma multiforme following initial surgical resection and adjuvant RCTx.

  10. TCGA Workshop: Genomics and Biology of Glioblastoma Multiforme (GBM) - TCGA

    Cancer.gov

    The National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI) held a workshop entitled, “Genomics and Biology of Glioblastoma Multiforme (GBM),” to review the initial GBM data from the TCGA pilot project.

  11. Problems of Glioblastoma Multiforme Drug Resistance.

    PubMed

    Stavrovskaya, A A; Shushanov, S S; Rybalkina, E Yu

    2016-02-01

    Glioblastoma multiforme (GBL) is the most common and aggressive brain neoplasm. A standard therapeutic approach for GBL involves combination therapy consisting of surgery, radiotherapy, and chemotherapy. The latter is based on temozolomide (TMZ). However, even by applying such a radical treatment strategy, the mean patient survival time is only 14.6 months. Here we review the molecular mechanisms underlying the resistance of GBL cells to TMZ including genetic and epigenetic mechanisms. Present data regarding a role for genes and proteins MGMT, IDH1/2, YB-1, MELK, MVP/LRP, MDR1 (ABCB1), and genes encoding other ABC transporters as well as Akt3 kinase in developing resistance of GBL to TMZ are discussed. Some epigenetic regulators of resistance to TMZ such as microRNA and EZH2 are reviewed. PMID:27260389

  12. Network Signatures of Survival in Glioblastoma Multiforme

    PubMed Central

    Patel, Vishal N.; Gokulrangan, Giridharan; Chowdhury, Salim A.; Chen, Yanwen; Sloan, Andrew E.; Koyutürk, Mehmet; Barnholtz-Sloan, Jill; Chance, Mark R.

    2013-01-01

    To determine a molecular basis for prognostic differences in glioblastoma multiforme (GBM), we employed a combinatorial network analysis framework to exhaustively search for molecular patterns in protein-protein interaction (PPI) networks. We identified a dysregulated molecular signature distinguishing short-term (survival<225 days) from long-term (survival>635 days) survivors of GBM using whole genome expression data from The Cancer Genome Atlas (TCGA). A 50-gene subnetwork signature achieved 80% prediction accuracy when tested against an independent gene expression dataset. Functional annotations for the subnetwork signature included “protein kinase cascade,” “IκB kinase/NFκB cascade,” and “regulation of programmed cell death” – all of which were not significant in signatures of existing subtypes. Finally, we used label-free proteomics to examine how our subnetwork signature predicted protein level expression differences in an independent GBM cohort of 16 patients. We found that the genes discovered using network biology had a higher probability of dysregulated protein expression than either genes exhibiting individual differential expression or genes derived from known GBM subtypes. In particular, the long-term survivor subtype was characterized by increased protein expression of DNM1 and MAPK1 and decreased expression of HSPA9, PSMD3, and CANX. Overall, we demonstrate that the combinatorial analysis of gene expression data constrained by PPIs outlines an approach for the discovery of robust and translatable molecular signatures in GBM. PMID:24068912

  13. Molecular and Genomic Alterations in Glioblastoma Multiforme.

    PubMed

    Crespo, Ines; Vital, Ana Louisa; Gonzalez-Tablas, María; Patino, María del Carmen; Otero, Alvaro; Lopes, María Celeste; de Oliveira, Catarina; Domingues, Patricia; Orfao, Alberto; Tabernero, Maria Dolores

    2015-07-01

    In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types. This translates into well-defined genomic profiles that have been recently classified by The Cancer Genome Atlas Consortium into four subtypes: classic, mesenchymal, proneural, and neural GBM. Herein, we review the most relevant genetic alterations of primary versus secondary GBM, the specific signaling pathways involved, and the overall genomic profile of this genetically heterogeneous group of malignant tumors.

  14. miR-340 suppresses glioblastoma multiforme

    PubMed Central

    Ge, Ruiguang; He, Lei; Li, Mei; Li, Yi; Peng, Ying

    2015-01-01

    Deregulation of microRNAs (miRs) contributes to tumorigenesis. Down-regulation of miR-340 is observed in multiple types of cancers. However, the biological function of miR-340 in glioblastoma multiforme (GBM) remains largely unknown. In the present study, we demonstrated that expression of miR-340 was downregulated in both glioma cell lines and tissues. Survival of GBM patients with high levels of miR-340 was significantly extended in comparison to patients expressing low miR-340 levels. Biological functional experiments showed that the restoration of miR-340 dramatically inhibited glioma cell proliferation, induced cell-cycle arrest and apoptosis, suppressed cell motility and promoted autophagy and terminal differentiation. Mechanistic studies disclosed that, miR-340 over-expression suppressed several oncogenes including p-AKT, EZH2, EGFR, BMI1 and XIAP. Furthermore, ROCK1 was validated as a direct functional target miR-340 and silencing of ROCK1 phenocopied the anti-tumor effect of mR-340. Our findings indicate an important role of miR-340 as a glioma killer, and suggest a potential prognosis biomarker and therapeutic target for GBM. PMID:25831237

  15. 'Goose bumps' as presenting feature of intraventricular glioblastoma multiforme.

    PubMed

    Asha, Mohammed J; Tansey, Rosamond J; Gan, Yee-Chiung

    2014-04-01

    'Goose-bumps' seizures are rare manifestations of epilepsy. They are rarely reported by patients and can be easily dismissed by clinicians. Clinically, it carries some diagnostic localising value especially with unilateral onset. In this report, we present a case of intraventricular glioblastoma multiforme with ipsilateral goose bumps and review the literature.

  16. Raman spectroscopy for diagnosis of glioblastoma multiforme

    NASA Astrophysics Data System (ADS)

    Clary, Candace Elise

    Glioblastoma multiforme (GBM), the most common and most fatal malignant brain tumor, is highly infiltrative and incurable. Although improved prognosis has been demonstrated by surgically resecting the bulk tumor, a lack of clear borders at the tumor margins complicates the selection decision during surgery. This dissertation investigates the potential of Raman spectroscopy for distinguishing between normal and malignant brain tissue and sets the groundwork for a surgical diagnostic guide for resection of gross malignant gliomas. These studies revealed that Raman spectroscopy was capable of discriminating between normal scid mouse brain tissue and human xenograft tumors induced in those mice. The spectra of normal and malignant tissue were normalized by dividing by the respective magnitudes of the peaks near 1440 cm -1. Spectral differences include the shape of the broad peaks near 1440 cm-1 and 1660 cm-1 and the relative magnitudes of the peaks at 1264 cm-1, 1287 cm-1, 1297 cm-1, 1556 cm -1, 1586 cm-1, 1614 cm-1, and 1683 cm-1. From these studies emerged questions regarding how to objectively normalize and compare spectra for future automation. Some differences in the Raman spectra were shown to be inherent in the disease states of the cells themselves via differences in the Raman spectra of normal human astrocytes in culture and cultured cells derived from GBM tumors. The spectra of astrocytes and glioma cells were normalized by dividing by the respective magnitudes of the peaks near 1450 cm-1. The differences between the Raman spectra of normal and transformed cells include the ratio of the 1450 cm-1/1650 cm-1 peaks and the relative magnitudes of the peaks at 1181 cm-1, 1191 cm-1, 1225 cm-1, 1263 cm -1, 1300 cm-1, 1336 cm-1, 1477 cm-1, 1494 cm-1, and 1695 cm -1. Previous Raman spectroscopic studies of biological cells have shown that the magnitude of the Raman signal decreases over time, indicating sample damage. Cells exposed to laser excitation at similar power

  17. c-MYC inhibition impairs hypoxia response in glioblastoma multiforme.

    PubMed

    Mongiardi, Maria Patrizia; Savino, Mauro; Falchetti, Maria Laura; Illi, Barbara; Bozzo, Francesca; Valle, Cristiana; Helmer-Citterich, Manuela; Ferrè, Fabrizio; Nasi, Sergio; Levi, Andrea

    2016-05-31

    The c-MYC oncoprotein is a DNA binding transcription factor that enhances the expression of many active genes. c-MYC transcriptional signatures vary according to the transcriptional program defined in each cell type during differentiation. Little is known on the involvement of c-MYC in regulation of gene expression programs that are induced by extracellular cues such as a changing microenvironment. Here we demonstrate that inhibition of c-MYC in glioblastoma multiforme cells blunts hypoxia-dependent glycolytic reprogramming and mitochondria fragmentation in hypoxia. This happens because c-MYC inhibition alters the cell transcriptional response to hypoxia and finely tunes the expression of a subset of Hypoxia Inducible Factor 1-regulated genes. We also show that genes whose expression in hypoxia is affected by c-MYC inhibition are able to distinguish the Proneural subtype of glioblastoma multiforme, thus potentially providing a molecular signature for this class of tumors that are the least tractable among glioblastomas. PMID:27119353

  18. Glioblastoma Multiforme: The Genetic Perspective of the Treatment Planning.

    PubMed

    Kalkan, Rasime

    2015-01-01

    Glioblastoma multiforme (GBM) is divided into two distinct disease entities called primary and secondary GBM. The genetic and the epigenetic background of these tumors are highly variable. These tumors are not successfully treated because of their cellular heterogeneity and intrinsic ability of the tumor cells to invade healthy tissues. The fatal outcomes of these tumors promote researchers to find new markers associated with prognosis and treatment planning. A better understanding of stem-like cells and the genetic and the epigenetic background of GBM are necessary for designing new effective treatments and developing novel molecular strategies to target tumor cells and glioblastoma stem cells. In this review, we discuss the new therapeutic targets. Focusing on inhibiting the signaling pathways, which are associated with hypoxia-mediated maintenance of glioblastoma stem cells or the knockdown of the hypoxia-inducible factor 1-alpha (HIF1α), may help to the develop new target-specific treatments.

  19. Glioblastoma multiforme in the Muir–Torre syndrome☆

    PubMed Central

    Binder, Zev A.; Johnson, Michael W.; Joshi, Avadhut; Hann, Christine L; Griffin, Constance A.; Olivi, Alessandro; Riggins, Gregory J.; Gallia, Gary L.

    2015-01-01

    Muir–Torre syndrome (MTS) is an autosomal dominant subtype of nonpolyposis colorectal carcinoma (HNPCC) characterized by the development of sebaceous gland tumors and visceral malignancies. The most common subtype of MTS is characterized by germline mutations in mismatch repair (MMR) genes leading to microsatellite instability (MSI). Central nervous system tumors have only rarely been associated with MTS. In this report, we describe the development of a glioblastoma multiforme (GBM) in a patient with MTS. Immunohistochemical analysis of the patient's colon carcinoma and his GBM both revealed loss of the mismatch repair proteins mutS homolog 2 (MSH2) and mutS homolog 6 (MSH6). PMID:21288634

  20. Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells.

    PubMed

    Choi, Jae Won; Schroeder, Mark A; Sarkaria, Jann N; Bram, Richard J

    2014-01-15

    Glioblastoma multiforme is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here, we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in glioblastoma multiforme cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human glioblastoma multiforme cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of glioblastoma multiforme cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-mitogen-activated protein kinase pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1, and Janus-activated kinase/STAT3 signaling. Elevated reactive oxygen species, ER expansion, and abnormal unfolded protein responses in CypB-depleted glioblastoma multiforme cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of glioblastoma multiforme tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for glioblastoma multiforme therapy. PMID:24272483

  1. Protocols for BNCT of glioblastoma multiforme at Brookhaven: Practical considerations

    SciTech Connect

    Chanana, A.D.; Coderre, J.A.; Joel, D.D.; Slatkin, D.N.

    1996-12-31

    In this report we discuss some issues considered in selecting initial protocols for boron neutron capture therapy (BNCT) of human glioblastoma multiforme. First the tolerance of normal tissues, especially the brain, to the radiation field. Radiation doses limits were based on results with human and animal exposures. Estimates of tumor control doses were based on the results of single-fraction photon therapy and single fraction BNCT both in humans and experimental animals. Of the two boron compounds (BSH and BPA), BPA was chosen since a FDA-sanctioned protocol for distribution in humans was in effect at the time the first BNCT protocols were written and therapy studies in experimental animals had shown it to be more effective than BSH.

  2. Nanotechnology to augment immunotherapy for the treatment of glioblastoma multiforme.

    PubMed

    Ung, Nolan; Yang, Isaac

    2015-07-01

    Glioblastoma multiforme (GBM) is characterized as one of the most common and most deadly malignant primary brain tumors. Current treatment modalities include the use of surgical resection and adjuvant chemotherapy and radiation therapy, though survival is still limited. Because of this, new treatment strategies are needed to improve overall survival. Immunotherapy has emerged as a potential treatment, but still possesses certain limitations to have a substantial clinical effect. In addition, nanotechnology has emerged as potent treatment effectors that have been shown to augment the effects of therapies including chemotherapy, gene therapy, and more. Nanoparticles possess a novel approach due to the myriad of functional groups that can create targeted treatments, though further optimization is still required. In this review, the authors will present the current uses and abilities of nanotechnology and its implication for use with immunotherapy in the treatment of GBM.

  3. Cystic glioblastoma multiforme masquerading as a cerebral tuberculoma

    PubMed Central

    Hasan, Mahboob; Siddiqui, Bushra; Qadri, Shagufta; Faridi, Shahbaz

    2014-01-01

    Glioblastoma multiforme (GBM) is by far the most common and most aggressive malignant neoplasm of the primary brain tumours. It arises from the astrocytes and classified as WHO grade 4 astrocytoma. Diagnosis of GBM is sometimes difficult as radiological picture sometimes mimic with cerebral tuberculoma. In both the cases contrast-enhanced CT may show similar finding of a mass lesion with a hypodense centre surrounded by a ring of enhancement and any cyst if present. In the present case, a 45-year-old male patient presented with seizures and headache, a provisional diagnosis of tuberculoma was made on the basis of clinical and CT findings. However, on grounds of suspicion the patient was operated and fluid from the cyst was sent peroperatively for cytopathological examination which suggested the diagnosis of cystic GBM. This helped the surgeon to do maximum debulking of the tumour. Diagnosis was further confirmed by histopathology. PMID:25326570

  4. Hypothesis: are neoplastic macrophages/microglia present in glioblastoma multiforme?

    PubMed Central

    Huysentruyt, Leanne C; Akgoc, Zeynep; Seyfried, Thomas N

    2011-01-01

    Most malignant brain tumours contain various numbers of cells with characteristics of activated or dysmorphic macrophages/microglia. These cells are generally considered part of the tumour stroma and are often described as TAM (tumour-associated macrophages). These types of cells are thought to either enhance or inhibit brain tumour progression. Recent evidence indicates that neoplastic cells with macrophage characteristics are found in numerous metastatic cancers of non-CNS (central nervous system) origin. Evidence is presented here suggesting that subpopulations of cells within human gliomas, specifically GBM (glioblastoma multiforme), are neoplastic macrophages/microglia. These cells are thought to arise following mitochondrial damage in fusion hybrids between neoplastic stem cells and macrophages/microglia. PMID:21834792

  5. Visualization of microvascularity in glioblastoma multiforme with 8-T high-spatial-resolution MR imaging.

    PubMed

    Christoforidis, Gregory A; Grecula, John C; Newton, Herbert B; Kangarlu, Allahyar; Abduljalil, Amir M; Schmalbrock, Petra; Chakeres, Donald W

    2002-10-01

    We used 8-T high-spatial-resolution gradient-echo MR imaging to directly visualize microvascularity in pathologically proved glioblastoma multiforme. Images were compared with 1.5-T high-spatial-resolution fast spin-echo T2-weighted images and digital subtraction angiograms. Preliminary data indicate that 8-T high-spatial-resolution MR imaging may enable the identification of areas of abnormal microvascularity in glioblastoma multiforme that are not visible with other routine clinical techniques.

  6. Computational Trials: Unraveling Motility Phenotypes, Progression Patterns, and Treatment Options for Glioblastoma Multiforme

    PubMed Central

    Raman, Fabio; Scribner, Elizabeth; Saut, Olivier; Wenger, Cornelia; Colin, Thierry; Fathallah-Shaykh, Hassan M.

    2016-01-01

    Glioblastoma multiforme is a malignant brain tumor with poor prognosis and high morbidity due to its invasiveness. Hypoxia-driven motility and concentration-driven motility are two mechanisms of glioblastoma multiforme invasion in the brain. The use of anti-angiogenic drugs has uncovered new progression patterns of glioblastoma multiforme associated with significant differences in overall survival. Here, we apply a mathematical model of glioblastoma multiforme growth and invasion in humans and design computational trials using agents that target angiogenesis, tumor replication rates, or motility. The findings link highly-dispersive, moderately-dispersive, and hypoxia-driven tumors to the patterns observed in glioblastoma multiforme treated by anti-angiogenesis, consisting of progression by Expanding FLAIR, Expanding FLAIR + Necrosis, and Expanding Necrosis, respectively. Furthermore, replication rate-reducing strategies (e.g. Tumor Treating Fields) appear to be effective in highly-dispersive and moderately-dispersive tumors but not in hypoxia-driven tumors. The latter may respond to motility-reducing agents. In a population computational trial, with all three phenotypes, a correlation was observed between the efficacy of the rate-reducing agent and the prolongation of overall survival times. This research highlights the potential applications of computational trials and supports new hypotheses on glioblastoma multiforme phenotypes and treatment options. PMID:26756205

  7. Hypothermia secondary to glioblastoma multiforme? Autopsy findings in two cases.

    PubMed

    Morgan, Matthew; Schwartz, Liliana; Duflou, Johan

    2015-03-01

    Death due to accidental primary hypothermia in cold climates is relatively common, with previous case series reflecting this. In contrast, hypothermia-related death as a result of an underlying medical cause, such as a brain tumor, is rare. The literature clearly illustrates a theoretical causal relationship between brain neoplasms and hypothermia through the infiltration of the hypothalamus; however, the number of reported cases is minimal. Two cases are presented where autopsy confirmed hypothermia as the cause of death with both cases revealing widespread glioblastoma multiforme in the brain. Both decedents were elderly with a number of comorbidities identified during autopsy that could explain death; however, hypothermia was deemed the most likely cause. It is proposed that both decedents died of hypothermia as a result of the tumor's effect on thermoregulation. These cases underline the importance of forensic pathologists to be aware of the relationship between brain tumors and hypothermia and to not dismiss death as being due to other disease processes. PMID:25644717

  8. Glioblastoma multiforme: emerging treatments and stratification markers beyond new drugs

    PubMed Central

    Seidlitz, A; Kitzler, H H; Beuthien-Baumann, B; Krause, M

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults. The standard therapy for GBM is maximal surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). In spite of the extensive treatment, the disease is associated with poor clinical outcome. Further intensification of the standard treatment is limited by the infiltrating growth of the GBM in normal brain areas, the expected neurological toxicities with radiation doses >60 Gy and the dose-limiting toxicities induced by systemic therapy. To improve the outcome of patients with GBM, alternative treatment modalities which add low or no additional toxicities to the standard treatment are needed. Many Phase II trials on new chemotherapeutics or targeted drugs have indicated potential efficacy but failed to improve the overall or progression-free survival in Phase III clinical trials. In this review, we will discuss contemporary issues related to recent technical developments and new metabolic strategies for patients with GBM including MR (spectroscopy) imaging, (amino acid) positron emission tomography (PET), amino acid PET, surgery, radiogenomics, particle therapy, radioimmunotherapy and diets. PMID:26159214

  9. p53 regulates the mevalonate pathway in human glioblastoma multiforme

    PubMed Central

    Laezza, C; D'Alessandro, A; Di Croce, L; Picardi, P; Ciaglia, E; Pisanti, S; Malfitano, A M; Comegna, M; Faraonio, R; Gazzerro, P; Bifulco, M

    2015-01-01

    The mevalonate (MVA) pathway is an important metabolic pathway implicated in multiple aspects of tumorigenesis. In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3′-hydroxy-3′-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs. Genetic and pharmacologic perturbation of p53 directly influences the expression of these genes. Furthermore, p53 is recruited to the gene promoters in designated p53-responsive elements, thereby increasing their transcription. Such effect was abolished by site-directed mutagenesis in the p53-responsive element of promoter of the genes. These findings highlight another aspect of p53 functions unrelated to tumor suppression and suggest p53 as a novel regulator of the MVA pathway providing insight into the role of this pathway in cancer progression. PMID:26469958

  10. Glioblastoma multiforme: emerging treatments and stratification markers beyond new drugs.

    PubMed

    von Neubeck, C; Seidlitz, A; Kitzler, H H; Beuthien-Baumann, B; Krause, M

    2015-09-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults. The standard therapy for GBM is maximal surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). In spite of the extensive treatment, the disease is associated with poor clinical outcome. Further intensification of the standard treatment is limited by the infiltrating growth of the GBM in normal brain areas, the expected neurological toxicities with radiation doses >60 Gy and the dose-limiting toxicities induced by systemic therapy. To improve the outcome of patients with GBM, alternative treatment modalities which add low or no additional toxicities to the standard treatment are needed. Many Phase II trials on new chemotherapeutics or targeted drugs have indicated potential efficacy but failed to improve the overall or progression-free survival in Phase III clinical trials. In this review, we will discuss contemporary issues related to recent technical developments and new metabolic strategies for patients with GBM including MR (spectroscopy) imaging, (amino acid) positron emission tomography (PET), amino acid PET, surgery, radiogenomics, particle therapy, radioimmunotherapy and diets. PMID:26159214

  11. Postoperative epilepsy in patients undergoing craniotomy for glioblastoma multiforme.

    PubMed

    Telfeian, A E; Philips, M F; Crino, P B; Judy, K D

    2001-03-01

    Glioblastoma multiforme (GBM) has associated with it one of the poorest prognoses among brain tumors. Postoperative seizures and the side effects of anticonvulsants, routinely given for prophylactic purposes, add to patient morbidity. The primary goal of this study was to determine who, of those undergoing craniotomy for GBM resection, is at risk for epilepsy. We studied 72 consecutive patients who underwent craniotomy and palliative resection for GBM. Twenty-nine presented with seizures and 17 had postoperative seizures. All patients were treated with a postoperative anticonvulsant for at least six months; anticonvulsants were continued longer if there was a postoperative seizure. Patient factors examined for an association with risk for postoperative seizure included age, sex, tumor size, tumor location, adjuvant therapy, postoperative complications and history of preoperative seizures. The majority of patients with no prior seizure history and who seized postoperatively had their first seizure after withdrawal from their anticonvulsant medication. All, but one, of the patients with both pre- and postoperative seizures had their first postoperative seizure while still on anticonvulsants. Smaller tumor size and frontal resection were associated with an increased risk of postoperative seizures. Our data suggests that those who do not present with seizures and undergo GBM resection may still be prone to seize but more easily protected from postoperative seizures with anticonvulsant therapy than patients who present with seizures; resection of frontal tumors and smaller tumors seemed to indicate an increased risk for postoperative seizures. PMID:11370829

  12. Voltage-Gated Proton Channel in Human Glioblastoma Multiforme Cells.

    PubMed

    Ribeiro-Silva, Luisa; Queiroz, Fernanda Oliveira; da Silva, Annielle Mendes Brito; Hirata, Aparecida Emiko; Arcisio-Miranda, Manoel

    2016-07-20

    Solid tumors tend to have a more glycolytic metabolism leading to an accumulation of acidic metabolites in their cytosol, and consequently, their intracellular pH (pHi) turns critically lower if the cells do not handle the acid excess. Recently, it was proposed that the voltage gated proton channels (HV1) can regulate the pHi in several cancers. Here we report the functional expression of voltage gated proton channels in a human glioblastoma multiforme (GBM) cell line, the most common and lethal brain tumor. T98G cells presented an outward, slow activating voltage-dependent proton current, which was also ΔpH-dependent and inhibited by ZnCl2, characterizing it as being conducted by HV1 channels. Furthermore, blocking HV1 channels with ZnCl2 significantly reduced the pHi, cell survival, and migration, indicating an important role for HV1 for tumor proliferation and progression in GBM. Overall, our results suggest that HV1 channels can be a new therapeutic target for GBM. PMID:27225904

  13. The role of metabolic therapy in treating glioblastoma multiforme

    PubMed Central

    Maroon, Joseph C.; Seyfried, Thomas N.; Donohue, Joseph P.; Bost, Jeffrey

    2015-01-01

    Glioblastoma multiforme (GBM) is an aggressive and nearly uniformly fatal malignancy of the central nervous system. Despite extensive research and clinical trials over the past 50 years, very little progress has been made to significantly alter its lethal prognosis. The current standard of care (SOC) includes maximal surgical resection, radiation therapy and chemotherapy and temozolomide (TMZ), including the selective use of glucocorticoids for symptom control. These same treatments, however, have the potential to create an environment that may actually facilitate tumor growth and survival. Research investigating the unique metabolic needs of tumor cells has led to the proposal of a new metabolic treatment for various cancers including GBMs that may enhance the effectiveness of the SOC. The goal of metabolic cancer therapy is to restrict GBM cells of glucose, their main energy substrate. By recognizing the underlying energy production requirements of cancer cells, newly proposed metabolic therapy is being used as an adjunct to standard GBM therapies. This review will discuss the calorie restricted ketogenic diet (CR-KD) as a promising potential adjunctive metabolic therapy for patients with GBMs. The effectiveness of the CR-KD is based on the “Warburg Effect” of cancer metabolism and the microenvironment of GBM tumors. We will review recent case reports, clinical studies, review articles, and animal model research using the CR-KD and explain the principles of the Warburg Effect as it relates to CR-KD and GBMs. PMID:25949849

  14. Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma.

    PubMed

    Solomon, David A; Kim, Jung-Sik; Cronin, Julia C; Sibenaller, Zita; Ryken, Timothy; Rosenberg, Steven A; Ressom, Habtom; Jean, Walter; Bigner, Darell; Yan, Hai; Samuels, Yardena; Waldman, Todd

    2008-12-15

    An additional tumor suppressor gene on chromosome 9p telomeric to the CDKN2A/B locus has long been postulated to exist. Using Affymetrix 250K single nucleotide polymorphism arrays to screen for copy number changes in glioblastoma multiforme (GBM), we detected a high frequency of deletions of the PTPRD gene, which encodes a receptor protein tyrosine phosphatase at chromosome 9p23-24.1. Missense and nonsense mutations of PTPRD were identified in a subset of the samples lacking deletions, including an inherited mutation with somatic loss of the wild-type allele. We then sequenced the gene in melanoma and identified 10 somatic mutations in 7 of 57 tumors (12%). Reconstitution of PTPRD expression in GBM and melanoma cells harboring deletions or mutations led to growth suppression and apoptosis that was alleviated by both the somatic and constitutional mutations. These data implicate PTPRD in the pathogenesis of tumors of neuroectodermal origin and, when taken together with other recent reports of PTPRD mutations in adenocarcinoma of the colon and lung, suggest that PTPRD may be one of a select group of tumor suppressor genes that are inactivated in a wide range of common human tumor types.

  15. Socio-economic characteristics of patients with glioblastoma multiforme.

    PubMed

    Muquit, Samiul; Parks, Ruth; Basu, Surajit

    2015-11-01

    The incidence of glioblastoma multiforme (GBM) varies across the world and also within subpopulations within each nation. Many cancers show correlation with socioeconomic status and we hypothesised that incidence of GBM also does the same. We performed a retrospective analysis of all patients treated with brain tumours at a single hospital over a 6-year period. For these patients we examined markers of socioeconomic status and reviewed their histopathological diagnosis. A total of 2859 patients had surgery between April 2006 and April 2012. Of these 880 had histological diagnosis of GBM. Records for all patients were reviewed. Based on postcodes, socioeconomic data was obtained at ward level from government sources. Markers were: average weekly household income, percentage unemployed, population density, indices of deprivation and percentage of households with no car. Data was analysed for trends between incidence per ward and socio-economic markers. Increasing incidence of GBM was associated with increasing wage (p = 0.044), less unemployment (p = 0.0002), Indices of Multiple Deprivation (p = 0.05), lower population density (p = 0.0015) and greater ownership of cars (p = 0.0005). There are unique socioeconomic characteristics for patients with GBM. Although a link to aetiology cannot be established from this limited epidemiological study, these results identify issues that these patients are more likely to face. These should be taken into account when planning support services and patient care following surgery. PMID:26334316

  16. Third Ventricular Glioblastoma Multiforme: Case Report and Literature Review

    PubMed Central

    Hariri, Omid R.; Quadri, Syed A.; Farr, Saman; Gupta, Ravi; Bieber, Andrew J.; Dyurgerova, Anya; Corsino, Casey; Miulli, Dan; Siddiqi, Javed

    2015-01-01

    Background Glioblastoma multiforme (GBM) typically presents in the supratentorial white matter, commonly within the centrum semiovale as a ring-enhancing lesion with areas of necrosis. An atypical presentation of this lesion, both anatomically as well as radiographically, is significant and must be part of the differential for a neoplasm in this anatomical location. Case Description We present a case of a 62-year-old woman with headaches, increasing somnolence, and cognitive decline for several weeks. Magnetic resonance imaging demonstrated mild left ventricular dilatation with a well-marginated, homogeneous, and nonhemorrhagic lesion located at the ceiling of the third ventricle within the junction of the septum pellucidum and fornix, without exhibiting the typical radiographic features of hemorrhage or necrosis. Final pathology reports confirmed the diagnosis of GBM. Conclusion This case report describes an unusual location for the most common primary brain neoplasm. Moreover, this case identifies the origin of a GBM related to the paracentral ventricular structures infiltrating the body of the fornix and leaves of the septum pellucidum. To our knowledge this report is the first reported case of a GBM found in this anatomical location with an entirely atypical radiographic presentation. PMID:26623232

  17. The role of metabolic therapy in treating glioblastoma multiforme.

    PubMed

    Maroon, Joseph C; Seyfried, Thomas N; Donohue, Joseph P; Bost, Jeffrey

    2015-01-01

    Glioblastoma multiforme (GBM) is an aggressive and nearly uniformly fatal malignancy of the central nervous system. Despite extensive research and clinical trials over the past 50 years, very little progress has been made to significantly alter its lethal prognosis. The current standard of care (SOC) includes maximal surgical resection, radiation therapy and chemotherapy and temozolomide (TMZ), including the selective use of glucocorticoids for symptom control. These same treatments, however, have the potential to create an environment that may actually facilitate tumor growth and survival. Research investigating the unique metabolic needs of tumor cells has led to the proposal of a new metabolic treatment for various cancers including GBMs that may enhance the effectiveness of the SOC. The goal of metabolic cancer therapy is to restrict GBM cells of glucose, their main energy substrate. By recognizing the underlying energy production requirements of cancer cells, newly proposed metabolic therapy is being used as an adjunct to standard GBM therapies. This review will discuss the calorie restricted ketogenic diet (CR-KD) as a promising potential adjunctive metabolic therapy for patients with GBMs. The effectiveness of the CR-KD is based on the "Warburg Effect" of cancer metabolism and the microenvironment of GBM tumors. We will review recent case reports, clinical studies, review articles, and animal model research using the CR-KD and explain the principles of the Warburg Effect as it relates to CR-KD and GBMs. PMID:25949849

  18. The role of octamer binding transcription factors in glioblastoma multiforme.

    PubMed

    Rooj, A K; Bronisz, A; Godlewski, J

    2016-06-01

    A group of transcription factors (TF) that are master developmental regulators of the establishment and maintenance of pluripotency during embryogenesis play additional roles to control tissue homeostasis and regeneration in adults. Among these TFs, members of the octamer-binding transcription factor (OCT) gene family are well documented as major regulators controlling the self-renewal and pluripotency of stem cells isolated from different adult organs including the brain. In the last few years a large number of studies show the aberrant expression and dysfunction of OCT in different types of cancers including glioblastoma multiforme (GBM). GBM is the most common malignant primary brain tumor, and contains a subpopulation of undifferentiated stem cells (GSCs), with self-renewal and tumorigenic potential that contribute to tumor initiation, invasion, recurrence, and therapeutic resistance. In this review, we have summarized the current knowledge about OCT family in GBM and their crucial role in the initiation, maintenance and drug resistance properties of GSCs. This article is part of a Special Issue entitled: The Oct Transcription Factor Family, edited by Dr. Dean Tantin. PMID:26968235

  19. Understanding cytoskeleton regulators in glioblastoma multiforme for therapy design

    PubMed Central

    Masoumi, Samaneh; Harisankar, Aditya; Gracias, Aileen; Bachinger, Fabian; Fufa, Temesgen; Chandrasekar, Gayathri; Gaunitz, Frank; Walfridsson, Julian; Kitambi, Satish S

    2016-01-01

    The cellular cytoskeleton forms the primary basis through which a cell governs the changes in size, shape, migration, proliferation, and forms the primary means through which the cells respond to their environment. Indeed, cell and tissue morphologies are used routinely not only to grade tumors but also in various high-content screening methods with an aim to identify new small molecules with therapeutic potential. This study examines the expression of various cytoskeleton regulators in glioblastoma multiforme (GBM). GBM is a very aggressive disease with a low life expectancy even after chemo- and radiotherapy. Cancer cells of GBM are notorious for their invasiveness, ability to develop resistance to chemo- and radiotherapy, and to form secondary site tumors. This study aims to gain insight into cytoskeleton regulators in GBM cells and to understand the effect of various oncology drugs, including temozolomide, on cytoskeleton regulators. We compare the expression of various cytoskeleton regulators in GBM-derived tumor and normal tissue, CD133-postive and -negative cells from GBM and neural cells, and GBM stem-like and differentiated cells. In addition, the correlation between the expression of cytoskeleton regulators with the clinical outcome was examined to identify genes associated with longer patient survival. This was followed by a small molecule screening with US Food and Drug Administration (FDA)-approved oncology drugs, and its effect on cellular cytoskeleton was compared to treatment with temozolomide. This study identifies various groups of cytoskeletal regulators that have an important effect on patient survival and tumor development. Importantly, this work highlights the advantage of using cytoskeleton regulators as biomarkers for assessing prognosis and treatment design for GBM.

  20. Genome-Wide Methylation Analyses in Glioblastoma Multiforme

    PubMed Central

    Lai, Rose K.; Chen, Yanwen; Guan, Xiaowei; Nousome, Darryl; Sharma, Charu; Canoll, Peter; Bruce, Jeffrey; Sloan, Andrew E.; Cortes, Etty; Vonsattel, Jean-Paul; Su, Tao; Delgado-Cruzata, Lissette; Gurvich, Irina; Santella, Regina M.; Ostrom, Quinn; Lee, Annette; Gregersen, Peter; Barnholtz-Sloan, Jill

    2014-01-01

    Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1), 5 methyl-deoxycytidine (5m-dC) and 5 hydroxylmethyl-deoxycytidine (5hm-dC) in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes) that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal. PMID:24586730

  1. Understanding cytoskeleton regulators in glioblastoma multiforme for therapy design

    PubMed Central

    Masoumi, Samaneh; Harisankar, Aditya; Gracias, Aileen; Bachinger, Fabian; Fufa, Temesgen; Chandrasekar, Gayathri; Gaunitz, Frank; Walfridsson, Julian; Kitambi, Satish S

    2016-01-01

    The cellular cytoskeleton forms the primary basis through which a cell governs the changes in size, shape, migration, proliferation, and forms the primary means through which the cells respond to their environment. Indeed, cell and tissue morphologies are used routinely not only to grade tumors but also in various high-content screening methods with an aim to identify new small molecules with therapeutic potential. This study examines the expression of various cytoskeleton regulators in glioblastoma multiforme (GBM). GBM is a very aggressive disease with a low life expectancy even after chemo- and radiotherapy. Cancer cells of GBM are notorious for their invasiveness, ability to develop resistance to chemo- and radiotherapy, and to form secondary site tumors. This study aims to gain insight into cytoskeleton regulators in GBM cells and to understand the effect of various oncology drugs, including temozolomide, on cytoskeleton regulators. We compare the expression of various cytoskeleton regulators in GBM-derived tumor and normal tissue, CD133-postive and -negative cells from GBM and neural cells, and GBM stem-like and differentiated cells. In addition, the correlation between the expression of cytoskeleton regulators with the clinical outcome was examined to identify genes associated with longer patient survival. This was followed by a small molecule screening with US Food and Drug Administration (FDA)-approved oncology drugs, and its effect on cellular cytoskeleton was compared to treatment with temozolomide. This study identifies various groups of cytoskeletal regulators that have an important effect on patient survival and tumor development. Importantly, this work highlights the advantage of using cytoskeleton regulators as biomarkers for assessing prognosis and treatment design for GBM. PMID:27672311

  2. β-Elemene enhances the efficacy of gefitinib on glioblastoma multiforme cells through the inhibition of the EGFR signaling pathway.

    PubMed

    Mu, Lin; Wang, Tianjiao; Chen, Yanwei; Tang, Xinqiang; Yuan, Yuhui; Zhao, Yongshun

    2016-10-01

    Glioblastoma multiforme (GBM) is the most common and severe form of primary tumor in the central nervous system of adults which has poor prognosis and limited therapeutic options. Epidermal growth factor receptor (EGFR) inhibitor, such as gefitinib (brand name Iressa, ZD1839), has been approved as a targeted medicine for several types of tumor including glioblastoma multiforme. However, gefitinib exerted very limited effects on some glioblastoma multiforme patients after a period of treatment due to intrinsic and acquired drug resistance. β-Elemene, a natural plant drug extracted from Curcuma wenyujin, has shown promising anticancer effects against a broad spectrum of tumors. In the present study, we found that β-elemene could enhance the chemosensitivity of glioblastoma multiforme cells to gefitinib. The combination medication of β-elemene and gefitinib not only inhibited the survival and proliferation of glioblastoma multiforme cells via inhibition of EGFR signaling pathway but also induced more distinct apoptosis and autophagy in the glioblastoma multiforme cells than the gefitinib monotherapy. These results showed that β-elemene might be one potential adjuvant to enhance the effect of EGFR inhibitor and reduce the resistance of gefitinib in glioblastoma multiforme. PMID:27498706

  3. Uptake of the BPA into glioblastoma multiforme correlates with tumor cellularity

    SciTech Connect

    Joel, D.D.; Chanana, A.D.; Coderre, J.A.

    1996-12-31

    Fourteen patients scheduled to undergo craniotomy for glioblastoma multiforme were infused with p-boronophenylalanine fructose intravenously for 2 hours prior to surgery. Tissues removed during the procedure and blood obtained at its conclusion were analyzed for boron by direct current plasma-atomic emission spectroscopy. The results are presented herein.

  4. A Phase 1 trial of intravenous boronophenylalanine-fructose complex in patients with glioblastoma multiforme

    SciTech Connect

    Bergland, R.; Elowitz, E.; Chadha, M.; Coderre, J.A.; Joel, D.

    1996-10-01

    Boron neutron capture therapy (BNCT) of glioblastoma multiforme was initially performed at the Brookhaven National Laboratory in the early 1950`s While this treatment for malignant brain tumors has continued in Japan, new worldwide interest has been stimulated by the development of new and more selective boron compounds. Boronophenylalanine (BPA) is a blood-brain barrier penetrating compound that has been used in BNCT of malignant melanomas. SPA has been employed experimentally in BNCT of rat gliosarcoma and has potential use in the treatment of human glioblastoma. As a preface to clinical BNCT trials, we studied the biodistribution of SPA in patients with glioblastoma.

  5. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

    SciTech Connect

    Parra, N. Andres; Maudsley, Andrew A.; Gupta, Rakesh K.; Ishkanian, Fazilat; Huang, Kris; Walker, Gail R.; Padgett, Kyle; Roy, Bhaswati; Panoff, Joseph; Markoe, Arnold; Stoyanova, Radka

    2014-10-01

    Purpose: Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials: Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV{sub 46} and CTV{sub 60}, respectively). MTV{sub Cho} and MTV{sub NAA} were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results: The MRSI coverage of the brain was between 70% and 76%. The MTV{sub NAA} were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTV{sub Cho} was outside of the edema (median, 33%) and for some patients it was also outside of the CTV{sub 46} and CTV{sub 60}. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTV{sub Cho} for these patients were outside of CTV{sub 60}. Conclusions: This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on

  6. Gliosarcoma: A rare variant of glioblastoma multiforme in paediatric patient: Case report and review of literature

    PubMed Central

    Meena, Ugan Singh; Sharma, Sumit; Chopra, Sanjeev; Jain, Shashi Kant

    2016-01-01

    Gliosarcoma is rare central nervous system tumour and a variant of glioblastoma multiforme with bimorphic histological pattern of glial and sarcomatous differentiation. It occurs in elderly between 5th and 6th decades of life and extremely rare in children. It is highly aggressive tumour and managed like glioblastoma multiforme. A 12-year-old female child presented with complaints of headache and vomiting from 15 d and blurring of vision from 3 d. Magnetic resonance imaging of brain shows heterogeneous mass in right parieto-occipital cortex. A right parieto-occipito-temporal craniotomy with complete excision of mass revealed a primary glioblastoma on histopathological investigation. Treatment consists of maximum surgical excision followed by adjuvant radiotherapy. The etiopathogenesis, treatment modalities and prognosis is discussed. The available literature is also reviewed.

  7. Gliosarcoma: A rare variant of glioblastoma multiforme in paediatric patient: Case report and review of literature

    PubMed Central

    Meena, Ugan Singh; Sharma, Sumit; Chopra, Sanjeev; Jain, Shashi Kant

    2016-01-01

    Gliosarcoma is rare central nervous system tumour and a variant of glioblastoma multiforme with bimorphic histological pattern of glial and sarcomatous differentiation. It occurs in elderly between 5th and 6th decades of life and extremely rare in children. It is highly aggressive tumour and managed like glioblastoma multiforme. A 12-year-old female child presented with complaints of headache and vomiting from 15 d and blurring of vision from 3 d. Magnetic resonance imaging of brain shows heterogeneous mass in right parieto-occipital cortex. A right parieto-occipito-temporal craniotomy with complete excision of mass revealed a primary glioblastoma on histopathological investigation. Treatment consists of maximum surgical excision followed by adjuvant radiotherapy. The etiopathogenesis, treatment modalities and prognosis is discussed. The available literature is also reviewed. PMID:27672648

  8. Gliosarcoma: A rare variant of glioblastoma multiforme in paediatric patient: Case report and review of literature.

    PubMed

    Meena, Ugan Singh; Sharma, Sumit; Chopra, Sanjeev; Jain, Shashi Kant

    2016-09-16

    Gliosarcoma is rare central nervous system tumour and a variant of glioblastoma multiforme with bimorphic histological pattern of glial and sarcomatous differentiation. It occurs in elderly between 5(th) and 6(th) decades of life and extremely rare in children. It is highly aggressive tumour and managed like glioblastoma multiforme. A 12-year-old female child presented with complaints of headache and vomiting from 15 d and blurring of vision from 3 d. Magnetic resonance imaging of brain shows heterogeneous mass in right parieto-occipital cortex. A right parieto-occipito-temporal craniotomy with complete excision of mass revealed a primary glioblastoma on histopathological investigation. Treatment consists of maximum surgical excision followed by adjuvant radiotherapy. The etiopathogenesis, treatment modalities and prognosis is discussed. The available literature is also reviewed. PMID:27672648

  9. Gene expressions of TRP channels in glioblastoma multiforme and relation with survival.

    PubMed

    Alptekin, M; Eroglu, S; Tutar, E; Sencan, S; Geyik, M A; Ulasli, M; Demiryurek, A T; Camci, C

    2015-12-01

    Glioblastoma multiforme (GBM) is one of the most lethal forms of cancer in humans, with a median survival of 10 to 12 months. Glioblastoma is highly malignant since the cells are supported by a great number of blood vessels. Although new treatments have been developed by increasing knowledge of molecular nature of the disease, surgical operation remains the standard of care. The TRP (transient receptor potential) superfamily consists of cation-selective channels that have roles in sensory physiology such as thermo- and osmosensation and in several complex diseases such as cancer, cardiovascular, and neuronal diseases. The aim of this study was to investigate the expression levels of TRP channel genes in patients with glioblastoma multiforme and to evaluate the relationship between TRP gene expressions and survival of the patients. Thirty-three patients diagnosed with glioblastoma were enrolled to the study. The expression levels of 21 TRP genes were quantified by using qRT-PCR with dynamic array 48 × 48 chip (BioMark HD System, Fluidigm, South San Francisco, CA, USA). TRPC1, TRPC6, TRPM2, TRPM3, TRPM7, TRPM8, TRPV1, and TRPV2 were found significantly higher in glioblastoma patients. Moreover, there was a significant relationship between the overexpression of TRP genes and the survival of the patients. These results demonstrate for the first time that TRP channels contribute to the progression and survival of the glioblastoma patients. PMID:26088448

  10. Function of carbonic anhydrase IX in glioblastoma multiforme.

    PubMed

    Proescholdt, Martin A; Merrill, Marsha J; Stoerr, Eva-Maria; Lohmeier, Annette; Pohl, Fabian; Brawanski, Alexander

    2012-11-01

    Carbonic anhydrase (CA) IX is over-expressed in glioblastoma; however, its functions in this context are unknown. Metabolically, glioblastomas are highly glycolytic, leading to a significant lactic acid load. Paradoxically, the intracellular pH is alkaline. We hypothesized that CAIX contributes to the extrusion of hydrogen ions into the extracellular space, thereby moderating intra- and extracellular pH and creating an environment conductive to enhanced invasion. We investigated the role of CAIX as a prognostic marker in patients with glioblastoma and its biological function in vitro. CAIX expression was analyzed in 59 patients with glioblastoma by immunohistochemistry. The expression levels were correlated to overall survival. In vitro, U251 and Ln 18 glioblastoma cells were incubated under hypoxia to induce CAIX expression, and RNA interference (RNAi) was used to examine the function of CAIX on cell attachment, invasion, intracellular energy transfer, and susceptibility to adjuvant treatment. High CAIX expression was identified as an independent factor for poor survival in patients with glioblastoma. In vitro, cell attachment and invasion were strongly reduced after knockdown of CAIX. Finally, the effects of radiation and chemotherapy were strongly augmented after CAIX interference and were accompanied by a higher rate of apoptotic cell death. CAIX is an independent prognostic factor for poor outcome in patients with glioblastoma. Cell attachment, invasion, and survival during adjuvant treatment are significantly influenced by high CAIX expression. These results indicate that inhibition of CAIX is a potential metabolic target for the treatment of patients with glioblastoma. PMID:23074198

  11. Canadian recommendations for the treatment of glioblastoma multiforme.

    PubMed

    Mason, W P; Maestro, R Del; Eisenstat, D; Forsyth, P; Fulton, D; Laperrière, N; Macdonald, D; Perry, J; Thiessen, B

    2007-06-01

    RECOMMENDATION 1: Management of patients with glioblastoma multiforme (GBM) should be highly individualized and should take a multidisciplinary approach involving neuro-oncology, neurosurgery, radiation oncology, and pathology, to optimize treatment outcomes. Patients and caregivers should be kept informed of the progress of treatment at every stage. RECOMMENDATION 2: Sufficient tissue should be obtained during surgery for cytogenetic analysis and, whenever feasible, for tumour banking. RECOMMENDATION 3: Surgery is an integral part of the treatment plan, to establish a histopathologic diagnosis and to achieve safe, maximal, and feasible tumour resection, which may improve clinical signs and symptoms. RECOMMENDATION 4: The preoperative imaging modality of choice is magnetic resonance imaging (MRI) with gadolinium as the contrast agent. Other imaging modalities, such as positron emission tomography with [(18)F]-fluoro-deoxy-d-glucose, may also be considered in selected cases. Postoperative imaging (mri or computed tomography) is recommended within 72 hours of surgery to evaluate the extent of resection. RECOMMENDATION 5: Postoperative external-beam radiotherapy is recommended as standard therapy for patients with gbm. The recommended dose is 60 Gy in 2-Gy fractions. The recommended clinical target volume should be identified with gadolinium-enhanced T1-weighted mri, with a margin in the order of 2-3 cm. Target volumes should be determined based on a postsurgical planning MRI. A shorter course of radiation may be considered for older patients with poor performance status. RECOMMENDATION 6: During RT, temozolomide 75 mg/m(2) should be administered concurrently for the full duration of radio-therapy, typically 42 days. Temozolomide should be given approximately 1 hour before radiation therapy, and at the same time on the days that no radiotherapy is scheduled. RECOMMENDATION 7: Adjuvant temozolomide 150 mg/m(2), in a 5/28-day schedule, is recommended for cycle 1

  12. Large-scale data integration framework provides a comprehensive view on glioblastoma multiforme

    PubMed Central

    2010-01-01

    Background Coordinated efforts to collect large-scale data sets provide a basis for systems level understanding of complex diseases. In order to translate these fragmented and heterogeneous data sets into knowledge and medical benefits, advanced computational methods for data analysis, integration and visualization are needed. Methods We introduce a novel data integration framework, Anduril, for translating fragmented large-scale data into testable predictions. The Anduril framework allows rapid integration of heterogeneous data with state-of-the-art computational methods and existing knowledge in bio-databases. Anduril automatically generates thorough summary reports and a website that shows the most relevant features of each gene at a glance, allows sorting of data based on different parameters, and provides direct links to more detailed data on genes, transcripts or genomic regions. Anduril is open-source; all methods and documentation are freely available. Results We have integrated multidimensional molecular and clinical data from 338 subjects having glioblastoma multiforme, one of the deadliest and most poorly understood cancers, using Anduril. The central objective of our approach is to identify genetic loci and genes that have significant survival effect. Our results suggest several novel genetic alterations linked to glioblastoma multiforme progression and, more specifically, reveal Moesin as a novel glioblastoma multiforme-associated gene that has a strong survival effect and whose depletion in vitro significantly inhibited cell proliferation. All analysis results are available as a comprehensive website. Conclusions Our results demonstrate that integrated analysis and visualization of multidimensional and heterogeneous data by Anduril enables drawing conclusions on functional consequences of large-scale molecular data. Many of the identified genetic loci and genes having significant survival effect have not been reported earlier in the context of

  13. Intermediate-term outcome in lung transplantation from a donor with glioblastoma multiforme.

    PubMed

    Chen, Fengshi; Karolak, Wojtek; Cypel, Marcelo; Keshavjee, Shaf; Pierre, Andrew

    2009-10-01

    A 19-year-old man with cystic fibrosis, who was on extracorporeal membrane oxygenation, underwent bilateral lung transplantation from a donor with glioblastoma multiforme. Because the risk of tumor transmission from donor-related central nervous system malignancies remains unclear, the use of these extended donors remains controversial. In fact, there are few reports on the outcomes of lung transplantation from donors with central nervous system malignancy. This patient was critically ill with extracorporeal membrane oxygenation support before transplantation, but is well without any sign of malignancy 20 months after transplantation. PMID:19782299

  14. Analysis of Electronic Densities and Integrated Doses in Multiform Glioblastomas Stereotactic Radiotherapy

    SciTech Connect

    Baron-Aznar, C.; Moreno-Jimenez, S.; Celis, M. A.; Ballesteros-Zebadua, P.; Larraga-Gutierrez, J. M.

    2008-08-11

    Integrated dose is the total energy delivered in a radiotherapy target. This physical parameter could be a predictor for complications such as brain edema and radionecrosis after stereotactic radiotherapy treatments for brain tumors. Integrated Dose depends on the tissue density and volume. Using CT patients images from the National Institute of Neurology and Neurosurgery and BrainScan(c) software, this work presents the mean density of 21 multiform glioblastomas, comparative results for normal tissue and estimated integrated dose for each case. The relationship between integrated dose and the probability of complications is discussed.

  15. Apoptosis-inducing effects of Melissa officinalis L. essential oil in glioblastoma multiforme cells.

    PubMed

    Queiroz, Rafaela Muniz de; Takiya, Christina Maeda; Guimarães, Lívia Paes Tavares Pacheco; Rocha, Gleice da Graça; Alviano, Daniela Sales; Blank, Arie Fitzgerald; Alviano, Celuta Sales; Gattass, Cerli Rocha

    2014-07-01

    Current therapies for glioblastoma multiforme (GBM) are not effective. This study investigated the activity of the M. officinalis essential oil (EO) and its major component (citral) in GBM cell lines. Both EO and citral decreased the viability and induced apoptosis of GBM cells as demonstrated by DNA fragmentation and caspase-3 activation. Antioxidant prevented citral-induced death, indicating its dependence on the production of reactive oxygen species. Citral downmodulated the activity and inhibited the expression of multidrug resistance associated protein 1 (MRP1). These results show that EO, through its major component, citral, may be of potential interest for the treatment of GBM.

  16. Analysis of Electronic Densities and Integrated Doses in Multiform Glioblastomas Stereotactic Radiotherapy

    NASA Astrophysics Data System (ADS)

    Barón-Aznar, C.; Moreno-Jiménez, S.; Celis, M. A.; Lárraga-Gutiérrez, J. M.; Ballesteros-Zebadúa, P.

    2008-08-01

    Integrated dose is the total energy delivered in a radiotherapy target. This physical parameter could be a predictor for complications such as brain edema and radionecrosis after stereotactic radiotherapy treatments for brain tumors. Integrated Dose depends on the tissue density and volume. Using CT patients images from the National Institute of Neurology and Neurosurgery and BrainScansoftware, this work presents the mean density of 21 multiform glioblastomas, comparative results for normal tissue and estimated integrated dose for each case. The relationship between integrated dose and the probability of complications is discussed.

  17. [Glioblastoma multiforme with intra- and extramedullary dissemination to the spinal cord].

    PubMed

    Hansson, Karin; Gutte, Henrik; Idris, Fadi

    2013-04-15

    Metastases to the spinal cord from glioblastoma multiforme (GBM) are uncommon, but important to have in mind when patients with a history of GBM present with symptoms that do not correlate with the primary disease pattern. We report a rare case, where a male with GBM, six months after tumour excision followed by concomitant radio- and chemotherapy, presented with gait disturbance and unspecific neurological symptoms of the lower right limb. Magnetic resonance imaging of columna totalis revealed both intra- and extramedullary metastases in the spinal cord. The patient died one month later.

  18. Magnetic Resonance-Guided Laser Induced Thermal Therapy for Glioblastoma Multiforme: A Review

    PubMed Central

    Norred, Sarah E.; Johnson, Jacqueline Anne

    2014-01-01

    Magnetic resonance-guided laser induced thermotherapy (MRgLITT) has become an increasingly relevant therapy for tumor ablation due to its minimally invasive approach and broad applicability across many tissue types. The current state of the art applies laser irradiation via cooled optical fiber applicators in order to generate ablative heat and necrosis in tumor tissue. Magnetic resonance temperature imaging (MRTI) is used concurrently with this therapy to plan treatments and visualize tumor necrosis. Though application in neurosurgery remains in its infancy, MRgLITT has been found to be a promising therapy for many types of brain tumors. This review examines the current use of MRgLITT with regard to the special clinical challenge of glioblastoma multiforme and examines the potential applications of next-generation nanotherapy specific to the treatment of glioblastoma. PMID:24527455

  19. The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence.

    PubMed

    Auffinger, Brenda; Spencer, Drew; Pytel, Peter; Ahmed, Atique U; Lesniak, Maciej S

    2015-01-01

    Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific glioblastoma multiforme (GBM) subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major factor contributing to the inevitable recurrence in GBM patients after treatment. Here, we discuss the molecular mechanisms of chemoresistance of GSCs and the reasons why complete eradication of GSCs is so difficult to achieve. We will also describe the targeted therapies currently available for GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse.

  20. Glioblastoma multiforme of the brain stem in a patient with acquired immunodeficiency syndrome.

    PubMed

    Wolff, R; Zimmermann, M; Marquardt, Gerhard; Lanfermann, H; Nafe, R; Seifert, V

    2002-09-01

    Glioblastoma of the brain stem is rare and there is no description of such a lesion in patients suffering from acquired immunodeficiency syndrome. The majority of intracerebral mass lesions are due either to toxoplasmosis or primary central nervous system lymphomas so that it is usually not included in the differential diagnosis of enhancing lesions of the central nervous system in these patients. A 31-year-old human immunodeficiency virus (HIV) infected man presented with a four months history of slowly progressive deterioration of brainstem associated symptoms despite antitoxoplasmic therapy. Magnetic resonance imaging revealed a large ring enhancing lesion in the brainstem. Clinical and neuroradiological data could not establish a proper diagnosis and a stereotactic serial biopsy was undertaken. Histological examination of the specimen showed a glioblastoma multiforme (GBM) as the first reported case of GBM located in the brainstem in an acquired immunodeficiency syndrome (AIDS) patient. Patient management and effectiveness of stereotactic serial biopsy are discussed.

  1. Effects of Flavonoids from Food and Dietary Supplements on Glial and Glioblastoma Multiforme Cells.

    PubMed

    Vidak, Marko; Rozman, Damjana; Komel, Radovan

    2015-10-23

    Quercetin, catechins and proanthocyanidins are flavonoids that are prominently featured in foodstuffs and dietary supplements, and may possess anti-carcinogenic activity. Glioblastoma multiforme is the most dangerous form of glioma, a malignancy of the brain connective tissue. This review assesses molecular structures of these flavonoids, their importance as components of diet and dietary supplements, their bioavailability and ability to cross the blood-brain barrier, their reported beneficial health effects, and their effects on non-malignant glial as well as glioblastoma tumor cells. The reviewed flavonoids appear to protect glial cells via reduction of oxidative stress, while some also attenuate glutamate-induced excitotoxicity and reduce neuroinflammation. Most of the reviewed flavonoids inhibit proliferation of glioblastoma cells and induce their death. Moreover, some of them inhibit pro-oncogene signaling pathways and intensify the effect of conventional anti-cancer therapies. However, most of these anti-glioblastoma effects have only been observed in vitro or in animal models. Due to limited ability of the reviewed flavonoids to access the brain, their normal dietary intake is likely insufficient to produce significant anti-cancer effects in this organ, and supplementation is needed.

  2. Genome-wide copy number analysis in pediatric glioblastoma multiforme

    PubMed Central

    Giunti, Laura; Pantaleo, Marilena; Sardi, Iacopo; Provenzano, Aldesia; Magi, Alberto; Cardellicchio, Stefania; Castiglione, Francesca; Tattini, Lorenzo; Novara, Francesca; Buccoliero, Anna Maria; de Martino, Maurizio; Genitori, Lorenzo; Zuffardi, Orsetta; Giglio, Sabrina

    2014-01-01

    Glioblastoma (GBM) is a very aggressive and lethal brain tumor with poor prognosis. Despite new treatment strategies, patients’ median survival is still less than 1 year in most cases. Few studies have focused exclusively on this disease in children and most of our understanding of the disease process and its clinical outcome has come from studies on malignant gliomas in childhood, combining children with the diagnosis of GBM with other pediatric patients harboring high grade malignant tumors other than GBM. In this study we investigated, using array-CGH platforms, children (median age of 9 years) affected by GBM (WHO-grade IV). We identified recurrent Copy Number Alterations demonstrating that different chromosome regions are involved, in various combinations. These observations suggest a condition of strong genomic instability. Since cancer is an acquired disease and inherited factors play a significant role, we compared for the first time the constitutional Copy Number Variations with the Copy Number Alterations found in tumor biopsy. We speculate that genes included in the recurrent 9p21.3 and 16p13.3 deletions and 1q32.1-q44 duplication play a crucial role for tumorigenesis and/or progression. In particular we suggest that the A2BP1 gene (16p13.3) is one possible culprit of the disease. Given the rarity of the disease, the poor quality and quantity of bioptic material and the scarcity of data in the literature, our findings may better elucidate the genomic background of these tumors. The recognition of candidate genes underlying this disease could then improve treatment strategies for this devastating tumor. PMID:24959384

  3. GlioLab-a space system for Glioblastoma multiforme cells on orbit behavior study

    NASA Astrophysics Data System (ADS)

    Cappelletti, Chantal; Twiggs, Robert J.

    Microgravity conditions and ionizing radiation pose significant health risks for human life in space. This is a concern for future missions and also for future space tourism flights. Nev-ertheless, at the same time it is very interesting to study the effects of these conditions in unhealthy organism like biological samples affected by cancer. It is possible that space envi-ronment increases, decreases or doesn't have any effect on cancer cells. In any case the test results give important informations about cancer treatment or space tourism flight for people affected by cancer. GlioLab is a joint project between GAUSS-Group of Astrodynamics at the "Sapienza" University of Roma and the Morehead State University (MSU) Space Science Center in Kentucky. The main goal of this project is the design and manufacturing of an autonomous space system to investigate potential effects of the space environment exposure on a human glioblastoma multiforme cell line derived from a 65-year-old male and on Normal Human Astrocytes (NHA). In particular the samples are Glioblastoma multiforme cancer cells because the radiotherapy using ionizing radiation is the only treatment after surgery that can give on ground an improvement on the survival rate for this very malignant cancer. During a mission on the ISS, GlioLab mission has to test the in orbit behavior of glioblastoma cancer cells and healthy neuronal cells, which are extremely fragile and require complex experimentation and testing. In this paper engineering solutions to design and manufacturing of an autonomous space system that can allow to keep alive these kind of cells are described. This autonomous system is characterized also by an optical device dedicated to cells behavior analysis and by microdosimeters for monitoring space radiation environment.

  4. The role of basic fibroblast growth factor in glioblastoma multiforme and glioblastoma stem cells and in their in vitro culture.

    PubMed

    Haley, Elizabeth M; Kim, Yonghyun

    2014-04-28

    Glioblastoma multiforme (GBM) is the most malignant form of central nervous system tumor, and current therapies are largely ineffective at treating the cancer. Developing a more complete understanding of the mechanisms controlling the tumor is important in order to explore new possible treatment options. It is speculated that the presence of glioblastoma stem or stem-like cells (GSCs), a rare type of pluripotent cancer cell that possesses the ability to self-renew and generate tumors, could be an important factor contributing to the resistance to treatment and deadliness of the cancer. A comprehensive knowledge of the mechanisms controlling the expression and properties of GSCs is currently lacking, and one promising area for further exploration is in the influence of basic fibroblast growth factor (FGF-2) on GSCs. Recent studies reveal that FGF-2 plays a significant part in regulating GBM, and the growth factor is commonly included as a supplement in media used to culture GSCs in vitro. However, the particular role that FGF-2 plays in GSCs has not been as extensively explored. Therefore, understanding how FGF-2 is involved in GSCs and in GBMs could be an important step towards a more complete comprehension of the managing the disease. In this review, we look at the structure, signaling pathways, and specific role of FGF-2 in GBM and GSCs. In addition, we explore the use of FGF-2 in cell culture and using its synthetic analogs as a potential alternative to the growth factor in culture medium.

  5. Cancer stem cells and microglia in the processes of glioblastoma multiforme invasive growth

    PubMed Central

    Bryukhovetskiy, Igor; Manzhulo, Igor; Mischenko, Polina; Milkina, Elena; Dyuizen, Inessa; Bryukhovetskiy, Andrey; Khotimchenko, Yuri

    2016-01-01

    The development of antitumor medication based on autologous stem cells is one of the most advanced methods in glioblastoma multiforme (GBM) treatment. However, there are no objective criteria for evaluating the effectiveness of this medication on cancer stem cells (CSCs). One possible criterion could be a change in the number of microglial cells and their specific location in the tumor. The present study aimed to understand the interaction between microglial cells and CSCs in an experimental glioblastoma model. C6 glioma cells were used to create a glioblastoma model, as they have the immunophenotypic characteristics of CSCs. The glioma cells (0.2×106) were stereotactically implanted into the brains of 60 rats. On the 10th, 20th and 30th days after implantation, the animals were 15 of the animals were sacrificed, and the obtained materials were analyzed by morphological and immunohistochemical analysis. Implantation of glioma cells into the rat brains caused rapid development of tumors characterized by invasive growth, angiogenesis and a high rate of proliferation. The maximum concentration of microglia was observed in the tumor nodule between days 10 and 20; a high proliferation rate of cancer cells was also observed in this area. By day 30, necrosis advancement was observed and the maximum number of microglial cells was concentrated in the invasive area; the invasive area also exhibited positive staining for CSC marker antibodies. Microglial cells have a key role in the invasive growth processes of glioblastoma, as demonstrated by the location of CSCs in the areas of microglia maximum concentration. Therefore, the present study indicates that changes in microglia position and corresponding suppression of tumor growth may be objective criteria for evaluating the effectiveness of biomedical treatment against CSCs.

  6. Cancer stem cells and microglia in the processes of glioblastoma multiforme invasive growth

    PubMed Central

    Bryukhovetskiy, Igor; Manzhulo, Igor; Mischenko, Polina; Milkina, Elena; Dyuizen, Inessa; Bryukhovetskiy, Andrey; Khotimchenko, Yuri

    2016-01-01

    The development of antitumor medication based on autologous stem cells is one of the most advanced methods in glioblastoma multiforme (GBM) treatment. However, there are no objective criteria for evaluating the effectiveness of this medication on cancer stem cells (CSCs). One possible criterion could be a change in the number of microglial cells and their specific location in the tumor. The present study aimed to understand the interaction between microglial cells and CSCs in an experimental glioblastoma model. C6 glioma cells were used to create a glioblastoma model, as they have the immunophenotypic characteristics of CSCs. The glioma cells (0.2×106) were stereotactically implanted into the brains of 60 rats. On the 10th, 20th and 30th days after implantation, the animals were 15 of the animals were sacrificed, and the obtained materials were analyzed by morphological and immunohistochemical analysis. Implantation of glioma cells into the rat brains caused rapid development of tumors characterized by invasive growth, angiogenesis and a high rate of proliferation. The maximum concentration of microglia was observed in the tumor nodule between days 10 and 20; a high proliferation rate of cancer cells was also observed in this area. By day 30, necrosis advancement was observed and the maximum number of microglial cells was concentrated in the invasive area; the invasive area also exhibited positive staining for CSC marker antibodies. Microglial cells have a key role in the invasive growth processes of glioblastoma, as demonstrated by the location of CSCs in the areas of microglia maximum concentration. Therefore, the present study indicates that changes in microglia position and corresponding suppression of tumor growth may be objective criteria for evaluating the effectiveness of biomedical treatment against CSCs. PMID:27602106

  7. Cluster and Principal Component Analysis of Human Glioblastoma Multiforme (GBM) Tumor Proteome

    PubMed Central

    Pooladi, Mehdi; Rezaei-Tavirani, Mostafa; Hashemi, Mehrdad; Hesami-Tackallou, Saeed; Khaghani-Razi-Abad, Solmaz; Moradi, Afshin; Zali, Ali Reza; Mousavi, Masoumeh; Firozi-Dalvand, Leila; Rakhshan, Azadeh; Zamanian Azodi, Mona

    2014-01-01

    Background Glioblastoma Multiforme (GBM) or grade IV astrocytoma is the most common and lethal adult malignant brain tumor. Several of the molecular alterations detected in gliomas may have diagnostic and/or prognostic implications. Proteomics has been widely applied in various areas of science, ranging from the deciphering of molecular pathogen nests of discuses. Methods In this study proteins were extracted from the tumor and normal brain tissues and then the protein purity was evaluated by Bradford test and spectrophotometry. In this study, proteins were separated by 2-Dimensional Gel (2DG) electrophoresis method and the spots were then analyzed and compared using statistical data and specific software. Protein clustering analysis was performed on the list of proteins deemed significantly altered in glioblastoma tumors (t-test and one-way ANOVA; P< 0.05). Results The 2D gel showed totally 876 spots. We reported, 172 spots were exhibited differently in expression level (fold > 2) for glioblastoma. On each analytical 2D gel, an average of 876 spots was observed. In this study, 188 spots exhibited up regulation of expression level, whereas the remaining 232 spots were decreased in glioblastoma tumor relative to normal tissue. Results demonstrate that functional clustering (up and down regulated) and Principal Component Analysis (PCA) has considerable merits in aiding the interpretation of proteomic data. Conclusion 2D gel electrophoresis is the core of proteomics which permitted the separation of thousands of proteins. High resolution 2DE can resolve up to 5,000 proteins simultaneously. Using cluster analysis, we can also form groups of related variables, similar to what is practiced in factor analysis. PMID:25250155

  8. Significant anti-tumor effect of bevacizumab in treatment of pineal gland glioblastoma multiforme.

    PubMed

    Mansour, Joshua; Fields, Braxton; Macomson, Samuel; Rixe, Olivier

    2014-12-01

    Glioblastoma multiforme (GBM) is the most aggressive subtype of malignant gliomas. Current standard treatment for GBM involves a combination of cytoreduction through surgical resection, followed by radiation with concomitant and adjuvant chemotherapy (temozolomide). The role of bevacizumab in the treatment of GBM continues to be a topic of ongoing research and debate. Despite aggressive treatment, these tumors remain undoubtedly fatal, especially in the elderly. Furthermore, tumors present in the pineal gland are extremely rare, accounting for only 0.1-0.4 % of all adult brain tumors, with this location adding to the complexity of treatment. We present a case of GBM, at the rare location of pineal gland, in an elderly patient who was refractory to initial standard of care treatment with radiation and concomitant and adjuvant temozolomide, but who developed a significant response to anti-angiogenic therapy using bevacizumab.

  9. 5-aminolevulinic acid guidance during awake craniotomy to maximise extent of safe resection of glioblastoma multiforme.

    PubMed

    Corns, Robert; Mukherjee, Soumya; Johansen, Anja; Sivakumar, Gnanamurthy

    2015-01-01

    Overall survival for patients with glioblastoma multiforme (GBM) has been consistently shown to improve when the surgeon achieves a gross total resection of the tumour. It has also been demonstrated that surgical adjuncts such as 5-aminolevulinic acid (5-ALA) fluorescence--which delineates malignant tumour tissue--normal brain tissue margin seen using violet-blue excitation under an operating microscope--helps achieve this. We describe the case of a patient with recurrent left frontal GBM encroaching on Broca's area (eloquent brain). Gross total resection of the tumour was achieved by combining two techniques, awake resection to prevent damage to eloquent brain and 5-ALA fluorescence guidance to maximise the extent of tumour resection.This technique led to gross total resection of all T1-enhancing tumour with the avoidance of neurological deficit. The authors recommend this technique in patients when awake surgery can be tolerated and gross total resection is the aim of surgery. PMID:26177997

  10. The emerging role of stereotactic radiosurgery in the treatment of glioblastoma multiforme.

    PubMed

    Barbarisi, Manlio; Romanelli, Pantaleo

    2012-10-01

    Stereotactic radiosurgery is an emerging treatment option offered to patients with Glioblastoma multiforme (GBM). Radiosurgery is performed as an outpatient procedure and provides a safe and effective non invasive treatment for focal GBM. High energy beams originating from cobalt sources placed into an helmet (Gamma-Knife) or generated by a linear accelerator (LINAC) rotating on a gantry (X-Knife, Novalis) or maneuvered by a robotic arm (CyberKnife) are delivered with submillimetric accuracy to a selected intracranial target. Treatment accuracy is provided by image-guided volumetric CT and MR studies complemented with advanced metabolic neuroimaging techniques such as CT-PET. Radiosurgery is typically used as a salvage treatment in patients with recurrent GBM to avoid further surgical procedures or as a complement to conventional fractionated radiotherapy. This paper reviews the emerging role of stereotactic radiosurgery in the treatment of GBM. PMID:22642423

  11. High-grade astrocytoma (Glioblastoma Multiforme) in an Atlantic spotted dolphin (Stenella frontalis).

    PubMed

    Díaz-Delgado, J; Sacchini, S; Suárez-Bonnet, A; Sierra, E; Arbelo, M; Espinosa, A; Rodríguez-Grau Bassas, E; Mompeo, B; Pérez, L; Fernández, A

    2015-01-01

    This report describes the gross, microscopical and immunohistochemical features of a high-grade astrocytoma (glioblastoma multiforme) in an adult male Atlantic spotted dolphin (Stenella frontalis). On necropsy examination, a 5 × 2.5 × 2 cm, poorly demarcated, red, friable and locally expansile mass effaced the thalamus and the left periventricular region and extended to the left lateral ventricle of the brain. Microscopically, the mass consisted of haphazardly arranged bundles and rows of interweaving polygonal to spindle-shaped cells. These often palisaded along serpentine foci of necrosis and were surrounded by prominent vessels. Immunohistochemically, the neoplastic cells expressed glial fibrillary acidic protein, but not vimentin, S100 protein, neuron-specific enolase or neurofilament protein. A diagnosis of high-grade astrocytoma was made and this represents the first description of a glioma in a cetacean species. PMID:25728810

  12. Boron Neutron Capture Therapy (BNCT) Dose Calculation using Geometrical Factors Spherical Interface for Glioblastoma Multiforme

    SciTech Connect

    Zasneda, Sabriani; Widita, Rena

    2010-06-22

    Boron Neutron Capture Therapy (BNCT) is a cancer therapy by utilizing thermal neutron to produce alpha particles and lithium nuclei. The superiority of BNCT is that the radiation effects could be limited only for the tumor cells. BNCT radiation dose depends on the distribution of boron in the tumor. Absorbed dose to the cells from the reaction 10B (n, {alpha}) 7Li was calculated near interface medium containing boron and boron-free region. The method considers the contribution of the alpha particle and recoiled lithium particle to the absorbed dose and the variation of Linear Energy Transfer (LET) charged particles energy. Geometrical factor data of boron distribution for the spherical surface is used to calculate the energy absorbed in the tumor cells, brain and scalp for case Glioblastoma Multiforme. The result shows that the optimal dose in tumor is obtained for boron concentrations of 22.1 mg {sup 10}B/g blood.

  13. Radiation-induced glioblastoma multiforme in a remitted acute lymphocytic leukemia patient.

    PubMed

    Joh, Daewon; Park, Bong Jin; Lim, Young Jin

    2011-09-01

    Radiation therapy has been widely applied for cancer treatment. Childhood acute lymphocytic leukemia (ALL), characterized by frequent central nervous system involvement, is a well documented disease for the effect of prophylactic cranio-spinal irradiation. Irradiation, however, acts as an oncogenic factor as a delayed effect and it is rare that glioblastoma multiforme develops during the remission period of ALL. We experienced a pediatric radiation-induced GBM patient which developed during the remission period of ALL, who were primarily treated with chemotherapeutic agents and brain radiation therapy for the prevention of central nervous system (CNS) relapse. Additionally, we reviewed the related literature regarding on the effects of brain irradiation in childhood and on the prognosis of radiation induced GBM.

  14. Transcription factor 3 controls cell proliferation and migration in glioblastoma multiforme cell lines.

    PubMed

    Li, Ruiting; Li, Yinghui; Hu, Xin; Lian, Haiwei; Wang, Lei; Fu, Hui

    2016-06-01

    Transcription factor 3 (TCF3) is a member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family. Recent studies have demonstrated its potential carcinogenic properties. Here we show that TCF3 was upregulated in glioma tissues compared with normal brain tissues. This upregulation of the TCF3 gene probably has functional significance in brain-tumor progression. Our studies on glioblastoma multiforme (GBM) cell lines show that knock-down of TCF3 induced apoptosis and inhibited cell migration. Further analysis revealed that down-regulation of TCF3 gene expression inhibits Akt and Erk1/2 activation, suggesting that the carcinogenic properties of TCF3 in GBM are partially mediated by the phosphatidylinositol 3-kinase-Akt and MAPK-Erk signaling pathways. Considered together, the results of this study demonstrate that high levels of TCF3 in gliomas potentially promote glioma development through the Akt and Erk pathways. PMID:27105323

  15. Metallofullerene-Nanoplatform-Delivered Interstitial Brachytherapy Improved Survival in a Murine Model of Glioblastoma Multiforme

    PubMed Central

    Wilson, John D.; Broaddus, William C.; Dorn, Harry C.; Fatouros, Panos P.; Chalfant, Charles E.; Shultz, Michael D.

    2012-01-01

    Fullerenes are used across scientific disciplines because of their diverse properties gained by altering encapsulated or surface bound components. In this study, the recently developed theranostic agent based on a radiolabeled functionalized metallofullerene (177Lu-DOTA-f-Gd3N@C80) was synthesized with high radiochemical yield and purity. The efficacy of this agent was demonstrated in two orthotopic xenograft brain tumor models of glioblastoma multiforme (GBM). A dose-dependent improvement in survival was also shown. The in vivo stability of the agent was verified through dual label measurements of biological elimination from the tumor. Overall, these results provide evidence that nanomaterial platforms can be used to deliver effective interstitial brachytherapy. PMID:22881865

  16. Modeling the Treatment of Glioblastoma Multiforme and Cancer Stem Cells with Ordinary Differential Equations

    PubMed Central

    Abernathy, Kristen; Burke, Jeremy

    2016-01-01

    Despite improvements in cancer therapy and treatments, tumor recurrence is a common event in cancer patients. One explanation of recurrence is that cancer therapy focuses on treatment of tumor cells and does not eradicate cancer stem cells (CSCs). CSCs are postulated to behave similar to normal stem cells in that their role is to maintain homeostasis. That is, when the population of tumor cells is reduced or depleted by treatment, CSCs will repopulate the tumor, causing recurrence. In this paper, we study the application of the CSC Hypothesis to the treatment of glioblastoma multiforme by immunotherapy. We extend the work of Kogan et al. (2008) to incorporate the dynamics of CSCs, prove the existence of a recurrence state, and provide an analysis of possible cancerous states and their dependence on treatment levels. PMID:27022405

  17. Comparing predictive models of glioblastoma multiforme built using multi-institutional and local data sources.

    PubMed

    Singleton, Kyle W; Hsu, William; Bui, Alex A T

    2012-01-01

    The growing amount of electronic data collected from patient care and clinical trials is motivating the creation of national repositories where multiple institutions share data about their patient cohorts. Such efforts aim to provide sufficient sample sizes for data mining and predictive modeling, ultimately improving treatment recommendations and patient outcome prediction. While these repositories offer the potential to improve our understanding of a disease, potential issues need to be addressed to ensure that multi-site data and resultant predictive models are useful to non-contributing institutions. In this paper we examine the challenges of utilizing National Cancer Institute datasets for modeling glioblastoma multiforme. We created several types of prognostic models and compared their results against models generated using data solely from our institution. While overall model performance between the data sources was similar, different variables were selected during model generation, suggesting that mapping data resources between models is not a straightforward issue.

  18. Mechanisms of tumor development and anti-angiogenic therapy in glioblastoma multiforme.

    PubMed

    Onishi, Manabu; Kurozumi, Kazuhiko; Ichikawa, Tomotsugu; Date, Isao

    2013-01-01

    Despite advances in surgical and medical therapy, glioblastoma multiforme (GBM) remains a fatal disease. There has been no significant increase in survival for patients with this disease over the last 20 years. Tumor vasculature formation and glioma cell invasion along the white matter tracts both play a pivotal role in glioma development. Angiogenesis and invasion are the major factors believed to be responsible for treatment resistance in tumors, and a better understanding of the glioma invasion and angiogenesis mechanisms will lead to the development of potential new treatments. In this review, we focus on the molecular characteristics of angiogenesis and invasion in human malignant glioma. We discuss bevacizumab and cilengitide, which are used to inhibit angiogenesis in GBM.

  19. Survival of patients with glioblastoma multiforme treated by intraoperative high-activity cobalt 60 endocurietherapy

    SciTech Connect

    Kumar, P.P.; Good, R.R.; Jones, E.O.; Patil, A.A.; Leibrock, L.G.; McComb, R.D. )

    1989-10-01

    The authors report their initial treatment results in 49 patients with glioblastoma multiforme (GM) who received intraoperative endocurietherapy (ECT) with high-activity cobalt 60 ({sup 60}Co) probe. Thirty poor prognosis (unresectable tumor) patients (Group I) with newly diagnosed GM were treated by either biopsy or subtotal excision, followed by 20.00-Gy single-fraction {sup 60}Co probe ECT, and 60.00-Gy external-beam radiation therapy (EXRT) (80.00 Gy total tumor dose). Nineteen patients (Group II) with recurrent, previously resected and externally irradiated GM were retreated with 20.00-Gy single-fraction {sup 60}Co probe ECT alone. The authors' initial experience with intraoperative ECT of GM is discussed.

  20. A Common Sense Approach to Radiotherapy Planning of Glioblastoma Multiforme Situated in The Temporal Lobe

    SciTech Connect

    Bokstein, Felix Kovner, Felix; Blumenthal, Deborah T.; Ram, Zvi; Templehoff, Haim; Kanner, Andrew A.; Corn, Benjamin W.

    2008-11-01

    Purpose: Irradiation remains the cornerstone of management for glioblastoma multiforme. The Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer advocate encompassing the primary tumor plus a 2-cm margin in the high-dose volume. One shortcoming of this approach is the exposure of critical structures to radiation doses that could exceed organ tolerance. We investigated whether the temporal bone (rather than the aforementioned 2-cm radius) would serve as a barrier to tumor spread when regarded as the anterior margin for temporal lobe lesions. We hypothesized that by using the temporal bone as the radiation field margin, toxicity could be reduced without compromising tumor control. Methods and Materials: Between 2003 and 2007, 342 patients with newly diagnosed glioblastoma multiforme were treated with surgery and primary irradiation at our institution. Of these 342 patients, 50 had lesions confined to the temporal lobe. The clinical target volume included the primary lesion, the area of edema when present, and a 2-cm margin, except in the direction of the temporal bone. Results: Of the 50 patients, 40 were available for evaluation. At a median follow-up of 12.95 months, 8 patients had not yet shown signs of tumor progression, 24 had local failure, 7 had distant or mixed (local plus distant) failure, and only 1 patient had failure in the infratemporal fossa. Conclusions: The results of the study have demonstrated an acceptable level of recurrence when the temporal bone, rather than a 2-cm margin, is used as the anterior border of the clinical target volume. The strategy we have proposed achieves tumor control and respects optic tolerance without resorting to complex, expensive approaches such as intensity-modulated radiotherapy.

  1. Cancer stem cells from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall

    PubMed Central

    2012-01-01

    Background The cancer stem cell (CSC) hypothesis posits that deregulated neural stem cells (NSCs) form the basis of brain tumors such as glioblastoma multiforme (GBM). GBM, however, usually forms in the cerebral white matter while normal NSCs reside in subventricular and hippocampal regions. We attempted to characterize CSCs from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall. Methods We described isolating CSCs from a GBM involving the lateral ventricles and characterized these cells with in vitro molecular biomarker profiling, cellular behavior, ex vivo and in vivo techniques. Results The patient’s MRI revealed a heterogeneous mass with associated edema, involving the left subventricular zone. Histological examination of the tumor established it as being a high-grade glial neoplasm, characterized by polygonal and fusiform cells with marked nuclear atypia, amphophilic cytoplasm, prominent nucleoli, frequent mitotic figures, irregular zones of necrosis and vascular hyperplasia. Recurrence of the tumor occurred shortly after the surgical resection. CD133-positive cells, isolated from the tumor, expressed stem cell markers including nestin, CD133, Ki67, Sox2, EFNB1, EFNB2, EFNB3, Cav-1, Musashi, Nucleostemin, Notch 2, Notch 4, and Pax6. Biomarkers expressed in differentiated cells included Cathepsin L, Cathepsin B, Mucin18, Mucin24, c-Myc, NSE, and TIMP1. Expression of unique cancer-related transcripts in these CD133-positive cells, such as caveolin-1 and −2, do not appear to have been previously reported in the literature. Ex vivo organotypic brain slice co-culture showed that the CD133+ cells behaved like tumor cells. The CD133-positive cells also induced tumor formation when they were stereotactically transplanted into the brains of the immune-deficient NOD/SCID mice. Conclusions This brain tumor involving the neurogenic lateral ventricular wall was comprised of tumor-forming, CD133-positive cancer stem cells, which are likely

  2. Phase I Trial of Tipifarnib (R115777) Concurrent With Radiotherapy in Patients with Glioblastoma Multiforme

    SciTech Connect

    Cohen-Jonathan Moyal, Elizabeth . E-mail: moyal.elizabeth@claudiusregaud.fr; Laprie, Anne; Delannes, Martine; Poublanc, Muriel; Catalaa, Isabelle; Dalenc, Florence; Berchery, Delphine; Sabatier, Jean; Bousquet, Philippe; De Porre, Peter; Alaux, Beatrice; Toulas, Christine

    2007-08-01

    Purpose: To conduct a Phase I trial to determine the maximally tolerated dose (MTD) of tipifarnib in combination with conventional three-dimensional conformal radiotherapy (RT) for patients with glioblastoma multiforme. Methods and Materials: After resection or biopsy, tipifarnib was given 1 week before and then continuously during RT (60 Gy), followed by adjuvant administration until progression. The tipifarnib dose during RT was escalated in cohorts of 3 starting at 200 mg/day. Results: Thirteen patients were enrolled, and 12 were evaluable for MTD. Of these patients, 7 had undergone biopsy, 4 had partial resection, and 1 had gross total resection. No dose-limiting toxicity (DLT) was observed during the concomitant treatment at 200 mg. All 3 patients at 300 mg experienced DLT during the concomitant treatment: 1 with sudden death and 2 with acute pneumonitis. The MTD was reached at 300 mg. The adjuvant treatment was suppressed from the protocol after a case of pneumonitis during this treatment. Six additional patients were included at 200 mg/day of the new protocol, confirming the safety of this treatment. Of the 9 evaluable patients, 1 had partial response, 4 had stable disease, and 3 had rapid progression; the patient with gross total resection was relapse-free after 21 months. Median survival of the evaluable patients was 12 months (range, 5.2-21 months). Conclusion: Tipifarnib (200 mg/day) concurrent with standard radiotherapy is well tolerated in patients with glioblastoma. Preliminary efficacy results are encouraging.

  3. Nanocarriers for the treatment of glioblastoma multiforme: Current state-of-the-art.

    PubMed

    Karim, Reatul; Palazzo, Claudio; Evrard, Brigitte; Piel, Geraldine

    2016-04-10

    Glioblastoma multiforme, a grade IV glioma, is the most frequently occurring and invasive primary tumor of the central nervous system, which causes about 4% of cancer-associated-deaths, making it one of the most fatal cancers. With present treatments, using state-of-the-art technologies, the median survival is about 14 months and 2 year survival rate is merely 3-5%. Hence, novel therapeutic approaches are urgently necessary. However, most drug molecules are not able to cross the blood-brain barrier, which is one of the major difficulties in glioblastoma treatment. This review describes the features of blood-brain barrier, and its anatomical changes with different stages of tumor growth. Moreover, various strategies to improve brain drug delivery i.e. tight junction opening, chemical modification of the drug, efflux transporter inhibition, convection-enhanced delivery, craniotomy-based drug delivery and drug delivery nanosystems are discussed. Nanocarriers are one of the highly potential drug transport systems that have gained huge research focus over the last few decades for site specific drug delivery, including drug delivery to the brain. Properly designed nanocolloids are capable to cross the blood-brain barrier and specifically deliver the drug in the brain tumor tissue. They can carry both hydrophilic and hydrophobic drugs, protect them from degradation, release the drug for sustained period, significantly improve the plasma circulation half-life and reduce toxic effects. Among various nanocarriers, liposomes, polymeric nanoparticles and lipid nanocapsules are the most widely studied, and are discussed in this review. For each type of nanocarrier, a general discussion describing their composition, characteristics, types and various uses is followed by their specific application to glioblastoma treatment. Moreover, some of the main challenges regarding toxicity and standardized evaluation techniques are narrated in brief.

  4. Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme

    PubMed Central

    2013-01-01

    Background Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient’s prognosis. Beside promoter methylation of the O 6 -methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM. Methods Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples. Results Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM. Conclusions In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients’ survival. PMID:24380367

  5. Deciphering the Finger Prints of Brain Cancer Glioblastoma Multiforme from Four Different Patients by Using Near Infrared Raman Spectroscopy

    PubMed Central

    Banerjee, Hirendra Nath; Banerji, Arnold; Banerjee, Arunendra Nath; Riddick, Eilena; Petis, Jenae; Evans, Shavonda; Patel, Megha; Parson, Carl; Smith, Valerie; Gwebu, E.; Voisin, Sarah

    2015-01-01

    To explore the effectiveness of Raman spectra to diagnose brain cancer glioblastoma multiforme (GBM), we investigated the Raman spectra of single cell from four different GBM cell lines developed from four different patients and analyzed the spectra. The Raman spectra of brain cancer (GBM) cells were similar in all these cell lines. The results indicate that Raman spectra can offer the experimental basis for the cancer diagnosis and treatment. PMID:25937869

  6. Association of epidermal growth factor receptor gene amplification with loss of chromosome 10 in human glioblastoma multiforme.

    PubMed

    von Deimling, A; Louis, D N; von Ammon, K; Petersen, I; Hoell, T; Chung, R Y; Martuza, R L; Schoenfeld, D A; Yaşargil, M G; Wiestler, O D

    1992-08-01

    Although the loss of tumor suppressor genes and the activation of oncogenes have been established as two of the fundamental mechanisms of tumorigenesis in human cancer, little is known about the possible interactions between these two mechanisms. Loss of genetic material on chromosome 10 and amplification of the epidermal growth factor receptor (EGFR) gene are the most frequently reported genetic abnormalities in glioblastoma multiforme. In order to examine a possible correlation between these two genetic aberrations, the authors studied 106 gliomas (58 glioblastomas, 14 anaplastic astrocytomas, five astrocytomas, nine pilocytic astrocytomas, seven mixed gliomas, six oligodendrogliomas, two ependymomas, one subependymoma, one subependymal giant-cell astrocytoma, and three gangliogliomas) with Southern blot analysis for loss of heterozygosity on both arms of chromosome 10 and for amplification of the EGFR gene. Both the loss of genetic material on chromosome 10 and EGFR gene amplification were restricted to the glioblastomas. Of the 58 glioblastoma patients, 72% showed loss of chromosome 10 and 38% showed EGFR gene amplification. The remaining 28% had neither loss of chromosome 10 nor EGFR gene amplification. Without exception, the glioblastomas that exhibited EGFR gene amplification had also lost genetic material on chromosome 10 (p less than 0.001). This invariable association suggests a relationship between the two genetic events. Moreover, the presence of 15 cases of glioblastoma with loss of chromosome 10 but without EGFR gene amplification may further imply that the loss of a tumor suppressor gene (or genes) on chromosome 10 precedes EGFR gene amplification in glioblastoma tumorigenesis.

  7. Dual targeting of glioblastoma multiforme with a proteasome inhibitor (Velcade) and a phosphatidylinositol 3-kinase inhibitor (ZSTK474).

    PubMed

    Lin, Lehang; Gaut, Daria; Hu, Kaishun; Yan, Haiyan; Yin, Dong; Koeffler, H Phillip

    2014-02-01

    Proteasome inhibitors have been proven to be effective anticancer compounds in many tumor models, including glioblastoma multiforme (GBM). In this study, we found that the proteasome inhibitor Velcade (PS-341/bortezomib) caused GBM cell death while simultaneously activating the PI3K/Akt pathway. Therefore, we sought to investigate if the PI3K inhibitor ZSTK474 would enhance the effectiveness of Velcade in anticancer therapy. Two GBM cell lines were used to detect the effects of Velcade and ZSTK474 alone or in combination in vitro. The combination of Velcade and ZSTK474 synergistically inhibited the proliferation of GBM cell lines. Cell apoptosis was increased when exposed to Velcade and ZSTK474 in combination as shown by Annexin V analysis. Treatment with both drugs led to downregulation of the p-Akt, p-4EBP1 and p-mTOR proteins as determined by western blot analysis. The anticancer ability of Velcade for glioblastoma multiforme was, therefore, enhanced by combination with the PI3K pathway inhibitor ZSTK474 in glioblastoma multiforme.

  8. Theranostic Application of Mixed Gold and Superparamagnetic Iron Oxide Nanoparticle Micelles in Glioblastoma Multiforme.

    PubMed

    Sun, Lova; Joh, Daniel Y; Al-Zaki, Ajlan; Stangl, Melissa; Murty, Surya; Davis, James J; Baumann, Brian C; Alonso-Basanta, Michelle; Kaol, Gary D; Tsourkas, Andrew; Dorsey, Jay F

    2016-02-01

    The treatment of glioblastoma multiforme, the most prevalent and lethal form of brain cancer in humans, has been limited in part by poor delivery of drugs through the blood-brain barrier and by unclear delineation of the extent of infiltrating tumor margins. Nanoparticles, which selectively accumulate in tumor tissue due to their leaky vasculature and the enhanced permeability and retention effect, have shown promise as both therapeutic and diagnostic agents for brain tumors. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) have been leveraged as T2-weighted MRI contrast agents for tumor detection and imaging; and gold nanoparticles (AuNP) have been demonstrated as radiosensitizers capable of propagating electron and free radical-induced radiation damage to tumor cells. In this study, we investigated the potential applications of novel gold and SPION-loaded micelles (GSMs) coated by polyethylene glycol-polycaprolactone (PEG-PCL) polymer. By quantifying gh2ax DNA damage foci in glioblastoma cell lines, we tested the radiosensitizing efficacy of these GSMs, and found that GSM administration in conjunction with radiation therapy (RT) led to ~2-fold increase in density of double-stranded DNA breaks. For imaging, we used GSMs as a contrast agent for both computed tomography (CT) and magnetic resonance imaging (MRI) studies of stereotactically implanted GBM tumors in a mouse model, and found that MRI but not CT was sufficiently sensitive to detect and delineate tumor borders after administration and accumulation of GSMs. These results suggest that with further development and testing, GSMs may potentially be integrated into both imaging and treatment of brain tumors, serving a theranostic purpose as both an MRI-based contrast agent and a radiosensitizer. PMID:27305768

  9. Theranostic Application of Mixed Gold and Superparamagnetic Iron Oxide Nanoparticle Micelles in Glioblastoma Multiforme

    PubMed Central

    Sun, Lova; Joh, Daniel Y.; Al-Zaki, Ajlan; Stangl, Melissa; Murty, Surya; Davis, James J.; Baumann, Brian C.; Alonso-Basanta, Michelle; Kao, Gary D.; Tsourkas, Andrew; Dorsey, Jay F.

    2016-01-01

    The treatment of glioblastoma multiforme, the most prevalent and lethal form of brain cancer in humans, has been limited in part by poor delivery of drugs through the blood-brain barrier and by unclear delineation of the extent of infiltrating tumor margins. Nanoparticles, which selectively accumulate in tumor tissue due to their leaky vasculature and the enhanced permeability and retention effect, have shown promise as both therapeutic and diagnostic agents for brain tumors. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) have been leveraged as T2-weighted MRI contrast agents for tumor detection and imaging; and gold nanoparticles (AuNP) have been demonstrated as radiosensitizers capable of propagating electron and free radical-induced radiation damage to tumor cells. In this study, we investigated the potential applications of novel gold and SPION-loaded micelles (GSMs) coated by polyethylene glycol-polycaprolactone (PEG-PCL) polymer. By quantifying gh2ax DNA damage foci in glioblastoma cell lines, we tested the radiosensitizing efficacy of these GSMs, and found that GSM administration in conjunction with radiation therapy (RT) led to ~2-fold increase in density of double-stranded DNA breaks. For imaging, we used GSMs as a contrast agent for both computed tomography (CT) and magnetic resonance imaging (MRI) studies of stereotactically implanted GBM tumors in a mouse model, and found that MRI but not CT was sufficiently sensitive to detect and delineate tumor borders after administration and accumulation of GSMs. These results suggest that with further development and testing, GSMs may potentially be integrated into both imaging and treatment of brain tumors, serving a theranostic purpose as both an MRI-based contrast agent and a radiosensitizer. PMID:27305768

  10. Pharmacologic inhibition of cdk4/6 arrests the growth of glioblastoma multiforme intracranial xenografts

    PubMed Central

    Michaud, Karine; Solomon, David A.; Oermann, Eric; Kim, Jung-Sik; Zhong, Wei-Zhu; Prados, Michael D.; Ozawa, Tomoko; James, C. David; Waldman, Todd

    2010-01-01

    Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6 specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induction of senescence in each of 16 Rb-proficient cell lines regardless of other genetic lesions, whereas each of 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. shRNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 had significant disease progression or died while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly-diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy. PMID:20354191

  11. Alternative Polyadenylation in Glioblastoma Multiforme and Changes in Predicted RNA Binding Protein Profiles

    PubMed Central

    Shao, Jiaofang; Zhang, Jing; Zhang, Zengming; Jiang, Huawei; Lou, Xiaoyan; Foltz, Gregory; Lan, Qing; Huang, Qiang

    2013-01-01

    Abstract Alternative polyadenylation (APA) is widely present in the human genome and plays a key role in carcinogenesis. We conducted a comprehensive analysis of the APA products in glioblastoma multiforme (GBM, one of the most lethal brain tumors) and normal brain tissues and further developed a computational pipeline, RNAelements (http://sysbio.zju.edu.cn/RNAelements/), using covariance model from known RNA binding protein (RBP) targets acquired by RNA Immunoprecipitation (RIP) analysis. We identified 4530 APA isoforms for 2733 genes in GBM, and found that 182 APA isoforms from 148 genes showed significant differential expression between normal and GBM brain tissues. We then focused on three genes with long and short APA isoforms that show inconsistent expression changes between normal and GBM brain tissues. These were myocyte enhancer factor 2D, heat shock factor binding protein 1, and polyhomeotic homolog 1 (Drosophila). Using the RNAelements program, we found that RBP binding sites were enriched in the alternative regions between the first and the last polyadenylation sites, which would result in the short APA forms escaping regulation from those RNA binding proteins. To the best of our knowledge, this report is the first comprehensive APA isoform dataset for GBM and normal brain tissues. Additionally, we demonstrated a putative novel APA-mediated mechanism for controlling RNA stability and translation for APA isoforms. These observations collectively lay a foundation for novel diagnostics and molecular mechanisms that can inform future therapeutic interventions for GBM. PMID:23421905

  12. Lactate dehydrogenase-A inhibition induces human glioblastoma multiforme stem cell differentiation and death

    PubMed Central

    Daniele, Simona; Giacomelli, Chiara; Zappelli, Elisa; Granchi, Carlotta; Trincavelli, Maria Letizia; Minutolo, Filippo; Martini, Claudia

    2015-01-01

    Therapies that target the signal transduction and metabolic pathways of cancer stem cells (CSCs) are innovative strategies to effectively reduce the recurrence and significantly improve the outcome of glioblastoma multiforme (GBM). CSCs exhibit an increased rate of glycolysis, thus rendering them intrinsically more sensitive to prospective therapeutic strategies based on the inhibition of the glycolytic pathway. The enzyme lactate dehydrogenase-A (LDH-A), which catalyses the interconversion of pyruvate and lactate, is up-regulated in human cancers, including GBM. Although several papers have explored the benefits of targeting cancer metabolism in GBM, the effects of direct LDH-A inhibition in glial tumours have not yet been investigated, particularly in the stem cell subpopulation. Here, two representative LDH-A inhibitors (NHI-1 and NHI-2) were studied in GBM-derived CSCs and compared to differentiated tumour cells. LDH-A inhibition was particularly effective in CSCs isolated from different GBM cell lines, where the two compounds blocked CSC formation and elicited long-lasting effects by triggering both apoptosis and cellular differentiation. These data demonstrate that GBM, particularly the stem cell subpopulation, is sensitive to glycolytic inhibition and shed light on the therapeutic potential of LDH-A inhibitors in this tumour type. PMID:26494310

  13. Astrocytoma grade IV (glioblastoma multiforme) displays 3 subtypes with unique expression profiles of intermediate filament proteins.

    PubMed

    Skalli, Omar; Wilhelmsson, Ulrika; Orndahl, Charlotte; Fekete, Boglarka; Malmgren, Kristina; Rydenhag, Bertil; Pekny, Milos

    2013-10-01

    Astrocytoma grade IV (glioblastoma multiforme) is the most common and most malignant tumor of the central nervous system and is currently noncurable. Here, we have examined a population-based cohort of 47 patients with grade IV astrocytoma, who underwent tumor surgery at Sahlgrenska University Hospital in Sweden and who survived after surgery for less than 200 days (short survivors, 28 patients) and more than 500 days (long survivors, 19 patients). For each tumor, we ascertained information on patient age, sex, tumor location, oncological treatment, and survival after surgery. The analysis of the tumor volume and the extent of tumor resection (incomplete versus complete resection of the macroscopic tumor) was made retrospectively from the preoperative radiological investigations and, when available, also from postoperative radiology. We performed semiquantitative immunohistochemical evaluation of the presence of intermediate filament (nanofilament) proteins glial fibrillary acidic protein, vimentin, nestin, and synemin in tumor cells. The intermediate filament system helps cells and tissues to cope with various types of stress, and thus, it might affect the malignant potential of grade IV astrocytoma. We propose a subclassification of astrocytomas grade IV with respect to the expression of the intermediate filament proteins glial fibrillary acidic protein, vimentin, nestin, and synemin, namely, type A, B, and C. Our results suggest that the expression of the intermediate filament proteins glial fibrillary acidic protein, vimentin, nestin, and synemin is coregulated in grade IV astrocytomas. The expression patterns of the intermediate filament proteins in astrocytoma type A, B, and C might have biological and clinical significance. PMID:23791210

  14. Integrative Network-based Analysis of Magnetic Resonance Spectroscopy and Genome Wide Expression in Glioblastoma multiforme

    PubMed Central

    Heiland, Dieter Henrik; Mader, Irina; Schlosser, Pascal; Pfeifer, Dietmar; Carro, Maria Stella; Lange, Thomas; Schwarzwald, Ralf; Vasilikos, Ioannis; Urbach, Horst; Weyerbrock, Astrid

    2016-01-01

    The goal of this study was to identify correlations between metabolites from proton MR spectroscopy and genetic pathway activity in glioblastoma multiforme (GBM). Twenty patients with primary GBM were analysed by short echo-time chemical shift imaging and genome-wide expression analyses. Weighed Gene Co-Expression Analysis was used for an integrative analysis of imaging and genetic data. N-acetylaspartate, normalised to the contralateral healthy side (nNAA), was significantly correlated to oligodendrocytic and neural development. For normalised creatine (nCr), a group with low nCr was linked to the mesenchymal subtype, while high nCr could be assigned to the proneural subtype. Moreover, clustering of normalised glutamine and glutamate (nGlx) revealed two groups, one with high nGlx being attributed to the neural subtype, and one with low nGlx associated with the classical subtype. Hence, the metabolites nNAA, nCr, and nGlx correlate with a specific gene expression pattern reflecting the previously described subtypes of GBM. Moreover high nNAA was associated with better clinical prognosis, whereas patients with lower nNAA revealed a shorter progression-free survival (PFS). PMID:27350391

  15. Fast Neutron Induced Autophagy Leads To Necrosis In Glioblastoma Multiforme Cells

    NASA Astrophysics Data System (ADS)

    Yasui, Linda; Gladden, Samantha; Andorf, Christine; Kroc, Thomas

    2011-06-01

    Fast neutrons are highly effective at killing glioblastoma multiforme (GBM), U87 and U251 cells. The mode of cell death was investigated using transmission electron microscopy (TEM) to identify the fraction of irradiated U87 or U251 cells having morphological features of autophagy and/or necrosis. U87 or U251 cells were irradiated with 2 Gy fast neturons or 10 Gy γ rays. A majority of U87 and U251 cells exhibit features of cell death with autophagy after irradiation with either 10 Gy γ rays or 2 Gy fast neutrons. Very few γ irradiated cells had features of necrosis (U87 or U251 cell samples processed for TEM 1 day after 10 Gy γ irradiation). In contrast, a significant increase was observed in necrotic U87 and U251 cells irradiated with fast neutrons. These results show a greater percentage of cells exhibit morphological evidence of necrosis induced by a lower dose of fast neutron irradiation compared to γ irradiation. Also, the evidence of necrosis in fast neutron irradiated U87 and U251 cells occurs in a background of autophagy. Since autophagy is observed before necrosis, autophagy may play a role in signaling programmed necrosis in fast neutron irradiated U87 and U251 cells.

  16. Fast Neutron Induced Autophagy Leads To Necrosis In Glioblastoma Multiforme Cells

    SciTech Connect

    Yasui, Linda; Gladden, Samantha; Andorf, Christine; Kroc, Thomas

    2011-06-01

    Fast neutrons are highly effective at killing glioblastoma multiforme (GBM), U87 and U251 cells. The mode of cell death was investigated using transmission electron microscopy (TEM) to identify the fraction of irradiated U87 or U251 cells having morphological features of autophagy and/or necrosis. U87 or U251 cells were irradiated with 2 Gy fast neturons or 10 Gy {gamma} rays. A majority of U87 and U251 cells exhibit features of cell death with autophagy after irradiation with either 10 Gy {gamma} rays or 2 Gy fast neutrons. Very few {gamma} irradiated cells had features of necrosis (U87 or U251 cell samples processed for TEM 1 day after 10 Gy {gamma} irradiation). In contrast, a significant increase was observed in necrotic U87 and U251 cells irradiated with fast neutrons. These results show a greater percentage of cells exhibit morphological evidence of necrosis induced by a lower dose of fast neutron irradiation compared to {gamma} irradiation. Also, the evidence of necrosis in fast neutron irradiated U87 and U251 cells occurs in a background of autophagy. Since autophagy is observed before necrosis, autophagy may play a role in signaling programmed necrosis in fast neutron irradiated U87 and U251 cells.

  17. An expression based REST signature predicts patient survival and therapeutic response for glioblastoma multiforme

    PubMed Central

    Liang, Jianfeng; Meng, Qinghua; Zhao, Wanni; Tong, Pan; Li, Ping; Zhao, Yuanli; Zhao, Xiaodong; Li, Hua

    2016-01-01

    Proper regulation of neuronal gene expression is crucial for the development and differentiation of the central nervous system. The transcriptional repressor REST (repressor element-1 silencing transcription factor) is a key regulator in differentiation of pluripotent stem cells to neuronal progenitors and mature neurons. Dysregulated REST activity has been implicated in various diseases, among which the most deadly is glioblastoma multiforme (GBM). Here we have developed an expression-based REST signature (EXPREST), a device providing quantitative measurements of REST activity for GBM tumors. EXPREST robustly quantifies REST activity (REST score) using gene expression profiles in absence of clinic-pathologic assessments of REST. Molecular characterization of REST activity identified global alterations at the DNA, RNA, protein and microRNA levels, suggesting a widespread role of REST in GBM tumorigenesis. Although originally aimed to capture REST activity, REST score was found to be a prognostic factor for overall survival. Further, cell lines with enhanced REST activity was found to be more sensitive to IGF1R, VEGFR and ABL inhibitors. In contrast, cell lines with low REST score were more sensitive to cytotoxic drugs including Mitomycin, Camptothecin and Cisplatin. Together, our work suggests that therapeutic targeting of REST provides a promising opportunity for GBM treatment. PMID:27698411

  18. Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study.

    PubMed

    Ferrari, Cristina; Asabella, Artor Niccoli; Villano, Carlo; Giacobbi, Beatrice; Coccetti, Daniela; Panichelli, Paola; Rubini, Giuseppe

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic) of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [(64)Cu]CuCl2. To evaluate the potential theranostic role of [(64)Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [(64)Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy.

  19. Survival time prediction of patients with glioblastoma multiforme tumors using spatial distance measurement

    NASA Astrophysics Data System (ADS)

    Zhou, Mu; Hall, Lawrence O.; Goldgof, Dmitry B.; Gillies, Robert J.; Gatenby, Robert A.

    2013-02-01

    Regional variations in tumor blood flow and necrosis are commonly observed in cross sectional imaging of clinical cancers. We hypothesize that radiologically-defined regional variations in tumor characteristics can be used to define distinct "habitats" that reflect the underlying evolutionary dynamics. Here we present an experimental framework to extract spatially-explicit variations in tumor features (habitats) from multiple MRI sequences performed on patients with Glioblastoma Multiforme (GBM). The MRI sequences consist of post gadolinium T1-weighted, FLAIR, and T2-weighted images from The Cancer Genome Atlas (TCGA). Our strategy is to identify spatially distinct, radiologically-defined intratumoral habitats by characterizing each small tumor regions based on their combined properties in 3 different MRI sequences. Initial tumor identification was performed by manually drawing a mask on a T1-weighted post contrast image slice. The extracted tumor was segmented into an enhancing and non-enhancing region by the Otsu segmentation algorithm, followed by a mask mapping procedure onto the corresponding FLAIR and T2-weighted images. Then Otsu was applied on the FLAIR and T2 images separately. We find that tumor heterogeneity measured through Distance Features (DF) can be used as a strong predictor of survival time. In an initial cohort of 16 cases slow progressing tumors have lower DF values (are less heterogeneous) compared to those with fast progression and short survival times.

  20. A Pilot Safety Study of Lenalidomide and Radiotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Drappatz, Jan Wong, Eric T.; Schiff, David; Kesari, Santosh; Batchelor, Tracy T.; Doherty, Lisa; LaFrankie, Debra Conrad

    2009-01-01

    Purpose: To define the maximum tolerated dose (MTD) of lenalidomide, an analogue of thalidomide with enhanced immunomodulatory and antiangiogenic properties and a more favorable toxicity profile, in patients with newly diagnosed glioblastoma multiforme (GBM) when given concurrently with radiotherapy. Patients and Methods: Patients with newly diagnosed GBM received radiotherapy concurrently with lenalidomide given for 3 weeks followed by a 1-week rest period and continued lenalidomide until tumor progression or unacceptable toxicity. Dose escalation occurred in groups of 6. Determination of the MTD was based on toxicities during the first 12 weeks of therapy. The primary endpoint was toxicity. Results: Twenty-three patients were enrolled, of whom 20 were treated and evaluable for both toxicity and tumor response and 2 were evaluable for toxicity only. Common toxicities included venous thromboembolic disease, fatigue, and nausea. Dose-limiting toxicities were eosinophilic pneumonitis and transaminase elevations. The MTD for lenalidomide was determined to be 15 mg/m{sup 2}/d. Conclusion: The recommended dose for lenalidomide with radiotherapy is 15 mg/m{sup 2}/d for 3 weeks followed by a 1-week rest period. Venous thromboembolic complications occurred in 4 patients, and prophylactic anticoagulation should be considered.

  1. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting-Ideal Versus Reality.

    PubMed

    Lee, Chooi Yeng; Ooi, Ing Hong

    2016-01-01

    Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ's efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach. PMID:27618068

  2. Diagnostic delay and prognosis in primary central nervous system lymphoma compared with glioblastoma multiforme.

    PubMed

    Cerqua, R; Balestrini, S; Perozzi, C; Cameriere, V; Renzi, S; Lagalla, G; Mancini, G; Montanari, M; Leoni, P; Scerrati, M; Iacoangeli, M; Silvestrini, M; Luzzi, S; Provinciali, L

    2016-01-01

    Glioblastoma multiforme (GBM) and primary central nervous system lymphoma (PCNSL) are malignant cerebral neoplasms associated with poor prognosis. Early diagnosis and subsequent planning of adequate treatment strategy are relevant to improve survival and reduce neurological deficit. Two groups of patients affected by GBM and PCNSL were compared to identify: (1) factors influencing the time necessary to obtain a correct diagnosis; (2) the influence of the interval time from clinical onset to diagnosis on the prognosis. Fifty-six patients (28 PCNSL and 28 GBM, 23 females and 33 males) referred to the same hospital setting were retrospectively evaluated. The mean age at diagnosis was 61 years. The two groups were comparable in terms of age, sex, clinical symptoms at onset and performance status. There was no relevant difference in time span from clinical onset to first neuroimaging examination, while time span from first neuroimaging to final morphological diagnosis was much longer in PCNSL patients (p = 0.008). Multivariate Cox regression analysis, including both PCNSL and GBM cases, showed a significant association of the overall survival with: time to diagnosis (HR 0.06), age at onset (HR 1.04). Our results show a significant diagnostic delay in PCNSL cases. Age at onset of disease and time to diagnosis emerge as clinical factors affecting overall survival in both groups. Stereotactic-guided biopsy should be chosen as routine method to early diagnose PCNSL. The clinical relevance of early diagnosis in GBM and PCNSL needs to be emphasized to maximize the overall survival in both neoplasms.

  3. Double minute chromosomes in glioblastoma multiforme are revealed by precise reconstruction of oncogenic amplicons

    PubMed Central

    Sanborn, J. Zachary; Salama, Sofie R.; Grifford, Mia; Brennan, Cameron W.; Mikkelsen, Tom; Jhanwar, Suresh; Katzman, Sol; Chin, Lynda; Haussler, David

    2013-01-01

    DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrangements, copy number in tumor genomes. Here we describe the development of methods to compute copy number and detect structural variants with data synthesis to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard short read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme (GBM) samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes (DM) in these tumors. Further, we find that some samples harbor multiple circular amplicons and in some cases further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization (FISH) analysis offered an initial confirmation of the presence of DMs. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one DM offered additional support for our local tumor genome assemblies, identifying the birth of a novel exon made possible through rearranged sequences present in the DM. Consistent with previous estimates, our method was also useful for analysis of a larger set of GBM tumors for which exome sequencing data is available, finding evidence for oncogenic DMs in over 20% of clinical specimens examined. PMID:23940299

  4. Aligned Nanotopography Promotes a Migratory State in Glioblastoma Multiforme Tumor Cells

    PubMed Central

    Beliveau, Alexander; Thomas, Gawain; Gong, Jiaxin; Wen, Qi; Jain, Anjana

    2016-01-01

    Glioblastoma multiforme (GBM) is an aggressive, Grade IV astrocytoma with a poor survival rate, primarily due to the GBM tumor cells migrating away from the primary tumor site along the nanotopography of white matter tracts and blood vessels. It is unclear whether this nanotopography influences the biomechanical properties (i.e. cytoskeletal stiffness) of GBM tumor cells. Although GBM tumor cells have an innate propensity to migrate, we believe this capability is enhanced due to the influence of nanotopography on the tumor cells’ biomechanical properties. In this study, we used an aligned nanofiber film that mimics the nanotopography in the tumor microenvironment to investigate the mechanical properties of GBM tumor cells in vitro. The data demonstrate that the cytoskeletal stiffness, cell traction stress, and focal adhesion area were significantly lower in the GBM tumor cells compared to healthy astrocytes. Moreover, the cytoskeletal stiffness was significantly reduced when cultured on aligned nanofiber films compared to smooth and randomly aligned nanofiber films. Gene expression analysis showed that tumor cells cultured on the aligned nanotopography upregulated key migratory genes and downregulated key proliferative genes. Therefore, our data suggest that the migratory potential is elevated when GBM tumor cells are migrating along aligned nanotopographical substrates. PMID:27189099

  5. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme.

    PubMed

    Champ, Colin E; Palmer, Joshua D; Volek, Jeff S; Werner-Wasik, Maria; Andrews, David W; Evans, James J; Glass, Jon; Kim, Lyndon; Shi, Wenyin

    2014-03-01

    Retrospective data suggests that low serum glucose levels during the treatment of glioblastoma multiforme (GBM) may improve clinical outcomes. As such, many patients are implementing a ketogenic diet (KD) in order to decrease serum glucose flux while simultaneously elevating circulating ketones during radiation therapy and chemotherapy for the treatment of GBM. With IRB approval, a retrospective review of patients with high-grade glioma treated with concurrent chemoradiotherapy and adjuvant chemotherapy was carried out from August 2010 to April 2013. Serum glucose and ketone levels, dexamethasone dose, and toxicity of patients undergoing a KD during treatment were also assessed. Blood glucose levels were compared between patients on an unspecified/standard diet and a KD. Toxicity was assessed by Common Terminology Criteria for Adverse Events version 4. In total, 53 patients were analyzed. Six underwent a KD during treatment. The diet was well tolerated with no grade III toxicity and one episode of grade II fatigue. No episodes of symptomatic hypoglycemia were experienced. Four patients are alive at a median follow-up of 14 months. The mean blood glucose of patients on a standard diet was 122 versus 84 mg/dl for those on a KD. Based on this retrospective study, a KD appears safe and well tolerated during the standard treatment of GBM. Dietary restriction of carbohydrates through a KD reduces serum glucose levels significantly, even in conjunction with high dose steroids, which may affect the response to standard treatment and prognosis. Larger prospective trials to confirm this relationship are warranted.

  6. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting—Ideal Versus Reality

    PubMed Central

    Lee, Chooi Yeng; Ooi, Ing Hong

    2016-01-01

    Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ’s efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach. PMID:27618068

  7. PHENOTYPIC CHARACTERIZATION OF BREAST INVASIVE CARCINOMA VIA TRANSFERABLE TISSUE MORPHOMETRIC PATTERNS LEARNED FROM GLIOBLASTOMA MULTIFORME

    PubMed Central

    Han, Ju; Fontenay, Gerald V.; Wang, Yunfu; Mao, Jian-Hua; Chang, Hang

    2016-01-01

    Quantitative analysis of whole slide images (WSIs) in a large cohort may provide predictive models of clinical outcome. However, the performance of the existing techniques is hindered as a result of large technical variations (e.g., fixation, staining) and biological heterogeneities (e.g., cell type, cell state) that are always present in a large cohort. Although unsupervised feature learning provides a promising way in learning pertinent features without human intervention, its capability can be greatly limited due to the lack of well-curated examples. In this paper, we explored the transferability of knowledge acquired from a well-curated Glioblastoma Multiforme (GBM) dataset through its application to the representation and characterization of tissue histology from the Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (BRCA) cohort. Our experimental results reveals two major phenotypic subtypes with statistically significantly different survival curves. Further differential expression analysis of these two subtypes indicates enrichment of genes regulated by NF-kB in response to TNF and genes up-regulated in response to IFNG. PMID:27390615

  8. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting-Ideal Versus Reality.

    PubMed

    Lee, Chooi Yeng; Ooi, Ing Hong

    2016-09-08

    Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ's efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach.

  9. Exploring miRNA-Associated Signatures with Diagnostic Relevance in Glioblastoma Multiforme and Breast Cancer Patients

    PubMed Central

    LeBlanc, Véronique C.; Morin, Pier Jr

    2015-01-01

    The growing attention that non-coding RNAs have attracted in the field of cancer research in recent years is undeniable. Whether investigated as prospective therapeutic targets or prognostic indicators or diagnostic biomarkers, the clinical relevance of these molecules is starting to emerge. In addition, identification of non-coding RNAs in a plethora of body fluids has further positioned these molecules as attractive non-invasive biomarkers. This review will first provide an overview of the synthetic cascade that leads to the production of the small non-coding RNAs microRNAs (miRNAs) and presents their strengths as biomarkers of disease. Our interest will next be directed at exploring the diagnostic utility of miRNAs in two types of cancer: the brain tumor glioblastoma multiforme (GBM) and breast cancer. Finally, we will discuss additional clinical implications associated with miRNA detection as well as introduce other non-coding RNAs that have generated recent interest in the cancer research community. PMID:26287251

  10. Results of the Phase I Dose-Escalating Study of Motexafin Gadolinium With Standard Radiotherapy in Patients With Glioblastoma Multiforme

    SciTech Connect

    Ford, Judith M. Seiferheld, Wendy; Alger, Jeffrey R.; Wu, Genevieve; Endicott, Thyra J.; Mehta, Minesh; Curran, Walter; Phan, See-Chun

    2007-11-01

    Purpose: Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. This Phase I trial studied the safety and tolerability of a 2-6-week course (10-22 doses) of MGd with radiotherapy for glioblastoma multiforme. Methods and Materials: A total of 33 glioblastoma multiforme patients received one of seven MGd regimens starting at 10 doses of 4 mg/kg/d MGd and escalating to 22 doses of 5.3 mg/kg/d MGd (5 or 10 daily doses then three times per week). The National Cancer Institute Cancer Therapy Evaluation Program toxicity and stopping rules were applied. Results: The maximal tolerated dose was 5.0 mg/kg/d MGd (5 d/wk for 2 weeks, then three times per week) for 22 doses. The dose-limiting toxicity was reversible transaminase elevation. Adverse reactions included rash/pruritus (45%), chills/fever (30%), and self-limiting vesiculobullous rash of the thumb and fingers (42%). The median survival of 17.6 months prompted a case-matched analysis. In the case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31) compared with the matched Radiation Therapy Oncology Group database patients with a median survival of 11.8 months (hazard ratio, 0.43; 95% confidence interval, 0.20-0.94). Conclusion: The maximal tolerated dose of MGd with radiotherapy for glioblastoma multiforme in this study was 5 mg/kg/d for 22 doses (daily for 2 weeks, then three times weekly). The baseline survival calculations suggest progression to Phase II trials is appropriate, with the addition of MGd to radiotherapy with concurrent and adjuvant temozolomide.

  11. Involvement of miRNAs in the Differentiation of Human Glioblastoma Multiforme Stem-Like Cells

    PubMed Central

    Aldaz, Beatriz; Sagardoy, Ainara; Nogueira, Lorena; Guruceaga, Elizabeth; Grande, Lara; Huse, Jason T.; Aznar, Maria A.; Díez-Valle, Ricardo; Tejada-Solís, Sonia; Alonso, Marta M.; Fernandez-Luna, Jose L.

    2013-01-01

    Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process. PMID:24155920

  12. Significant Association of Multiple Human Cytomegalovirus Genomic Loci with Glioblastoma Multiforme Samples

    PubMed Central

    Ranganathan, Padhma; Clark, Paul A.; Kuo, John S.; Salamat, M. Shahriar

    2012-01-01

    Viruses are appreciated as etiological agents of certain human tumors, but the number of different cancer types induced or exacerbated by viral infections is unknown. Glioblastoma multiforme (GBM)/astrocytoma grade IV is a malignant and lethal brain cancer of unknown origin. Over the past decade, several studies have searched for the presence of a prominent herpesvirus, human cytomegalovirus (HCMV), in GBM samples. While some have detected HCMV DNA, RNA, and proteins in GBM tissues, others have not. Therefore, any purported association of HCMV with GBM remains controversial. In most of the previous studies, only one or a select few viral targets were analyzed. Thus, it remains unclear the extent to which the entire viral genome was present when detected. Here we report the results of a survey of GBM specimens for as many as 20 different regions of the HCMV genome. Our findings indicate that multiple HCMV loci are statistically more likely to be found in GBM samples than in other brain tumors or epileptic brain specimens and that the viral genome was more often detected in frozen samples than in paraffin-embedded archival tissue samples. Finally, our experimental results indicate that cellular genomes substantially outnumber viral genomes in HCMV-positive GBM specimens, likely indicating that only a minority of the cells found in such samples harbor viral DNA. These data argue for the association of HCMV with GBM, defining the virus as oncoaccessory. Furthermore, they imply that, were HCMV to enhance the growth or survival of a tumor (i.e., if it is oncomodulatory), it would likely do so through mechanisms distinct from classic tumor viruses that express transforming viral oncoproteins in the overwhelming majority of tumor cells. PMID:22090104

  13. Socioeconomic status does not affect prognosis in patients with glioblastoma multiforme

    PubMed Central

    Kasl, Rebecca A.; Brinson, Philip R.; Chambless, Lola B.

    2016-01-01

    Background: Glioblastoma multiforme (GBM) is an aggressive malignancy, but there is marked heterogeneity in survival time. Health care disparities have demonstrated significance in oncologic outcomes but have not been clearly examined in this patient population. We investigated the role of sociodemographic variables in the prognosis of adult patients diagnosed with GBM. Methods: This retrospective analysis included patients with a histologically confirmed diagnosis of GBM, who underwent resection or biopsy at a single institution from 2000 to 2014. Socioeconomic status (SES) was determined by household income according to the US Census zip code tabulation areas and the US national poverty level. Multivariate Cox proportional hazards analysis calculated effects on patient survival. Results: Thirty percent of 218 subjects were of low SES, 57% mid, and 13% high. Low SES patients tended to be male (62%), Caucasian (92%), unmarried (91%), have dependents (100%), and limited to high school education (55%). SES did not predict insurance or employment status. SES was associated with marital status and number of cohabitants (P < 0.0001) but not clinical trial enrollment. Multivariate analysis demonstrated no relationship between SES and survival. Shorter prognosis was associated with history of military service (hazard ratio [HR] 2.06, P = 0.0125), elderly patients (HR 1.70, P = 0.0158), and multifocal disease (HR 1.75, P = 0.0119). Longer prognosis was associated with gross total resection (HR 0.49, P = 0.0009), radiation therapy (HR 0.12, P < 0.0001), and temozolomide (HR 0.28, P < 0.0001). Conclusions: SES alone does not predict prognosis in patients with newly diagnosed GBM. Sociodemographic variables such as old age, military service record, and insurance type may have a prognostication role. PMID:27217966

  14. Invariant Delineation of Nuclear Architecture in Glioblastoma Multiforme for Clinical and Molecular Association

    PubMed Central

    Han, Ju; Borowsky, Alexander; Loss, Leandro; Gray, Joe W.; Spellman, Paul T.

    2013-01-01

    Automated analysis of whole mount tissue sections can provide insights into tumor subtypes and the underlying molecular basis of neoplasm. However, since tumor sections are collected from different laboratories, inherent technical and biological variations impede analysis for very large datasets such as The Cancer Genome Atlas (TCGA). Our objective is to characterize tumor histopathology, through the delineation of the nuclear regions, from hematoxylin and eosin (H&E) stained tissue sections. Such a representation can then be mined for intrinsic subtypes across a large dataset for prediction and molecular association. Furthermore, nuclear segmentation is formulated within a multi-reference graph framework with geodesic constraints, which enables computation of multidimensional representations, on a cell-by-cell basis, for functional enrichment and bioinformatics analysis. Here, we present a novel method, Multi-Reference Graph Cut (MRGC), for nuclear segmentation that overcomes technical variations associated with sample preparation by incorporating prior knowledge from manually annotated reference images and local image features. The proposed approach has been validated on manually annotated samples and then applied to a dataset of 377 Glioblastoma Multiforme (GBM) whole slide images from 146 patients. For the GBM cohort, multidimensional representation of the nuclear features and their organization have identified (i) statistically significant subtypes based on several morphometric indices, (ii) whether each subtype can be predictive or not, and (iii) that the molecular correlates of predictive subtypes are consistent with the literature. Data and intermediaries for a number of tumor types (GBM, low grade glial, and kidney renal clear carcinoma) are available at: http://tcga.lbl.gov for correlation with TCGA molecular data. The website also provides an interface for panning and zooming of whole mount tissue sections with/without overlaid segmentation results for

  15. Diffusion Tensor Imaging in Patients with Glioblastoma Multiforme Using the Supertoroidal Model

    PubMed Central

    Mekkaoui, Choukri; Metellus, Philippe; Kostis, William J.; Martuzzi, Roberto; Pereira, Fabricio R.; Beregi, Jean-Paul; Reese, Timothy G.; Constable, Todd R.; Jackowski, Marcel P.

    2016-01-01

    Purpose Diffusion Tensor Imaging (DTI) is a powerful imaging technique that has led to improvements in the diagnosis and prognosis of cerebral lesions and neurosurgical guidance for tumor resection. Traditional tensor modeling, however, has difficulties in differentiating tumor-infiltrated regions and peritumoral edema. Here, we describe the supertoroidal model, which incorporates an increase in surface genus and a continuum of toroidal shapes to improve upon the characterization of Glioblastoma multiforme (GBM). Materials and Methods DTI brain datasets of 18 individuals with GBM and 18 normal subjects were acquired using a 3T scanner. A supertoroidal model of the diffusion tensor and two new diffusion tensor invariants, one to evaluate diffusivity, the toroidal volume (TV), and one to evaluate anisotropy, the toroidal curvature (TC), were applied and evaluated in the characterization of GBM brain tumors. TV and TC were compared with the mean diffusivity (MD) and fractional anisotropy (FA) indices inside the tumor, surrounding edema, as well as contralateral to the lesions, in the white matter (WM) and gray matter (GM). Results The supertoroidal model enhanced the borders between tumors and surrounding structures, refined the boundaries between WM and GM, and revealed the heterogeneity inherent to tumor-infiltrated tissue. Both MD and TV demonstrated high intensities in the tumor, with lower values in the surrounding edema, which in turn were higher than those of unaffected brain parenchyma. Both TC and FA were effective in revealing the structural degradation of WM tracts. Conclusions Our findings indicate that the supertoroidal model enables effective tensor visualization as well as quantitative scalar maps that improve the understanding of the underlying tissue structure properties. Hence, this approach has the potential to enhance diagnosis, preoperative planning, and intraoperative image guidance during surgical management of brain lesions. PMID:26761637

  16. Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

    SciTech Connect

    Badiyan, Shahed N.; Markovina, Stephanie; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd; Tran, David D.; Linette, Gerry; Jalalizadeh, Rohan; Dacey, Ralph; Rich, Keith M.; Chicoine, Michael R.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H.; Huang, Jiayi

    2014-11-15

    Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM. Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.

  17. Radiogenomic Mapping of Edema/Cellular Invasion MRI-Phenotypes in Glioblastoma Multiforme

    PubMed Central

    Zinn, Pascal O.; Majadan, Bhanu; Sathyan, Pratheesh; Singh, Sanjay K.; Majumder, Sadhan; Jolesz, Ferenc A.; Colen, Rivka R.

    2011-01-01

    Background Despite recent discoveries of new molecular targets and pathways, the search for an effective therapy for Glioblastoma Multiforme (GBM) continues. A newly emerged field, radiogenomics, links gene expression profiles with MRI phenotypes. MRI-FLAIR is a noninvasive diagnostic modality and was previously found to correlate with cellular invasion in GBM. Thus, our radiogenomic screen has the potential to reveal novel molecular determinants of invasion. Here, we present the first comprehensive radiogenomic analysis using quantitative MRI volumetrics and large-scale gene- and microRNA expression profiling in GBM. Methods Based on The Cancer Genome Atlas (TCGA), discovery and validation sets with gene, microRNA, and quantitative MR-imaging data were created. Top concordant genes and microRNAs correlated with high FLAIR volumes from both sets were further characterized by Kaplan Meier survival statistics, microRNA-gene correlation analyses, and GBM molecular subtype-specific distribution. Results The top upregulated gene in both the discovery (4 fold) and validation (11 fold) sets was PERIOSTIN (POSTN). The top downregulated microRNA in both sets was miR-219, which is predicted to bind to POSTN. Kaplan Meier analysis demonstrated that above median expression of POSTN resulted in significantly decreased survival and shorter time to disease progression (P<0.001). High POSTN and low miR-219 expression were significantly associated with the mesenchymal GBM subtype (P<0.0001). Conclusion Here, we propose a novel diagnostic method to screen for molecular cancer subtypes and genomic correlates of cellular invasion. Our findings also have potential therapeutic significance since successful molecular inhibition of invasion will improve therapy and patient survival in GBM. PMID:21998659

  18. Preoperative biomarkers of tumour vascularity are elevated in patients with glioblastoma multiforme.

    PubMed

    Bennett, Iwan E; Guo, Hui; Kountouri, Nicole; D'abaco, Giovanna M; Hovens, Christopher M; Moffat, Bradford A; Desmond, Patricia; Drummond, Katharine; Kaye, Andrew H; Morokoff, Andrew P

    2015-11-01

    We investigated the correlation between the circulating and imaging biomarkers of tumour vascularity, and examined whether they are prognostic of outcomes in patients with glioblastoma multiforme (GBM). Despite the increasing use of anti-angiogenic agents within neuro-oncology, there are still no validated biomarkers to monitor for a treatment response or relapse. The pre- and postoperative circulating endothelial cell (CEC) and progenitor cell (CEP) levels were assessed. Preoperative perfusion-weighted MRI (PWI) was also performed, and the relative cerebral blood volume (rCBV) histogram statistics of the contrast-enhancing tumour were analysed. A novel PWI parameter (rCBVload) was developed to estimate the total volume of perfused tumour vessels, and it was hypothesised that this parameter would correlate with CEC and CEP concentrations. In total, 24 GBM patients were included. The mean preoperative CEC concentration was significantly higher in GBM patients than the controls (p=0.019), and it then declined significantly postoperatively (p=0.009). The preoperative CEP levels were significantly correlated with the median tumour rCBV (Spearman rank-order coefficient=0.526; p=0.039). Neither CEC nor CEP was correlated with the total tumour vessel volume, as measured by rCBVload. None of the biomarkers that were investigated showed a significant correlation with progression-free or overall survival. We conclude that CEC are potentially useful biomarkers to monitor GBM patients during treatment. We found that CEC are increased in the presence of GBM, and that CEP levels appear to be proportional to tumour vascularity, as measured on PWI. However, in this study, none of the biomarkers of GBM vascularity were highly prognostic of patient outcomes.

  19. A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme

    PubMed Central

    de Aquino, Priscila F.; Carvalho, Paulo Costa; Nogueira, Fábio C. S.; da Fonseca, Clovis Orlando; de Souza Silva, Júlio Cesar Thomé; Carvalho, Maria da Gloria da Costa; Domont, Gilberto B.; Zanchin, Nilson I. T.; Fischer, Juliana de Saldanha da Gama

    2016-01-01

    Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM. For this, we profiled tumor fragments from the profound region of the same patient’s GBM but obtained from two surgeries a year’s time apart. Our analysis also included GBM‘s fragments from different anatomical regions. Our quantitative proteomic strategy employed 4-plex iTRAQ peptide labeling followed by a four-step strong cation chromatographic separation; each fraction was then analyzed by reversed-phase nano-chromatography coupled on-line with an Orbitrap-Velos mass spectrometer. Unsupervised clustering grouped the proteomic profiles into four major distinct groups and showed that most changes were related to the tumor’s anatomical region. Nevertheless, we report differentially abundant proteins from GBM’s fragments of the same region but obtained 1 year apart. We discuss several key proteins (e.g., S100A9) and enriched pathways linked with GBM such as the Ras pathway, RHO GTPases activate PKNs, and those related to apoptosis, to name a few. As far as we know, this is the only report that compares GBM fragments proteomic profiles from the same patient. Ultimately, our results fuel the forefront of scientific discussion on the importance in exploring the richness of subproteomes within a single tissue sample for a better understanding of the disease, as each tumor is unique. PMID:27597932

  20. Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: A phase I study†

    PubMed Central

    Butowski, Nicholas; Chang, Susan M.; Lamborn, Kathleen R.; Polley, Mei Yin; Parvataneni, R.; Hristova-Kazmierski, Maria; Musib, Luna; Nicol, Steven J.; Thornton, Donald E.; Prados, Michael D.

    2010-01-01

    We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCβ] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status ≥60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m2 daily) followed by adjuvant temozolomide (200 mg/m2) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if ≤1/6 patients had dose-limiting toxicity (DLT) during RT and the first adjuvant cycle. Patients continued treatment for 12 adjuvant cycles unless disease progression or unacceptable toxicity occurred. Twelve patients enrolled. There was no DLT in the first 6 patients treated with 250 mg enzastaurin. At 500 mg, 2 of 6 patients experienced a DLT (1 Grade 4 and 1 Grade 3 thrombocytopenia). The patient with Grade 3 DLT recovered to Grade <1 within 28 days and adjuvant temozolomide and enzastaurin was reinitiated with dose reductions. The other patient recovered to Grade <1 toxicity after 28 days and did not restart treatment. Enzastaurin 250 mg/d given concomitantly with RT and temozolomide and adjuvantly with temozolomide was well tolerated and is the recommended phase II dose. The proceeding phase II trial has finished accrual and results will be reported in 2009. PMID:20156802

  1. Glioblastoma multiforme of the optic chiasm: A rare case of common pathology

    PubMed Central

    Lyapichev, Kirill A.; Bregy, Amade; Cassel, Adrienne; Handfield, Chelsea; Velazquez-Vega, Jose; Kay, Matthew D.; Basil, Gregory; Komotar, Ricardo J.

    2016-01-01

    Background: Malignant optic and chiasmatic gliomas are extremely rare, and are classified pathologically as anaplastic astrocytoma or glioblastoma multiforme (GBM). Approximately 40 cases of optic GBM in adults have been reported in the literature, and only five of them were described to originate from the optic chiasm. Case Description: An 82-year-old male patient with a past medical history of diabetes mellitus type 2, melanoma, and bladder cancer presented with gradual vision loss of the left eye in a period of 1 month. After neuro-ophthalmological examination, the decision of thither magnetic resonance imaging (MRI) studies was made. It showed a contrast enhancing mass in the region of the optic chiasm. In this case, imaging study was not enough to establish an accurate diagnosis and a left pterional craniotomy for biopsy and resection of the optic chiasmal mass was performed. After histological evaluation of the mass tissue, the diagnosis of GBM was made. Taking into account the patient's poor condition and unfavorable prognosis he was moved to inpatient hospice. The patient deceased within 2 months after surgery. Conclusion: Chiasmal GBM is an extremely rare condition where a biopsy is necessary for accurate diagnosis and optimal treatment. Differential diagnosis for such lesions can be very difficult and include demyelinating optic neuritis and non-demyelinating inflammatory optic neuropathy (e.g., sarcoid), vascular lesions (e.g., cavernoma), compressive lesions of the optic apparatus, metastatic malignancy, and primary tumors of the anterior optic pathway. The role of chemotherapy and radiotherapy including novel stereotaxic radiosurgery methods is still unclear and will need to be evaluated. PMID:27512611

  2. A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme

    PubMed Central

    de Aquino, Priscila F.; Carvalho, Paulo Costa; Nogueira, Fábio C. S.; da Fonseca, Clovis Orlando; de Souza Silva, Júlio Cesar Thomé; Carvalho, Maria da Gloria da Costa; Domont, Gilberto B.; Zanchin, Nilson I. T.; Fischer, Juliana de Saldanha da Gama

    2016-01-01

    Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM. For this, we profiled tumor fragments from the profound region of the same patient’s GBM but obtained from two surgeries a year’s time apart. Our analysis also included GBM‘s fragments from different anatomical regions. Our quantitative proteomic strategy employed 4-plex iTRAQ peptide labeling followed by a four-step strong cation chromatographic separation; each fraction was then analyzed by reversed-phase nano-chromatography coupled on-line with an Orbitrap-Velos mass spectrometer. Unsupervised clustering grouped the proteomic profiles into four major distinct groups and showed that most changes were related to the tumor’s anatomical region. Nevertheless, we report differentially abundant proteins from GBM’s fragments of the same region but obtained 1 year apart. We discuss several key proteins (e.g., S100A9) and enriched pathways linked with GBM such as the Ras pathway, RHO GTPases activate PKNs, and those related to apoptosis, to name a few. As far as we know, this is the only report that compares GBM fragments proteomic profiles from the same patient. Ultimately, our results fuel the forefront of scientific discussion on the importance in exploring the richness of subproteomes within a single tissue sample for a better understanding of the disease, as each tumor is unique.

  3. Invariant delineation of nuclear architecture in glioblastoma multiforme for clinical and molecular association.

    PubMed

    Chang, Hang; Han, Ju; Borowsky, Alexander; Loss, Leandro; Gray, Joe W; Spellman, Paul T; Parvin, Bahram

    2013-04-01

    Automated analysis of whole mount tissue sections can provide insights into tumor subtypes and the underlying molecular basis of neoplasm. However, since tumor sections are collected from different laboratories, inherent technical and biological variations impede analysis for very large datasets such as The Cancer Genome Atlas (TCGA). Our objective is to characterize tumor histopathology, through the delineation of the nuclear regions, from hematoxylin and eosin (H&E) stained tissue sections. Such a representation can then be mined for intrinsic subtypes across a large dataset for prediction and molecular association. Furthermore, nuclear segmentation is formulated within a multi-reference graph framework with geodesic constraints, which enables computation of multidimensional representations, on a cell-by-cell basis, for functional enrichment and bioinformatics analysis. Here, we present a novel method, multi-reference graph cut (MRGC), for nuclear segmentation that overcomes technical variations associated with sample preparation by incorporating prior knowledge from manually annotated reference images and local image features. The proposed approach has been validated on manually annotated samples and then applied to a dataset of 377 Glioblastoma Multiforme (GBM) whole slide images from 146 patients. For the GBM cohort, multidimensional representation of the nuclear features and their organization have identified 1) statistically significant subtypes based on several morphometric indexes, 2) whether each subtype can be predictive or not, and 3) that the molecular correlates of predictive subtypes are consistent with the literature. Data and intermediaries for a number of tumor types (GBM, low grade glial, and kidney renal clear carcinoma) are available at: http://tcga.lbl.gov for correlation with TCGA molecular data. The website also provides an interface for panning and zooming of whole mount tissue sections with/without overlaid segmentation results for quality

  4. Molecular Predictors of Long-Term Survival in Glioblastoma Multiforme Patients

    PubMed Central

    Cowperthwaite, Matthew C.; Burnett, Mark G.; Shpak, Max

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and aggressive adult primary brain cancer, with <10% of patients surviving for more than 3 years. Demographic and clinical factors (e.g. age) and individual molecular biomarkers have been associated with prolonged survival in GBM patients. However, comprehensive systems-level analyses of molecular profiles associated with long-term survival (LTS) in GBM patients are still lacking. We present an integrative study of molecular data and clinical variables in these long-term survivors (LTSs, patients surviving >3 years) to identify biomarkers associated with prolonged survival, and to assess the possible similarity of molecular characteristics between LGG and LTS GBM. We analyzed the relationship between multivariable molecular data and LTS in GBM patients from the Cancer Genome Atlas (TCGA), including germline and somatic point mutation, gene expression, DNA methylation, copy number variation (CNV) and microRNA (miRNA) expression using logistic regression models. The molecular relationship between GBM LTS and LGG tumors was examined through cluster analysis. We identified 13, 94, 43, 29, and 1 significant predictors of LTS using Lasso logistic regression from the somatic point mutation, gene expression, DNA methylation, CNV, and miRNA expression data sets, respectively. Individually, DNA methylation provided the best prediction performance (AUC = 0.84). Combining multiple classes of molecular data into joint regression models did not improve prediction accuracy, but did identify additional genes that were not significantly predictive in individual models. PCA and clustering analyses showed that GBM LTS typically had gene expression profiles similar to non-LTS GBM. Furthermore, cluster analysis did not identify a close affinity between LTS GBM and LGG, nor did we find a significant association between LTS and secondary GBM. The absence of unique LTS profiles and the lack of similarity between LTS GBM and LGG, indicates

  5. Phase I/II Trial of Hyperfractionated Concomitant Boost Proton Radiotherapy for Supratentorial Glioblastoma Multiforme

    SciTech Connect

    Mizumoto, Masashi; Tsuboi, Koji; Igaki, Hiroshi; Yamamoto, Tetsuya; Takano, Shingo; Oshiro, Yoshiko; Hayashi, Yasutaka; Hashii, Haruko; Kanemoto, Ayae; Nakayama, Hidetsugu; Sugahara, Shinji; Sakurai, Hideyuki; Matsumura, Akira; Tokuuye, Koichi

    2010-05-01

    Purpose: To evaluate the safety and efficacy of postoperative hyperfractionated concomitant boost proton radiotherapy with nimustine hydrochloride for supratentorial glioblastoma multiforme (GBM). Methods and Materials: Twenty patients with histologically confirmed supratentorial GBM met the following criteria: (1) a Karnofsky performance status of >=60; (2) the diameter of the enhanced area before radiotherapy was <=40 cm; and (3) the enhanced area did not extend to the brain stem, hypothalamus, or thalamus. Magnetic resonance imaging (MRI) T{sub 2}-weighted high area (clinical tumor volume 3 [CTV3]) was treated by x-ray radiotherapy in the morning (50.4 Gy in 28 fractions). More than 6 hours later, 250 MeV proton beams were delivered to the enhanced area plus a 10-mm margin (CTV2) in the first half of the protocol (23.1 GyE in 14 fractions) and to the enhanced volume (CTV1) in the latter half (23.1 GyE in 14 fraction). The total dose to the CTV1 was 96.6 GyE. Nimustine hydrochloride (80 mg/m2) was administered during the first and fourth weeks. Results: Acute toxicity was mainly hematologic and was controllable. Late radiation necrosis and leukoencephalopathy were each seen in one patient. The overall survival rates after 1 and 2 years were 71.1% and 45.3%, respectively. The median survival period was 21.6 months. The 1- and 2-year progression-free survival rates were 45.0% and 15.5%, respectively. The median MRI change-free survival was 11.2 months. Conclusions: Hyperfractionated concomitant boost proton radiotherapy (96.6 GyE in 56 fractions) for GBM was tolerable and beneficial if the target size was well considered. Further studies are warranted to pursue the possibility of controlling border region recurrences.

  6. A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme.

    PubMed

    de Aquino, Priscila F; Carvalho, Paulo Costa; Nogueira, Fábio C S; da Fonseca, Clovis Orlando; de Souza Silva, Júlio Cesar Thomé; Carvalho, Maria da Gloria da Costa; Domont, Gilberto B; Zanchin, Nilson I T; Fischer, Juliana de Saldanha da Gama

    2016-01-01

    Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM. For this, we profiled tumor fragments from the profound region of the same patient's GBM but obtained from two surgeries a year's time apart. Our analysis also included GBM's fragments from different anatomical regions. Our quantitative proteomic strategy employed 4-plex iTRAQ peptide labeling followed by a four-step strong cation chromatographic separation; each fraction was then analyzed by reversed-phase nano-chromatography coupled on-line with an Orbitrap-Velos mass spectrometer. Unsupervised clustering grouped the proteomic profiles into four major distinct groups and showed that most changes were related to the tumor's anatomical region. Nevertheless, we report differentially abundant proteins from GBM's fragments of the same region but obtained 1 year apart. We discuss several key proteins (e.g., S100A9) and enriched pathways linked with GBM such as the Ras pathway, RHO GTPases activate PKNs, and those related to apoptosis, to name a few. As far as we know, this is the only report that compares GBM fragments proteomic profiles from the same patient. Ultimately, our results fuel the forefront of scientific discussion on the importance in exploring the richness of subproteomes within a single tissue sample for a better understanding of the disease, as each tumor is unique. PMID:27597932

  7. Differential Radiosensitizing Potential of Temozolomide in MGMT Promoter Methylated Glioblastoma Multiforme Cell Lines

    SciTech Connect

    Nifterik, Krista A. van; Berg, Jaap van den; Stalpers, Lukas J.A.; Lafleur, M. Vincent M.; Leenstra, Sieger; Slotman, Ben J.; Hulsebos, Theo J.M.; Sminia, Peter

    2007-11-15

    Purpose: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated {gamma}-irradiation. Methods and Materials: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of {gamma}-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells. Results: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 {mu}mol/L (AMC-3046), 3 {mu}mol/L (VU-109), and 2.5 {mu}mol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect. Conclusions: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to {gamma}-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gen000.

  8. Human Glioblastoma Multiforme: p53 Reactivation by a Novel MDM2 Inhibitor

    PubMed Central

    Costa, Barbara; Bendinelli, Sara; Gabelloni, Pamela; Da Pozzo, Eleonora; Daniele, Simona; Scatena, Fabrizio; Vanacore, Renato; Campiglia, Pietro; Bertamino, Alessia; Gomez-Monterrey, Isabel; Sorriento, Daniela; Del Giudice, Carmine; Iaccarino, Guido; Novellino, Ettore; Martini, Claudia

    2013-01-01

    Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM), p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2) oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ) produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients. PMID:23977270

  9. VEGFR-2 Expression in Glioblastoma Multiforme Depends on Inflammatory Tumor Microenvironment

    PubMed Central

    Jaal, Jana; Kase, Marju; Minajeva, Ave; Saretok, Mikk; Adamson, Aidi; Junninen, Jelizaveta; Metsaots, Tõnis; Jõgi, Tõnu; Joonsalu, Madis; Vardja, Markus; Asser, Toomas

    2015-01-01

    Glioblastoma multiforme (GBM) is one of the most angiogenic tumors. However, antiangiogenic therapy has not shown significant clinical efficacy. The aim of our study was to evaluate the impact of inflammatory tumor microenvironment on the expression of vascular endothelial growth factor receptor 2 (VEGFR-2). Surgically excised primary GBM tissues were histologically examined for overall extent of inflammation (score 1–3). After immunohistochemistry, the tissue expression of ICAM-1 (optical density), the number of VEGFR-2 positive (VEGFR-2+) blood vessels (per microscopic field), and the endothelial staining intensity of VEGFR-2 (score 0–3) were determined. In GBM, the extent of inflammation was 1.9 ± 0.7 (group mean ± SD). Mean optical density of inflammatory mediator ICAM-1 was 57.0 ± 27.1 (pixel values). The number of VEGFR-2+ blood vessels and endothelial VEGFR-2 staining intensity were 6.2 ± 2.4 and 1.2 ± 0.8, respectively. A positive association was found between endothelial VEGFR-2 staining intensity and the extent of inflammation (p = 0.005). Moreover, VEGFR-2 staining intensity correlated with the expression level of ICAM-1 (p = 0.026). The expression of VEGFR-2, one of the main targets of antiangiogenic therapy, depends on GBM microenvironment. Higher endothelial VEGFR-2 levels were seen in the presence of more pronounced inflammation. Target dependence on inflammatory tumor microenvironment has to be taken into consideration when treatment approaches that block VEGFR-2 signaling are designed. PMID:26798546

  10. Postoperative Treatment of Primary Glioblastoma Multiforme With Radiation and Concomitant Temozolomide in Elderly Patients

    SciTech Connect

    Combs, Stephanie E. Wagner, Johanna; Bischof, Marc; Welzel, Thomas; Wagner, Florian; Debus, Juergen; Schulz-Ertner, Daniela

    2008-03-15

    Purpose: To evaluate efficacy and toxicity in elderly patients with glioblastoma multiforme (GBM) treated with postoperative radiochemotherapy with temozolomide (TMZ). Patients and Methods: Forty-three patients aged 65 years or older were treated with postoperative with radiochemotherapy using TMZ for primary GBM. Median age at primary diagnosis was 67 years; 14 patients were female, 29 were male. A complete surgical resection was performed in 12 patients, subtotal resection in 17 patients, and biopsy only in 14 patients. Radiotherapy was applied with a median dose of 60 Gy, in a median fractionation of 5 x 2 Gy/wk. Thirty-five patients received concomitant TMZ at 50 mg/m{sup 2}, and in 8 patients 75 mg/m{sup 2} of TMZ was applied. Adjuvant cycles of TMZ were prescribed in 5 patients only. Results: Median overall survival was 11 months in all patients; the actuarial overall survival rate was 48% at 1 year and 8% at 2 years. Median overall survival was 18 months after complete resection, 16 months after subtotal resection, and 6 months after biopsy only. Median progression-free survival was 4 months; the actuarial progression-free survival rate was 41% at 6 months and 18% at 12 months. Radiochemotherapy was well tolerated in most patients and could be completed without interruption in 38 of 43 patients. Four patients developed hematologic side effects greater than Common Terminology Criteria Grade 2, which led to early discontinuation of TMZ in 1 patient. Conclusions: Radiochemotherapy is safe and effective in a subgroup of elderly patients with GBM and should be considered in patients without major comorbidities.

  11. Partial correlation analyses of global diffusion tensor imaging-derived metrics in glioblastoma multiforme: Pilot study

    PubMed Central

    Cortez-Conradis, David; Rios, Camilo; Moreno-Jimenez, Sergio; Roldan-Valadez, Ernesto

    2015-01-01

    AIM: To determine existing correlates among diffusion tensor imaging (DTI)-derived metrics in healthy brains and brains with glioblastoma multiforme (GBM). METHODS: Case-control study using DTI data from brain magnetic resonance imaging of 34 controls (mean, 41.47; SD, ± 21.94 years; range, 21-80 years) and 27 patients with GBM (mean, SD; 48.41 ± 15.18 years; range, 18-78 years). Image postprocessing using FSL software calculated eleven tensor metrics: fractional (FA) and relative anisotropy; pure isotropic (p) and anisotropic diffusions (q), total magnitude of diffusion (L); linear (Cl), planar (Cp) and spherical tensors (Cs); mean (MD), axial (AD) and radial diffusivities (RD). Partial correlation analyses (controlling the effect of age and gender) and multivariate Mancova were performed. RESULTS: There was a normal distribution for all metrics. Comparing healthy brains vs brains with GBM, there were significant very strong bivariate correlations only depicted in GBM: [FA↔Cl (+)], [FA↔q (+)], [p↔AD (+)], [AD↔MD (+)], and [MD↔RD (+)]. Among 56 pairs of bivariate correlations, only seven were significantly different. The diagnosis variable depicted a main effect [F-value (11, 23) = 11.842, P ≤ 0.001], with partial eta squared = 0.850, meaning a large effect size; age showed a similar result. The age also had a significant influence as a covariate [F (11, 23) = 10.523, P < 0.001], with a large effect size (partial eta squared = 0.834). CONCLUSION: DTI-derived metrics depict significant differences between healthy brains and brains with GBM, with specific magnitudes and correlations. This study provides reference data and makes a contribution to decrease the underlying empiricism in the use of DTI parameters in brain imaging. PMID:26644826

  12. New insights into the genetics of glioblastoma multiforme by familial exome sequencing

    PubMed Central

    Backes, Christina; Harz, Christian; Fischer, Ulrike; Schmitt, Jana; Ludwig, Nicole; Petersen, Britt-Sabina; Mueller, Sabine C.; Kim, Yoo-Jin; Wolf, Nadine M.; Katus, Hugo A.; Meder, Benjamin; Furtwängler, Rhoikos; Franke, Andre; Bohle, Rainer; Henn, Wolfram; Graf, Norbert; Keller, Andreas; Meese, Eckart

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors. We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g. PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g. Focal adhesion or ECM receptor interaction) and genomic proximity (e.g. chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma. The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease. PMID:25537509

  13. Contrast-enhancing computed tomography ring in glioblastoma multiforme after intraoperative endocurietherapy

    SciTech Connect

    Kumar, P.P.; Good, R.R.; Jones, E.O.; Skultety, F.M.; Leibrock, L.G.; McComb, R.D.

    1988-05-01

    The significance of the contrast-enhancing ring seen on serial follow-up postirradiation computed tomograms (CT) of the brain was evaluated in a group of 41 patients with glioblastoma multiforme (GM) who were treated in a phase I/II study by means of intraoperative remote afterloading endocurietherapy (ECT) with a high activity cobalt 60 probe (20.00 Gy) in one high-dose rate fraction), and conventional fractionated external-beam (EXRT) radiotherapy (60.00 Gy in 30 fractions in 7.5 weeks). All received minimum total tumor doses of 80.00 Gy. After completion of treatment, all patients were followed with serial CT scans of the brain. Two to 6 months after treatment, 27 of 41 patients developed the similar thin-walled, regular, contrast-enhancing CT rings with low-density attenuation inside and outside the ring. Postmortem study in two of these patients revealed that the thin-walled, regular, contrast-enhancing ring represented a continuous capsule of dilated cerebral vessels with inner low-density attenuation corresponding to necrosis, and outer low-density attenuation corresponding to edema. The CT appearance of the thin-walled, regular, contrast-enhancing ring produced after high-dose rate intraoperative ECT and EXRT is distinctly different from the CT ring characteristic of untreated or recurrent GM. After high-dose rate intracranial ECT and EXRT, the appearance of a post-ECT contrast-enhancing CT ring should not be automatically interpreted as recurrent disease as previously reported after conventional fractionated EXRT.

  14. Mechanisms of a Glial Modulating Agent, Propentofylline: Potential New Treatment for Glioblastoma Multiforme

    NASA Astrophysics Data System (ADS)

    Jacobs, Valerie

    Glioblastoma multiforme is the most common and aggressive primary brain tumor with a very poor prognosis despite multi-modalities of treatment. As a result, there is a critical need to develop alternative therapies. Propentofylline (PPF) is a methyl xanthine with glial modulating properties. Based on known mechanisms of PPF and the important role of glial cells in glioma growth, we hypothesized that PPF can target glial cells in the tumor microenvironment, decreasing tumor growth. More specifically, PPF can target microglia and astrocytes. In Chapter 3 we demonstrate that PPF decreases microglia migration towards CNS-1 cells, decreases CNS-1 cells invasion when cultured with microglia and decreases MMP-9 expression in microglia. In Chapter 4 we showed that PPF decreases TROY expression in microglia. In Chapter 5 we showed PPF causes astrocytes to increase glutamate uptake through the GLT-1 transporter, leading to less glutamate available for CNS-1 cells, ultimately resulting in increased CNS-1 cell apoptosis. Finally, in Chapter 6 we present supportive data that PPF uniquely targets resident microglia in the CNS due to pharmacological differences between species and cell types. This thesis describes the following major contributions to the field of glioma research: 1) identification of propentofylline as a possible new drug for GBM treatment that targets microglia and astrocytes, decreasing brain tumor growth in vivo, and further supporting a different functional role of microglia and infiltrating macrophages in the tumor microenvironment, 2) identification of TROY as a novel signaling molecule expressed in microglia in response to CNS-1 cells and involved in microglia migration, and 3) identification of differential responses between species and cell types with propentofylline treatment.

  15. Phase II Trial of Hypofractionated IMRT With Temozolomide for Patients With Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Reddy, Krishna; Damek, Denise; Gaspar, Laurie E.; Ney, Douglas; Waziri, Allen; Lillehei, Kevin; Stuhr, Kelly; Kavanagh, Brian D.; Chen Changhu

    2012-11-01

    Purpose: To report toxicity and overall survival (OS) in patients with newly diagnosed glioblastoma multiforme (GBM) treated with hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concurrent and adjuvant temozolomide (TMZ). Methods and Materials: Patients with newly diagnosed GBM after biopsy or resection and with adequate performance status and organ or bone marrow function were eligible for this study. Patients received postoperative hypo-IMRT to the surgical cavity and residual tumor seen on T1-weighted brain MRI with a 5-mm margin to a total dose of 60 Gy in 10 fractions (6 Gy/fraction) and to the T2 abnormality on T2-weighted MRI with 5-mm margin to 30 Gy in 10 fractions (3 Gy/fraction). Concurrent TMZ was given at 75 mg/m{sup 2}/day for 28 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m{sup 2}/day for 5 days every 28 days. Toxicities were defined using Common Terminology Criteria for Adverse Events version 3.0. Results: Twenty-four patients were treated, consisting of 14 men, 10 women; a median age of 60.5 years old (range, 27-77 years); and a median Karnofsky performance score of 80 (range, 60-90). All patients received hypo-IMRT and concurrent TMZ according to protocol, except for 2 patients who received only 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 6.5 (range, 0-14).With a median follow-up of 14.8 months (range, 2.7-34.2 months) for all patients and a minimum follow-up of 20.6 months for living patients, no instances of grade 3 or higher nonhematologic toxicity were observed. The median OS was 16.6 months (range, 4.1-35.9 months). Six patients underwent repeated surgery for suspected tumor recurrence; necrosis was found in 50% to 100% of the resected specimens. Conclusion: In selected GBM patients, 60 Gy hypo-IMRT delivered in 6-Gy fractions over 2 weeks with concurrent and adjuvant TMZ is safe. OS in this small cohort of patients was comparable to that treated with current standard of care

  16. Dissecting the complex regulation of Mad4 in glioblastoma multiforme cells

    PubMed Central

    Yang, Wensheng; Yang, Xiaolu; David, Gregory; Dorsey, Jay F.

    2012-01-01

    Among proteins in the c-Myc/Max/Mad/Sin3 regulatory complex, Mad4 and Sin3B are routinely detected in human glioblastoma multiforme (GBM) cell lines. In response to gamma radiation, the expression of Sin3B and Mad4 in GBM cells was upregulated in parallel over time, suggesting that Sin3B may play a role in the regulation of Mad4 stability. In agreement with this hypothesis, exogenously expressed Sin3B significantly stabilized co-transfected Mad4 and, to a lesser extent, endogenous Mad4. In addition, siRNA silencing of Sin3B induced an increase in the expression of c-Myc and Sin3A, which contributed to increased expression of Mad4. Simultaneous silencing of Sin3B, Sin3A and c-Myc decreased Mad4 stability to a greater extent than silencing of Sin3B alone. Although Mad1 was reported to be a target of c-IAP1 E3 ligase activity for degradation, the E3 ligase activity of c-IAP1 was not required for downregulation of Mad4 expression. The association of c-IAP1 with Sin3B or Mad4 suggested that Sin3B might interfere with the binding of c-IAP1 to Mad4; however, overexpression of Sin3B did not affect the interaction between Mad4 and c-IAP1. Instead, direct binding of Sin3B to c-IAP1 may protect Mad4 from degradation by c-IAP1, leading to enhanced stability of Mad4. Exogenous expression of Sin3B also inhibited c-IAP1-mediated degradation of Mad1, TRAF2, c-IAP2 and ASK1, known targets of c-IAP1 E3 ligase activity. These results indicate that Sin3B, together with other c-Myc regulatory members, maintain the steady-state level of Mad4, in part through inhibition of c-IAP1-mediated degradation of Mad4. PMID:22895069

  17. MERTK Inhibition Induces Polyploidy and Promotes Cell Death and Cellular Senescence in Glioblastoma Multiforme

    PubMed Central

    Sufit, Alexandra; Lee-Sherick, Alisa B.; DeRyckere, Deborah; Rupji, Manali; Dwivedi, Bhakti; Varella-Garcia, Marileila; Pierce, Angela M.; Kowalski, Jeanne; Wang, Xiaodong; Frye, Stephen V.; Earp, H. Shelton

    2016-01-01

    Background MER receptor tyrosine kinase (MERTK) is expressed in a variety of malignancies, including glioblastoma multiforme (GBM). Our previous work demonstrated that inhibition of MERTK using RNA interference induced cell death and chemosensitivity in GBM cells, implicating MERTK as a potential therapeutic target. Here we investigate whether a novel MERTK-selective small molecule tyrosine kinase inhibitor, UNC2025, has similar anti-tumor effects in GBM cell lines. Methods Correlations between expression of GAS6, a MERTK ligand, and prognosis were determined using data from the TCGA database. GBM cell lines (A172, SF188, U251) were treated in vitro with increasing doses of UNC2025 (50-400nM). Cell count and viability were determined by trypan blue exclusion. Cell cycle profiles and induction of apoptosis were assessed by flow cytometric analysis after BrdU or Po-Pro-1/propidium iodide staining, respectively. Polyploidy was detected by propidium iodide staining and metaphase spread. Cellular senescence was determined by β-galactosidase staining and senescence-associated secretory cytokine analysis. Results Decreased overall survival significantly correlated with high levels of GAS6 expression in GBM, highlighting the importance of TAM kinase signaling in GBM tumorigenesis and/or therapy resistance and providing strong rationale for targeting these pathways in the clinic. All three GBM cell lines exhibited dose dependent reductions in cell number and colony formation (>90% at 200nM) after treatment with UNC2025. Cell cycle analysis demonstrated accumulation of cells in the G2/M phase and development of polyploidy. After extended exposure, 60–80% of cells underwent apoptosis. The majority of surviving cells (65–95%) were senescent and did not recover after drug removal. Thus, UNC2025 mediates anti-tumor activity in GBM by multiple mechanisms. Conclusions The findings described here provide further evidence of oncogenic roles for MERTK in GBM, demonstrate the

  18. Talin1 targeting potentiates anti-angiogenic therapy by attenuating invasion and stem-like features of glioblastoma multiforme

    PubMed Central

    Kang, Wonyoung; Kim, Sung Heon; Cho, Hee Jin; Jin, Juyoun; Lee, Jeongwu; Joo, Kyeung Min; Nam, Do-Hyun

    2015-01-01

    Glioblastoma multiforme (GBM) possesses florid angiogenesis. However, the anti-angiogenic agent, Bevacizumab, did not improve overall survival of GBM patients. For more durable anti-angiogenic treatment, we interrogated resistant mechanisms of GBM against Bevacizumab. Serial orthotopic transplantation of in vivo Bevacizumab-treated GBM cells provoked complete refractoriness to the anti-angiogenic treatment. These tumors were also highly enriched with malignant phenotypes such as invasiveness, epithelial to mesenchymal transition, and stem-like features. Through transcriptome analysis, we identified that Talin1 (TLN1) significantly increased in the refractory GBMs. Inhibition of TLN1 not only attenuated malignant characteristics of GBM cells but also reversed the resistance to the Bevacizumab treatment. These data implicate TLN1 as a novel therapeutic target for GBM to overcome resistance to anti-angiogenic therapies. PMID:26336988

  19. Boron neutron capture therapy of glioblastoma multiforme using the p- boronophenylalanine-fructose complex and epithermal neutrons

    SciTech Connect

    Coderre, J.A.; Chanana, A.D.; Joel, D.D.; Liu, H.B.; Slatkin, D.N.; Wielopolski, L.; Bergland, R.; Elowitz, E.; Chadha, M.

    1994-12-31

    The amino acid analogue p-boronophenylalanine (BPA) is under investigation as a neutron capture agent for BNCT of glioblastoma multiforme. A series of patients undergoing surgical removal of tumor received BPA orally as the free amino acid. Favorable tumor/blood boron concentration ratios were obtained but the absolute amount of boron in the tumor would have been insufficient for BNCT. BPA can be solubilized at neutral pH by complexation with fructose (BPA-F). Studies with rats suggest that intraperitoneal injection of BPA-F complex produces a much higher tumor boron concentration to rat intracerebral 9L gliosarcoma that were possible with oral BPA. Higher boron concentrations have allowed higher tumor radiation doses to be delivered while maintaining the dose to the normal brain vascular endothelium below the threshold of tolerance. The experience to date of the administration of BPA-F to one patient is provided in this report.

  20. Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: Case study

    PubMed Central

    Heimberger, Amy B.; Sun, Wei; Hussain, S. Farzana; Dey, Mahua; Crutcher, Lamonne; Aldape, Ken; Gilbert, Mark; Hassenbusch, Samuel J.; Sawaya, Raymond; Schmittling, Bob; Archer, Gary E.; Mitchell, Duane A.; Bigner, Darell D.; Sampson, John H.

    2008-01-01

    Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide is an effective chemo-therapeutic agent for patients with glioblastoma multiforme, but it induces significant lymphopenia. Although there is monthly fluctuation of the white blood cell count, specifically the CD4 and CD8 counts, there was no cumulative decline in the patient described in this case report. Depriving patients of this agent, in order to treat with immunotherapy, is controversial. Despite conventional dogma, we demonstrated that chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. In fact, the temozolomide-induced lymphopenia may prove to be synergistic with a peptide vaccine secondary to inhibition of regulatory T cells or their delayed recovery. PMID:18079360

  1. Phase II study of accelerated fractionation radiation therapy with carboplatin followed by vincristine chemotherapy for the treatment of glioblastoma multiforme

    SciTech Connect

    Levin, V.A.; Yung, W.K.A.; Kyritsis, A.P.

    1995-09-30

    The purpose of this investigation was to conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with intravenous carboplatin for patients with previously untreated glioblastoma multiforme tumors. Between 1988 and 1992, 83 patients received 1.9-2.0 Gy radiation three times a day with 2-h infusions of 33 mg/m{sup 2} carboplatin for two 5-day cycles separated by 2 weeks. Seventy-four of the 83 patients (89%) received one or more courses of PCV; their median survival was 55 weeks. Total resection was performed in 20% (15 of 74), subtotal resection in 69% (51 or 74), and biospy in 11% (8 of 74); reoperation (total or subtotal resection) was performed in 28 patients (37%). Survival was worst for those {ge} 61 year old (median 35 weeks). Fits of the Cox proportional hazards regression model showed covariated individually predictive of improved survival were younger age (p <0.01), smaller log of radiation volume (p = 0.008), total or subtotal resection vs. biopsy (p = 0.056), and higher Karnofsky performance status (p = 0.055). A multivariate analysis showed that age (p = 0.013) and extent of initial surgery (p = 0.003) together were predictive of a better survival with no other variables providing additional significance. Only 8.4% (7 of 83) of patients had clinically documented therapy-associated neurotoxicity ({open_quotes}radiation necrosis{close_quotes}). When comparable selection criteria were applied, the survival in this study is similar to the results currently attainable with other chemoradiation approaches. The relative safety of accelerated fractionated radiotherapy, as used in this study with carboplatin, enables concomitant full-dose administration of chemotherapy or radiosensitizing agents in glioblastoma multiforme patients. 42 refs., 3 figs., 5 tabs.

  2. Folate Functionalized Boron Nitride Nanotubes and their Selective Uptake by Glioblastoma Multiforme Cells: Implications for their Use as Boron Carriers in Clinical Boron Neutron Capture Therapy

    PubMed Central

    2009-01-01

    Boron neutron capture therapy (BNCT) is increasingly being used in the treatment of several aggressive cancers, including cerebral glioblastoma multiforme. The main requirement for this therapy is selective targeting of tumor cells by sufficient quantities of10B atoms required for their capture/irradiation with low-energy thermal neutrons. The low content of boron targeting species in glioblastoma multiforme accounts for the difficulty in selective targeting of this very malignant cerebral tumor by this radiation modality. In the present study, we have used for the first time boron nitride nanotubes as carriers of boron atoms to overcome this problem and enhance the selective targeting and ablative efficacy of BNCT for these tumors. Following their dispersion in aqueous solution by noncovalent coating with biocompatible poly-l-lysine solutions, boron nitride nanotubes were functionalized with a fluorescent probe (quantum dots) to enable their tracking and with folic acid as selective tumor targeting ligand. Initial in vitro studies have confirmed substantive and selective uptake of these nanovectors by glioblastoma multiforme cells, an observation which confirms their potential clinical application for BNCT therapy for these malignant cerebral tumors. PMID:20596476

  3. Glioblastoma multiforme: Effect of hypoxia and hypoxia inducible factors on therapeutic approaches

    PubMed Central

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors. Hypoxic regions of glioblastoma exacerbate the prognosis and clinical outcomes of the patients as hypoxic tumor cells are resistant to chemo- and radiation therapy and are also protected by the malfunctional vasculature that developed due to hypoxia. Predominantly, hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF)/VEGF receptor, transforming growth factor-β, epidermal growth factor receptor and PI3 kinase/Akt signaling systems are involved in tumor progression and growth. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Abnormal vessel formation is crucial in generating pseudopalisading necrosis regions that protect cancer stem cells residing in that region from therapeutic agents and this facilitates the cancer stem cell niche to expand and contribute to cell proliferation and tumor growth. Therapeutic approaches that target hypoxia-induced factors, such as use of the monoclonal antibody against VEGF, bevacizumab, have been useful only in stabilizing the disease but failed to increase overall survival. Hypoxia-activated TH-302, a nitroimidazole prodrug of cytotoxin bromo-isophosphoramide mustard, appears to be more attractive due to its better beneficial effects in glioblastoma patients. A better understanding of the hypoxia-mediated protection of glioblastoma cells is required for developing more effective therapeutics. PMID:27698790

  4. Glioblastoma multiforme: Effect of hypoxia and hypoxia inducible factors on therapeutic approaches

    PubMed Central

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors. Hypoxic regions of glioblastoma exacerbate the prognosis and clinical outcomes of the patients as hypoxic tumor cells are resistant to chemo- and radiation therapy and are also protected by the malfunctional vasculature that developed due to hypoxia. Predominantly, hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF)/VEGF receptor, transforming growth factor-β, epidermal growth factor receptor and PI3 kinase/Akt signaling systems are involved in tumor progression and growth. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Abnormal vessel formation is crucial in generating pseudopalisading necrosis regions that protect cancer stem cells residing in that region from therapeutic agents and this facilitates the cancer stem cell niche to expand and contribute to cell proliferation and tumor growth. Therapeutic approaches that target hypoxia-induced factors, such as use of the monoclonal antibody against VEGF, bevacizumab, have been useful only in stabilizing the disease but failed to increase overall survival. Hypoxia-activated TH-302, a nitroimidazole prodrug of cytotoxin bromo-isophosphoramide mustard, appears to be more attractive due to its better beneficial effects in glioblastoma patients. A better understanding of the hypoxia-mediated protection of glioblastoma cells is required for developing more effective therapeutics.

  5. Phase I Trial of Hypofractionated Intensity-Modulated Radiotherapy With Temozolomide Chemotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Chen Changhu; Damek, Denise; Gaspar, Laurie E.; Waziri, Allen; Lillehei, Kevin; Kleinschmidt-DeMasters, B.K.; Robischon, Monica; Stuhr, Kelly; Rusthoven, Kyle E.; Kavanagh, Brian D.

    2011-11-15

    Purpose: To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme. Methods and Materials: Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m{sup 2}/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m{sup 2}/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used. Results: A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis. Conclusions: The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with

  6. The role of factor inhibiting HIF (FIH-1) in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme.

    PubMed

    Wang, Enfeng; Zhang, Chunyang; Polavaram, Navatha; Liu, Fengming; Wu, Gang; Schroeder, Mark A; Lau, Julie S; Mukhopadhyay, Debabrata; Jiang, Shi-Wen; O'Neill, Brian Patrick; Datta, Kaustubh; Li, Jinping

    2014-01-01

    Glioblastoma multiforme (GBM) accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1), which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis.

  7. Phase I Trial of Gross Total Resection, Permanent Iodine-125 Brachytherapy, and Hyperfractionated Radiotherapy for Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Chen, Allen M.; Chang, Susan; Pouliot, Jean; Sneed, Penny K.; Prados, Michael D.; Lamborn, Kathleen R.; Malec, Mary K.; McDermott, Michael W.; Berger, Mitchell S.; Larson, David A.

    2007-11-01

    Purpose: To evaluate the feasibility of gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy for patients with newly diagnosed glioblastoma. Methods and Materials: From April 1999 to May 2002, 21 patients with glioblastoma multiforme were enrolled on a Phase I protocol investigating planned gross total resection and immediate placement of permanent I-125 seeds, followed by postoperative hyperfractionated radiotherapy to a dose of 60 Gy at 100 cGy b.i.d., 5 days per week. Median age and Karnofsky performance status were 50 years (range, 32-65 years) and 90 (range, 70-100), respectively. Toxicity was assessed according to Radiation Therapy Oncology Group criteria. Results: Eighteen patients completed treatment according to protocol. The median preoperative tumor volume on magnetic resonance imaging was 18.6 cm{sup 3} (range, 4.4-41.2 cm{sup 3}). The median brachytherapy dose measured 5 mm radially outward from the resection cavity was 400 Gy (range, 200-600 Gy). Ten patients underwent 12 reoperations, with 11 of 12 reoperations demonstrating necrosis without evidence of tumor. Because of high toxicity, the study was terminated early. Median progression-free survival and overall survival were 57 and 114 weeks, respectively, but not significantly improved compared with historical patients treated at University of California, San Francisco, with gross total resection and radiotherapy without brachytherapy. Conclusions: Treatment with gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy as performed in this study results in high toxicity and reoperation rates, without demonstrated improvement in survival.

  8. Spatial Habitat Features Derived from Multiparametric Magnetic Resonance Imaging Data Are Associated with Molecular Subtype and 12-Month Survival Status in Glioblastoma Multiforme

    PubMed Central

    Lee, Joonsang; Narang, Shivali; Martinez, Juan; Rao, Ganesh; Rao, Arvind

    2015-01-01

    One of the most common and aggressive malignant brain tumors is Glioblastoma multiforme. Despite the multimodality treatment such as radiation therapy and chemotherapy (temozolomide: TMZ), the median survival rate of glioblastoma patient is less than 15 months. In this study, we investigated the association between measures of spatial diversity derived from spatial point pattern analysis of multiparametric magnetic resonance imaging (MRI) data with molecular status as well as 12-month survival in glioblastoma. We obtained 27 measures of spatial proximity (diversity) via spatial point pattern analysis of multiparametric T1 post-contrast and T2 fluid-attenuated inversion recovery MRI data. These measures were used to predict 12-month survival status (≤12 or >12 months) in 74 glioblastoma patients. Kaplan-Meier with receiver operating characteristic analyses was used to assess the relationship between derived spatial features and 12-month survival status as well as molecular subtype status in patients with glioblastoma. Kaplan-Meier survival analysis revealed that 14 spatial features were capable of stratifying overall survival in a statistically significant manner. For prediction of 12-month survival status based on these diversity indices, sensitivity and specificity were 0.86 and 0.64, respectively. The area under the receiver operating characteristic curve and the accuracy were 0.76 and 0.75, respectively. For prediction of molecular subtype status, proneural subtype shows highest accuracy of 0.93 among all molecular subtypes based on receiver operating characteristic analysis. We find that measures of spatial diversity from point pattern analysis of intensity habitats from T1 post-contrast and T2 fluid-attenuated inversion recovery images are associated with both tumor subtype status and 12-month survival status and may therefore be useful indicators of patient prognosis, in addition to providing potential guidance for molecularly-targeted therapies in

  9. The effect of silver nanoparticles (AgNPs) on proliferation and apoptosis of in ovo cultured glioblastoma multiforme (GBM) cells

    NASA Astrophysics Data System (ADS)

    Urbańska, Kaja; Pająk, Beata; Orzechowski, Arkadiusz; Sokołowska, Justyna; Grodzik, Marta; Sawosz, Ewa; Szmidt, Maciej; Sysa, Paweł

    2015-03-01

    Recently, it has been shown that silver nanoparticles (AgNPs) provide a unique approach to the treatment of tumors, especially those of neuroepithelial origin. Thus, the aim of this study was to evaluate the impact of AgNPs on proliferation and activation of the intrinsic apoptotic pathway of glioblastoma multiforme (GBM) cells cultured in an in ovo model. Human GBM cells, line U-87, were placed on chicken embryo chorioallantoic membrane. After 8 days, the tumors were divided into three groups: control (non-treated), treated with colloidal AgNPs (40 μg/ml), and placebo (tumors supplemented with vehicle only). At the end of the experiment, all tumors were isolated. Assessment of cell proliferation and cell apoptosis was estimated by histological, immunohistochemical, and Western blot analyses. The results show that AgNPs can influence GBM growth. AgNPs inhibit proliferation of GBM cells and seem to have proapoptotic properties. Although there were statistically significant differences between control and AgNP groups in the AI and the levels of active caspase 9 and active caspase 3, the level of these proteins in GBM cells treated with AgNPs seems to be on the border between the spontaneous apoptosis and the induced. Our results indicate that the antiproliferative properties of silver nanoparticles overwhelm proapoptotic ones. Further research focused on the cytotoxic effect of AgNPs on tumor and normal cells should be conducted.

  10. Graphene Functionalized with Arginine Decreases the Development of Glioblastoma Multiforme Tumor in a Gene-Dependent Manner

    PubMed Central

    Sawosz, Ewa; Jaworski, Sławomir; Kutwin, Marta; Vadalasetty, Krishna Prasad; Grodzik, Marta; Wierzbicki, Mateusz; Kurantowicz, Natalia; Strojny, Barbara; Hotowy, Anna; Lipińska, Ludwika; Jagiełło, Joanna; Chwalibog, André

    2015-01-01

    Our previous studies revealed that graphene had anticancer properties in experiments in vitro with glioblastoma multiforme (GBM) cells and in tumors cultured in vivo. We hypothesized that the addition of arginine or proline to graphene solutions might counteract graphene agglomeration and increase the activity of graphene. Experiments were performed in vitro with GBM U87 cells and in vivo with GBM tumors cultured on chicken embryo chorioallantoic membranes. The measurements included cell morphology, mortality, viability, tumor morphology, histology, and gene expression. The cells and tumors were treated with reduced graphene oxide (rGO) and rGO functionalized with arginine (rGO + Arg) or proline (rGO + Pro). The results confirmed the anticancer effect of graphene on GBM cells and tumor tissue. After functionalization with amino acids, nanoparticles were distributed more specifically, and the flakes of graphene were less agglomerated. The molecule of rGO + Arg did not increase the expression of TP53 in comparison to rGO, but did not increase the expression of MDM2 or the MDM2/TP53 ratio in the tumor, suggesting that arginine may block MDM2 expression. The expression of NQO1, known to be a strong protector of p53 protein in tumor tissue, was greatly increased. The results indicate that the complex of rGO + Arg has potential in GBM therapy. PMID:26512645

  11. [Perampanel in the treatment of a patient with glioblastoma multiforme without IDH1 mutation and without MGMT promotor methylation].

    PubMed

    Rösche, J; Piek, J; Hildebrandt, G; Grossmann, A; Kirschstein, T; Benecke, R

    2015-05-01

    Malignant gliomas like glioblastoma multiforme (GBM) release glutamate which causes excitotoxic death to surrounding neurons, thereby vacating room for tumor expansion. We report the case of a patient with GBM treated with the AMPA receptor blocker Perampanel (PER) in combination therapy for partial seizures. Histological work-up of a biopsy showed the tissue of a GBM without mutation of the isocitrate dehydrogenase 1 (IDH1) and without promotor methylation of the O6-methylguanine-DNA methyltransferase (MGMT). In a group of patients with IDH 1 wild type and non-methylated MGMT a median survival of 199 days after surgery (i. e. 6.5 months) was described. Our patient lived about one year longer. PER rendered our patient seizure-free for at least the last seven months of his life. It was well tolerated and did not increase the toxicity of temozolomide. When choosing an antiepileptic drug (AED) for the treatment of seizures in patients with malignant brain tumors, the efficacy, the tolerability and perhaps possible effects on tumor progression of the AED should be taken into account. PMID:26018396

  12. MiR-26a enhances the radiosensitivity of glioblastoma multiforme cells through targeting of ataxia–telangiectasia mutated

    SciTech Connect

    Guo, Pin; Lan, Jin; Ge, Jianwei; Nie, Quanmin; Guo, Liemei; Qiu, Yongming; Mao, Qing

    2014-01-15

    Glioblastoma multiforme (GBM) is notoriously resistant to radiation, and consequently, new radiosensitizers are urgently needed. MicroRNAs are a class of endogenous gene modulators with emerging roles in DNA repair. We found that overexpression of miR-26a can enhance radiosensitivity and reduce the DNA repair ability of U87 cells. However, knockdown miR-26a in U87 cells could act the converse manner. Mechanistically, this effect is mediated by direct targeting of miR-26a to the 3′UTR of ATM, which leads to reduced ATM levels and consequent inhibition of the homologous recombination repair pathway. These results suggest that miR-26a may act as a new radiosensitizer of GBM. - Highlights: ●miR-26a directly target ATM in GBM cells. ●miR-26a enhances the radiosensitivity of GBM cells. ●miR-26a could reduce the DNA repair capacity of GBM cells.

  13. Methylglyoxal (MGO) inhibits proliferation and induces cell death of human glioblastoma multiforme T98G and U87MG cells.

    PubMed

    Paul-Samojedny, Monika; Łasut, Barbara; Pudełko, Adam; Fila-Daniłow, Anna; Kowalczyk, Małgorzata; Suchanek-Raif, Renata; Zieliński, Michał; Borkowska, Paulina; Kowalski, Jan

    2016-05-01

    Glioblastoma multiforme (GBM) is the most malignant and invasive human brain tumor and it is characterized by a poor prognosis and short survival time. Current treatment strategies for GBM using surgery, chemotherapy and/or radiotherapy are ineffective. Thus new therapeutic strategies to target GBM are urgently needed. The effect of methylglyoxal (MGO) on the cell cycle, cell death and proliferation of human GBM cells was investigated. The T98G and U87MG cell lines were cultured in modified EMEM supplemented with 10% fetal bovine serum and maintained at 37°C in a humidified atmosphere of 5% CO2 in air. Cells were exposed to methylglyoxal (0.025mM) per 72h. The influence of MGO on T98G and U87MG cell cycle, proliferation and apoptosis was evaluated as well. Cell cycle phase distribution, proliferation, apoptosis were analyzed by flow cytometry. MGO causes changes in cell cycle and induces accumulation of G1/G0-phase cells and reduced fraction of cells in S and G2/M phases. We have also observed inhibition of cell proliferation and induction of apoptosis in cancer cells. We have also revealed that MGO induces senescence of U87MG but not T98G cells, but further studies are necessary in order to clarify and check mechanism of action of methylglyoxal and it Is a positive phenomenon for the treatment of GBM. PMID:27133062

  14. Nitric oxide released from JS-K induces cell death by mitotic catastrophe as part of necrosis in glioblastoma multiforme

    PubMed Central

    Günzle, Jessica; Osterberg, Nadja; Saavedra, Joseph E; Weyerbrock, Astrid

    2016-01-01

    The nitric oxide (NO) donor JS-K is specifically activated by glutathione S-transferases (GSTs) in GST-overexpressing cells. We have shown the induction of cell death in glioblastoma multiforme (GBM) cells at high JS-K doses but the mechanism remains unclear. The aim of this study was to determine whether NO-induced cell death is triggered by induction of apoptotic or necrotic pathways. For the first time, we demonstrate that NO induces cell death via mitotic catastrophe (MC) with non-apoptotic mechanisms in GBM cells. Moreover, the level of morphological changes indicating MC correlates with increased necrosis. Therefore, we conclude that MC is the main mechanism by which GBM cells undergo cell death after treatment with JS-K associated with necrosis rather than apoptosis. In addition, we show that PARP1 is not an exclusive marker for late apoptosis but is also involved in MC. Activating an alternative way of cell death can be useful for the multimodal cancer therapy of GBM known for its strong anti-apoptotic mechanisms and drug resistance. PMID:27584787

  15. Treatment of glioblastoma multiforme cells with temozolomide-BioShuttle ligated by the inverse Diels-Alder ligation chemistry

    PubMed Central

    Braun, Klaus; Wiessler, Manfred; Ehemann, Volker; Pipkorn, Ruediger; Spring, Herbert; Debus, Juergen; Didinger, Bernd; Koch, Mario; Muller, Gabriele; Waldeck, Waldemar

    2008-01-01

    Recurrent glioblastoma multiforme (GBM), insensitive against most therapeutic interventions, has low response and survival rates. Temozolomide (TMZ) was approved for second-line therapy of recurrent anaplastic astrocytoma. However, TMZ therapy in GBM patients reveals properties such as reduced tolerability and inauspicious hemogram. The solution addressed here concerning GBM therapy consolidates and uses the potential of organic and peptide chemistry with molecular medicine. We enhanced the pharmacologic potency with simultaneous reduction of unwanted adverse reactions of the highly efficient chemotherapeutic TMZ. The TMZ connection to transporter molecules (TMZ-BioShuttle) was investigated, resulting in a much higher pharmacological effect in glioma cell lines and also with reduced dose rate. From this result we can conclude that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation. The TMZ-BioShuttle dramatically enhanced the potential of TMZ for the treatment of brain tumors and is an attractive drug for combination chemotherapy. PMID:19920915

  16. Brain Stem and Entire Spinal Leptomeningeal Dissemination of Supratentorial Glioblastoma Multiforme in a Patient during Postoperative Radiochemotherapy

    PubMed Central

    Kong, Xiangyi; Wang, Yu; Liu, Shuai; Chen, Keyin; Zhou, Qiangyi; Yan, Chengrui; He, Huayu; Gao, Jun; Guan, Jian; Yang, Yi; Li, Yongning; Xing, Bing; Wang, Renzhi; Ma, Wenbin

    2015-01-01

    Abstract Glioblastoma multiforme (GBM) is the most common primary malignancy of the central nervous system in adults. Macroscopically evident and symptomatic spinal metastases occur rarely. Autopsy series suggest that approximately 25% of patients with intracranial GBM have evidence of spinal subarachnoid seeding, although the exact incidence is not known as postmortem examination of the spine is not routinely performed.1–3 Herein, we present a rare case of symptomatic brain stem and entire spinal dissemination of GBM in a 36-year-old patient during postoperative adjuvant radiochemotherapy with temozolomide and cisplatin. Visual deterioration, intractable stomachache, and limb paralysis were the main clinical features. The results of cytological and immunohistochemical tests on the cerebrospinal fluid cells were highly suggestive of spinal leptomeningeal dissemination. After 1 month, the patient's overall condition deteriorated and succumbed to his disease. To the best of our knowledge, this is the first reported case of GBM dissemination presenting in this manner. Because GBM extracranial dissemination is rare, we also reviewed pertinent literature regarding this uncommon entity. Although metastases to spinal cord from GBM are uncommon, it is always important to have in mind when patients with a history of GBM present with symptoms that do not correlate with the primary disease pattern.

  17. C-Myc negatively controls the tumor suppressor PTEN by upregulating miR-26a in glioblastoma multiforme cells

    SciTech Connect

    Guo, Pin; Nie, Quanmin; Lan, Jin; Ge, Jianwei; Qiu, Yongming; Mao, Qing

    2013-11-08

    Highlights: •The c-Myc oncogene directly upregulates miR-26a expression in GBM cells. •ChIP assays demonstrate that c-Myc interacts with the miR-26a promoter. •Luciferase reporter assays show that PTEN is a specific target of miR-26a. •C-Myc–miR-26a suppression of PTEN may regulate the PTEN/AKT pathway. •Overexpression of c-Myc enhances the proliferative capacity of GBM cells. -- Abstract: The c-Myc oncogene is amplified in many tumor types. It is an important regulator of cell proliferation and has been linked to altered miRNA expression, suggesting that c-Myc-regulated miRNAs might contribute to tumor progression. Although miR-26a has been reported to be upregulated in glioblastoma multiforme (GBM), the mechanism has not been established. We have shown that ectopic expression of miR-26a influenced cell proliferation by targeting PTEN, a tumor suppressor gene that is inactivated in many common malignancies, including GBM. Our findings suggest that c-Myc modulates genes associated with oncogenesis in GBM through deregulation of miRNAs via the c-Myc–miR-26a–PTEN signaling pathway. This may be of clinical relevance.

  18. Dysregulation of TFDP1 and of the cell cycle pathway in high-grade glioblastoma multiforme: a bioinformatic analysis.

    PubMed

    Lu, X; Lv, X D; Ren, Y H; Yang, W D; Li, Z B; Zhang, L; Bai, X F

    2016-01-01

    Despite extensive research, the prognosis of high-grade glioblastoma multiforme (GBM) has improved only slightly because of the limited response to standard treatments. Recent advances (discoveries of molecular biomarkers) provide new opportunities for the treatment of GBM. The aim of the present study was to identify diagnostic biomarkers of high-grade GBM. First, we combined 3 microarray expression datasets to screen them for genes differentially expressed in patients with high-grade GBM relative to healthy subjects. Next, the target network was constructed via the empirical Bayesian coexpression approach, and centrality analysis and a molecular complex detection (MCODE) algorithm were performed to explore hub genes and functional modules. Finally, a validation test was conducted to verify the bioinformatic results. A total of 277 differentially expressed genes were identified according to the criteria P < 0.05 and |log2(fold change)| ≥ 1.5. These genes were most significantly enriched in the cell cycle pathway. Centrality analysis uncovered 9 hub genes; among them, TFDP1 showed the highest degree of connectivity (43) and is a known participant in the cell cycle pathway; this finding pointed to the important role of TFDP1 in the progression of high-grade GBM. Experimental validation mostly supported the bioinformatic results. According to our study results, the gene TFDP1 and the cell cycle pathway are strongly associated with high-grade GBM; this result may provide new insights into the pathogenesis of GBM. PMID:27323154

  19. Graphene Functionalized with Arginine Decreases the Development of Glioblastoma Multiforme Tumor in a Gene-Dependent Manner.

    PubMed

    Sawosz, Ewa; Jaworski, Sławomir; Kutwin, Marta; Vadalasetty, Krishna Prasad; Grodzik, Marta; Wierzbicki, Mateusz; Kurantowicz, Natalia; Strojny, Barbara; Hotowy, Anna; Lipińska, Ludwika; Jagiełło, Joanna; Chwalibog, André

    2015-10-23

    Our previous studies revealed that graphene had anticancer properties in experiments in vitro with glioblastoma multiforme (GBM) cells and in tumors cultured in vivo. We hypothesized that the addition of arginine or proline to graphene solutions might counteract graphene agglomeration and increase the activity of graphene. Experiments were performed in vitro with GBM U87 cells and in vivo with GBM tumors cultured on chicken embryo chorioallantoic membranes. The measurements included cell morphology, mortality, viability, tumor morphology, histology, and gene expression. The cells and tumors were treated with reduced graphene oxide (rGO) and rGO functionalized with arginine (rGO + Arg) or proline (rGO + Pro). The results confirmed the anticancer effect of graphene on GBM cells and tumor tissue. After functionalization with amino acids, nanoparticles were distributed more specifically, and the flakes of graphene were less agglomerated. The molecule of rGO + Arg did not increase the expression of TP53 in comparison to rGO, but did not increase the expression of MDM2 or the MDM2/TP53 ratio in the tumor, suggesting that arginine may block MDM2 expression. The expression of NQO1, known to be a strong protector of p53 protein in tumor tissue, was greatly increased. The results indicate that the complex of rGO + Arg has potential in GBM therapy.

  20. Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines

    PubMed Central

    Binder, Zev A.; Wilson, Kelli M.; Salmasi, Vafi; Orr, Brent A.; Eberhart, Charles G.; Siu, I-Mei; Lim, Michael; Weingart, Jon D.; Quinones-Hinojosa, Alfredo; Bettegowda, Chetan; Kassam, Amin B.; Olivi, Alessandro; Brem, Henry; Riggins, Gregory J.; Gallia, Gary L.

    2016-01-01

    Objective Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of GBM cell lines including GBM variants. Methods Tumor tissue samples were obtained intra-operatively and cultured in neural stem cell conditions containing growth factors. Tumor lines were characterized in vitro using differentiation assays followed by immunostaining for lineage-specific markers. In vivo tumor formation was assayed by orthotopic injection in nude mice. Genetic uniqueness was confirmed via short tandem repeat (STR) DNA profiling. Results Thirteen oncosphere lines derived from GBM and GBM variants, including a GBM with PNET features and a GBM with oligodendroglioma component, were established. All unique lines showed distinct genetic profiles by STR profiling. The lines assayed demonstrated a range of in vitro growth rates. Multipotency was confirmed using in vitro differentiation. Tumor formation demonstrated histologic features consistent with high grade gliomas, including invasion, necrosis, abnormal vascularization, and high mitotic rate. Xenografts derived from the GBM variants maintained histopathological features of the primary tumors. Conclusions We have generated and characterized GBM suspension lines derived from patients with GBMs and GBM variants. These oncosphere cell lines will expand the resources available for preclinical study. PMID:27028405

  1. Cost-effectiveness analysis of the bevacizumab-irinotecan regimen in the treatment of primary glioblastoma multiforme recurrences

    PubMed Central

    Ruiz-Sánchez, Daniel; Peinado, Irene Iglesias; Alaguero-Calero, Miguel; Sastre-Heres, Alejandro José; Diez, Benito García; Peña-Díaz, Jaime

    2016-01-01

    The purpose of the present study was to calculate the cost-effectiveness of the inclusion of the bevacizumab (BVZ) + irinotecan (CPT-11) regimen in the second-line of treatment for primary glioblastoma multiforme. A retrospective cohort study with a control group was performed in which the cost-effectiveness of a course of chemotherapy was calculated based on survival time and the incremental cost between the two lines of treatment. A total of 77 patients were included, 36 of who formed the BVZ/CPT-11 cohort. The median survival time for the non-BVZ control cohort was 13.23 months [95% confidence interval (CI), 11.79–14.68], while for the BVZ/CPT-11 treatment cohort, the median survival time was 17.63 months (95% CI, 15.38–19.89). Overall, each year of life gained for each patient treated with BVZ/CPT-11 would cost €46,401.99. These results demonstrate the effectiveness of the BVZ/CPT-11 combination, but its incremental cost compared with other lines of treatment or the best care available does not appear to be acceptable for public health systems in the current situation of budgetary adjustments. PMID:27588142

  2. Ketoprofen-loaded polymeric nanocapsules selectively inhibit cancer cell growth in vitro and in preclinical model of glioblastoma multiforme.

    PubMed

    da Silveira, Elita F; Chassot, Janaine M; Teixeira, Fernanda C; Azambuja, Juliana H; Debom, Gabriela; Beira, Fátima T; Del Pino, Francisco A B; Lourenço, Adriana; Horn, Ana P; Cruz, Letícia; Spanevello, Roselia M; Braganhol, Elizandra

    2013-12-01

    Glioblastoma multiforme (GBM) is the worst and most common brain tumor, characterized by high proliferation and invasion rates. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted interest in recent years since they provide targeted delivery and may overcame the obstacle imposed by blood-brain barrier. Here we investigated the antitumoral effect of ketoprofen-loaded nanocapsules (Keto-NC) treatment on in vitro and in vivo glioma progression. We observed that Keto-NC treatment decreased selectively the cell viability of a panel of glioma cell lines, while did not exhibited toxicity to astrocytes. We further demonstrate that the treatment with sub-therapeutic dose of Keto-NC reduced the in vivo glioma growth as well as reduced the malignity characteristics of implanted tumors. Keto-NC treatment improved the weight, the locomotion/exploration behavior of glioma-bearing rats. Importantly, Keto-NC treatment neither induced mortality or peripheral damage. Finally, Ketoprofen also altered the extracellular nucleotide metabolism of peripheral lymphocytes, suggesting that antiinflammatory effects of ketoprofen could also be associated with the modulation of the adenine nucleotide metabolism in lymphocytes. Data indicate at first time the potential of Keto-NC as a promising therapeutic alterative to GBM treatment.

  3. EGF receptor inhibitors in the treatment of glioblastoma multiform: old clinical allies and newly emerging therapeutic concepts.

    PubMed

    Gadji, Macoura; Crous, Ana-Maria Tsanaclis; Fortin, David; Krcek, Jerry; Torchia, Mark; Mai, Sabine; Drouin, Regen; Klonisch, Thomas

    2009-12-25

    Glioblastoma multiform (GBM) is the most common malignant brain tumour in adults. Despite decades of experimentation to improve the outcome of patients with GBM this highly aggressive tumour remains fatal. Primary GBM are often characterized by the over-expression of epidermal growth factor (EGF) receptor/HER1 and/or its mutational variants, with ligand-independent, constitutively active EGF receptor vIII variant most frequently observed in GBM. EGF receptor signalling can promote tumorigenesis by increasing cell proliferation, tissue invasion, neoangiogenesis, tumour cell chemoresistance, and by inhibiting apoptosis of cancer cells. EGF receptor was the first receptor to serve as target for cancer therapy of many solid tumours. After 2 decades of intensive targeting of EGF receptor for molecular therapy, several anti-EGF receptor inhibitors are now available in the clinic. Therapeutic strategies to target EGF receptor and EGF receptor mutant forms in GBM include humanized monoclonal antibodies, tyrosine kinase inhibitors, and RNAi compounds. However, despite the fact that most EGF receptor-directed glioma therapies to date have focused on single therapeutic agents, a multi-directional approach involving targeted inhibition of multiple signalling pathways has emerged as a more robust therapeutical approach. Furthermore, the emergence of the hypothesis of "brain cancer stem cells" in the bulb of GBM identifies this population of cells with self-renewal capacity as novel obligatory targets for efficient cure of GBM. Here we summarize current findings on the clinical role of these EGF receptor inhibitory therapeutic agents in the treatment of GBM.

  4. An update in the use of antibodies to treat glioblastoma multiforme.

    PubMed

    Hernández-Pedro, Norma Y; Rangel-López, Edgar; Vargas Félix, Gustavo; Pineda, Benjamín; Sotelo, Julio

    2013-01-01

    Glioblastoma is a deadly brain disease and modest improvement in survival has been made. At initial diagnosis, treatment consists of maximum safe surgical resection, followed by temozolomide and chemoirradiation or adjuvant temozolomide alone. However, these treatments do not improve the prognosis and survival of patients. New treatment strategies are being sought according to the biology of tumors. The epidermal growth factor receptor has been considered as the hallmark in glioma tumors; thereby, some antibodies have been designed to bind to this receptor and block the downstream signaling pathways. Also, it is known that vascularization plays an important role in supplying new vessels to the tumor; therefore, new therapy has been guided to inhibit angiogenic growth factors in order to limit tumor growth. An innovative strategy in the treatment of glial tumors is the use of toxins produced by bacteria, which may be coupled to specific carrier-ligands and used for tumoral targeting. These carrier-ligands provide tumor-selective properties by the recognition of a cell-surface receptor on the tumor cells and promote their binding of the toxin-carrier complex prior to entry into the cell. Here, we reviewed some strategies to improve the management and treatment of glioblastoma and focused on the use of antibodies.

  5. Reassessing the Role of Intra-Arterial Drug Delivery for Glioblastoma Multiforme Treatment

    PubMed Central

    Ellis, Jason A.; Banu, Matei; Hossain, Shaolie S.; Singh-Moon, Rajinder; Lavine, Sean D.; Bruce, Jeffrey N.; Joshi, Shailendra

    2015-01-01

    Effective treatment for glioblastoma (GBM) will likely require targeted delivery of several specific pharmacological agents simultaneously. Intra-arterial (IA) delivery is one technique for targeting the tumor site with multiple agents. Although IA chemotherapy for glioblastoma (GBM) has been attempted since the 1950s, the predicted benefits remain unproven in clinical practice. This review focuses on innovative approaches to IA drug delivery in treating GBM. Guided by novel in vitro and in vivo optical measurements, newer pharmacokinetic models promise to better define the complex relationship between background cerebral blood flow and drug injection parameters. Advanced optical technologies and tracers, unique nanoparticles designs, new cellular targets, and rational drug formulations are continuously modifying the therapeutic landscape for GBM. Personalized treatment approaches are emerging; however, such tailored approaches will largely depend on effective drug delivery techniques and on the ability to simultaneously deliver multidrug regimens. These new paradigms for tumor-selective drug delivery herald dramatic improvements in the effectiveness of IA chemotherapy for GBM. Therefore, within this context of so-called “precision medicine,” the role of IA delivery for GBM is thoroughly reassessed. PMID:26819758

  6. The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence

    PubMed Central

    Auffinger, Brenda; Spencer, Drew; Pytel, Peter; Ahmed, Atique U.; Lesniak, Maciej S.

    2016-01-01

    Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific GBM subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major factor contributing to the inevitable recurrence in GBM patients following treatment. Here, we discuss the molecular mechanisms of chemoresistance of GSCs and the reasons why complete eradication of GSCs is so difficult to achieve. We will also describe the targeted therapies currently available towards GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse. PMID:26027432

  7. A case of symptomatic synchronous cervical and cerebellar metastasis after resection of thoracal metastasis from temporal glioblastoma multiforme without any local recurrence

    PubMed Central

    Karatas, Yasar; Cengiz, Sahika Liva; Ustun, Mehmet Erkan

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and the most malignant primary intracranial tumor in adults and it is usually occurs between the age of 40 and 60 years. It is local invasive and recurrent tumor and hence that has a poor prognosis. However, recent advances in tumor surgery, irradiation and chemotherapeutic agent permit long survival and metastasis which is symptomatic. Previously studies reported spinal metastasis, but we report a first case of synchronous symptomatic cerebellar and cervical spinal metastasis after resection of symptomatic thoracic spinal metastasis from temporal GBM without any recurrence of excision areas.

  8. A case of symptomatic synchronous cervical and cerebellar metastasis after resection of thoracal metastasis from temporal glioblastoma multiforme without any local recurrence

    PubMed Central

    Karatas, Yasar; Cengiz, Sahika Liva; Ustun, Mehmet Erkan

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and the most malignant primary intracranial tumor in adults and it is usually occurs between the age of 40 and 60 years. It is local invasive and recurrent tumor and hence that has a poor prognosis. However, recent advances in tumor surgery, irradiation and chemotherapeutic agent permit long survival and metastasis which is symptomatic. Previously studies reported spinal metastasis, but we report a first case of synchronous symptomatic cerebellar and cervical spinal metastasis after resection of symptomatic thoracic spinal metastasis from temporal GBM without any recurrence of excision areas. PMID:27695566

  9. Prognosis classification in glioblastoma multiforme using multimodal MRI derived heterogeneity textural features: impact of pre-processing choices

    NASA Astrophysics Data System (ADS)

    Upadhaya, Taman; Morvan, Yannick; Stindel, Eric; Le Reste, Pierre-Jean; Hatt, Mathieu

    2016-03-01

    Heterogeneity image-derived features of Glioblastoma multiforme (GBM) tumors from multimodal MRI sequences may provide higher prognostic value than standard parameters used in routine clinical practice. We previously developed a framework for automatic extraction and combination of image-derived features (also called "Radiomics") through support vector machines (SVM) for predictive model building. The results we obtained in a cohort of 40 GBM suggested these features could be used to identify patients with poorer outcome. However, extraction of these features is a delicate multi-step process and their values may therefore depend on the pre-processing of images. The original developed workflow included skull removal, bias homogeneity correction, and multimodal tumor segmentation, followed by textural features computation, and lastly ranking, selection and combination through a SVM-based classifier. The goal of the present work was to specifically investigate the potential benefit and respective impact of the addition of several MRI pre-processing steps (spatial resampling for isotropic voxels, intensities quantization and normalization) before textural features computation, on the resulting accuracy of the classifier. Eighteen patients datasets were also added for the present work (58 patients in total). A classification accuracy of 83% (sensitivity 79%, specificity 85%) was obtained using the original framework. The addition of the new pre-processing steps increased it to 93% (sensitivity 93%, specificity 93%) in identifying patients with poorer survival (below the median of 12 months). Among the three considered pre-processing steps, spatial resampling was found to have the most important impact. This shows the crucial importance of investigating appropriate image pre-processing steps to be used for methodologies based on textural features extraction in medical imaging.

  10. Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling.

    PubMed

    Atif, Fahim; Yousuf, Seema; Stein, Donald G

    2015-02-01

    Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with a mean patient survival of 13-15 months despite surgical resection, radiation therapy and standard-of-care chemotherapy. We investigated the chemotherapeutic effects of the hormone progesterone (P4) on the growth of human GBM in four genetically different cell lines (U87MG, U87dEGFR, U118MG, LN-229) in vitro and in a U87MG subcutaneous xenograft mouse model. At high concentrations (20, 40, and 80 μM), P4 significantly (P<0.05) decreased tumor cell viability in all cell lines except LN-229. This effect was not blocked by the P4 receptor antagonist RU468. Conversely, at low physiological concentrations (0.1, 1, and 5 μM) P4 showed a proliferative effect in all cell lines which was blocked by RU486. In nude mice, P4 (100 and 200 mg/kg) inhibited tumor growth significantly (P<0.05) over 5 weeks of treatment and extended survival time of tumor-bearing mice by 60% without signs of systemic toxicity. P4 suppressed tumor vascularization as indicated by the expression of CD31, vascular endothelial growth factor and matrix metalloproteinase-9. Apoptosis in tumor tissue was detected by the expression of cleaved caspase-3, BCl-2, BAD and p53 proteins and confirmed by TUNEL assay. P4 treatment also suppressed PI3K/Akt/mTOR signaling, which regulates tumor growth, as demonstrated by the suppression of proliferating cell nuclear antigen. Our data can be interpreted to suggest that P4 suppresses the growth of human GBM cells both in vitro and in vivo and enhances survival time in mice without any demonstrable side effects. This article is part of a Special Issue entitled 'Sex steroids and brain disorders'.

  11. Addition of Bevacizumab to Standard Radiation Therapy and Daily Temozolomide Is Associated With Minimal Toxicity in Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Vredenburgh, James J.; Desjardins, Annick; Kirkpatrick, John P.; Reardon, David A.; Peters, Katherine B.; Herndon, James E.; Marcello, Jennifer; Bailey, Leighann; Threatt, Stevie; Sampson, John; Friedman, Allan; Friedman, Henry S.

    2012-01-01

    Purpose: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM). Methods and Materials: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m{sup 2} daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively. Results: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study. Conclusions: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.

  12. A study of loss of heterozygosity at 70 loci in anaplastic astrocytoma and glioblastoma multiforme with implications for tumor evolution.

    PubMed Central

    Wooten, E. C.; Fults, D.; Duggirala, R.; Williams, K.; Kyritsis, A. P.; Bondy, M. L.; Levin, V. A.; O'Connell, P.

    1999-01-01

    Cancers that arise from astrocytes in the adult CNS present as either anaplastic astrocytomas (AAs) or as more aggressive glioblastomas multiforme (GBMs). GBMs either form de novo or progress from AAs. We proposed to examine the molecular genetic relationship between these CNS tumors by conducting a genome-wide allelic imbalance analysis that included 70 loci on examples of AA and GBM. We found significant loss of heterozygosity (LOH) at 13 discrete chromosomal loci in both AAs and GBMs. Loss was significant in both AAs and GBMs at 9 of these loci. AAs show the highest rates of LOH at chromosomes 1p, 4q, 6p, 9p, 11p, 11q, 13q, 14q, 15p, 17p, 17q, and 19q. GBMs showed the greatest losses at 1p, 6q, 8p, 9p, 10p, 10q, 11p, 13q, 17p, 17q, 18p, 18q, and 19q. GBMs also demonstrated significant amplification at the epidermal growth factor receptor locus (7p12). These data suggest that there are three classes of loci involved in glioma evolution. First are loci that are likely involved in early events in the evolution of both AAs and GBMs. The second class consists of AA-specific loci, typified by higher LOH frequency than observed in GBMs (4q, 6p, 17p, 17q, 19q). The third class consists of GBM-specific loci (6q, 8p, 10, 18q). Damage at these loci may either lead to de novo GBMs or permit existing AAs to progress to GBMs. Glioma-related LOH profiles may have prognostic implications that could lead to better diagnosis and treatment of brain cancer patients. PMID:11550311

  13. Stratification of pseudoprogression and true progression of glioblastoma multiform based on longitudinal diffusion tensor imaging without segmentation

    PubMed Central

    Qian, Xiaohua; Tan, Hua; Zhang, Jian; Zhao, Weilin; Chan, Michael D.; Zhou, Xiaobo

    2016-01-01

    Purpose: Pseudoprogression (PsP) can mimic true tumor progression (TTP) on magnetic resonance imaging in patients with glioblastoma multiform (GBM). The phenotypical similarity between PsP and TTP makes it a challenging task for physicians to distinguish these entities. So far, no approved biomarkers or computer-aided diagnosis systems have been used clinically for this purpose. Methods: To address this challenge, the authors developed an objective classification system for PsP and TTP based on longitudinal diffusion tensor imaging. A novel spatio-temporal discriminative dictionary learning scheme was proposed to differentiate PsP and TTP, thereby avoiding segmentation of the region of interest. The authors constructed a novel discriminative sparse matrix with the classification-oriented dictionary learning approach by excluding the shared features of two categories, so that the pooled features captured the subtle difference between PsP and TTP. The most discriminating features were then identified from the pooled features by their feature scoring system. Finally, the authors stratified patients with GBM into PsP and TTP by a support vector machine approach. Tenfold cross-validation (CV) and the area under the receiver operating characteristic (AUC) were used to assess the robustness of the developed system. Results: The average accuracy and AUC values after ten rounds of tenfold CV were 0.867 and 0.92, respectively. The authors also assessed the effects of different methods and factors (such as data types, pooling techniques, and dimensionality reduction approaches) on the performance of their classification system which obtained the best performance. Conclusions: The proposed objective classification system without segmentation achieved a desirable and reliable performance in differentiating PsP from TTP. Thus, the developed approach is expected to advance the clinical research and diagnosis of PsP and TTP. PMID:27806598

  14. Expression of S1P metabolizing enzymes and receptors correlate with survival time and regulate cell migration in glioblastoma multiforme

    PubMed Central

    Bien-Möller, Sandra; Lange, Sandra; Holm, Tobias; Böhm, Andreas; Paland, Heiko; Küpper, Johannes; Herzog, Susann; Weitmann, Kerstin; Havemann, Christoph; Vogelgesang, Silke; Marx, Sascha; Hoffmann, Wolfgang; Schroeder, Henry W.S.; Rauch, Bernhard H.

    2016-01-01

    A signaling molecule which is involved in proliferation and migration of malignant cells is the lipid mediator sphingosine-1-phosphate (S1P). There are hints for a potential role of S1P signaling in malignant brain tumors such as glioblastoma multiforme (GBM) which is characterized by a poor prognosis. Therefore, a comprehensive expression analysis of S1P receptors (S1P1-S1P5) and S1P metabolizing enzymes in human GBM (n = 117) compared to healthy brain (n = 10) was performed to evaluate their role for patient's survival. Furthermore, influence of S1P receptor inhibition on proliferation and migration were studied in LN18 GBM cells. Compared to control brain, mRNA levels of S1P1, S1P2, S1P3 and S1P generating sphingosine kinase-1 were elevated in GBM. Kaplan-Meier analyses demonstrated an association between S1P1 and S1P2 with patient's survival times. In vitro, an inhibitory effect of the SphK inhibitor SKI-II on viability of LN18 cells was shown. S1P itself had no effect on viability but stimulated LN18 migration which was blocked by inhibition of S1P1 and S1P2. The participation of S1P1 and S1P2 in LN18 migration was further supported by siRNA-mediated silencing of these receptors. Immunoblots and inhibition experiments suggest an involvement of the PI3-kinase/AKT1 pathway in the chemotactic effect of S1P in LN18 cells. In summary, our data argue for a role of S1P signaling in proliferation and migration of GBM cells. Individual components of the S1P pathway represent prognostic factors for patients with GBM. Perspectively, a selective modulation of S1P receptor subtypes could represent a therapeutic approach for GBM patients and requires further evaluation. PMID:26887055

  15. Differentiation between Glioblastoma Multiforme and Primary Cerebral Lymphoma: Additional Benefits of Quantitative Diffusion-Weighted MR Imaging

    PubMed Central

    Li, Chien Feng; Chen, Tai Yuan; Shu, Ginger; Kuo, Yu Ting; Lee, Yu Chang

    2016-01-01

    The differentiation between glioblastoma multiforme (GBM) and primary cerebral lymphoma (PCL) is important because the treatments are substantially different. The purpose of this article is to describe the MR imaging characteristics of GBM and PCL with emphasis on the quantitative ADC analysis in the tumor necrosis, the most strongly-enhanced tumor area, and the peritumoral edema. This retrospective cohort study collected 104 GBM (WHO grade IV) patients and 22 immune-competent PCL (diffuse large B cell lymphoma) patients. All these patients had pretreatment brain MR DWI and ADC imaging. Analysis of conventional MR imaging and quantitative ADC measurement including the tumor necrosis (ADCn), the most strongly-enhanced tumor area (ADCt), and the peritumoral edema (ADCe) were done. ROC analysis with optimal cut-off values and area-under-the ROC curve (AUC) was performed. For conventional MR imaging, there are statistical differences in tumor size, tumor location, tumor margin, and the presence of tumor necrosis between GBM and PCL. Quantitative ADC analysis shows that GBM tended to have significantly (P<0.05) higher ADC in the most strongly-enhanced area (ADCt) and lower ADC in the peritumoral edema (ADCe) as compared with PCL. Excellent AUC (0.94) with optimal sensitivity of 90% and specificity of 86% for differentiating between GBM and PCL was obtained by combination of ADC in the tumor necrosis (ADCn), the most strongly-enhanced tumor area (ADCt), and the peritumoral edema (ADCe). Besides, there are positive ADC gradients in the peritumoral edema in a subset of GBMs but not in the PCLs. Quantitative ADC analysis in these three areas can thus be implemented to improve diagnostic accuracy for these two brain tumor types. The histological correlation of the ADC difference deserves further investigation. PMID:27631626

  16. Differentiation between Glioblastoma Multiforme and Primary Cerebral Lymphoma: Additional Benefits of Quantitative Diffusion-Weighted MR Imaging.

    PubMed

    Ko, Ching Chung; Tai, Ming Hong; Li, Chien Feng; Chen, Tai Yuan; Chen, Jeon Hor; Shu, Ginger; Kuo, Yu Ting; Lee, Yu Chang

    2016-01-01

    The differentiation between glioblastoma multiforme (GBM) and primary cerebral lymphoma (PCL) is important because the treatments are substantially different. The purpose of this article is to describe the MR imaging characteristics of GBM and PCL with emphasis on the quantitative ADC analysis in the tumor necrosis, the most strongly-enhanced tumor area, and the peritumoral edema. This retrospective cohort study collected 104 GBM (WHO grade IV) patients and 22 immune-competent PCL (diffuse large B cell lymphoma) patients. All these patients had pretreatment brain MR DWI and ADC imaging. Analysis of conventional MR imaging and quantitative ADC measurement including the tumor necrosis (ADCn), the most strongly-enhanced tumor area (ADCt), and the peritumoral edema (ADCe) were done. ROC analysis with optimal cut-off values and area-under-the ROC curve (AUC) was performed. For conventional MR imaging, there are statistical differences in tumor size, tumor location, tumor margin, and the presence of tumor necrosis between GBM and PCL. Quantitative ADC analysis shows that GBM tended to have significantly (P<0.05) higher ADC in the most strongly-enhanced area (ADCt) and lower ADC in the peritumoral edema (ADCe) as compared with PCL. Excellent AUC (0.94) with optimal sensitivity of 90% and specificity of 86% for differentiating between GBM and PCL was obtained by combination of ADC in the tumor necrosis (ADCn), the most strongly-enhanced tumor area (ADCt), and the peritumoral edema (ADCe). Besides, there are positive ADC gradients in the peritumoral edema in a subset of GBMs but not in the PCLs. Quantitative ADC analysis in these three areas can thus be implemented to improve diagnostic accuracy for these two brain tumor types. The histological correlation of the ADC difference deserves further investigation. PMID:27631626

  17. Pulsed Versus Conventional Radiation Therapy in Combination With Temozolomide in a Murine Orthotopic Model of Glioblastoma Multiforme

    SciTech Connect

    Lee, David Y.; Chunta, John L.; Park, Sean S.; Huang, Jiayi; Martinez, Alvaro A.; Grills, Inga S.; Krueger, Sarah A.; Wilson, George D.; Marples, Brian

    2013-08-01

    Purpose: To evaluate the efficacy of pulsed low-dose radiation therapy (PLRT) combined with temozolomide (TMZ) as a novel treatment approach for radioresistant glioblastoma multiforme (GBM) in a murine model. Methods and Materials: Orthotopic U87MG hGBM tumors were established in Nu-Foxn1{sup nu} mice and imaged weekly using a small-animal micropositron emission tomography (PET)/computed tomography (CT) system. Tumor volume was determined from contrast-enhanced microCT images and tumor metabolic activity (SUVmax) from the F18-FDG microPET scan. Tumors were irradiated 7 to 10 days after implantation with a total dose of 14 Gy in 7 consecutive days. The daily treatment was given as a single continuous 2-Gy dose (RT) or 10 pulses of 0.2 Gy using an interpulse interval of 3 minutes (PLRT). TMZ (10 mg/kg) was given daily by oral gavage 1 hour before RT. Tumor vascularity and normal brain damage were assessed by immunohistochemistry. Results: Radiation therapy with TMZ resulted in a significant 3- to 4-week tumor growth delay compared with controls, with PLRT+TMZ the most effective. PLRT+TMZ resulted in a larger decline in SUVmax than RT+TMZ. Significant differences in survival were evident. Treatment after PLRT+TMZ was associated with increased vascularization compared with RT+TMZ. Significantly fewer degenerating neurons were seen in normal brain after PLRT+TMZ compared with RT+TMZ. Conclusions: PLRT+TMZ produced superior tumor growth delay and less normal brain damage when compared with RT+TMZ. The differential effect of PLRT on vascularization may confirm new treatment avenues for GBM.

  18. Forkhead Box M1 Is Essential for Nuclear Localization of Glioma-associated Oncogene Homolog 1 in Glioblastoma Multiforme Cells by Promoting Importin-7 Expression*

    PubMed Central

    Xue, Jianfei; Zhou, Aidong; Tan, Christina; Wu, Yamei; Lee, Hsueh-Te; Li, Wenliang; Xie, Keping; Huang, Suyun

    2015-01-01

    The transcription factors glioma-associated oncogene homolog 1 (GLI1), a primary marker of Hedgehog pathway activation, and Forkhead box M1 (FOXM1) are aberrantly activated in a wide range of malignancies, including glioma. However, the mechanism of nuclear localization of GLI1 and whether FOXM1 regulates the Hedgehog signaling pathway are poorly understood. Here we found that FOXM1 promotes nuclear import of GLI1 in glioblastoma multiforme cells and thus increases the expression of its target genes. Conversely, knockdown of FOXM1 expression with FOXM1 siRNA abrogated its nuclear import and inhibited the expression of its target genes. Also, genetic deletion of FOXM1 in mouse embryonic fibroblasts abolished nuclear localization of GLI1. We observed that FOXM1 directly binds to the importin-7 (IPO7) promoter and increases its promoter activity. IPO7 interacted with GLI1, leading to enhanced nuclear import of GLI1. Depletion of IPO7 by IPO7 siRNA reduced nuclear accumulation of GLI1. In addition, FOXM1 induced nuclear import of GLI1 by promoting IPO7 expression. Moreover, the FOXM1/IPO7/GLI1 axis promoted cell proliferation, migration, and invasion in vitro. Finally, expression of FOXM1 was markedly correlated with that of GLI1 in human glioblastoma specimens. These data suggest that FOXM1 and GLI1 form a positive feedback loop that contributes to glioblastoma development. Furthermore, our study revealed a mechanism that controls nuclear import of GLI1 in glioblastoma multiforme cells. PMID:26085085

  19. Graphene nanoribbons as a drug delivery agent for lucanthone mediated therapy of glioblastoma multiforme

    DOE PAGES

    Chowdhury, Sayan Mullick; Surhland, Cassandra; Sanchez, Zina; Chaudhary, Pankaj; Suresh Kumar, M. A.; Lee, Stephen; Peña, Louis A.; Waring, Michael; Sitharaman, Balaji; Naidu, Mamta

    2014-08-13

    We report use of PEG-DSPE coated oxidized graphene nanoribbons (O-GNR-PEG-DSPE) as agent for delivery of anti-tumor drug Lucanthone (Luc) into Glioblastoma Multiformae (GBM) cells targeting base excision repair enzyme APE-1 (Apurinic endonuclease-1). Lucanthone, an endonuclease inhibitor of APE-1, was loaded onto O-GNR-PEG-DSPEs using a simple non-covalent method. We found its uptake by GBM cell line U251 exceeding 67% and 60% in APE-1-overexpressing U251, post 24 hours (h). However, their uptake was ~38% and 29% by MCF-7 and rat glial progenitor cells (CG-4), respectively. TEM analysis of U251 showed large aggregates of O-GNR-PEG-DSPE in vesicles. Luc-O-GNR-PEG-DSPE was significantly toxic to U251more » but showed little / no toxicity when exposed to MCF-7/CG-4 cells. This differential uptake effect can be exploited to use O-GNR-PEG-DSPEs as a vehicle for Luc delivery to GBM, while reducing nonspecific cytotoxicity to the surrounding healthy tissue. In conclusion, cell death in U251 was necrotic, probably due to oxidative degradation of APE-1.« less

  20. Graphene nanoribbons as a drug delivery agent for lucanthone mediated therapy of glioblastoma multiforme

    SciTech Connect

    Chowdhury, Sayan Mullick; Surhland, Cassandra; Sanchez, Zina; Chaudhary, Pankaj; Suresh Kumar, M. A.; Lee, Stephen; Peña, Louis A.; Waring, Michael; Sitharaman, Balaji; Naidu, Mamta

    2014-08-13

    We report use of PEG-DSPE coated oxidized graphene nanoribbons (O-GNR-PEG-DSPE) as agent for delivery of anti-tumor drug Lucanthone (Luc) into Glioblastoma Multiformae (GBM) cells targeting base excision repair enzyme APE-1 (Apurinic endonuclease-1). Lucanthone, an endonuclease inhibitor of APE-1, was loaded onto O-GNR-PEG-DSPEs using a simple non-covalent method. We found its uptake by GBM cell line U251 exceeding 67% and 60% in APE-1-overexpressing U251, post 24 hours (h). However, their uptake was ~38% and 29% by MCF-7 and rat glial progenitor cells (CG-4), respectively. TEM analysis of U251 showed large aggregates of O-GNR-PEG-DSPE in vesicles. Luc-O-GNR-PEG-DSPE was significantly toxic to U251 but showed little / no toxicity when exposed to MCF-7/CG-4 cells. This differential uptake effect can be exploited to use O-GNR-PEG-DSPEs as a vehicle for Luc delivery to GBM, while reducing nonspecific cytotoxicity to the surrounding healthy tissue. In conclusion, cell death in U251 was necrotic, probably due to oxidative degradation of APE-1.

  1. Graphene Nanoribbons as a Drug Delivery Agent for Lucanthone Mediated Therapy of Glioblastoma Multiforme

    PubMed Central

    Chowdhury, Sayan Mullick; Surhland, Cassandra; Sanchez, Zina; Chaudhary, Pankaj; Kumar, M.A. Suresh; Lee, Stephen; Peña, Louis A.; Waring, Michael; Sitharaman, Balaji; Naidu, Mamta

    2014-01-01

    We report use of PEG-DSPE coated oxidized graphene nanoribbons (O-GNR-PEG-DSPE) as agent for delivery of anti-tumor drug Lucanthone (Luc) into Glioblastoma Multiformae (GBM) cells targeting base excision repair enzyme APE-1 (Apurinic endonuclease-1). Lucanthone, an endonuclease inhibitor of APE-1, was loaded onto O-GNR-PEG-DSPEs using a simple non-covalent method. We found its uptake by GBM cell line U251 exceeding 67% and 60% in APE-1-overexpressing U251, post 24 hours (h). However, their uptake was ~38% and 29% by MCF-7 and rat glial progenitor cells (CG-4), respectively. TEM analysis of U251 showed large aggregates of O-GNR-PEG-DSPE in vesicles. Luc-O-GNR-PEG-DSPE was significantly toxic to U251 but showed little / no toxicity when exposed to MCF-7/CG-4 cells. This differential uptake effect can be exploited to use O-GNR-PEG-DSPEs as a vehicle for Luc delivery to GBM, while reducing nonspecific cytotoxicity to the surrounding healthy tissue. Cell death in U251 was necrotic, probably due to oxidative degradation of APE-1. PMID:25131339

  2. TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance.

    PubMed

    Costa, Barbara; Da Pozzo, Eleonora; Giacomelli, Chiara; Taliani, Sabrina; Bendinelli, Sara; Barresi, Elisabetta; Da Settimo, Federico; Martini, Claudia

    2015-03-01

    Ligands addressed to the mitochondrial Translocator Protein (TSPO) have been suggested as cell death/life and steroidogenesis modulators. Thus, TSPO ligands have been proposed as drug candidates in several diseases; nevertheless, a correlation between their binding affinity and in vitro efficacy has not been demonstrated yet, questioning the specificity of the observed effects. Since drug-target residence time is an emerging parameter able to influence drug pharmacological features, herein, the interaction between TSPO and irDE-MPIGA, a covalent TSPO ligand, was investigated in order to explore TSPO control on death/life processes in a standardized glioblastoma cell setting. After 90 min irDE-MPIGA cell treatment, 25 nM ligand concentration saturated irreversibly all TSPO binding sites; after 24 h, TSPO de-novo synthesis occurred and about 40 % TSPO binding sites resulted covalently bound to irDE-MPIGA. During cell culture treatments, several dynamic events were observed: (a) early apoptotic markers appeared, such as mitochondrial membrane potential collapse (at 3 h) and externalization of phosphatidylserine (at 6 h); (b) cell viability was reduced (at 6 h), without cell cycle arrest. After digitonin-permeabilized cell suspension treatment, a modulation of mitochondrial permeability transition pore was evidenced. Similar effects were elicited by the reversible TSPO ligand PIGA only when applied at micromolar dose. Interestingly, after 6 h, irDE-MPIGA cell exposure restored cell survival parameters. These results highlighted the ligand-target residence time and the cellular setting are crucial parameters that should be taken into account to understand the drug binding affinity and efficacy correlation and, above all, to translate efficiently cellular drug responses from bench to bedside.

  3. Secretory prostate apoptosis response (Par)-4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen-induced cell death

    PubMed Central

    Jagtap, Jayashree C.; Parveen, D.; Shah, Reecha D.; Desai, Aarti; Bhosale, Dipali; Chugh, Ashish; Ranade, Deepak; Karnik, Swapnil; Khedkar, Bhushan; Mathur, Aaishwarya; Natesh, Kumar; Chandrika, Goparaju; Shastry, Padma

    2014-01-01

    Glioblastoma multiforme (GBM) is the most malignant form of brain tumor and is associated with resistance to conventional therapy and poor patient survival. Prostate apoptosis response (Par)-4, a tumor suppressor, is expressed as both an intracellular and secretory/extracellular protein. Though secretory Par-4 induces apoptosis in cancer cells, its potential in drug-resistant tumors remains to be fully explored. Multicellular spheroids (MCS) of cancer cells often acquire multi-drug resistance and serve as ideal experimental models. We investigated the role of Par-4 in Tamoxifen (TAM)-induced cell death in MCS of human cell lines and primary cultures of GBM tumors. TCGA and REMBRANT data analysis revealed that low levels of Par-4 correlated with low survival period (21.85 ± 19.30 days) in GBM but not in astrocytomas (59.13 ± 47.26 days) and oligodendrogliomas (58.04 ± 59.80 days) suggesting low PAWR expression as a predictive risk factor in GBM. Consistently, MCS of human cell lines and primary cultures displayed low Par-4 expression, high level of chemo-resistance genes and were resistant to TAM-induced cytotoxicity. In monolayer cells, TAM-induced cytotoxicity was associated with enhanced expression of Par-4 and was alleviated by silencing of Par-4 using specific siRNA. TAM effectively induced secretory Par-4 in conditioned medium (CM) of cells cultured as monolayer but not in MCS. Moreover, MCS were rendered sensitive to TAM-induced cell death by exposure to conditioned medium (CM)-containing Par-4 (derived from TAM-treated monolayer cells). Also TAM reduced the expression of Akt and PKCζ in GBM cells cultured as monolayer but not in MCS. Importantly, combination of TAM with inhibitors to PI3K inhibitor (LY294002) or PKCζ resulted in secretion of Par-4 and cell death in MCS. Since membrane GRP78 is overexpressed in most cancer cells but not normal cells, and secretory Par-4 induces apoptosis by binding to membrane GRP78, secretory Par-4 is an

  4. Incorporating Cancer Stem Cells in Radiation Therapy Treatment Response Modeling and the Implication in Glioblastoma Multiforme Treatment Resistance

    SciTech Connect

    Yu, Victoria Y.; Nguyen, Dan; Pajonk, Frank; Kupelian, Patrick; Kaprealian, Tania; Selch, Michael; Low, Daniel A.; Sheng, Ke

    2015-03-15

    Purpose: To perform a preliminary exploration with a simplistic mathematical cancer stem cell (CSC) interaction model to determine whether the tumor-intrinsic heterogeneity and dynamic equilibrium between CSCs and differentiated cancer cells (DCCs) can better explain radiation therapy treatment response with a dual-compartment linear-quadratic (DLQ) model. Methods and Materials: The radiosensitivity parameters of CSCs and DCCs for cancer cell lines including glioblastoma multiforme (GBM), non–small cell lung cancer, melanoma, osteosarcoma, and prostate, cervical, and breast cancer were determined by performing robust least-square fitting using the DLQ model on published clonogenic survival data. Fitting performance was compared with the single-compartment LQ (SLQ) and universal survival curve models. The fitting results were then used in an ordinary differential equation describing the kinetics of DCCs and CSCs in response to 2- to 14.3-Gy fractionated treatments. The total dose to achieve tumor control and the fraction size that achieved the least normal biological equivalent dose were calculated. Results: Smaller cell survival fitting errors were observed using DLQ, with the exception of melanoma, which had a low α/β = 0.16 in SLQ. Ordinary differential equation simulation indicated lower normal tissue biological equivalent dose to achieve the same tumor control with a hypofractionated approach for 4 cell lines for the DLQ model, in contrast to SLQ, which favored 2 Gy per fraction for all cells except melanoma. The DLQ model indicated greater tumor radioresistance than SLQ, but the radioresistance was overcome by hypofractionation, other than the GBM cells, which responded poorly to all fractionations. Conclusion: The distinct radiosensitivity and dynamics between CSCs and DCCs in radiation therapy response could perhaps be one possible explanation for the heterogeneous intertumor response to hypofractionation and in some cases superior outcome from

  5. Identification of hub genes and regulatory factors of glioblastoma multiforme subgroups by RNA-seq data analysis

    PubMed Central

    Li, Yanan; Min, Weijie; Li, Mengmeng; Han, Guosheng; Dai, Dongwei; Zhang, Lei; Chen, Xin; Wang, Xinglai; Zhang, Yuhui; Yue, Zhijian; Liu, Jianmin

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor. This study aimed to identify the hub genes and regulatory factors of GBM subgroups by RNA sequencing (RNA-seq) data analysis, in order to explore the possible mechanisms responsbile for the progression of GBM. The dataset RNASeqV2 was downloaded by TCGA-Assembler, containing 169 GBM and 5 normal samples. Gene expression was calculated by the reads per kilobase per million reads measurement, and nor malized with tag count comparison. Following subgroup classification by the non-negative matrix factorization, the differentially expressed genes (DEGs) were screened in 4 GBM subgroups using the method of significance analysis of microarrays. Functional enrichment analysis was performed by DAVID, and the protein-protein interaction (PPI) network was constructed based on the HPRD database. The subgroup-related microRNAs (miRNAs or miRs), transcription factors (TFs) and small molecule drugs were predicted with predefined criteria. A cohort of 19,515 DEGs between the GBM and control samples was screened, which were predominantly enriched in cell cycle- and immunoreaction-related pathways. In the PPI network, lymphocyte cytosolic protein 2 (LCP2), breast cancer 1 (BRCA1), specificity protein 1 (Sp1) and chromodomain-helicase-DNA-binding protein 3 (CHD3) were the hub nodes in subgroups 1–4, respectively. Paired box 5 (PAX5), adipocyte protein 2 (aP2), E2F transcription factor 1 (E2F1) and cAMP-response element-binding protein-1 (CREB1) were the specific TFs in subgroups 1–4, respectively. miR-147b, miR-770-5p, miR-220a and miR-1247 were the particular miRNAs in subgroups 1–4, respectively. Natalizumab was the predicted small molecule drug in subgroup 2. In conclusion, the molecular regulatory mechanisms of GBM pathogenesis were distinct in the different subgroups. Several crucial genes, TFs, miRNAs and small molecules in the different GBM subgroups were identified, which may be used as potential

  6. Identification of hub genes and regulatory factors of glioblastoma multiforme subgroups by RNA-seq data analysis.

    PubMed

    Li, Yanan; Min, Weijie; Li, Mengmeng; Han, Guosheng; Dai, Dongwei; Zhang, Lei; Chen, Xin; Wang, Xinglai; Zhang, Yuhui; Yue, Zhijian; Liu, Jianmin

    2016-10-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor. This study aimed to identify the hub genes and regulatory factors of GBM subgroups by RNA sequencing (RNA-seq) data analysis, in order to explore the possible mechanisms responsbile for the progression of GBM. The dataset RNASeqV2 was downloaded by TCGA-Assembler, containing 169 GBM and 5 normal samples. Gene expression was calculated by the reads per kilobase per million reads measurement, and nor malized with tag count comparison. Following subgroup classification by the non-negative matrix factorization, the differentially expressed genes (DEGs) were screened in 4 GBM subgroups using the method of significance analysis of microarrays. Functional enrichment analysis was performed by DAVID, and the protein-protein interaction (PPI) network was constructed based on the HPRD database. The subgroup-related microRNAs (miRNAs or miRs), transcription factors (TFs) and small molecule drugs were predicted with pre-defined criteria. A cohort of 19,515 DEGs between the GBM and control samples was screened, which were predominantly enriched in cell cycle- and immunoreaction-related pathways. In the PPI network, lymphocyte cytosolic protein 2 (LCP2), breast cancer 1 (BRCA1), specificity protein 1 (Sp1) and chromodomain-helicase-DNA-binding protein 3 (CHD3) were the hub nodes in subgroups 1-4, respectively. Paired box 5 (PAX5), adipocyte protein 2 (aP2), E2F transcription factor 1 (E2F1) and cAMP-response element-binding protein-1 (CREB1) were the specific TFs in subgroups 1-4, respectively. miR‑147b, miR‑770-5p, miR‑220a and miR‑1247 were the particular miRNAs in subgroups 1-4, respectively. Natalizumab was the predicted small molecule drug in subgroup 2. In conclusion, the molecular regulatory mechanisms of GBM pathogenesis were distinct in the different subgroups. Several crucial genes, TFs, miRNAs and small molecules in the different GBM subgroups were identified

  7. Glioblastoma Multiforme: A Controlled Trial to Assess the Value of Specific Active Immunotherapy in Patients Treated by Radical Surgery and Radiotherapy

    PubMed Central

    Bloom, H. J. G.; Peckham, M. J.; Richardson, A. E.; Alexander, P. A.; Payne, P. M.

    1973-01-01

    The results are reported of a randomized prospective clinical trial carried out to assess the value of specific active immunotherapy using irradiated autologous tumour cells in patients with glioblastoma multiforme treated by radical surgery and post-operative irradiation. The results in 62 patients show no statistically significant difference in survival between the group receiving adjuvant autologous tumour cells and those treated with surgery and radiotherapy alone. All 27 patients receiving tumour cells were dead at 30 months, whereas 7 of the 35 controls were alive at this time. The results were considered sufficiently discouraging to abandon the trial at this stage on the grounds that there was sufficient evidence in this study that the administration of irradiated autologous cells was of no benefit to patients with high grade astrocytomata. PMID:4348472

  8. Fatal Liver and Bone Marrow Toxicity by Combination Treatment of Dichloroacetate and Artesunate in a Glioblastoma Multiforme Patient: Case Report and Review of the Literature

    PubMed Central

    Uhl, Martin; Schwab, Stefan; Efferth, Thomas

    2016-01-01

    A 52-year-old male patient was treated with standard radiochemotherapy with temozolomide for glioblastoma multiforme (GBM). After worsening of his clinical condition, further tumor-specific treatment was unlikely to be successful, and the patient seeked help from an alternative practitioner, who administered a combination of dichloroacetate (DCA) and artesunate (ART). A few days later, the patient showed clinical and laboratory signs of liver damage and bone marrow toxicity (leukopenia, thrombocytopenia). Despite successful restoration of laboratory parameters upon symptomatic treatment, the patient died 10 days after the infusion. DCA bears a well-documented hepatotoxic risk, while ART can be considered as safe concerning hepatotoxicity. Bone marrow toxicity can appear upon ART application as reduced reticulocyte counts and disturbed erythropoiesis. It can be assumed that the simultaneous use of both drugs caused liver injury and bone marrow toxicity. The compassionate use of DCA/ART combination therapy outside of clinical trials cannot be recommended for GBM treatment. PMID:27774434

  9. Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression

    PubMed Central

    Gao, Yong-tao; Chen, Xiao-bing; Liu, Hong-lin

    2016-01-01

    MicroRNAs (miRNA) are believed to play an important role in glioblastoma multiforme (GBM)chemotherapy. Our study aims to investigate potential miRNA biomarkers in GBM. Sixty GBM patients, which were given temozolomide (TMZ) chemotherapy and recurrent radiotherapy, were recruited. miRNA array was performed in cancerous and in paired normal tissues. Microarray results were further validated by a quantitative real-time PCR in selected tissues and GBM cell lines. TMZ resistance cells were developed and cell proliferation along with colony formation assays was determined. Our study employed H2AX formation and flow cytometry to analyse the role of miRNA in DNA damage and apoptosis. Our study illustrated 16 miRNA in which 9 were up-regulated and 7 down-regulated. and their differential expression were demonstrated in a recurrent GBM tissue. Among them, miRNA-370-3p demonstrated the highest level of down- regulation in tissues and in TMZ resistance cells. miRNA-370-3p mimic increased its expression and sensitivity of GBM cells to TMZ by suppressing the self-reparative ability of tumour cell DNA. O6-methylguanine-DNA methyltransferase (MGMT) was identified as the direct target gene of miR-370-3p, and it was found to be inversely correlated with miR-370-3p expression in tissue samples obtained. Thus, our study demonstrated a critical clinical role of an up-regulated miR-370-3p expression in glioblastoma multiforme chemotherapy sensitivity. PMID:27595933

  10. A New Approach in Gene Therapy of Glioblastoma Multiforme: Human Olfactory Ensheathing Cells as a Novel Carrier for Suicide Gene Delivery.

    PubMed

    Hashemi, Mansoureh; Fallah, Ali; Aghayan, Hamid Reza; Arjmand, Babak; Yazdani, Nasrin; Verdi, Javad; Ghodsi, Seyed Mohammad; Miri, Seyed Mojtaba; Hadjighassem, Mahmoudreza

    2016-10-01

    Olfactory ensheathing cells (OECs) of human olfactory mucosa are a type of glial-like cells that possess good migratory and tropism properties. We believe that neuronal-derived vehicle may have better capability to receive to the site of injury. In addition to, obtaining of such vehicle from the patient reduces risk of unwanted complications. So, in this study, we investigate whether human olfactory ensheathing cells can be used as a cell source for the first time in gene delivery to assay the tumoricidal effect of herpes simplex virus thymidine kinase gene (HSV-tk) on glioblastoma multiforme (GBM). We obtained OECs from superior turbinate of human nasal cavity mucosa, and cell phenotype was confirmed by the expression of cell-specific antigens including low-affinity nerve growth factor receptor (p75 neurotrophin receptor), microtubule-associated protein-2 (MAP2), and S100 calcium binding protein B (S100-beta) using immunocytochemistry. Then, these cells were transduced by lentiviral vector for transient and stable expression of the herpes simplex virus thymidine kinase gene (OEC-tk). The migratory capacity of OEC-tk, their potency to convert prodrug ganciclovir to toxic form, and cytotoxic effect on astrocyte cells were assayed in vitro. The OECs showed fibroblast-like morphology and expressed specific antigens such as p75 neurotrophin receptor, S100-beta, and MAP2. Our results indicated that OECs-tk were able to migrate toward primary cultured human glioblastoma multiforme and affected survival rate of tumor cells according to exposure time and concentration of ganciclovir. Also, OECs-HSV-tk was capable of inducing apoptosis in tumor cells. Our findings suggest that human OECs could employ as a possible tool to transfer anticancer agent in gene therapy of brain tumor.

  11. Systematic review and meta-analysis of phase I/II targeted therapy combined with radiotherapy in patients with glioblastoma multiforme: quality of report, toxicity, and survival.

    PubMed

    dos Santos, Marcos A; Pignon, Jean-Pierre; Blanchard, Pierre; Lefeuvre, Delphine; Levy, Antonin; Touat, Mehdi; Louvel, Guillaume; Dhermain, Frédéric; Soria, Jean-Charles; Deutsch, Eric; Le Teuff, Gwénaël

    2015-06-01

    To perform a systematic review and meta-analysis of severe adverse events (SAE) reported in early trials combining molecularly targeted therapies (MTT) with radiotherapy (RT), and to compare them to standard therapy. A summary data meta-analysis was performed and compared to the historical standard. Inclusion criteria were phase I and/or II trials published between 2000 and 2011, with glioblastoma multiforme patients treated with RT and MTT. Pooled incidence rates (IR) of SAE were estimated as well as the pooled median progression-free survival (PFS) and overall survival (OS). Nineteen prospective trials (9 phase I, 1 phase I/II and 9 phase II) out of 29 initially selected were included (n = 755 patients). The exact number of patients who had experienced SAE was mentioned in 37 % of the trials, concerning only 17 % of the patients. Information such as the period during which adverse events were monitored, the planned treatment duration, and late toxicity were not reported in the trials. The pooled IR of overall SAE was 131.2 (95 % CI 88.8-193.7) per 1000 person-months compared to 74.7 (63.6-87.8) for standard therapy (p < 0.01). Significant differences were observed for gastrointestinal events (p = 0.05) and treatment-related deaths (p = 0.02), in favour of standard therapy. No significant difference was observed in PFS and OS. Reporting a summary of toxicity data in early clinical trials should be stringently standardized. The use of MTT with RT compared to standard therapy increased SAE while yielded comparable survival in glioblastoma multiforme patients.

  12. Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression.

    PubMed

    Gao, Yong-Tao; Chen, Xiao-Bing; Liu, Hong-Lin

    2016-01-01

    MicroRNAs (miRNA) are believed to play an important role in glioblastoma multiforme (GBM)chemotherapy. Our study aims to investigate potential miRNA biomarkers in GBM. Sixty GBM patients, which were given temozolomide (TMZ) chemotherapy and recurrent radiotherapy, were recruited. miRNA array was performed in cancerous and in paired normal tissues. Microarray results were further validated by a quantitative real-time PCR in selected tissues and GBM cell lines. TMZ resistance cells were developed and cell proliferation along with colony formation assays was determined. Our study employed H2AX formation and flow cytometry to analyse the role of miRNA in DNA damage and apoptosis. Our study illustrated 16 miRNA in which 9 were up-regulated and 7 down-regulated. and their differential expression were demonstrated in a recurrent GBM tissue. Among them, miRNA-370-3p demonstrated the highest level of down- regulation in tissues and in TMZ resistance cells. miRNA-370-3p mimic increased its expression and sensitivity of GBM cells to TMZ by suppressing the self-reparative ability of tumour cell DNA. O(6)-methylguanine-DNA methyltransferase (MGMT) was identified as the direct target gene of miR-370-3p, and it was found to be inversely correlated with miR-370-3p expression in tissue samples obtained. Thus, our study demonstrated a critical clinical role of an up-regulated miR-370-3p expression in glioblastoma multiforme chemotherapy sensitivity. PMID:27595933

  13. Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression.

    PubMed

    Gao, Yong-Tao; Chen, Xiao-Bing; Liu, Hong-Lin

    2016-01-01

    MicroRNAs (miRNA) are believed to play an important role in glioblastoma multiforme (GBM)chemotherapy. Our study aims to investigate potential miRNA biomarkers in GBM. Sixty GBM patients, which were given temozolomide (TMZ) chemotherapy and recurrent radiotherapy, were recruited. miRNA array was performed in cancerous and in paired normal tissues. Microarray results were further validated by a quantitative real-time PCR in selected tissues and GBM cell lines. TMZ resistance cells were developed and cell proliferation along with colony formation assays was determined. Our study employed H2AX formation and flow cytometry to analyse the role of miRNA in DNA damage and apoptosis. Our study illustrated 16 miRNA in which 9 were up-regulated and 7 down-regulated. and their differential expression were demonstrated in a recurrent GBM tissue. Among them, miRNA-370-3p demonstrated the highest level of down- regulation in tissues and in TMZ resistance cells. miRNA-370-3p mimic increased its expression and sensitivity of GBM cells to TMZ by suppressing the self-reparative ability of tumour cell DNA. O(6)-methylguanine-DNA methyltransferase (MGMT) was identified as the direct target gene of miR-370-3p, and it was found to be inversely correlated with miR-370-3p expression in tissue samples obtained. Thus, our study demonstrated a critical clinical role of an up-regulated miR-370-3p expression in glioblastoma multiforme chemotherapy sensitivity.

  14. SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme.

    PubMed

    Lewis, C A; Brault, C; Peck, B; Bensaad, K; Griffiths, B; Mitter, R; Chakravarty, P; East, P; Dankworth, B; Alibhai, D; Harris, A L; Schulze, A

    2015-10-01

    Oxygen and nutrient limitation are common features of the tumor microenvironment and are associated with cancer progression and induction of metastasis. The inefficient vascularization of tumor tissue also limits the penetration of other serum-derived factors, such as lipids and lipoproteins, which can be rate limiting for cell proliferation and survival. Here we have investigated the effect of hypoxia and serum deprivation on sterol regulatory element-binding protein (SREBP) activity and the expression of lipid metabolism genes in human glioblastoma multiforme (GBM) cancer cells. We found that SREBP transcriptional activity was induced by serum depletion both in normoxic and hypoxic cells and that activation of SREBP was required to maintain the expression of fatty acid and cholesterol metabolism genes under hypoxic conditions. Moreover, expression of stearoyl-CoA desaturase, the enzyme required for the generation of mono-unsaturated fatty acids, and fatty acid-binding protein 7, a regulator of glioma stem cell function, was strongly dependent on SREBP function. Inhibition of SREBP function blocked lipid biosynthesis in hypoxic cancer cells and impaired cell survival under hypoxia and in a three-dimensional spheroid model. Finally, gene expression analysis revealed that SREBP defines a gene signature that is associated with poor survival in glioblastoma. PMID:25619842

  15. Glioblastoma

    MedlinePlus

    ... most common form of glioblastoma; it is very aggressive. Secondary: These tumors have a longer, somewhat slower growth history, but still are very aggressive. They may begin as lower-grade tumors which ...

  16. Glioblastoma.

    PubMed

    Wirsching, Hans-Georg; Galanis, Evanthia; Weller, Michael

    2016-01-01

    Glioblastoma is the most common and aggressive primary brain tumor in adults. Defining histopathologic features are necrosis and endothelial proliferation, resulting in the assignment of grade IV, the highest grade in the World Health Organization (WHO) classification of brain tumors. The classic clinical term "secondary glioblastoma" refers to a minority of glioblastomas that evolve from previously diagnosed WHO grade II or grade III gliomas. Specific point mutations of the genes encoding isocitrate dehydrogenase (IDH) 1 or 2 appear to define molecularly these tumors that are associated with younger age and more favorable outcome; the vast majority of glioblastomas are IDH wild-type. Typical molecular changes in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signaling. Standard treatment of glioblastoma includes surgery, radiotherapy, and alkylating chemotherapy. Promoter methylation of the gene encoding the DNA repair protein, O(6)-methylguanyl DNA methyltransferase (MGMT), predicts benefit from alkylating chemotherapy with temozolomide and guides choice of first-line treatment in elderly patients. Current developments focus on targeting the molecular characteristics that drive the malignant phenotype, including altered signal transduction and angiogenesis, and more recently, various approaches of immunotherapy. PMID:26948367

  17. Dysregulated miR-671-5p / CDR1-AS / CDR1 / VSNL1 axis is involved in glioblastoma multiforme.

    PubMed

    Barbagallo, Davide; Condorelli, Angelo; Ragusa, Marco; Salito, Loredana; Sammito, Mariangela; Banelli, Barbara; Caltabiano, Rosario; Barbagallo, Giuseppe; Zappalà, Agata; Battaglia, Rosalia; Cirnigliaro, Matilde; Lanzafame, Salvatore; Vasquez, Enrico; Parenti, Rosalba; Cicirata, Federico; Di Pietro, Cinzia; Romani, Massimo; Purrello, Michele

    2016-01-26

    MiR-671-5p is encoded by a gene localized at 7q36.1, a region amplified in human glioblastoma multiforme (GBM), the most malignant brain cancer. To investigate whether expression of miR-671-5p were altered in GBM, we analyzed biopsies from a cohort of forty-five GBM patients and from five GBM cell lines. Our data show significant overexpression of miR-671-5p in both biopsies and cell lines. By exploiting specific miRNA mimics and inhibitors, we demonstrated that miR-671-5p overexpression significantly increases migration and to a less extent proliferation rates of GBM cells. Through a combined in silico and in vitro approach, we identified CDR1-AS, CDR1, VSNL1 as downstream miR-671-5p targets in GBM. Expression of these genes significantly decreased both in GBM biopsies and cell lines and negatively correlated with that of miR-671-5p. Based on our data, we propose that the axis miR-671-5p / CDR1-AS / CDR1 / VSNL1 is functionally altered in GBM cells and is involved in the modification of their biopathological profile.

  18. Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells

    PubMed Central

    Kore, Rajshekhar A.; Abraham, Edathara C.

    2014-01-01

    In the brain, levels of inflammatory cytokines, interleukin-1 beta (IL-1β) and tumor Necrosis factor-alpha (TNF-α), are elevated under traumatic brain injury, neuroinflammatory conditions and glioblastoma multiforme (GBM). In GBM, the levels of small heat shock protein, CRYAB (HspB5) are also reported to be elevated, where it has been shown to exert anti-apoptotic activity. Interestingly, CRYAB is secreted via exosomes by various cells. In order to understand the relation between inflammatory cytokines and CRYAB, U373 glioma cells, were stimulated with proinflammatory cytokines, IL-1β and TNF-α, and their effect on CRYAB levels in cells and secreted exosomes was studied. Our results show that U373 cells produce and secrete CRYAB via exosomes and that stimulation with IL-1β and TNF-α significantly increase the levels of CRYAB in not only the cells but also in the secreted exosomes. In addition, cytokine stimulation of U373 cells brings about changes in the secreted exosomal proteome, many of which are involved in cancer progression. PMID:25261722

  19. Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells.

    PubMed

    Kore, Rajshekhar A; Abraham, Edathara C

    2014-10-24

    In the brain, levels of inflammatory cytokines, interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), are elevated under traumatic brain injury, neuroinflammatory conditions and glioblastoma multiforme (GBM). In GBM, the levels of small heat shock protein, CRYAB (HspB5) are also reported to be elevated, where it has been shown to exert anti-apoptotic activity. Interestingly, CRYAB is secreted via exosomes by various cells. In order to understand the relation between inflammatory cytokines and CRYAB, U373 glioma cells, were stimulated with proinflammatory cytokines, IL-1β and TNF-α, and their effect on CRYAB levels in cells and secreted exosomes was studied. Our results show that U373 cells produce and secrete CRYAB via exosomes and that stimulation with IL-1β and TNF-α significantly increase the levels of CRYAB in not only the cells but also in the secreted exosomes. In addition, cytokine stimulation of U373 cells brings about changes in the secreted exosomal proteome, many of which are involved in cancer progression.

  20. Protein Co-Expression Analysis as a Strategy to Complement a Standard Quantitative Proteomics Approach: Case of a Glioblastoma Multiforme Study

    PubMed Central

    Deighton, Ruth F.

    2016-01-01

    Although correlation network studies from co-expression analysis are increasingly popular, they are rarely applied to proteomics datasets. Protein co-expression analysis provides a complementary view of underlying trends, which can be overlooked by conventional data analysis. The core of the present study is based on Weighted Gene Co-expression Network Analysis applied to a glioblastoma multiforme proteomic dataset. Using this method, we have identified three main modules which are associated with three different membrane associated groups; mitochondrial, endoplasmic reticulum, and a vesicle fraction. The three networks based on protein co-expression were assessed against a publicly available database (STRING) and show a statistically significant overlap. Each of the three main modules were de-clustered into smaller networks using different strategies based on the identification of highly connected networks, hierarchical clustering and enrichment of Gene Ontology functional terms. Most of the highly connected proteins found in the endoplasmic reticulum module were associated with redox activity while a core of the unfolded protein response was identified in addition to proteins involved in oxidative stress pathways. The proteins composing the electron transfer chain were found differently affected with proteins from mitochondrial Complex I being more down-regulated than proteins from Complex III. Finally, the two pyruvate kinases isoforms show major differences in their co-expressed protein networks suggesting roles in different cellular locations. PMID:27571357

  1. Decreased survival of glioma patients with astrocytoma grade IV (glioblastoma multiforme) associated with long-term use of mobile and cordless phones.

    PubMed

    Carlberg, Michael; Hardell, Lennart

    2014-10-16

    On 31 May 2011 the WHO International Agency for Research on Cancer (IARC) categorised radiofrequency electromagnetic fields (RF-EMFs) from mobile phones, and from other devices that emit similar non-ionising electromagnetic fields, as a Group 2B, i.e., a "possible", human carcinogen. A causal association would be strengthened if it could be shown that the use of wireless phones has an impact on the survival of glioma patients. We analysed survival of 1678 glioma patients in our 1997-2003 and 2007-2009 case-control studies. Use of wireless phones in the >20 years latency group (time since first use) yielded an increased hazard ratio (HR) = 1.7, 95% confidence interval (CI) = 1.2-2.3 for glioma. For astrocytoma grade IV (glioblastoma multiforme; n = 926) mobile phone use yielded HR = 2.0, 95% CI = 1.4-2.9 and cordless phone use HR = 3.4, 95% CI = 1.04-11 in the same latency category. The hazard ratio for astrocytoma grade IV increased statistically significant per year of latency for wireless phones, HR = 1.020, 95% CI = 1.007-1.033, but not per 100 h cumulative use, HR = 1.002, 95% CI = 0.999-1.005. HR was not statistically significant increased for other types of glioma. Due to the relationship with survival the classification of IARC is strengthened and RF-EMF should be regarded as human carcinogen requiring urgent revision of current exposure guidelines.

  2. MicroRNA-139-5p acts as a tumor suppressor by targeting ELTD1 and regulating cell cycle in glioblastoma multiforme.

    PubMed

    Dai, Shouping; Wang, Xianjun; Li, Xiao; Cao, Yuandong

    2015-11-13

    MicroRNA-139-5p was identified to be significantly down-regulated in glioblastoma multiform (GBM) by miRNA array. In this report we aimed to clarify its biological function, molecular mechanisms and direct target gene in GBM. Twelve patients with GBM were analyzed for the expression of miR-139-5p by quantitative RT-PCR. miR-139-5p overexpression was established by transfecting miR-139-5p-mimic into U87MG and T98G cells, and its effects on cell proliferation were studied using MTT assay and colony formation assays. We concluded that ectopic expression of miR-139-5p in GBM cell lines significantly suppressed cell proliferation and inducing apoptosis. Bioinformatics coupled with luciferase and western blot assays also revealed that miR-139-5p suppresses glioma cell proliferation by targeting ELTD1 and regulating cell cycle. PMID:26449464

  3. Pre-clinical analysis of changes in intra-cellular biochemistry of glioblastoma multiforme (GBM) cells due to c-Myc silencing.

    PubMed

    Rajagopalan, Vishal; Vaidyanathan, Muthukumar; Janardhanam, Vanisree Arambakkam; Bradner, James E

    2014-10-01

    Glioblastoma Multiforme (GBM) is an aggressive form of brain Tumor that has few cures. In this study, we analyze the anti-proliferative effects of a new molecule JQ1 against GBMs induced in Wistar Rats. JQ1 is essentially a Myc inhibitor. c-Myc is also known for altering the biochemistry of a tumor cell. Therefore, the study is intended to analyze certain other oncogenes associated with c-Myc and also the change in cellular biochemistry upon c-Myc inhibition. The quantitative analysis of gene expression gave a co-expressive pattern for all the three genes involved namely; c-Myc, Bcl-2, and Akt. The cellular biochemistry analysis by transmission electron microscopy revealed high glycogen and lipid aggregation in Myc inhibited cells and excessive autophagy. The study demonstrates the role of c-Myc as a central metabolic regulator and Bcl-2 and Akt assisting in extending c-Myc half-life as well as in regulation of autophagy, so as to regulate cell survival on the whole. The study also demonstrates that transient treatment by JQ1 leads to aggressive development of tumor and therefore, accelerating death, emphasizing the importance of dosage fixation, and duration for clinical use in future.

  4. Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system.

    PubMed

    Sarganas, Giselle; Orzechowski, Hans D; Klimpel, Andreas; Thomae, Michael; Kauffmann, Wolfgang; Herbst, Hermann; Bronder, Elisabeth; Garbe, Edeltraut

    2012-05-01

    Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults. Its established first-line adjuvant treatment is radiotherapy in combination with temozolomide (TZM). Hematotoxicity is listed as a frequent adverse drug reaction in the US prescribing information and hepatotoxicity has been reported infrequently in the postmarketing period. We here present the case of a patient diagnosed with GBM who developed severe sustained cholestatic hepatitis following treatment with TZM. The cholestasis was not reversible after withdrawal of TZM during 6 months before the patient's death. Another 2 published case reports of sustained cholestasis following TZM treatment were identified; however, the sustained nature of cholestasis was not emphasized in these reports. Sixteen cases of cholestatic hepatitis/cholestasis associated with TZM were identified in the FDA spontaneous reporting system between 2007 and 2010. Information on the course of the cholestasis in these cases could not be retrieved. In the literature there are other published reports of hepatotoxicity associated with TZM that have reported reversibility upon withdrawal of the drug. Thus, TZM appears to cause different types of hepatotoxicity. Particular attention should be paid to sustained cholestasis as a very serious type of TZM-associated liver toxicity. PMID:22394496

  5. Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system

    PubMed Central

    Sarganas, Giselle; Orzechowski, Hans D.; Klimpel, Andreas; Thomae, Michael; Kauffmann, Wolfgang; Herbst, Hermann; Bronder, Elisabeth; Garbe, Edeltraut

    2012-01-01

    Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults. Its established first-line adjuvant treatment is radiotherapy in combination with temozolomide (TZM). Hematotoxicity is listed as a frequent adverse drug reaction in the US prescribing information and hepatotoxicity has been reported infrequently in the postmarketing period. We here present the case of a patient diagnosed with GBM who developed severe sustained cholestatic hepatitis following treatment with TZM. The cholestasis was not reversible after withdrawal of TZM during 6 months before the patient's death. Another 2 published case reports of sustained cholestasis following TZM treatment were identified; however, the sustained nature of cholestasis was not emphasized in these reports. Sixteen cases of cholestatic hepatitis/cholestasis associated with TZM were identified in the FDA spontaneous reporting system between 2007 and 2010. Information on the course of the cholestasis in these cases could not be retrieved. In the literature there are other published reports of hepatotoxicity associated with TZM that have reported reversibility upon withdrawal of the drug. Thus, TZM appears to cause different types of hepatotoxicity. Particular attention should be paid to sustained cholestasis as a very serious type of TZM-associated liver toxicity. PMID:22394496

  6. Pilot Study to Explore the Accuracy of Current Prediction Equations in Assessing Energy Needs of Patients with Newly Diagnosed Glioblastoma Multiforme.

    PubMed

    Little, Rebecca B; Oster, Robert A; Darnell, Betty E; Demark-Wahnefried, Wendy; Nabors, L Burt

    2016-01-01

    Glioblastoma multiforme (GBM) is rare, yet it is the most common brain malignancy and has a poor prognosis. In regard to GBM, there is a dearth of research on resting energy expenditure (REE) and the accuracy of extant prediction equations. The aim of this cross-sectional study was to compare measured REE (mREE) to commonly used prediction equations in newly diagnosed GBM patients. REE was collected by indirect calorimetry in 20 GBM patients. Calculated REE was derived from Harris-Benedict (again with weight adjusted for obesity), Mifflin-St Jeor, and the 20 kcal/kg body weight ratio method. Paired t-tests and Bland-Altman analyses were used to compare group means, evaluate the bias, and find the limits of agreement. Clinical accuracy was assessed by determining the percentage of patients with predicted REE within ±10% of mREE. Subjects were evenly distributed with regard to gender, primarily Caucasian, and largely overweight or obese and had a mean age of 57 years. All equations overestimated mREE. Mifflin-St Jeor and adjusted Harris-Benedict had the narrowest limits of agreement and accurately predicted 60% and 65% of subjects, respectively. Clinicians should be aware of the discrepancy between commonly used prediction equations and REE. More research is needed to verify these findings and decipher the cause and significance in the GBM population. PMID:27341142

  7. Quantification of microheterogeneity in glioblastoma multiforme with ex vivo high-resolution magic-angle spinning (HRMAS) proton magnetic resonance spectroscopy.

    PubMed Central

    Cheng, L. L.; Anthony, D. C.; Comite, A. R.; Black, P. M.; Tzika, A. A.; Gonzalez, R. G.

    2000-01-01

    Microheterogeneity is a routinely observed neuropathologic characteristic in brain tumor pathology. Although microheterogeneity is readily documented by routine histologic techniques, these techniques only measure tumor status at the time of biopsy or surgery and do not indicate likely tumor progression. A biochemical screening technique calibrated against pathologic standards would greatly assist in predicting tumor progression from its biological activity. Here we demonstrate for the first time that proton magnetic resonance spectroscopy (1H MRS) with high-resolution magic-angle spinning (HRMAS), a technique introduced in 1997, can preserve tissue histopathologic features while producing well-resolved spectra of cellular metabolites in the identical intact tissue specimens. Observed biochemical alterations and tumor histopathologic characteristics can thus be correlated for the same surgical specimen, obviating the problems caused by tumor microheterogeneity. We analyzed multiple specimens of a single human glioblastoma multiforme surgically removed from a 44-year-old patient. Each specimen was first measured with HRMAS 1H MRS to determine tumor metabolites, then evaluated by quantitative histopathology. The concentrations of lactate and mobile lipids measured with HRMAS linearly reflected the percentage of tumor necrosis. Moreover, metabolic ratios of phosphorylcholine to choline correlated linearly with the percentage of the highly cellular malignant glioma. The quantification of tumor metabolic changes with HRMAS 1H MRS, in conjunction with subsequent histopathology of the same tumor specimen, has the potential to further our knowledge of the biochemistry of tumor heterogeneity during development, and thus ultimately to improve our accuracy in diagnosing, characterizing, and evaluating tumor progression. PMID:11303625

  8. Risk of Adverse Vascular Events in Newly Diagnosed Glioblastoma Multiforme Patients Treated with Bevacizumab: a Systematic Review and Meta-Analysis.

    PubMed

    Li, Xiaoqing; Huang, Rongzhong; Xu, Zhongye

    2015-01-01

    Previous evidence suggests that the humanized anti-VEGF antibody bevacizumab increases thrombosis risk in glioma patients. Here, we comprehensively assessed the risk of adverse vascular events in adult glioma patients receiving bevacizumab therapy. Systematic searches of MEDLINE, EMBASE, and the Cochrane Library were conducted to find prospective phase II/III clinical trials on adult bevacizumab-treated glioma patients and non-bevacizumab-treated controls that reported data on adverse vascular events. Four high-quality trials were finally included in the systematic review, scoring greater than or equal to 7/8 on the Newcastle-Ottawa Scale. Three trials provided sufficient data for four meta-analytical comparisons between bevacizumab-treated and control groups of newly diagnosed glioblastoma multiforme (GBM) patients: all-cause discontinuation, thrombocytopenia, deep vein thrombosis (DVT), and pulmonary embolism. None of these adverse outcomes were found to be significantly different between bevacizumab-treated and control groups (P > 0.05); however, there was a trend toward significance with regard to bevacizumab therapy and the risk of pulmonary embolism (P = 0.07). As there was a trend toward significance with regard to bevacizumab therapy and the risk of pulmonary embolism, anticoagulation may be advisable in certain newly diagnosed adult GBM patients who display a history of thromboembolism and/or more serious risk factors for thromboembolic events.

  9. Radiosensitisation by pharmacological ascorbate in glioblastoma multiforme cells, human glial cells, and HUVECs depends on their antioxidant and DNA repair capabilities and is not cancer specific.

    PubMed

    Castro, M Leticia; McConnell, Melanie J; Herst, Patries M

    2014-09-01

    We previously showed that 5 mM ascorbate radiosensitized early passage radioresistant glioblastoma multiforme (GBM) cells derived from one patient tumor. Here we investigate the sensitivity of a panel of cell lines to 5 mM ascorbate and 6 Gy ionizing radiation, made up of three primary human GBM cells, three GBM cell lines, a human glial cell line, and primary human vascular endothelial cells. The response of different cells lines to ascorbate and/or radiation was determined by measuring viability, colony-forming ability, generation and repair of double-stranded DNA breaks (DSBs), cell cycle progression, antioxidant capacity and generation of reactive oxygen species. Individually, radiation and ascorbate both decreased viability and clonogenicity by inducing DNA damage, but had differential effects on cell cycle progression. Radiation led to G2/M arrest in most cells whereas ascorbate caused accumulation in S phase, which was moderately associated with poor DSB repair. While high dose ascorbate radiosensitized all cell lines in clonogenic assays, the sensitivity to radiation, high dose ascorbate, and combined treatment varied between cell lines. Normal glial cells were similar to GBM cells with respect to free radical scavenging potential and effect of treatment on DNA damage and repair, viability, and clonogenicity. Both GBM cells and normal cells coped equally poorly with oxidative stress caused by radiation and/or high dose ascorbate, dependent primarily on their antioxidant and DSB repair capacity.

  10. Dysregulated miR-671-5p / CDR1-AS / CDR1 / VSNL1 axis is involved in glioblastoma multiforme

    PubMed Central

    Salito, Loredana; Sammito, Mariangela; Banelli, Barbara; Caltabiano, Rosario; Barbagallo, Giuseppe; Zappalà, Agata; Battaglia, Rosalia; Cirnigliaro, Matilde; Lanzafame, Salvatore; Vasquez, Enrico; Parenti, Rosalba; Cicirata, Federico; Di Pietro, Cinzia; Romani, Massimo; Purrello, Michele

    2016-01-01

    MiR-671-5p is encoded by a gene localized at 7q36.1, a region amplified in human glioblastoma multiforme (GBM), the most malignant brain cancer. To investigate whether expression of miR-671-5p were altered in GBM, we analyzed biopsies from a cohort of forty-five GBM patients and from five GBM cell lines. Our data show significant overexpression of miR-671-5p in both biopsies and cell lines. By exploiting specific miRNA mimics and inhibitors, we demonstrated that miR-671-5p overexpression significantly increases migration and to a less extent proliferation rates of GBM cells. Through a combined in silico and in vitro approach, we identified CDR1-AS, CDR1, VSNL1 as downstream miR-671-5p targets in GBM. Expression of these genes significantly decreased both in GBM biopsies and cell lines and negatively correlated with that of miR-671-5p. Based on our data, we propose that the axis miR-671-5p / CDR1-AS / CDR1 / VSNL1 is functionally altered in GBM cells and is involved in the modification of their biopathological profile. PMID:26683098

  11. Protein Co-Expression Analysis as a Strategy to Complement a Standard Quantitative Proteomics Approach: Case of a Glioblastoma Multiforme Study.

    PubMed

    Kanonidis, Evangelos I; Roy, Marcia M; Deighton, Ruth F; Le Bihan, Thierry

    2016-01-01

    Although correlation network studies from co-expression analysis are increasingly popular, they are rarely applied to proteomics datasets. Protein co-expression analysis provides a complementary view of underlying trends, which can be overlooked by conventional data analysis. The core of the present study is based on Weighted Gene Co-expression Network Analysis applied to a glioblastoma multiforme proteomic dataset. Using this method, we have identified three main modules which are associated with three different membrane associated groups; mitochondrial, endoplasmic reticulum, and a vesicle fraction. The three networks based on protein co-expression were assessed against a publicly available database (STRING) and show a statistically significant overlap. Each of the three main modules were de-clustered into smaller networks using different strategies based on the identification of highly connected networks, hierarchical clustering and enrichment of Gene Ontology functional terms. Most of the highly connected proteins found in the endoplasmic reticulum module were associated with redox activity while a core of the unfolded protein response was identified in addition to proteins involved in oxidative stress pathways. The proteins composing the electron transfer chain were found differently affected with proteins from mitochondrial Complex I being more down-regulated than proteins from Complex III. Finally, the two pyruvate kinases isoforms show major differences in their co-expressed protein networks suggesting roles in different cellular locations. PMID:27571357

  12. Modulating Roles of Amiloride in Irradiation-Induced Antiproliferative Effects in Glioblastoma Multiforme Cells Involving Akt Phosphorylation and the Alternative Splicing of Apoptotic Genes

    PubMed Central

    Tang, Jen-Yang

    2013-01-01

    Apoptosis is a key mechanism for enhanced cellular radiosensitivity in radiation therapy. Studies suggest that Akt signaling may play a role in apoptosis and radioresistance. This study evaluates the possible modulating role of amiloride, an antihypertensive agent with a modulating effect to alternative splicing for regulating apoptosis, in the antiproliferative effects induced by ionizing radiation (IR) in glioblastoma multiforme (GBM) 8401 cells. Analysis of cell viability showed that amiloride treatment significantly inhibited cell proliferation in irradiated GBM8401 cells (p<0.05) in a time-dependent manner, especially in cells treated with amiloride with IR post-treatment. In comparison with GBM8401 cells treated with amiloride alone, with GBM8401 cells treated with IR alone, and with human embryonic lung fibroblast control cells (HEL 299), GBM8401 cells treated with IR combined with amiloride showed increased overexpression of phosphorylated Akt, regardless of whether IR treatment was performed before or after amiloride administration. The alternative splicing pattern of apoptotic protease-activating factor-1 (APAF1) in cells treated with amiloride alone, IR alone, and combined amiloride-IR treatments showed more consistent cell proliferation compared to that in other apoptosis-related genes such as baculoviral IAP repeat containing 5 (BIRC5), Bcl-X, and homeodomain interacting protein kinase-3 (HIPK3). In GBM8401 cells treated with amiloride with IR post-treatment, the ratio of prosurvival (-XL,-LC) to proapoptotic (-LN,-S) splice variants of APAF1 was lower than that seen in cells treated with amiloride with IR pretreatment, suggesting that proapoptotic splice variants of APAF1 (APAF1-LN,-S) were higher in the glioblastoma cells treated with amiloride with IR post-treatment, as compared to glioblastoma cells and fibroblast control cells that had received other treatments. Together, these results suggest that amiloride modulates cell radiosensitivity

  13. Effects of Concurrent Topotecan and Radiation on 6-Month Progression-Free Survival in the Primary Treatment of Glioblastoma Multiforme

    SciTech Connect

    Grabenbauer, Gerhard G. Gerber, Klaus-Dieter; Ganslandt, Oliver; Richter, Andrea M.S.; Klautke, Gunther; Birkmann, Josef; Meyer, Martin

    2009-09-01

    Purpose: To report a prospective, randomized, Phase II trial of radiotherapy with and without topotecan for the treatment of glioblastoma. Patients and Methods: Inclusion criteria were histology of glioblastoma, age <60 years, and Eastern Cooperative Oncology Group status 0-2. Patients were stratified according to recursive partitioning analysis class, center, and enzyme-inducing antiepileptic medication. Magnetic resonance imaging scans, neurologic examinations, and quality of life assessments were done every 3 months. The primary endpoint was the progression-free survival rate at 6 months (6-m-PFS). This trial was designed as an exploratory, randomized, Phase II trial with an accrual of 140 patients to detect a difference of 15-20% in 6-m-PFS. An interim analysis was scheduled after 60 patients. Median follow-up was 14 months (range, 1-50 months). Results: The 6-m-PFS was 56% and 40% for patients with and without topotecan, respectively. This benefit disappeared within 2 months. Mean (range) progression-free survival time was 8 (5-10.9) months and 6.7 (4-9.5) months for patients with and without topotecan, respectively. The corresponding 2-year-overall survival rates were 28% vs. 22% (nonsignificant difference), and mean (range) survival time was 20.7 (13.9-27.5) months vs. 18.9 (13.5-24.4) months (nonsignificant difference). Conclusions: A slight but measurable increase of 16% was detected in 6-m-PFS for patients receiving topotecan with radiation as compared with patients having radiotherapy alone. These data might support further investigations into topotecan for the treatment of glioblastoma.

  14. Prognostic Value of Early [{sup 18}F]Fluoroethyltyrosine Positron Emission Tomography After Radiochemotherapy in Glioblastoma Multiforme

    SciTech Connect

    Piroth, Marc D.; Pinkawa, Michael; Holy, Richard; Klotz, Jens; Nussen, Sandra; Stoffels, Gabriele; Coenen, Heinz H.; Kaiser, Hans J.; Langen, Karl J.; Eble, Michael J.

    2011-05-01

    Purpose: Early detection of treatment response in glioma patients after radiochemotherapy (RCX) is uncertain because treatment-related contrast enhancement in magnetic resonance imaging can mimic tumor progression. Positron emission tomography (PET) using the amino acid tracer [{sup 18}F]fluoroethyltyrosine (FET) seems to be a promising tool for treatment monitoring. The aim of this prospective study was to evaluate the prognostic value of early changes of FET uptake after postoperative RCX in glioblastomas. Methods and Materials: Twenty-two patients with glioblastoma were treated by surgery and subsequent RCX (whole dose 60-72 Gy). The FET-PET studies were performed before RCX, 7-10 days and 6-8 weeks after completion of RCX. Early treatment response in PET was defined as a decrease of the maximal tumor-to-brain ratio (TBR{sub max}) of FET uptake after RCX of more than 10%. The prognostic value of early changes of FET uptake after RCX was evaluated using Kaplan-Maier estimates for median disease-free survival and overall survival. Results: The median overall and disease-free survival of the patients was 14.8 and 7.8 months. There were 16 early responders in FET-PET (72.7%) and 6 nonresponders (27.3%). Early PET responders had a significantly longer median disease-free survival (10.3 vs. 5.8 months; p < 0.01) and overall survival ('not reached' vs. 9.3 months; p < 0.001). No statistically significant differences between the patient subgroups were found concerning the defined prognostic parameters. Conclusions: FET-PET is a sensitive tool to predict treatment response in patients with glioblastomas at an early stage after RCX.

  15. The SOX2 response program in glioblastoma multiforme: an integrated ChIP-seq, expression microarray, and microRNA analysis

    PubMed Central

    2011-01-01

    Background SOX2 is a key gene implicated in maintaining the stemness of embryonic and adult stem cells. SOX2 appears to re-activate in several human cancers including glioblastoma multiforme (GBM), however, the detailed response program of SOX2 in GBM has not yet been defined. Results We show that knockdown of the SOX2 gene in LN229 GBM cells reduces cell proliferation and colony formation. We then comprehensively characterize the SOX2 response program by an integrated analysis using several advanced genomic technologies including ChIP-seq, microarray profiling, and microRNA sequencing. Using ChIP-seq technology, we identified 4883 SOX2 binding regions in the GBM cancer genome. SOX2 binding regions contain the consensus sequence wwTGnwTw that occurred 3931 instances in 2312 SOX2 binding regions. Microarray analysis identified 489 genes whose expression altered in response to SOX2 knockdown. Interesting findings include that SOX2 regulates the expression of SOX family proteins SOX1 and SOX18, and that SOX2 down regulates BEX1 (brain expressed X-linked 1) and BEX2 (brain expressed X-linked 2), two genes with tumor suppressor activity in GBM. Using next generation sequencing, we identified 105 precursor microRNAs (corresponding to 95 mature miRNAs) regulated by SOX2, including down regulation of miR-143, -145, -253-5p and miR-452. We also show that miR-145 and SOX2 form a double negative feedback loop in GBM cells, potentially creating a bistable system in GBM cells. Conclusions We present an integrated dataset of ChIP-seq, expression microarrays and microRNA sequencing representing the SOX2 response program in LN229 GBM cells. The insights gained from our integrated analysis further our understanding of the potential actions of SOX2 in carcinogenesis and serves as a useful resource for the research community. PMID:21211035

  16. Peripheral blood-derived, γ9δ2 t cell-enriched cell lines from glioblastoma multiforme patients exert anti-tumoral effects in vitro.

    PubMed

    Marcu-Malina, V; Garelick, D; Peshes-Yeloz, N; Wohl, A; Zach, L; Nagar, M; Amariglio, N; Besser, M J; Cohen, Z R; Bank, I

    2016-01-01

    The goal of this work was to assess the potential of T cells expressing Vγ9Vδ2+ T cell receptors (TCR, γ9δ2T cells) present in peripheral blood (PB) m ononuclear cells (MC, PBMC) of glioblastoma multiforme (GBM) patients to act as anti-tumoral agents. We found that γ9δ2T cell levels were decreased in patients' PB relative to a cohort of healthy donors (HD) (respectively 0.52±0.55%, n=16, vs 1.12±0.6%, n=14, p=0.008) but did not significantly correlate with postoperative survival (R=0.6, p=0.063). Importantly, however, the γ9δ2T cells could be expanded in vitro to consist 51±23% of the cultured lymphocytes (98% CD3+). This was achieved after 14 days of culture in medium containing the amino-bisphosphonate (ABP) Zoledronate (Zol) and interleukin (IL)-2, resulting in γ9δ2T cell-enriched lines (gdTCEL) similar to those of HD derived gdTCEL (54±19%). Moreover, gdTCEL from patients and HD mediated cytotoxicity to GBM-derived cell lines (GBMDCL), which was abrogated by immune-magnetic removal of the γ9δ2T cells. Furthermore, low level interferon (IFN) γ secretion was induced by gdTCEL briefly co-cultured with GBMDCL or autologous - tumor-derived cells, which was greatly amplified in the presence of Zol. Importantly, IFNγ secretion was inhibited by mevastatin but enhanced by cross-linking of butyrophilin 3A1 (CD277) on a CD277+ GBMDCL (U251MG) or by pretreatment of GBMDCL with temozolomide (TMZ). Taken together, these data suggest that γ9δ2T cells in PB of GBM patients can give rise to gdTCEL that mediate anti-tumoral activities. PMID:27049073

  17. Targeting cancer stem cells in glioblastoma multiforme using mTOR inhibitors and the differentiating agent all-trans retinoic acid.

    PubMed

    Friedman, Marissa D; Jeevan, Dhruve S; Tobias, Michael; Murali, Raj; Jhanwar-Uniyal, Meena

    2013-10-01

    Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, portends a poor prognosis despite current treatment modalities. Recurrence of tumor growth is attributed to the presence of treatment-resistant cancer stem cells (CSCs). The targeting of these CSCs is therefore essential in the treatment of this disease. Mechanistic target of rapamycin (mTOR) forms two multiprotein complexes, mTORC1 and mTORC2, which regulate proliferation and migration, respectively. Aberrant function of mTOR has been shown to be present in GBM CSCs. All-trans retinoic acid (ATRA), a derivative of retinol, causes differentiation of CSCs as well as normal neural progenitor cells. The purpose of this investigation was to delineate the role of mTOR in CSC maintenance, and to establish the mechanism of targeting GBM CSCs using differentiating agents along with inhibitors of the mTOR pathways. The results demonstrated that ATRA caused differentiation of CSCs, as demonstrated by the loss of the stem cell marker Nestin. These observations were confirmed by western blotting, which demonstrated a time-dependent decrease in Nestin expression following ATRA treatment. This effect occurred despite combination with mTOR (rapamycin), PI3K (LY294002) and MEK1/2 (U0126) inhibitors. Expression of activated extracellular signal-regulated kinase 1/2 (pERK1/2) was enhanced following treatment with ATRA, independent of mTOR pathway inhibitors. Proliferation of CSCs, determined by neurosphere diameter, was decreased following treatment with ATRA alone and in combination with rapamycin. The motility of GBM cells was mitigated by treatment with ATRA, rapamycin and LY29002 alone. However, combination treatment augmented the inhibitory effect on migration suggesting synergism. These findings indicate that ATRA-induced differentiation is mediated via the ERK1/2 pathway, and underscores the significance of including differentiating agents along with inhibitors of mTOR pathways in the treatment of GBM.

  18. MicroPET/CT Imaging of an Orthotopic Model of Human Glioblastoma Multiforme and Evaluation of Pulsed Low-Dose Irradiation

    SciTech Connect

    Park, Sean S.; Chunta, John L.; Robertson, John M.; Martinez, Alvaro A.; Oliver Wong, Ching-Yee; Amin, Mitual; Wilson, George D.; Marples, Brian

    2011-07-01

    Purpose: Glioblastoma multiforme (GBM) is an aggressive tumor that typically causes death due to local progression. To assess a novel low-dose radiotherapy regimen for treating GBM, we developed an orthotopic murine model of human GBM and evaluated in vivo treatment efficacy using micro-positron-emission tomography/computed tomography (microPET/CT) tumor imaging. Methods: Orthotopic GBM xenografts were established in nude mice and treated with standard 2-Gy fractionation or 10 0.2-Gy pulses with 3-min interpulse intervals, for 7 consecutive days, for a total dose of 14 Gy. Tumor growth was quantified weekly using the Flex Triumph (GE Healthcare/Gamma Medica-Ideas, Waukesha, WI) combined PET-single-photon emission CT (SPECT)-CT imaging system and necropsy histopathology. Normal tissue damage was assessed by counting dead neural cells in tissue sections from irradiated fields. Results: Tumor engraftment efficiency for U87MG cells was 86%. Implanting 0.5 x 10{sup 6} cells produced a 50- to 70-mm{sup 3} tumor in 10 to 14 days. A significant correlation was seen between CT-derived tumor volume and histopathology-measured volume (p = 0.018). The low-dose 0.2-Gy pulsed regimen produced a significantly longer tumor growth delay than standard 2-Gy fractionation (p = 0.045). Less normal neuronal cell death was observed after the pulsed delivery method (p = 0.004). Conclusion: This study successfully demonstrated the feasibility of in vivo brain tumor imaging and longitudinal assessment of tumor growth and treatment response with microPET/CT. Pulsed radiation treatment was more efficacious than the standard fractionated treatment and was associated with less normal tissue damage.

  19. Metronomic chemotherapy with daily low-dose temozolomide and celecoxib in elderly patients with newly diagnosed glioblastoma multiforme: a retrospective analysis.

    PubMed

    Welzel, Grit; Gehweiler, Julian; Brehmer, Stefanie; Appelt, Jens-Uwe; von Deimling, Andreas; Seiz-Rosenhagen, Marcel; Schmiedek, Peter; Wenz, Frederik; Giordano, Frank A

    2015-09-01

    Chemotherapy is often omitted in elderly patients with glioblastoma multiforme due to a fear of side effects. We applied metronomic chemotherapy with low-dose temozolomide and celecoxib (LD-TEM/CEL) during and after external beam radiotherapy (EBRT) and here report on how this regimen compares to standard temozolomide radiochemotherapy (SD-TEM) in elderly patients. We retrospectively analyzed records of 146 patients aged 65 years and older that underwent EBRT. Factors of interest were age, performance status, comorbidities, MGMT status, therapy (resection/biopsy, radiotherapy/dose, chemotherapy/regimen/dose), progression-free (PFS) and overall survival (OS) status. Irrespective of the regimen, addition of chemotherapy more than doubled median survival rates (EBRT only: 4.2 months; EBRT + LD-TEM/CEL: 8.5 months; EBRT + SD-TEM: 10.8 months; p ≤ 0.008). Although patients receiving metronomic LD-TEM/CEL were significantly older (62 % were ≥75 years vs. 22 %; p < 0.001), had significantly lower performance scores (50 % had a KPS <70 vs. 28 %; p = 0.049) and were significantly more comorbid (73 % had ≥4 comorbidities vs. 37 %; p = 0.002) than patients of the SD-TEM group, there were no significant differences in PFS and OS. Independent of other factors, omission of chemotherapy significantly impairs progression-free and overall survival. With all the limitations of a retrospective analysis, our data suggest that metronomic chemotherapy with LD-TEM/CEL may be equieffective and eventually better tolerated than SD-TEM. It may be offered to elderly patients that are not eligible for standard chemotherapy.

  20. Phase I trial of erlotinib with radiation therapy in patients with glioblastoma multiforme: Results of North Central Cancer Treatment Group protocol N0177

    SciTech Connect

    Krishnan, Sunil . E-mail: skrishnan@mdanderson.org; Brown, Paul D.; Ballman, Karla V.; Fiveash, John B.; Uhm, Joon H.; Giannini, Caterina; Jaeckle, Kurt A.; Geoffroy, Francois J.; Nabors, L. Burt; Buckner, Jan C.

    2006-07-15

    Purpose: To evaluate the toxicity and maximum tolerated dose (MTD) of erlotinib plus radiation therapy (RT) in patients with glioblastoma multiforme (GBM) in a multicenter phase I trial. Methods and Materials: Patients were stratified on the basis of the use of enzyme-inducing anticonvulsants (EIACs). After resection or biopsy, patients were treated with erlotinib for 1 week before concurrent erlotinib and 6 weeks (60 Gy) of RT and maintained on erlotinib until progression. The erlotinib dose was escalated in cohorts of 3 starting at 100 mg/day. Results: Twenty patients were enrolled and 19 were evaluable for the MTD and efficacy endpoints. Of these patients, 14 were males and 5 were females, with a median age of 54 years. Seven had undergone biopsy only, 5 had subtotal resections, and 7 had gross total resections. The highest dose level was 150 mg/day erlotinib for patients not on EIACs (Group 1) and 200 mg/day for patients on EIACs (Group 2). MTD was not reached in either group. In Group 1 at 100 mg (n = 6) and at 150 mg (n = 4), only 1 dose-limiting toxicity (DLT) occurred (stomatitis at 100 mg). No DLTs have occurred in Group 2 at 100 mg (n = 3), 150 mg (n = 3), and 200 mg (n = 3). With a median follow-up of 52 weeks, progression was documented in 16 patients and 13 deaths occurred. Median time to progression was 26 weeks, and median survival was 55 weeks. Conclusion: Toxicity is acceptable at the current doses of erlotinib plus RT. The study was modified to include concurrent and adjuvant temozolomide, and accrual is in progress.

  1. Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma

    PubMed Central

    Butowski, Nicholas; Chang, Susan M.; Lamborn, Kathleen R.; Polley, Mei–Yin; Pieper, Russell; Costello, Joseph F.; Vandenberg, Scott; Parvataneni, Rupa; Nicole, Angelina; Sneed, Patricia K.; Clarke, Jennifer; Hsieh, Emily; Costa, Bruno M.; Reis, Rui M.; Hristova-Kazmierski, Maria; Nicol, Steven J.; Thornton, Donald E.; Prados, Michael D.

    2011-01-01

    This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m2 daily during RT and then adjuvantly at 200 mg/m2 daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotininb and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials. PMID:21896554

  2. Phase II Study of Erlotinib Plus Temozolomide During and After Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

    PubMed Central

    Prados, Michael D.; Chang, Susan M.; Butowski, Nicholas; DeBoer, Rebecca; Parvataneni, Rupa; Carliner, Hannah; Kabuubi, Paul; Ayers-Ringler, Jennifer; Rabbitt, Jane; Page, Margaretta; Fedoroff, Anne; Sneed, Penny K.; Berger, Mitchel S.; McDermott, Michael W.; Parsa, Andrew T.; Vandenberg, Scott; James, C. David; Lamborn, Kathleen R.; Stokoe, David; Haas-Kogan, Daphne A.

    2009-01-01

    Purpose This open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response. Patients and Methods Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials. Results Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival. Conclusion Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted. PMID:19075262

  3. Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma.

    PubMed

    Butowski, Nicholas; Chang, Susan M; Lamborn, Kathleen R; Polley, Mei-Yin; Pieper, Russell; Costello, Joseph F; Vandenberg, Scott; Parvataneni, Rupa; Nicole, Angelina; Sneed, Patricia K; Clarke, Jennifer; Hsieh, Emily; Costa, Bruno M; Reis, Rui M; Hristova-Kazmierski, Maria; Nicol, Steven J; Thornton, Donald E; Prados, Michael D

    2011-12-01

    This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

  4. Radiosensitizing Effects of Temozolomide Observed in vivo only in a Subset of O6-Methylguanine-DNA Methyltransferase Methylated Glioblastoma Multiforme Xenografts

    SciTech Connect

    Carlson, Brett L.; Grogan, Patrick T.; Mladek, Ann C.; Schroeder, Mark A.; Kitange, Gaspar J.; Decker, Paul A.; Giannini, Caterina; Wu Wenting; Ballman, Karla A.; James, C. David; Sarkaria, Jann N.

    2009-09-01

    Purpose: Concurrent temozolomide (TMZ) and radiation therapy (RT) followed by adjuvant TMZ is standard treatment for patients with glioblastoma multiforme (GBM), although the relative contribution of concurrent versus adjuvant TMZ is unknown. In this study, the efficacy of TMZ/RT was tested with a panel of 20 primary GBM xenografts. Methods and Materials: Mice with intracranial xenografts were treated with TMZ, RT, TMZ/RT, or placebo. Survival ratio for a given treatment/line was defined as the ratio of median survival for treatment vs. placebo. Results: The median survival ratio was significantly higher for O6-methylguanine-DNA methyltransferase (MGMT) methylated tumors versus unmethylated tumors following treatment with TMZ (median survival ratio, 3.6 vs. 1.5, respectively; p = 0.008) or TMZ/RT (5.7 vs. 2.3, respectively; p = 0.001) but not RT alone (1.7 vs. 1.6; p = 0.47). In an analysis of variance, MGMT methylation status and p53 mutation status were significantly associated with treatment response. When we analyzed the additional survival benefit conferred specifically by combined therapy, only a subset (5 of 11) of MGMT methylated tumors derived substantial additional benefit from combined therapy, while none of the MGMT unmethylated tumors did. Consistent with a true radiosensitizing effect of TMZ, sequential treatment in which RT (week 1) was followed by TMZ (week 2) proved significantly less effective than TMZ followed by RT or concurrent TMZ/RT (survival ratios of 4.0, 9.6 and 12.9, respectively; p < 0.0001). Conclusions: Concurrent treatment with TMZ and RT provides significant survival benefit only in a subset of MGMT methylated tumors and provides superior antitumor activity relative to sequential administration of RT and TMZ.

  5. Polish Natural Bee Honeys Are Anti-Proliferative and Anti-Metastatic Agents in Human Glioblastoma multiforme U87MG Cell Line

    PubMed Central

    Moskwa, Justyna; Borawska, Maria H.; Markiewicz-Zukowska, Renata; Puscion-Jakubik, Anna; Naliwajko, Sylwia K.; Socha, Katarzyna; Soroczynska, Jolanta

    2014-01-01

    Honey has been used as food and a traditional medicament since ancient times. However, recently many scientists have been concentrating on the anti-oxidant, anti-proliferative, anti-inflammatory and other properties of honey. In this study, we investigated for the first time an anticancer effect of different honeys from Poland on tumor cell line - glioblastoma multiforme U87MG. Anti-proliferative activity of honeys and its interferences with temozolomide were determined by a cytotoxicity test and DNA binding by [H3]-thymidine incorporation. A gelatin zymography was used to conduct an evaluation of metalloproteinases (MMP-2 and MMP-9) expression in U87MG treatment with honey samples. The honeys were previously tested qualitatively (diastase activity, total phenolic content, lead and cadmium content). The data demonstrated that the examined honeys have a potent anti-proliferative effect on U87MG cell line in a time- and dose-dependent manner, being effective at concentrations as low as 0.5% (multifloral light honey - viability 53% after 72 h of incubation). We observed that after 48 h, combining honey with temozolomide showed a significantly higher inhibitory effect than the samples of honey alone. We observed a strong inhibition of MMP-2 and MMP-9 for the tested honeys (from 20 to 56% and from 5 to 58% compared to control, respectively). Our results suggest that Polish honeys have an anti-proliferative and anti-metastatic effect on U87MG cell line. Therefore, natural bee honey can be considered as a promising adjuvant treatment for brain tumors. PMID:24594866

  6. Polish natural bee honeys are anti-proliferative and anti-metastatic agents in human glioblastoma multiforme U87MG cell line.

    PubMed

    Moskwa, Justyna; Borawska, Maria H; Markiewicz-Zukowska, Renata; Puscion-Jakubik, Anna; Naliwajko, Sylwia K; Socha, Katarzyna; Soroczynska, Jolanta

    2014-01-01

    Honey has been used as food and a traditional medicament since ancient times. However, recently many scientists have been concentrating on the anti-oxidant, anti-proliferative, anti-inflammatory and other properties of honey. In this study, we investigated for the first time an anticancer effect of different honeys from Poland on tumor cell line - glioblastoma multiforme U87MG. Anti-proliferative activity of honeys and its interferences with temozolomide were determined by a cytotoxicity test and DNA binding by [H3]-thymidine incorporation. A gelatin zymography was used to conduct an evaluation of metalloproteinases (MMP-2 and MMP-9) expression in U87MG treatment with honey samples. The honeys were previously tested qualitatively (diastase activity, total phenolic content, lead and cadmium content). The data demonstrated that the examined honeys have a potent anti-proliferative effect on U87MG cell line in a time- and dose-dependent manner, being effective at concentrations as low as 0.5% (multifloral light honey - viability 53% after 72 h of incubation). We observed that after 48 h, combining honey with temozolomide showed a significantly higher inhibitory effect than the samples of honey alone. We observed a strong inhibition of MMP-2 and MMP-9 for the tested honeys (from 20 to 56% and from 5 to 58% compared to control, respectively). Our results suggest that Polish honeys have an anti-proliferative and anti-metastatic effect on U87MG cell line. Therefore, natural bee honey can be considered as a promising adjuvant treatment for brain tumors.

  7. Systemic approaches identify a garlic-derived chemical, Z-ajoene, as a glioblastoma multiforme cancer stem cell-specific targeting agent.

    PubMed

    Jung, Yuchae; Park, Heejoo; Zhao, Hui-Yuan; Jeon, Raok; Ryu, Jae-Ha; Kim, Woo-Young

    2014-07-01

    Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and TGFβ signaling pathways are key mediators of Z-ajoene's action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs.

  8. Pentavalent technetium-99m-dimercaptosuccinic acid [Tc-99m (V) DMSA] brain SPECT: does it have a place in predicting survival in patients with glioblastoma multiforme?

    PubMed

    Amin, Amr; Mustafa, M; Abd El-Hadi, E; Monier, A; Badwey, A; Saad, E

    2015-01-01

    Pentavalent technetium-99m dimercaptosuccinic acid (Tc-99m (V) DMSA) is reported as a useful tool for detection of residual or recurrent gliomas. We aimed to investigate the prognostic value of Tc-99m (V) DMSA brain SPECT in patients with glioblastoma multiforme (GBM). 40 patients [21 males and 19 females; mean age 48.6 ± 12.2 years] with GBM were included. Tc-99m (V) DMSA brain SPECT was done after surgery and before onset of radiation therapy or chemotherapy (Baseline study), at 4-6 weeks and at 6 months as a follow-up after therapy. The end point of the study was clinical follow-up for 2 years and/or death. 4-6 weeks after therapy, 40 and 60 % had negative and positive Tc-99m (V) DMSA for viable tumor tissues respectively (P = 0.09). At 6 months follow-up, 62.5 % of (V) DMSA negative patients and 12.5 % of the positive subjects were responders (P = 0.001). The median over-all survival (OS) of all patients was 12.3 month [range 5-24 month]. Patients with positive (V) DMSA had worse survival (8.87 month) compared to the negative ones (16.67 month) (P = 0.0001). Multivariate Cox regression analysis showed that Tc-99m (V) DMSA brain SPECT studies at 4-6 weeks and 6-months follow-up were independent prognostic factors for survival [OR 1.069; 95 % CI 1.417-2.174; P = 0.03 and OR 1.055; 95 % CI 0.821-1.186; P = 0.01 respectively]. Stratification of tumors into risk groups based on prognostic parameters may improve outcome by altering or intensifying treatment methods. Technetium-99m dimercaptosuccinic acid brain SPECT may have an additional prognostic role in patients with GBM which needs further evaluation in larger future series.

  9. Progression-free and overall survival in patients with recurrent Glioblastoma multiforme treated with last-line bevacizumab versus bevacizumab/lomustine.

    PubMed

    Heiland, D H; Masalha, W; Franco, P; Machein, M R; Weyerbrock, A

    2016-02-01

    Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma multiforme (GBM). 1-(2-Chlorethyl)-cyclohexyl-nitrosourea (CCNU, lomustine) monotherapy is an approved chemotherapeutical option for recurrent GBM. Recent evidence demonstrated a survival benefit of combined treatment with BEV and CCNU in patients with a first recurrence of GBM. We examined the outcome of recurrent GBM patients with BEV monotherapy versus BEV/CCNU therapy when used as last-line therapy. 35 patients with recurrent GBM treated between 2010 and 2014 were included in this retrospective study. Progression-free and overall survival was determined with reference to the beginning of BEV or BEV/CCNU therapy and initial diagnosis. 17 patients received BEV monotherapy, 18 patients received combined BEV and CCNU therapy. The impact of parameters such as IDH mutation, MGMT promoter methylation, tumor localization, histology and the number of surgeries were included in a multivariate ANOVA analysis. Furthermore, Karnofsky performance score (KPS), neurological function and toxicity were assessed. BEV/CCNU treatment led to an extension of PFS (6.11 months; 95% CL 3.41-12.98 months; log-rank p = 0.00241) and OS (6.59 months; 95% CL 5.51-16.3 months; log-rank p = 0.0238) of 2 months compared to BEV monotherapy. This survival advantage was independent of histology, IDH mutation status or the number of previous surgeries. Neurological function, KPS and toxicity were not significantly different between both treatment groups. Last-line therapy with BEV/CCNU results in a longer PFS and OS compared to BEV monotherapy and is well-tolerated. These findings confirm the role of these agents in the treatment of recurrent GBM and are in line with other studies. PMID:26614518

  10. Haematological toxicity of Valproic acid compared to Levetiracetam in patients with glioblastoma multiforme undergoing concomitant radio-chemotherapy: a retrospective cohort study.

    PubMed

    Tinchon, Alexander; Oberndorfer, Stefan; Marosi, Christine; Gleiss, Andreas; Geroldinger, Angelika; Sax, Cornelia; Sherif, Camillo; Moser, Walter; Grisold, Wolfgang

    2015-01-01

    Patients with glioblastoma multiforme (GBM) and symptomatic seizures are in need of a sufficient antiepileptic treatment. Haematological toxicity is a limiting side effect of both, first line radio-chemotherapy with temozolomide (TMZ) and co-medication with antiepileptic drugs. Valproic acid (VPA) and levetiracetam (LEV) are considered favourable agents in brain tumor patients with seizures, but are commonly reported to induce haematological side effects on their own. We hypothesized, that antiepileptic treatment with these agents has no increased impact on haematological side effects during radio-chemotherapy in the first line setting. We included 104 patients from two neuro-oncologic centres with GBM and standard radio-chemotherapy in a retrospective cohort study. Patients were divided according to their antiepileptic treatment with either VPA, LEV or without antiepileptic drug therapy (control group). Declines in haemoglobin levels and absolute blood cell counts for neutrophil granulocytes, lymphocytes and thrombocytes were analyzed twice during concomitant and once during adjuvant phase. A comparison between the examined groups was performed, using a linear mixed model. Neutrophil granulocytes, lymphocytes and thrombocytes significantly decreased over time in all three groups (all p < 0.012), but there was no significant difference between the compared groups. A significant decline in haemoglobin was observed in the LEV treated group (p = 0.044), but did not differ between the compared groups. As a novel finding, this study demonstrates that co-medication either with VPA or LEV in GBM patients undergoing first line radio-chemotherapy with TMZ has no additional impact on medium-term haematological toxicity.

  11. SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells

    PubMed Central

    Talarico, Cristina; Dattilo, Vincenzo; D'Antona, Lucia; Barone, Agnese; Amodio, Nicola; Belviso, Stefania; Musumeci, Francesca; Abbruzzese, Claudia; Bianco, Cataldo; Trapasso, Francesco; Schenone, Silvia; Alcaro, Stefano; Ortuso, Francesco; Florio, Tullio; Paggi, Marco G.; Perrotti, Nicola; Amato, Rosario

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive CNS tumor and is characterized by a very high frequency of clinical relapse after therapy and thus by a dismal prognosis, which strongly compromises patients survival. We have recently identified the small molecule SI113, as a potent and selective inhibitor of SGK1, a serine/threonine protein kinase, that modulates several oncogenic signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation and perturbs cell cycle progression by modulating SGK1-related substrates. SI113 is also able to strongly and consistently block, in vitro and in vivo, growth and survival of human hepatocellular-carcinomas, either used as a single agent or in combination with ionizing radiations. In the present paper we aim to study the effect of SI113 on human GBM cell lines with variable p53 expression. Cell viability, cell death, caspase activation and cell cycle progression were then analyzed by FACS and WB-based assays, after exposure to SI113, with or without oxidative stress and ionizing radiations. Moreover, autophagy and related reticulum stress response were evaluated. We show here, that i) SGK1 is over-expressed in highly malignant gliomas and that the treatment with SI113 leads to ii) significant increase in caspase-mediated apoptotic cell death in GBM cell lines but not in normal fibroblasts; iii)enhancement of the effects of ionizing radiations; iv) modulation of the response to oxidative reticulum stress; v) induction of cytotoxic autophagy. Evidence reported here underlines the therapeutic potential of SI113 in GBM, suggesting a new therapeutic strategy either alone or in combination with radiotherapy. PMID:26908461

  12. miR-29b attenuates tumorigenicity and stemness maintenance in human glioblastoma multiforme by directly targeting BCL2L2

    PubMed Central

    Chung, Hyun Joo; Choi, Young Eun; Kim, Eun Sook; Han, Young-Hoon; Park, Myung-Jin; Bae, In Hwa

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor and exhibits aggressive and invasive behavior. We previously identified four miRNAs—miR-29b, 494, 193a-3p, and 30e—with enhanced expression in GBM following treatment of ionizing radiation by miRNA microarray analysis. In this study, we found that only miR-29b inhibited tumor cell migration and invasion by reducing MMP-2 activity via phospho-AKT/β-catenin signaling, and stimulated a more epithelial-like morphology. Moreover, miR-29b inhibits angiogenesis by attenuating tube formation and the expression of VEGF and Ang-2, and stemness maintenance in GBM cells, as demonstrated by decreasing neurosphere formation and cancer stem cell marker protein expression. These findings support the anti-tumor properties of miR-29b in human GBM cells. Furthermore, miR-29b expression was inversely proportional to that of BCL2L2 mRNA or protein in various cancer cell types. Interestingly, BCL2L2 mRNA is highly expressed in the mesenchymal type of GBM. To further elucidate the relationship between miR-29b and BCL2L2 in GBM, we performed co-transfection reporter assays and determined that miR-29b downregulates BCL2L2 expression by directly binding its 3′UTR. Finally, we confirmed that BCL2L2 repression is of central importance to miR-29b anti-tumor activity using functional assays to examine cell migration, invasion, angiogenesis, and stemness. From these data, we propose that miR-29b may be a useful therapeutic agent in GBM. PMID:26155940

  13. Systemic Approaches Identify a Garlic-Derived Chemical, Z-ajoene, as a Glioblastoma Multiforme Cancer Stem Cell-Specific Targeting Agent

    PubMed Central

    Jung, Yuchae; Park, Heejoo; Zhao, Hui-Yuan; Jeon, Raok; Ryu, Jae-Ha; Kim, Woo-Young

    2014-01-01

    Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and TGFβ signaling pathways are key mediators of Z–ajoene’s action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs. PMID:25078449

  14. Improved treatment planning for boron neutron capture therapy for glioblastoma multiforme using fluorine-18 labeled boronophenylalanine and positron emission tomography.

    PubMed

    Nichols, Trent L; Kabalka, George W; Miller, Laurence F; Khan, Mohammad K; Smith, Gary T

    2002-10-01

    Boron neutron capture therapy (BNCT) is a cancer brachytherapy based upon the thermal neutron reaction: 10B(n,alpha)7Li. The efficacy of the treatment depends primarily upon two conditions being met: (a) the preferential concentration of a boronated compound in the neoplasm and (b) an adequate fluence of thermal neutrons delivered to the neoplasm. The boronated amino acid, para-boronophenylalanine (BPA), is the agent widely used in clinical trials to deliver 10B to the malignancy. Positron emission tomography (PET) can be used to generate in vivo boron distribution maps by labeling BPA with the positron emitting nuclide fluorine-18. The incorporation of the PET-derived boron distribution maps into current treatment planning protocols is shown to provide improved treatment plans. Using previously established protocols, six patients with glioblastoma had 18BPA PET scans. The PET distribution maps obtained were used in the conventional BNCT treatment codes. The isodose curves derived from the PET data are shown to differ both qualitatively and quantitatively from the conventional isodose curves that were derived from calculations based upon the assumption of uniform uptake of the pharmaceutical in tumor and normal brain regions. The clinical course of each of the patients who eventually received BNCT (five of the six patients) was compared using both sets of isodose calculations. The isodose contours based upon PET derived distribution data appear to be more consistent with the patients' clinical course. PMID:12408309

  15. Erythema multiforme

    MedlinePlus

    Lyell's syndrome; Stevens-Johnson syndrome; Erythema multiforme minor; Erythema multiforme major ... more severe. It is also known as Stevens-Johnson syndrome. This form is usually caused by reactions ...

  16. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy†

    PubMed Central

    Raizer, Jeffrey J.; Abrey, Lauren E.; Lassman, Andrew B.; Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Yung, W.K. Alfred; Gilbert, Mark R.; Aldape, Kenneth A.; Wen, Patrick Y.; Fine, Howard A.; Mehta, Minesh; DeAngelis, Lisa M.; Lieberman, Frank; Cloughesy, Timothy F.; Robins, H. Ian; Dancey, Janet; Prados, Michael D.

    2010-01-01

    Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was not allowed. Patients received 150 mg/day erlotinib. Patients requiring surgery were treated 7 days prior to tumor removal for PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) and intracellular signaling pathways. Ninety-six patients were evaluable (53 recurrent MG and 43 NP GBM); 5 patients were not evaluable for response. PFS-6 in recurrent GBM was 3% with a median PFS of 2 months; PFS-6 in recurrent AG was 27% with a median PFS of 2 months. Twelve-month survival was 57% in NP GBMs post-RT. Primary toxicity was dermatologic. The tissue-to-plasma ratio normalized to nanograms per gram dry weight for erlotinib and OSI-420 ranged from 25% to 44% and 30% to 59%, respectively, for pretreated surgical patients. No effect on EGFR or intratumoral signaling was seen. Patients with NP GBM post-RT who developed rash in cycle 1 had improved survival (P < .001). Single-agent activity of erlotinib is minimal for recurrent MGs and marginally beneficial following RT for NP GBM patients. Development of rash in cycle 1 correlates with survival in patients with NP GBM after RT. PMID:20150372

  17. Differential expression in glioblastoma multiforme and cerebral hemangioblastoma of cytoplasmic proteins that bind two different domains within the 3'-untranslated region of the human glucose transporter 1 (GLUT1) messenger RNA.

    PubMed Central

    Tsukamoto, H; Boado, R J; Pardridge, W M

    1996-01-01

    The glucose transporter 1 (GLUT1) protein is underexpressed in human glioblastoma multiforme and is overexpressed in human cerebral hemangioblastoma. To gain in-sight into possible posttranscriptional mechanisms regulating the expression of the GLUT1 protein in human brain tumors, cytosolic proteins were prepared from these two tumors and used in RNase T1 protection assays that employed [32P]human GLUT1 synthetic RNA prepared from transcription plasmids. Gel shift mobility assays and ultra-violet light cross-linking studies demonstrated the formation of specific RNA/protein complexes that migrated with a mol mass of 120, 44, and 41 kD. RNase T1 mapping and oligodeoxynucleotide competition studies showed that the 120 kD complex was comprised of an RNA fragment that localized to nucleotides 2186-2203 of the GLUT1 mRNA. The 44 kD complex contained an adenosine-uridine-rich RNA fragment that localized to nucleotides 1885-1906 of the human GLUT1 mRNA, and the formation of this complex was inhibited by synthetic RNA enriched in adenosine-uridine sequences. The 44 kD complex was selectively downregulated in hemangioblastoma as compared to glioblastoma multiforme. These studies demonstrate that human brain tumors have differential regulation of cytosolic proteins that specifically interact with two different domains in the 3'-untranslated region of the GLUT1 mRNA, which may serve to mediate the posttranscriptional regulation of GLUT1 gene expression in these tumors. PMID:8675694

  18. Dose-escalated intensity-modulated radiotherapy and irradiation of subventricular zones in relation to tumor control outcomes of patients with glioblastoma multiforme

    PubMed Central

    Kusumawidjaja, Grace; Gan, Patricia Zhun Hong; Ong, Whee Sze; Teyateeti, Achiraya; Dankulchai, Pittaya; Tan, Daniel Yat Harn; Chua, Eu Tiong; Chua, Kevin Lee Min; Tham, Chee Kian; Wong, Fuh Yong; Chua, Melvin Lee Kiang

    2016-01-01

    Background Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with high relapse rate. In this study, we aimed to determine if dose-escalated (DE) radiotherapy improved tumor control and survival in GBM patients. Methods We conducted a retrospective analysis of 49 and 23 newly-diagnosed histology-proven GBM patients, treated with DE radiotherapy delivered in 70 Gy (2.33 Gy per fraction) and conventional doses (60 Gy), respectively, between 2007 and 2013. Clinical target volumes for 70 and 60 Gy were defined by 0.5 and 2.0 cm expansion of magnetic resonance imaging T1-gadolinium-enhanced tumor/surgical cavity, respectively. Bilateral subventricular zones (SVZ) were contoured on a co-registered pre-treatment magnetic resonance imaging and planning computed tomography dataset as a 5 mm wide structure along the lateral margins of the lateral ventricles. Survival outcomes of both cohorts were compared using log-rank test. Radiation dose to SVZ in the DE cohort was evaluated. Results Median follow-up was 13.6 and 15.1 months for the DE- and conventionally-treated cohorts, respectively. Median overall survival (OS) of patients who received DE radiotherapy was 15.2 months (95% confidence interval [CI] =11.0–18.6), while median OS of the latter cohort was 18.4 months (95% CI =12.5–31.4, P=0.253). Univariate analyses of clinical and dosimetric parameters among the DE cohort demonstrated a trend of longer progression-free survival, but not OS, with incremental radiation doses to the ipsilateral SVZ (hazard ratio [HR] =0.95, 95% CI =0.90–1.00, P=0.052) and proportion of ipsilateral SVZ receiving 50 Gy (HR =0.98, 95% CI =0.97–1.00, P=0.017). Conclusion DE radiotherapy did not improve survival in patients with GBM. Incorporation of ipsilateral SVZ as a radiotherapy target volume for patients with GBM requires prospective validation. PMID:27042103

  19. A meta-analysis of bevacizumab alone and in combination with irinotecan in the treatment of patients with recurrent glioblastoma multiforme.

    PubMed

    Zhang, Guobin; Huang, Shengyue; Wang, Zhongcheng

    2012-12-01

    Combining bevacizumab with irinotecan is a new chemotherapy regimen for patients with recurrent glioblastoma multiforme (GBM). Recent phase II trials suggest that this combined chemotherapy is beneficial to patients, but the subsequent adverse events may lead to treatment discontinuation. No comparison has yet demonstrated conclusively that the combined chemotherapy is more beneficial than single-agent chemotherapy. Thus, a meta-analysis was conducted to assess the efficacy and safety of bevacizumab compared to bevacizumab combined with irinotecan for the treatment of recurrent GBM. A total of 480 patients were included in the study, with 183 patients (38.1%) in the bevacizumab group and 297 patients (61.9%) in the bevacizumab plus irinotecan group. The median overall survival was 8.63 months (95% confidence interval [CI], 8.54-8.72 months) and 8.91 months (95% CI, 8.69-9.13 months), respectively. The mean objective response rate (complete response plus partial response rate) was 33.9% (95% CI, 18.1-52.1%) and 45.8% (95% CI, 28.2-66.7%), respectively. The 6-month progression-free survival rates (PFS-6) were 38.8% (95% CI, 18.8-57.0%) and 48.3% (95% CI, 25.4-54.3%), respectively. The rate of discontinuation was 5.5% and 20.0%, respectively. Compared with patients treated with bevacizumab only, those in the bevacizumab plus irinotecan group had higher PFS-6 (p=0.046), objective response (p=0.013) and rate of discontinuation (p=0.000) but there was no statistically significant difference in overall survival between the groups (p=0.487). Thus, although the combination of bevacizumab and irinotecan may increase the rate of discontinuation, it provided no obvious improvement in overall survival in patients with recurrent GBM. Therefore, the benefits of drug combination are outweighed by the treatment discontinuity and quality of life effects of drug toxicity and should be considered on an individual patient basis only.

  20. Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513

    SciTech Connect

    Brachman, David G.; Pugh, Stephanie L.; Ashby, Lynn S.; Thomas, Theresa A.; Dunbar, Erin M.; Narayan, Samir; Robins, H. Ian; Bovi, Joseph A.; Rockhill, Jason K.; Won, Minhee; Curran, Walter P.

    2015-04-01

    Purpose: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. Methods and Materials: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. Results: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. Conclusions: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

  1. The autotaxin-lysophosphatidic acid-lysophosphatidic acid receptor cascade: proposal of a novel potential therapeutic target for treating glioblastoma multiforme.

    PubMed

    Tabuchi, Sadaharu

    2015-01-01

    Glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Its prognosis is one of the worst among all cancer types, and it is considered a fatal malignancy, incurable with conventional therapeutic strategies. As the bioactive multifunctional lipid mediator lysophosphatidic acid (LPA) is well recognized to be involved in the tumorigenesis of cancers by acting on G-protein-coupled receptors, LPA receptor (LPAR) antagonists and LPA synthesis inhibitors have been proposed as promising drugs for cancer treatment. Six LPARs, named LPA1-6, are currently recognized. Among them, LPA1 is the dominant LPAR in the CNS and is highly expressed in GBM in combination with the overexpression of autotaxin (ATX), the enzyme (a phosphodiesterase, which is a potent cell motility-stimulating factor) that produces LPA.Invasion is a defining hallmark of GBM. LPA is significantly related to cell adhesion, cell motility, and invasion through the Rho family GTPases Rho and Rac. LPA1 is responsible for LPA-driven cell motility, which is attenuated by LPA4. GBM is among the most vascular human tumors. Although anti-angiogenic therapy (through the inhibition of vascular endothelial growth factor (VEGF)) was established, sufficient results have not been obtained because of the increased invasiveness triggered by anti-angiogenesis. As both ATX and LPA play a significant role in angiogenesis, similar to VEGF, inhibition of the ATX/LPA axis may be beneficial as a two-pronged therapy that includes anti-angiogenic and anti-invasion therapy. Conventional approaches to GBM are predominantly directed at cell proliferation. Recurrent tumors regrow from cells that have invaded brain tissues and are less proliferative, and are thus quite resistant to conventional drugs and radiation, which preferentially kill rapidly proliferating cells. A novel approach that targets this invasive subpopulation of GBM cells may improve the prognosis of GBM. Patients with GBM that

  2. Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme.

    PubMed

    Phuong, Loi K; Allen, Cory; Peng, Kah-Whye; Giannini, Caterina; Greiner, Suzanne; TenEyck, Cynthia J; Mishra, Prasanna K; Macura, Slobodan I; Russell, Stephen J; Galanis, Evanthia C

    2003-05-15

    Despite the most aggressive medical and surgical treatments, glioblastoma multiforme remains incurable with a median survival of <1 year. We investigated the antitumor potential of a novel viral agent, an attenuated strain of measles virus (MV), derived from the Edmonston vaccine lineage, genetically engineered to produce carcinoembryonic antigen (CEA). CEA production as the virus replicates can serve as a marker of viral gene expression. Infection of a variety of glioblastoma cell lines including U87, U118, and U251 at MOIs 0.1, 1, and 10 resulted in significant cytopathic effect consisting of excessive syncycial formation and massive cell death at 72-96 h from infection. terminal deoxynucleotidyltransferase-mediated nick end labeling assays demonstrated the mechanism of cell death to be predominantly apoptotic. The efficacy of this approach in vivo was examined in BALB/c nude mice by using both s.c. and intracranial orthotopic U87 tumor models. In the s.c. U87 model, mice with established xenografts were treated with a total dose of 8 x 10(7) plaque forming units of MV-CEA, administered i.v. Mice treated with UV light inactivated MV, and untreated mice with established U87 tumors were used as controls. There was statistically significant regression of s.c. tumors (P < 0.001) and prolongation of survival (P = 0.007) in MV-CEA treated animals compared with the two control groups. In the intracranial orthotopic U87 model, there was significant regression of intracranial U87 tumors treated with intratumoral administration of MV-CEA at a total dose of 1.8 x 10(6) plaque forming units as assessed by magnetic resonance image (P = 0.002), and statistically significant prolongation of survival as compared with mice that received UV-inactivated virus and untreated mice (P = 0.02). Histological examination of brains of MV-CEA-treated animals revealed complete regression of the tumor with the presence of a residual glial scar and reactive changes, mainly presence of

  3. Genomic understanding of glioblastoma expanded

    Cancer.gov

    Glioblastoma multiforme (GBM) was the first cancer type to be systematically studied by TCGA in 2008. In a new, complementary report, TCGA experts examined more than 590 GBM samples--the largest to date utilizing genomic characterization techniques and ne

  4. Differential distribution of erbB receptors in human glioblastoma multiforme: expression of erbB3 in CD133-positive putative cancer stem cells

    PubMed Central

    Duhem-Tonnelle, Véronique; Bièche, Ivan; Vacher, Sophie; Loyens, Anne; Maurage, Claude-Alain; Collier, Francis; Baroncini, Marc; Blond, Serge; Prevot, Vincent; Sharif, Ariane

    2010-01-01

    Glioblastomas are the most common CNS tumors in adults, and they remain resistant to current treatments. ErbB1 signaling is frequently altered in these tumors, which indicates that the erbB receptor family is a promising target for molecular therapy. However, data on erbB signaling in glioblastomas are still sparse. Therefore, we undertook a comprehensive analysis of erbB receptor and ligand expression profiles in a panel of nine glioblastomas that were compared to non-neoplastic cerebral tissue containing neocortex and corresponding portions of subcortical convolutional white matter and we determined the distribution patterns of erbB receptors among the main neural cell types that are present in these tumors, particularly the putative tumoral stem cell population. Using quantitative RT-PCR and western blot analysis, we showed that erbB1 signaling and erbB2 receptors exhibited highly variable deregulation profiles among tumors, ranging from under- to overexpression, while erbB3 and erbB4 were down-regulated. Immunohistochemistry revealed an important inter- and intra-tumoral heterogeneity in all four erbB expression profiles. However, each receptor exhibited a distinct repartition pattern among the GFAP-, Olig2-, NeuN- and CD133-positive populations. Interestingly, while erbB1 immunoreactivity was only detected in small subsets of CD133-positive putative tumoral stem cells, erbB3 immunoreactivity was prominent in this cell population thus suggesting that erbB3 may represent a new potential target for molecular therapy. PMID:20467331

  5. Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation

    PubMed Central

    Jha, Prerana; Pia Patric, Irene Rosita; Shukla, Sudhanshu; Pathak, Pankaj; Pal, Jagriti; Sharma, Vikas; Thinagararanjan, Sivaarumugam; Santosh, Vani; Suri, Vaishali; Sharma, Mehar Chand; Arivazhagan, Arimappamagan; Suri, Ashish; Gupta, Deepak; Somasundaram, Kumaravel; Sarkar, Chitra

    2014-01-01

    Background Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH)1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways. Methods Genome-wide methylation profiling of 21 pediatric GBM cases was done and compared with adult GBM data (GSE22867). We performed gene mutation analysis of IDH1 and H3 histone family 3A (H3F3A), status evaluation of glioma cytosine–phosphate–guanine island methylator phenotype (G-CIMP), and Gene Ontology analysis. Experimental evaluation of reactive oxygen species (ROS) association was also done. Results Distinct differences were noted between methylomes of pediatric and adult GBM. Pediatric GBM was characterized by 94 hypermethylated and 1206 hypomethylated cytosine–phosphate–guanine (CpG) islands, with 3 distinct clusters, having a trend to prognostic correlation. Interestingly, none of the pediatric GBM cases showed G-CIMP/IDH1 mutation. Gene Ontology analysis identified ROS association in pediatric GBM, which was experimentally validated. H3F3A mutants (36.4%; all K27M) harbored distinct methylomes and showed enrichment of processes related to neuronal development, differentiation, and cell-fate commitment. Conclusions Our study confirms that pediatric GBM has a distinct methylome compared with that of adults. Presence of distinct clusters and an H3F3A mutation–specific methylome indicate existence of epigenetic subgroups within pediatric GBM. Absence of IDH1/G-CIMP status further indicates that findings in adult GBM cannot be simply extrapolated to pediatric GBM and that there is a strong need for identification of separate prognostic markers. A possible role of ROS in pediatric GBM pathogenesis is demonstrated for the first time and

  6. Targeting delivery of etoposide to inhibit the growth of human glioblastoma multiforme using lactoferrin- and folic acid-grafted poly(lactide-co-glycolide) nanoparticles.

    PubMed

    Kuo, Yung-Chih; Chen, Yu-Chun

    2015-02-01

    Lactoferrin (Lf) and folic acid (FA) were crosslinked on poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) for transporting etoposide across the blood-brain barrier (BBB) and treating human brain malignant glioblastoma. Lf- and FA-grafted PLGA NPs (Lf/FA/PLGA NPs) were employed to permeate the monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes and to inhibit the multiplication of U87MG cells. Lf/FA/PLGA NPs showed a satisfactory entrapment efficiency of etoposide and characteristics of sustained drug release. When compared with PLGA NPs, the permeability coefficient for etoposide across the BBB using Lf/FA/PLGA NPs increased about twofold. The antiproliferative efficacy against the growth of U87MG cells was in the following order: Lf/FA/PLGA NPs>FA/PLGA NPs>PLGA NPs>free etoposide solution. In addition, the targeting ability of Lf/FA/PLGA NPs was evidenced by immunostaining of Lf receptor on HBMECs and folate receptor on U87MG cells during endocytosis. Lf/FA/PLGA NPs with loaded etoposide can be a promising anticancer pharmacotherapy to enhance the delivery of etoposide to malignant brain tumors for preclinical trials.

  7. Evo-Devo and the evolution of cancer: a hypothesis for metamorphic therapies for the cancers of prolactin-influenced tumourigenesis: with special reference to glioblastoma multiforme (GBM).

    PubMed

    Pearson, Roy Douglas

    2009-06-01

    Recalling the remarkable developmental similarities between cancer cells and embryonic tissues, this paper argues that, by the process of retrodifferentiation and heterochronization, stem cells that have become neoplastic could be said to have undergone "cellular heterochrony." It theorizes, therefore, that hormones are the major factor in the non-random regulation of cellular heterochrony in tumourigenesis. Two recent articles confirm that there is low thyroxine and high prolactin in glioblastomas. Thyroxine metamorphoses vertebrates' tissues so as to mature the tissues, e.g., in amphibian metamorphosis. In 1896, thyroxine (horse thyroid extract) was the first successful hormonal product to be used against a fulminating breast cancer. Recent work confirms the important role of prolactin in the induction and progression of mammary, prostate and colorectal tumours. Although the pituitary is the main source of prolactin in vertebrates, there is also placental production of prolactin, and paracrine production of prolactin by tumours themselves. Since tumours produce their own prolactin, shutting down the pituitary source has not proven wholly successful. Research to find prolactin receptor antagonists is ongoing. Therefore, prolactin inhibitors (dopamine agonists), prolactin receptor antagonists, plus thyroxine comprise a plausible metamorphic therapy for shrinking solid tumour mass. By contrast with "differentiation" therapies currently sought by stem cell oncologists, this paper advocates "metamorphic" therapies, to introduce hormonal oncological knowledge of how to modulate signalling pathways that are aberrant in the stem cells that give rise to tumours. Despite subtle differences in these signalling translation pathways and cascades, strategies exist that will allow these evolved populations, going back to their stem precursors, to "metamorphose" or perhaps apoptotically cease proliferation.

  8. Phase II Trial of Radiosurgery to Magnetic Resonance Spectroscopy–Defined High-Risk Tumor Volumes in Patients With Glioblastoma Multiforme

    PubMed Central

    Einstein, Douglas B.; Wessels, Barry; Bangert, Barbara; Fu, Pingfu; Nelson, A. Dennis; Cohen, Mark; Sagar, Stephen; Lewin, Jonathan; Sloan, Andrew; Zheng, Yiran; Williams, Jordonna; Colussi, Valdir; Vinkler, Robert; Maciunas, Robert

    2015-01-01

    Purpose To determine the efficacy of a Gamma Knife stereotactic radiosurgery (SRS) boost to areas of high risk determined by magnetic resonance spectroscopy (MRS) functional imaging in addition to standard radiotherapy for patients with glioblastoma (GBM). Methods and Materials Thirty-five patients in this prospective Phase II trial underwent surgical resection or biopsy for a GBM followed by SRS directed toward areas of MRS-determined high biological activity within 2 cm of the postoperative enhancing surgical bed. The MRS regions were determined by identifying those voxels within the postoperative T2 magnetic resonance imaging volume that contained an elevated choline/N-acetylaspartate ratio in excess of 2:1. These voxels were marked, digitally fused with the SRS planning magnetic resonance image, targeted with an 8-mm isocenter per voxel, and treated using Radiation Therapy Oncology Group SRS dose guidelines. All patients then received conformal radiotherapy to a total dose of 60 Gy in 2-Gy daily fractions. The primary endpoint was overall survival. Results The median survival for the entire cohort was 15.8 months. With 75% of recursive partitioning analysis (RPA) Class 3 patients still alive 18 months after treatment, the median survival for RPA Class 3 has not yet been reached. The median survivals for RPA Class 4, 5, and 6 patients were 18.7, 12.5, and 3.9 months, respectively, compared with Radiation Therapy Oncology Group radiotherapy-alone historical control survivals of 11.1, 8.9, and 4.6 months. For the 16 of 35 patients who received concurrent temozolomide in addition to protocol radiotherapeutic treatment, the median survival was 20.8 months, compared with European Organization for Research and Treatment of Cancer historical controls of 14.6 months using radiotherapy and temozolomide. Grade 3/4 toxicities possibly attributable to treatment were 11%. Conclusions This represents the first prospective trial using selective MRS-targeted functional SRS

  9. Phase II Trial of Radiosurgery to Magnetic Resonance Spectroscopy-Defined High-Risk Tumor Volumes in Patients With Glioblastoma Multiforme

    SciTech Connect

    Einstein, Douglas B.; Wessels, Barry; Bangert, Barbara; Fu, Pingfu; Nelson, A. Dennis; Cohen, Mark; Sagar, Stephen; Lewin, Jonathan; Sloan, Andrew; Zheng Yiran; Williams, Jordonna; Colussi, Valdir; Vinkler, Robert; Maciunas, Robert

    2012-11-01

    Purpose: To determine the efficacy of a Gamma Knife stereotactic radiosurgery (SRS) boost to areas of high risk determined by magnetic resonance spectroscopy (MRS) functional imaging in addition to standard radiotherapy for patients with glioblastoma (GBM). Methods and Materials: Thirty-five patients in this prospective Phase II trial underwent surgical resection or biopsy for a GBM followed by SRS directed toward areas of MRS-determined high biological activity within 2 cm of the postoperative enhancing surgical bed. The MRS regions were determined by identifying those voxels within the postoperative T2 magnetic resonance imaging volume that contained an elevated choline/N-acetylaspartate ratio in excess of 2:1. These voxels were marked, digitally fused with the SRS planning magnetic resonance image, targeted with an 8-mm isocenter per voxel, and treated using Radiation Therapy Oncology Group SRS dose guidelines. All patients then received conformal radiotherapy to a total dose of 60 Gy in 2-Gy daily fractions. The primary endpoint was overall survival. Results: The median survival for the entire cohort was 15.8 months. With 75% of recursive partitioning analysis (RPA) Class 3 patients still alive 18 months after treatment, the median survival for RPA Class 3 has not yet been reached. The median survivals for RPA Class 4, 5, and 6 patients were 18.7, 12.5, and 3.9 months, respectively, compared with Radiation Therapy Oncology Group radiotherapy-alone historical control survivals of 11.1, 8.9, and 4.6 months. For the 16 of 35 patients who received concurrent temozolomide in addition to protocol radiotherapeutic treatment, the median survival was 20.8 months, compared with European Organization for Research and Treatment of Cancer historical controls of 14.6 months using radiotherapy and temozolomide. Grade 3/4 toxicities possibly attributable to treatment were 11%. Conclusions: This represents the first prospective trial using selective MRS-targeted functional SRS

  10. An update on the epigenetics of glioblastomas.

    PubMed

    Ferreira, Wallax Augusto Silva; Pinheiro, Danilo do Rosário; Costa Junior, Carlos Antonio da; Rodrigues-Antunes, Symara; Araújo, Mariana Diniz; Leão Barros, Mariceli Baia; Teixeira, Adriana Corrêa de Souza; Faro, Thamirys Aline Silva; Burbano, Rommel Rodriguez; Oliveira, Edivaldo Herculano Correa de; Harada, Maria Lúcia; Borges, Bárbara do Nascimento

    2016-09-01

    Glioblastomas, also known as glioblastoma multiforme (GBM), are the most aggressive and malignant type of primary brain tumor in adults, exhibiting notable variability at the histopathological, genetic and epigenetic levels. Recently, epigenetic alterations have emerged as a common hallmark of many tumors, including GBM. Considering that a deeper understanding of the epigenetic modifications that occur in GBM may increase the knowledge regarding the tumorigenesis, progression and recurrence of this disease, in this review we discuss the recent major advances in GBM epigenetics research involving histone modification, glioblastoma stem cells, DNA methylation, noncoding RNAs expression, including their main alterations and the use of epigenetic therapy as a valid option for GBM treatment. PMID:27585647

  11. Phase II Pilot Study of Bevacizumab in Combination with Temozolomide and Regional Radiation Therapy for Up-Front Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Interim Analysis of Safety and Tolerability

    SciTech Connect

    Lai, Albert Filka, Emese; McGibbon, Bruce; Nghiemphu, Phioanh Leia; Graham, Carrie; Yong, William H.; Mischel, Paul; Liau, Linda M.; Bergsneider, Marvin; Pope, Whitney; Selch, Michael; Cloughesy, Tim

    2008-08-01

    Purpose: To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma. Methods and Materials: All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m{sup 2} for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion of RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m{sup 2} for 5 days every 4 weeks and continuation of BV every 2 weeks. Results: For these 10 patients, toxicities were compiled until study discontinuation or up to {approx}40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or delayed neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed. Conclusion: The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.

  12. Recurrent Glioblastoma: Where we stand

    PubMed Central

    Roy, Sanjoy; Lahiri, Debarshi; Maji, Tapas; Biswas, Jaydip

    2015-01-01

    Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM) treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment with targeted agents or cytotoxic chemotherapy, reirradiation, or radiosurgery. Research into novel therapies is investigating alternative temozolomide regimens, convection-enhanced delivery, immunotherapy, gene therapy, antiangiogenic agents, poly ADP ribose polymerase inhibitors, or cancer stem cell signaling pathways. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy. PMID:26981507

  13. Role of Receptor Tyrosine Kinases and Their Ligands in Glioblastoma

    PubMed Central

    Carrasco-García, Estefanía; Saceda, Miguel; Martínez-Lacaci, Isabel

    2014-01-01

    Glioblastoma multiforme is the most frequent, aggressive and fatal type of brain tumor. Glioblastomas are characterized by their infiltrating nature, high proliferation rate and resistance to chemotherapy and radiation. Recently, oncologic therapy experienced a rapid evolution towards “targeted therapy,” which is the employment of drugs directed against particular targets that play essential roles in proliferation, survival and invasiveness of cancer cells. A number of molecules involved in signal transduction pathways are used as molecular targets for the treatment of various tumors. In fact, inhibitors of these molecules have already entered the clinic or are undergoing clinical trials. Cellular receptors are clear examples of such targets and in the case of glioblastoma multiforme, some of these receptors and their ligands have become relevant. In this review, the importance of glioblastoma multiforme in signaling pathways initiated by extracellular tyrosine kinase receptors such as EGFR, PDGFR and IGF-1R will be discussed. We will describe their ligands, family members, structure, activation mechanism, downstream molecules, as well as the interaction among these pathways. Lastly, we will provide an up-to-date review of the current targeted therapies in cancer, in particular glioblastoma that employ inhibitors of these pathways and their benefits. PMID:24709958

  14. [The Relevance of MicroRNAs in Glioblastoma Stem Cells].

    PubMed

    Kleinová, R; Slabý, O; Šána, J

    2015-01-01

    Glioblastoma multiforme is the most common intracranial malignity of astrocyte origin in adults. Despite complex therapy consisting of maximal surgical resection, adjuvant concomitant chemoradiotherapy with temozolomide followed by temozolomide in monotherapy, the median of survival ranges between 12 and 15 months from dia-gnosis. This infaust prognosis is very often caused by both impossibility of achieving of sufficient radical surgical resection and tumor resistance to adjuvant therapy, which relates to the presence of glioblastoma stem cells. Similarly to normal stem cells, glioblastoma stem cells are capable of self -renewal, differentiation, and unlimited slow proliferation. Their resistance to conventional therapy is also due to higher expressions of DNA repair enzymes, antiapoptotic factors and multidrug transporters. Therefore, targeting these unique properties could be a novel promising therapeutic approach leading to more effective therapy and better prognosis of glioblastoma multiforme patients. One of the approaches how to successfully regulate above -mentioned properties is targeted regulation of microRNAs (miRNAs). These small noncoding RNA molecules posttranscriptionally regulate expression of more than 2/ 3 of all human genes that are also involved in stem cell associated signaling pathways. Moreover, deregulated expression of some miRNAs has been observed in many cancers, including glioblastoma multiforme. PMID:26480861

  15. Evaluation of the Lactate-to-N-Acetyl-aspartate Ratio Defined With Magnetic Resonance Spectroscopic Imaging Before Radiation Therapy as a New Predictive Marker of the Site of Relapse in Patients With Glioblastoma Multiforme

    SciTech Connect

    Deviers, Alexandra; Ken, Soléakhéna; Filleron, Thomas; Rowland, Benjamin; Laruelo, Andrea; Catalaa, Isabelle; Lubrano, Vincent; Celsis, Pierre; and others

    2014-10-01

    Purpose: Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-{sup 1}H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM). Methods and Materials: Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis of the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence. Results: A LNR of ≥0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm{sup 3}; range: 6-49 cm{sup 3}). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01). Conclusions: Pre-RT LNR-0.4 in GBM

  16. Resveratrol sensitizes glioblastoma-initiating cells to temozolomide by inducing cell apoptosis and promoting differentiation.

    PubMed

    Li, Hao; Liu, Yaodong; Jiao, Yumin; Guo, Anchen; Xu, Xiaoxue; Qu, Xianjun; Wang, Shuo; Zhao, Jizong; Li, Ye; Cao, Yong

    2016-01-01

    Glioblastoma-initiating cells play crucial roles in the origin, growth, and recurrence of glioblastoma multiforme. The elimination of glioblastoma-initiating cells is believed to be a key strategy for achieving long-term survival of glioblastoma patients due to the highly resistant property of glioblastoma-initiating cells to temozolomide. Resveratrol, a naturally occurring polyphenol, has been widely studied as a promising candidate for cancer prevention and treatment. Whether resveratrol could enhance the sensitivity of glioblastoma-initiating cells to temozolomide therapy has not yet been reported. Here, using patient-derived glioblastoma-initiating cell lines, we found that resveratrol sensitized glioblastoma-initiating cells to temozolomide both in vitro and in vivo. Furthermore, we showed that resveratrol enhanced glioblastoma-initiating cells to temozolomide-induced apoptosis through DNA double-stranded breaks/pATM/pATR/p53 pathway activation, and promoted glioblastoma-initiating cell differentiation involving p-STAT3 inactivation. Our results propose that temozolomide and resveratrol combination strategy may be effective in the management of glioblastoma patients, particularly for those patients who have been present with a high abundance of glioblastoma-initiating cells in their tumors and show slight responsiveness to temozolomide.

  17. Glioblastoma Multiforme with Hemorrhage Mimicking an Aneurysm: Lessons Learnt

    PubMed Central

    Singla, Navneet; Aggarwal, Ashish; Vyas, Sameer; Sanghvi, Ankur; Salunke, Pravin; Garg, Ravi

    2016-01-01

    Background A sudden onset of neurological symptoms in patients is conventionally thought to be due to vascular phenomenon, with one common differential diagnosis being subarachnoid hemorrhage. Another important differential diagnosis is ischemic stroke. An uncommon cause of such acute symptoms can be hemorrhage in a pre-existing tumor, that is, intratumoral hemorrhage (ITH). Purpose ITH is an important, though uncommon differential diagnosis in cases of sudden onset of neurological deterioration. Methods and Result A 60-year-old male presented with seizures and loss of consciousness 12 h prior to admission. The episode was sudden in onset. After detailed clinical and radiological investigations, the patient was diagnosed with glioma with bleed and was successfully operated upon. Conclusion The combination of hemorrhage and ischemic stroke pointed more towards an aneurysm rather than a tumor bleed. There were pointers both in favor of and against both the diagnosis. Therefore, a complex hemorrhagic cerebral tumor with acute presentation and discordant finding on CT or CT angiography should be characterized preoperatively. A large thrombosed aneurysm remains an important differential diagnosis. PMID:27780994

  18. Bevacizumab and Temozolomide Plus Radiation Regimen for Glioblastoma Multiforme

    PubMed Central

    Rutledge, Matthew R.; Waddell, J. Aubrey; Solimando, Dominic A.

    2015-01-01

    The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. PMID:26823616

  19. Interstitial /sup 252/Cf neutron therapy for glioblastoma multiforme

    SciTech Connect

    Maruyama, Y.; Chin, H.W.; Young, A.B.; Bean, J.; Tibbs, P.; Beach, J.L.

    1982-12-01

    /sup 252/Cf brachytherapy has been combined with whole brain photon beam therapy to 6000 rads in 5-7 weeks. In early phase I studies, all patients selected for study tolerated the procedure and the subsequent photon beam therapy. All showed improvement in performance status and decreased tumor size by CT scan evaluation, but it became clear that these tumors are of large size and bulk, produce marked adjacent brain edema, and require individualized implant therapy as well as high-dose external beam irradiation if response is to occur.

  20. Granuloma multiforme: first case report in Tunisia.

    PubMed

    Ziadi, S; Trimèche, M; Sriha, B; Denguezli, M; Amri, I; Mestiri, S; Belajouza, C; Korbi, S

    2007-12-01

    Granuloma multiforme is a rare granulomatous skin disease, usually reported in sub-Saharan African countries. The exact aetiology of granuloma multiforme is still unknown. We report the case of a patient who presented clinical and histopathological features of granuloma multiforme that can be considered the first described case in Tunisia.

  1. Nanoparticles: Novel vehicles in treatment of Glioblastoma.

    PubMed

    Pourgholi, Fatemeh; Hajivalili, Mahsa; Farhad, Jadidi-Niaragh; Kafil, Hossein Samadi; Yousefi, Mehdi

    2016-02-01

    Glioblastoma multiform (GBM) is the most common brain tumor. The current GBM treatments comprise of radiation therapy, chemotherapy and surgery. One of the most important problems regarding the treatment of GBM is the presence of blood brain barrier (BBB) which inhibits the efficient drug delivery into central nervous system (CNS). Nanothechnology can help to deliver therapeutic drugs into CNS through crossing the BBB. There are different types of nanoparticles (Nps) which can be manipulated for clinical applications as a treatment for CNS-related disorders. In this review, we will discuss the role of Nps in the treatment of GBM.

  2. Extraneural Metastases of Glioblastoma without Simultaneous Central Nervous System Recurrence

    PubMed Central

    Kim, Wonki; Yoo, Heon; Shin, Sang Hoon; Gwak, Ho Shin

    2014-01-01

    Glioblastoma multiforme (GBM) is well known as the most common malignant primary brain tumor. It could easily spread into the adjacent or distant brain tissue by infiltration, direct extension and cerebro-spinal fluid dissemination. The extranueural metastatic spread of GBM is relatively rare but it could have more progressive disease course. We report a 39-year-old man who had multiple bone metastases and malignant pleural effusion of the GBM without primary site recurrence. PMID:25408938

  3. Sarcoma with true epithelial differentiation secondary to irradiated glioblastoma

    PubMed Central

    Pimentel, J.; Marques, J.; Pereira, P.; Roque, L.; Martins, C.; Campos, A.

    2011-01-01

    Glioblastoma multiforme rarely shows true, immunohistochemically confirmed, epithelial differentiation. Furthermore, radiotherapy may induce cerebral sarcomatous tumors, and postsurgery glioblastoma irradiation may give rise to secondary gliosarcomas. We report a case of a 48-year-old male operated on a primary glioblastoma, followed by radiotherapy. A local recurrence occurred 23 months later that was operated too, and a second diagnosis of a fibrosarcoma with true epithelial differentiation was made. Primary systemic neoplasms were largely excluded. The patient died shortly after, and postmortem showed another cerebral dural-attached mass corresponding to a sarcoma without epithelial differentiation, and leptomeningeal seeding composed of malignant epithelial elements only. Cytogenetics, however, disclosed the second tumor to be similar to the primary one.

  4. Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma.

    PubMed

    Zhang, Issan; Cui, Yiming; Amiri, Abdolali; Ding, Yidan; Campbell, Robert E; Maysinger, Dusica

    2016-03-01

    Increased lipid droplet number and fatty acid synthesis allow glioblastoma multiforme, the most common and aggressive type of brain cancer, to withstand accelerated metabolic rates and resist therapeutic treatments. Lipid droplets are postulated to sequester hydrophobic therapeutic agents, thereby reducing drug effectiveness. We hypothesized that the inhibition of lipid droplet accumulation in glioblastoma cells using pyrrolidine-2, a cytoplasmic phospholipase A2 alpha inhibitor, can sensitize cancer cells to the killing effect of curcumin, a promising anticancer agent isolated from the turmeric spice. We observed that curcumin localized in the lipid droplets of human U251N glioblastoma cells. Reduction of lipid droplet number using pyrrolidine-2 drastically enhanced the therapeutic effect of curcumin in both 2D and 3D glioblastoma cell models. The mode of cell death involved was found to be mediated by caspase-3. Comparatively, the current clinical chemotherapeutic standard, temozolomide, was significantly less effective in inducing glioblastoma cell death. Together, our results suggest that the inhibition of lipid droplet accumulation is an effective way to enhance the chemotherapeutic effect of curcumin against glioblastoma multiforme.

  5. Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth.

    PubMed

    Powers, Ciaran; Aigner, Achim; Stoica, Gerald E; McDonnell, Kevin; Wellstein, Anton

    2002-04-19

    Glioblastoma multiforme is the most common highly aggressive human brain cancer, and receptor tyrosine kinases have been implicated in the progression of this malignancy. We have recently identified anaplastic lymphoma kinase (ALK) as a tyrosine kinase receptor for pleiotrophin, a secreted growth factor that is highly expressed during embryonic brain development and in tumors of the central nervous system. Here we report on the contribution of pleiotrophin-ALK signaling to glioblastoma growth. We found ALK overexpressed in human glioblastoma relative to normal brain and detected ALK mRNA in glioblastoma cell lines. We reduced the endogenous ALK in glioblastoma cells by ribozyme targeting and demonstrated that this prevents pleiotrophin-stimulated phosphorylation of the anti-apoptotic protein Akt. Furthermore, this depletion of ALK reduced tumor growth of xenografts in athymic nude mice and prolonged survival of the animals because of increased apoptosis in the tumors. These findings directly implicate ALK signaling as a rate-limiting factor in the growth of glioblastoma multiforme and suggest potential utility of therapeutic targeting of ALK.

  6. Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma.

    PubMed

    Johansson, Erik; Zhai, Qiwei; Zeng, Zhao-Jun; Yoshida, Takeshi; Funa, Keiko

    2016-05-01

    TLX (also called NR2E1) is an orphan nuclear receptor that maintains stemness of neuronal stem cells. TLX is highly expressed in the most malignant form of glioma, glioblastoma multiforme (GBM), and is important for the proliferation and maintenance of the stem/progenitor cells of the tumor. Transforming Growth Factor-β (TGF-β) is a cytokine regulating many different cellular processes such as differentiation, migration, adhesion, cell death and proliferation. TGF-β has an important function in cancer where it can work as either a tumor suppressor or oncogene, depending on the cancer type and stage of tumor development. Since glioblastoma often have dysfunctional TGF-β signaling we wanted to find out if there is any interaction between TLX and TGF-β in glioblastoma cells. We demonstrate that knockdown of TLX enhances the canonical TGF-β signaling response in glioblastoma cell lines. TLX physically interacts with and stabilizes Smurf1, which can ubiquitinate and target TGF-β receptor II for degradation, whereas knockdown of TLX leads to stabilization of TGF-β receptor II, increased nuclear translocation of Smad2/3 and enhanced expression of TGF-β target genes. The interaction between TLX and TGF-β may play an important role in the regulation of proliferation and tumor-initiating properties of glioblastoma cells.

  7. TSPO as a target for glioblastoma therapeutics.

    PubMed

    Werry, Eryn L; Barron, Melissa L; Kassiou, Michael

    2015-08-01

    The translocator protein (TSPO) is an 18-kDa five-transmembrane protein, which is primarily found in the outer mitochondrial membrane. Levels of this protein are up-regulated in the most aggressive and common glioma, glioblastoma multiforme (GM). Levels of TSPO also correlate with GM clinical outcome, suggesting that TSPO may be a novel GM diagnostic imaging agent. Therapeutically, targeting the TSPO may provide a mechanism to abrogate the apoptotic-resistant, invasive and aggressive nature of GM and may also provide a way of targeting other anti-cancer treatments to GM sites. This review highlights recent progress in research on TSPO-based diagnostic imaging and therapeutics for GM.

  8. Applicable advances in the molecular pathology of glioblastoma.

    PubMed

    Ranjit, Melissa; Motomura, Kazuya; Ohka, Fumiharu; Wakabayashi, Toshihiko; Natsume, Atsushi

    2015-07-01

    Comprising more than 80% of malignant brain tumors, glioma has proven to be a daunting cause of mortality in a vast majority of the human population. Progressive and extensive research on malignant glioma has substantially enhanced our understanding of glioma cell biology and molecular pathology. Subtypes of glioma such as astrocytoma and oligodendroglioma are currently grouped together into one pathological class, where they show many differences in histology and molecular etiology. This indicates that it may be beneficial to consider a new and radical subclassification. Thus, we summarize recent developments in glioblastoma multiforme (GBM) subtypes, immunohistochemical analyses useful for diagnoses and the biological evaluation and therapeutic implications of gliomas in this review.

  9. Role of Nitric Oxide in Glioblastoma Therapy: Another Step to Resolve the Terrible Puzzle ?

    PubMed

    Altieri, R; Fontanella, M; Agnoletti, A; Panciani, P P; Spena, G; Crobeddu, E; Pilloni, G; Tardivo, V; Lanotte, M; Zenga, F; Ducati, A; Garbossa, D

    2015-01-01

    Glioblastoma Multiforme, the most common and aggressive primary brain tumor, remains incurable despite of the advent of modern surgical and medical treatments. This poor prognosis depends by the recurrence after surgery and intrinsic or acquired resistance to chemotherapy and radiotherapy. Nitric oxide is a small molecule that plays a key roles in glioma pathophysiology. Many researches showing that NO is involved in induction of apoptosis, radiosensitization and chemosensitization. Therefore, NO role, if clarified, may improve the knowledge about this unsolved puzzle called GBM.

  10. Language areas involving the inferior temporal cortex on intraoperative mapping in a bilingual patient with glioblastoma.

    PubMed

    Kin, Hidehiro; Ishikawa, Eiichi; Takano, Shingo; Ayuzawa, Satoshi; Matsushita, Akira; Muragaki, Yoshihiro; Aiyama, Hitoshi; Sakamoto, Noriaki; Yamamoto, Tetsuya; Matsumura, Akira

    2013-01-01

    A 40-year-old bilingual man underwent removal of glioblastoma multiforme with intraoperative language mapping, mainly using the picture-naming and auditory responsive-naming tasks under cortical stimulation. Multiple language areas were identified, including one located in the middle of the inferior temporal cortex (ITC). Individual mapping for glioma patients must be performed because language areas might be located in various and unexpected regions, including the ITC.

  11. Multicentric spinal cord and brain glioblastoma without previous craniotomy

    PubMed Central

    de Eulate-Beramendi, Sayoa A.; Piña-Batista, Kelvin M.; Rodrigo, Victor; Torres-Rivas, Hector E.; Rial-Basalo, Juan C.

    2016-01-01

    Background: Glioblastoma multiforme (GBS) is a highly malignant glioma that rarely presents as an infratentorial tumor. Multicentric gliomas lesions are widely separated in site and/or time and its incidence has been reported between 0.15 and 10%. Multicentric gliomas involving supratentorial and infratentorial region are even more rare. In most cases, infratentorial disease is seen after surgical manipulation or radiation therapy and is usually located in the cerebellum or cervical region. Case Report: We present a rare case of symptomatic multicentric glioma in the brain, fourth ventricle, cervical as well as lumbar glioblastoma in an adult without previous therapeutic intervention. We also review the literature of this rare presentation. Conclusions: This report suggests that GBM is a diffuse disease; the more extended the disease, the worse prognosis it has. The management still remains controversial and further studies are required to understand the prognosis factors of dissemination. PMID:27512613

  12. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    SciTech Connect

    Lee, Dae-Hee; Kim, Dong-Wook; Jung, Chang-Hwa; Lee, Yong J.; Park, Daeho

    2014-09-15

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway.

  13. Sildenafil: A rare cause of erythema multiforme.

    PubMed

    Sharma, Nidhi Raghunandan; Sharma, Sudhanshu; Ahmad, Javid; Nadkarni, Nitin; Rana, Shweta; Kalhan, Shivani

    2016-01-01

    Erythema multiforme (EM) is an acute self-limiting mucocutaneous condition of uncertain etiopathogenesis. The most common precipitating factors are herpes simplex virus infection, mycoplasma infection, drugs, and vaccination. We report a case of EM following sildenafil used for loss of libido. EM induced by sildenafil has not been reported so far. PMID:27190421

  14. Advances in treating glioblastoma

    PubMed Central

    Weathers, Shiao-Pei

    2014-01-01

    Glioblastoma is the most common and most aggressive primary brain tumor in adults. Optimized standard treatment only confers a modest improvement in progression and overall survival, underscoring the pressing need for the development of novel therapies. Our understanding of glioblastoma (a molecularly heterogeneous disorder) has been accelerated in the setting of large scale genomic analyses, lending insight into potential actionable targets. Antiangiogenic therapies have been used in the treatment of glioblastoma, and our understanding of the means to optimize the role of these agents is continuing to evolve. Recently, immunotherapy has garnered increasing attention as a therapeutic approach in the treatment of gliomas. Promising novel approaches are under active development in the treatment of glioblastoma. PMID:24991423

  15. Bevacizumab for glioblastoma

    PubMed Central

    Narita, Yoshitaka

    2015-01-01

    Individuals with glioblastoma are often characterized by older age, advanced neurologic manifestations at the primary stage, and unresectable tumors, and these factors are associated with poor treatment outcomes. Administration of bevacizumab (BV, Avastin®) promotes tumor regression and improves cerebral edema, and is expected to improve neurologic findings in many patients with malignant gliomas, including glioblastoma. Although the addition of BV to the conventional standard therapy (chemoradiotherapy with temozolomide) for newly diagnosed glioblastoma prolonged the progression-free survival time and the performance status of patients, it failed to extend overall survival time. However, more than 50% of glioblastoma patients show Karnofsky performance status ≤70 at initial presentation; therefore, BV should be used to improve or maintain their performance status as an initial treatment. Most of the adverse events of BV, except hypertension and proteinuria, occur as complications of glioblastoma, and explanation of the advantages and disadvantages of BV administration to patients is important. Herein, the efficacy, safety, and challenges of using BV for treating glioblastoma were reviewed. PMID:26664126

  16. Biomarker-based adaptive trials for patients with glioblastoma--lessons from I-SPY 2.

    PubMed

    Alexander, Brian M; Wen, Patrick Y; Trippa, Lorenzo; Reardon, David A; Yung, Wai-Kwan Alfred; Parmigiani, Giovanni; Berry, Donald A

    2013-08-01

    The traditional clinical trials infrastructure may not be ideally suited to evaluate the numerous therapeutic hypotheses that result from the increasing number of available targeted agents combined with the various methodologies to molecularly subclassify patients with glioblastoma. Additionally, results from smaller screening studies are rarely translated to successful larger confirmatory studies, potentially related to a lack of efficient control arms or the use of unvalidated surrogate endpoints. Streamlining clinical trials and providing a flexible infrastructure for biomarker development is clearly needed for patients with glioblastoma. The experience developing and implementing the I-SPY studies in breast cancer may serve as a guide to developing such trials in neuro-oncology.

  17. A reappraisal of macrophage polarization in glioblastoma: Histopathological and immunohistochemical findings and review of the literature.

    PubMed

    Mignogna, Chiara; Signorelli, Francesco; Vismara, Marco Flavio Michele; Zeppa, Pio; Camastra, Caterina; Barni, Tullio; Donato, Giuseppe; Di Vito, Anna

    2016-06-01

    The survival rate in glioblastoma multiforme patients has scarcely improved in the last decades; however, many new therapeutic strategies have been theorized or developed for these neoplasias. Recently, the inverse correlation observed between patient prognosis and tumor-associated macrophages (TAMs) density in solid tumors has encouraged the development of anti-tumor strategies aiming to target TAMs. As expected, TAMs polarization is influenced by both macrophage localization and tumor microenvironment signals, resulting in a more complex scenario than the simple M1/M2 activation status. Macrophage polarization in glioblastoma has not yet been fully elucidated, and most results have been obtained in experimental non-human settings, with some apparent contradiction. The authors performed a histopathological and immunohistochemical study of 37 cases of glioblastoma in order to characterize the M1 and M2 macrophage populations within TAMs. A high prevalence of CD163+ M2-polarized macrophages was detected in this cohort, whereas iNOS+ macrophages were rarely found. The down-regulation of CD68 expression in microglia/macrophage infiltrating glioblastomas is also reported for the first time. Such a finding is associated with a specific location of TAMs within the lesion, as confirmed by the fact that CD68 staining was lower than CD163, mainly in perivascular areas. The authors discuss the recent literature about the global scenario of macrophage plasticity and polarization in glioblastoma, and suggest some pivotal points for therapeutic applications.

  18. Canine Butterfly Glioblastomas: A Neuroradiological Review.

    PubMed

    Rossmeisl, John H; Clapp, Kemba; Pancotto, Theresa E; Emch, Samantha; Robertson, John L; Debinski, Waldemar

    2016-01-01

    In humans, high-grade gliomas may infiltrate across the corpus callosum resulting in bihemispheric lesions that may have symmetrical, winged-like appearances. This particular tumor manifestation has been coined a "butterfly" glioma (BG). While canine and human gliomas share many neuroradiological and pathological features, the BG morphology has not been previously reported in dogs. Here, we describe the magnetic resonance imaging (MRI) characteristics of BG in three dogs and review the potential differential diagnoses based on neuroimaging findings. All dogs presented for generalized seizures and interictal neurological deficits referable to multifocal or diffuse forebrain disease. MRI examinations revealed asymmetrical (2/3) or symmetrical (1/3), bihemispheric intra-axial mass lesions that predominantly affected the frontoparietal lobes that were associated with extensive perilesional edema, and involvement of the corpus callosum. The masses displayed heterogeneous T1, T2, and fluid-attenuated inversion recovery signal intensities, variable contrast enhancement (2/3), and mass effect. All tumors demonstrated classical histopathological features of glioblastoma multiforme (GBM), including glial cell pseudopalisading, serpentine necrosis, microvascular proliferation as well as invasion of the corpus callosum by neoplastic astrocytes. Although rare, GBM should be considered a differential diagnosis in dogs with an MRI evidence of asymmetric or symmetric bilateral, intra-axial cerebral mass lesions with signal characteristics compatible with glioma. PMID:27458589

  19. Canine Butterfly Glioblastomas: A Neuroradiological Review

    PubMed Central

    Rossmeisl, John H.; Clapp, Kemba; Pancotto, Theresa E.; Emch, Samantha; Robertson, John L.; Debinski, Waldemar

    2016-01-01

    In humans, high-grade gliomas may infiltrate across the corpus callosum resulting in bihemispheric lesions that may have symmetrical, winged-like appearances. This particular tumor manifestation has been coined a “butterfly” glioma (BG). While canine and human gliomas share many neuroradiological and pathological features, the BG morphology has not been previously reported in dogs. Here, we describe the magnetic resonance imaging (MRI) characteristics of BG in three dogs and review the potential differential diagnoses based on neuroimaging findings. All dogs presented for generalized seizures and interictal neurological deficits referable to multifocal or diffuse forebrain disease. MRI examinations revealed asymmetrical (2/3) or symmetrical (1/3), bihemispheric intra-axial mass lesions that predominantly affected the frontoparietal lobes that were associated with extensive perilesional edema, and involvement of the corpus callosum. The masses displayed heterogeneous T1, T2, and fluid-attenuated inversion recovery signal intensities, variable contrast enhancement (2/3), and mass effect. All tumors demonstrated classical histopathological features of glioblastoma multiforme (GBM), including glial cell pseudopalisading, serpentine necrosis, microvascular proliferation as well as invasion of the corpus callosum by neoplastic astrocytes. Although rare, GBM should be considered a differential diagnosis in dogs with an MRI evidence of asymmetric or symmetric bilateral, intra-axial cerebral mass lesions with signal characteristics compatible with glioma. PMID:27458589

  20. Engineering Strategies to Mimic the Glioblastoma Microenvironment

    PubMed Central

    Rape, Andrew; Ananthanarayanan, Badriprasad; Kumar, Sanjay

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and deadly brain tumor, with a mean survival time of only 21 months. Despite the dramatic improvements in our understanding of GBM fueled by recent revolutions in molecular and systems biology, treatment advances for GBM have progressed inadequately slowly, which is due in part to the wide cellular and molecular heterogeneity both across tumors and within a single tumor. Thus, there is increasing clinical interest in targeting cell-extrinsic factors as way of slowing or halting the progression of GBM. These cell-extrinsic factors, collectively termed the microenvironment, include the extracellular matrix, blood vessels, stromal cells that surround tumor cells, and all associated soluble and scaffold-bound signals. In this review, we will first describe the regulation of GBM tumors by these microenvironmental factors. Next, we will discuss the various in vitro approaches that have been exploited to recapitulate and model the GBM tumor microenvironment in vitro. We conclude by identifying future challenges and opportunities in this field, including the development of microenvironmental platforms amenable to high-throughput discovery and screening. We anticipate that these ongoing efforts will prove to be valuable both as enabling tools for accelerating our understanding of microenvironmental regulation in GBM and as foundations for next-generation molecular screening platforms that may serve as a conceptual bridge between traditional reductionist systems and animal or clinical studies. PMID:25174308

  1. Repurposing antipsychotics as glioblastoma therapeutics: Potentials and challenges

    PubMed Central

    LEE, JIN-KU; NAM, DO-HYUN; LEE, JEONGWU

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and most lethal primary brain tumor, with tragically little therapeutic progress over the last 30 years. Surgery provides a modest benefit, and GBM cells are resistant to radiation and chemotherapy. Despite significant development of the molecularly targeting strategies, the clinical outcome of GBM patients remains dismal. The challenges inherent in developing effective GBM treatments have become increasingly clear, and include resistance to standard treatments, the blood-brain barrier, resistance of GBM stem-like cells, and the genetic complexity and molecular adaptability of GBM. Recent studies have collectively suggested that certain antipsychotics harbor antitumor effects and have potential utilities as anti-GBM therapeutics. In the present review, the anti-tumorigenic effects and putative mechanisms of antipsychotics, and the challenges for the potential use of antipsychotic drugs as anti-GBM therapeutics are reviewed. PMID:26893731

  2. Novel synthetic chalcones induces apoptosis in human glioblastoma cells.

    PubMed

    Bittencourt, Lucas Felipe Fernandes; Oliveira, Karen Andrinéia de; Cardoso, Carine Bropp; Lopes, Flávia Garcia; Dal-Cim, Tharine; Chiaradia-Delatorre, Louise Domeneghini; Mascarello, Alessandra; Maluf, Sharbel Weidner; Yunes, Rosendo Augusto; Garcez, Ricardo Castilho; Tasca, Carla Inês; Nedel, Cláudia Beatriz

    2016-05-25

    Glioblastoma multiforme is the main and most frequent tumor in adults' central nervous system. With a survival average of 5% two years after diagnosis, this type of cancer is a main health problem. Substances like the chalcones have been tested in order to develop new treatments. Here, we studied the effects of three synthetic chalcones (A23, C31 and J11) on A172 and surgery obtained-glioma cells. All chalcones showed a decrease in cell viability, mainly C31. An increase in apoptosis levels with no further increase of necrosis was observed. This augmentation may be linked to the high oxidative effect found, caused by the increased presence of reactive oxygen species and nitric oxide production. Cell cycle distribution showed an arrest at G0/G1 and S phases, suggesting that C31 interferes in cell cycle control. Our results shall aid in directing future research with this substance and its antitumor effect.

  3. Genomic Analysis of the BMP Family in Glioblastomas.

    PubMed

    Hover, Laura D; Abel, Ty W; Owens, Philip

    2015-01-01

    Glioblastoma multiforme (GBM) is a grade IV glioma with a median survival of 15 months. Recently, bone morphogenetic protein (BMP) signaling has been shown to promote survival in xenograft murine models. To gain a better understanding of the role of BMP signaling in human GBMs, we examined the genomic alterations of 90 genes associated with BMP signaling in GBM patient samples. We completed this analysis using publically available datasets compiled through Te Cancer Genome Atlas and the Glioma Molecular Diagnostic Initiative. Here we show how mRNA expression is altered in GBM samples and how that is associated with patient survival, highlighting both known and novel associations between BMP signaling and GBM biology.

  4. Nanoparticles for hyperthermic therapy: synthesis strategies and applications in glioblastoma

    PubMed Central

    Verma, Jyoti; Lal, Sumit; Van Noorden, Cornelis JF

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Current GBM treatment includes surgery, radiation therapy, and chemotherapy, sometimes supplemented with novel therapies. Despite recent advances, survival of GBM patients remains poor. Major challenges in GBM treatment are drug delivery across the blood–brain barrier, restriction of damage to healthy brain tissues, and limitation of resistance to therapies. This article reviews recent advances in the application of magnetic nanoparticles (MNPs), gold nanorods (GNRs), and carbon nanotubes (CNTs) for hyperthermia ablation of GBM. First, the article introduces GBM, its current treatment, and hyperthermia as a potential modality for the management of GBM. Second, it introduces MNPs, GNRs, and CNTs as inorganic agents to induce hyperthermia in GBM. Third, it discusses different methodologies for synthesis of each inorganic agent. Finally, it reviews in vitro and in vivo studies in which MNPs, GNRs, and CNTs have been applied for hyperthermia ablation and drug delivery in GBM. PMID:24959075

  5. Glioblastoma Stem-Like Cells—Biology and Therapeutic Implications

    PubMed Central

    Gürsel, Demirkan B.; Shin, Benjamin J.; Burkhardt, Jan-Karl; Kesavabhotla, Kartik; Schlaff, Cody D.; Boockvar, John A.

    2011-01-01

    The cancer stem-cell hypothesis proposes that malignant tumors are likely to encompass a cellular hierarchy that parallels normal tissue and may be responsible for the maintenance and recurrence of glioblastoma multiforme (GBM) in patients. The purpose of this manuscript is to review methods for optimizing the derivation and culturing of stem-like cells also known as tumor stem cells (TSCs) from patient-derived GBM tissue samples. The hallmarks of TSCs are that they must be able to self-renew and retain tumorigenicity. The isolation, optimization and derivation of TSCs as outlined in this review, will be important in understanding biology and therapeutic applications related to these cells. PMID:21796273

  6. 40 CFR 80.167 - Confirmatory testing.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) REGULATION OF FUELS AND FUEL ADDITIVES Detergent Gasoline § 80.167 Confirmatory testing. EPA may test a detergent to confirm that the required performance levels are met. Based on the findings of this confirmatory testing, a detergent certification may be denied or revoked under the provisions of §...

  7. Conditional Probability of Survival in Patients With Newly Diagnosed Glioblastoma

    PubMed Central

    Polley, Mei-Yin C.; Lamborn, Kathleen R.; Chang, Susan M.; Butowski, Nicholas; Clarke, Jennifer L.; Prados, Michael

    2011-01-01

    Purpose The disease outcome for patients with cancer is typically described in terms of estimated survival from diagnosis. Conditional probability offers more relevant information regarding survival for patients once they have survived for some time. We report conditional survival probabilities on the basis of 498 patients with glioblastoma multiforme receiving radiation and chemotherapy. For 1-year survivors, we evaluated variables that may inform subsequent survival. Motivated by the trend in data, we also evaluated the assumption of constant hazard. Patients and Methods Patients enrolled onto seven phase II protocols between 1975 and 2007 were included. Conditional survival probabilities and 95% CIs were calculated. The Cox proportional hazards model was used to evaluate prognostic values of age, Karnofsky performance score (KPS), and prior progression 1-year post diagnosis. To assess the constant hazard assumption, we used a likelihood-ratio test to compare the Weibull and exponential distributions. Results The probabilities of surviving an additional year given survival to 1, 2, 3, and 4 years were 35%, 49%, 69%, and 93%, respectively. For patients who survived for 1 year, lower KPS and progression were significantly predictive of shorter survival (both P < .001), but age was not (hazard ratio, 1.22 for a 10-year increase; P = .25). The Weibull distribution fits the data significantly better than exponential (P = .02), suggesting nonconstant hazard. Conclusion Conditional probabilities provide encouraging information regarding life expectancy to survivors of glioblastoma multiforme. Our data also showed that the constant hazard assumption may be violated in modern brain tumor trials. For single-arm trials, we advise using individual patient data from historical data sets for efficacy comparisons. PMID:21969507

  8. Boron neutron capture therapy for glioblastoma: improvement of boron biodistribution by hyaluronidase.

    PubMed

    Haselsberger, K; Radner, H; Pendl, G

    1998-09-11

    Boron neutron capture therapy (BNCT) represents a highly promising therapeutic alternative for the treatment of the most common malignant brain tumor, glioblastoma multiforme. Both the efficacy and safety of BNCT are greatly dependent on the pattern of 10B biodistribution. The present study investigates the influence of systemic hyaluronidase applied in combination with Na2B12H11SH (BSH), a boron carrier used in current clinical trials. The application of hyaluronidase was associated with a statistically significant improvement in the tumor/blood boron concentration ratio which suggests that hyaluronidase is capable of enhancing the therapeutic potential of BSH.

  9. Modeling invasion of brain tissue by glioblastoma cells: ECM alignment and motility

    NASA Astrophysics Data System (ADS)

    Sander, L. M.

    2013-03-01

    A key stage in the development of highly malignant brain tumors (Glioblastoma Multiforme) is invasion of normal brain tissue by motile cells moving through a crowded, complex environment. Evidence from in vitro experiments suggests the cell motion is accompanied by considerable deformation and alignment of the extra-cellular matrix (ECM) of the brain. In the case of breast cancer, alignment effects of this sort have been seen in vivo. We have modeled features of this system including stress confinement in the non-linear elasticity of the ECM and contact guidance of the cell motion.

  10. Pediatric spinal glioblastoma of the conus medullaris: a case report of long survival.

    PubMed

    Cacchione, Antonella; Mastronuzzi, Angela; Cefalo, Maria Giuseppina; Colafati, Giovanna Stefania; Diomedi-Camassei, Francesca; Rizzi, Michele; De Benedictis, Alessandro; Carai, Andrea

    2016-05-09

    High-grade gliomas of the spinal cord represent a rare entity in children. Their biology, behavior, and controversial treatment options have been discussed in a few pediatric cases. These tumors are associated with severe disability and poor prognosis. We report a case of a 4-year-old child diagnosed with an isolated glioblastoma multiforme of the conus medullaris. The patient underwent subtotal surgical excision, followed by adjuvant radiotherapy and oral chemotherapy. He is alive with mild neurologic deficits at 52 months after diagnosis. We describe the peculiar characteristics of this rare condition in pediatric oncology. We also provide an overview of current multidisciplinary therapeutic approaches and prognostic factors for this disease.

  11. Role of Nitric Oxide in Glioblastoma Therapy: Another Step to Resolve the Terrible Puzzle ?

    PubMed Central

    Altieri, R.; Fontanella, M.; Agnoletti, A.; Panciani, P.P.; Spena, G.; Crobeddu, E.; Pilloni, G.; Tardivo, V.; Lanotte, M.; Zenga, F.; Ducati, A.; Garbossa, D.

    2015-01-01

    Glioblastoma Multiforme, the most common and aggressive primary brain tumor, remains incurable despite of the advent of modern surgical and medical treatments. This poor prognosis depends by the recurrence after surgery and intrinsic or acquired resistance to chemotherapy and radiotherapy. Nitric oxide is a small molecule that plays a key roles in glioma pathophysiology. Many researches showing that NO is involved in induction of apoptosis, radiosensitization and chemosensitization. Therefore, NO role, if clarified, may improve the knowledge about this unsolved puzzle called GBM. PMID:26535188

  12. Differential localization of glioblastoma subtype: implications on glioblastoma pathogenesis

    PubMed Central

    Steed, Tyler C.; Treiber, Jeffrey M.; Patel, Kunal; Ramakrishnan, Valya; Merk, Alexander; Smith, Amanda R.; Carter, Bob S.; Dale, Anders M.; Chow, Lionel M. L.; Chen, Clark C.

    2016-01-01

    Introduction The subventricular zone (SVZ) has been implicated in the pathogenesis of glioblastoma. Whether molecular subtypes of glioblastoma arise from unique niches of the brain relative to the SVZ remains largely unknown. Here, we tested whether these subtypes of glioblastoma occupy distinct regions of the cerebrum and examined glioblastoma localization in relation to the SVZ. Methods Pre-operative MR images from 217 glioblastoma patients from The Cancer Imaging Archive were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Probabilistic maps of tumor location were generated for each subtype and distances were calculated from the centroid of CE tumor volumes to the SVZ. Glioblastomas that arose in a Genetically Modified Murine Model (GEMM) model were also analyzed with regard to SVZ distance and molecular subtype. Results Classical and mesenchymal glioblastomas were more diffusely distributed and located farther from the SVZ. In contrast, proneural and neural glioblastomas were more likely to be located in closer proximity to the SVZ. Moreover, in a GFAP-CreER; PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; Rbl1−/− GEMM model of glioblastoma where tumor can spontaneously arise in different regions of the cerebrum, tumors that arose near the SVZ were more likely to be of proneural subtype (p < 0.0001). Conclusions Glioblastoma subtypes occupy different regions of the brain and vary in proximity to the SVZ. These findings harbor implications pertaining to the pathogenesis of glioblastoma subtypes. PMID:27056901

  13. REST regulates oncogenic properties of glioblastoma stem cells

    PubMed Central

    Kamal, Mohamed M.; Sathyan, Pratheesh; Singh, Sanjay K.; Zinn, Pascal O.; Marisetty, Anantha L.; Liang, Shoudan; Gumin, Joy; El-Mesallamy, Hala Osman; Suki, Dima; Colman, Howard; Fuller, Gregory N.; Lang, Frederick F.; Majumder, Sadhan

    2013-01-01

    Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. Although many GBM tumors are believed to be caused by self-renewing, glioblastoma-derived stem-like cells (GSCs), the mechanisms that regulate self-renewal and other oncogenic properties of GSCs are only now being unraveled. Here we showed that GSCs derived from GBM patient specimens express varying levels of the transcriptional repressor REST, suggesting heterogeneity across different GSC lines. Loss- and gain-of-function experiments indicated that REST maintains self-renewal of GSCs. High REST-expressing GSCs (HR-GSCs) produced tumors histopathologically distinct from those generated by low REST-expressing GSCs (LR-GSCs) in orthotopic mouse brain tumor models. Knockdown of REST in HR-GSCs resulted in increased survival in GSC-transplanted mice and produced tumors with higher apoptotic and lower invasive properties. Conversely, forced expression of exogenous REST in LR-GSCs produced decreased survival in mice and produced tumors with lower apoptotic and higher invasive properties, similar to HR-GSCs. Thus, based on our results, we propose that a novel function of REST is to maintain self-renewal and other oncogenic properties of GSCs and that REST can play a major role in mediating tumorigenicity in GBM. PMID:22228704

  14. Glioblastoma cancer stem cells: Biomarker and therapeutic advances.

    PubMed

    Pointer, Kelli B; Clark, Paul A; Zorniak, Michael; Alrfaei, Bahauddeen M; Kuo, John S

    2014-05-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans. It accounts for fifty-two percent of primary brain malignancies in the United States and twenty percent of all primary intracranial tumors. Despite the current standard therapies of maximal safe surgical resection followed by temozolomide and radiotherapy, the median patient survival is still less than 2 years due to inevitable tumor recurrence. Glioblastoma cancer stem cells (GSCs) are a subgroup of tumor cells that are radiation and chemotherapy resistant and likely contribute to rapid tumor recurrence. In order to gain a better understanding of the many GBM-associated mutations, analysis of the GBM cancer genome is on-going; however, innovative strategies to target GSCs and overcome tumor resistance are needed to improve patient survival. Cancer stem cell biology studies reveal basic understandings of GSC resistance patterns and therapeutic responses. Membrane proteomics using phage and yeast display libraries provides a method to identify novel antibodies and surface antigens to better recognize, isolate, and target GSCs. Altogether, basic GBM and GSC genetics and proteomics studies combined with strategies to discover GSC-targeting agents could lead to novel treatments that significantly improve patient survival and quality of life.

  15. Immunological Evasion in Glioblastoma

    PubMed Central

    Magaña-Maldonado, Roxana; Chávez-Cortez, Elda Georgina; Olascoaga-Arellano, Nora Karen; López-Mejía, Mariana; Maldonado-Leal, Fernando Manuel; Sotelo, Julio

    2016-01-01

    Glioblastoma is the most aggressive tumor in Central Nervous System in adults. Among its features, modulation of immune system stands out. Although immune system is capable of detecting and eliminating tumor cells mainly by cytotoxic T and NK cells, tumor microenvironment suppresses an effective response through recruitment of modulator cells such as regulatory T cells, monocyte-derived suppressor cells, M2 macrophages, and microglia as well as secretion of immunomodulators including IL-6, IL-10, CSF-1, TGF-β, and CCL2. Other mechanisms that induce immunosuppression include enzymes as indolamine 2,3-dioxygenase. For this reason it is important to develop new therapies that avoid this immune evasion to promote an effective response against glioblastoma. PMID:27294132

  16. Nanotechnology Applications for Glioblastoma

    PubMed Central

    Nduom, Edjah; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G.

    2012-01-01

    Synopsis Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. While conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting the residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds much promise in the use of multifunctional nanoparticles for the imaging and targeted therapy of GBM.. Nanoparticles have emerged as potential “theranostic” agents that can permit the diagnosis and therapeutic treatment of GBM tumors. A recent human clinical trial with magnetic nanoparticles has provided feasibility and efficacy data for potential treatment of GBM patients with thermotherapy. Here we examine the current state of nanotechnology in the treatment of glioblastoma and interesting directions of further study. PMID:22748656

  17. Angiopep2-functionalized polymersomes for targeted doxorubicin delivery to glioblastoma cells.

    PubMed

    Figueiredo, Patrícia; Balasubramanian, Vimalkumar; Shahbazi, Mohammad-Ali; Correia, Alexandra; Wu, Dalin; Palivan, Cornelia G; Hirvonen, Jouni T; Santos, Hélder A

    2016-09-25

    A targeted drug delivery nanosystem for glioblastoma multiforme (GBM) based on polymersomes (Ps) made of poly(dimethylsiloxane)-poly(2-methyloxazoline) (PDMS-PMOXA) diblock copolymers was developed to evaluate their potential to actively target brain cancer cells and deliver anticancer drugs. Angiopep2 was conjugated to the surface of preformed Ps to target the low density lipoprotein receptor-related protein 1 that are overexpressed in blood brain barrier (BBB) and glioma cells. The conjugation efficiency yield for angiopep2 was estimated to be 24%. The angiopep2-functionalized Ps showed no cellular toxicity after 24h and enhanced the cellular uptake around 5 times more in U87MG glioblastoma cells compared to the non-targeted Ps. The encapsulation efficiency of doxorubicin (DOX) in Ps was 13% by co-solvent method, compared to a film rehydration method (4%). The release profiles of the DOX from Ps showed a release of 42% at pH 5.5 and 40% at pH 7.4 after 24h, indicating that Ps can efficiently retain the DOX with a slow release rate. Furthermore, the in vitro antiproliferative activity of DOX-loaded Ps-Angiopep2 showed enhanced toxicity to U87MG glioblastoma cells, compared to non-targeted Ps. Overall, our in vitro results suggested that angiopep2-conjugated Ps can be used as nanocarriers for efficient targeted DOX delivery to glioblastoma cells.

  18. p73 promotes glioblastoma cell invasion by directly activating POSTN (periostin) expression

    PubMed Central

    Landré, Vivien; Antonov, Alexey; Knight, Richard; Melino, Gerry

    2016-01-01

    Glioblastoma Multiforme is one of the most highly metastatic cancers and constitutes 70% of all gliomas. Despite aggressive treatments these tumours have an exceptionally bad prognosis, mainly due to therapy resistance and tumour recurrence. Here we show that the transcription factor p73 confers an invasive phenotype by directly activating expression of POSTN (periostin, HGNC:16953) in glioblastoma cells. Knock down of endogenous p73 reduces invasiveness and chemo-resistance, and promotes differentiation in vitro. Using chromatin immunoprecipitation and reporter assays we demonstrate that POSTN, an integrin binding protein that has recently been shown to play a major role in metastasis, is a transcriptional target of TAp73. We further show that POSTN overexpression is sufficient to rescue the invasive phenotype of glioblastoma cells after p73 knock down. Additionally, bioinformatics analysis revealed that an intact p73/POSTN axis, where POSTN and p73 expression is correlated, predicts bad prognosis in several cancer types. Taken together, our results support a novel role of TAp73 in controlling glioblastoma cell invasion by regulating the expression of the matricellular protein POSTN. PMID:26930720

  19. Angiopep2-functionalized polymersomes for targeted doxorubicin delivery to glioblastoma cells.

    PubMed

    Figueiredo, Patrícia; Balasubramanian, Vimalkumar; Shahbazi, Mohammad-Ali; Correia, Alexandra; Wu, Dalin; Palivan, Cornelia G; Hirvonen, Jouni T; Santos, Hélder A

    2016-09-25

    A targeted drug delivery nanosystem for glioblastoma multiforme (GBM) based on polymersomes (Ps) made of poly(dimethylsiloxane)-poly(2-methyloxazoline) (PDMS-PMOXA) diblock copolymers was developed to evaluate their potential to actively target brain cancer cells and deliver anticancer drugs. Angiopep2 was conjugated to the surface of preformed Ps to target the low density lipoprotein receptor-related protein 1 that are overexpressed in blood brain barrier (BBB) and glioma cells. The conjugation efficiency yield for angiopep2 was estimated to be 24%. The angiopep2-functionalized Ps showed no cellular toxicity after 24h and enhanced the cellular uptake around 5 times more in U87MG glioblastoma cells compared to the non-targeted Ps. The encapsulation efficiency of doxorubicin (DOX) in Ps was 13% by co-solvent method, compared to a film rehydration method (4%). The release profiles of the DOX from Ps showed a release of 42% at pH 5.5 and 40% at pH 7.4 after 24h, indicating that Ps can efficiently retain the DOX with a slow release rate. Furthermore, the in vitro antiproliferative activity of DOX-loaded Ps-Angiopep2 showed enhanced toxicity to U87MG glioblastoma cells, compared to non-targeted Ps. Overall, our in vitro results suggested that angiopep2-conjugated Ps can be used as nanocarriers for efficient targeted DOX delivery to glioblastoma cells. PMID:27484836

  20. Suppression of the Eag1 potassium channel sensitizes glioblastoma cells to injury caused by temozolomide

    PubMed Central

    Sales, Thais Torquato; Resende, Fernando Francisco Borges; Chaves, Natália Lemos; Titze-De-Almeida, Simoneide Souza; Báo, Sônia Nair; Brettas, Marcella Lemos; Titze-De-Almeida, Ricardo

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma. PMID:27698831

  1. Suppression of the Eag1 potassium channel sensitizes glioblastoma cells to injury caused by temozolomide

    PubMed Central

    Sales, Thais Torquato; Resende, Fernando Francisco Borges; Chaves, Natália Lemos; Titze-De-Almeida, Simoneide Souza; Báo, Sônia Nair; Brettas, Marcella Lemos; Titze-De-Almeida, Ricardo

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma.

  2. Microarray Analysis in Glioblastomas

    PubMed Central

    Bhawe, Kaumudi M.; Aghi, Manish K.

    2016-01-01

    Microarray analysis in glioblastomas is done using either cell lines or patient samples as starting material. A survey of the current literature points to transcript-based microarrays and immunohistochemistry (IHC)-based tissue microarrays as being the preferred methods of choice in cancers of neurological origin. Microarray analysis may be carried out for various purposes including the following: To correlate gene expression signatures of glioblastoma cell lines or tumors with response to chemotherapy (DeLay et al., Clin Cancer Res 18(10):2930–2942, 2012)To correlate gene expression patterns with biological features like proliferation or invasiveness of the glioblastoma cells (Jiang et al., PLoS One 8(6):e66008, 2013)To discover new tumor classificatory systems based on gene expression signature, and to correlate therapeutic response and prognosis with these signatures (Huse et al., Annu Rev Med 64(1):59–70, 2013; Verhaak et al., Cancer Cell 17(1):98–110, 2010) While investigators can sometimes use archived tumor gene expression data available from repositories such as the NCBI Gene Expression Omnibus to answer their questions, new arrays must often be run to adequately answer specific questions. Here, we provide a detailed description of microarray methodologies, how to select the appropriate methodology for a given question, and analytical strategies that can be used. Experimental methodology for protein microarrays is outside the scope of this chapter, but basic sample preparation techniques for transcript-based microarrays are included here. PMID:26113463

  3. Microarray Analysis in Glioblastomas.

    PubMed

    Bhawe, Kaumudi M; Aghi, Manish K

    2016-01-01

    Microarray analysis in glioblastomas is done using either cell lines or patient samples as starting material. A survey of the current literature points to transcript-based microarrays and immunohistochemistry (IHC)-based tissue microarrays as being the preferred methods of choice in cancers of neurological origin. Microarray analysis may be carried out for various purposes including the following: i. To correlate gene expression signatures of glioblastoma cell lines or tumors with response to chemotherapy (DeLay et al., Clin Cancer Res 18(10):2930-2942, 2012). ii. To correlate gene expression patterns with biological features like proliferation or invasiveness of the glioblastoma cells (Jiang et al., PLoS One 8(6):e66008, 2013). iii. To discover new tumor classificatory systems based on gene expression signature, and to correlate therapeutic response and prognosis with these signatures (Huse et al., Annu Rev Med 64(1):59-70, 2013; Verhaak et al., Cancer Cell 17(1):98-110, 2010). While investigators can sometimes use archived tumor gene expression data available from repositories such as the NCBI Gene Expression Omnibus to answer their questions, new arrays must often be run to adequately answer specific questions. Here, we provide a detailed description of microarray methodologies, how to select the appropriate methodology for a given question, and analytical strategies that can be used. Experimental methodology for protein microarrays is outside the scope of this chapter, but basic sample preparation techniques for transcript-based microarrays are included here. PMID:26113463

  4. Erythema Multiforme Major Following Treatment with Infliximab

    PubMed Central

    Edwards, Dean; Boritz, Eli; Cowen, Edward W.; Brown, Ronald S.

    2012-01-01

    Background The growth in the use of anti-TNF-α agents for treatment of inflammatory conditions has led to increased recognition of the side effects associated with this class of drugs. Case Description We report a case of a patient who developed erythema multiforme (EM) major with characteristic oral and cutaneous lesions following treatment with the anti-TNF-α medication infliximab therapy for Crohn’s Disease (CD). Clinical Implications To our knowledge, this is the first reported case of infliximab-induced EM secondary to the treatment of CD. It is important for dental clinicians evaluating patients using anti-TNF-α agents to be aware of this possible complication. PMID:23036796

  5. Predicting the growth of glioblastoma multiforme spheroids using a multiphase porous media model.

    PubMed

    Mascheroni, Pietro; Stigliano, Cinzia; Carfagna, Melania; Boso, Daniela P; Preziosi, Luigi; Decuzzi, Paolo; Schrefler, Bernhard A

    2016-10-01

    Tumor spheroids constitute an effective in vitro tool to investigate the avascular stage of tumor growth. These three-dimensional cell aggregates reproduce the nutrient and proliferation gradients found in the early stages of cancer and can be grown with a strict control of their environmental conditions. In the last years, new experimental techniques have been developed to determine the effect of mechanical stress on the growth of tumor spheroids. These studies report a reduction in cell proliferation as a function of increasingly applied stress on the surface of the spheroids. This work presents a specialization for tumor spheroid growth of a previous more general multiphase model. The equations of the model are derived in the framework of porous media theory, and constitutive relations for the mass transfer terms and the stress are formulated on the basis of experimental observations. A set of experiments is performed, investigating the growth of U-87MG spheroids both freely growing in the culture medium and subjected to an external mechanical pressure induced by a Dextran solution. The growth curves of the model are compared to the experimental data, with good agreement for both the experimental settings. A new mathematical law regulating the inhibitory effect of mechanical compression on cancer cell proliferation is presented at the end of the paper. This new law is validated against experimental data and provides better results compared to other expressions in the literature.

  6. MRI biomarkers identify the differential response of glioblastoma multiforme to anti-angiogenic therapy

    PubMed Central

    Jalali, Shahrzad; Chung, Caroline; Foltz, Warren; Burrell, Kelly; Singh, Sanjay; Hill, Richard; Zadeh, Gelareh

    2014-01-01

    Background Although anti-angiogenic therapy (AATx) holds great promise for treatment of malignant gliomas, its therapeutic efficacy is not well understood and can potentially increase the aggressive recurrence of gliomas. It is essential to establish sensitive, noninvasive biomarkers that can detect failure of AATx and tumor recurrence early so that timely adaptive therapy can be instituted. We investigated the efficacy of MRI biomarkers that can detect response to different classes of AATxs used alone or in combination with radiation. Methods Murine intracranial glioma xenografts (NOD/SCID) were treated with sunitinib, VEGF-trap or B20 (a bevacizumab equivalent) alone or in combination with radiation. MRI images were acquired longitudinally before and after treatment, and various MRI parameters (apparent diffusion coefficient, T1w + contrast, dynamic contrast-enhanced [DCE], initial area under the contrast enhancement curve, and cerebral blood flow) were correlated to tumor cell proliferation, overall tumor growth, and tumor vascularity. Results Combinatorial therapies reduced tumor growth rate more efficiently than monotherapies. Apparent diffusion coefficient was an accurate measure of tumor cell density. Vascular endothelial growth factor (VEGF)-trap or B20, but not sunitinib, resulted in significant reduction or complete loss of contrast enhancement. This reduction was not due to a reduction in tumor growth or microvascular density, but rather was explained by a reduction in vessel permeability and perfusion. We established that contrast enhancement does not accurately reflect tumor volume or vascular density; however, DCE-derived parameters can be used as efficient noninvasive biomarkers of response to AATx. Conclusions MRI parameters following therapy vary based on class of AATx. Validation of clinically relevant MRI parameters for individual AATx agents is necessary before incorporation into routine practice. PMID:24759636

  7. Nanoparticles containing allotropes of carbon have genotoxic effects on glioblastoma multiforme cells.

    PubMed

    Hinzmann, Mateusz; Jaworski, Sławomir; Kutwin, Marta; Jagiełło, Joanna; Koziński, Rafał; Wierzbicki, Mateusz; Grodzik, Marta; Lipińska, Ludwika; Sawosz, Ewa; Chwalibog, Andrè

    2014-01-01

    The carbon-based nanomaterial family consists of nanoparticles containing allotropes of carbon, which may have a number of interactions with biological systems. The objective of this study was to evaluate the toxicity of nanoparticles comprised of pristine graphene, reduced graphene oxide, graphene oxide, graphite, and ultradispersed detonation diamond in a U87 cell line. The scope of the work consisted of structural analysis of the nanoparticles using transmission electron microscopy, evaluation of cell morphology, and assessment of cell viability by Trypan blue assay and level of DNA fragmentation of U87 cells after 24 hours of incubation with 50 μg/mL carbon nanoparticles. DNA fragmentation was studied using single-cell gel electrophoresis. Incubation with nanoparticles containing the allotropes of carbon did not alter the morphology of the U87 cancer cells. However, incubation with pristine graphene and reduced graphene oxide led to a significant decrease in cell viability, whereas incubation with graphene oxide, graphite, and ultradispersed detonation diamond led to a smaller decrease in cell viability. The results of a comet assay demonstrated that pristine graphene, reduced graphene oxide, graphite, and ultradispersed detonation diamond caused DNA damage and were therefore genotoxic in U87 cells, whereas graphene oxide was not. PMID:24876774

  8. Case numbers for a randomized clinical trial of boron neutron capture therapy for Glioblastoma multiforme.

    PubMed

    Sander, Anja; Wosniok, Werner; Gabel, Detlef

    2014-06-01

    Boron neutron capture therapy (BNCT) with Na2B12H11SH (BSH) or p-dihydroxyborylphenylalanine (BPA), and with a combination of both, was compared to radiotherapy with temozolomide, and the number of patients required to show statistically significant differences between the treatments was calculated. Whereas arms using BPA require excessive number of patients in each arm, a two-armed clinical trial with BSH and radiotherapy plus temozolomide is feasible. PMID:24373823

  9. Synthetic Nano-Low Density Lipoprotein as Targeted Drug DeliveryVehicle for Glioblastoma Multiforme

    SciTech Connect

    Nikanjam, Mina; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Shu,Xiao; Budinger, Thomas F.; Forte, Trudy M.

    2006-06-14

    This paper discribes a synthetic low density lipoprotein(LDL) made by complexing a 29 amino acid that consists of a lipid bindingdomain and the LDL receptor binding domain with a lipid microemulsion.The nano-LDL particles were intermdiate in size between LDL and HDL andbound to LDL receptors on GBM brain tumor cells. Synthetic nano-LDLuptake by GBM cells was LDL receptor specific and dependent on cellreceptor number. It is suggested that these synthetic particles can serveas a delivery vehicle for hydophobic anti-tumor drugs by targeting theLDL receptor.

  10. Nanoparticles containing allotropes of carbon have genotoxic effects on glioblastoma multiforme cells.

    PubMed

    Hinzmann, Mateusz; Jaworski, Sławomir; Kutwin, Marta; Jagiełło, Joanna; Koziński, Rafał; Wierzbicki, Mateusz; Grodzik, Marta; Lipińska, Ludwika; Sawosz, Ewa; Chwalibog, Andrè

    2014-01-01

    The carbon-based nanomaterial family consists of nanoparticles containing allotropes of carbon, which may have a number of interactions with biological systems. The objective of this study was to evaluate the toxicity of nanoparticles comprised of pristine graphene, reduced graphene oxide, graphene oxide, graphite, and ultradispersed detonation diamond in a U87 cell line. The scope of the work consisted of structural analysis of the nanoparticles using transmission electron microscopy, evaluation of cell morphology, and assessment of cell viability by Trypan blue assay and level of DNA fragmentation of U87 cells after 24 hours of incubation with 50 μg/mL carbon nanoparticles. DNA fragmentation was studied using single-cell gel electrophoresis. Incubation with nanoparticles containing the allotropes of carbon did not alter the morphology of the U87 cancer cells. However, incubation with pristine graphene and reduced graphene oxide led to a significant decrease in cell viability, whereas incubation with graphene oxide, graphite, and ultradispersed detonation diamond led to a smaller decrease in cell viability. The results of a comet assay demonstrated that pristine graphene, reduced graphene oxide, graphite, and ultradispersed detonation diamond caused DNA damage and were therefore genotoxic in U87 cells, whereas graphene oxide was not.

  11. Prognostic factors for survival of patients with glioblastoma: Recursive partitioning analysis1

    PubMed Central

    Lamborn, Kathleen R.; Chang, Susan M.; Prados, Michael D.

    2004-01-01

    Survival for patients with glioblastoma multiforme is short, and current treatments provide limited benefit. Therefore, there is interest in conducting phase 2 trials of experimental treatments in newly diagnosed patients. However, this requires historical data with which to compare the experimental therapies. Knowledge of prognostic markers would also allow stratification into risk groups for phase 3 randomized trials. In this retrospective study of 832 glioblastoma multiforme patients enrolled into prospective clinical trials at the time of initial diagnosis, we evaluated several potential prognostic markers for survival to establish risk groups. Analyses were done using both Cox proportional hazards modeling and recursive partitioning analyses. Initially, patients from 8 clinical trials, 6 of which included adjuvant chemotherapy, were included. Subsequent analyses excluded trials with interstitial brachytherapy, and finally included only nonbrachytherapy trials with planned adjuvant chemotherapy. The initial analysis defined 4 risk groups. The 2 lower risk groups included patients under the age of 40, the lowest risk group being young patients with tumor in the frontal lobe only. An intermediate-risk group included patients with Karnofsky performance status (KPS) >70, subtotal or total resection, and age between 40 and 65. The highest risk group included all patients over 65 and patients between 40 and 65 with either KPS < 80 or biopsy only. Subgroup analyses indicated that inclusion of adjuvant chemotherapy provides an increase in survival, although that improvement tends to be minimal for patients over age 65, for patients over age 40 with KPS less than 80, and for those treated with brachytherapy. PMID:15279715

  12. Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis.

    PubMed

    Lamborn, Kathleen R; Chang, Susan M; Prados, Michael D

    2004-07-01

    Survival for patients with glioblastoma multiforme is short, and current treatments provide limited benefit. Therefore, there is interest in conducting phase 2 trials of experimental treatments in newly diagnosed patients. However, this requires historical data with which to compare the experimental therapies. Knowledge of prognostic markers would also allow stratification into risk groups for phase 3 randomized trials. In this retrospective study of 832 glioblastoma multiforme patients enrolled into prospective clinical trials at the time of initial diagnosis, we evaluated several potential prognostic markers for survival to establish risk groups. Analyses were done using both Cox proportional hazards modeling and recursive partitioning analyses. Initially, patients from 8 clinical trials, 6 of which included adjuvant chemotherapy, were included. Subsequent analyses excluded trials with interstitial brachytherapy, and finally included only nonbrachytherapy trials with planned adjuvant chemotherapy. The initial analysis defined 4 risk groups. The 2 lower risk groups included patients under the age of 40, the lowest risk group being young patients with tumor in the frontal lobe only. An intermediate-risk group included patients with Karnofsky performance status (KPS) >70, subtotal or total resection, and age between 40 and 65. The highest risk group included all patients over 65 and patients between 40 and 65 with either KPS<80 or biopsy only. Subgroup analyses indicated that inclusion of adjuvant chemotherapy provides an increase in survival, although that improvement tends to be minimal for patients over age 65, for patients over age 40 with KPS less than 80, and for those treated with brachytherapy.

  13. Glioblastoma extracellular vesicles: reservoirs of potential biomarkers

    PubMed Central

    Redzic, Jasmina S; Ung, Timothy H; Graner, Michael W

    2014-01-01

    Glioblastoma multiforme (GBM) is the most frequent and most devastating of the primary central nervous system tumors, with few patients living beyond 2 years postdiagnosis. The damage caused by the disease and our treatments for the patients often leave them physically and cognitively debilitated. Generally, GBMs appear after very short clinical histories and are discovered by imaging (using magnetic resonance imaging [MRI]), and the diagnosis is validated by pathology, following surgical resection. The treatment response and diagnosis of tumor recurrence are also tracked by MRI, but there are numerous problems encountered with these monitoring modalities, such as ambiguous interpretation and forms of pseudoprogression. Diagnostic, prognostic, and predictive biomarkers would be an immense boon in following treatment schemes and in determining recurrence, which often requires an invasive intracranial biopsy to verify imaging data. Extracellular vesicles (EVs) are stable, membrane-enclosed, virus-sized particles released from either the cell surface or from endosomal pathways that lead to the systemic release of EVs into accessible biofluids, such as serum/plasma, urine, cerebrospinal fluid, and saliva. EVs carry a wide variety of proteins, nucleic acids, lipids, and other metabolites, with many common features but with enough individuality to be able to identify the cell of origin of the vesicles. These components, if properly interrogated, could allow for the identification of tumor-derived EVs in biofluids, indicating tumor progression, relapse, or treatment failure. That knowledge would allow clinicians to continue with treatment regimens that were actually effective or to change course if the therapies were failing. Here, we review the features of GBM EVs, in terms of EV content and activities that may lead to the use of EVs as serially accessible biomarkers for diagnosis and treatment response in neuro-oncology. PMID:24634586

  14. Emerging targets for glioblastoma stem cell therapy

    PubMed Central

    Safa, Ahmad R.; Saadatzadeh, Mohammad Reza; Cohen-Gadol, Aaron A.; Pollok, Karen E.; Bijangi-Vishehsaraei, Khadijeh

    2016-01-01

    Abstract Glioblastoma multiforme (GBM), designated as World Health Organization (WHO) grade IV astrocytoma, is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations, including GBM stem cells (GSCs) which are believed to contribute to tumor recurrence following initial response to therapies. Emerging evidence demonstrates that GBM tumors are initiated from GSCs. The development and use of novel therapies including small molecule inhibitors of specific proteins in signaling pathways that regulate stemness, proliferation and migration of GSCs, immunotherapy, and non-coding microRNAs may provide better means of treating GBM. Identification and characterization of GSC-specific signaling pathways would be necessary to identify specific therapeutic targets which may lead to the development of more efficient therapies selectively targeting GSCs. Several signaling pathways including mTOR, AKT, maternal embryonic leucine zipper kinase (MELK), NOTCH1 and Wnt/β-catenin as well as expression of cancer stem cell markers CD133, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain GSC properties. Moreover, the data published in the Cancer Genome Atlas (TCGA) specifically demonstrated the activated PI3K/AKT/mTOR pathway in GBM tumorigenesis. Studying such pathways may help to understand GSC biology and lead to the development of potential therapeutic interventions to render them more sensitive to chemotherapy and radiation therapy. Furthemore, recent demonstration of dedifferentiation of GBM cell lines into CSC-like cells prove that any successful therapeutic agent or combination of drugs for GBM therapy must eliminate not only GSCs, but the differentiated GBM cells and the entire bulk of tumor cells. PMID:26616589

  15. Erythema multiforme caused by sildenafil in an HIV(+) subject.

    PubMed

    Pitsios, C

    2016-03-01

    Erythema multiforme is mainly caused by drug allergy and infections. This is the case of a HIV-positive, 49-year-old male, recently cured for syphilis, that presented erythema multiforme minor, five days after taking sildenafil. He had a fast recovery, only with the use of antihistamines. Cell-mediated allergy to sildenafil was confirmed six months later, with the use of patch-tests. PMID:26934741

  16. [Erythema multiforme secondary to cutaneous Trichophyton mentagrophytes infection].

    PubMed

    Contreras-Barrera, Martha E; Moreno-Coutiño, Gabriela; Torres-Guerrero, D Edoardo; Aguilar-Donis, Adriana; Arenas, Roberto

    2009-06-30

    Erythema multiforme is an acute self-limited cutaneous syndrome associated in more than 50% of the cases with herpes simplex virus infection; but it can also be a consequence of other infectious agents or drugs. We report on a 24 year-old female patient with erythema multiforme secondary to Trichophyton mentagrophytes var. mentagrophytes cutaneous infection acquired from contact with animals in a research laboratory.

  17. Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression

    PubMed Central

    Prados, Jose; Caba, Octavio; Cabeza, Laura; Berdasco, Maria; Gónzalez, Beatriz; Melguizo, Consolación

    2015-01-01

    Background The use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated. Methods Four nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2’-deoxycytidine was used to demethylate the MGMT promoter and O(6)-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed. Results Our results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229) and high (SF268 and SK-N-SH) basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC50 showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC50 did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC50, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines. Conclusions These results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma

  18. Investigating the therapeutic role and molecular biology of curcumin as a treatment for glioblastoma

    PubMed Central

    Rodriguez, Gregor A.; Shah, Ashish H.; Gersey, Zachary C.; Shah, Sumedh S.; Bregy, Amade; Komotar, Ricardo J.; Graham, Regina M.

    2016-01-01

    Objectives: Despite the aggressive standard of care for patients with glioblastoma multiforme, survival rates typically do not exceed 2 years. Therefore, current research is focusing on discovering new therapeutics or rediscovering older medications that may increase the overall survival of patients with glioblastoma. Curcumin, a component of the Indian natural spice, turmeric, also known for its antioxidant and anti-inflammatory properties, has been found to be an effective inhibitor of proliferation and inducer of apoptosis in many cancers. The goal of this study was to investigate the expanded utility of curcumin as an antiglioma agent. Methods: Using the PubMed MeSH database, we conducted a systematic review of the literature to include pertinent studies on the growth inhibitory effects of curcumin on glioblastoma cell lines based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 19 in vitro and five in vivo studies were analyzed. All of the studies indicated that curcumin decreased glioblastoma cell viability through various pathways (i.e. decrease in prosurvival proteins such as nuclear factor κB, activator protein 1, and phosphoinositide 3 kinase, and upregulation of apoptotic pathways like p21, p53, and executor caspase 3). Curcumin treatment also increased animal survival compared with control groups. Conclusions: Curcumin inhibits proliferation and induces apoptosis in certain subpopulations of glioblastoma tumors, and its ability to target multiple signaling pathways involved in cell death makes it an attractive therapeutic agent. As such, it should be considered as a potent anticancer treatment. Further experiments are warranted to elucidate the use of a bioavailable form of curcumin in clinical trials. PMID:27482284

  19. Glioblastoma with oligodendroglial components: glioblastoma or anaplastic oligodendroglial tumors.

    PubMed

    Takeuchi, Hiroaki; Hosoda, Tetsuya; Kitai, Ryuhei; Kodera, Toshiaki; Arishima, Hidetaka; Tsunetoshi, Kenzo; Neishi, Hiroyuki; Yamauchi, Takahiro; Sato, Kazufumi; Imamura, Yoshiyuki; Itoh, Hiroshi; Kubota, Toshihiko; Kikuta, Ken-ichiro

    2012-07-01

    There have been some recent reports about glioblastoma with oligodendroglial (OG) components and malignant glioma with primitive neuroectodermal tumor (PNET)-like components. We investigated whether the presence and extent of OG components and PNET-like components influenced the prognosis in patients with glioblastoma. Eighty-six patients with glioblastoma were divided into an OG group (28 %), which revealed areas with a honeycomb appearance, and a non-OG group (72 %) without a honeycomb appearance. Patients with glioblastoma were also divided into a PNET group (27 %), which revealed areas with PNET-like features defined as neoplastic cells with high N/C ratios and hyperchromatic oval-carrot-shaped nuclei, and lacked the typical honeycomb appearance, and a non-PNET group (73 %) without PNET features. There were no significant differences in overall survival among the OG, the non-OG, the PNET, and the non-PNET groups. Two patients who survived longer than 36 months had both OG and PNET components with 1p or 19q loss of heterozygosity. Perinuclear halo, which is a characteristic feature of oligodendrogliomas, is an artifact of tissue fixation. Therefore, we should not readily use the term glioblastoma with OG components. PNET-like components, which are considered rare in malignant gliomas, may be frequently identified in glioblastomas. PMID:22527749

  20. Therapeutic effects of dihydroartemisinin and transferrin against glioblastoma

    PubMed Central

    Kim, Suk Hee; Kang, Seong Hee

    2016-01-01

    BACKGROUND/OBJECTIVES Artemisinin, a natural product isolated from Gaeddongssuk (artemisia annua L.) and its main active derivative, dihydroartemisinin (DHA), have long been used as antimalarial drugs. Recent studies reported that artemisinin is efficacious for curing diseases, including cancers, and for improving the immune system. Many researchers have shown the therapeutic effects of artemisinin on tumors such as breast cancer, liver cancer and kidney cancer, but there is still insufficient data regarding glioblastoma (GBM). Glioblastoma accounts for 12-15% of brain cancer, and the median survival is less than a year, despite medical treatments such as surgery, radiation therapy, and chemotherapy. In this study, we investigated the anti-cancer effects of DHA and transferrin against glioblastoma (glioblastoma multiforme, GBM). MATERIALS/METHODS This study was performed through in vitro experiments using C6 cells. The toxicity dependence of DHA and transferrin (TF) on time and concentration was analyzed by MTT assay and cell cycle assay. Observations of cellular morphology were recorded with an optical microscope and color digital camera. The anti-cancer mechanism of DHA and TF against GBM were studied by flow cytometry with Annexin V and caspase 3/7. RESULTS MTT assay revealed that TF enhanced the cytotoxicity of DHA against C6 cells. An Annexin V immune-precipitation assay showed that the percentages of apoptosis of cells treated with TF, DHA alone, DHA in combination with TF, and the control group were 7.15 ± 4.15%, 34.3 ± 5.15%, 66.42 ± 5.98%, and 1.2 ± 0.15%, respectively. The results of the Annexin V assay were consistent with those of the MTT assay. DHA induced apoptosis in C6 cells through DNA damage, and TF enhanced the effects of DHA. CONCLUSION The results of this study demonstrated that DHA, the derivative of the active ingredient in Gaeddongssuk, is effective against GBM, apparently via inhibition of cancer cell proliferation by a pharmacological

  1. A Primer on Confirmatory Factor Analysis.

    ERIC Educational Resources Information Center

    Gillaspy, James Arthur, Jr.

    This introduction to confirmatory factor analysis presents an overview of its basic concepts and processes. Conventional factor analysis can be described as set of analytic techniques designed to examine the covariance structure of a set of variables and to provide an explanation of the relationships among those variables in terms of a smaller…

  2. Confirmatory Measurement Model Comparisons Using Latent Means.

    ERIC Educational Resources Information Center

    Millsap, Roger E.; Everson, Howard

    1991-01-01

    Use of confirmatory factor analysis (CFA) with nonzero latent means in testing six different measurement models from classical test theory is discussed. Implications of the six models for observed mean and covariance structures are described, and three examples of the use of CFA in testing the models are presented. (SLD)

  3. Comparisons of Exploratory and Confirmatory Factor Analysis.

    ERIC Educational Resources Information Center

    Daniel, Larry G.

    Historically, most researchers conducting factor analysis have used exploratory methods. However, more recently, confirmatory factor analytic methods have been developed that can directly test theory either during factor rotation using "best fit" rotation methods or during factor extraction, as with the LISREL computer programs developed by K. G.…

  4. [Palliative care for glioblastoma].

    PubMed

    Dieudonné, Nathalie; De Micheli, Rita; Hottinger, Andreas

    2016-04-27

    Patients with glioblastoma have a limited life expectancy and an impaired quality of life and they should be offered palliative care soon after the diagnosis is established. Still, only a quarter of patients aged over 65 return home or medical institution after completing treatments. Home care must be promoted by coordinating assistance and care, combining disciplines such as physiotherapy and ergotherapy, medical and nursing care and psychosocial support. Patients are at risk of mood, personality and behavioural disorders. Limited awareness of these troubles and their physical limitations alter their capacity of rehabilitation and social relationships. Isolation of relatives, exhaustion and misunderstandings should be prevented. The therapeutic goals should be discussed and determined upstream to anticipate difficulties and questions concerning end of life. PMID:27281945

  5. A chemo-resistant protein expression pattern of glioblastoma cells (A172) to perillyl alcohol

    PubMed Central

    Fischer, Juliana de Saldanha da Gama; Carvalho, Paulo Costa; Fonseca, Clovis Orlando da; Liao, Lujian; Degrave, Wim M; Carvalho, Maria da Gloria da Costa; Yates, John R; Domont, Gilberto B

    2010-01-01

    Glioblastoma multiform (GBM) is by far the most malignant glioma. We have introduced a new treatment for GBMs that comprises the inhalation of a naturally occurring terpene with chemotherapeutic properties known as perillyl alcohol (POH). Clinical trial results on recurrent GBM patients showed that POH extends the average life by more than eight months, temporarily slows tumor growth, and in some cases even decreases tumor size. After approximately seven months the tumor continues to grow and leads to a dismal prognosis. To investigate how these tumors become resistant to POH we generated an A172 human glioblastoma cell culture tolerant to 0.06 mM of POH (A172r). We used Multidimensional Protein Identification Technology (MudPIT) to compare the protein expression profile of A172r cells to the established glioblastoma A172 cell line. Our results include a list of identified proteins unique to either the resistant or the non-resistant cell line. These proteins are related to cellular growth, negative apoptosis regulation, Ras pathway, and other key cellular functions that could be connected to the underlying mechanisms of resistance. PMID:20806975

  6. Suppression of Glioblastoma Angiogenicity and Tumorigenicity by Inhibition of Endogenous Expression of Vascular Endothelial Growth Factor

    NASA Astrophysics Data System (ADS)

    Cheng, Shi-Yuan; Huang, H.-J. Su; Nagane, Motoo; Ji, Xiang-Dong; Wang, Degui; Shih, Charles C.-Y.; Arap, Wadih; Huang, Chun-Ming; Cavenee, Webster K.

    1996-08-01

    The development of new capillary networks from the normal microvasculature of the host appears to be required for growth of solid tumors. Tumor cells influence this process by producing both inhibitors and positive effectors of angiogenesis. Among the latter, the vascular endothelial growth factor (VEGF) has assumed prime candidacy as a major positive physiological effector. Here, we have directly tested this hypothesis in the brain tumor, glioblastoma multiforme, one of the most highly vascularized human cancers. We introduced an antisense VEGF expression construct into glioblastoma cells and found that (i) VEGF mRNA and protein levels were markedly reduced, (ii) the modified cells did not secrete sufficient factors so as to be chemoattractive for primary human microvascular endothelial cells, (iii) the modified cells were not able to sustain tumor growth in immunodeficient animals, and (iv) the density of in vivo blood vessel formation was reduced in direct relation to the reduction of VEGF secretion and tumor formation. Moreover, revertant cells that recovered the ability to secrete VEGF regained each of these tumorigenic properties. These results suggest that VEGF plays a major angiogenic role in glioblastoma.

  7. 77 FR 58587 - Mr. James Chaisson; Confirmatory Order (Effective Immediately)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-21

    ..., arranged through Cornell University's Institute on Conflict Resolution. This Confirmatory Order is issued... Confirmatory Order is the result of an agreement reached during an alternative dispute resolution (ADR... opportunity to request a predecisional enforcement conference (PEC), or request alternative dispute...

  8. Glioblastoma Stem Cells as a New Therapeutic Target for Glioblastoma

    PubMed Central

    Kalkan, Rasime

    2015-01-01

    Primary and secondary glioblastomas (GBMs) are two distinct diseases. The genetic and epigenetic background of these tumors is highly variable. The treatment procedure for these tumors is often unsuccessful because of the cellular heterogeneity and intrinsic ability of the tumor cells to invade healthy tissues. The fatal outcome of these tumors promotes researchers to find out new markers associated with the prognosis and treatment planning. In this communication, the role of glioblastoma stem cells in tumor progression and the malignant behavior of GBMs are summarized with attention to the signaling pathways and molecular regulators that are involved in maintaining the glioblastoma stem cell phenotype. A better understanding of these stem cell-like cells is necessary for designing new effective treatments and developing novel molecular strategies to target glioblastoma stem cells. We discuss hypoxia as a new therapeutic target for GBM. We focus on the inhibition of signaling pathways, which are associated with the hypoxia-mediated maintenance of glioblastoma stem cells, and the knockdown of hypoxia-inducible factors, which could be identified as attractive molecular target approaches for GBM therapeutics. PMID:26617463

  9. Calcium signaling orchestrates glioblastoma development: Facts and conjunctures.

    PubMed

    Leclerc, Catherine; Haeich, Jacques; Aulestia, Francisco J; Kilhoffer, Marie-Claude; Miller, Andrew L; Néant, Isabelle; Webb, Sarah E; Schaeffer, Etienne; Junier, Marie-Pierre; Chneiweiss, Hervé; Moreau, Marc

    2016-06-01

    While it is a relatively rare disease, glioblastoma multiform (GBM) is one of the more deadly adult cancers. Following current interventions, the tumor is never eliminated whatever the treatment performed; whether it is radiotherapy, chemotherapy, or surgery. One hypothesis to explain this poor outcome is the "cancer stem cell" hypothesis. This concept proposes that a minority of cells within the tumor mass share many of the properties of adult neural stem cells and it is these that are responsible for the growth of the tumor and its resistance to existing therapies. Accumulating evidence suggests that Ca(2+) might also be an important positive regulator of tumorigenesis in GBM, in processes involving quiescence, maintenance, proliferation, or migration. Glioblastoma tumors are generally thought to develop by co-opting pathways that are involved in the formation of an organ. We propose that the cells initiating the tumor, and subsequently the cells of the tumor mass, must hijack the different checkpoints that evolution has selected in order to prevent the pathological development of an organ. In this article, two main points are discussed. (i) The first is the establishment of a so-called "cellular society," which is required to create a favorable microenvironment. (ii) The second is that GBM can be considered to be an organism, which fights to survive and develop. Since GBM evolves in a limited space, its only chance of development is to overcome the evolutionary checkpoints. For example, the deregulation of the normal Ca(2+) signaling elements contributes to the progression of the disease. Thus, by manipulating the Ca(2+) signaling, the GBM cells might not be killed, but might be reprogrammed toward a new fate that is either easy to cure or that has no aberrant functioning. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.

  10. Calcium signaling orchestrates glioblastoma development: Facts and conjunctures.

    PubMed

    Leclerc, Catherine; Haeich, Jacques; Aulestia, Francisco J; Kilhoffer, Marie-Claude; Miller, Andrew L; Néant, Isabelle; Webb, Sarah E; Schaeffer, Etienne; Junier, Marie-Pierre; Chneiweiss, Hervé; Moreau, Marc

    2016-06-01

    While it is a relatively rare disease, glioblastoma multiform (GBM) is one of the more deadly adult cancers. Following current interventions, the tumor is never eliminated whatever the treatment performed; whether it is radiotherapy, chemotherapy, or surgery. One hypothesis to explain this poor outcome is the "cancer stem cell" hypothesis. This concept proposes that a minority of cells within the tumor mass share many of the properties of adult neural stem cells and it is these that are responsible for the growth of the tumor and its resistance to existing therapies. Accumulating evidence suggests that Ca(2+) might also be an important positive regulator of tumorigenesis in GBM, in processes involving quiescence, maintenance, proliferation, or migration. Glioblastoma tumors are generally thought to develop by co-opting pathways that are involved in the formation of an organ. We propose that the cells initiating the tumor, and subsequently the cells of the tumor mass, must hijack the different checkpoints that evolution has selected in order to prevent the pathological development of an organ. In this article, two main points are discussed. (i) The first is the establishment of a so-called "cellular society," which is required to create a favorable microenvironment. (ii) The second is that GBM can be considered to be an organism, which fights to survive and develop. Since GBM evolves in a limited space, its only chance of development is to overcome the evolutionary checkpoints. For example, the deregulation of the normal Ca(2+) signaling elements contributes to the progression of the disease. Thus, by manipulating the Ca(2+) signaling, the GBM cells might not be killed, but might be reprogrammed toward a new fate that is either easy to cure or that has no aberrant functioning. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. PMID:26826650

  11. Dendritic cell vaccination in glioblastoma after fluorescence-guided resection

    PubMed Central

    Valle, Ricardo Diez; de Cerio, Ascension Lopez-Diaz; Inoges, Susana; Tejada, Sonia; Pastor, Fernando; Villanueva, Helena; Gallego, Jaime; Espinos, Jaime; Aristu, Javier; Idoate, Miguel Angel; Andreu, Enrique; Bendandi, Maurizio

    2012-01-01

    AIM: To assess whether the addition of a customized, active immunotherapy to standard of care including fluorescence-guided surgery, may provide hints of an improved survival for patients with poor-prognosis, incurable glioblastoma multiform. METHODS: Preliminary to our ongoing, phase-II clinical trial, we conducted a small pilot study enrolling five consecutive patients with resectable glioblastoma. In terms of Recursive Partitioning Analysis, four patients were class V and one was class IV. In all five cases, fluorescence-guided surgery was employed, followed by rapid steroid discontinuation. Patients were then treated with a combination of standard radio-chemotherapy with temozolomide and tumor lysate-pulsed, mature dendritic cell-based vaccinations. RESULTS: Though all five patients ultimately progressed, with any further treatment left to the sole decision of the treating oncologist, active immunotherapy was very well tolerated and induced specific immune responses in all three patients for whom enough material was available for such an assessment. Median progression-free survival was 16.1 mo. Even more important, median and mean overall survival were 27 mo and 26 mo, respectively. Three patients have died with an overall survival of 9 mo, 27 mo and 27.4 mo, while the other two are still alive at 32 mo and 36 mo, the former receiving treatment with bevacizumab, while the latter has now been off therapy for 12 mo. Four of five patients were alive at two years. CONCLUSION: Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-II study is ongoing to possibly improve further on our very encouraging clinical results. PMID:23293753

  12. BC3EE2,9B, a synthetic carbazole derivative, upregulates autophagy and synergistically sensitizes human GBM8901 glioblastoma cells to temozolomide.

    PubMed

    Chen, Chien-Min; Syu, Jhih-Pu; Way, Tzong-Der; Huang, Li-Jiau; Kuo, Sheng-Chu; Lin, Chung-Tien; Lin, Chih-Li

    2015-11-01

    Glioblastoma multiforme (GBM) is the most fatal form of human brain cancer. Although temozolomide (TMZ), an oral alkylating chemotherapeutic agent, improves the survival rate, the prognosis of patients with GBM remains poor. Naturally occurring carbazole alkaloids isolated from curry leaves (Murraya koenigii Spreng.) have been shown to possess a wide range of anticancer properties. However, the effects of carbazole derivatives on glioblastoma cells remain poorly understood. In the present study, anti‑glioblastoma profiles of a series of synthetic carbazole derivatives were evaluated in vitro. The most promising derivative in this series was BC3EE2,9B, which showed significant anti‑proliferative effects in GBM8401 and GBM8901 cells. BC3EE2,9B also triggered cell‑cycle arrest, most prominently at the G1 stage, and suppressed glioblastoma cell invasion and migration. Furthermore, BC3EE2,9B induced autophagy‑mediated cell death and synergistically sensitized GBM cells to TMZ cytotoxicity. The possible mechanism underlying BC3EE2,9B‑induced autophagy may involve activation of adenosine monophosphate-activated protein kinase and the attenuation of the Akt and mammalian target of the rapamycin downstream signaling pathway. Taken together, the present results provide molecular evidence for the mode of action governing the ability of BC3EE2,9B to sensitize drug‑resistant glioblastoma cells to the chemotherapeutic agent TMZ.

  13. BC3EE2,9B, a synthetic carbazole derivative, upregulates autophagy and synergistically sensitizes human GBM8901 glioblastoma cells to temozolomide

    PubMed Central

    CHEN, CHIEN-MIN; SYU, JHIH-PU; WAY, TZONG-DER; HUANG, LI-JIAU; KUO, SHENG-CHU; LIN, CHUNG-TIEN; LIN, CHIH-LI

    2015-01-01

    Glioblastoma multiforme (GBM) is the most fatal form of human brain cancer. Although temozolomide (TMZ), an oral alkylating chemotherapeutic agent, improves the survival rate, the prognosis of patients with GBM remains poor. Naturally occurring carbazole alkaloids isolated from curry leaves (Murraya koenigii Spreng.) have been shown to possess a wide range of anticancer properties. However, the effects of carbazole derivatives on glioblastoma cells remain poorly understood. In the present study, anti-glioblastoma profiles of a series of synthetic carbazole derivatives were evaluated in vitro. The most promising derivative in this series was BC3EE2,9B, which showed significant anti-proliferative effects in GBM8401 and GBM8901 cells. BC3EE2,9B also triggered cell-cycle arrest, most prominently at the G1 stage, and suppressed glioblastoma cell invasion and migration. Furthermore, BC3EE2,9B induced autophagy-mediated cell death and synergistically sensitized GBM cells to TMZ cytotoxicity. The possible mechanism underlying BC3EE2,9B-induced autophagy may involve activation of adenosine monophosphate-activated protein kinase and the attenuation of the Akt and mammalian target of the rapamycin downstream signaling pathway. Taken together, the present results provide molecular evidence for the mode of action governing the ability of BC3EE2,9B to sensitize drug-resistant glioblastoma cells to the chemotherapeutic agent TMZ. PMID:26329365

  14. Molecular therapy for glioblastoma.

    PubMed

    Karpati, G; Li, H; Nalbantoglu, J

    1999-10-01

    Glioblastoma (GB), the relatively frequent and most malignant form of primary brain tumor, is fatal within 1 to 2 years of onset of symptoms, despite conventional therapy. Molecular therapy promises to be an effective and possibly curative treatment. Several molecular strategies have been tested, either in animal models or clinical trials. These include: prodrug activating systems, introduction of tumor suppressor or cell-cycle-related genes, inhibition of growth factors and/or their receptors, inhibition of neovascularization, immunomodulatory maneuvers, oncolytic viruses and inhibition of matrix metalloproteinases. Of special interest for the development of optimal molecular therapy of GB, is the choice of the most efficient and least toxic gene vectors (adenovirus, retrovirus, herpes simplex virus), the route of administration of the therapeutic agent (intratumoral with or without debulking and intracarotid), avoidance of collateral damage to the perineoplastic neuropil and adequate preclinical studies. The ultimate molecular therapy will probably involve the application of multiple simultaneous (combinatorial) therapeutic modalities. The safety and efficiency of these in humans can only be judged by properly controlled therapeutic trials. PMID:11249660

  15. Stereotactic Radiosurgery for Glioblastoma.

    PubMed

    Redmond, Kristin J; Mehta, Minesh

    2015-01-01

    Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and one of the most aggressive of all human cancers. GBM tumors are highly infiltrative and relatively resistant to conventional therapies. Aggressive management of GBM using a combination of surgical resection, followed by fractionated radiotherapy and chemotherapy has been shown to improve overall survival; however, GBM tumors recur in the majority of patients and the disease is most often fatal. There is a need to develop new treatment regimens and technological innovations to improve the overall survival of GBM patients. The role of stereotactic radiosurgery (SRS) for the treatment of GBM has been explored and is controversial. SRS utilizes highly precise radiation techniques to allow dose escalation and delivery of ablative radiation doses to the tumor while minimizing dose to the adjacent normal structures. In some studies, SRS with concurrent chemotherapy has shown improved local control with acceptable toxicities in select GBM patients. However, because GBM is a highly infiltrative disease, skeptics argue that local therapies, such as SRS, do not improve overall survival. The purpose of this article is to review the literature regarding SRS in both newly diagnosed and recurrent GBM, to describe SRS techniques, potential eligible SRS candidates, and treatment-related toxicities. In addition, this article will propose promising areas for future research for SRS in the treatment of GBM. PMID:26848407

  16. Molecular mechanisms of the effect of TGF-β1 on U87 human glioblastoma cells

    PubMed Central

    Bryukhovetskiy, Igor; Shevchenko, Valeriy

    2016-01-01

    Glioblastoma multiforme (GBM) is the most widespread and aggressive type of primary brain tumor. The prognosis following diagnosis with GBM is poor, with a median survival time of 14 months. Tumor cell invasion, metastasis and proliferation are the major causes of mortality in patients with GBM. In order to develop effective GBM treatment methods it is necessary to identify novel targets involved in these processes. Recently, there has been increasing interest in investigating the signaling pathways involved in GBM development, and the transforming growth factor-β (TGF-β) signaling pathway is understood to be significant for regulating the behavior of GBM, as well as stimulating its invasion and metastatic development. Particular interest has been given to investigating the modulation of TGF-β-induced epithelial-to-mesenchymal transition (EMT); during this process, epithelial cells transdifferentiate into mobile cells with a mesenchymal phenotype. The induction of EMT increases the invasiveness of various types of carcinoma; however, the role of TGF-β in this process remains to be elucidated, particularly in the case of GBM. The current study presents a comparative proteome mapping of the U87 human glioblastoma cell line, with and without TGF-β1 treatment. Proteome analysis identified numerous proteins involved in the molecular mechanisms of GBM oncogenesis and TGF-β1 signaling in glioblastoma. The results of the present study facilitated the identification of novel potential markers of metastasis and candidates for targeted glioblastoma therapy, which may potentially be validated and used in clinical medicine to develop improved approaches for GBM diagnosis and treatment. PMID:27446475

  17. Decitabine nanoconjugate sensitizes human glioblastoma cells to temozolomide.

    PubMed

    Cui, Yi; Naz, Asia; Thompson, David H; Irudayaraj, Joseph

    2015-04-01

    In this study, we developed and characterized a delivery system for the epigenetic demethylating drug, decitabine, to sensitize temozolomide-resistant human glioblastoma multiforme (GBM) cells to alkylating chemotherapy. A poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) based nanoconjugate was fabricated to encapsulate decitabine and achieved a better therapeutic response in GBM cells than that with the free drug. After synthesis, the highly efficient uptake process and intracellular dynamics of this nanoconjugate were monitored by single-molecule fluorescence tools. Our experiments demonstrated that, under an acidic pH due to active glycolysis in cancer cells, the PLGA-PEG nanovector could release the conjugated decitabine at a faster rate, after which the hydrolyzed lactic acid and glycolic acid would further acidify the intracellular microenvironment, thus providing positive feedback to increase the effective drug concentration and realize growth inhibition. In temozolomide-resistant GBM cells, decitabine can potentiate the cytotoxic DNA alkylation by counteracting cytosine methylation and reactivating tumor suppressor genes, such as p53 and p21. Owing to the excellent internalization and endolysosomal escape enabled by the PLGA-PEG backbone, the encapsulated decitabine exhibited a better anti-GBM potential than that of free drug molecules. Hence, the synthesized nanoconjugate and temozolomide could act in synergy to deliver a more potent and long-term antiproliferative effect against malignant GBM cells.

  18. Decitabine Nano-conjugate Sensitizing Human Glioblastoma Cells to Temozolomide

    PubMed Central

    Cui, Yi; Naz, Asia; Thompson, David H.; Irudayaraj, Joseph

    2015-01-01

    In this study we developed and characterized a delivery system for the epigenetic demethylating drug, decitabine, to sensitize temozolomide-resistant human glioblastoma multiforme (GBM) cells to alkylating chemotherapy. A poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) based nano-conjugate was fabricated to encapsulate decitabine and achieved a better therapeutic response in GBM cells. After synthesis, the highly efficient uptake process and intracellular dynamics of this nano-conjugate was monitored by single-molecule fluorescence tools. Our experiments demonstrated that, under an acidic pH due to active glycolysis in cancer cells, the PLGA-PEG nano-vector could release the conjugated decitabine at a faster rate, after which the hydrolyzed lactic acid and glycolic acid would further acidify the intracellular microenvironment, thus providing a “positive feedback” to increase the effective drug concentration and realize growth inhibition. In temozolomide-resistant GBM cells, decitabine can potentiate the cytotoxic DNA alkylation by counteracting cytosine methylation and reactivating tumor suppressor genes, such as p53 and p21. Owing to excellent internalization and endo-lysosomal escape enabled by the PLGA-PEG backbone, the encapsulated decitabine exhibited a better anti-GBM potential than free drug molecules. Hence, the synthesized nano-conjugate and temozolomide could act in synergy to deliver a more potent and long-term anti-proliferation effect against malignant GBM cells. PMID:25751281

  19. Reversing the Warburg effect as a treatment for glioblastoma.

    PubMed

    Poteet, Ethan; Choudhury, Gourav Roy; Winters, Ali; Li, Wenjun; Ryou, Myoung-Gwi; Liu, Ran; Tang, Lin; Ghorpade, Anuja; Wen, Yi; Yuan, Fang; Keir, Stephen T; Yan, Hai; Bigner, Darell D; Simpkins, James W; Yang, Shao-Hua

    2013-03-29

    Glioblastoma multiforme (GBM), like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect. Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in GBM cell lines. MB decreases GBM cell proliferation and halts the cell cycle in S phase. Through activation of AMP-activated protein kinase, MB inactivates downstream acetyl-CoA carboxylase and decreases cyclin expression. Structure-activity relationship analysis demonstrated that toluidine blue O, an MB derivative with similar bioenergetic actions, exerts similar action in GBM cell proliferation. In contrast, two other MB derivatives, 2-chlorophenothiazine and promethazine, exert no effect on cellular bioenergetics and do not inhibit GBM cell proliferation. MB inhibits cell proliferation in both temozolomide-sensitive and -insensitive GBM cell lines. In a human GBM xenograft model, a single daily dosage of MB does not activate AMP-activated protein kinase signaling, and no tumor regression was observed. In summary, the current study provides the first in vitro proof of concept that reversal of Warburg effect might be a novel therapy for GBM.

  20. Role of Redox Status in Development of Glioblastoma

    PubMed Central

    Salazar-Ramiro, Aleli; Ramírez-Ortega, Daniela; Pérez de la Cruz, Verónica; Hérnandez-Pedro, Norma Y.; González-Esquivel, Dinora Fabiola; Sotelo, Julio; Pineda, Benjamín

    2016-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive neoplasia, prognosis remains dismal, and current therapy is mostly palliative. There are no known risk factors associated with gliomagenesis; however, it is well established that chronic inflammation in brain tissue induces oxidative stress in astrocytes and microglia. High quantities of reactive species of oxygen into the cells can react with several macromolecules, including chromosomal and mitochondrial DNA, leading to damage and malfunction of DNA repair enzymes. These changes bring genetic instability and abnormal metabolic processes, favoring oxidative environment and increase rate of cell proliferation. In GBM, a high metabolic rate and increased basal levels of reactive oxygen species play an important role as chemical mediators in the regulation of signal transduction, protecting malignant cells from apoptosis, thus creating an immunosuppressive environment. New redox therapeutics could reduce oxidative stress preventing cellular damage and high mutation rate accompanied by chromosomal instability, reducing the immunosuppressive environment. In addition, therapies directed to modulate redox rate reduce resistance and moderate the high rate of cell proliferation, favoring apoptosis of tumoral cells. This review describes the redox status in GBM, and how this imbalance could promote gliomagenesis through genomic and mitochondrial DNA damage, inducing the pro-oxidant and proinflammatory environment involved in tumor cell proliferation, resistance, and immune escape. In addition, some therapeutic agents that modulate redox status and might be advantageous in therapy against GBM are described. PMID:27199982

  1. Stable and Efficient Paclitaxel Nanoparticles for Targeted Glioblastoma Therapy

    PubMed Central

    Mu, Qingxin; Jeon, Mike; Hsiao, Meng-Hsuan; Patton, Victoria K.; Wang, Kui; Press, Oliver W.

    2015-01-01

    Development of efficient nanoparticles (NPs) for cancer therapy remains a challenge. NPs are required to have high stability, uniform size, sufficient drug loading, targeting capability, and ability to overcome drug resistance. In this study, we report the development of a nanoparticle formulation that can meet all these challenging requirements for targeted glioblastoma multiform (GBM) therapy. This multifunctional nanoparticle is composed of a polyethylene glycol (PEG) coated magnetic iron oxide NP conjugated with cyclodextrin (CD) and chlorotoxin (CTX) and loaded with fluorescein and paclitaxel (PTX) (IONP-PTX-CTX-FL). The physicochemical properties of the IONP-PTX-CTX-FL were characterized by TEM, dynamic light scattering (DLS), and HPLC. The cellular uptake of NPs was studied using flow cytometry and confocal microscopy. Cell viability and apoptosis were assessed with the Alamar Blue viability assay and flow cytometry, respectively. The IONP-PTX-CTX-FL had a uniform size of ~44 nm and high stability in cell culture medium. Importantly, the presence of CTX on NPs enhanced the uptake of the NPs by GBM cells and improved the efficacy of PTX in killing both GBM and GBM drug-resistant cells. The IONP-PTX-CTX-FL has demonstrated its great potential for brain cancer therapy and may also be used to deliver PTX to treat other cancers. PMID:25761648

  2. Stable and efficient Paclitaxel nanoparticles for targeted glioblastoma therapy.

    PubMed

    Mu, Qingxin; Jeon, Mike; Hsiao, Meng-Hsuan; Patton, Victoria K; Wang, Kui; Press, Oliver W; Zhang, Miqin

    2015-06-01

    Development of efficient nanoparticles (NPs) for cancer therapy remains a challenge. NPs are required to have high stability, uniform size, sufficient drug loading, targeting capability, and ability to overcome drug resistance. In this study, the development of a NP formulation that can meet all these challenging requirements for targeted glioblastoma multiform (GBM) therapy is reported. This multifunctional NP is composed of a polyethylene glycol-coated magnetic iron oxide NP conjugated with cyclodextrin and chlorotoxin (CTX) and loaded with fluorescein and paclitaxel (PTX) (IONP-PTX-CTX-FL). The physicochemical properties of the IONP-PTX-CTX-FL are characterized by transmission electron microscope, dynamic light scattering, and high-performance liquid chromatography. The cellular uptake of NPs is studied using flow cytometry and confocal microscopy. Cell viability and apoptosis are assessed with the Alamar Blue viability assay and flow cytometry, respectively. The IONP-PTX-CTX-FL had a uniform size of ≈44 nm and high stability in cell culture medium. Importantly, the presence of CTX on NPs enhanced the uptake of the NPs by GBM cells and improved the efficacy of PTX in killing both GBM and GBM drug-resistant cells. The IONP-PTX-CTX-FL demonstrated its great potential for brain cancer therapy and may also be used to deliver PTX to treat other cancers.

  3. Methionine Uptake and Required Radiation Dose to Control Glioblastoma

    SciTech Connect

    Iuchi, Toshihiko; Hatano, Kazuo; Uchino, Yoshio; Itami, Makiko; Hasegawa, Yuzo; Kawasaki, Koichiro; Sakaida, Tsukasa; Hara, Ryusuke

    2015-09-01

    Purpose: The purpose of this study was to retrospectively assess the feasibility of radiation therapy planning for glioblastoma multiforme (GBM) based on the use of methionine (MET) positron emission tomography (PET), and the correlation among MET uptake, radiation dose, and tumor control. Methods and Materials: Twenty-two patients with GBM who underwent MET-PET prior to radiation therapy were enrolled. MET uptake in 30 regions of interest (ROIs) from 22 GBMs, biologically effective doses (BEDs) for the ROIs and their ratios (MET uptake:BED) were compared in terms of whether the ROIs were controlled for >12 months. Results: MET uptake was significantly correlated with tumor control (odds ratio [OR], 10.0; P=.005); however, there was a higher level of correlation between MET uptake:BED ratio and tumor control (OR, 40.0; P<.0001). These data indicated that the required BEDs for controlling the ROIs could be predicted in terms of MET uptake; BED could be calculated as [34.0 × MET uptake] Gy from the optimal threshold of the MET uptake:BED ratio for tumor control. Conclusions: Target delineation based on MET-PET was demonstrated to be feasible for radiation therapy treatment planning. MET-PET could not only provide precise visualization of infiltrating tumor cells but also predict the required radiation doses to control target regions.

  4. Anti-Epidermal Growth Factor Receptor Gene Therapy for Glioblastoma

    PubMed Central

    Hicks, Martin J.; Chiuchiolo, Maria J.; Ballon, Douglas; Dyke, Jonathan P.; Aronowitz, Eric; Funato, Kosuke; Tabar, Viviane; Havlicek, David; Fan, Fan; Sondhi, Dolan; Kaminsky, Stephen M.; Crystal, Ronald G.

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial brain tumor in adults with a mean survival of 14 to 15 months. Aberrant activation of the epidermal growth factor receptor (EGFR) plays a significant role in GBM progression, with amplification or overexpression of EGFR in 60% of GBM tumors. To target EGFR expressed by GBM, we have developed a strategy to deliver the coding sequence for cetuximab, an anti-EGFR antibody, directly to the CNS using an adeno-associated virus serotype rh.10 gene transfer vector. The data demonstrates that single, local delivery of an anti-EGFR antibody by an AAVrh.10 vector coding for cetuximab (AAVrh.10Cetmab) reduces GBM tumor growth and increases survival in xenograft mouse models of a human GBM EGFR-expressing cell line and patient-derived GBM. AAVrh10.CetMab-treated mice displayed a reduction in cachexia, a significant decrease in tumor volume and a prolonged survival following therapy. Adeno-associated-directed delivery of a gene encoding a therapeutic anti-EGFR monoclonal antibody may be an effective strategy to treat GBM. PMID:27711187

  5. Association between SET expression and glioblastoma cell apoptosis and proliferation

    PubMed Central

    He, Kunyan; Shi, Lihong; Jiang, Tingting; Li, Qiang; Chen, Yao; Meng, Chuan

    2016-01-01

    Glioblastoma multiforme (GBM) was one of the first cancer types systematically studied at a genomic and transcriptomic level due to its high incidence and aggressivity; however, the detailed mechanism remains unclear, even though it is known that numerous cytokines are involved in the occurrence and development of GBM. The present study aimed to determine whether the SET gene has a role in human glioblastoma carcinogenesis. A total of 32 samples, including 18 cases of glioma, 2 cases of meningioma and 12 normal brain tissue samples, were detected using the streptavidin-peroxidase method through immunohistochemistry. To reduce SET gene expression in U251 and U87MG cell lines, the RNA interference technique was used and transfection with small interfering (si)RNA of the SET gene was performed. Cell apoptosis was detected by flow cytometry, cell migration was examined by Transwell migration assay and cell proliferation was determined by Cell Counting Kit-8. SET, Bcl-2, Bax and caspase-3 mRNA and protein expression levels were detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Positive protein expression of SET was observed in the cell nucleus, with the expression level of SET significantly higher in glioma tissues compared with normal brain tissue (P=0.001). Elevated expression of SET was significantly associated with gender (P=0.002), tumors classified as World Health Organization grade II (P=0.031), III (P=0.003) or IV (P=0.001), and moderately (P=0.031) or poorly differentiated (P=0.001) tumors. Compared with the negative and non-treatment (blank) control cells, SET gene expression was significantly inhibited (P=0.006 and P<0.001), cell apoptosis was significantly increased (P=0.001 and P<0.001), cell proliferation was significantly inhibited (P=0.002 and P=0.015), and cell migration was significantly decreased (P=0.001 and P=0.001) in siRNA-transfected U87MG−SET and U251−SET cells, respectively. In

  6. Significance of Epidermal Growth Factor Receptor in the Radiation Resistance of Glioblastoma Tumors

    NASA Astrophysics Data System (ADS)

    Petrás, Miklós; Lajtos, Tamás; Pintye, Éva; Feuerstein, Burt G.; Szöllősi, János; Vereb, György

    2008-12-01

    In the United States, a dramatically increased incidence and mortality of brain tumors have been observed over the past decades. Of the ˜44 thousand new cases of primary malignant and benign brain tumors diagnosed per year, high grade astrocytomas or multiform glioblastomas show particularly bad prognosis in spite of therapeutic developments. Current management of multiform glioblastoma includes the most extensive surgical resection possible, followed by adjuvant radio- and chemotherapy. However, treatment is frequently hampered by decreased radiosensitivity of the tumor. Recent studies revealed that subpopulations of glioblastoma cells show amplified checkpoint activation of the cell cycle upon ionizing radiation, which induces overactivation of DNA repair processes and leads to maintained proliferation rate as well as clinically observed radioresistance and recurrence of the tumor over time. In addition, overexpression of some transmembrane receptors has also been implicated in radioresistance. However, the role of the overexpressed proteins can only be interpreted reliably if their multi-faceted molecular interactions are properly characterized. Thus, based on recent evidence for the functional crosstalk between certain cell adhesion molecules and receptor tyrosine kinases, we have examined the molecular interactions of the receptor tyrosine kinase EGFR and the cell adhesion molecule β1-integrin using flow cytometric and microscopic fluorescence resosnance energy transfer (FRET) measurements on two cellular model systems showing similar expression patterns to low and high grade astrocytomas. On the one hand, U251 glioblastoma clones established by introducing varying amounts of extra chromosome 7 into the cells, and on the other hand stable, high and low EGFR expressing transfenctant U251 NCI sublines were investigated. The results revealed that increased EGFR and β1-integrin expression levels correlate with stronger EGFR—β1-integrin heteroassociation

  7. Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma.

    PubMed

    Setua, Sonali; Ouberai, Myriam; Piccirillo, Sara G; Watts, Colin; Welland, Mark

    2014-09-21

    Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies.

  8. Stopping cancer in its tracks: using small molecular inhibitors to target glioblastoma migrating cells.

    PubMed

    Mattox, Austin K; Li, Jing; Adamson, David C

    2012-12-01

    Glioblastoma multiforme (GBM) represents one of the most common aggressive types of primary brain tumors. Despite advances in surgical resection, novel neuroimaging procedures, and the most recent adjuvant radiotherapy and chemotherapy, the median survival after diagnosis is about 12-14 months. Targeting migrating GBM cells is a key research strategy in the fight against this devastating cancer. Though the vast majority of the primary tumor focus can be surgically resected, these migrating cells are responsible for its universal recurrence. Numerous strategies and technologies are being explored to target migrating glioma cells, with small molecular inhibitors as one of the most commonly studied. Small molecule inhibitors, such as protein kinase inhibitors, phosphorylation site inhibitors, protease inhibitors, and antisense oligonucleotides show promise in slowing the progression of this disease. A better understanding of these small molecule inhibitors and how they target various extra- and intracellular signaling pathways may eventually lead to a cure for GBM.

  9. Extracranial metastatic glioblastoma: Appearance on thallium-201-chloride/technetium-99m-HMPAO SPECT images

    SciTech Connect

    Carvalho, P.A.; Schwartz, R.B.; Alexander, E. III; Loeffler, J.S.; Zimmerman, R.E.; Nagel, J.S.; Holman, B.L. )

    1991-02-01

    Sequential thallium-201-chloride and technetium-99m-hexamethylpropyleneamine oxime single-photon emission computed tomography (SPECT) images were obtained in a patient with extracranial metastatic glioblastoma multiforme. Thallium-201 uptake was high (three times the scalp background) in all pathologically confirmed extracranial metastases and moderate (1.6 times scalp background) intracranially, where most biopsy specimens showed gliosis with scattered atypical astrocytes. Technetium-99m-HMPAO uptake was decreased intracranially in the right frontal and parietal lobes which had been irradiated. It was also decreased in one well-encapsulated scalp lesion and high in another scalp mass with less defined borders. Possible mechanisms of tumor uptake of these agents are reviewed.

  10. Intractable vomiting from glioblastoma metastatic to the fourth ventricle: three case studies.

    PubMed Central

    Cohen, Zvi R.; Hassenbusch, Samuel J.; Maor, Moshe H.; Pfeffer, Raphael M.; Ram, Zvi

    2002-01-01

    Dissemination of malignant glioma to the fourth ventricle with metastatic deposits and intractable vomiting is rare. Leptomeningeal extension of malignant glioma is an uncommon condition that has been reported in patients with end-stage disease and is usually unresponsive to any treatment modality. We describe 3 patients with progressing recurrent glioblastoma multiforme in whom leptomeningeal invasion manifested itself as intractable vomiting due to tumor metastases in the floor of the fourth ventricle. All patients received additional radiation therapy focused to the posterior fossa, with complete resolution of vomiting occurring within 10 days after irradiation. The remission of symptoms in these patients persisted until their death 3-4 months after the repeat radiation therapy. These reports indicate that additional focused radiation should be considered because of its significant therapeutic effect in alleviating intractable nausea and vomiting in patients with glioma metastasized to the posterior fossa. PMID:11916505

  11. Nondestructive assay confirmatory assessment experiments: mixed oxide

    SciTech Connect

    Lemming, J.F.

    1980-04-30

    The confirmatory assessment experiments demonstrate traceable nondestructive assay (NDA) measurements of plutonium in mixed oxide powder using commercially available spontaneous-fission assay systems. The experiments illustrate two major concepts: the production of calibration materials using calorimetric assay, and the use of paired measurements for measurement assurance. Two batches of well-characterized mixed oxide powder were used to establish the random and systematic error components. The major components of an NDA measurement assurance technique to establish and maintain traceability are identified and their functions are demonstrated. 20 refs., 10 figs., 10 tabs.

  12. STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma

    SciTech Connect

    Geng Ling; Shinohara, Eric T.; Kim, Dong; Tan Jiahuai; Osusky, Kate; Shyr, Yu; Hallahan, Dennis E. . E-mail: Dennis.Hallahan@mcmail.vanderbilt.edu

    2006-01-01

    Purpose: Glioblastoma multiforme (GBM) is a devastating brain neoplasm that is essentially incurable. Although radiation therapy prolongs survival, GBMs progress within areas of irradiation. Recent studies in invertebrates have shown that STI571 (Gleevec; Novartis, East Hanover, NJ) enhances the cytotoxicity of ionizing radiation. In the present study, the effectiveness of STI571 in combination with radiation was studied in mouse models of GBM. Methods and Materials: Murine GL261 and human D54 GBM cell lines formed tumors in brains and hind limbs of C57BL6 and nude mice, respectively. GL261 and D54 cells were treated with 5 {mu}mol/L of STI571 for 1 h and/or irradiated with 3 Gy. Protein was analyzed by Western immunoblots probed with antibodies to caspase 3, cleaved caspase 3, phospho-Akt, Akt, and platelet-derived growth factor receptor (PDGFR) {alpha} and {beta}. Tumor volumes were assessed in mice bearing GL261 or D54 tumors treated with 21 Gy administered in seven fractionated doses. Histologic sections from STI571-treated mice were stained with phospho-Akt and phospho-PDGFR {beta} antibodies. Kaplan-Meier survival curves were used to study the response of mice bearing intracranial implants of GL261. Results: STI571 penetrated the blood-brain barrier, which resulted in a reduction in phospho-PDGFR in GBM. STI571-induced apoptosis in GBM was significantly enhanced by irradiation. STI571 combined with irradiation induced caspase 3 cleavage in GBM cells. Glioblastoma multiforme response to therapy correlated with an increase in tumor growth delay and survival when STI571 was administered in conjunction with daily irradiation. Conclusion: These findings suggest that STI571 has the potential to augment radiotherapy and thereby improve median survival.

  13. Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma

    NASA Astrophysics Data System (ADS)

    Setua, Sonali; Ouberai, Myriam; Piccirillo, Sara G.; Watts, Colin; Welland, Mark

    2014-08-01

    Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies.Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies. Electronic supplementary information (ESI) available: Additional figures. See DOI: 10.1039/c

  14. Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro

    SciTech Connect

    Bernhart, Eva; Damm, Sabine; Wintersperger, Andrea; DeVaney, Trevor; Zimmer, Andreas; Raynham, Tony; Ireson, Christopher; Sattler, Wolfgang

    2013-08-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which, despite combined modality treatment, reoccurs and is invariably fatal for affected patients. Recently, a member of the serine/threonine protein kinase D (PRKD) family, PRKD2, was shown to be a potent mediator of glioblastoma growth. Here we studied the role of PRKD2 in U87MG glioblastoma cell migration and invasion in response to sphingosine-1-phosphate (S1P), an activator of PRKD2 and a GBM mitogen. Time-lapse microscopy demonstrated that random cell migration was significantly diminished in response to PRKD2 silencing. The pharmacological PRKD family inhibitor CRT0066101 decreased chemotactic migration and invasion across uncoated or matrigel-coated Transwell inserts. Silencing of PRKD2 attenuated migration and invasion of U87MG cells even more effectively. In terms of downstream signaling, CRT0066101 prevented PRKD2 autophosphorylation and inhibited p44/42 MAPK and to a smaller extent p54/46 JNK and p38 MAPK activation. PRKD2 silencing impaired activation of p44/42 MAPK and p54/46 JNK, downregulated nuclear c-Jun protein levels and decreased c-Jun{sup S73} phosphorylation without affecting the NFκB pathway. Finally, qPCR array analyses revealed that silencing of PRKD2 downregulates mRNA levels of integrin alpha-2 and -4 (ITGA2 and -4), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and matrix metallopeptidase 1 (MMP1). Findings of the present study identify PRKD2 as a potential target to interfere with glioblastoma cell migration and invasion, two major determinants contributing to recurrence of glioblastoma after multimodality treatment. Highlights: • Sphingosine-1-phosphate induces glioma cell migration and invasion. • Part of the effects is mediated by protein kinase D2 (PRKD2) activation. • Inactivation of PRKD2 attenuates glioblastoma cell migration and invasion. • Both, RNAi and pharmacological inhibition of PRKD2 inhibits MAPK

  15. Corticosteroids compromise survival in glioblastoma.

    PubMed

    Pitter, Kenneth L; Tamagno, Ilaria; Alikhanyan, Kristina; Hosni-Ahmed, Amira; Pattwell, Siobhan S; Donnola, Shannon; Dai, Charles; Ozawa, Tatsuya; Chang, Maria; Chan, Timothy A; Beal, Kathryn; Bishop, Andrew J; Barker, Christopher A; Jones, Terreia S; Hentschel, Bettina; Gorlia, Thierry; Schlegel, Uwe; Stupp, Roger; Weller, Michael; Holland, Eric C; Hambardzumyan, Dolores

    2016-05-01

    Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten

  16. Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy

    PubMed Central

    Verlut, Clotilde; Mouillet, Guillaume; Magnin, Eloi; Buffet-Miny, Joëlle; Viennet, Gabriel; Cattin, Françoise; Billon-Grand, Nora Clelia; Bonnet, Emilie; Servagi-Vernat, Stéphanie; Godard, Joël; Billon-Grand, Romain; Petit, Antoine; Moulin, Thierry; Cals, Laurent; Pivot, Xavier; Curtit, Elsa

    2016-01-01

    INTRODUCTION Temozolomide and concomitant radiotherapy followed by temozolomide has been used as a standard therapy for the treatment of newly diagnosed glioblastoma multiform since 2005. A search for prognostic factors was conducted in patients with glioblastoma routinely treated by this strategy in our institution. METHODS This retrospective study included all patients with histologically proven glioblastoma diagnosed between June 1, 2005, and January 1, 2012, in the Franche-Comté region and treated by radiotherapy (daily fractions of 2 Gy for a total of 60 Gy) combined with temozolomide at a dose of 75 mg/m2 per day, followed by six cycles of maintenance temozolomide (150–200 mg/m2, five consecutive days per month). The primary aim was to identify prognostic factors associated with overall survival (OS) in this cohort of patients. RESULTS One hundred three patients were included in this study. The median age was 64 years. The median OS was 13.7 months (95% confidence interval, 12.5–15.9 months). In multivariate analysis, age over 65 years (hazard ratio [HR] = 1.88; P = 0.01), Medical Research Council (MRC) scale 3–4 (HR = 1.62; P = 0.038), and occurrence of postoperative complications (HR = 2.15; P = 0.028) were associated with unfavorable OS. CONCLUSIONS This study identified three prognostic factors in patients with glioblastoma eligible to the standard chemotherapy and radiotherapy treatment. Age over 65 years, MRC scale 3–4, and occurrence of postoperative complications were associated with unfavorable OS. A simple clinical evaluation including these three factors enables to estimate the patient prognosis. MRC neurological scale could be a useful, quick, and simple measure to assess neurological status in glioblastoma patients. PMID:27559302

  17. Glioblastoma care in the elderly.

    PubMed

    Jordan, Justin T; Gerstner, Elizabeth R; Batchelor, Tracy T; Cahill, Daniel P; Plotkin, Scott R

    2016-01-15

    Glioblastoma is common among elderly patients, a group in which comorbidities and a poor prognosis raise important considerations when designing neuro-oncologic care. Although the standard of care for nonelderly patients with glioblastoma includes maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide, the safety and efficacy of these modalities in elderly patients are less certain given the population's underrepresentation in many clinical trials. The authors reviewed the clinical trial literature for reports on the treatment of elderly patients with glioblastoma to provide evidence-based guidance for practitioners. In elderly patients with glioblastoma, there is a survival advantage for those who undergo maximal safe resection, which likely includes an incremental benefit with increasing completeness of resection. Radiotherapy extends survival in selected patients, and hypofractionation appears to be more tolerable than standard fractionation. In addition, temozolomide chemotherapy is safe and extends the survival of patients with tumors that harbor O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The combination of standard radiation with concurrent and adjuvant temozolomide has not been studied in this population. Although many questions remain unanswered regarding the treatment of glioblastoma in elderly patients, the available evidence provides a framework on which providers may base individual treatment decisions. The importance of tumor biomarkers is increasingly apparent in elderly patients, for whom the therapeutic efficacy of any treatment must be weighed against its potential toxicity. MGMT promoter methylation status has specifically demonstrated utility in predicting the efficacy of temozolomide and should be considered in treatment decisions when possible. Cancer 2016;122:189-197. © 2015 American Cancer Society. PMID:26618888

  18. Erythema multiforme-like eruption due to carbamates and thiuram.

    PubMed

    Leis-Dosil, Vicente M; Campos-Domínguez, Minia; Zamberk-Majlis, Pamela E; Suárez-Fernández, Ricardo M; Lázaro-Ochaita, Pablo

    2006-01-01

    Report of a case of erythema multiforme-like eruption due to the use of rubber gloves. After several complementary studies, including epicutaneous and skin prick tests, we concluded that the eruption was secondary to sensitization to carbamates and thiuram. The main differential diagnosis in this case was allergic contact dermatitis to latex in natural rubber gloves. This entity is less frequent than might be expected, because it is usually due to intermediate chemical compounds used in rubber manufacturing, such as vulcanization accelerators; among of these latter compounds are thiurams and carbamates. Erythema multiforme-like eruption is a rare manifestation of contact dermatitis. Several cases have been reported, most of which have been due to contact with plants, metals or topical non-steroidal anti-inflammatory drugs. Its mechanism is still unclear, but it seems to be a type IV hypersensitivity reaction. PMID:16750123

  19. Effects of single or combined treatments with radiation and chemotherapy on survival and danger signals expression in glioblastoma cell lines.

    PubMed

    Pasi, Francesca; Paolini, Alessandro; Nano, Rosanna; Di Liberto, Riccardo; Capelli, Enrica

    2014-01-01

    The success of chemo- and radiotherapy in glioblastoma multiforme, the most common and lethal primary brain tumour, could rely on the induction of immunogenic tumour cell death and on the induction of anticancer immune response. In this study we investigated cell survival to single treatments or combination of X-rays and temozolomide in glioblastoma cell lines (T98G and U251MG) and we attempted to identify danger signals (HMGB1 and HSP70) released by dying cells in the microenvironment that could activate antitumour immunity contributing to the therapeutic efficacy of conventional treatments. Our data suggest that HSP70 translocates from cytoplasm to extracellular environment after an increase in radiation dose and HMGB1 translocates from the nucleus to the cytoplasm and subsequently is released into the extracellular space, confirming a role of these proteins as signals released after radiation-induced damage in glioblastoma cells. We also could state that TMZ had limited effectiveness in activating HMGB1 and HSP70 signalling and, instead, an adjuvant effect was observed in some combined treatments, depending on schedule, cell line, and timing. A big challenge in tumour therapy is, therefore, to identify the most beneficial combination and chronology of multiple treatment options to contribute to the improvement of the therapeutic outcome.

  20. A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation.

    PubMed

    Chen, Xishan; Tai, Lingyu; Gao, Jie; Qian, Jianchang; Zhang, Mingfei; Li, Beibei; Xie, Cao; Lu, Linwei; Lu, Wuyuan; Lu, Weiyue

    2015-11-28

    Antagonizing MDM2 and MDMX to activate the tumor suppressor protein p53 is an attractive therapeutic paradigm for the treatment of glioblastoma multiforme (GBM). However, challenges remain with respect to the poor ability of p53 activators to efficiently cross the blood-brain barrier and/or blood-brain tumor barrier and to specifically target tumor cells. To circumvent these problems, we developed a cyclic RGD peptide-conjugated poly(ethylene glycol)-co-poly(lactic acid) polymeric micelle (RGD-M) that carried a stapled peptide antagonist of both MDM2 and MDMX (sPMI). The peptide-carrying micelle RGD-M/sPMI was prepared via film-hydration method with high encapsulation efficiency and loading capacity as well as ideal size distribution. Micelle encapsulation dramatically increased the solubility of sPMI, thus alleviating its serum sequestration. In vitro studies showed that RGD-M/sPMI efficiently inhibited the proliferation of glioma cells in the presence of serum by activating the p53 signaling pathway. Further, RGD-M/sPMI exerted potent tumor growth inhibitory activity against human glioblastoma in nude mouse xenograft models. Importantly, the combination of RGD-M/sPMI and temozolomide--a standard chemotherapy drug for GBM increased antitumor efficacy against glioblastoma in experimental animals. Our results validate a combination therapy using p53 activators with temozolomide as a more effective treatment for GBM. PMID:26428461

  1. Factorial invariance in multilevel confirmatory factor analysis.

    PubMed

    Ryu, Ehri

    2014-02-01

    This paper presents a procedure to test factorial invariance in multilevel confirmatory factor analysis. When the group membership is at level 2, multilevel factorial invariance can be tested by a simple extension of the standard procedure. However level-1 group membership raises problems which cannot be appropriately handled by the standard procedure, because the dependency between members of different level-1 groups is not appropriately taken into account. The procedure presented in this article provides a solution to this problem. This paper also shows Muthén's maximum likelihood (MUML) estimation for testing multilevel factorial invariance across level-1 groups as a viable alternative to maximum likelihood estimation. Testing multilevel factorial invariance across level-2 groups and testing multilevel factorial invariance across level-1 groups are illustrated using empirical examples. SAS macro and Mplus syntax are provided.

  2. Glucose transport: meeting the metabolic demands of cancer, and applications in glioblastoma treatment

    PubMed Central

    Labak, Collin M; Wang, Paul Y; Arora, Rishab; Guda, Maheedhara R; Asuthkar, Swapna; Tsung, Andrew J; Velpula, Kiran K

    2016-01-01

    GLUT1, and to a lesser extent, GLUT3, appear to be interesting targets in the treatment of glioblastoma multiforme. The current review aims to give a brief history of the scientific community’s understanding of these glucose transporters and to relate their importance to the metabolic changes that occur as a result of cancer. One of the primary changes that occurs in cancer, the Warburg Effect, is characterized by an extreme shift toward glycolysis from the usual reliance on oxidative phosphorylation and is currently being investigated to target the upstream and downstream factors responsible for Warburg-induced changes. Further, it aims to explain the differential expression of GLUT1 and GLUT3 in glioblastoma tissue, and how these modulations in expression can serve as targets to restore a more normal metabolism. Additionally, hypoxia-induced factor-1α’s (HIF1α) role in a number of transcriptional changes typical to GBM will be discussed, including its role in GLUT upregulation. Finally, the four known subtypes of GBM [proneural, neural, mesenchymal, and classical] will be characterized in order to discuss how metabolic changes differ in each subtype. These changes have the potential to be selectively targeted in order to provide specificity to the clinical treatment options in GBM. PMID:27648352

  3. The role of intra-arterial chemotherapy as an adjuvant treatment for glioblastoma.

    PubMed

    Theodotou, Christian; Shah, Ashish H; Hayes, Seth; Bregy, Amade; Johnson, Jeremiah N; Aziz-Sultan, Mohammad A; Komotar, Ricardo J

    2014-08-01

    Glioblastoma multiforme (GBM) is an aggressive tumor with poor survival outcomes and limited treatment options. We conducted a literature review to compare the survival outcomes of intra-arterial (IA) and intravenous (IV) chemotherapy delivery for GBM. Nine studies of IA chemotherapy infusion with 301 total patients met our criteria for inclusion and three studies contained IV treatment groups for comparison (n = 230 for IA, n = 71 for IV). The studies were grouped by either using newly diagnosed or recurrent GBM patients. In the newly diagnosed group, IV chemotherapy produced a statistically higher median overall survival (MOS; 16.3 months) compared with IA treatment (14.02 months). However, the total number of adverse events in IA chemotherapy was 1.08 per patient whereas for IV it was higher at 1.54 events per patient. Our recurrent GBM group includes only patients treated with IA chemotherapy which resulted in an average MOS of 10.84 months. This group had 2.7 adverse events per patient but no IV group is available for comparison. Historically, the survival of patients with recurrent GBM ranges from 3 to 9 months (Gil-Gil et al. Bevacizumab for the treatment of glioblastoma. Clin Med Insights Oncol 2013;7:123-35). For this reason, we believe IA chemotherapy to be a viable methodology in recurrent GBM patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications. PMID:24432794

  4. Disrupting the PIKE-A/Akt interaction inhibits glioblastoma cell survival, migration, invasion and colony formation

    PubMed Central

    Qi, Q; He, K; Liu, X; Pham, C; Meyerkord, C; Fu, H; Ye, K

    2013-01-01

    The cyclin-dependent kinase 4 (CDK4) amplicon is frequently amplified in numerous human cancers including gliomas. PIKE-A, a proto-oncogene that is one of the important components of the CDK4 amplicon, binds to and enhances the kinase activity of Akt, thereby promoting cancer progression. To define the roles of the PIKE-A/Akt interaction in glioblastoma multiform (GBM) progression, we used biochemical protein/protein interaction (PPI) assays and live cell fluorescence-based protein complementation assays to search for small peptide antagonist from these proteins that were able to block their interaction. Here, we show that disruption of the interaction between PIKE-A and Akt by the small peptides significantly reduces glioblastoma cell proliferation, colony formation, migration and invasion. Disruption of PIKE-A/Akt association potently suppressed GBM cell proliferation and sensitized the cells to two clinical drugs that are currently used to treat GBM. Interestingly, GBM cells containing the CDK4 amplicon were more responsive to the inhibition of the PIKE-A/Akt interaction than GBM cells lacking this amplicon. Taken together, our findings provide proof-of-principle that blocking a PPI that is essential for cancer progression provides a valuable strategy for therapeutic discovery. PMID:22450747

  5. Glucose transport: meeting the metabolic demands of cancer, and applications in glioblastoma treatment

    PubMed Central

    Labak, Collin M; Wang, Paul Y; Arora, Rishab; Guda, Maheedhara R; Asuthkar, Swapna; Tsung, Andrew J; Velpula, Kiran K

    2016-01-01

    GLUT1, and to a lesser extent, GLUT3, appear to be interesting targets in the treatment of glioblastoma multiforme. The current review aims to give a brief history of the scientific community’s understanding of these glucose transporters and to relate their importance to the metabolic changes that occur as a result of cancer. One of the primary changes that occurs in cancer, the Warburg Effect, is characterized by an extreme shift toward glycolysis from the usual reliance on oxidative phosphorylation and is currently being investigated to target the upstream and downstream factors responsible for Warburg-induced changes. Further, it aims to explain the differential expression of GLUT1 and GLUT3 in glioblastoma tissue, and how these modulations in expression can serve as targets to restore a more normal metabolism. Additionally, hypoxia-induced factor-1α’s (HIF1α) role in a number of transcriptional changes typical to GBM will be discussed, including its role in GLUT upregulation. Finally, the four known subtypes of GBM [proneural, neural, mesenchymal, and classical] will be characterized in order to discuss how metabolic changes differ in each subtype. These changes have the potential to be selectively targeted in order to provide specificity to the clinical treatment options in GBM.

  6. Glucose transport: meeting the metabolic demands of cancer, and applications in glioblastoma treatment.

    PubMed

    Labak, Collin M; Wang, Paul Y; Arora, Rishab; Guda, Maheedhara R; Asuthkar, Swapna; Tsung, Andrew J; Velpula, Kiran K

    2016-01-01

    GLUT1, and to a lesser extent, GLUT3, appear to be interesting targets in the treatment of glioblastoma multiforme. The current review aims to give a brief history of the scientific community's understanding of these glucose transporters and to relate their importance to the metabolic changes that occur as a result of cancer. One of the primary changes that occurs in cancer, the Warburg Effect, is characterized by an extreme shift toward glycolysis from the usual reliance on oxidative phosphorylation and is currently being investigated to target the upstream and downstream factors responsible for Warburg-induced changes. Further, it aims to explain the differential expression of GLUT1 and GLUT3 in glioblastoma tissue, and how these modulations in expression can serve as targets to restore a more normal metabolism. Additionally, hypoxia-induced factor-1α's (HIF1α) role in a number of transcriptional changes typical to GBM will be discussed, including its role in GLUT upregulation. Finally, the four known subtypes of GBM [proneural, neural, mesenchymal, and classical] will be characterized in order to discuss how metabolic changes differ in each subtype. These changes have the potential to be selectively targeted in order to provide specificity to the clinical treatment options in GBM. PMID:27648352

  7. Model Misspecification and Invariance Testing Using Confirmatory Factor Analytic Procedures

    ERIC Educational Resources Information Center

    French, Brian F.; Finch, W. Holmes

    2011-01-01

    Confirmatory factor analytic procedures are routinely implemented to provide evidence of measurement invariance. Current lines of research focus on the accuracy of common analytic steps used in confirmatory factor analysis for invariance testing. However, the few studies that have examined this procedure have done so with perfectly or near…

  8. Temozolomide downregulates P-glycoprotein expression in glioblastoma stem cells by interfering with the Wnt3a/glycogen synthase-3 kinase/β-catenin pathway

    PubMed Central

    Riganti, Chiara; Salaroglio, Iris Chiara; Caldera, Valentina; Campia, Ivana; Kopecka, Joanna; Mellai, Marta; Annovazzi, Laura; Bosia, Amalia; Ghigo, Dario; Schiffer, Davide

    2013-01-01

    Background Glioblastoma multiforme stem cells display a highly chemoresistant phenotype, whose molecular basis is poorly known. We aim to clarify this issue and to investigate the effects of temozolomide on chemoresistant stem cells. Methods A panel of human glioblastoma cultures, grown as stem cells (neurospheres) and adherent cells, was used. Results Neurospheres had a multidrug resistant phenotype compared with adherent cells. Such chemoresistance was overcome by apparently noncytotoxic doses of temozolomide, which chemosensitized glioblastoma cells to doxorubicin, vinblastine, and etoposide. This effect was selective for P-glycoprotein (Pgp) substrates and for stem cells, leading to an investigation of whether there was a correlation between the expression of Pgp and the activity of typical stemness pathways. We found that Wnt3a and ABCB1, which encodes for Pgp, were both highly expressed in glioblastoma stem cells and reduced by temozolomide. Temozolomide-treated cells had increased methylation of the cytosine–phosphate–guanine islands in the Wnt3a gene promoter, decreased expression of Wnt3a, disrupted glycogen synthase-3 kinase/β-catenin axis, reduced transcriptional activation of ABCB1, and a lower amount and activity of Pgp. Wnt3a overexpression was sufficient to transform adherent cells into neurospheres and to simultaneously increase proliferation and ABCB1 expression. On the contrary, glioblastoma stem cells silenced for Wnt3a lost the ability to form neurospheres and reduced at the same time the proliferation rate and ABCB1 levels. Conclusions Our work suggests that Wnt3a is an autocrine mediator of stemness, proliferation, and chemoresistance in human glioblastoma and that temozolomide may chemosensitize the stem cell population by downregulating Wnt3a signaling. PMID:23897632

  9. Heterogeneous glioblastoma cell cross-talk promotes phenotype alterations and enhanced drug resistance.

    PubMed

    Motaln, Helena; Koren, Ana; Gruden, Kristina; Ramšak, Živa; Schichor, Christian; Lah, Tamara T

    2015-12-01

    Glioblastoma multiforme is the most lethal of brain cancer, and it comprises a heterogeneous mixture of functionally distinct cancer cells that affect tumor progression. We examined the U87, U251, and U373 malignant cell lines as in vitro models to determine the impact of cellular cross-talk on their phenotypic alterations in co-cultures. These cells were also studied at the transcriptome level, to define the mechanisms of their observed mutually affected genomic stability, proliferation, invasion and resistance to temozolomide. This is the first direct demonstration of the neural and mesenchymal molecular fingerprints of U87 and U373 cells, respectively. U87-cell conditioned medium lowered the genomic stability of U373 (U251) cells, without affecting cell proliferation. In contrast, upon exposure of U87 cells to U373 (U251) conditioned medium, U87 cells showed increased genomic stability, decreased proliferation rates and increased invasion, due to a plethora of produced cytokines identified in the co-culture media. This cross talk altered the expression 264 genes in U87 cells that are associated with proliferation, inflammation, migration, and adhesion, and 221 genes in U373 cells that are associated with apoptosis, the cell cycle, cell differentiation and migration. Indirect and direct co-culturing of U87 and U373 cells showed mutually opposite effects on temozolomide resistance. In conclusion, definition of transcriptional alterations of distinct glioblastoma cells upon co-culturing provides better understanding of the mechanisms of glioblastoma heterogeneity, which will provide the basis for more informed glioma treatment in the future. PMID:26517510

  10. Heterogeneous glioblastoma cell cross-talk promotes phenotype alterations and enhanced drug resistance

    PubMed Central

    Motaln, Helena; Koren, Ana; Gruden, Kristina; Ramšak, Živa; Schichor, Christian; Lah, Tamara T.

    2015-01-01

    Glioblastoma multiforme is the most lethal of brain cancer, and it comprises a heterogeneous mixture of functionally distinct cancer cells that affect tumor progression. We examined the U87, U251, and U373 malignant cell lines as in vitro models to determine the impact of cellular cross-talk on their phenotypic alterations in co-cultures. These cells were also studied at the transcriptome level, to define the mechanisms of their observed mutually affected genomic stability, proliferation, invasion and resistance to temozolomide. This is the first direct demonstration of the neural and mesenchymal molecular fingerprints of U87 and U373 cells, respectively. U87-cell conditioned medium lowered the genomic stability of U373 (U251) cells, without affecting cell proliferation. In contrast, upon exposure of U87 cells to U373 (U251) conditioned medium, U87 cells showed increased genomic stability, decreased proliferation rates and increased invasion, due to a plethora of produced cytokines identified in the co-culture media. This cross talk altered the expression 264 genes in U87 cells that are associated with proliferation, inflammation, migration, and adhesion, and 221 genes in U373 cells that are associated with apoptosis, the cell cycle, cell differentiation and migration. Indirect and direct co-culturing of U87 and U373 cells showed mutually opposite effects on temozolomide resistance. In conclusion, definition of transcriptional alterations of distinct glioblastoma cells upon co-culturing provides better understanding of the mechanisms of glioblastoma heterogeneity, which will provide the basis for more informed glioma treatment in the future. PMID:26517510

  11. Glioblastoma: A Pathogenic Crosstalk between Tumor Cells and Pericytes

    PubMed Central

    Redondo-Garcia, Carolina; Martinez, Salvador

    2014-01-01

    Cancers likely originate in progenitor zones containing stem cells and perivascular stromal cells. Much evidence suggests stromal cells play a central role in tumor initiation and progression. Brain perivascular cells (pericytes) are contractile and function normally to regulate vessel tone and morphology, have stem cell properties, are interconvertible with macrophages and are involved in new vessel formation during angiogenesis. Nevertheless, how pericytes contribute to brain tumor infiltration is not known. In this study we have investigated the underlying mechanism by which the most lethal brain cancer, Glioblastoma Multiforme (GBM) interacts with pre-existing blood vessels (co-option) to promote tumor initiation and progression. Here, using mouse xenografts and laminin-coated silicone substrates, we show that GBM malignancy proceeds via specific and previously unknown interactions of tumor cells with brain pericytes. Two-photon and confocal live imaging revealed that GBM cells employ novel, Cdc42-dependent and actin-based cytoplasmic extensions, that we call flectopodia, to modify the normal contractile activity of pericytes. This results in the co-option of modified pre-existing blood vessels that support the expansion of the tumor margin. Furthermore, our data provide evidence for GBM cell/pericyte fusion-hybrids, some of which are located on abnormally constricted vessels ahead of the tumor and linked to tumor-promoting hypoxia. Remarkably, inhibiting Cdc42 function impairs vessel co-option and converts pericytes to a phagocytic/macrophage-like phenotype, thus favoring an innate immune response against the tumor. Our work, therefore, identifies for the first time a key GBM contact-dependent interaction that switches pericyte function from tumor-suppressor to tumor-promoter, indicating that GBM may harbor the seeds of its own destruction. These data support the development of therapeutic strategies directed against co-option (preventing incorporation and

  12. Erythema Multiforme as a Result of Orf Disease; a Case Report

    PubMed Central

    Biazar, Tahmine; shokri, Mehran; Hosseinnia, Hajar; Bayani, Masomeh

    2016-01-01

    Orf is a mucocutaneous disease that occurs when non-intact skin comes into contact with contaminated sheep saliva. The lesions may complicate to lymphangitis or secondary bacterial infection, but systemic complications such as erythema multiforme, maculopapular rash, and generalized lymphadenopathy are rare. In this paper, we present two cases of erythema multiforme following Orf disease. PMID:27299148

  13. Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma.

    PubMed

    Ahmad, F; Dixit, D; Sharma, V; Kumar, A; Joshi, S D; Sarkar, C; Sen, E

    2016-05-05

    Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) - two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the in vitro findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells.

  14. Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma

    PubMed Central

    Ahmad, F; Dixit, D; Sharma, V; Kumar, A; Joshi, S D; Sarkar, C; Sen, E

    2016-01-01

    Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) – two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the in vitro findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells. PMID:27148686

  15. Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma

    PubMed Central

    Larson, Erik W; Peterson, Halloran E; Lamoreaux, Wayne T; MacKay, Alexander R; Fairbanks, Robert K; Call, Jason A; Carlson, Jonathan D; Ling, Benjamin C; Demakas, John J; Cooke, Barton S; Lee, Christopher M

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with a survival prognosis of 14-16 mo for the highest functioning patients. Despite aggressive, multimodal upfront therapies, the majority of GBMs will recur in approximately six months. Salvage therapy options for recurrent GBM (rGBM) are an area of intense research. This study compares recent survival and quality of life outcomes following Gamma Knife radiosurgery (GKRS) salvage therapy. Following a PubMed search for studies using GKRS as salvage therapy for malignant gliomas, nine articles from 2005 to July 2013 were identified which evaluated rGBM treatment. In this review, we compare Overall survival following diagnosis, Overall survival following salvage treatment, Progression-free survival, Time to recurrence, Local tumor control, and adverse radiation effects. This report discusses results for rGBM patient populations alone, not for mixed populations with other tumor histology grades. All nine studies reported median overall survival rates (from diagnosis, range: 16.7-33.2 mo; from salvage, range: 9-17.9 mo). Three studies identified median progression-free survival (range: 4.6-14.9 mo). Two showed median time to recurrence of GBM. Two discussed local tumor control. Six studies reported adverse radiation effects (range: 0%-46% of patients). The greatest survival advantages were seen in patients who received GKRS salvage along with other treatments, like resection or bevacizumab, suggesting that appropriately tailored multimodal therapy should be considered with each rGBM patient. However, there needs to be a randomized clinical trial to test GKRS for rGBM before the possibility of selection bias can be dismissed. PMID:24829861

  16. Next-generation confirmatory disease diagnostics

    NASA Astrophysics Data System (ADS)

    Lin, Robert; Gerver, Rachel; Karns, Kelly; Apori, Akwasi A.; Denisin, Aleksandra K.; Herr, Amy E.

    2014-06-01

    Microfluidic tools are advancing capabilities in screening diagnostics for use in near-patient settings. Here, we review three case studies to illustrate the flexibility and analytical power offered by microanalytical tools. We first overview a near-patient tool for detection of protein markers found in cerebrospinal fluid (CSF), as a means to identify the presence of cerebrospinal fluid in nasal mucous - an indication that CSF is leaking into the nasal cavity. Microfluidic design allowed integration of several up-stream preparatory steps and rapid, specific completion of the human CSF protein assay. Second, we overview a tear fluid based assay for lactoferrin, a protein produced in the lacrimal gland, then secreted into tear fluid. Tear Lf is a putative biomarker for primary SS. A critical contribution of this and related work being measurement of Lf, even in light of well-known and significant matrix interactions and losses during the tear fluid collection and preparation. Lastly, we review a microfluidic barcode platform that enables rapid measurement of multiple infectious disease biomarkers in human sera. The assay presents a new approach to multiplexed biomarker detection, yet in a simple straight microchannel - thus providing a streamlined, simplified microanalytical platform, as is relevant to robust operation in diagnostic settings. We view microfluidic design and analytical chemistry as the basis for emerging, sophisticated assays that will advance not just screening diagnostic technology, but confirmatory assays, sample preparation and handling, and thus introduction and utilization of new biomarkers and assay formats.

  17. Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: Inhibition of tumor angiogenesis with extensive tumor necrosis

    SciTech Connect

    Kang, Khong Bee . E-mail: dmskkb@nccs.com.sg; Wang, Ting Ting; Woon, Chow Thai; Cheah, Elizabeth S.; Moore, Xiao Lei; Zhu Congju; Wong, Meng Cheong

    2007-03-01

    Purpose: Toward improved glioblastoma multiforme treatment, we determined whether celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, could enhance glioblastoma radiosensitivity by inducing tumor necrosis and inhibiting tumor angiogenesis. Methods and Materials: U-87MG cells treated with celecoxib, irradiation, or both were assayed for clonogenic survival and angiogenic factor protein analysis (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor [VEGF]). In vivo, survival of mice intracranially implanted with U-87MG cells and treated with celecoxib and/or irradiation was monitored. Isolated tumors were assessed for tumor necrosis and tumor microvascular density by von Williebrand's factor (vWF) immunohistochemical staining. Results: Celecoxib (4 and 30 {mu}M; 24, 48, and 72 h) enhanced U-87MG cell radiosensitivity by significantly reducing clonogenic survival of irradiated cells. Angiopoietin-1 and VEGF proteins were decreased, whereas angiopoietin-2 expression increased after 72 h of celecoxib alone and when combined with irradiation. In vivo, median survival of control mice intracranially implanted with U-87MG cells was 18 days. Celecoxib (100 mg/kg/day, 2 weeks) significantly extended median survival of irradiated mice (24 Gy total) from 34 to 41 days, with extensive tumor necrosis [24.5 {+-} 8.6% of tumor region, compared with irradiation alone (2.7 {+-} 1.8%)]. Tumor microvascular density was significantly reduced in combined celecoxib and irradiated tumors (52.5 {+-} 2.9 microvessels per mm{sup 2} tumor region), compared with irradiated tumors alone (65.4 {+-} 4.0 microvessels per mm{sup 2}). Conclusion: Celecoxib significantly enhanced glioblastoma radiosensitivity, reduced clonogenic survival, and prolonged survival of glioblastoma-implanted mice by inhibition of tumor angiogenesis with extensive tumor necr0010os.

  18. MiR-422a acts as a tumor suppressor in glioblastoma by targeting PIK3CA

    PubMed Central

    Liang, Haiqian; Wang, Renjie; Jin, Ying; Li, Jianwei; Zhang, Sai

    2016-01-01

    Although surgical treatment, chemotherapy, and radiotherapy have improved the overall survival rate in glioblastoma multiforme (GBM), further intensive research of GBM’s molecular mechanism is still needed. In this study, we observed that miR-422a was downregulated in GBM tissues and cell lines by quantitative real-time polymerase chain reaction (PCR) and primer extension assay. Overexpression of miR-422a significantly reduced the cell proliferation, migration, and invasion of GBM cells. Functional study indicated that miR-422a inhibited cell proliferation, invasion, and migration by targeting PIK3CA, an important member of PI3K/Akt signal pathway. These results demonstrate that the miR-422a/PIK3CA axis may constitute a potential target for GBM therapy. PMID:27648359

  19. Label-free multimodal microspectroscopic differentiation of glioblastoma tumor model cell lines combined with multivariate data analysis

    NASA Astrophysics Data System (ADS)

    Ostertag, Edwin; Boldrini, Barbara; Luckow, Sabrina; Kessler, Rudolf W.

    2012-06-01

    Glioblastoma multiforme represents a highly lethal brain tumor. A tumor model has been developed based on the U-251 MG cell line from a human explant. The tumor model simulates different malignancies by controlled expression of the tumor suppressor proteins PTEN and TP53 within the cell lines derived from the wild type. The cells from each different malignant cell line are grown on slides, followed by a paraformaldehyde fixation. UV / VIS and IR spectra are recorded in the cell nuclei. For the differentiation of the cell lines a principal component analysis (PCA) is performed. The PCA demonstrates a good separation of the tumor model cell lines both with UV / VIS spectroscopy and with IR spectroscopy.

  20. MiR-422a acts as a tumor suppressor in glioblastoma by targeting PIK3CA

    PubMed Central

    Liang, Haiqian; Wang, Renjie; Jin, Ying; Li, Jianwei; Zhang, Sai

    2016-01-01

    Although surgical treatment, chemotherapy, and radiotherapy have improved the overall survival rate in glioblastoma multiforme (GBM), further intensive research of GBM’s molecular mechanism is still needed. In this study, we observed that miR-422a was downregulated in GBM tissues and cell lines by quantitative real-time polymerase chain reaction (PCR) and primer extension assay. Overexpression of miR-422a significantly reduced the cell proliferation, migration, and invasion of GBM cells. Functional study indicated that miR-422a inhibited cell proliferation, invasion, and migration by targeting PIK3CA, an important member of PI3K/Akt signal pathway. These results demonstrate that the miR-422a/PIK3CA axis may constitute a potential target for GBM therapy.

  1. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

    SciTech Connect

    Verhaak, Roel GW; Hoadley, Katherine A; Purdom, Elizabeth; Wang, Victoria; Qi, Yuan; Wilkerson, Matthew D; Miller, C Ryan; Ding, Li; Golub, Todd; Mesirov, Jill P; Alexe, Gabriele; Lawrence, Michael; O'Kelly, Michael; Tamayo, Pablo; Weir, Barbara A; Gabriel, Stacey; Winckler, Wendy; Gupta, Supriya; Jakkula, Lakshmi; Feiler, Heidi S; Hodgson, J Graeme; James, C David; Sarkaria, Jann N; Brennan, Cameron; Kahn, Ari; Spellman, Paul T; Wilson, Richard K; Speed, Terence P; Gray, Joe W; Meyerson, Matthew; Getz, Gad; Perou, Charles M; Hayes, D Neil; Network, The Cancer Genome Atlas Research

    2009-09-03

    The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.

  2. MiR-422a acts as a tumor suppressor in glioblastoma by targeting PIK3CA.

    PubMed

    Liang, Haiqian; Wang, Renjie; Jin, Ying; Li, Jianwei; Zhang, Sai

    2016-01-01

    Although surgical treatment, chemotherapy, and radiotherapy have improved the overall survival rate in glioblastoma multiforme (GBM), further intensive research of GBM's molecular mechanism is still needed. In this study, we observed that miR-422a was downregulated in GBM tissues and cell lines by quantitative real-time polymerase chain reaction (PCR) and primer extension assay. Overexpression of miR-422a significantly reduced the cell proliferation, migration, and invasion of GBM cells. Functional study indicated that miR-422a inhibited cell proliferation, invasion, and migration by targeting PIK3CA, an important member of PI3K/Akt signal pathway. These results demonstrate that the miR-422a/PIK3CA axis may constitute a potential target for GBM therapy. PMID:27648359

  3. Multiscale modelling of palisade formation in gliobastoma multiforme.

    PubMed

    Caiazzo, Alfonso; Ramis-Conde, Ignacio

    2015-10-21

    Palisades are characteristic tissue aberrations that arise in glioblastomas. Observation of palisades is considered as a clinical indicator of the transition from a noninvasive to an invasive tumour. In this paper we propose a computational model to study the influence of the hypoxic switch in palisade formation. For this we produced three-dimensional realistic simulations, based on a multiscale hybrid model, coupling the evolution of tumour cells and the oxygen diffusion in tissue, that depict the shape of palisades during its formation. Our results can be summarized as follows: (1) the presented simulations can provide clinicians and biologists with a better understanding of three-dimensional structure of palisades as well as of glioblastomas growth dynamics; (2) we show that heterogeneity in cell response to hypoxia is a relevant factor in palisade and pseudopalisade formation; (3) we show how selective processes based on the hypoxia switch influence the tumour proliferation.

  4. SU-E-T-183: Feasibility of Extreme Dose Escalation for Glioblastoma Multiforme Using 4π Radiotherapy

    SciTech Connect

    Nguyen, D; Rwigema, J; Yu, V; Kaprealian, T; Kupelian, P; Selch, M; Low, D; Sheng, K

    2014-06-01

    Purpose: GBM recurrence primarily occurs inside or near the high-dose radiation field of original tumor site requiring greater than 100 Gy to significantly improve local control. We utilize 4π non-coplanar radiotherapy to test the feasibility of planning target volume (PTV) margin expansions or extreme dose escalations without incurring additional radiation toxicities. Methods: 11 GBM patients treated with VMAT to a prescription dose of 59.4 Gy or 60 Gy were replanned with 4π. Original VMAT plans were created with 2 to 4 coplanar or non-coplanar arcs using 3 mm hi-res MLC. The 4π optimization, using 5 mm MLC, selected and inverse optimized 30 beams from a candidate pool of 1162 beams evenly distributed through 4π steradians. 4π plans were first compared to clinical plans using the same prescription dose. Two more studies were then performed to respectively escalate the GTV and PTV doses to 100 Gy, followed by a fourth plan expanding the PTV by 5 mm and maintaining the prescription dose. Results: The standard 4π plan significantly reduced (p<0.01) max and mean doses to critical structures by a range of 47.0–98.4% and 61.0–99.2%, respectively. The high dose PTV/high dose GTV/expanded PTV studies showed a reduction (p<0.05) or unchanged* (p>0.05) maximum dose of 72.1%/86.7%/77.1% (chiasm), 7.2%*/27.7%*/30.7% (brainstem), 39.8%*/84.2%/51.9%* (spinal cord), 69.0%/87.0%/66.9% (L eye), 76.2%/88.1%/84.1% (R eye), 95.0%/98.6%/97.5% (L lens), 93.9%/98.8%/97.6% (R lens), 74.3%/88.5%/72.4% (L optical nerve), 80.4%/91.3%/75.7% (R optical nerve), 64.8%/84.2%/44.9%* (L cochlea), and 85.2%/93.0%/78.0% (R cochlea), respectively. V30 and V36 for both brain and (brain - PTV) were reduced for all cases except the high dose PTV plan. PTV dose coverage increased for all 4π plans. Conclusion: Extreme dose escalation or further margin expansion is achievable using 4π, maintaining or reducing OAR doses. This study indicates that clinical trials employing 4π delivery using prescription doses up to 100 Gy are feasible. Funding support partially contributed by Varian.

  5. A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas†

    PubMed Central

    Raizer, Jeffrey J.; Abrey, Lauren E.; Lassman, Andrew B.; Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Yung, W.K. Alfred; Gilbert, Mark R.; Aldape, Kenneth D.; Wen, Patrick Y.; Fine, Howard A.; Mehta, Minesh; DeAngelis, Lisa M.; Lieberman, Frank; Cloughesy, Timothy F.; Robins, H. Ian; Dancey, Janet; Prados, Michael D.

    2010-01-01

    The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 × 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where ≤1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs. PMID:20150371

  6. Knockdown of ASIC1 and epithelial sodium channel subunits inhibits glioblastoma whole cell current and cell migration.

    PubMed

    Kapoor, Niren; Bartoszewski, Rafal; Qadri, Yawar J; Bebok, Zsuzsanna; Bubien, James K; Fuller, Catherine M; Benos, Dale J

    2009-09-01

    High grade gliomas such as glioblastoma multiforme express multiple members of the epithelial sodium channel (ENaC)/Degenerin family, characteristically displaying a basally active amiloride-sensitive cation current not seen in normal human astrocytes or lower grade gliomas. Using quantitative real time PCR, we have shown higher expression of ASIC1, alphaENaC, and gammaENaC in D54-MG human glioblastoma multiforme cells compared with primary human astrocytes. We hypothesize that this glioma current is mediated by a hybrid channel composed of a mixture of ENaC and acid-sensing ion channel (ASIC) subunits. To test this hypothesis we made dominant negative cDNAs for ASIC1, alphaENaC, gammaENaC, and deltaENaC. D54-MG cells transfected with the dominant negative constructs for ASIC1, alphaENaC, or gammaENaC showed reduced protein expression and a significant reduction in the amiloride-sensitive whole cell current as compared with untransfected D54-MG cells. Knocking down alphaENaC or gammaENaC also abolished the high P(K)(+)/P(Na)(+) of D54-MG cells. Knocking down deltaENaC in D54-MG cells reduced deltaENaC protein expression but had no effect on either the whole cell current or K(+) permeability. Using co-immunoprecipitation we show interactions between ASIC1, alphaENaC, and gammaENaC, consistent with these subunits interacting with each other to form an ion channel in glioma cells. We also found a significant inhibition of D54-MG cell migration after ASIC1, alphaENaC, or gammaENaC knockdown, consistent with the hypothesis that ENaC/Degenerin subunits play an important role in glioma cell biology. PMID:19561078

  7. Tetanus shot may improve glioblastoma treatment.

    PubMed

    2015-06-01

    Preconditioning the immune system with a tetanus/diphtheria toxoid significantly improved the effectiveness of dendritic cell immunotherapy and extended overall survival in a small, randomized study of patients with glioblastoma.

  8. MicroRNA involvement in glioblastoma pathogenesis

    SciTech Connect

    Novakova, Jana; Slaby, Ondrej; Vyzula, Rostislav; Michalek, Jaroslav

    2009-08-14

    MicroRNAs are endogenously expressed regulatory noncoding RNAs. Altered expression levels of several microRNAs have been observed in glioblastomas. Functions and direct mRNA targets for these microRNAs have been relatively well studied over the last years. According to these data, it is now evident, that impairment of microRNA regulatory network is one of the key mechanisms in glioblastoma pathogenesis. MicroRNA deregulation is involved in processes such as cell proliferation, apoptosis, cell cycle regulation, invasion, glioma stem cell behavior, and angiogenesis. In this review, we summarize the current knowledge of miRNA functions in glioblastoma with an emphasis on its significance in glioblastoma oncogenic signaling and its potential to serve as a disease biomarker and a novel therapeutic target in oncology.

  9. Immune Evasion Strategies of Glioblastoma

    PubMed Central

    Razavi, Seyed-Mostafa; Lee, Karen E.; Jin, Benjamin E.; Aujla, Parvir S.; Gholamin, Sharareh; Li, Gordon

    2016-01-01

    Glioblastoma (GBM) is the most devastating brain tumor, with associated poor prognosis. Despite advances in surgery and chemoradiation, the survival of afflicted patients has not improved significantly in the past three decades. Immunotherapy has been heralded as a promising approach in treatment of various cancers; however, the immune privileged environment of the brain usually curbs the optimal expected response in central nervous system malignancies. In addition, GBM cells create an immunosuppressive microenvironment and employ various methods to escape immune surveillance. The purpose of this review is to highlight the strategies by which GBM cells evade the host immune system. Further understanding of these strategies and the biology of this tumor will pave the way for developing novel immunotherapeutic approaches for treatment of GBM. PMID:26973839

  10. Nuclear translocation of fibroblast growth factor-2 (FGF2) is regulated by Karyopherin-β2 and Ran GTPase in human glioblastoma cells.

    PubMed

    Wang, Feng; Yang, Lijun; Shi, Lin; Li, Qian; Zhang, Gengshen; Wu, Jianliang; Zheng, Jun; Jiao, Baohua

    2015-08-28

    Human glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Fibroblast growth factor-2 (FGF2) belongs to the FGF superfamily and functions as a potential oncoprotein in GBM. FGF2 has low molecular weight (18K) and high molecular weight (HMW) isoforms. Nuclear accumulation of HMW-FGF2 strongly promotes glioblastoma cell proliferation, yet mechanism governing such cellular distribution remains unexplored. We investigated the mechanisms regulating FGF2 cellular localization in T98G human brain glioblastoma cells. We found HMW-FGF2, but not 18K-FGF2, is primarily located in the nucleus and interacts with nuclear transport protein Karyopherin-β2/Transportin (Kapβ2). SiRNA-directed Kapβ2 knockdown significantly reduced HMW-FGF2's nuclear translocation. Moreover, inhibiting Ran GTPase activity also resulted in decreased HMW-FGF2 nuclear accumulation. Proliferation of T98G cells is greatly enhanced with transfections HMW-FGF2. Decreased PTEN expression and activated Akt signaling were observed upon HMW-FGF2 overexpression and might mediate pro-survival effect of FGF2. Interestingly, addition of nuclear localization signal (NLS) to 18K-FGF2 forced its nuclear import and dramatically increased cell proliferation and Akt activation. These findings demonstrated for the first time the molecular mechanisms for FGF2's nuclear import, which promotes GBM cell proliferation and survival, providing novel insights to the development of GBM treatments. PMID:26056081

  11. Nuclear translocation of fibroblast growth factor-2 (FGF2) is regulated by Karyopherin-β2 and Ran GTPase in human glioblastoma cells.

    PubMed

    Wang, Feng; Yang, Lijun; Shi, Lin; Li, Qian; Zhang, Gengshen; Wu, Jianliang; Zheng, Jun; Jiao, Baohua

    2015-08-28

    Human glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Fibroblast growth factor-2 (FGF2) belongs to the FGF superfamily and functions as a potential oncoprotein in GBM. FGF2 has low molecular weight (18K) and high molecular weight (HMW) isoforms. Nuclear accumulation of HMW-FGF2 strongly promotes glioblastoma cell proliferation, yet mechanism governing such cellular distribution remains unexplored. We investigated the mechanisms regulating FGF2 cellular localization in T98G human brain glioblastoma cells. We found HMW-FGF2, but not 18K-FGF2, is primarily located in the nucleus and interacts with nuclear transport protein Karyopherin-β2/Transportin (Kapβ2). SiRNA-directed Kapβ2 knockdown significantly reduced HMW-FGF2's nuclear translocation. Moreover, inhibiting Ran GTPase activity also resulted in decreased HMW-FGF2 nuclear accumulation. Proliferation of T98G cells is greatly enhanced with transfections HMW-FGF2. Decreased PTEN expression and activated Akt signaling were observed upon HMW-FGF2 overexpression and might mediate pro-survival effect of FGF2. Interestingly, addition of nuclear localization signal (NLS) to 18K-FGF2 forced its nuclear import and dramatically increased cell proliferation and Akt activation. These findings demonstrated for the first time the molecular mechanisms for FGF2's nuclear import, which promotes GBM cell proliferation and survival, providing novel insights to the development of GBM treatments.

  12. Validation of the Effectiveness and Safety of Temozolomide during and after Radiotherapy for Newly Diagnosed Glioblastomas: 10-year Experience of a Single Institution

    PubMed Central

    Joo, Jin-Deok; Kim, Hansol; Kim, Young-Hoon; Han, Jung Ho

    2015-01-01

    This study was performed to validate the effectiveness and safety of concurrent chemoradiotherapy and adjuvant therapy with temozolomide for newly diagnosed glioblastoma multiforme as a standard treatment protocol. Between 2004 and 2011, patients newly diagnosed with glioblastoma who were treated with temozolomide during concurrent chemoradiotherapy and adjuvant chemotherapy were included from a single institution and analyzed retrospectively. The primary endpoint was overall survival, and the secondary endpoints were progression-free survival, response, and safety. A total of 71 patients were enrolled in this study. The response rate was 41% (29/71), and the tumor control rate was 80% (57/71). In the 67 patients who completed the concurrent chemoradiotherapy with temozolomide, the median overall survival was 19 months and the 1- and 2-yr overall survival rates were 78.3% and 41.7%, respectively. The median progression free survival was 9 months, and the 1- and 2-yr progression free survival rates were 33.8% and 14.3%, respectively. The mean duration of survival after progression of disease in salvage treatment group was 11.9 (1.3-53.2) months. Concurrent chemoradiotherapy with temozolomide resulted in grade 3 or 4 hematologic toxic effects in 2.8% of the patients. The current protocol of temozolomide during and after radiation therapy is both effective and safe and is still appropriate as the standard protocol for treatment of glioblastoma. An active salvage treatment might be required for a better prognosis. PMID:26539003

  13. Expression of Ferritin Light Chain (FTL) Is Elevated in Glioblastoma, and FTL Silencing Inhibits Glioblastoma Cell Proliferation via the GADD45/JNK Pathway

    PubMed Central

    Wu, Tingfeng; Li, Yuntao; Liu, Baohui; Zhang, Shenqi; Wu, Liquan; Zhu, Xiaonan; Chen, Qianxue

    2016-01-01

    Accumulating evidence suggests that iron-associated proteins contribute to tumor initiation and development. Ferritin light chain (FTL), a key protein in iron metabolism, is associated with the survival of glioblastoma multiforme (GBM) patients; however, the molecular mechanisms underlying this association remain largely unclear. Therefore, in the present study, we investigated the role of FTL in the pathogenesis of GBM. By using quantitative real-time RT-PCR, we found that expression of FTL was higher in patients with GBM than in those with low-grade glioma. Immunofluorescence showed that FTL was mainly localized in the nucleus of GBM cells and was closely associated with mitotic spindles. Knockdown of FTL resulted in inhibition of cell growth and activation of the GADD45A/JNK pathway in GBM cells. Immunoblotting revealed that levels of GADD45A protein decreased in GBM cells when FTL expression increased. Furthermore, transfection of GADD45A in GBM cells significantly decreased cell viability, and this effect was impeded by co-transfection of FTL. Moreover, FTL was found to localize with GADD45A in GBM cells, and a coimmunoprecipitation experiment showed that the two proteins physically interacted. Taken together, these results demonstrate a novel mechanism by which FTL regulates the growth of GBM cells via the GADD45/JNK pathway. PMID:26871431

  14. Subcellular SIMS imaging of gadolinium isotopes in human glioblastoma cells treated with a gadolinium containing MRI agent

    NASA Astrophysics Data System (ADS)

    Smith, Duane R.; Lorey, Daniel R.; Chandra, Subhash

    2004-06-01

    Neutron capture therapy is an experimental binary radiotherapeutic modality for the treatment of brain tumors such as glioblastoma multiforme. Recently, neutron capture therapy with gadolinium-157 has gained attention, and techniques for studying the subcellular distribution of gadolinium-157 are needed. In this preliminary study, we have been able to image the subcellular distribution of gadolinium-157, as well as the other six naturally abundant isotopes of gadolinium, with SIMS ion microscopy. T98G human glioblastoma cells were treated for 24 h with 25 mg/ml of the metal ion complex diethylenetriaminepentaacetic acid Gd(III) dihydrogen salt hydrate (Gd-DTPA). Gd-DTPA is a contrast enhancing agent used for MRI of brain tumors, blood-brain barrier impairment, diseases of the central nervous system, etc. A highly heterogeneous subcellular distribution was observed for gadolinium-157. The nuclei in each cell were distinctly lower in gadolinium-157 than in the cytoplasm. Even within the cytoplasm the gadolinium-157 was heterogeneously distributed. The other six naturally abundant isotopes of gadolinium were imaged from the same cells and exhibited a subcellular distribution consistent with that observed for gadolinium-157. These observations indicate that SIMS ion microscopy may be a viable approach for subcellular studies of gadolinium containing neutron capture therapy drugs and may even play a major role in the development and validation of new gadolinium contrast enhancing agents for diagnostic MRI applications.

  15. CPEB1 restrains proliferation of Glioblastoma cells through the regulation of p27Kip1 mRNA translation

    PubMed Central

    Galardi, Silvia; Petretich, Massimo; Pinna, Guillaume; D’Amico, Silvia; Loreni, Fabrizio; Michienzi, Alessandro; Groisman, Irina; Ciafrè, Silvia Anna

    2016-01-01

    The cytoplasmic element binding protein 1 (CPEB1) regulates many important biological processes ranging from cell cycle control to learning and memory formation, by controlling mRNA translation efficiency via 3′ untranslated regions (3′UTR). In the present study, we show that CPEB1 is significantly downregulated in human Glioblastoma Multiforme (GBM) tissues and that the restoration of its expression impairs glioma cell lines growth. We demonstrate that CPEB1 promotes the expression of the cell cycle inhibitor p27Kip1 by specifically targeting its 3′UTR, and competes with miR-221/222 binding at an overlapping site in the 3′UTR, thus impairing miR-221/222 inhibitory activity. Upon binding to p27Kip1 3′UTR, CPEB1 promotes elongation of poly-A tail and the subsequent translation of p27Kip1 mRNA. This leads to higher levels of p27Kip1 in the cell, in turn significantly inhibiting cell proliferation, and confers to CPEB1 a potential value as a tumor suppressor in Glioblastoma. PMID:27142352

  16. PACAP and VIP Inhibit the Invasiveness of Glioblastoma Cells Exposed to Hypoxia through the Regulation of HIFs and EGFR Expression

    PubMed Central

    Maugeri, Grazia; Grazia D’Amico, Agata; Reitano, Rita; Magro, Gaetano; Cavallaro, Sebastiano; Salomone, Salvatore; D’Agata, Velia

    2016-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) through the binding of vasoactive intestinal peptide receptors (VIPRs), perform a wide variety of effects in human cancers, including glioblastoma multiforme (GBM). This tumor is characterized by extensive areas of hypoxia, which triggers the expression of hypoxia-inducible factors (HIFs). HIFs not only mediate angiogenesis but also tumor cell migration and invasion. Furthermore, HIFs activation is linked to epidermal growth factor receptor (EGFR) overexpression. Previous studies have shown that VIP interferes with the invasive nature of gliomas by regulating cell migration. However, the role of VIP family members in GBM infiltration under low oxygen tension has not been clarified yet. Therefore, in the present study we have investigated, for the first time, the molecular mechanisms involved in the anti-invasive effect of PACAP or VIP in U87MG glioblastoma cells exposed to hypoxia induced by treatment with desferrioxamine (DFX). The results suggest that either PACAP or VIP exert an anti-infiltrative effect under low oxygen tension by modulating HIFs and EGFR expression, key elements involved in cell migration and angiogenesis. These peptides act through the inhibition of PI3K/Akt and MAPK/ERK signaling pathways, which are known to have a crucial role in HIFs regulation. PMID:27303300

  17. Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B

    SciTech Connect

    Hamm, Rebecca; Zeino, Maen; Frewert, Simon; Efferth, Thomas

    2014-11-15

    Treatment of glioblastoma multiforme (GBM), the most common and aggressive lethal brain tumor, represents a great challenge. Despite decades of research, the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B, a potent vacuolar H{sup +}-ATPase inhibitor influencing cellular pH values, is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol, a main component of cellular membranes, is known to be essential for GBM growth and cells bearing EGFRvIII mutation are highly dependent on exogenous cholesterol. Archazolid B caused excessive accumulation of free cholesterol within intracellular compartments thus depleting cellular cholesterol and leading to up-regulation of SREBP targeted genes, including LDLR and HMGCR, the key enzyme of cholesterol biosynthesis. This cholesterol response is considered to be a novel resistance mechanism induced by archazolid B. We surmise that re-elevation of cholesterol levels in archazolid B treated cells may be mediated by newly synthesized cholesterol, since the drug leads to endosomal/lysosomal malfunction and cholesterol accumulation.

  18. New insights into the anticancer activity of carnosol: p53 reactivation in the U87MG human glioblastoma cell line.

    PubMed

    Giacomelli, Chiara; Natali, Letizia; Trincavelli, Maria Letizia; Daniele, Simona; Bertoli, Alessandra; Flamini, Guido; Braca, Alessandra; Martini, Claudia

    2016-05-01

    Glioblastoma multiforme (GBM) is an aggressive brain tumour with high resistance to radio- and chemotherapy. As such, increasing attention has focused on developing new therapeutic strategies to improve treatment responses. Recently, attention has been shifted to natural compounds that are able to halt tumour development. Among them, carnosol (CAR), a phenolic diterpene present in rosemary, has become a promising molecule that is able to prevent certain types of solid cancer. However, no data are available on the effects of CAR in GBM. Here, CAR activity decreased the proliferation of different human glioblastoma cell lines, particularly cells that express wild type p53. The p53 pathway is involved in the control of apoptosis and is often impaired in GBM. Notably, CAR, through the dissociation of p53 from its endogenous inhibitor MDM2, was able to increase the intracellular p53 levels in GBM cells. Accordingly, functional reactivation of p53 was demonstrated by the stimulation of p53 target genes' transcription, the induction of apoptosis and cell cycle blockade. Most importantly, CAR produced synergistic effects with temozolomide (TMZ) and reduced the restoration of the tumour cells' proliferation after drug removal. Thus, for the first time, these data highlighted the potential use of the diterpene in the sensitization of GBM cells to chemotherapy through a direct re-activation of p53 pathway. Furthermore, progress has been made in delineating the biochemical mechanisms underlying the pro-apoptotic effects of this molecule. PMID:26939786

  19. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma.

    PubMed

    Scholz, Alexander; Harter, Patrick N; Cremer, Sebastian; Yalcin, Burak H; Gurnik, Stefanie; Yamaji, Maiko; Di Tacchio, Mariangela; Sommer, Kathleen; Baumgarten, Peter; Bähr, Oliver; Steinbach, Joachim P; Trojan, Jörg; Glas, Martin; Herrlinger, Ulrich; Krex, Dietmar; Meinhardt, Matthias; Weyerbrock, Astrid; Timmer, Marco; Goldbrunner, Roland; Deckert, Martina; Braun, Christian; Schittenhelm, Jens; Frueh, Jochen T; Ullrich, Evelyn; Mittelbronn, Michel; Plate, Karl H; Reiss, Yvonne

    2015-12-14

    Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti-angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin-2 (Ang-2) as a potential target in both naive and bevacizumab-treated glioblastoma. Ang-2 expression was absent in normal human brain endothelium, while the highest Ang-2 levels were observed in bevacizumab-treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang-2, whereas the combined inhibition of VEGF and Ang-2 leads to extended survival, decreased vascular permeability, depletion of tumor-associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206(+) (M2-like) macrophages were identified as potential novel targets following anti-angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang-2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang-2 may potentially overcome resistance to bevacizumab therapy.

  20. Guanylate binding protein-1 mediates EGFRvIII and promotes glioblastoma growth in vivo but not in vitro

    PubMed Central

    Cheng, Yanwei; Mukasa, Akitaki; Ma, Jiawei; Hong, Lei; Yu, Shuye; Sun, Lili; Huang, Qiang; Purow, Benjamin; Li, Ming

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor in adults. Epidermal growth factor receptor (EGFR) is frequently amplified and mutated in GBM. We previously reported that Guanylate binding protein-1 (GBP1) is a novel transcriptional target gene of EGFR and plays a role in GBM invasion. Here we demonstrate that GBP1 can also be induced by EGFRvIII at the transcriptional level through the p38 MAPK/Yin Yang 1 (YY1) signaling pathway. Silencing of GBP1 by RNA interference significantly inhibits EGFRvIII-mediated GBM cell proliferation in vitro and in a mouse model. Overexpression of GBP1 has no obvious effect on glioblastoma cell proliferation in vitro. In contrast, in an orthotopic glioma mouse model GBP1 overexpression significantly promotes glioma growth and reduces survival rate of glioma-bearing mice by increasing cell proliferation and decreasing cell apoptosis in tumor. Clinically, GBP1 expression is elevated in human GBM tumors and positively correlates with EGFRvIII status in GBM specimens, and its expression is inversely correlated with the survival rate of GBM patients. Taken together, these results reveal that GBP1 may serve as a potential therapeutic target for GBMs with EGFRvIII mutation. PMID:26848767

  1. A patient-specific computational model of hypoxia-modulated radiation resistance in glioblastoma using 18F-FMISO-PET

    PubMed Central

    Rockne, Russell C.; Trister, Andrew D.; Jacobs, Joshua; Hawkins-Daarud, Andrea J.; Neal, Maxwell L.; Hendrickson, Kristi; Mrugala, Maciej M.; Rockhill, Jason K.; Kinahan, Paul; Krohn, Kenneth A.; Swanson, Kristin R.

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly invasive primary brain tumour that has poor prognosis despite aggressive treatment. A hallmark of these tumours is diffuse invasion into the surrounding brain, necessitating a multi-modal treatment approach, including surgery, radiation and chemotherapy. We have previously demonstrated the ability of our model to predict radiographic response immediately following radiation therapy in individual GBM patients using a simplified geometry of the brain and theoretical radiation dose. Using only two pre-treatment magnetic resonance imaging scans, we calculate net rates of proliferation and invasion as well as radiation sensitivity for a patient's disease. Here, we present the application of our clinically targeted modelling approach to a single glioblastoma patient as a demonstration of our method. We apply our model in the full three-dimensional architecture of the brain to quantify the effects of regional resistance to radiation owing to hypoxia in vivo determined by [18F]-fluoromisonidazole positron emission tomography (FMISO-PET) and the patient-specific three-dimensional radiation treatment plan. Incorporation of hypoxia into our model with FMISO-PET increases the model–data agreement by an order of magnitude. This improvement was robust to our definition of hypoxia or the degree of radiation resistance quantified with the FMISO-PET image and our computational model, respectively. This work demonstrates a useful application of patient-specific modelling in personalized medicine and how mathematical modelling has the potential to unify multi-modality imaging and radiation treatment planning. PMID:25540239

  2. ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1

    PubMed Central

    Day, Bryan W.; Stringer, Brett W.; Spanevello, Mark D.; Charmsaz, Sara; Jamieson, Paul R.; Ensbey, Kathleen S.; Carter, Jacinta C.; Cox, Joanne M.; Ellis, Vicky J.; Brown, Christopher L.; Walker, David G.; Inglis, Po L.; Allan, Suzanne; Reynolds, Brent A.; Lickliter, Jason D.; Boyd, Andrew W.

    2011-01-01

    Glioma is the most common adult primary brain tumor. Its most malignant form, glioblastoma multiforme (GBM), is almost invariably fatal, due in part to the intrinsic resistance of GBM to radiation- and chemotherapy-induced apoptosis. We analyzed B-cell leukemia–2 (Bcl-2) anti-apoptotic proteins in GBM and found myeloid cell leukemia–1 (Mcl-1) to be the highest expressed in the majority of malignant gliomas. Mcl-1 was functionally important, as neutralization of Mcl-1 induced apoptosis and increased chemotherapy-induced apoptosis. To determine how Mcl-1 was regulated in glioma, we analyzed the promoter and identified a novel functional single nucleotide polymorphism in an uncharacterized E26 transformation-specific (ETS) binding site. We identified the ETS transcription factor ELK4 as a critical regulator of Mcl-1 in glioma, since ELK4 downregulation was shown to reduce Mcl-1 and increase sensitivity to apoptosis. Importantly the presence of the single nucleotide polymorphism, which ablated ELK4 binding in gliomas, was associated with lower Mcl-1 levels and a greater dependence on Bcl-xL. Furthermore, in vivo, ELK4 downregulation reduced tumor formation in glioblastoma xenograft models. The critical role of ELK4 in Mcl-1 expression and protection from apoptosis in glioma defines ELK4 as a novel potential therapeutic target for GBM. PMID:21846680

  3. Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future direction

    PubMed Central

    Mallick, Supriya; Gandhi, Ajeet Kumar; Rath, Goura Kishor

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor. Maximal safe surgical resection followed by adjuvant partial brain radiation with concurrent and adjuvant temozolomide (TMZ) (oral alkylating agent) is the standard of care. Five years survival in TMZ treated patient reaches 9.8%. We aimed to summarize the changes in the management of GBM beyond conventional temozolomide based adjuvant treatment. We searched the PUBMED with the following key words: Glioblastoma, phase III trial, Phase II trial, adjuvant treatment in GBM. Clinical research has found a wide range of molecular aberrations in GBM and attempts are being made to further improve survival with the addition of different classes of drugs. Angiogenesis inhibitors, oncolytic vaccines, dose dense TMZ, and anti-epidermal growth factor receptor monoclonal antibody in phase III trials have failed to improve survival. Recent studies have also shown that the management strategies might be different and needs to be customized as per the age of patients such as pediatric and elderly patients. In addition, treatments should be personalized depending on the molecular aberrations. We reviewed all published phase III trials for newly diagnosed GBM as well as also looked into possible future directions in this review. Limited progress has happed beyond conventional TMZ in the adjuvant treatment of GBM. Newer insights are emerging about treatment intensification and introduction of newer molecular targeted drugs with more information about molecular aberrations. PMID:26811592

  4. Distinguishing between exploratory and confirmatory preclinical research will improve translation.

    PubMed

    Kimmelman, Jonathan; Mogil, Jeffrey S; Dirnagl, Ulrich

    2014-05-01

    Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode.

  5. Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells

    PubMed Central

    Spina, Raffaella; Voss, Dillon M.; Asnaghi, Laura; Sloan, Andrew; Bar, Eli E.

    2016-01-01

    Glioblastoma multiforme (GBM) are the most common primary malignant brain tumor in adults, with a median survival of about one year. This poor prognosis is attributed primarily to therapeutic resistance and tumor recurrence after surgical removal, with the root cause suggested to be found in glioblastoma stem cells (GSCs). Using glial fibrillary acidic protein (GFAP) as a reporter of astrocytic differentiation, we isolated multiple clones from three independent GSC lines which express GFAP in a remarkably stable fashion. We next show that elevated expression of GFAP is associated with reduced clonogenicity in vitro and tumorigenicity in vivo. Utilizing this in vitro cell-based differentiation reporter system we screened chemical libraries and identified the non-depolarizing neuromuscular blocker (NNMB), Atracurium Besylate, as a small molecule which effectively induces astroglial but not neuronal differentiation of GSCs. Functionally, Atracurium Besylate treatment significantly inhibited the clonogenic capacity of several independent patient-derived GSC neurosphere lines, a phenomenon which was largely irreversible. A second NNMB, Vecuronium, also induced GSC astrocytic differentiation while Dimethylphenylpiperazinium (DMPP), a nicotinic acetylcholine receptor (nAChR) agonist, significantly blocked Atracurium Besylate pro-differentiation activity. To investigate the clinical importance of nAChRs in gliomas, we examined clinical outcomes and found that glioma patients with tumors overexpressing CHRNA1 or CHRNA9 (encoding for the AChR-α1 or AChR-α9) exhibit significant shorter overall survival. Finally, we found that ex-vivo pre-treatment of GSCs, expressing CHRNA1 and CHRNA9, with Atracurium Besylate significantly increased the survival of mice xenotransplanted with these cells, therefore suggesting that tumor initiating subpopulations have been reduced. PMID:26575950

  6. Role of glycosyltransferase PomGnT1 in glioblastoma progression

    PubMed Central

    Lan, Jin; Guo, Pin; Lin, Yingying; Mao, Qing; Guo, Liemei; Ge, Jianwei; Li, Xiaoxiong; Jiang, Jiyao; Lin, Xinjian; Qiu, Yongming

    2015-01-01

    Background Glioblastoma multiforme (GBM) is the most aggressive and invasive brain tumor, for which novel prognostic markers and predictors of therapeutic response are urgently needed. We reported previously that levels of peptide-O-linked mannose β-1,2-N-acetylglucosaminyltransferase 1 (PomGnT1) in glioma specimens correlated with tumor grade. However, the prognostic significance of PomGnT1 in glioma patients and its function in GBM progression remain unknown. Methods Clinical relevance of PomGnT1 in GBM patients' prognosis was analyzed both in a clinically annotated expression dataset of 446 GBM tumor specimens and in 82 GBM tumor samples collected at our institution. The function of PomGnT1 in glioma growth and invasion, and the underlying mechanisms of PomGnT1 regulation were explored in vitro and in vivo. Results PomGnT1 expression in GBM tissues was closely associated with poor prognosis in GBM patients. Forced overexpression of PomGnT1 in glioblastoma cells impaired cell adhesion and increased their proliferation and invasion in vitro. Subsequent in vivo experiments showed that overexpression of PomGnT1 promoted tumor growth and shortened the survival time of tumor-bearing mice in an orthotopic model. Conversely, stable short hairpin RNA–mediated knockdown of PomGnT1 expression produced opposite effects both in vitro and in vivo. Mechanistic studies revealed that activation of epidermal growth factor receptor (EGFR) resulted in EGFR/extracellular signal-regulated kinase–dependent upregulation of PomGnT1, downregulation of receptor-type protein tyrosine phosphatase β, and activation of β-catenin pathway signaling. Conclusion These findings suggest that PomGnT1 promotes GBM progression via activation of β-catenin and may serve as a prognostic factor for glioma patient survival as well as a novel molecular target for anticancer therapy in malignant glioma. PMID:25085363

  7. The questionable use of unequal allocation in confirmatory trials.

    PubMed

    Hey, Spencer Phillips; Kimmelman, Jonathan

    2014-01-01

    Randomization is the standard means for addressing known and unknown confounders within the patient population in clinical trials. Although random assignment to treatment arms on a 1:1 basis has long been the norm, many 2-armed confirmatory trials now use unequal allocation schemes where the number of patients receiving investigational interventions exceeds those in the comparator arm. In what follows, we offer 3 arguments for why investigators, institutional review boards, and data and safety monitoring boards should exercise caution when planning or reviewing 2-armed confirmatory trials involving unequal allocation ratios. We close by laying out some of the conditions where uneven allocation can be justified ethically.

  8. Adaptive Design of Confirmatory Trials: Advances and Challenges

    PubMed Central

    Lai, Tze Leung; Lavori, Philip W.; Tsang, Ka Wai

    2015-01-01

    The past decade witnessed major developments in innovative designs of confirmatory clinical trials, and adaptive designs represent the most active area of these developments. We give an overview of the developments and associated statistical methods in several classes of adaptive designs of confirmatory trials. We also discuss their statistical difficulties and implementation challenges, and show how these problems are connected to other branches of mainstream Statistics, which we then apply to resolve the difficulties and bypass the bottlenecks in the development of adaptive designs for the next decade. PMID:26079372

  9. Targeting miR-381-NEFL axis sensitizes glioblastoma cells to temozolomide by regulating stemness factors and multidrug resistance factors

    PubMed Central

    Wang, Zeyou; Yang, Jing; Xu, Gang; Wang, Wei; Liu, Changhong; Yang, Honghui; Yu, Zhibin; Lei, Qianqian; Xiao, Lan; Xiong, Jing; Zeng, Liang; Xiang, Juanjuan; Ma, Jian; Li, Guiyuan; Wu, Minghua

    2015-01-01

    MicroRNA-381 (miR-381) is a highly expressed onco-miRNA that is involved in malignant progression and has been suggested to be a good target for glioblastoma multiforme (GBM) therapy. In this study, we employed two-dimensional fluorescence differential gel electrophoresis (2-D DIGE) and MALDI–TOF/TOF-MS/MS to identify 27 differentially expressed proteins, including the significantly upregulated neurofilament light polypeptide (NEFL), in glioblastoma cells in which miR-381 expression was inhibited. We identified NEFL as a novel target molecule of miR-381 and a tumor suppressor gene. In human astrocytoma clinical specimens, NEFL was downregulated with increased levels of miR-381 expression. Either suppressing miR-381 or enforcing NEFL expression dramatically sensitized glioblastoma cells to temozolomide (TMZ), a promising chemotherapeutic agent for treating GBMs. The mechanism by which these cells were sensitized to TMZ was investigated by inhibiting various multidrug resistance factors (ABCG2, ABCC3, and ABCC5) and stemness factors (ALDH1, CD44, CKIT, KLF4, Nanog, Nestin, and SOX2). Our results further demonstrated that miR-381 overexpression reversed the viability of U251 cells exhibiting NEFL-mediated TMZ sensitivity. In addition, NEFL-siRNA also reversed the proliferation rate of U251 cells exhibiting locked nucleic acid (LNA)-anti-miR-381-mediated TMZ sensitivity. Overall, the miR-381-NEFL axis is important for TMZ resistance in GBM and may potentially serve as a novel therapeutic target for glioma. PMID:25605243

  10. Cytomegalovirus and glioblastoma; controversies and opportunities.

    PubMed

    Lawler, Sean E

    2015-07-01

    One of the more polarized ongoing debates in the brain tumor field over recent years has centered on the association of cytomegalovirus (CMV) with glioblastoma. Several laboratories have reported the presence of CMV antigens in glioblastoma patient specimens, whereas others have failed to detect them. CMV genomic DNA and mRNAs have been detected by PCR, but not in next-generation sequencing studies. CMV promotes high grade glioma progression in a mouse genetic model, and many CMV proteins promote cancer hallmarks in vitro, but actively replicating virus has not been isolated from tumor samples. A consensus is gradually emerging in which the presence of CMV antigens in glioblastoma is increasingly accepted. However, it remains challenging to understand this mechanistically due to the low levels of CMV nucleic acids and the absence of viral replication observed in tumors thus far. Nonetheless, these observations have inspired the development of novel therapeutic approaches based on anti-viral drugs and immunotherapy. The potential benefit of valganciclovir in glioblastoma has generated great interest, but efficacy remains to be established in a randomized trial. Also, early stage immunotherapy trials targeting CMV have shown promise. In the near future we will know more answers to these questions, and although areas of controversy may remain, and the mechanisms and roles of CMV in tumor growth are yet to be clearly defined, this widespread virus may have created important new therapeutic concepts and opportunities for the treatment of glioblastoma. PMID:25682092

  11. New perspectives in glioblastoma antiangiogenic therapy

    PubMed Central

    Popescu, Alisa Madalina; Purcaru, Stefana Oana; Alexandru, Oana

    2015-01-01

    Glioblastoma (GB) is highly vascularised tumour, known to exhibit enhanced infiltrative potential. One of the characteristics of glioblastoma is microvascular proliferation surrounding necrotic areas, as a response to a hypoxic environment, which in turn increases the expression of angiogenic factors and their signalling pathways (RAS/RAF/ERK/MAPK pathway, PI3K/Akt signalling pathway and WTN signalling cascade). Currently, a small number of anti-angiogenic drugs, extending glioblastoma patients survival, are available for clinical use. Most medications are ineffective in clinical therapy of glioblastoma due to acquired malignant cells or intrinsic resistance, angiogenic receptors cross-activation and redundant intracellular signalling, or the inability of the drug to cross the blood-brain barrier and to reach its target in vivo. Researchers have also observed that GB tumours are different in many aspects, even when they derive from the same tissue, which is the reason for personalised therapy. An understanding of the molecular mechanisms regulating glioblastoma angiogenesis and invasion may be important in the future development of curative therapeutic approaches for the treatment of this devastating disease. PMID:27358588

  12. Progression pattern and adverse events with bevacizumab in glioblastoma

    PubMed Central

    Mamo, A.; Baig, A.; Azam, M.; Rho, Y.S.; Sahebjam, S.; Muanza, T.; Owen, S.; Petrecca, K.; Guiot, M.C.; Al-Shami, J.; Sharma, R.; Kavan, P.

    2016-01-01

    Background The use of bevacizumab in the management of glioblastoma multiforme (gbm) remains controversial. In Canada, bevacizumab is approved for the treatment of recurrent gbm. We describe a pattern of progression across treatment lines in gbm. Methods During 2008–2014, 64 patients diagnosed with gbm were treated with bevacizumab at McGill University hospitals. Of those patients, 30 (46.9%) received bevacizumab in the first line (B1L), and 34 (53.1%) received it in the second line and beyond (B2L+). The average length of treatment with bevacizumab was 24.4 weeks (range: 0–232.7 weeks). The patterns of progression were categorized as local, distant, diffuse, multifocal, or multi-pattern. Results Local progression was seen in 46.7% of B1L patients and 26.5% of B2L+ patients, distant in 3.3% and 2.9%, diffuse in 20% and 47%, multifocal in 10% and 8.8%, and multi-pattern in 3.3% and 11.8%. No differences between the groups were observed for the distant (p = 0.3) or diffuse (p = 0.4) patterns. Grades 3 and 4 adverse events in the B1L and B2L+ groups were fatigue (33.3% vs. 17.6% respectively), hypertension (26.7% vs. 5.9%), thrombocytopenia (26.7% vs. 11.8%), neutropenia (26.7% vs. 11.8%), anemia (23.3% vs. 11.8%), leucopenia (20% vs. 8.8%), deep vein thrombosis (23.3% vs. 5.9%), seizure (16.7% vs. 8.8%), brain hemorrhage (6.7% vs. <1%), and delayed wound healing (6.7% vs. 2.9%). More total grades 3 and 4 adverse events occurred in the B1L group (p = 0.000519). Conclusions In our cohort, patterns of progression were not different in B1L and B2L+ patients. Moreover, both groups experienced similar adverse events, although more grades 3 and 4 events occurred in the B1L group, implying that severe adverse events in B1L patients could negatively affect survival outcomes.

  13. Cancer stem cells in glioblastoma

    PubMed Central

    Lathia, Justin D.; Mack, Stephen C.; Mulkearns-Hubert, Erin E.; Valentim, Claudia L.L.; Rich, Jeremy N.

    2015-01-01

    Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial. PMID:26109046

  14. Evolving Molecular Genetics of Glioblastoma

    PubMed Central

    Li, Qiu-Ju; Cai, Jin-Quan; Liu, Cheng-Yin

    2016-01-01

    Objective: To summary the recent advances in molecular research of glioblastoma (GBM) and current trends in personalized therapy of this disease. Data Sources: Data cited in this review were obtained mainly from PubMed in English up to 2015, with keywords “molecular”, “genetics”, “GBM”, “isocitrate dehydrogenase”, “telomerase reverse transcriptase”, “epidermal growth factor receptor”, “PTPRZ1-MET”, and “clinical treatment”. Study Selection: Articles regarding the morphological pathology of GBM, the epidemiology of GBM, genetic alteration of GBM, and the development of treatment for GBM patients were identified, retrieved, and reviewed. Results: There is a large amount of data supporting the view that these recurrent genetic aberrations occur in a specific context of cellular origin, co-oncogenic hits and are present in distinct patient populations. Primary and secondary GBMs are distinct disease entities that affect different age groups of patients and develop through distinct genetic aberrations. These differences are important, especially because they may affect sensitivity to radio- and chemo-therapy and should thus be considered in the identification of targets for novel therapeutic approaches. Conclusion: This review highlights the molecular and genetic alterations of GBM, indicating that they are of potential value in the diagnosis and treatment for patients with GBM. PMID:26879021

  15. The Factor Structure of Adolescent Drug Use: A Confirmatory Analysis

    ERIC Educational Resources Information Center

    Kallmen, Hakan; Wennberg, Peter

    2005-01-01

    A study comparing four models of substance misuse were performed. Alcohol drinking, tobacco use, sniffing of a dissolvent and cannabis use were proposed to depend on one, two, three, or four latent factors. In confirmatory factor analyses the fit of the models were tested against empirical data from a group of adolescent school pupils. The result…

  16. Confirmatory Factor Analysis of the Cancer Locus of Control Scale.

    ERIC Educational Resources Information Center

    Henderson, Jessica W.; Donatelle, Rebecca J.; Acock, Alan C.

    2002-01-01

    Conducted a confirmatory factor analysis of the Cancer Locus of Control scale (M. Watson and others, 1990), administered to 543 women with a history of breast cancer. Results support a three-factor model of the scale and support use of the scale to assess control dimensions. (SLD)

  17. 77 FR 3800 - Accurate NDE & Inspection, LLC; Confirmatory Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... COMMISSION Accurate NDE & Inspection, LLC; Confirmatory Order In the Matter of Accurate NDE & Docket: 150... request ADR with the NRC in an attempt to resolve issues associated with this matter. In response, on August 9, 2011, Accurate NDE requested ADR to resolve this matter with the NRC. On September 28,...

  18. Confirmatory Factor Analysis and Profile Analysis via Multidimensional Scaling

    ERIC Educational Resources Information Center

    Kim, Se-Kang; Davison, Mark L.; Frisby, Craig L.

    2007-01-01

    This paper describes the Confirmatory Factor Analysis (CFA) parameterization of the Profile Analysis via Multidimensional Scaling (PAMS) model to demonstrate validation of profile pattern hypotheses derived from multidimensional scaling (MDS). Profile Analysis via Multidimensional Scaling (PAMS) is an exploratory method for identifying major…

  19. Studying Children's Early Literacy Development: Confirmatory Multidimensional Scaling Growth Modeling

    ERIC Educational Resources Information Center

    Ding, Cody

    2012-01-01

    There has been considerable debate over the ways in which children's early literacy skills develop over time. Using confirmatory multidimensional scaling (MDS) growth analysis, this paper directly tested the hypothesis of a cumulative trajectory versus a compensatory trajectory of development in early literacy skills among a group of 1233…

  20. Multigroup Confirmatory Factor Analysis: Locating the Invariant Referent Sets

    ERIC Educational Resources Information Center

    French, Brian F.; Finch, W. Holmes

    2008-01-01

    Multigroup confirmatory factor analysis (MCFA) is a popular method for the examination of measurement invariance and specifically, factor invariance. Recent research has begun to focus on using MCFA to detect invariance for test items. MCFA requires certain parameters (e.g., factor loadings) to be constrained for model identification, which are…

  1. A Confirmatory Factor Analysis of the Professional Opinion Scale

    ERIC Educational Resources Information Center

    Greeno, Elizabeth J.; Hughes, Anne K.; Hayward, R. Anna; Parker, Karen L.

    2007-01-01

    The Professional Opinion Scale (POS) was developed to measure social work values orientation. Objective: A confirmatory factor analysis was performed on the POS. Method: This cross-sectional study used a mailed survey design with a national random (simple) sample of members of the National Association of Social Workers. Results: The study…

  2. Random Effects Structure for Confirmatory Hypothesis Testing: Keep It Maximal

    ERIC Educational Resources Information Center

    Barr, Dale J.; Levy, Roger; Scheepers, Christoph; Tily, Harry J.

    2013-01-01

    Linear mixed-effects models (LMEMs) have become increasingly prominent in psycholinguistics and related areas. However, many researchers do not seem to appreciate how random effects structures affect the generalizability of an analysis. Here, we argue that researchers using LMEMs for confirmatory hypothesis testing should minimally adhere to the…

  3. Confirmatory Factor Analysis on the Big 5 Personality Test Inventory

    ERIC Educational Resources Information Center

    Kamarulzaman, Wirawani; Nordin, Mohamad Sahari

    2012-01-01

    This paper is intended to examine the validity of Big 5 Personality test inventory of 44 questions with 5-Likert Scale measurement. Confirmatory factory analysis (CFA) was conducted to determine the good fit indices of the 5 personality types. Those types are 1) extraversion, 2) agreeableness, 3) conscientiousness, 4) openness and 5) neuroticism.…

  4. Comparisons of Means Using Exploratory and Confirmatory Approaches

    ERIC Educational Resources Information Center

    Kuiper, Rebecca M.; Hoijtink, Herbert

    2010-01-01

    This article discusses comparisons of means using exploratory and confirmatory approaches. Three methods are discussed: hypothesis testing, model selection based on information criteria, and Bayesian model selection. Throughout the article, an example is used to illustrate and evaluate the two approaches and the three methods. We demonstrate that…

  5. Exploratory and Confirmatory Factor Analyses of the Multicultural Teaching Scale

    ERIC Educational Resources Information Center

    Yang, Yan; Montgomery, Diane

    2011-01-01

    The ongoing conceptual controversy of cultural competence for preservice teachers led to the current study that explored the underlying structure of cultural competence through exploratory factor analysis (EFA) and confirmatory factor analysis methods. A total of 793 preservice teachers from two large Midwestern universities completed the…

  6. Endoscopy-verified occult subependymal dissemination of glioblastoma and brain metastasis undetected by MRI: prognostic significance

    PubMed Central

    Iacoangeli, Maurizio; Di Rienzo, Alessandro; Colasanti, Roberto; Zizzi, Antonio; Gladi, Maurizio; Alvaro, Lorenzo; Nocchi, Niccolò; Di Somma, Lucia Giovanna Maria; Scarpelli, Marina; Scerrati, Massimo

    2012-01-01

    Although various prognostic indices exist for patients with malignant brain tumors, the prognostic significance of the subependymal spread of intracranial tumors is still a matter of debate. In this paper, we report the cases of two intraventricular lesions, a recurrent glioblastoma multiforme (GBM) and a brain metastasis, each successfully treated with a neuroendoscopic approach. Thanks to this minimally invasive approach, we achieved good therapeutic results: we obtained a histological diagnosis; we controlled intracranial hypertension by treating the associated hydrocephalus and, above all, compared with a microsurgical approach, we reduced the risks related to dissection and brain retraction. Moreover, in both cases, neuroendoscopy enabled us to identify an initial, precocious subependymal tumor spreading below the threshold of magnetic resonance imaging (MRI) detection. This finding, undetected in pre-operative MRI scans, was then evident during follow-up neuroimaging studies. In light of these data, a neuroendoscopic approach might play a leading role in better defining the prognosis and optimally tailored management protocols for GBM and brain metastasis. PMID:23271915

  7. The potential of polymeric micelles in the context of glioblastoma therapy

    PubMed Central

    Morshed, Ramin A.; Cheng, Yu; Auffinger, Brenda; Wegscheid, Michelle L.; Lesniak, Maciej S.

    2013-01-01

    Glioblastoma multiforme (GBM), a type of malignant glioma, is the most common form of brain cancer found in adults. The current standard of care for GBM involves adjuvant temozolomide-based chemotherapy in conjunction with radiotherapy, yet patients still suffer from poor outcomes with a median survival of 14.6 months. Many novel therapeutic agents that are toxic to GBM cells in vitro cannot sufficiently accumulate at the site of an intracranial tumor after systemic administration. Thus, new delivery strategies must be developed to allow for adequate intratumoral accumulation of such therapeutic agents. Polymeric micelles offer the potential to improve delivery to brain tumors as they have demonstrated the capacity to be effective carriers of chemotherapy drugs, genes, and proteins in various preclinical GBM studies. In addition to this, targeting moieties and trigger-dependent release mechanisms incorporated into the design of these particles can promote more specific delivery of a therapeutic agent to a tumor site. However, despite these advantages, there are currently no micelle formulations targeting brain cancer in clinical trials. Here, we highlight key aspects of the design of polymeric micelles as therapeutic delivery systems with a review of their clinical applications in several non-brain tumor cancer types. We also discuss their potential to serve as nanocarriers targeting GBM, the major barriers preventing their clinical implementation in this disease context, as well as current approaches to overcome these limitations. PMID:24416018

  8. Pediatric thalamic glioblastoma associated with Ollier disease (multiple enchondromatosis): a rare case of concurrence.

    PubMed

    Ranger, Adrianna; Szymczak, Artur; Hammond, Robert R; Zelcer, Shayna

    2009-10-01

    Ollier disease and Maffucci syndrome are rare syndromes in which there is deforming dysplasia of cartilage, primarily but not exclusively involving the metaphyses and diaphyses of long bones. In a minority of patients, dysplasia can lead to sarcomatous degeneration, producing chondrosarcomas. There also appears to be an association with other neoplasms. Little has been written about the association between Ollier disease and intracranial tumors, and these papers have largely consisted of case reports in adults. The authors present the case of a 6-year-old girl with left arm osseous changes consistent with Ollier disease and a biopsy-proven thalamic glioblastoma multiforme. They then examine the co-occurrence of brain tumors in conjunction with a dyschondroplasia syndrome in children and adolescents to assess the presentation, treatment offered, and disease course of similar cases. Eight other such cases were identified, 6 in patients with Ollier disease (ranging in age from 7 to 18 years), and 2 with Maffucci syndrome (both in late adolescence). Including our own patient, 7 of the 9 cases of comorbid dyschondroplasia and intracranial malignancy occurred in girls. Some patients presented soon after the acute onset of symptoms, and others had a more subtle, protracted course over as many as 2 years. Some tumors were deemed resectable and others not. In only 1 instance was follow-up beyond 1 year reported.

  9. REST controls self-renewal and tumorigenic competence of human glioblastoma cells.

    PubMed

    Conti, Luciano; Crisafulli, Laura; Caldera, Valentina; Tortoreto, Monica; Brilli, Elisa; Conforti, Paola; Zunino, Franco; Magrassi, Lorenzo; Schiffer, Davide; Cattaneo, Elena

    2012-01-01

    The Repressor Element 1 Silencing Transcription factor (REST/NRSF) is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM) specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets. PMID:22701651

  10. The role of ion channels in the hypoxia-induced aggressiveness of glioblastoma

    PubMed Central

    Sforna, Luigi; Cenciarini, Marta; Belia, Silvia; D’Adamo, Maria Cristina; Pessia, Mauro; Franciolini, Fabio; Catacuzzeno, Luigi

    2015-01-01

    The malignancy of glioblastoma multiform (GBM), the most common and aggressive form of human brain tumors, strongly correlates with the presence of hypoxic areas, but the mechanisms controlling the hypoxia-induced aggressiveness are still unclear. GBM cells express a number of ion channels whose activity supports cell volume changes and increases in the cytosolic Ca2+ concentration, ultimately leading to cell proliferation, migration or death. In several cell types it has previously been shown that low oxygen levels regulate the expression and activity of these channels, and more recent data indicate that this also occurs in GBM cells. Based on these findings, it may be hypothesized that the modulation of ion channel activity or expression by the hypoxic environment may participate in the acquisition of the aggressive phenotype observed in GBM cells residing in a hypoxic environment. If this hypothesis will be confirmed, the use of available ion channels modulators may be considered for implementing novel therapeutic strategies against these tumors. PMID:25642170

  11. Effects of Anti-Angiogenesis on Glioblastoma Growth and Migration: Model to Clinical Predictions

    PubMed Central

    Scribner, Elizabeth; Saut, Olivier; Province, Paula; Bag, Asim; Colin, Thierry; Fathallah-Shaykh, Hassan M.

    2014-01-01

    Glioblastoma multiforme (GBM) causes significant neurological morbidity and short survival times. Brain invasion by GBM is associated with poor prognosis. Recent clinical trials of bevacizumab in newly-diagnosed GBM found no beneficial effects on overall survival times; however, the baseline health-related quality of life and performance status were maintained longer in the bevacizumab group and the glucocorticoid requirement was lower. Here, we construct a clinical-scale model of GBM whose predictions uncover a new pattern of recurrence in 11/70 bevacizumab-treated patients. The findings support an exception to the Folkman hypothesis: GBM grows in the absence of angiogenesis by a cycle of proliferation and brain invasion that expands necrosis. Furthermore, necrosis is positively correlated with brain invasion in 26 newly-diagnosed GBM. The unintuitive results explain the unusual clinical effects of bevacizumab and suggest new hypotheses on the dynamic clinical effects of migration by active transport, a mechanism of hypoxia-driven brain invasion. PMID:25506702

  12. Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation

    PubMed Central

    Blake, Sophia M; Stricker, Stefan H; Halavach, Hanna; Poetsch, Anna R; Cresswell, George; Kelly, Gavin; Kanu, Nnennaya; Marino, Silvia; Luscombe, Nicholas M; Pollard, Steven M; Behrens, Axel

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors. DOI: http://dx.doi.org/10.7554/eLife.08711.001 PMID:26984279

  13. Phenotypic dynamics of microglial and monocyte-derived cells in glioblastoma-bearing mice

    PubMed Central

    Ricard, Clément; Tchoghandjian, Aurélie; Luche, Hervé; Grenot, Pierre; Figarella-Branger, Dominique; Rougon, Geneviève; Malissen, Marie; Debarbieux, Franck

    2016-01-01

    Inflammatory cells, an integral component of tumor evolution, are present in Glioblastomas multiforme (GBM). To address the cellular basis and dynamics of the inflammatory microenvironment in GBM, we established an orthotopic syngenic model by grafting GL261-DsRed cells in immunocompetent transgenic LysM-EGFP//CD11c-EYFP reporter mice. We combined dynamic spectral two-photon imaging with multiparametric cytometry and multicolor immunostaining to characterize spatio-temporal distribution, morphology and activity of microglia and blood-derived infiltrating myeloid cells in live mice. Early stages of tumor development were dominated by microglial EYFP+ cells invading the tumor, followed by massive recruitment of circulating LysM-EGFP+ cells. Fluorescent invading cells were conventional XCR1+ and monocyte-derived dendritic cells distributed in subpopulations of different maturation stages, located in different areas relative to the tumor core. The lethal stage of the disease was characterized by the progressive accumulation of EGFP+/EYFP+ monocyte-derived dendritic cells. This local phenotypic regulation of monocyte subtypes marked a transition in the immune response. PMID:27193333

  14. Glioblastoma stem cells: radiobiological response to ionising radiations of different qualities.

    PubMed

    Pecchia, I; Dini, V; Ricci-Vitiani, L; Biffoni, M; Balduzzi, M; Fratini, E; Belli, M; Campa, A; Esposito, G; Cirrone, G; Romano, F; Stancampiano, C; Pelacchi, F; Pallini, R; Tabocchini, M A

    2015-09-01

    Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour, with very poor prognosis. The high recurrence rate and failure of conventional treatments are expected to be related to the presence of radio-resistant cancer stem cells (CSCs) inside the tumour mass. CSCs can both self-renew and differentiate into the heterogeneous lineages of cancer cells. Recent evidence showed a higher effectiveness of C-ions and protons in inactivating CSCs, suggesting a potential advantage of Hadrontherapy compared with conventional radiotherapy for GBM treatment. To investigate the mechanisms involved in the molecular and cellular responses of CSCs to ionising radiations, two GBM stem cell (GSC) lines, named lines 1 and 83, which were derived from patients with different clinical outcomes and having different metabolic profiles (as shown by NMR spectroscopy), were irradiated with (137)Cs photons and with protons or C-ions of 62 MeV u(-1) in the dose range of 5-40 Gy. The biological effects investigated were: cell death, cell cycle progression, and DNA damage induction and repair. Preliminary results show a different response to ionising radiation between the two GSC lines for the different end points investigated. Further experiments are in progress to consolidate the data and to get more insights on the influence of radiation quality.

  15. High-Throughput Chemical Screens Identify Disulfiram as an Inhibitor of Human Glioblastoma Stem Cells

    PubMed Central

    Hothi, Parvinder; Martins, Timothy J.; Chen, LiPing; Deleyrolle, Loic; Yoon, Jae-Geun; Reynolds, Brent; Foltz, Greg

    2012-01-01

    Glioblastoma Multiforme (GBM) continues to have a poor patient prognosis despite optimal standard of care. Glioma stem cells (GSCs) have been implicated as the presumed cause of tumor recurrence and resistance to therapy. With this in mind, we screened a diverse chemical library of 2,000 compounds to identify therapeutic agents that inhibit GSC proliferation and therefore have the potential to extend patient survival. High-throughput screens (HTS) identified 78 compounds that repeatedly inhibited cellular proliferation, of which 47 are clinically approved for other indications and 31 are experimental drugs. Several compounds (such as digitoxin, deguelin, patulin and phenethyl caffeate) exhibited high cytotoxicity, with half maximal inhibitory concentrations (IC50) in the low nanomolar range. In particular, the FDA approved drug for the treatment of alcoholism, disulfiram (DSF), was significantly potent across multiple patient samples (IC50 of 31.1 nM). The activity of DSF was potentiated by copper (Cu), which markedly increased GSC death. DSF–Cu inhibited the chymotrypsin-like proteasomal activity in cultured GSCs, consistent with inactivation of the ubiquitin-proteasome pathway and the subsequent induction of tumor cell death. Given that DSF is a relatively non-toxic drug that can penetrate the blood-brain barrier, we suggest that DSF should be tested (as either a monotherapy or as an adjuvant) in pre-clinical models of human GBM. Data also support targeting of the ubiquitin-proteasome pathway as a therapeutic approach in the treatment of GBM. PMID:23165409

  16. Self-assembled 20-nm (64)Cu-micelles enhance accumulation in rat glioblastoma.

    PubMed

    Seo, Jai Woong; Ang, JooChuan; Mahakian, Lisa M; Tam, Sarah; Fite, Brett; Ingham, Elizabeth S; Beyer, Janine; Forsayeth, John; Bankiewicz, Krystof S; Xu, Ting; Ferrara, Katherine W

    2015-12-28

    There is an urgent need to develop nanocarriers for the treatment of glioblastoma multiforme (GBM). Using co-registered positron emission tomography (PET) and magnetic resonance (MR) images, here we performed systematic studies to investigate how a nanocarrier's size affects the pharmacokinetics and biodistribution in rodents with a GBM xenograft. In particular, highly stable, long-circulating three-helix micelles (3HM), based on a coiled-coil protein tertiary structure, were evaluated as an alternative to larger nanocarriers. While the circulation half-life of the 3HM was similar to 110-nm PEGylated liposomes (t1/2=15.5 and 16.5h, respectively), the 20-nm micelles greatly enhanced accumulation within a U87MG xenograft in nu/nu rats after intravenous injection. After accounting for tumor blood volume, the extravasated nanoparticles were quantified from the PET images, yielding ~0.77%ID/cm(3) for the micelles and 0.45%ID/cm(3) for the liposomes. For GBM lesions with a volume greater than 100mm(3), 3HM accumulation was enhanced both within the detectable tumor and in the surrounding brain parenchyma. Further, the nanoparticle accumulation was shown to extend to the margins of the GBM xenograft. In summary, 3HM provides an attractive nanovehicle for carrying treatment to GBM.

  17. Amplified and Homozygously Deleted Genes in Glioblastoma: Impact on Gene Expression Levels

    PubMed Central

    Crespo, Inês; Tão, Hermínio; Nieto, Ana Belen; Rebelo, Olinda; Domingues, Patrícia; Vital, Ana Luísa; Patino, Maria del Carmen; Barbosa, Marcos; Lopes, Maria Celeste; Oliveira, Catarina Resende; Orfao, Alberto; Tabernero, María Dolores

    2012-01-01

    Background Glioblastoma multiforme (GBM) displays multiple amplicons and homozygous deletions that involve relevant pathogenic genes and other genes whose role remains unknown. Methodology Single-nucleotide polymorphism (SNP)-arrays were used to determine the frequency of recurrent amplicons and homozygous deletions in GBM (n = 46), and to evaluate the impact of copy number alterations (CNA) on mRNA levels of the genes involved. Principal Findings Recurrent amplicons were detected for chromosomes 7 (50%), 12 (22%), 1 (11%), 4 (9%), 11 (4%), and 17 (4%), whereas homozygous deletions involved chromosomes 9p21 (52%) and 10q (22%). Most genes that displayed a high correlation between DNA CNA and mRNA levels were coded in the amplified chromosomes. For some amplicons the impact of DNA CNA on mRNA expression was restricted to a single gene (e.g., EGFR at 7p11.2), while for others it involved multiple genes (e.g., 11 and 5 genes at 12q14.1–q15 and 4q12, respectively). Despite homozygous del(9p21) and del(10q23.31) included multiple genes, association between these DNA CNA and RNA expression was restricted to the MTAP gene. Conclusions Overall, our results showed a high frequency of amplicons and homozygous deletions in GBM with variable impact on the expression of the genes involved, and they contributed to the identification of other potentially relevant genes. PMID:23029397

  18. The DNA damage/repair cascade in glioblastoma cell lines after chemotherapeutic agent treatment.

    PubMed

    Annovazzi, Laura; Caldera, Valentina; Mellai, Marta; Riganti, Chiara; Battaglia, Luigi; Chirio, Daniela; Melcarne, Antonio; Schiffer, Davide

    2015-01-01

    Therapeutic resistance in glioblastoma multiforme (GBM) has been linked to a subpopulation of cells with stem cell-like properties, the glioma stem cells (GSCs), responsible for cancer progression and recurrence. This study investigated the in vitro cytotoxicity of three chemotherapeutics, temozolomide (TMZ), doxorubicin (Dox) and paclitaxel (PTX) on glioma cell lines, by analyzing the molecular mechanisms leading to DNA repair and cell resistance, or to cell death. The drugs were tested on 16 GBM cell lines, grown as neurospheres (NS) or adherent cells (AC), by studying DNA damage occurrence by Comet assay, the expression by immunofluorescence and western blotting of checkpoint/repair molecules and apoptosis. The three drugs were able to provoke a genotoxic injury and to inhibit dose- and time-dependently cell proliferation, more evidently in AC than in NS. The first cell response to DNA damage was the activation of the damage sensors (p-ATM, p-53BP1, γ-H2AX), followed by repair effectors; the expression of checkpoint/repair molecules appeared higher in NS than in AC. The non-homologous repair pathway (NHEJ) seemed more involved than the homologous one (HR). Apoptosis occurred after long treatment times, but only a small percentage of cells in NS underwent death, even at high drug concentration, whereas most cells survived in a quiescent state and resumed proliferation after drug removal. In tumor specimens, checkpoint/repair proteins were constitutively expressed in GBMs, but not in low-grade gliomas.

  19. Systematic Genetic Analysis Identifies Cis-eQTL Target Genes Associated with Glioblastoma Patient Survival

    PubMed Central

    Chen, Qing-Rong; Hu, Ying; Yan, Chunhua; Buetow, Kenneth; Meerzaman, Daoud

    2014-01-01

    Prior expression quantitative trait locus (eQTL) studies have demonstrated heritable variation determining differences in gene expression. The majority of eQTL studies were based on cell lines and normal tissues. We performed cis-eQTL analysis using glioblastoma multiforme (GBM) data sets obtained from The Cancer Genome Atlas (TCGA) to systematically investigate germline variation’s contribution to tumor gene expression levels. We identified 985 significant cis-eQTL associations (FDR<0.05) mapped to 978 SNP loci and 159 unique genes. Approximately 57% of these eQTLs have been previously linked to the gene expression in cell lines and normal tissues; 43% of these share cis associations known to be associated with functional annotations. About 25% of these cis-eQTL associations are also common to those identified in Breast Cancer from a recent study. Further investigation of the relationship between gene expression and patient clinical information identified 13 eQTL genes whose expression level significantly correlates with GBM patient survival (p<0.05). Most of these genes are also differentially expressed in tumor samples and organ-specific controls (p<0.05). Our results demonstrated a significant relationship of germline variation with gene expression levels in GBM. The identification of eQTLs-based expression associated survival might be important to the understanding of genetic contribution to GBM cancer prognosis. PMID:25133526

  20. Cancer association study of aminoacyl-tRNA synthetase signaling network in glioblastoma.

    PubMed

    Kim, Yong-Wan; Kwon, Changhyuk; Liu, Juinn-Lin; Kim, Se Hoon; Kim, Sunghoon

    2012-01-01

    Aminoacyl-tRNA synthetases (ARSs) and ARS-interacting multifunctional proteins (AIMPs) exhibit remarkable functional versatility beyond their catalytic activities in protein synthesis. Their non-canonical functions have been pathologically linked to cancers. Here we described our integrative genome-wide analysis of ARSs to show cancer-associated activities in glioblastoma multiforme (GBM), the most aggressive malignant primary brain tumor. We first selected 23 ARS/AIMPs (together referred to as ARSN), 124 cancer-associated druggable target genes (DTGs) and 404 protein-protein interactors (PPIs) of ARSs using NCI's cancer gene index. 254 GBM affymetrix microarray data in The Cancer Genome Atlas (TCGA) were used to identify the probe sets whose expression were most strongly correlated with survival (Kaplan-Meier plots versus survival times, log-rank t-test <0.05). The analysis identified 122 probe sets as survival signatures, including 5 of ARSN (VARS, QARS, CARS, NARS, FARS), and 115 of DTGs and PPIs (PARD3, RXRB, ATP5C1, HSP90AA1, CD44, THRA, TRAF2, KRT10, MED12, etc). Of note, 61 survival-related probes were differentially expressed in three different prognosis subgroups in GBM patients and showed correlation with established prognosis markers such as age and phenotypic molecular signatures. CARS and FARS also showed significantly higher association with different molecular networks in GBM patients. Taken together, our findings demonstrate evidence for an ARSN biology-dominant contribution in the biology of GBM.

  1. Impact of the biophysical features of a 3D gelatin microenvironment on glioblastoma malignancy.

    PubMed

    Pedron, S; Harley, B A C

    2013-12-01

    Three-dimensional tissue engineered constructs provide a platform to examine how the local extracellular matrix (ECM) contributes to the malignancy of cancers such as human glioblastoma multiforme. Improved resolution of how local matrix biophysical features impact glioma proliferation, genomic and signal transduction paths, as well as phenotypic malignancy markers would complement recent improvements in our understanding of molecular mechanisms associated with enhanced malignancy. Here, we report the use of a gelatin methacrylate (GelMA) platform to create libraries of three-dimensional biomaterials to identify combinations of biophysical features that promote malignant phenotypes of human U87MG glioma cells. We noted key biophysical properties, namely matrix density, crosslinking density, and biodegradability, that significantly impact glioma cell morphology, proliferation, and motility. Gene expression profiles and secreted markers of increased malignancy, notably VEGF, MMP-2, MMP-9, HIF-1, and the ECM protein fibronectin, were also significantly impacted by the local biophysical environment as well as matrix-induced deficits in diffusion-mediated oxygen and nutrient biotransport. Overall, this biomaterial system provides a flexible platform to explore the role biophysical factors play in the etiology, growth, and subsequent invasive spreading of gliomas.

  2. Reconstructed Metabolic Network Models Predict Flux-Level Metabolic Reprogramming in Glioblastoma

    PubMed Central

    Özcan, Emrah; Çakır, Tunahan

    2016-01-01

    Developments in genome scale metabolic modeling techniques and omics technologies have enabled the reconstruction of context-specific metabolic models. In this study, glioblastoma multiforme (GBM), one of the most common and aggressive malignant brain tumors, is investigated by mapping GBM gene expression data on the growth-implemented brain specific genome-scale metabolic network, and GBM-specific models are generated. The models are used to calculate metabolic flux distributions in the tumor cells. Metabolic phenotypes predicted by the GBM-specific metabolic models reconstructed in this work reflect the general metabolic reprogramming of GBM, reported both in in-vitro and in-vivo experiments. The computed flux profiles quantitatively predict that major sources of the acetyl-CoA and oxaloacetic acid pool used in TCA cycle are pyruvate dehydrogenase from glycolysis and anaplerotic flux from glutaminolysis, respectively. Also, our results, in accordance with recent studies, predict a contribution of oxidative phosphorylation to ATP pool via a slightly active TCA cycle in addition to the major contributor aerobic glycolysis. We verified our results by using different computational methods that incorporate transcriptome data with genome-scale models and by using different transcriptome datasets. Correct predictions of flux distributions in glycolysis, glutaminolysis, TCA cycle and lipid precursor metabolism validate the reconstructed models for further use in future to simulate more specific metabolic patterns for GBM. PMID:27147948

  3. miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma

    PubMed Central

    Kouri, Fotini M.; Hurley, Lisa A.; Daniel, Weston L.; Day, Emily S.; Hua, Youjia; Hao, Liangliang; Peng, Chian-Yu; Merkel, Timothy J.; Queisser, Markus A.; Ritner, Carissa; Zhang, Hailei; James, C. David; Sznajder, Jacob I.; Chin, Lynda; Giljohann, David A.; Kessler, John A.; Peter, Marcus E.; Mirkin, Chad A.

    2015-01-01

    Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c-Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182-SNAs penetrated the blood–brain/blood–tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM. PMID:25838542

  4. PEGylated squalenoyl-gemcitabine nanoparticles for the treatment of glioblastoma.

    PubMed

    Gaudin, Alice; Song, Eric; King, Amanda R; Saucier-Sawyer, Jennifer K; Bindra, Ranjit; Desmaële, Didier; Couvreur, Patrick; Saltzman, W Mark

    2016-10-01

    New treatments for glioblastoma multiforme (GBM) are desperately needed, as GBM prognosis remains poor, mainly due to treatment resistance, poor distribution of therapeutics in the tumor tissue, and fast metabolism of chemotherapeutic drugs in the brain extracellular space. Convection-enhanced delivery (CED) of nanoparticles (NPs) has been shown to improve the delivery of chemotherapeutic drugs to the tumor bed, providing sustained release, and enhancing survival of animals with intracranial tumors. Here we administered gemcitabine, a nucleoside analog used as a first line treatment for a wide variety of extracranial solid tumors, within squalene-based NPs using CED, to overcome the above-mentioned challenges of GBM treatment. Small percentages of poly(ethylene) glycol (PEG) dramatically enhanced the distribution of squalene-gemcitabine nanoparticles (SQ-Gem NPs) in healthy animals and tumor-bearing animals after administration by CED. When tested in an orthotopic model of GBM, SQ-Gem-PEG NPs demonstrated significantly improved therapeutic efficacy compared to free gemcitabine, both as a chemotherapeutic drug and as a radiosensitizer. Furthermore, MR contrast agents were incorporated into the SQ-Gem-PEG NP formulation, providing a way to non-invasively track the NPs during infusion. PMID:27521616

  5. PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas.

    PubMed

    Ozawa, Tatsuya; Brennan, Cameron W; Wang, Lu; Squatrito, Massimo; Sasayama, Takashi; Nakada, Mitsutoshi; Huse, Jason T; Pedraza, Alicia; Utsuki, Satoshi; Yasui, Yoshie; Tandon, Adesh; Fomchenko, Elena I; Oka, Hidehiro; Levine, Ross L; Fujii, Kiyotaka; Ladanyi, Marc; Holland, Eric C

    2010-10-01

    Gene rearrangement in the form of an intragenic deletion is the primary mechanism of oncogenic mutation of the epidermal growth factor receptor (EGFR) gene in gliomas. However, the incidence of platelet-derived growth factor receptor-α (PDGFRA) gene rearrangement in these tumors is unknown. We investigated the PDGFRA locus in PDGFRA-amplified gliomas and identified two rearrangements, including the first case of a gene fusion between kinase insert domain receptor (KDR) (VEGFRII) and the PDGFRA gene, and six cases of PDGFRA(Δ8, 9), an intragenic deletion rearrangement. The PDGFRA(Δ8, 9) mutant was common, being present in 40% of the glioblastoma multiformes (GBMs) with PDGFRA amplification. Tumors with these two types of PDGFRA rearrangement displayed histologic features of oligodendroglioma, and the gene products of both rearrangements showed constitutively elevated tyrosine kinase activity and transforming potential that was reversed by PDGFR blockade. These results suggest the possibility that these PDGFRA mutants behave as oncogenes in this subset of gliomas, and that the prevalence of such rearrangements may have been considerably underestimated. PMID:20889717

  6. Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma

    PubMed Central

    Shao, Huilin; Chung, Jaehoon; Lee, Kyungheon; Balaj, Leonora; Min, Changwook; Carter, Bob S.; Hochberg, Fred H.; Breakefield, Xandra O.; Lee, Hakho; Weissleder, Ralph

    2015-01-01

    Real-time monitoring of drug efficacy in glioblastoma multiforme (GBM) is a major clinical problem as serial re-biopsy of primary tumours is often not a clinical option. MGMT (O6-methylguanine DNA methyltransferase) and APNG (alkylpurine-DNA-N-glycosylase) are key enzymes capable of repairing temozolomide-induced DNA damages and their levels in tissue are inversely related to treatment efficacy. Yet, serial clinical analysis remains difficult, and, when done, primarily relies on promoter methylation studies of tumour biopsy material at the time of initial surgery. Here we present a microfluidic chip to analyse mRNA levels of MGMT and APNG in enriched tumour exosomes obtained from blood. We show that exosomal mRNA levels of these enzymes correlate well with levels found in parental cells and that levels change considerably during treatment of seven patients. We propose that if validated on a larger cohort of patients, the method may be used to predict drug response in GBM patients. PMID:25959588

  7. Hyaluronic acid-conjugated liposome nanoparticles for targeted delivery to CD44 overexpressing glioblastoma cells

    PubMed Central

    Hayward, Stephen L.; Wilson, Christina L.; Kidambi, Srivatsan

    2016-01-01

    Glioblastoma Multiforme (GBM) is a highly prevalent and deadly brain malignancy characterized by poor prognosis and restricted disease management potential. Despite the success of nanocarrier systems to improve drug/gene therapy for cancer, active targeting specificity remains a major hurdle for GBM. Additionally, since the brain is a multi-cell type organ, there is a critical need to develop an approach to distinguish between GBM cells and healthy brain cells for safe and successful treatment. In this report, we have incorporated hyaluronic acid (HA) as an active targeting ligand for GBM. To do so, we employed HA conjugated liposomes (HALNPs) to study the uptake pathway in key cells in the brain including primary astrocytes, microglia, and human GBM cells. We observed that the HALNPs specifically target GBM cells over other brain cells due to higher expression of CD44 in tumor cells. Furthermore, CD44 driven HALNP uptake into GBM cells resulted in lysosomal evasion and increased efficacy of Doxorubicin, a model anti-neoplastic agent, while the astrocytes and microglia cells exhibited extensive HALNP-lysosome co-localization and decreased antineoplastic potency. In summary, novel CD44 targeted lipid based nanocarriers appear to be proficient in mediating site-specific delivery of drugs via CD44 receptors in GBM cells, with an improved therapeutic margin and safety. PMID:27120809

  8. Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma.

    PubMed

    Hicks, M J; Funato, K; Wang, L; Aronowitz, E; Dyke, J P; Ballon, D J; Havlicek, D F; Frenk, E Z; De, B P; Chiuchiolo, M J; Sondhi, D; Hackett, N R; Kaminsky, S M; Tabar, V; Crystal, R G

    2015-01-01

    The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice. AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin), an anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and western blotting. Immunohistochemistry showed that bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density and tumor volume, and increased survival. Administration of AAVrh.10BevMab 1 week after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. These data support the strategy of AAV-mediated central nervous system gene therapy to treat GBM, overcoming the blood-brain barrier through local, persistent delivery of an anti-angiogenesis monoclonal antibody.

  9. Engineering a High-Throughput 3-D In Vitro Glioblastoma Model

    PubMed Central

    Fan, Yantao; Avci, Naze G.; Nguyen, Duong T.; Dragomir, Andrei; Xu, Feng; Akay, Metin

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults because of its highly invasive behavior. The existing treatment for GBM, which involves a combination of resection, chemotherapy, and radiotherapy, has a very limited success rate with a median survival rate of <1 year. This is mainly because of the failure of early detection and effective treatment. We designed a novel 3-D GBM cell culture model based on microwells that could mimic in vitro environment and help to bypass the lack of suitable animal models for preclinical toxicity tests. Microwells were fabricated from simple and inexpensive polyethylene glycol material for the control of in vitro 3-D culture. We applied the 3-D micropatterning system to GBM (U-87) cells using the photolithography technique to control the cell spheroids’ shape, size, and thickness. Our preliminary results suggested that uniform GBM spheroids can be formed in 3-D, and the size of these GBM spheroids depends on the size of microwells. The viability of the spheroids generated in this manner was quantitatively evaluated using live/dead assay and shown to improve over 21 days. We believe that in vitro 3-D cell culture model could help to reduce the time of the preclinical brain tumor growth studies. The proposed novel platform could be useful and cost-effective for high-throughput screening of cancer drugs and assessment of treatment responses. PMID:27170911

  10. c-Met–mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma

    PubMed Central

    Huang, Menggui; Liu, Tianrun; Ma, Peihong; Mitteer, R. Alan; Zhang, Zhenting; Kim, Hyun Jun; Yeo, Eujin; Zhang, Duo; Cai, Peiqiang; Li, Chunsheng; Zhang, Lin; Zhao, Botao; Roccograndi, Laura; O’Rourke, Donald M.; Dahmane, Nadia; Gong, Yanqing; Koumenis, Constantinos

    2016-01-01

    Aberrant vascularization is a hallmark of cancer progression and treatment resistance. Here, we have shown that endothelial cell (EC) plasticity drives aberrant vascularization and chemoresistance in glioblastoma multiforme (GBM). By utilizing human patient specimens, as well as allograft and genetic murine GBM models, we revealed that a robust endothelial plasticity in GBM allows acquisition of fibroblast transformation (also known as endothelial mesenchymal transition [Endo-MT]), which is characterized by EC expression of fibroblast markers, and determined that a prominent population of GBM-associated fibroblast-like cells have EC origin. Tumor ECs acquired the mesenchymal gene signature without the loss of EC functions, leading to enhanced cell proliferation and migration, as well as vessel permeability. Furthermore, we identified a c-Met/ETS-1/matrix metalloproteinase–14 (MMP-14) axis that controls VE-cadherin degradation, Endo-MT, and vascular abnormality. Pharmacological c-Met inhibition induced vessel normalization in patient tumor–derived ECs. Finally, EC-specific KO of Met inhibited vascular transformation, normalized blood vessels, and reduced intratumoral hypoxia, culminating in suppressed tumor growth and prolonged survival in GBM-bearing mice after temozolomide treatment. Together, these findings illustrate a mechanism that controls aberrant tumor vascularization and suggest that targeting Endo-MT may offer selective and efficient strategies for antivascular and vessel normalization therapies in GBM, and possibly other malignant tumors. PMID:27043280

  11. The Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells

    PubMed Central

    Atif, Fahim; Patel, Neil R.; Yousuf, Seema; Stein, Donald G.

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common and most aggressive malignant brain tumor. Despite optimal treatment and evolving standard of care, the median survival of patients diagnosed with GBM is only 12–15 months. In this study, we combined progesterone (PROG) and temozolomide (TMZ), a standard chemotherapeutic agent for human GBM, to test whether PROG enhances the antitumor effects of TMZ and reduces its side effects. Two WHO grade IV human GBM cells lines (U87MG and U118MG) and primary human dermal fibroblasts (HDFs) were repeatedly exposed to PROG and TMZ either alone or in combination for 3 and 6 days. Cell death was measured by MTT reduction assay. PROG and TMZ individually induced tumor cell death in a dose-dependent manner. PROG at high doses produced more cell death than TMZ alone. When combined, PROG enhanced the cell death-inducing effect of TMZ. In HDFs, PROG did not reduce viability even at the same high cytotoxic doses, but TMZ did so in a dose-dependent manner. In combination, PROG reduced TMZ toxicity in HDFs. PROG alone and in combination with TMZ suppressed the EGFR/PI3K/Akt/mTOR signaling pathway and MGMT expression in U87MG cells, thus suppressing cell proliferation. PROG and TMZ individually reduced cell migration in U87MG cells but did so more effectively in combination. PROG enhances the cytotoxic effects of TMZ in GBM cells and reduces its toxic side effects in healthy primary cells. PMID:26110872

  12. ILKAP, ILK and PINCH1 control cell survival of p53-wildtype glioblastoma cells after irradiation

    PubMed Central

    Hausmann, Christina; Temme, Achim; Cordes, Nils; Eke, Iris

    2015-01-01

    The prognosis is generally poor for patients suffering from glioblastoma multiforme (GBM) due to radiation and drug resistance. Prosurvival signaling originating from focal adhesion hubs essentially contributes to therapy resistance and tumor aggressiveness. As the underlying molecular mechanisms remain largely elusive, we addressed whether targeting of the focal adhesion proteins particularly interesting new cysteine-histidine-rich 1 (PINCH1), integrin-linked kinase (ILK) and ILK associated phosphatase (ILKAP) modulates GBM cell radioresistance. Intriguingly, PINCH1, ILK and ILKAP depletion sensitized p53-wildtype, but not p53-mutant, GBM cells to radiotherapy. Concomitantly, these cells showed inactivated Glycogen synthase kinase-3β (GSK3β) and reduced proliferation. For PINCH1 and ILKAP knockdown, elevated levels of radiation-induced γH2AX/53BP1-positive foci, as a marker for DNA double strand breaks, were observed. Mechanistically, we identified radiation-induced phosphorylation of DNA protein kinase (DNAPK), an important DNA repair protein, to be dependent on ILKAP. This interaction was fundamental to radiation survival of p53-wildtype GBM cells. Conclusively, our data suggest an essential role of PINCH1, ILK and ILKAP for the radioresistance of p53-wildtype GBM cells and provide evidence for DNAPK functioning as a central mediator of ILKAP signaling. Strategies for targeting focal adhesion proteins in combination with radiotherapy might be a promising approach for patients with GBM. PMID:26460618

  13. Expression and prognostic value of SFRP1 and β-catenin in patients with glioblastoma

    PubMed Central

    CHANG, LIANG; LEI, XUHUI; QIN, YU; ZENG, GUANGCHUN; ZHANG, XUEXIN; JIN, HUA; WANG, CHAO; WANG, XIN; SU, JUN

    2016-01-01

    The roles of secreted frizzled-related protein-1 (SFRP1) and β-catenin in human cancer have been widely studied, and it has recently been demonstrated that these proteins are associated with numerous human carcinomas. However, their clinical significance in glioblastoma multiforme (GBM) has not been examined. The current study aimed to analyze the correlation between the expression of SFRP1 and β-catenin, and clinicopathological characteristics in GBM patients. The expression of SFRP1 and β-catenin was assessed by immunohistochemistry in 113 samples of GBM and 40 normal brain tissues. Compared with normal brain tissues, GBM tissues exhibited significantly lower expression of SFRP1, and higher expression of β-catenin (both P<0.05). A Kaplan-Meier analysis revealed that patients with positive SFRP1 expression had a significantly longer overall survival (OS) time relative to those with negative SFRP1 expression (P<0.000), and that patients with positive β-catenin expression had a shorter OS time than those with negative β-catenin expression (P<0.000). A multivariate Cox regression analysis indicated that adjuvant treatment, SFRP1 expression and β-catenin expression were independent prognostic factors for OS (P<0.000, P=0.008 and P=0.001, respectively) in patients with GBM. The current data suggest that expression of SFRP1 and β-catenin may be considered significant prognostic indicators for patients with GBM. PMID:26870169

  14. Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation.

    PubMed

    Blake, Sophia M; Stricker, Stefan H; Halavach, Hanna; Poetsch, Anna R; Cresswell, George; Kelly, Gavin; Kanu, Nnennaya; Marino, Silvia; Luscombe, Nicholas M; Pollard, Steven M; Behrens, Axel

    2016-03-17

    Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors.

  15. Evaluation of novel imidazotetrazine analogues designed to overcome temozolomide resistance and glioblastoma regrowth.

    PubMed

    Ramirez, Yulian P; Mladek, Ann C; Phillips, Roger M; Gynther, Mikko; Rautio, Jarkko; Ross, Alonzo H; Wheelhouse, Richard T; Sakaria, Jann N

    2015-01-01

    The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multiforme (GBM) cell lines and primary culture models are reported. Dose-response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repopulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR functions. DP68-induced interstrand DNA cross-links were demonstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell-cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced antiglioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collectively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DNA.

  16. P17.69FOTEMUSTINE TRATMENT: WHAT ABOUT GLIOBLASTOMA PATIENTS' QUALITY OF LIFE?

    PubMed Central

    Petruzzi, A.; Finocchiaro, C.Y.; Simonetti, G.; Gaviani, P.; Casali, C.; Silvani, A.; Lamperti, E.

    2014-01-01

    Glioblastoma Multiforme (GBM) is the most common and aggressive type of adult primary central nervous system tumor. The median survival in GBM patients is about 14 months. The prognosis of GBM is poor and in addition there is a very high probability of recurrence. For most patients with newly diagnosed GBM, the gold standard first-line treatment is represented by postoperative radiotherapy plus temozolomide (TMZ). There is not yet a standard of care for treatment of recurrent GBM. Recent phase II studies have demonstrated the efficacy of fotemustine (FTM) in the treatment of recurrent gliomas. To the best of our knowledge, however, no studies have investigated the quality of life in GBM patients treated with FTM as second-line treatment. We therefore sought to assess the quality of life of recurrent glioblastoma patients treated with FTM standard schedule as proposed by Addeo et al. (a dose of 80 mg/sqm every 2 weeks for five consecutive administrations as the induction phase and every 4 weeks at 80 mg/sqm as the maintenance phase). We approached 54 recurrent glioblastoma patients treated with FTM. Of these 54 eligible patients, we excluded 4 patients because they were not willing to participate in the research study and 10 because they did not meet one of the inclusion criteria, i.e. Mini Mental State Examination ≥ 25. We evaluated overall patients' quality of life through various tools: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC brain cancer module (QLQ-BN20), Beck Depression Inventory (BDI), State-Trait Anxiety Inventory form Y (STAI-Y), Hospital Anxiety and Depression Scale (HADS), Psychological Distress Inventory (PDI). Of the total of 40 patients, 18 patients completed the battery of tests both at the beginning of therapy and 2 months after the start of therapy. We found that patients reported higher levels of distress at two months after the start of therapy (mean value = 22.4) as compared to those experienced at the

  17. Annular bullous lesions with atypical erythema multiforme in leprosy.

    PubMed

    Shah, Aishani; Mahajan, Rashmi; Ninama, Kishan; Bilimoria, Freny

    2014-09-01

    Erythema nodosum leprosum (ENL) is an immune complex-mediated reaction that may complicate the course of multibacillary leprosy. Bullous lesions in Type II reaction, though reported, are exceedingly rare. We report the case of a 32 year old female patient who presented initially at our OPD with erythema nodosum. Cutaneous examination revealed impaired sensation over dorsum of right foot and thickened right lateral popliteal nerve. Slit skin smear (SSS) from ear lobes revealed AFB with a bacteriological index of 2+. She was started on MDT, tablet ofloxacin 200 mg twice a day, and 30 mg oral prednisolone. Two months later, she presented with generalised pruritus, large target lesions over the back, and hemorrhagic bullae over lower extremities and annular pattern of bullae, over both arms. A SSS was repeated which was positive for AFB. Histopathology from bullous lesions was consistent with ENL. Direct Immunofluorescence (DIF) study was negative. Our patient improved rapidly after she was started on thalidomide 100 mg twice daily, with withdrawal of ofloxacin. Erythema Multiforme (EMF) and annular bullous lesions have been reported in patients on treatment with ofloxacin. This case is being presented due to the unusual and varied manifestation of Type II lepra reaction in a 34 year old female patient. PMID:25509721

  18. Phenytoin Induced Erythema Multiforme after Cranial Radiation Therapy

    PubMed Central

    Tekkök, İsmail Hakkı

    2015-01-01

    The prophylactic use of phenytoin during and after brain surgery and cranial irradiation is a common measure in brain tumor therapy. Phenytoin has been associated with variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis. EM associated with phenytoin and cranial radiation therapy (EMPACT) is a rare specific entity among patients with brain tumors receiving radiation therapy while on prophylactic anti-convulsive therapy. Herein we report a 41-year-old female patient with left temporal glial tumor who underwent surgery and then received whole brain radiation therapy and chemotherapy. After 24 days of continous prophylactic phenytoin therapy the patient developed minor skin reactions and 2 days later the patient returned with generalized erythamatous and itchy maculopapuler rash involving neck, chest, face, trunk, extremities. There was significant periorbital and perioral edema. Painful mucosal lesions consisting of oral and platal erosions also occurred and prevented oral intake significantly. Phenytoin was discontinued gradually. Systemic admistration of corticosteroids combined with topical usage of steroids for oral lesions resulted in complete resolution of eruptions in 3 weeks. All cutaneous lesions in patients with phenytoin usage with the radiotherapy must be evoluated with suspicion for EM. PMID:26361537

  19. Construction of multiform scFv antibodies using linker peptide.

    PubMed

    Wang, Shihua; Zheng, Cengjie; Liu, Ying; Zheng, Huirong; Wang, Zonghua

    2008-05-01

    Multiform single chain variable fragments (scFvs) including different length linker scFvs and bispecific scFv were constructed. The linker lengths of 0, 3, 5, 8, 12, and 15 amino acids between V(H) and V(L) of antideoxynivalenol (anti-DON) scFv were used to analyze the affinities of scFvs. The affinity constants of these scFvs increased when the linker was lower than 12 amino acids. The affinity constant would not change when the linker was longer than 12 amino acids. Fusion gene of anti-DON scFv and antizearalenone (anti-ZEN) scFv was also constructed through connection by a short peptide linker DNA to express a bispecific scFv. The affinity constants assay showed that the two scFvs of fusion bispecific scFv remained their own affinity compared to their parental scFvs. Competitive direct enzyme linked immunosorbent assay was used to detect DON and ZEN in contaminated wheat (Triticum aestivum L.) samples, and the results indicated that this bispecific scFv was applicable in DON and ZEN detection. This work confirmed that bispecific scFv could be successfully obtained, and might also have an application in diagnosing fungal infection, and breeding transgenic plants.

  20. Development, characterization, and in vitro trials of chloroaluminum phthalocyanine-magnetic nanoemulsion to hyperthermia and photodynamic therapies on glioblastoma as a biological model

    NASA Astrophysics Data System (ADS)

    de Paula, L. B.; Primo, F. L.; Jardim, D. R.; Morais, P. C.; Tedesco, A. C.

    2012-04-01

    A glioblastoma multiforme (GBM) is the highest grade glioma tumor (grade IV) and is the most malignant form of astrocytomas. Grade IV tumors, which are the most malignant and aggressive, affect people between the ages of 45 and 70 years. A GBM exhibits remarkable characteristics that include excessive proliferation, necrosis, genetic instability, and chemoresistance. Because of these characteristics, GBMs are difficult to treat and have a poor prognosis with a median survival of less than one year. New methods to achieve widespread distribution of therapeutic agents across infiltrative gliomas significantly improve brain tumor therapy. Photodynamic therapy (PDT) and hyperthermia (HPT) are well-established tumor therapies with minimal side effects while acting synergistically. This study introduces a new promising nanocarrier for the synergistic application of PDT and magnetic hyperthermia therapy against human glioma cell line T98 G, with cellular viability reduction down to as low as 17% compared with the control.

  1. MicroRNA-873 (MiRNA-873) Inhibits Glioblastoma Tumorigenesis and Metastasis by Suppressing the Expression of IGF2BP1

    PubMed Central

    Wang, Ren-jie; Li, Jian-wei; Bao, Bu-he; Wu, Huan-cheng; Du, Zhen-hua; Su, Jing-liang; Zhang, Ming-hua; Liang, Hai-qian

    2015-01-01

    Glioblastoma multiforme (GBM) is known as a highly malignant brain tumor with a poor prognosis, despite intensive research and clinical efforts. In this study, we observed that microRNA-873 (miR-873) was expressed at low levels in GBM and that the overexpression of miR-873 dramatically reduced the cell proliferation, migration, and invasion of GBM cells. Our further investigations of the inhibition mechanism indicated that miR-873 negatively affected the carcinogenesis and metastasis of GBM by down-regulating the expression of IGF2BP1, which stabilizes the mRNA transcripts of its target genes. These results demonstrate that miR-873 may constitute a potential target for GBM therapy. PMID:25670861

  2. Venous thromboembolism (VTE) and glioblastoma.

    PubMed

    Yust-Katz, Shlomit; Mandel, Jacob J; Wu, Jimin; Yuan, Ying; Webre, Courtney; Pawar, Tushar A; Lhadha, Harshad S; Gilbert, Mark R; Armstrong, Terri S

    2015-08-01

    The risk of venous thromboembolism (VTE) is high for patients with brain tumors (11-20 %). Glioblastoma (GBM) patients, in particular, have the highest risk of VTE (24-30 %). The Khorana scale is the most commonly used clinical scale to evaluate the risk of VTE in cancer patients but its efficacy in patients with GBM remains unclear. The aim of this study is to estimate the frequency of VTE in GBM patients and identify potential risk factors for the development of VTE during adjuvant chemotherapy. Furthermore, we intend to examine whether the Khorana scale accurately predicts the risk of VTE in GBM patients. We retrospectively reviewed the medical records of GBM patients treated at MD Anderson during the years 2005-2011. The study cohort included 440 patients of which 64 (14.5 %) developed VTE after the start of adjuvant treatment. The median time to develop VTE was 6.5 months from the start of adjuvant treatment. On multivariate analysis male sex, BMI ≥ 35, KPS ≤ 80, history of VTE and steroid therapy were significantly associated with the development of VTE. The Khorana scale was found to be an invalid VTE predictive model in GBM patients due to poor specificity. Of the 64 patients who developed a VTE, 36 were treated with anticoagulation, 2 with an IVC filter, and 21 with both. Complications (intracranial hemorrhage, bleeding in other organs and thrombocytopenia) secondary to anticoagulation were reported in 16 % (n = 10). VTE is common in patients with GBM. Our results did not validate the Khorana scale in GBM patients. Additional studies identifying which GBM patients are at highest risk for VTE are needed to enable further evaluation of VTE preventive measures in this selected group.

  3. Does gender matter in glioblastoma?

    PubMed

    Verger, E; Valduvieco, I; Caral, Ll; Pujol, T; Ribalta, T; Viñolas, N; Boget, T; Oleaga, L; Blanco, Y; Graus, F

    2011-10-01

    BACKGROUND The clinical outcome of glioblastoma (GBM) patients who receive radiotherapy alone or with chemotherapy is well established. However, little is known about how many patients do not receive this treatment. We consider it is important to investigate why a proportion of operated patients do not receive further treatment after surgery. METHODS We reviewed all consecutive GBM patients operated on in our hospital between January 2000 and December 2008. RESULTS A total of 216 patients with GBM were identified. Fifty-five (25%) did not receive any treatment after surgery. Univariate analysis showed that factors associated with no further treatment after surgery were older than 60 years (p=0.002), of female gender (p=0.03), had a KPS<70 (p<0.001) and had had a biopsy (p<0.001). Multivariate analysis indicated that age =60 years and KPS <70 were independent predictors of no further treatment after surgery. Gender was not an independent variable. However, women in the whole series were older than 60 years (p=0.01), and they had a worse KPS (p=0.02) and more biopsies (p=0.04) than men. In the whole group, median survival time was 10.4 months for men (n=125) vs. 7.2 months for women (n=91), log rank p<0.04. This difference was not observed in the group that was treated after surgery. CONCLUSIONS One out of four patients could not be treated after surgery. Independent predictors were older age and low KPS. These poor risk variables were more frequent in women and their survival was therefore lower than men in our series. PMID:21975336

  4. 10 CFR 26.101 - Conducting a confirmatory test for alcohol.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Conducting a confirmatory test for alcohol. 26.101 Section... Testing § 26.101 Conducting a confirmatory test for alcohol. (a) The confirmatory test must begin as soon... that meets the requirements of § 26.91(b) and (c) was used for the initial alcohol test, the same...

  5. Glioblastoma after radiotherapy for craniopharyngioma: case report

    SciTech Connect

    Ushio, Y.; Arita, N.; Yoshimine, T.; Nagatani, M.; Mogami, H.

    1987-07-01

    A 6-year-old girl developed a glioblastoma in the basal ganglia and brain stem 5 years after surgical excision and local irradiation (5460 cGy) for craniopharyngioma. Clinical and histological details are presented, and the literature on radiation-induced gliomas is reviewed.

  6. A case of contact dermatitis, erythema multiforme, and toxic epidermal necrolysis.

    PubMed

    Thompson, J A; Wansker, B A

    1981-12-01

    A young adult female patient, on prolonged corticosteroid therapy for nephrotic syndrome, developed erythema multiforme and toxic epidermal necrolysis following a double exposure to a locally applied perfume. We believe that this route of exposure should be re-emphasized. Toxic epidermal necrolysis, or the scalded skin syndrome, has become a well-recognized entity which may be divided into three distinct subgroups: the staphylococcal scalded skin syndrome, nonstaphylococcal or drug-induced scalded skin syndrome, and idiopathic. We present a patient who developed a dermatitis on her chest and abdomen after using a spray cologne, which resulted in the development of erythema multiforme with progression toxic epidermal necrolysis and, ultimately, her death.

  7. PCDH10 is required for the tumorigenicity of glioblastoma cells

    SciTech Connect

    Echizen, Kanae; Nakada, Mitsutoshi; Hayashi, Tomoatsu; Sabit, Hemragul; Furuta, Takuya; Nakai, Miyuki; Koyama-Nasu, Ryo; Nishimura, Yukiko; Taniue, Kenzui; Morishita, Yasuyuki; Hirano, Shinji; Terai, Kenta; Todo, Tomoki; Ino, Yasushi; Mukasa, Akitake; Takayanagi, Shunsaku; Ohtani, Ryohei; Saito, Nobuhito; Akiyama, Tetsu

    2014-01-31

    Highlights: • PCDH10 is required for the proliferation, survival and self-renewal of glioblastoma cells. • PCDH10 is required for glioblastoma cell migration and invasion. • PCDH10 is required for the tumorigenicity of glioblastoma cells. • PCDH10 may be a promising target for the therapy of glioblastoma. - Abstract: Protocadherin10 (PCDH10)/OL-protocadherin is a cadherin-related transmembrane protein that has multiple roles in the brain, including facilitating specific cell–cell connections, cell migration and axon guidance. It has recently been reported that PCDH10 functions as a tumor suppressor and that its overexpression inhibits proliferation or invasion of multiple tumor cells. However, the function of PCDH10 in glioblastoma cells has not been elucidated. In contrast to previous reports on other tumors, we show here that suppression of the expression of PCDH10 by RNA interference (RNAi) induces the growth arrest and apoptosis of glioblastoma cells in vitro. Furthermore, we demonstrate that knockdown of PCDH10 inhibits the growth of glioblastoma cells xenografted into immunocompromised mice. These results suggest that PCDH10 is required for the proliferation and tumorigenicity of glioblastoma cells. We speculate that PCDH10 may be a promising target for the therapy of glioblastoma.

  8. Fangchinoline suppresses the growth and invasion of human glioblastoma cells by inhibiting the kinase activity of Akt and Akt-mediated signaling cascades.

    PubMed

    Guo, Bingyu; Xie, Peng; Su, Jingyuan; Zhang, Tingting; Li, Xiaoming; Liang, Guobiao

    2016-02-01

    Glioblastoma multiforme (GBM) is one of the most palindromic and malignant central nervous system neoplasms, and the current treatment is not effectual for GBM. Research of specific medicine for GBM is significant. Fangchinoline possesses a wide range of pharmacological activities and attracts more attentions due to its anti-tumor effects. In this study, two WHO grade IV human GBM cell lines (U87 MG and U118 MG) were exposed to fangchinoline, and we found that fangchinoline specifically inhibits the kinase activity of Akt and markedly suppresses the phosphorylation of Thr308 and Ser473 of Akt in human GBM cells. We also observed that fangchinoline inhibits tumor cell proliferation and invasiveness and induces apoptosis through suppressing the Akt-mediated signaling cascades, including Akt/p21, Akt/Bad, and Akt/matrix metalloproteinases (MMPs). These data demonstrated that fangchinoline exerts its anti-tumor effects in human glioblastoma cells, at least partly by inhibiting the kinase activity of Akt and suppressing Akt-mediated signaling cascades. PMID:26408176

  9. Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma.

    PubMed

    Rais, Rana; Jančařík, Andrej; Tenora, Lukáš; Nedelcovych, Michael; Alt, Jesse; Englert, Judson; Rojas, Camilo; Le, Anne; Elgogary, Amira; Tan, Jessica; Monincová, Lenka; Pate, Kelly; Adams, Robert; Ferraris, Dana; Powell, Jonathan; Majer, Pavel; Slusher, Barbara S

    2016-09-22

    The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DON's therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DON's amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients. PMID:27560860

  10. Use of miRNA Response Sequences to Block Off-target Replication and Increase the Safety of an Unattenuated, Glioblastoma-targeted Oncolytic HSV

    PubMed Central

    Mazzacurati, Lucia; Marzulli, Marco; Reinhart, Bonnie; Miyagawa, Yoshitaka; Uchida, Hiroaki; Goins, William F; Li, Aofei; Kaur, Balveen; Caligiuri, Michael; Cripe, Timothy; Chiocca, Nino; Amankulor, Nduka; Cohen, Justus B; Glorioso, Joseph C; Grandi, Paola

    2015-01-01

    Glioblastoma multiforme (GBM) is an aggressive brain cancer for which there is no effective treatment. Oncolytic HSV vectors (oHSVs) are attenuated lytic viruses that have shown promise in the treatment of human GBM models in animals, but their efficacy in early phase patient trials has been limited. Instead of attenuating the virus with mutations in virulence genes, we engineered four copies of the recognition sequence for miR-124 into the 3′UTR of the essential ICP4 gene to protect healthy tissue against lytic virus replication; miR-124 is expressed in neurons but not in glioblastoma cells. Following intracranial inoculation into nude mice, the miR-124-sensitive vector failed to replicate or show overt signs of pathogenesis. To address the concern that this safety feature may reduce oncolytic activity, we inserted the miR-124 response elements into an unattenuated, human receptor (EGFR/EGFRvIII)-specific HSV vector. We found that miR-124 sensitivity did not cause a loss of treatment efficiency in an orthotopic model of primary human GBM in nude mice. These results demonstrate that engineered miR-124 responsiveness can eliminate off-target replication by unattenuated oHSV without compromising oncolytic activity, thereby providing increased safety. PMID:25200130

  11. Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma.

    PubMed

    Rais, Rana; Jančařík, Andrej; Tenora, Lukáš; Nedelcovych, Michael; Alt, Jesse; Englert, Judson; Rojas, Camilo; Le, Anne; Elgogary, Amira; Tan, Jessica; Monincová, Lenka; Pate, Kelly; Adams, Robert; Ferraris, Dana; Powell, Jonathan; Majer, Pavel; Slusher, Barbara S

    2016-09-22

    The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DON's therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DON's amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.

  12. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02

    PubMed Central

    Lee, Eudocia Q.; Kuhn, John; Lamborn, Kathleen R.; Abrey, Lauren; DeAngelis, Lisa M.; Lieberman, Frank; Robins, H. Ian; Chang, Susan M.; Yung, W. K. Alfred; Drappatz, Jan; Mehta, Minesh P.; Levin, Victor A.; Aldape, Kenneth; Dancey, Janet E.; Wright, John J.; Prados, Michael D.; Cloughesy, Timothy F.; Gilbert, Mark R.; Wen, Patrick Y.

    2012-01-01

    The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor–β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents. PMID:23099651

  13. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02.

    PubMed

    Lee, Eudocia Q; Kuhn, John; Lamborn, Kathleen R; Abrey, Lauren; DeAngelis, Lisa M; Lieberman, Frank; Robins, H Ian; Chang, Susan M; Yung, W K Alfred; Drappatz, Jan; Mehta, Minesh P; Levin, Victor A; Aldape, Kenneth; Dancey, Janet E; Wright, John J; Prados, Michael D; Cloughesy, Timothy F; Gilbert, Mark R; Wen, Patrick Y

    2012-12-01

    The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.

  14. Specific combinations of the chromatin-modifying enzyme modulators significantly attenuate glioblastoma cell proliferation and viability while exerting minimal effect on normal adult stem cells growth.

    PubMed

    Alexanian, Arshak R; Huang, Yi-Wen

    2015-11-01

    The discoveries of recent decade showed that all critical changes in cancer cells, such as silencing of tumor-suppressor genes and activation of oncogenes, are caused not only by genetic but also by epigenetic mechanisms. Although epigenetic changes are somatically heritable, in contrast to genetic changes, they are potentially reversible, making them good targets for therapeutic intervention. Covalent modifications of chromatin such as methylation and acetylation of histones and methylation of DNA are the important components of epigenetic machinery. In this study, we investigated the effect of different modulators of DNA and histone covalent-modifying enzymes on the proliferation and viability of normal adult stem cells, such as human bone marrow mesenchymal stem cells (hMSCs), and on malignant tumor cells, such as glioblastoma (GB) D54 cells. Results demonstrated that specific combinations of histone methyltransferases and deacetylases inhibitors significantly attenuated D54 cells viability but having only a small effect on hMSCs growth. Taken together, these studies suggest that specific combinations of histone covalent modifiers could be an effective treatment option for the most aggressive type of primary brain tumors such as glioblastoma multiforme.

  15. STAT3 Regulation of Glioblastoma Pathogenesis

    PubMed Central

    de la Iglesia, Núria; Puram, Sidharth V.; Bonni, Azad

    2009-01-01

    Malignant gliomas are the most common primary brain tumors. Despite efforts to find effective treatments, these tumors remain incurable. The failure of malignant gliomas to respond to conventional cancer therapies may reflect the unique biology of these tumors, underscoring the need for new approaches in their investigation. Recently, progress has been made in characterization of the molecular pathogenesis of glioblastoma using a developmental neurobiological perspective, by exploring the role of signaling pathways that control the differentiation of neural stem cells along the glial lineage. The transcription factor STAT3, which has an established function in neural stem cell and astrocyte development, has been found to play dual tumor suppressive and oncogenic roles in glial malignancy depending on the mutational profile of the tumor. These findings establish a novel developmental paradigm in the study of glioblastoma pathogenesis and provide the rationale for patient-tailored therapy in the treatment of this devastating disease. PMID:19601808

  16. Glioblastoma arising within a mediastinal mature teratoma.

    PubMed

    Liu, Liping; Jentoft, Mark E; Boland, Jennifer M

    2016-10-01

    Herein we present the case of a 42-year-old man who presented with an anterior mediastinal mass, which was found to represent a mature teratoma. Within it, there was a secondary somatic malignant glial neoplasm with mitotic activity and necrosis, compatible with glioblastoma. He experienced early local recurrence and lymph node metastasis, but is alive and well 3 1/2 years after diagnosis. Neither the teratoma nor the glioblastoma components had abnormalities of chromosome 12, which may implicate that this teratoma was more closely related to those arising along the midline of infants and children (type I germ cell tumor) than to the typically malignant testicular examples, which often contain mixed germ cell elements (type II germ cell tumor). PMID:27327191

  17. How I treat glioblastoma in older patients.

    PubMed

    Mohile, Nimish A

    2016-01-01

    Glioblastoma, a WHO grade IV astrocytoma, is the most common primary malignant brain tumor in adults. It is characterized by molecular heterogeneity and aggressive behavior. Glioblastoma is almost always incurable and most older patients survive less than 6 months. Supportive care with steroids and anti-epileptic drugs is critical to improving and maintain quality of life. Young age, good performance status and methylation of the methyl guanyl methyl transferase promoter are important positive prognostic factors. Several recent clinical trials suggest that there is a subset of the elderly with prolonged survival that is comparable to younger patients. Treatment of glioblastoma in older patients includes maximal safe resection followed by either radiation, chemotherapy or combined modality therapy. Recent advances suggest that some patients can avoid radiation entirely and be treated with chemotherapy alone. Decisions about therapy are individual and based on a patient's performance status, family support and molecular features. Future work needs to better determine the role for comprehensive geriatric assessments in this patient population to better identify patients who may most benefit from aggressive therapies. PMID:26725536

  18. Biomarker-based prognostic stratification of young adult glioblastoma.

    PubMed

    Zhang, Rui-Qi; Shi, Zhifeng; Chen, Hong; Chung, Nellie Yuk-Fei; Yin, Zi; Li, Kay Ka-Wai; Chan, Danny Tat-Ming; Poon, Wai Sang; Wu, Jinsong; Zhou, Liangfu; Chan, Aden Ka-Yin; Mao, Ying; Ng, Ho-Keung

    2016-01-26

    While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF, H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF-V600E (15%), H3F3A-K27M (15.9%), H3F3A-G34R/V (2.8%) and IDH1-R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERTp mutation were only detected in 3.7% and 8.4% in young adult glioblastomas, respectively. BRAF-V600E identified a clinically favorable subset of glioblastomas with younger age, frequent CDKN2A homozygous deletion, and was more amendable to surgical resection. H3F3A-K27M mutated glioblastomas were tightly associated with midline locations and showed dismal prognosis. IDH1-R132H was associated with older age and favorable outcome. Interestingly, tumors with positive PDGFRA immunohistochemical expression exhibited poorer prognosis and identified an aggressive subset of tumors among K27M mutated glioblastomas. Combining BRAF, H3F3A and IDH1 mutations allowed stratification of young adult glioblastomas into four prognostic subgroups. In summary, our study demonstrates the clinical values of stratifying young adult glioblastomas with BRAF, H3F3A and IDH1 mutations, which has important implications in refining prognostic classification of glioblastomas. PMID:26452024

  19. Biomarker-based prognostic stratification of young adult glioblastoma

    PubMed Central

    Chen, Hong; Chung, Nellie Yuk-Fei; Yin, Zi; Li, Kay Ka-Wai; Chan, Danny Tat-Ming; Poon, Wai Sang; Wu, Jinsong; Zhou, Liangfu; Chan, Aden Ka-yin; Mao, Ying; Ng, Ho-Keung

    2016-01-01

    While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF, H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF-V600E (15%), H3F3A-K27M (15.9%), H3F3A-G34R/V (2.8%) and IDH1-R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERTp mutation were only detected in 3.7% and 8.4% in young adult glioblastomas, respectively. BRAF-V600E identified a clinically favorable subset of glioblastomas with younger age, frequent CDKN2A homozygous deletion, and was more amendable to surgical resection. H3F3A-K27M mutated glioblastomas were tightly associated with midline locations and showed dismal prognosis. IDH1-R132H was associated with older age and favorable outcome. Interestingly, tumors with positive PDGFRA immunohistochemical expression exhibited poorer prognosis and identified an aggressive subset of tumors among K27M mutated glioblastomas. Combining BRAF, H3F3A and IDH1 mutations allowed stratification of young adult glioblastomas into four prognostic subgroups. In summary, our study demonstrates the clinical values of stratifying young adult glioblastomas with BRAF, H3F3A and IDH1 mutations, which has important implications in refining prognostic classification of glioblastomas. PMID:26452024

  20. A Combined Approach Employing Chlorotoxin-Nanovectors and Low Dose Radiation To Reach Infiltrating Tumor Niches in Glioblastoma.

    PubMed

    Tamborini, Matteo; Locatelli, Erica; Rasile, Marco; Monaco, Ilaria; Rodighiero, Simona; Corradini, Irene; Franchini, Mauro Comes; Passoni, Lorena; Matteoli, Michela

    2016-02-23

    Glioblastoma multiforme (GBM) is the most aggressive form of glioma, with life expectancy of around 2 years after diagnosis, due to recidivism and to the blood-brain barrier (BBB) limiting the amount of drugs which reach the residual malignant cells, thus contributing to the failure of chemotherapies. To bypass the obstacles imposed by the BBB, we investigated the use of nanotechnologies combined with radiotherapy, as a potential therapeutic strategy for GBM. We used poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PNP) conjugated to chlorotoxin (CTX), a peptide reported to bind selectively to glioma cells. Silver nanoparticles were entrapped inside the functionalized nanoparticles (Ag-PNP-CTX), to allow detection and quantification of the cellular uptake by confocal microscopy, both in vitro and in vivo. In vitro experiments performed with different human glioblastoma cell lines showed higher cytoplasmic uptake of Ag-PNP-CTX, with respect to nonfunctionalized nanoparticles. In vivo experiments showed that Ag-NP-CTX efficiently targets the tumor, but are scarcely effective in crossing the blood brain barrier in the healthy brain, where dispersed metastatic cells are present. We show here that single whole brain X-ray irradiation, performed 20 h before nanoparticle injection, enhances the expression of the CTX targets, MMP-2 and ClC-3, and, through BBB permeabilization, potently increases the amount of internalized Ag-PNP-CTX even in dispersed cells, and generated an efficient antitumor synergistic effect able to inhibit in vivo tumor growth. Notably, the application of Ag-PNP-CTX to irradiated tumor cells decreases the extracellular activity of MMP-2. By targeting dispersed GBM cells and reducing MMP-2 activity, the combined use of CTX-nanovectors with radiotherapy may represent a promising therapeutic approach toward GBM.

  1. A Combined Approach Employing Chlorotoxin-Nanovectors and Low Dose Radiation To Reach Infiltrating Tumor Niches in Glioblastoma.

    PubMed

    Tamborini, Matteo; Locatelli, Erica; Rasile, Marco; Monaco, Ilaria; Rodighiero, Simona; Corradini, Irene; Franchini, Mauro Comes; Passoni, Lorena; Matteoli, Michela

    2016-02-23

    Glioblastoma multiforme (GBM) is the most aggressive form of glioma, with life expectancy of around 2 years after diagnosis, due to recidivism and to the blood-brain barrier (BBB) limiting the amount of drugs which reach the residual malignant cells, thus contributing to the failure of chemotherapies. To bypass the obstacles imposed by the BBB, we investigated the use of nanotechnologies combined with radiotherapy, as a potential therapeutic strategy for GBM. We used poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PNP) conjugated to chlorotoxin (CTX), a peptide reported to bind selectively to glioma cells. Silver nanoparticles were entrapped inside the functionalized nanoparticles (Ag-PNP-CTX), to allow detection and quantification of the cellular uptake by confocal microscopy, both in vitro and in vivo. In vitro experiments performed with different human glioblastoma cell lines showed higher cytoplasmic uptake of Ag-PNP-CTX, with respect to nonfunctionalized nanoparticles. In vivo experiments showed that Ag-NP-CTX efficiently targets the tumor, but are scarcely effective in crossing the blood brain barrier in the healthy brain, where dispersed metastatic cells are present. We show here that single whole brain X-ray irradiation, performed 20 h before nanoparticle injection, enhances the expression of the CTX targets, MMP-2 and ClC-3, and, through BBB permeabilization, potently increases the amount of internalized Ag-PNP-CTX even in dispersed cells, and generated an efficient antitumor synergistic effect able to inhibit in vivo tumor growth. Notably, the application of Ag-PNP-CTX to irradiated tumor cells decreases the extracellular activity of MMP-2. By targeting dispersed GBM cells and reducing MMP-2 activity, the combined use of CTX-nanovectors with radiotherapy may represent a promising therapeutic approach toward GBM. PMID:26745323

  2. Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line.

    PubMed

    Ashizawa, Tadashi; Akiyama, Yasuto; Miyata, Haruo; Iizuka, Akira; Komiyama, Masaru; Kume, Akiko; Omiya, Maho; Sugino, Takashi; Asai, Akira; Hayashi, Nakamasa; Mitsuya, Koichi; Nakasu, Yoko; Yamaguchi, Ken

    2014-07-01

    Glioblastoma multiforme (GBM) is one of the most malignant and aggressive tumors and has a very poor prognosis, with a median survival time of less than 2 years. Once recurrence develops, there are few therapeutic approaches to control the growth of glioblastoma. In particular, temozolomide (TMZ)-resistant (TMZ-R) GBM is very difficult to treat, and a novel approach to overcome resistance is eagerly awaited. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the current study, the efficacy of STX-0119 was evaluated against our established TMZ-resistant U87 cell line using quantitative PCR-based gene expression analysis, in vitro assay and animal experiments. The growth inhibitory effect of STX-0119 on U87 and TMZ-R U87 cells was moderate (IC₅₀, 34 and 45 µM, respectively). In particular, STX-0119 did not show significant inhibition of U87 tumor growth; however, it suppressed the growth of the TMZ-R U87 tumor in nude mice by more than 50%, and prolonged the median survival time compared to the control group. Q