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Sample records for glioblastoma multiforme treated

  1. 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

  2. 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

  3. Lactate levels with glioblastoma multiforme.

    PubMed

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

    2016-07-01

    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

  4. 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

  5. Longitudinal Magnetic Resonance Imaging Features of Glioblastoma Multiforme Treated With Radiotherapy With or Without Brachytherapy

    SciTech Connect

    Aiken, Ashley H. Chang, Susan M.; Larson, David; Butowski, Nicholas; Cha, Soonmee

    2008-12-01

    Purpose: To compare temporal patterns of recurrent contrast enhancement in patients with glioblastoma multiforme (GBM) treated with brachytherapy plus external beam radiotherapy (EBRT) vs. EBRT alone. Methods and Materials: We evaluated serial MRI scans for 15 patients who received brachytherapy followed by EBRT (6000 cGy) and 20 patients who received standard EBRT alone (5940-6000 cGy). Brachytherapy consisted of permanent, low-activity {sup 125}I seeds placed around the resection cavity at the time of initial gross total resection. Contrast enhancement (linear, nodular, feathery, or solid), serial progression, and location of contrast enhancement were described. Results: In the EBRT group, 14 patients demonstrated focal nodular contrast enhancement along the resection cavity within 4 months. The 6 remaining EBRT patients developed either transient linear enhancement or no abnormal enhancement. In the brachytherapy plus EBRT group, 7 patients initially developed linear rim enhancement within 4 months that progressed to feathery contrast enhancement over the course of 1 to 2 years. Histopathology confirmed radiation necrosis in all 7 patients. The remaining 8 brachytherapy patients eventually developed focal nodular contrast enhancement along the resection cavity and tumor recurrence. Conclusions: Our data suggest that longitudinal MRI features differ between GBM patients treated with EBRT vs. brachytherapy plus EBRT. In both groups, nodular enhancement adjacent to or remote from the resection cavity strongly suggested tumor recurrence. Feathery enhancement, which progressed from linear rim enhancement immediately adjacent to the cavity, seen only in brachytherapy patients, strongly indicated radiation necrosis.

  6. 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

  7. 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

  8. Management of glioblastoma multiforme in pregnancy.

    PubMed

    Jayasekera, Bodiabaduge A P; Bacon, Andrew D; Whitfield, Peter C

    2012-06-01

    Glioblastoma multiforme presenting during pregnancy presents unique challenges to the clinician. In planning treatment, potential benefits to the mother must be balanced against the risks to the fetus. In addition, evidence relating to timing of surgery and the use of radiotherapy and chemotherapy in pregnancy is limited. Management of peritumoral edema and seizures in pregnancy is also complicated by the potential for drug-related teratogenic effects and adverse neonatal outcomes on the fetus. The general anesthetic used for surgery must factor obstetric and neurosurgical considerations. In this review article, the authors seek to examine the role, safety, and timing of therapies for glioblastoma in the context of pregnancy. This covers the use of radiotherapy and chemotherapy, timing of surgery, postoperative care, anesthetic considerations, and use of anticonvulsant medications and steroids. The authors hope that this will provide a framework for clinicians treating pregnant patients with glioblastomas. PMID:22404670

  9. 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

  10. Emerging treatment strategies for glioblastoma multiforme

    PubMed Central

    Carlsson, Steven K; Brothers, Shaun P; Wahlestedt, Claes

    2014-01-01

    Glioblastoma multiforme (GBM) is the deadliest form of brain tumor with a more than 90% 5-year mortality. GBM has a paltry median survival of 12.6 months attributed to the unique treatment limitations such as the high average age of onset, tumor location, and poor current understandings of the tumor pathophysiology. The resection techniques, chemotherapic strategies, and radiation therapy currently used to treat GBM have slowly evolved, but the improvements have not translated to marked increases in patient survival. Here, we will discuss the recent progress in our understanding of GBM pathophysiology, and the diagnostic techniques and treatment options. The discussion will include biomarkers, tumor imaging, novel therapies such as monoclonal antibodies and small-molecule inhibitors, and the heterogeneity resulting from the GBM cancer stem cell population. PMID:25312641

  11. An Update in the Use of Antibodies to Treat Glioblastoma Multiforme

    PubMed Central

    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. PMID:24294521

  12. Advanced case of glioblastoma multiforme and pregnancy. An ethical dilemma.

    PubMed

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

    2015-10-01

    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

  13. 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

  14. Cerebellar Glioblastoma Multiforme in an Adult

    PubMed Central

    Hur, Hyuk; Jung, Tae-Young; Kim, In-Young

    2008-01-01

    Primary cerebellar glioblastoma multiforme (GBM) is a rare tumor in adults that accounts for just 1% of all cases of GBM. Due to their rarity, cerebellar GBMs are not yet completely understood about the pathogenesis and the prognosis. Here, we present a case of GBM in a 69-year-old man. Neurologic examination revealed the presence of cerebellar signs. Magnetic resonance imaging (MRI) showed a 4.5 × 3.6 cm-sized, ill-defined, heterogeneously enhancing mass in the left cerebellum and two patchy hyperintense lesions in the right cerebellum with minimal enhancement. After operation, glioblastoma was histologically confirmed. Postoperative radiotherapy with concomitant and adjuvant temozolomide chemotherapy was subsequently followed. Here, a case of unusual GBM in the cerebellum is reported with review of literature regarding the pathogenesis, the differential diagnosis and prognosis. There was no evidence of recurrence during postoperative one year. This patient showed a good prognosis in spite of the multiple lesions. PMID:19096643

  15. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme.

    PubMed

    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

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

    PubMed

    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

  17. 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

  18. 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.

  19. Glioblastoma Multiforme Therapy and Mechanisms of Resistance

    PubMed Central

    Ramirez, Yulian P.; Weatherbee, Jessica L.; Wheelhouse, Richard T.; Ross, Alonzo H.

    2013-01-01

    Glioblastoma multiforme (GBM) is a grade IV brain tumor characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy. The current standard of care, comprised of surgical resection followed by radiation and the chemotherapeutic agent temozolomide, only provides patients with a 12–14 month survival period post-diagnosis. Long-term survival for GBM patients remains uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. In this review we will describe the mechanisms of resistance, and how they may be overcome to improve the survival of GBM patients by implementing novel chemotherapy drugs, new drug combinations and new approaches relating to DNA damage, angiogenesis and autophagy. PMID:24287492

  20. 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

  1. Glioblastoma Multiforme in a Patient with Isolated Hemimegalencephaly

    PubMed Central

    Chrastina, Jan; Novak, Zdenek; Brazdil, Milan; Hermanova, Marketa

    2015-01-01

    We present an exceptional case of a patient with hemimegalencephaly and secondary intractable epilepsy treated with vagus nerve stimulation (VNS) and subsequent glioblastoma development in the hemimegalencephalic hemisphere 6 years after surgery. VNS (at age 18 years) led to a 60% reduction of intractable seizures. However, symptoms of intracranial hypertension suddenly occurred 6 years after surgery. A computed tomography scan revealed a brain tumor in the hemimegalencephalic hemisphere. Pathologic examination confirmed glioblastoma multiforme. The genetic background of hemimegalencephaly is discussed here, with attention paid to the available data about the malignant transformation of malformations of cortical development (MCDs). The case points to the need for adequate clinical and radiologic follow-up care for patients with MCDs including hemimegalencephaly. PMID:26251796

  2. Glioblastoma multiforme in the very elderly.

    PubMed

    Connon, Felicity V; Rosenthal, Mark A; Drummond, Katherine

    2016-01-01

    Glioblastoma is the most malignant and most common primary brain tumour and is treated with resection followed by post-operative radiotherapy and chemotherapy. However, a significant amount of patients are older than 80 years, and such an approach may not be appropriate. Data on patients aged 80 or older with glioblastoma from two hospitals was collected using the CNS Tumour Database on the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD) system operated by BioGrid. Between 2008 and July 2011, 40 patients aged 80 years or older were diagnosed with glioblastoma. The median ECOG PS was 2 and the ASA score was 3. All 40 patients underwent surgery and 33% had a gross total resection. Only six patients (15%) had either post-operative radiotherapy or chemotherapy. The overall median survival was 4 months (range 0-18 months) and 28% of patients lived between 6 and 24 months. This is the largest reported cohort of very elderly patients with glioblastoma. Patients tolerated surgery but few went on to receive post-operative radiotherapy or chemotherapy. This patient population requires special attention and in particular would benefit from participation in suitable clinical trials to determine the best care regime. PMID:26208944

  3. miR-340 suppresses glioblastoma multiforme.

    PubMed

    Huang, Daquan; Qiu, Shuwei; Ge, Ruiguang; He, Lei; Li, Mei; Li, Yi; Peng, Ying

    2015-04-20

    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

  4. Fluorescence lifetime spectroscopy of glioblastoma multiforme.

    PubMed

    Marcu, Laura; Jo, Javier A; Butte, Pramod V; Yong, William H; Pikul, Brian K; Black, Keith L; Thompson, Reid C

    2004-01-01

    Fluorescence spectroscopy of the endogenous emission of brain tumors has been researched as a potentially important method for the intraoperative localization of brain tumor margins. We investigated the use of time-resolved, laser-induced fluorescence spectroscopy for demarcation of primary brain tumors by studying the time-resolved spectra of gliomas. The fluorescence of human brain samples (glioblastoma multiforme, cortex and white matter: six patients, 23 sites) was induced ex vivo with a pulsed nitrogen laser (337 nm, 3 ns). The time-resolved spectra were detected in a 360-550 nm wavelength range using a fast digitizer and gated detection. Parameters derived from both the spectral- (intensities from narrow spectral bands) and the time domain (average lifetime) measured at 390 and 460 nm were used for tissue characterization. We determined that high-grade gliomas are characterized by fluorescence lifetimes that varied with the emission wavelength (>3 ns at 390 nm, <1 ns at 460 nm) and their emission is overall longer than that of normal brain tissue. Our study demonstrates that the use of fluorescence lifetime not only improves the specificity of fluorescence measurements but also allows a more robust evaluation of data collected from brain tissue. Combined information from both the spectral- and the time domain can enhance the ability of fluorescence-based techniques to diagnose and detect brain tumor margins intraoperatively. PMID:15339216

  5. NTRK1 Fusion in Glioblastoma Multiforme

    PubMed Central

    Cho, Hee-Jin; Lee, Young-Eun; An, Jaeyeol; Cho, Gye-Hyun; Ko, Young-Hyeh; Joo, Kyeung Min; Nam, Do-Hyun

    2014-01-01

    Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor, yet with no targeted therapy with substantial survival benefit. Recent studies on solid tumors showed that fusion genes often play driver roles and are promising targets for pharmaceutical intervention. To survey potential fusion genes in GBMs, we analysed RNA-Seq data from 162 GBM patients available through The Cancer Genome Atlas (TCGA), and found that 3′ exons of neurotrophic tyrosine kinase receptor type 1 (NTRK1, encoding TrkA) are fused to 5′ exons of the genes that are highly expressed in neuronal tissues, neurofascin (NFASC) and brevican (BCAN). The fusions preserved both the transmembrane and kinase domains of NTRK1 in frame. NTRK1 is a mediator of the pro-survival signaling of nerve growth factor (NGF) and is a known oncogene, found commonly altered in human cancer. While GBMs largely lacked NTRK1 expression, the fusion-positive GBMs expressed fusion transcripts in high abundance, and showed elevated NTRK1-pathway activity. Lentiviral transduction of the NFASC-NTRK1 fusion gene in NIH 3T3 cells increased proliferation in vitro, colony formation in soft agar, and tumor formation in mice, suggesting the possibility that the fusion contributed to the initiation or maintenance of the fusion-positive GBMs, and therefore may be a rational drug target. PMID:24647444

  6. Multifocal Glioblastoma Multiforme: Prognostic Factors and Patterns of Progression

    SciTech Connect

    Showalter, Timothy N.; Andrel, Jocelyn; Andrews, David W.; Curran, Walter J.; Daskalakis, Constantine; Werner-Wasik, Maria

    2007-11-01

    Purpose: To assess the progression patterns in patients with multifocal glioblastoma multiforme who had undergone whole brain radiotherapy (WBRT), the historical standard, versus three-dimensional conformal radiotherapy, and to identify predictive treatment and pretreatment factors. Methods and Materials: The records of 50 patients with multifocal glioblastoma multiforme treated with RT were reviewed. Univariate analyses were performed using survival methods and the Cox proportional hazards regression method. Multivariate analyses were performed using the Cox proportional hazards regression method. Results: The mean age was 61 years, and 71% had a Karnofsky performance status (KPS) score of {>=}70. Of the 50 patients, 32% underwent WBRT and 68%, three-dimensional conformal RT. Progression was local in all evaluable patients, as determined by imaging in 38 patients and early neurologic progression in 12. The median time to progression (TTP) was 3.1 months, and the median survival time (MST) was 8.1 months. The significant independent predictors of TTP on multivariate analysis were a KPS score <70 (p = 0.001), the extent of surgery (p = 0.040), a radiation dose <60 Gy (p = 0.027), and the lack of chemotherapy (p = 0.001). The significant independent predictors of a reduced MST were a KPS score <70 (p = 0.022) and the absence of salvage surgery (p = 0.011) and salvage chemotherapy (p = 0.003). Conclusion: Local progression was observed in all patients. On multivariate analysis, no significant difference was found in the TTP or MST between three-dimensional conformal radiotherapy and WBRT. The KPS was a consistent independent predictor of both TTP and MST. On the basis of the progression pattern, we do not recommend WBRT as a mandatory component of the treatment of multifocal glioblastoma multi0011for.

  7. Patterns of Failure for Pediatric Glioblastoma Multiforme Following Radiation Therapy.

    PubMed

    Shabason, Jacob E; Sutton, David; Kenton, Owen; Guttmann, David M; Lustig, Robert A; Hill-Kayser, Christine

    2016-08-01

    Despite aggressive multimodal therapy for pediatric glioblastoma multiforme (GBM), patient survival remains poor. This retrospective review of patients with GBM aims to evaluate the patterns of failure after radiation therapy (RT). The study included 14 pediatric patients treated with RT at the Children's Hospital of Philadelphia from 2007 to 2015. With a median follow-up of 16.9 months, 13 (92.9%) developed recurrent disease. Of recurrences, nine (69.2%) were in-field, three (23.1%) were marginal, and one (7.7%) was distant. The majority of patients treated with adjuvant radiation failed in the region of high-dose RT, indicating the need for improvements in local therapy. PMID:27128519

  8. 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

  9. Glioblastoma Multiforme in an HIV-Infected Patient: An Unexpected Diagnosis.

    PubMed

    Oliveira, Victor Costa Morais de; Gomes, Thalita; Ferreira, Luiz Carlos Lima; Damian, Márcia Melo; Silva, Vera Márcia Fonseca Queiroz; Araújo, José Ribamar; Safe, Izabella Picinin; Ramasawmy, Rajendranath

    2014-01-01

    We reported a case of glioblastoma multiforme in a 42-year-old female patient with HIV infection, who had a rapid progression to AIDS. She was diagnosed with an intracerebral mass and treated as neurotoxoplasmosis with improvement in the first week of therapy. On the fourth week she had a clinical worsening evolving to death, receiving the diagnosis at necropsy. PMID:24935693

  10. Prevalence of glioblastoma multiforme in subjects with prior therapeutic radiation

    SciTech Connect

    Hodges, L.C.; Smith, J.L.; Garrett, A.; Tate, S. )

    1992-04-01

    This retrospective study profiled subjects with glioblastoma multiforme (GBM) who had previously received therapeutic radiation. A chart review was conducted of 100 adult patients diagnosed with GBM and referred to a major medical center in the southwestern United States. Seventeen patients received previous radiation therapy with an average dose of 48.5 Grey (Gy) and an average latency period of 15 years between initial therapy and GBM diagnosis. Of these 17, four white females fit all four attribution criteria for radiation-induced GBM. Two had been treated with radiation for prolactinomas, one for pinealoma and one for squamous cell cancer of the ethmoid sinus. The addition of these four case studies to the previously published descriptions of 80 cases of gliomas, 36 of which were GBM, subsequent to radiation therapy provides additional support for considering therapeutic radiation as a risk factor for GBM development.

  11. Challenges in Immunotherapy Presented by the Glioblastoma Multiforme Microenvironment

    PubMed Central

    Jackson, Christopher; Ruzevick, Jacob; Phallen, Jillian; Belcaid, Zineb; Lim, Michael

    2011-01-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite intensive treatment, the prognosis for patients with GBM remains grim with a median survival of only 14.6 months. Immunotherapy has emerged as a promising approach for treating many cancers and affords the advantages of cellular-level specificity and the potential to generate durable immune surveillance. The complexity of the tumor microenvironment poses a significant challenge to the development of immunotherapy for GBM, as multiple signaling pathways, cytokines, and cell types are intricately coordinated to generate an immunosuppressive milieu. The development of new immunotherapy approaches frequently uncovers new mechanisms of tumor-mediated immunosuppression. In this review, we discuss many of the current approaches to immunotherapy and focus on the challenges presented by the tumor microenvironment. PMID:22190972

  12. Nanoparticles of carbon allotropes inhibit glioblastoma multiforme angiogenesis in ovo

    PubMed Central

    Grodzik, Marta; Sawosz, Ewa; Wierzbicki, Mateusz; Orlowski, Piotr; Hotowy, Anna; Niemiec, Tomasz; Szmidt, Maciej; Mitura, Katarzyna; Chwalibog, André

    2011-01-01

    The objective of the study was to determine the effect of carbon nanoparticles produced by different methods on the growth of brain tumor and the development of blood vessels. Glioblastoma multiforme cells were cultured on the chorioallantoic membrane of chicken embryo and after 7 days of incubation, were treated with carbon nanoparticles administered in ovo to the tumor. Both types of nanoparticles significantly decreased tumor mass and volume, and vessel area. Quantitative real-time polymerase chain reaction analysis showed downregulated fibroblast growth factor-2 and vascular endothelial growth factor expression at the messenger ribonucleic acid level. The present results demonstrate antiangiogenic activity of carbon nanoparticles, making them potential factors for anticancer therapy. PMID:22162660

  13. SAT1 and glioblastoma multiforme: Disarming the resistance

    PubMed Central

    Brett-Morris, Adina; Mislmani, Mazen; Welford, Scott M

    2015-01-01

    Glioblastoma multiforme is the most common and most detrimental form of brain tumor, with a current survival time of as little as 14 months. We have recently identified a novel mechanism of therapeutic resistance based on overexpression of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase, which promotes DNA repair via chromatin modification. PMID:27308461

  14. 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

  15. Pattern of relapse of glioblastoma multiforme treated with radical radio-chemotherapy: Could a margin reduction be proposed?

    PubMed

    Buglione, Michela; Pedretti, Sara; Poliani, Pietro Luigi; Liserre, Roberto; Gipponi, Stefano; Spena, Giannantonio; Borghetti, Paolo; Pegurri, Ludovica; Saiani, Federica; Spiazzi, Luigi; Tesini, Giulia; Uccelli, Chiara; Triggiani, Luca; Magrini, Stefano Maria

    2016-06-01

    To analyse the pattern of recurrence of patients treated with Stupp protocol in relation to technique, to compare in silico plans with reduced margin (1 cm) with the original ones and to analyse toxicity. 105 patients were treated: 85 had local recurrence and 68 of them were analysed. Recurrence was considered in field, marginal and distant if >80 %, 20-80 % or <20 % of the relapse volume was included in the 95 %-isodose. In silico plans were retrospectively recalculated using the same technique, fields angles and treatment planning system of the original ones. The pattern of recurrence was in field, marginal and distant in 88, 10 and 2 % respectively and was similar in in silico plans. The margin reduction appears to spare 100 cc of healthy brain by 57 Gy-volume (p = 0.02). The target coverage was worse in standard plans (pt student < 0.001), especially if the tumour was near to organs at risk (pχ2 < 0.001). PTV coverage was better with IMRT and helical-IMRT, than conformal-3D (pAnova test = 0.038). This difference was no more significant with in silico planning. A higher incidence of asthenia and leuko-encephalopathy was observed in patients with greater percentage of healthy brain included in 57 Gy-volume. No differences in the pattern of recurrence according to margins were found. The margin reduction determines sparing of healthy brain and could possibly reduce the incidence of late toxicity. Margin reduction could allow to use less sophisticated techniques, ensuring appropriate target coverage, and the choice of more costly techniques could be reserved to selected cases. PMID:27025858

  16. Expression of cytomegalovirus in glioblastoma multiforme: Myth or reality?

    PubMed

    Taha, Mahmoud S; Abdalhamid, Baha A; El-Badawy, Samy A; Sorour, Yasser M; Almsned, Fahad M; Al-Abbadi, Mousa A

    2016-06-01

    A role for human cytomegalovirus (HCMV) in the pathogenesis of glioblastoma multiforme (GBM) was proposed more than a decade ago and has since generated a considerable debate as a possible therapeutic target. We investigate the presence of HCMV in the specimens of patients with GBM treated in our centre. This is a retrospective cohort study to investigate the presence of HCMV by routine immunohistochemical stains and polymerase chain reaction (PCR)-based molecular analysis on formalin-fixed-paraffin-embedded tissue of all patients with GBM treated in our hospital in 2009-2013 (5 years). The evaluation of positivity by immunohistochemistry (IHC) was semi-quantitative. The molecular analysis was performed by extracting the tumour DNA from representative paraffin-embedded tissue blocks and amplified for detection by a sensitive real time PCR (RT-PCR) CMV assay. During the study period, we treated 45 patients with GBM; however, adequate pathology tissue materials were available only for 32 patients. All the pathology material was reviewed and the diagnosis was confirmed. All the cases were found to be negative for CMV expression by our IHC and RT-PCR CMV assay. Our study has shown no expression of CMV in GBM. Our results were similar to other recent reports that concluded insufficient evidence to recommend routine testing for CMV in GBM or treatment as an add-on therapy. PMID:26742571

  17. Genetic investigation of multicentric glioblastoma multiforme: case report.

    PubMed

    Schroeder, Brett; Shah, Nameeta; Rostad, Steve; McCullough, Brendan; Aguedan, Brian; Foltz, Greg; Cobbs, Charles

    2016-05-01

    The authors report a case of multicentric glioblastoma multiforme (GBM) in which all 4 tumor foci were resected and evaluated using both comparative genomic hybridization array and RNA sequencing. Genetic analysis showed that the tumors shared a common origin, although each had its own unique set of genetic aberrations. The authors note that the genetic heterogeneity of multicentric GBM likely contributes to the failures of current treatments. The case underscores the necessity of increased genetic investigation. PMID:26473785

  18. Dendritic Cell-Based Immunotherapy Treatment for Glioblastoma Multiforme

    PubMed Central

    Yang, Liu; Guo, Geng; Niu, Xiao-yuan; Liu, Jing

    2015-01-01

    Glioblastoma multiforme (GBM) is the most malignant glioma and patients diagnosed with this disease had poor outcomes even treated with the combination of conventional treatment (surgery, chemotherapy, and radiation). Dendritic cells (DCs) are the most powerful antigen presenting cells and DC-based vaccination has the potential to target and eliminate GBM cells and enhance the responses of these cells to the existing therapies with minimal damage to the healthy tissues around them. It can enhance recognition of GBM cells by the patients' immune system and activate vast, potent, and long-lasting immune reactions to eliminate them. Therefore, this therapy can prolong the survival of GBM patients and has wide and bright future in the treatment of GBM. Also, the efficacy of this therapy can be strengthened in several ways at some degree: the manipulation of immune regulatory components or costimulatory molecules on DCs; the appropriate choices of antigens for loading to enhance the effectiveness of the therapy; regulation of positive regulators or negative regulators in GBM microenvironment. PMID:26167495

  19. Chromosomal Instability and Phosphoinositide Pathway Gene Signatures in Glioblastoma Multiforme.

    PubMed

    Waugh, Mark G

    2016-01-01

    Structural rearrangements of chromosome 10 are frequently observed in glioblastoma multiforme and over 80 % of tumour samples archived in the catalogue of somatic mutations in cancer database had gene copy number loss for PI4K2A which encodes phosphatidylinositol 4-kinase type IIalpha. PI4K2A loss of heterozygosity mirrored that of PTEN, another enzyme that regulates phosphoinositide levels and also PIK3AP1, MINPP1, INPP5A and INPP5F. These results indicated a reduction in copy number for a set of phosphoinositide signalling genes that co-localise to chromosome 10q. This analysis was extended to a panel of phosphoinositide pathway genes on other chromosomes and revealed a number of previously unreported associations with glioblastoma multiforme. Of particular note were highly penetrant copy number losses for a group of X-linked phosphoinositide phosphatase genes OCRL, MTM1 and MTMR8; copy number amplifications for the chromosome 19 genes PIP5K1C, AKT2 and PIK3R2, and also for the phospholipase C genes PLCB1, PLCB4 and PLCG1 on chromosome 20. These mutations are likely to affect signalling and trafficking functions dependent on the PI(4,5)P2, PI(3,4,5)P3 and PI(3,5)P2 lipids as well as the inositol phosphates IP3, IP5 and IP6. Analysis of flanking genes with functionally unrelated products indicated that chromosomal instability as opposed to a phosphoinositide-specific process underlay this pattern of copy number variation. This in silico study suggests that in glioblastoma multiforme, karyotypic changes have the potential to cause multiple abnormalities in sets of genes involved in phosphoinositide metabolism and this may be important for understanding drug resistance and phosphoinositide pathway redundancy in the advanced disease state. PMID:25502460

  20. 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

  1. 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

  2. Molecular analysis of WWOX expression correlation with proliferation and apoptosis in glioblastoma multiforme

    PubMed Central

    Pluciennik, Elzbieta; Kurzyk, Agata; Jesionek-Kupnicka, Dorota; Kordek, Radzislaw; Potemski, Piotr; Bednarek, Andrzej K.

    2010-01-01

    Glioblastoma multiforme is the most common type of primary brain tumor in adults. WWOX is a tumor suppressor gene involved in carcinogenesis and cancer progression in many different neoplasms. Reduced WWOX expression is associated with more aggressive phenotype and poor patient outcome in several cancers. We investigated alternations of WWOX expression and its correlation with proliferation, apoptosis and signal trafficking in 67 glioblastoma multiforme specimens. Moreover, we examined the level of WWOX LOH and methylation status in WWOX promoter region. Our results suggest that loss of heterozygosity (relatively frequent in glioblastoma multiforme) along with promoter methylation may decrease the expression of this tumor suppressor gene. Our experiment revealed positive correlations between WWOX and Bcl2 and between WWOX and Ki67. We also confirmed that WWOX is positively correlated with ErbB4 signaling pathway in glioblastoma multiforme. PMID:20535528

  3. 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

  4. Long term responses with cetuximab therapy in glioblastoma multiforme.

    PubMed

    Belda-Iniesta, Cristóbal; Carpeño, Javier de Castro; Saenz, Enrique Casado; Gutiérrez, Manuel; Perona, Rosario; Barón, Manuel González

    2006-08-01

    Glioblastoma multiforme (GBM) is responsible for most of the deaths associated with primary brain tumors. Standard treatment includes maximal surgical resection followed by chemotherapy and concomitant radiotherapy. Most patients, however, recur shortly after treatment. Second line treatment has little efficacy and the majority of patients die soon from the disease. Recent advances in molecular biology have implicated the epidermal growth factor receptor (EGFR) signaling pathways in the progression and resistance to standard therapies for GBM. This has prompted the evaluation of EGFR tyrosine- kinase inhibitors with encouraging results. Cetuximab is a monoclonal antibody targeted against the extra cellular domain of the EGFR with activity against different tumor types, either alone or in combination with chemotherapy and/or radiation therapy. Here we describe three patients with recurrent, heavily pretreated, EGFR expressing GBM who responded to treatment with single agent cetuximab. PMID:16929166

  5. Late adult onset of Langerhans cell histiocytosis mimicking glioblastoma multiforme.

    PubMed

    Perren, F; Fankhauser, L; Thiévent, B; Pache, J-C; Delavelle, J; Rochat, T; Landis, T; Chizzolini, C

    2011-02-15

    Langerhans cell histiocytosis (LCH) with multiple organ involvement is a rare disorder in adults. Extrapituitary involvement of the central nervous system (CNS) is uncommon. We report the unusual case of a 55-year-old woman presenting with a left-sided hemiataxia-hemiparesis, left hemisensory loss and short-lasting episodes of an alien left hand due to lesions of the internal capsule and the right thalamus, extending into the mesencephalon associated with extensive surrounding edema, without pituitary involvement. The neuroradiological image suggested glioblastoma multiforme. Brain biopsy revealed inflammatory tissue and "pseudotumoral" multiple sclerosis was suspected. Biopsy of concomitant lung and bone lesions disclosed Langerhans cell histiocytosis. The treatment with pulsed steroids in association with mycophenolate mofetil led to a sustained, clinical neurological remission. PMID:21131007

  6. 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.

  7. The evolution of the EGFRvIII (rindopepimut) immunotherapy for glioblastoma multiforme patients

    PubMed Central

    Paff, Michelle; Alexandru-Abrams, Daniela; Hsu, Frank P K; Bota, Daniela A

    2015-01-01

    Glioblastoma Multiforme (GBM) is the most common type of brain tumor and it is uniformly fatal. The community standard of treatment for this disease is gross or subtotal resection of the tumor, followed by radiation and temozolomide. At recurrence bevacizumab can be added for increased progression free survival. Many challenges are encountered while trying to devise new drugs to treat GBM, such as the presence of the blood brain barrier which is impermeable to most drugs. Therefore in the past few years attention was turned to immunological means for the treatment of this devastating disease. EGFRvIII targeting has proven a good way to attack glioblastoma cells by using the immune system. Although in still in development, this approach holds the promise as a great first step toward immune-tailored drugs for the treatment of brain cancers. PMID:25625931

  8. Novel cellular and post-genomic technologies in the treatment of glioblastoma multiforme (Review).

    PubMed

    Bryukhovetskiy, Igor; Bryukhovetskiy, Andrey; Khotimchenko, Yuri; Mischenko, Polina

    2016-02-01

    Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors. The majority of modern treatment methods for GBM are not sufficiently effective with a median survival varying from 9 to 14 months. One of the main reasons for the therapeutic resistance of GBM is attributed to cancer stem cells. Pharmaceuticals that can effectively eliminate cancer stem cells do not exist. Experimentally, we have shown that cancer stem cells can be specifically affected to arrest adhesion, proliferation and migration, and other key functions. The main target of this therapy involves membrane intracellular signaling pathways of cancer stem cells that are not subject to neoplastic transformation. An effect on such a complex target requires the development of innovative biotechnological approaches. The research analysis of modern approaches towards creating biomedical drugs for treating cancer stem cells of glioblastoma multiforme is based on advances in the latest cellular and post-genomic technologies. The combination of targeted therapy with regulation of the key functions of cancer stem cells using cell systems with a remodeled proteome is suggested. PMID:26548844

  9. Oncolytic Virus Therapy of Glioblastoma Multiforme – Concepts and Candidates

    PubMed Central

    Wollmann, Guido; Ozduman, Koray; van den Pol, Anthony N.

    2012-01-01

    Twenty years of oncolytic virus (OV) development have created a field that is driven by the potential promise of lasting impact on our cancer treatment repertoire. With the field constantly expanding – over 20 viruses have been recognized as potential OVs – new virus candidates continue to emerge even as established viruses reach clinical trials. They all share the defining commonalities of selective replication in tumors, subsequent tumor cell lysis, and dispersion within the tumor. Members from diverse virus classes with distinctly different biologies and host species have been identified. Of these viruses, 15 have been tested on human glioblastoma multiforme (GBM). So far, 20 clinical trials have been conducted or initiated using attenuated strains of 7 different oncolytic viruses against GBM. In this review, we present an overview of viruses that have been developed or considered for GBM treatment. We outline the principles of tumor targeting and selective viral replication, which include mechanisms of tumor-selective binding, and molecular elements usurping cellular biosynthetic machinery in transformed cells. Results from clinical trials have clearly established the proof of concept and have confirmed the general safety of OV application in the brain. The moderate clinical efficacy has not yet matched the promising preclinical lab results; next-generation OVs that are either “armed” with therapeutic genes or that are embedded in a multimodality treatment regimen should enhance the clinical results. PMID:22290260

  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. 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

  12. Lipidomic Analysis of Glioblastoma Multiforme Using Mass Spectrometry

    PubMed Central

    Ha, Soo Jung; Showalter, Gordon; Cai, Shanbao; Wang, Haiyan; Liu, Wei Michael; Cohen-Gadol, Aaron A.; Sarkaria, Jann N.; Rickus, Jenna; Springer, John; Adamec, Jiri; Pollok, Karen E.; Clase, Kari L.

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant form of primary brain tumors. It is highly invasive and current treatment options have not improved the survival rate over the past twenty years. Novel approaches and technologies from systems biology have the potential to identify biomarkers that could serve as new therapeutic targets for GBM. This study employed lipid profiling technology to investigate lipid biomarkers in ectopic and orthotopic human GBM xenograft models. Primary patient cell lines, GBM10 and GBM43, were injected into the flank and the right cerebral hemisphere of NOD/SCID mice. Tumors were harvested from the brain and flank and proteins, metabolites, and lipids extracted from each sample. Reverse phase based high performance liquid chromatography coupled with Fourier transform ion cyclotron resonance mass spectrometry (LC-FTMS) was used to analyze the lipid profiles of tumor samples. Statistical and clustering analyses were performed to detect differences. Over 500 lipids were identified in each tumor model and lipids with the greatest fold effect in the comparison of ectopic versus orthotopic tumor models fell predominantly into four main classes of lipids: glycosphingolipids, glycerophoshpoethanolamines, triradylglycerols, and glycerophosphoserines. Lipidomic analysis revealed differences in glycosphingolipid and triglyceride profiles when the same tumor was propagated in the flank versus the brain. These results underscore the importance of the surrounding physiological environment on tumor development and are consistent with the hypothesis that specific classes of lipids are critical for GBM tumor growth in different anatomical sites. PMID:17929901

  13. 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

  14. 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

  15. 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

  16. Altered Expression of Polycomb Group Genes in Glioblastoma Multiforme

    PubMed Central

    Li, Gang; Warden, Charles; Zou, Zhaoxia; Neman, Josh; Krueger, Joseph S.; Jain, Alisha; Jandial, Rahul; Chen, Mike

    2013-01-01

    The Polycomb group (PcG) proteins play a critical role in histone mediated epigenetics which has been implicated in the malignant evolution of glioblastoma multiforme (GBM). By systematically interrogating The Cancer Genome Atlas (TCGA), we discovered widespread aberrant expression of the PcG members in GBM samples compared to normal brain. The most striking differences were upregulation of EZH2, PHF19, CBX8 and PHC2 and downregulation of CBX7, CBX6, EZH1 and RYBP. Interestingly, changes in EZH2, PHF19, CBX7, CBX6 and EZH1 occurred progressively as astrocytoma grade increased. We validated the aberrant expression of CBX6, CBX7, CBX8 and EZH2 in GBM cell lines by Western blotting and qRT-PCR, and further the aberrant expression of CBX6 in GBM tissue samples by immunohistochemical staining. To determine if there was functional significance to the diminished CBX6 levels in GBM, CBX6 was overexpressed in GBM cells resulting in decreased proliferative capacity. In conclusion, aberrant expression of PcG proteins in GBMs may play a role in the development or maintenance of the malignancy. PMID:24260522

  17. Glioblastoma multiforme: State of the art and future therapeutics

    PubMed Central

    Wilson, Taylor A.; Karajannis, Matthias A.; Harter, David H.

    2014-01-01

    Background: Glioblastoma multiforme (GBM) is the most common and lethal primary malignancy of the central nervous system (CNS). Despite the proven benefit of surgical resection and aggressive treatment with chemo- and radiotherapy, the prognosis remains very poor. Recent advances of our understanding of the biology and pathophysiology of GBM have allowed the development of a wide array of novel therapeutic approaches, which have been developed. These novel approaches include molecularly targeted therapies, immunotherapies, and gene therapy. Methods: We offer a brief review of the current standard of care, and a survey of novel therapeutic approaches for treatment of GBM. Results: Despite promising results in preclinical trials, many of these therapies have demonstrated limited therapeutic efficacy in human clinical trials. Thus, although survival of patients with GBM continues to slowly improve, treatment of GBM remains extremely challenging. Conclusion: Continued research and development of targeted therapies, based on a detailed understanding of molecular pathogenesis can reasonably be expected to yield improved outcomes for patients with GBM. PMID:24991467

  18. 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

  19. Molecular Characteristics in MRI-Classified Group 1 Glioblastoma Multiforme

    PubMed Central

    Haskins, William E.; Zablotsky, Bethany L.; Foret, Michael R.; Ihrie, Rebecca A.; Alvarez-Buylla, Arturo; Eisenman, Robert N.; Berger, Mitchel S.; Lin, Chin-Hsing Annie

    2013-01-01

    Glioblastoma multiforme (GBM) is a clinically and pathologically heterogeneous brain tumor. Previous studies of transcriptional profiling have revealed biologically relevant GBM subtypes associated with specific mutations and dysregulated pathways. Here, we applied a modified proteome to uncover abnormal protein expression profile in a MRI-classified group I GBM (GBM1), which has a spatial relationship with one of the adult neural stem cell niches, subventricular zone (SVZ). Most importantly, we identified molecular characteristics in this type of GBM that include up-regulation of metabolic enzymes, ribosomal proteins, and heat shock proteins. As GBM1 often recurs at great distances from the initial lesion, the rewiring of metabolism, and ribosomal biogenesis may facilitate cancer cells’ growth and survival during tumor progression. The intimate contact between GBM1 and the SVZ raises the possibility that tumor cells in GBM1 may be most related to SVZ cells. In support of this notion, we found that markers representing SVZ cells are highly expressed in GBM1. Emerged findings from our study provide a specific protein expression profile in GBM1 and offer better prediction or therapeutic implication for this multifocal GBM. PMID:23875172

  20. Investigation of serum proteome alterations in human glioblastoma multiforme.

    PubMed

    Gollapalli, Kishore; Ray, Sandipan; Srivastava, Rajneesh; Renu, Durairaj; Singh, Prateek; Dhali, Snigdha; Bajpai Dikshit, Jyoti; Srikanth, Rapole; Moiyadi, Aliasgar; Srivastava, Sanjeeva

    2012-08-01

    Glioblastoma multiforme (GBM) or grade IV astrocytoma is the most common and lethal adult malignant brain tumor. The present study was conducted to investigate the alterations in the serum proteome in GBM patients compared to healthy controls. Comparative proteomic analysis was performed employing classical 2DE and 2D-DIGE combined with MALDI TOF/TOF MS and results were further validated through Western blotting and immunoturbidimetric assay. Comparison of the serum proteome of GBM and healthy subjects revealed 55 differentially expressed and statistically significant (p <0.05) protein spots. Among the identified proteins, haptoglobin, plasminogen precursor, apolipoprotein A-1 and M, and transthyretin are very significant due to their functional consequences in glioma tumor growth and migration, and could further be studied as glioma biomarkers and grade-specific protein signatures. Analysis of the lipoprotein pattern indicated elevated serum levels of cholesterol, triacylglycerol, and low-density lipoproteins in GBM patients. Functional pathway analysis was performed using multiple software including ingenuity pathway analysis (IPA), protein analysis through evolutionary relationships (PANTHER), database for annotation, visualization and integrated discovery (DAVID), and GeneSpring to investigate the biological context of the identified proteins, which revealed the association of candidate proteins in a few essential physiological pathways such as intrinsic prothrombin activation pathway, plasminogen activating cascade, coagulation system, glioma invasiveness signaling, and PI3K signaling in B lymphocytes. A subset of the differentially expressed proteins was applied to build statistical sample class prediction models for discrimination of GBM patients and healthy controls employing partial least squares discriminant analysis (PLS-DA) and other machine learning methods such as support vector machine (SVM), Decision Tree and Naïve Bayes, and excellent

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. GliaSite Brachytherapy Boost as Part of Initial Treatment of Glioblastoma Multiforme: A Retrospective Multi-Institutional Pilot Study

    SciTech Connect

    Welsh, James; Sanan, Abhay; Gabayan, Arash J.; Green, Sylvan B.; Lustig, Robert; Burri, Stuart; Kwong, Edmund; Stea, Baldassarre . E-mail: bstea@email.ariozna.edu

    2007-05-01

    Purpose: To report on a retrospective analysis of the cumulative experience from eight institutions using the GliaSite Radiotherapy System as a brachytherapy boost in the initial management of glioblastoma multiforme. Methods and Materials: Eight institutions provided data on 20 patients with histologically proven glioblastoma multiforme with a median age of 59 years (range, 39-76) and median Karnofsky performance scale of 80 (range, 50-100). After maximal surgical debulking, patients were treated with GliaSite brachytherapy to a median dose of 50 Gy, followed by external beam radiotherapy to a median dose of 60 Gy (range, 46-60 Gy), for a cumulative dose escalation of 110 Gy (range, 84-130 Gy). Results: The average survival for this study population was 11.4 months (range, 4-29). When the patients' survival was compared with that of historical controls according to their Radiation Therapy Oncology Group recursive partitioning analysis class, the average survival was increased by 3 months (95% confidence interval, 0.23-4.9) corresponding to a 43% increase (p = 0.033). Three patients (14%) experienced Radiation Therapy Oncology Group Grade 3 central nervous system toxicity. Of the treatment failures, 50% were >2 cm from the edge of the balloon. Conclusion: The results of this analysis have demonstrated that dose escalation (>100 Gy) with GliaSite is well tolerated and associated with minimal toxicity. Local control improved with the use of GliaSite brachytherapy. The putative survival advantage seen in this study needs to be interpreted with caution; nevertheless, the data provide sufficient justification to investigate the potential role of radiation dose escalation in conjunction with GliaSite in the initial treatment of glioblastoma multiforme.

  7. Historical controls for phase II surgically based trials requiring gross total resection of glioblastoma multiforme.

    PubMed

    Butowski, Nicholas; Lamborn, Kathleen R; Berger, Mitchel S; Prados, Michael D; Chang, Susan M

    2007-10-01

    New treatments for patients with glioblastoma multiforme (GBM) are frequently tested in phase II surgically based clinical trials that require gross total resection (GTR). In order to determine efficacy in such single-arm phase II clinical trials, the results are often compared to those from a historical control group that is not limited to patients with GTR. Recursive partitioning analysis (RPA) can define risk groups within historical control groups; however, RPA analyses to date included patients irrespective of whether a patient had a GTR or not. To provide a more appropriate historical control group for surgically based trials requiring a GTR, we sought to determine survival for a group of patients with newly diagnosed GBM, all of who underwent GTR and were treated on prospective clinical trials. GTR was defined as removal of >90% of the enhancing mass, determined by postoperative magnetic resonance imaging. Of 893 patients with GBM treated during these trials, 153 underwent GTR. The median survival for the GTR group was 71 weeks (95% CI 65-76) which was better than those who did not have a GTR. Within the GTR group, the median age was 54 years (range 25-77 years), and median Karnofsky Performance Score was 90 (range 60-100). Considering only patients with GTR, age at diagnosis continued to be a statistically significant prognostic factor. Patients treated during surgically based phase II studies should be matched with a historical control group restricted to patients with similar pretreatment variables, including GTR. PMID:17457513

  8. Pediatric glioblastoma multiforme in association with Turner's syndrome: a case report.

    PubMed

    Hanaei, Sara; Habibi, Zohreh; Nejat, Farideh; Sayarifard, Fatemeh; Vasei, Mohammad

    2015-01-01

    The Ullrich-Turner syndrome (complete or partial X-chromosome monosomy) has been found to be associated with an increased rate of some extragonadal neoplasms. Sporadic reports of the Turner syndrome with various brain tumors, including few cases of glioblastoma multiforme, have been found in the literature. However, published data are insufficient to establish a definite relationship between these tumors and the Turner syndrome. Herein, a rare case of primary pediatric glioblastoma multiforme in a 7-year-old girl with Turner's syndrome is reported, and various aspects regarding clinical and pathophysiological issues have been discussed. Although Turner's syndrome is not one of the congenital chromosomal abnormalities which demand routine CNS screening, neurological assessment may be of value in those with relevant clinical findings. PMID:25720952

  9. Hemolytic anemia in two patients with glioblastoma multiforme: A possible interaction between vorinostat and dapsone.

    PubMed

    Lewis, Jennifer A; Petty, William J; Harmon, Michele; Peacock, James E; Valente, Kari; Owen, John; Pirmohamed, Munir; Lesser, Glenn J

    2015-06-01

    Patients undergoing treatment for glioblastoma multiforme are routinely placed on prophylactic treatment for Pneumocystis jirovecii pneumonia because of significant therapy-induced lymphopenia. In patients with sulfa allergies, dapsone prophylaxis is often used due to its efficacy, long half-life, cost effectiveness, and general safety at low doses. However, dapsone may uncommonly induce a hemolytic anemia, particularly in patients deficient of glucose-6-phosphate dehydrogenase. This hemolysis is thought to be a result of oxidative stress on red blood cells induced by dapsone metabolites which produce reactive oxygen species that disrupt the red blood cell membrane and promote splenic sequestration. A single case report of dapsone-induced hemolytic anemia in a patient with glioblastoma multiforme has been reported. We present two patients with glioblastoma multiforme who developed severe hemolytic anemia shortly after initiating therapy with vorinostat, a pan-active histone deacetylase inhibitor, while on prophylactic dapsone. There are several potential mechanisms by which histone deacetylase inhibition may alter dapsone metabolism including changes in hepatic acetylation or N-glucuronidation leading to an increase in the bioavailability of dapsone's hematotoxic metabolites. In addition, vorinostat may lead to increased hemolysis through inhibition of heat shock protein-90, a chaperone protein that maintains the integrity of the red blood cell membrane cytoskeleton. The potential interaction between dapsone and vorinostat may have important clinical implications as more than 10 clinical trials evaluating drug combinations with vorinostat in patients with malignant glioma are either ongoing or planned in North America. PMID:24576944

  10. Glioblastoma Multiforme: Relationship to Subventricular Zone and Recurrence

    PubMed Central

    Kimura, Margareth; Lee, Yeuh; Miller, Ryan; Castillo, Mauricio

    2013-01-01

    Summary Neurogenesis in the adult mammalian brain is active in two areas: the subgranular zone in the dentate gyrus of the hippocampus and the subventricular zone. Cancer stem cells have been isolated from malignant brain tumors and it is widely believed they arise from transformed endogenous stem cells. We sought to determine if the initial location of glioblastoma (GB) as seen on conventional MRI and its relationship to the subventricular zone (SVZ) predicts the pattern of recurrence. We analyzed the initial (prior to any treatment) and last follow-up MR studies in 49 patients with GB. On post contrast images all non-treated GB were divided into three groups according to the relationship of their enhancing margins to the SVZ: Group I (directly in contact with the SVZ), Group II (in the subcortical [SC] region) and Group III (in both the SVZ and SC regions). Recurrences or continuous growth seen as enhancing areas on follow-up studies were characterized as local, spread, or distant according to their contact with the surgical bed and correlated with the locations of the initial tumors. Local and spread patterns of recurrence occurred with nearly equal frequency (45 and 43% each, respectively) and distant in 12%. In Group I, 80% showed a spread pattern, 20% a local pattern, and none a distant pattern. In Group II, 45% showed a spread pattern, 35% a local pattern, and a 20% distant one. In Group III, 58% showed a local pattern, 33% a spread pattern, and 8% distant one. Unlike other reports, the location of GB in relation to the SVZ in our patients did not predict the pattern of tumor recurrence and/or extension in our patients. PMID:24199814

  11. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge

    PubMed Central

    Sturm, Dominik; Bender, Sebastian; Jones, David T.W.; Lichter, Peter; Grill, Jacques; Becher, Oren; Hawkins, Cynthia; Majewski, Jacek; Jones, Chris; Costello, Joseph F.; Iavarone, Antonio; Aldape, Kenneth; Brennan, Cameron W.; Jabado, Nada; Pfister, Stefan M.

    2014-01-01

    Preface We have extended our understanding of the molecular biology underlying adult glioblastoma over many years. In contrast, high-grade gliomas in children and adolescents have remained a relatively under-investigated disease. The latest large-scale genomic and epigenomic profiling studies have yielded an unprecedented abundance of novel data and revealed deeper insights into gliomagenesis across all age groups, highlighting key distinctions, but also some commonalities. As we are on the verge of dissecting glioblastomas into meaningful biological subgroups, this Review summarizes the hallmark genetic alterations associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease, and examines the complex interplay between the glioblastoma genome and epigenome. PMID:24457416

  12. 5-ALA Fluorescence Image Guided Resection of Glioblastoma Multiforme: A Meta-Analysis of the Literature

    PubMed Central

    Eljamel, Samy

    2015-01-01

    Background: Glioblastoma multiforme (GBM) is one of the most deadly cancers in humans. Despite recent advances in anti-cancer therapies, most patients with GBM die from local disease progression. Fluorescence image guided surgical resection (FIGR) was recently advocated to enhance local control of GBM. This is meta-analyses of 5-aminolevulinic (5-ALA) induced FIGR. Materials: Review of the literature produced 503 potential publications; only 20 of these fulfilled the inclusion criteria of this analysis, including a total of 565 patients treated with 5-ALA-FIGR reporting on its outcomes and 800 histological samples reporting 5-ALA-FIGR sensitivity and specificity. Results: The mean gross total resection (GTR) rate was 75.4% (95% CI: 67.4–83.5, p < 0.001). The mean time to tumor progression (TTP) was 8.1 months (95% CI: 4.7–12, p < 0.001). The mean overall survival gain reported was 6.2 months (95% CI: −1–13, p < 0.001). The specificity was 88.9% (95% CI: 83.9–93.9, p < 0.001) and the sensitivity was 82.6% (95% CI: 73.9–91.9, p < 0.001). Conclusion: 5-ALA-FIGR in GBM is highly sensitive and specific, and imparts significant benefits to patients in terms of improved GTR and TTP. PMID:25961952

  13. Rad51 Protein Expression and Survival in Patients with Glioblastoma Multiforme

    SciTech Connect

    Welsh, James W. Ellsworth, Ron K.; Kumar, Rachit; Fjerstad, Kyle; Martinez, Jesse; Nagel, Raymond B.; Eschbacher, Jennifer; Stea, Baldassarre

    2009-07-15

    Purpose: Treatment of glioblastoma multiforme (GBM) continues to pose a significant therapeutic challenge, with most tumors recurring within the previously irradiated tumor bed. To improve outcomes, we must be able to identify and treat resistant cell populations. Rad51, an enzyme involved in homologous recombinational repair, leads to increased resistance of tumor cells to cytotoxic treatments such as radiotherapy. We hypothesized that Rad51 might contribute to GBM's apparent radioresistance and consequently influence survival. Methods and Materials: A total of 68 patients with an initial diagnosis of GBM were retrospectively evaluated; for 10 of these patients, recurrent tumor specimens were used to construct a tissue microarray. Rad51 protein expression was then correlated with the actual and predicted survival using recursive partitioning analysis. Results: Rad51 protein was elevated in 53% of the GBM specimens at surgery. The Rad51 levels correlated directly with survival, with a median survival of 15 months for patients with elevated Rad51 compared with 9 months for patients with low or absent levels of Rad51 (p = .05). At disease recurrence, 70% of patients had additional increases in Rad51 protein. Increased Rad51 levels at disease recurrence similarly predicted for improved overall survival, with a mean survival of 16 months from the second craniotomy compared with only 4 months for patients with low Rad51 levels (p = .13). Conclusion: Elevated levels of the double-stranded DNA repair protein Rad51 predicted for an increase survival duration in patients with GBM, at both initial tumor presentation and disease recurrence.

  14. Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA.

    PubMed

    Heo, Jin-Chul; Jung, Tae-Hoon; Lee, Sungjin; Kim, Hyun Young; Choi, Gildon; Jung, Myungeun; Jung, Daeyoung; Lee, Heung Kyoung; Lee, Jung-Ok; Park, Ji-Hwan; Hwang, Daehee; Seol, Ho Jun; Cho, Heeyeong

    2016-06-01

    Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM. PMID:26957434

  15. Isocitrate Dehydrogenase-1 Mutations as Prognostic Biomarker in Glioblastoma Multiforme Patients in West Bohemia

    PubMed Central

    Polivka, J.; Polivka, J.; Rohan, V.; Pesta, M.; Repik, T.; Pitule, P.; Topolcan, O.

    2014-01-01

    Introduction. Glioblastoma multiforme (GBM) is the most malignant primary brain tumor in adults. Recent whole-genome studies revealed novel GBM prognostic biomarkers such as mutations in metabolic enzyme IDH—isocitrate dehydrogenases (IDH1 and IDH2). The distinctive mutation IDH1 R132H was uncovered to be a strong prognostic biomarker for glioma patients. We investigated the prognostic role of IDH1 R132H mutation in GBM patients in West Bohemia. Methods. The IDH1 R132H mutation was assessed by the RT-PCR in the tumor samples from 45 GBM patients treated in the Faculty Hospital in Pilsen and was correlated with the progression free and overall survival. Results. The IDH1 R132H mutation was identified in 20 from 44 GBM tumor samples (45.4%). The majority of mutated tumors were secondary GBMs (16 in 18, 89.9%). Low frequency of IDH1 mutations was observed in primary GBMs (4 in 26, 15.3%). Patients with IDH R132H mutation had longer PFS, 136 versus 51 days (P < 0.021, Wilcoxon), and OS, 270 versus 130 days (P < 0.024, Wilcoxon test). Summary. The prognostic value of IDH1 R132H mutation in GBM patients was verified. Patients with mutation had significantly longer PFS and OS than patients with wild-type IDH1 and suffered more likely from secondary GBMs. PMID:24511544

  16. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme

    PubMed Central

    Bai, Ren-Yuan; Staedtke, Verena; Aprhys, Colette M.; Gallia, Gary L.; Riggins, Gregory J.

    2011-01-01

    Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer, and despite treatment advances, patient prognosis remains poor. During routine animal studies, we serendipitously observed that fenbendazole, a benzimidazole antihelminthic used to treat pinworm infection, inhibited brain tumor engraftment. Subsequent in vitro and in vivo experiments with benzimidazoles identified mebendazole as the more promising drug for GBM therapy. In GBM cell lines, mebendazole displayed cytotoxicity, with half-maximal inhibitory concentrations ranging from 0.1 to 0.3 µM. Mebendazole disrupted microtubule formation in GBM cells, and in vitro activity was correlated with reduced tubulin polymerization. Subsequently, we showed that mebendazole significantly extended mean survival up to 63% in syngeneic and xenograft orthotopic mouse glioma models. Mebendazole has been approved by the US Food and Drug Administration for parasitic infections, has a long track-record of safe human use, and was effective in our animal models with doses documented as safe in humans. Our findings indicate that mebendazole is a possible novel anti-brain tumor therapeutic that could be further tested in clinical trials. PMID:21764822

  17. 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.

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

    PubMed Central

    Ferrari, Cristina; Niccoli Asabella, Artor; 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 [64Cu]CuCl2. To evaluate the potential theranostic role of [64Cu]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 [64Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy. PMID:26649294

  19. Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme

    PubMed Central

    Larson, David A.; Suplica, Jeffrey M.; Chang, Susan M.; Lamborn, Kathleen R.; McDermott, Michael W.; Sneed, Penny K.; Prados, Michael D.; Wara, William M.; Nicholas, M. Kelly; Berger, Mitchel S.

    2004-01-01

    This study reports the initial experience at the University of California San Francisco (UCSF) with tumor resection and permanent, low-activity iodine 125 (125I) brachytherapy in patients with progressive or recurrent glioblastoma multiforme (GM) and compares these results to those of similar patients treated previously at UCSF with temporary brachytherapy without tumor resection. Thirty-eight patients with progressive or recurrent GM were treated at UCSF with repeat craniotomy, tumor resection, and permanent, low-activity 125I brachytherapy between June 1997 and May 1998. Selection criteria were Karnofsky performance score ⩾60, unifocal, contrast-enhancing, well-circumscribed progressive or recurrent GM that was judged to be completely resectable, and no evidence of leptomeningeal or subependymal spread. The median brachytherapy dose 5 mm exterior to the resection cavity was 300 Gy (range, 150–500 Gy). One patient was excluded from analysis. Median survival was 52 weeks from the date of brachytherapy. Age, Karnofsky performance score, and preimplant tumor volume were all statistically significant on univariate analyses. Multivariate analysis for survival showed only age to be significant. Median time to progression was 16 weeks. Both univariate and multivariate analysis of freedom from progression showed only preoperative tumor volume to be significant. Comparison to temporary brachytherapy patients showed no apparent difference in survival time. Chronic steroid requirements were low in patients with minimal postoperative residual tumor. We conclude that permanent 125I brachytherapy for recurrent or progressive GM is well tolerated. Survival time was comparable to that of a similar group of patients treated with temporary brachytherapy. PMID:15134626

  20. 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.

  1. 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.

  2. 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.

  3. 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. PMID:24745610

  4. 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. PMID:26027432

  5. 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

  6. Outcome of treatment of recurrent glioblastoma multiforme in elderly and/or frail patients.

    PubMed

    Socha, Joanna; Kepka, Lucyna; Ghosh, Sunita; Roa, Wilson; Kumar, Narendra; Sinaika, Valery; Matiello, Juliana; Lomidze, Darejan; de Castro, Douglas Guedes; Hentati, Dalenda; Fidarova, Elena

    2016-02-01

    Optimal treatment of recurrent glioblastoma multiforme (rGBM) in elderly and/or frail patients remains virtually unexplored, the best supportive care (BSC) only is routinely administered due to the fatal prognosis. We evaluated the impact of different treatment methods on post-progression survival (PPS) and overall survival (OS) of such patients. Data from 98 elderly and/or frail rGBM patients, treated initially with 1-week or 3-week radiotherapy (RT) within the phase III IAEA study (2010-2013), were analyzed. KPS at relapse and salvage treatment methods were recorded. Kaplan-Meier method was used to estimate PPS and OS for different treatment modalities. Eighty-four patients experienced recurrence: 47 (56%) received BSC, 21 (25%)-chemotherapy (CHT), 8 (9.5%)-surgery, 3 (3.5%)-RT, for 5 (6%) the data was unavailable. Median OS from randomization for all 84 patients was 35 weeks: 55 versus 30 weeks for any treatment versus BSC, p < 0.0001. Median PPS was 15 weeks: 23 weeks with any treatment versus 9 weeks with BSC, p < 0.0001. For local treatment (surgery and/or RT) median PPS was 51 versus 21 weeks for CHT, p = 0.36. In patients with poor KPS (≤60) at relapse median PPS was 9 weeks with BSC versus 21 weeks with any treatment, p = 0.014. In poor KPS patients median PPS for local treatment was 14 weeks versus 21 weeks with CHT, p = 0.88. An active therapeutic approach may be beneficial for selected elderly and/or frail rGBM patients. Poor KPS patients may also benefit from active treatment, but there is no benefit of local treatment over CHT. PMID:26542030

  7. 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

  8. Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: a phase I study.

    PubMed

    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

    2010-06-01

    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 [PKCbeta] 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 > or =60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m(2) daily) followed by adjuvant temozolomide (200 mg/m(2)) 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 < or =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

  9. 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.

  10. 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.

  11. Role of Collagen Matrix in Tumor Angiogenesis and Glioblastoma Multiforme Progression

    PubMed Central

    Mammoto, Tadanori; Jiang, Amanda; Jiang, Elisabeth; Panigrahy, Dipak; Kieran, Mark W.; Mammoto, Akiko

    2014-01-01

    Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor β-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression. PMID:23928381

  12. 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

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

    PubMed

    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

  14. Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

    PubMed Central

    Lin, Yu-Ling; Chang, Kai-Fu; Huang, Xiao-Fan; Hung, Che-Lun; Chen, Shyh-Chang; Chao, Wan-Ru; Liao, Kuang-Wen; Tsai, Nu-Man

    2015-01-01

    Background The natural compound n-butylidenephthalide (BP) can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo. Objective The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery. Methods To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC). Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections. Results When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than that of free BP (~4.5- to 8.5-fold). This increased cytotoxic activity of BP/LPPC is attributable to its rapid transport across the cell membrane. In an animal study, a subcutaneously xenografted glioblastoma multiforme mouse that was treated with BP by intratumoral and intravenous administration showed inhibited tumor growth. The same dose of BP/LPPC was significantly more effective in terms of tumor inhibition. Conclusion LPPC encapsulation technology is able to protect BP’s structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy. PMID:26451107

  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. 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.

  17. 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

  18. Clinical outcome of gliosarcoma compared with glioblastoma multiforme: a clinical study in Chinese patients.

    PubMed

    Zhang, Guobin; Huang, Shengyue; Zhang, Junting; Wu, Zhen; Lin, Song; Wang, Yonggang

    2016-04-01

    Gliosarcoma (GSM) is a rare biphasic neoplasms of the central nervous system composed of a glioblastoma multiforme (GBM) admixed with a sarcomatous component. In clinical practice GSM is generally managed similarly to GBM. However, there are conflicting reports regarding their clinical aggressiveness, cell line of origin and possible prognosis compared with those of GBM. The objective of this study was to compare clinic-pathological features in GSM patients with the GBM patients during the same study period. 518 patients with GBM were treated at our hospital between 2008 and 2013, among them 51 were GSM. In this series the GSMs represented 9.8 % of all GBMs and included 58.8 % male with a median age of 44.7 years. The locations, all supratentorial, included temporal in 41.2 %, frontal in 25.5 %, parietal in 19.6 %, and occipital in 13.7 %. All patients underwent tumor resection followed by post-operative radiation and adjuvant chemotherapy. The O6-methylguanine-DNA methyltransferase promoter methylation studies were significantly more frequent in the GBMs than GSMs (80.1 % vs. 44.7 %, P < 0.001). The median progression free survival and overall survival for the patients with GSM were 8.0 and 13.0 months, respectively, as compared with 9.0 and 14.0 months in the GBM group (log rank test P = 0.001 and 0.004, respectively). The Cox proportional hazards regression model indicated that the extent of tumor resection (HR = 1.518, P = 0.009) and pathological types (HR = 0.608, P = 0.002) were the significant prognostic factors in our own series. With regard to clinical features and outcomes, GSM and GBM cannot be distinguished clinically. GSM in China may be managed similarly to GBM, with maximal safe surgical resection followed by chemo-radiotherapy. Our study adds further evidence to support GSM as a unique clinical entity with a likely worse prognosis than GBM. PMID:26725096

  19. 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

  20. Unusual manifestations of primary Glioblastoma Multiforme: A report of three cases

    PubMed Central

    Sanli, Ahmet Metin; Turkoglu, Erhan; Dolgun, Habibullah; Sekerci, Zeki

    2010-01-01

    Background: Brain tumors, especially high-grade gliomas, can present with focal or generalized signs due to mass effect, parenchymal infiltration and destruction. In general, at the time of diagnosis, tumors could cause common neurological symptoms and major clinical signs depending on their localization. In rare instances, brain tumors colud be manifested with unusual symptoms. Case Description: We describe three cases presenting with unusual clinical symptoms: ulnar neuropathy, vertigo and syncope attacks. Microscopic total tumor excision was done and histopathological analysis revealed that these tumors were glioblastoma multiforme. Both external beam radiotherapy and chemotherapy were given as adjuvant treatments. Conclusions: Physicians should keep brain tumors in mind in the case of patients who present with atypical symptoms such as those reported here. Brain imaging should be performed over a prolonged period following presentation if the patient’s symptoms remain unresolved after adequate treatment. PMID:21206896

  1. Irinotecan-based regimens for recurrent glioblastoma multiforme: [corrected] a systematic review.

    PubMed

    Abdel-Rahman, Omar; Fouad, Mona

    2015-01-01

    This systematic review aims to assess irinotecan-based salvage regimens for patients with recurrent glioblastoma multiforme (GBM) beyond first line treatment. Eligible trials were identified using databases search and 25 studies were included in the final analysis. Among the 25 studies, PFS-6 rate was reported in 15 studies and it ranged from 16% to 63%. Median PFS was reported in 18 studies and it ranged from 1 to 7.6 months. While for median OS, it was reported in 17 studies and it ranged from 5.8 months to 17.9 months. The available data suggests that routine use of irinotecan-based salvage regimens cannot be recommended outside the setting of well-controlled prospective randomized studies investigating novel combinations of irinotecan. PMID:26469869

  2. 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

  3. 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.

  4. Hexamethylene bisacetamide induces morphologic changes and increased synthesis of procollagen in cell line from glioblastoma multiforme.

    PubMed Central

    Rabson, A S; Stern, R; Tralka, T S; Costa, J; Wilczek, J

    1977-01-01

    Addition to hexamethylene bisacetamide (diacetyldiaminohexane) to cultures of a malignant mesenchymal cell line derived from a human glioblastoma multiforme induces morphological changes and stimulates the synthesis of procollagen. The morphological changes include cell elongation, an increase of extracellular material with staining properties of collagen by light microscopy, and an increase in extracellular 220-A fibrils by electron microscopy. The rate of procollagen synthesis increased as much as 20-fold, and the ratio of type I:type III procollagen changed, with type I becoming the predominant form. The change in type I:type III ratio is similar to that seen in the maturation of normal fetal to adult connective tissue. Images PMID:200944

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

    NASA Astrophysics Data System (ADS)

    Zasneda, Sabriani; Widita, Rena

    2010-06-01

    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, α) 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 10B/g blood.

  6. 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

  7. 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. PMID:23304418

  8. 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

  9. 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

  10. 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

  11. 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.

  12. Giant pediatric glioblastoma multiforme causing primary calvarial erosion and sutural diastasis presenting with enlarged head

    PubMed Central

    Satyarthee, Guru Dutta; Mahapatra, A. K.

    2015-01-01

    Authors report a rare case of supratentorial glioblastoma multiforme in a 13-year-old boy, who had headache, vomiting and left sided hemiparesis for last 6 months. On evaluation by primary physician he was labeled as hydrocephalus in view of enlarged head with papilledema on fundoscopic evaluation and no imaging was carried out. On current admission, magnetic resonance imaging brain revealed a large heterogeneous mass lesion involving right frontoparietal region associated with massive perilesional edema causing significant mass effect. He underwent right fronto-temporal craniotomy and intraoperatively erosion of parietal bone was observed, unassociated with any extradural deposit of tumor. After surgery, he noticed improvement in headache along with hemiparesis. Primary calvarial erosion in glioblastoma is extremely rare, and there is paucity of literature as evident from the few case reports reported previously and all occurred in elderly, so current case is the first pediatric case having primary calvarial erosion. Management of such case and pertinent literature is briefly discussed. PMID:26557181

  13. 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.

  14. Primary Spinal Glioblastoma Multiforme with Secondary Manifestation as a Cerebral “Angioglioma.” Literature Review and Case Report

    PubMed Central

    Linsenmann, Thomas; Westermaier, Thomas; Vince, Giles Hamilton; Monoranu, Camelia Maria; Löhr, Mario; Ernestus, Ralf-Ingo; Stetter, Christian

    2015-01-01

    Primary intramedullary spinal glioblastoma multiforme (sGBM) with a secondary cerebral manifestation is a very rare entity with a poor outcome. Case studies show a mean average of survival of 10 months after diagnosis. These tumors tend to develop at a young age. A combination with an arteriovenous malformation in the same location has never been published before. Vascular malformations in association with cerebral glioblastomas have only been reported in five cases so far. Proangiogenic factors are assumed to be involved in the appearance of both entities. We present a case study and a review of the literature. PMID:26251789

  15. 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

  16. 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 14months and 2year 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. PMID:26892752

  17. Glioblastoma multiforme following prophylactic cranial irradiation and intrathecal methotrexate in a child with acute lymphocytic leukemia. [. gamma. rays; infants

    SciTech Connect

    Chung, C.K.; Stryker, J.A.; Cruse, R.; Vannuci, R.; Towfighi, J.

    1981-06-01

    Cases of radiation-induced glioma in humans are extremely rare. A 2-year-old boy with acute lymphocytic leukemia had received prophylactic cranial irradiation (2400 rad/2 1/2 weeks) and intrathecal methotrexate. Five years later he developed a glioblastoma multiforme on the left cerebral hemisphere while the leukemia was in remission. This is the first reported association of these disorders. It is possible that the glioma may have been induced by radiation and/or chemotherapy.

  18. Late onset leptomeningeal and whole spine metastasis from supratentorial Glioblastoma multiforme: An uncommon manifestation of a common tumor

    PubMed Central

    Sharma, Divyam; Gupta, Anshul; Dhillon, Gurupal S; Chhabra, Satnam Singh

    2016-01-01

    Glioblastoma multiforme (GBM) is one of the most common and aggressive primary brain tumors, composing 12-20% of all the intracranial tumors in adults with a highly malignant course and average life expectancy of approximately 12-14 months following initial diagnosis. Leptomeningeal or intramedullary metastasis from primary GBM is a rare phenomenon with a poor prognosis. We present a rare case of GBM with late onset intramedullary, extramedullary, as well as leptomeningeal spinal metastasis. PMID:27217661

  19. Late onset leptomeningeal and whole spine metastasis from supratentorial Glioblastoma multiforme: An uncommon manifestation of a common tumor.

    PubMed

    Sharma, Divyam; Gupta, Anshul; Dhillon, Gurupal S; Chhabra, Satnam Singh

    2016-01-01

    Glioblastoma multiforme (GBM) is one of the most common and aggressive primary brain tumors, composing 12-20% of all the intracranial tumors in adults with a highly malignant course and average life expectancy of approximately 12-14 months following initial diagnosis. Leptomeningeal or intramedullary metastasis from primary GBM is a rare phenomenon with a poor prognosis. We present a rare case of GBM with late onset intramedullary, extramedullary, as well as leptomeningeal spinal metastasis. PMID:27217661

  20. 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

  1. 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.

  2. [F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: Clinical outcomes and patterns of failure

    SciTech Connect

    Douglas, James G. . E-mail: drjay@u.washington.edu; Stelzer, Keith J.; Mankoff, David A.; Tralins, Kevin S.; Krohn, Kenneth A.; Muzi, Mark; Silbergeld, Daniel L.; Rostomily, Robert C.; Scharnhorst, Jeffrey B.S.; Spence, Alexander M.

    2006-03-01

    Purpose: [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for brain tumors has been shown to identify areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme may lead to improved disease control. Based on these premises, we initiated a prospective study of FDG-PET for the treatment planning of radiation dose escalation for the treatment of glioblastoma multiforme. Methods and Materials: Forty patients were enrolled. Patients were treated with standard conformal fractionated radiotherapy with volumes defined by MRI imaging. When patients reached a dose of 45-50.4 Gy, they underwent FDG-PET imaging for boost target delineation, for an additional 20 Gy (2 Gy per fraction) to a total dose of 79.4 Gy (n = 30). Results: The estimated 1-year and 2-year overall survival (OS) for the entire group was 70% and 17%, respectively, with a median overall survival of 70 weeks. The estimated 1-year and 2-year progression-free survival (PFS) was 18% and 3%, respectively, with a median of 24 weeks. No significant improvements in OS or PFS were observed for the study group in comparison to institutional historical controls. Conclusions: Radiation dose escalation to 79.4 Gy based on FDG-PET imaging demonstrated no improvement in OS or PFS. This study establishes the feasibility of integrating PET metabolic imaging into radiotherapy treatment planning.

  3. Comparison of intensity-modulated radiotherapy with three-dimensional conformal radiation therapy planning for glioblastoma multiforme

    SciTech Connect

    Chan, Maria F.; Schupak, Karen; Burman, Chandra; Chui, C.-S.; Ling, C. Clifton

    2003-12-31

    This study was designed to assess the feasibility and potential benefit of using intensity-modulated radiotherapy (IMRT) planning for patients newly diagnosed with glioblastoma multiforme (GBM). Five consecutive patients with confirmed histopathologically GBM were entered into the study. These patients were planned and treated with 3-dimensional conformal radiation therapy (3DCRT) using our standard plan of 3 noncoplanar wedged fields. They were then replanned with the IMRT method that included a simultaneous boost to the gross tumor volume (GTV). The dose distributions and dose-volume histograms (DHVs) for the planning treatment volume (PTV), GTV, and the relevant critical structures, as obtained with 3DCRT and IMRT, respectively, were compared. In both the 3DCRT and IMRT plans, 59.4 Gy was delivered to the GTV plus a margin of 2.5 cm, with doses to critical structures below the tolerance threshold. However, with the simultaneous boost in IMRT, a higher tumor dose of {approx}70 Gy could be delivered to the GTV, while still maintaining the uninvolved brain at dose levels of the 3DCRT technique. In addition, our experience indicated that IMRT planning is less labor intensive and time consuming than 3DCRT planning. Our study shows that IMRT planning is feasible and efficient for radiotherapy of GBM. In particular, IMRT can deliver a simultaneous boost to the GTV while better sparing the normal brain and other critical structures.

  4. [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

  5. 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

  6. 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

  7. 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

  8. Pathway analysis of single-nucleotide polymorphisms potentially associated with glioblastoma multiforme susceptibility using random forests.

    PubMed

    Chang, Jeffrey S; Yeh, Ru-Fang; Wiencke, John K; Wiemels, Joseph L; Smirnov, Ivan; Pico, Alexander R; Tihan, Tarik; Patoka, Joe; Miike, Rei; Sison, Jennette D; Rice, Terri; Wrensch, Margaret R

    2008-06-01

    Glioma is a complex disease that is unlikely to result from the effect of a single gene. Genetic analysis at the pathway level involving multiple genes may be more likely to capture gene-disease associations than analyzing genes one at a time. The current pilot study included 112 Caucasians with glioblastoma multiforme and 112 Caucasian healthy controls frequency matched to cases by age and gender. Subjects were genotyped using a commercially available (ParAllele/Affymetrix) assay panel of 10,177 nonsynonymous coding single-nucleotide polymorphisms (SNP) spanning the genome known at the time the panel was constructed. For this analysis, we selected 10 pathways potentially involved in gliomagenesis that had SNPs represented on the panel. We performed random forests (RF) analyses of SNPs within each pathway group and logistic regression to assess interaction among genes in the one pathway for which the RF prediction error was better than chance and the permutation P < 0.10. Only the DNA repair pathway had a better than chance classification of case-control status with a prediction error of 45.5% and P = 0.09. Three SNPs (rs1047840 of EXO1, rs12450550 of EME1, and rs799917 of BRCA1) of the DNA repair pathway were identified as promising candidates for further replication. In addition, statistically significant interactions (P < 0.05) between rs1047840 of EXO1 and rs799917 or rs1799966 of BRCA1 were observed. Despite less than complete inclusion of genes and SNPs relevant to glioma and a small sample size, RF analysis identified one important biological pathway and several SNPs potentially associated with the development of glioblastoma. PMID:18559551

  9. 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

  10. Neuronatin in a Subset of Glioblastoma Multiforme Tumor Progenitor Cells Is Associated with Increased Cell Proliferation and Shorter Patient Survival

    PubMed Central

    Bründl, Elisabeth; Brawanski, Alexander; Fang, Xueping; Lee, Cheng S.; Weil, Robert J.; Zhuang, Zhengping; Lonser, Russell R.

    2012-01-01

    Glioblastoma multiforme is the most common and malignant primary brain tumor. Recent evidence indicates that a subset of glioblastoma tumor cells have a stem cell like phenotype that underlies chemotherapy resistance and tumor recurrence. We utilized a new “multidimensional” capillary isoelectric focusing nano-reversed-phase liquid chromatography platform with tandem mass spectrometry to compare the proteomes of isolated glioblastoma tumor stem cell and differentiated tumor cell populations. This proteomic analysis yielded new candidate proteins that were differentially expressed. Specifically, two isoforms of the membrane proteolipid neuronatin (NNAT) were expressed exclusively within the tumor stem cells. We surveyed the expression of NNAT across 10 WHO grade II and III gliomas and 23 glioblastoma (grade IV) human tumor samples and found NNAT was expressed in a subset of primary glioblastoma tumors. Through additional in vitro studies utilizing the U87 glioma cell line, we found that expression of NNAT is associated with significant increases in cellular proliferation. Paralleling the in vitro results, when NNAT levels were evaluated in tumor specimens from a consecutive cohort of 59 glioblastoma patients, the presence of increased levels of NNAT were found to be a an independent risk factor (P = 0.006) for decreased patient survival through Kaplan-Meier and multivariate analysis. These findings indicate that NNAT may have utility as a prognostic biomarker, as well as a cell-surface target for chemotherapeutic agents. PMID:22624064

  11. 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.

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

    PubMed

    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

  13. 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.

  14. 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.

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

    PubMed

    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

  16. 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

  17. A combination of tyrosine kinase inhibitors, crizotinib and dasatinib for the treatment of glioblastoma multiforme

    PubMed Central

    Nehoff, Hayley; Parayath, Neha N.; McConnell, Melanie J.; Taurin, Sebastien; Greish, Khaled

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Despite the advances in surgery, radiotherapy and chemotherapy, patient survival averages only 14.6 months. In most GBM tumors, tyrosine kinases show increased activity and/or expression and actively contribute to the development, recurrence and onset of treatment resistance; making their inhibition an appealing therapeutic strategy. We compared the cytotoxicity of 12 tyrosine kinase inhibitors in vitro. A combination of crizotinib and dasatinib emerged as the most cytotoxic across established and primary human GBM cell lines. The combination treatment induced apoptotic cell death and polyploidy. Furthermore, the combination treatment led to the altered expression and localization of several tyrosine kinase receptors such as Met and EGFR and downstream effectors as such as SRC. Furthermore, the combination treatment reduced the migration and invasion of GBM cells and prevented endothelial cell tube formation in vitro. Overall, our study demonstrated the broad specificity of a combination of crizotinib and dasatinib across multiple GBM cell lines. These findings provide insight into the development of alternative therapy for the treatment of GBM. PMID:26517812

  18. Toward 3D Biomimetic Models to Understand the Behavior of Glioblastoma Multiforme Cells

    PubMed Central

    Rao, Shreyas S.; Lannutti, John J.; Viapiano, Mariano S.; Sarkar, Atom

    2014-01-01

    Glioblastoma multiforme (GBM) tumors are one of the most deadly forms of human cancer and despite improved treatments, median survival time for the majority of patients is a dismal 12–15 months. A hallmark of these aggressive tumors is their unique ability to diffusively infiltrate normal brain tissue. To understand this behavior and successfully target the mechanisms underlying tumor progression, it is crucial to develop robust experimental ex vivo disease models. This review discusses current two-dimensional (2D) experimental models, as well as animal-based models used to examine GBM cell migration, including their advantages and disadvantages. Recent attempts to develop three-dimensional (3D) tissue engineering-inspired models and their utility in unraveling the role of microenvironment on tumor cell behaviors are also highlighted. Further, the use of 3D models to bridge the gap between 2D and animal models is explored. Finally, the broad utility of such models in the context of brain cancer research is examined. PMID:24044776

  19. 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

  20. 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

  1. A Fourier transform infrared microspectroscopic imaging investigation into an animal model exhibiting glioblastoma multiforme.

    PubMed

    Bambery, K R; Schültke, E; Wood, B R; Rigley MacDonald, S T; Ataelmannan, K; Griebel, R W; Juurlink, B H J; McNaughton, D

    2006-07-01

    Glioblastoma multiforme (GBM) is a highly malignant human brain tumour for which no cure is available at present. Numerous clinical studies as well as animal experiments are under way with the goal being to understand tumour biology and develop potential therapeutic approaches. C6 cell glioma in the adult rat is a frequently used and well accepted animal model for the malignant human glial tumour. By combining standard analytical methods such as histology and immunohistochemistry with Fourier Transform Infrared (FTIR) microspectroscopic imaging and multivariate statistical approaches, we are developing a novel approach to tumour diagnosis which allows us to obtain information about the structure and composition of tumour tissues that could not be obtained easily with either method alone. We have used a "Stingray" FTIR imaging spectrometer to analyse and compare the compositions of coronal brain tissue sections of a tumour-bearing animal and those from a healthy animal. We have found that the tumour tissue has a characteristic chemical signature, which distinguishes it from tumour-free brain tissue. The physical-chemical differences, determined by image and spectral comparison are consistent with changes in total protein absorbance, phosphodiester absorbance and physical dispersive artefacts. The results indicate that FTIR imaging analysis could become a valuable analytic method in brain tumour research and possibly in the diagnosis of human brain tumours. PMID:16815240

  2. The PEP-3-KLH (CDX-110) vaccine in glioblastoma multiforme patients

    PubMed Central

    Heimberger, Amy B.; Sampson, John H

    2009-01-01

    Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively resulting in non-specific toxicity. Immune targeting of tumor-specific mutations may allow for more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation that is widely expressed on GBM and other neoplasms and its expression enhances tumorigenicity. This in-frame deletion mutation splits a codon resulting in a novel glycine at the fusion junction producing a tumor-specific epitope target for cellular or humoral immunotherapy. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction (PEPvIII-KLH/CDX-110) is an efficacious immunotherapy in syngeneic murine models. In this review, we summarize our results in GBM patients targeting this mutation in multiple, multi-institutional Phase II immunotherapy trials. These trials demonstrated that a selected population of GBM patients who received the vaccines targeting EGFRvIII had an unexpectedly long survival time. Further therapeutic strategies and potential pitfalls using this approach are discussed. PMID:19591631

  3. Expression of SPRR3 is associated with tumor cell proliferation and invasion in glioblastoma multiforme.

    PubMed

    Liu, Qingyang; Zhang, Chuanbao; Ma, Guofo; Zhang, Quangeng

    2014-02-01

    Esophagin, also known as small proline-rich protein 3 (SPRR3), has been demonstrated to be important in the initiation and progression of numerous types of tumor, including colorectal and breast cancer. However, studies concerning the biological functions of SPRR3 in glioblastoma multiforme (GBM) are limited. Therefore, we aimed to identify the functions and molecular mechanisms underlying the role of SPRR3 in GBM. Hypomethylation of SPRR3 was observed and associated with a poor clinical outcome in GBM patients compared with healthy individuals by using gene methylation profiling. The present study was performed to investigate the expression status and effects of SPRR3 in GBM. The U251 cell line was used in the functional analyses. Cell growth was examined by MTT and colony formation assay. Cell invasion was measured using the Transwell invasion assay. The expression of SPRR3 in tissue samples was examined by immunohistochemistry. The results revealed that the overexpression of SPRR3 accelerates U251 cell proliferation and invasion. It was also observed that SPRR3 was markedly upregulated in 72.7% of GBM samples (24/33) compared with the normal tissue. These results suggest that an increased expression of SPRR3 is involved in tumorigenesis. PMID:24396461

  4. Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme

    PubMed Central

    Liang, Yu; Diehn, Maximilian; Watson, Nathan; Bollen, Andrew W.; Aldape, Ken D.; Nicholas, M. Kelly; Lamborn, Kathleen R.; Berger, Mitchel S.; Botstein, David; Brown, Patrick O.; Israel, Mark A.

    2005-01-01

    Glioblastoma multiforme (GBM) is the most common form of malignant glioma, characterized by genetic instability, intratumoral histopathological variability, and unpredictable clinical behavior. We investigated global gene expression in surgical samples of brain tumors. Gene expression profiling revealed large differences between normal brain samples and tumor tissues and between GBMs and lower-grade oligodendroglial tumors. Extensive differences in gene expression were found among GBMs, particularly in genes involved in angiogenesis, immune cell infiltration, and extracellular matrix remodeling. We found that the gene expression patterns in paired specimens from the same GBM invariably were more closely related to each other than to any other tumor, even when the paired specimens had strikingly divergent histologies. Survival analyses revealed a set of ≈70 genes more highly expressed in rapidly progressing tumors that stratified GBMs into two groups that differed by >4-fold in median duration of survival. We further investigated one gene from the group, FABP7, and confirmed its association with survival in two unrelated cohorts totaling 105 patients. Expression of FABP7 enhanced the motility of glioma-derived cells in vitro. Our analyses thus identify and validate a prognostic marker of both biologic and clinical significance and provide a series of putative markers for additional evaluation. PMID:15827123

  5. Dendritic cell vaccination for glioblastoma multiforme: review with focus on predictive factors for treatment response

    PubMed Central

    Dejaegher, Joost; Van Gool, Stefaan; De Vleeschouwer, Steven

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and most aggressive type of primary brain cancer. Since median overall survival with multimodal standard therapy is only 15 months, there is a clear need for additional effective and long-lasting treatments. Dendritic cell (DC) vaccination is an experimental immunotherapy being tested in several Phase I and Phase II clinical trials. In these trials, safety and feasibility have been proven, and promising clinical results have been reported. On the other hand, it is becoming clear that not every GBM patient will benefit from this highly personalized treatment. Defining the subgroup of patients likely to respond to DC vaccination will position this option correctly amongst other new GBM treatment modalities, and pave the way to incorporation in standard therapy. This review provides an overview of GBM treatment options and focuses on the currently known prognostic and predictive factors for response to DC vaccination. In this way, it will provide the clinician with the theoretical background to refer patients who might benefit from this treatment.

  6. Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines

    PubMed Central

    Anderson, Joshua C.; Duarte, Christine W.; Welaya, Karim; Rohrbach, Timothy D.; Bredel, Markus; Yang, Eddy S.; Choradia, Nirmal; Thottassery, Jaideep V.; Gillespie, G. Yancey; Bonner, James A.; Willey, Christopher D.

    2014-01-01

    Background and Purpose Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or “xenolines”). Materials and Methods Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling. Results Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance. Conclusions GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance. PMID:24813092

  7. Element distribution is altered in a zone surrounding human glioblastoma multiforme.

    PubMed

    Dehnhardt, Markus; Zoriy, Myroslav V; Khan, Zahidul; Reifenberger, Guido; Ekström, Tomas J; Sabine Becker, J; Zilles, Karl; Bauer, Andreas

    2008-01-01

    Recent data indicate that A(1) adenosine receptor (A(1)AR) density is increased in a zone surrounding human and experimental gliomas. On the contrary, tumor tissue and adjacent brain tissue show low to intermediate A(1)AR densities. In order to assess whether changes in A(1)AR expression are indicating further processes of a chemical reorganization of the peritumoral zone, we investigated element concentrations and distribution patterns of copper and zinc in six human glioblastoma multiforme (GBM) specimens by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Uranium and lead were used as external standards. Copper and zinc levels were increased in a peritumoral zone corresponding to the region of elevated A(1)AR density. They showed a lower density in the solid tumor in comparison to surrounding brain tissue, although the cellular density was higher within GBM. Our findings suggest that the immediate vicinity of GBM is characterized by increased levels of copper and zinc supporting the view that higher A(1)AR density surrounding GBM is not an isolated alteration of peritumoral tissue but an indicator of complex changes in the vicinity of infiltrative tumors. Further research is needed to explore the pathophysiological consequences of altered peritumoral element distribution. PMID:18319136

  8. 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

  9. 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

  10. Radiologically Defined Ecological Dynamics and Clinical Outcomes in Glioblastoma Multiforme: Preliminary Results1

    PubMed Central

    Zhou, Mu; Hall, Lawrence; Goldgof, Dmitry; Russo, Robin; Balagurunathan, Yoganand; Gillies, Robert; Gatenby, Robert

    2014-01-01

    MATERIALS AND METHODS: We examined pretreatment magnetic resonance imaging (MRI) examinations from 32 patients with glioblastoma multiforme (GBM) enrolled in The Cancer Genome Atlas (TCGA). Spatial variations in T1 post-gadolinium and either T2-weighted or fluid attenuated inversion recovery sequences from each tumor MRI study were used to characterize each small region of the tumor by its local contrast enhancement and edema/cellularity (“habitat”). The patient cohort was divided into group 1 (survival < 400 days, n = 16) and group 2 (survival > 400 days, n = 16). RESULTS: Histograms of relative values in each sequence demonstrated that the tumor regions were consistently divided into high and low blood contrast enhancement, each of which could be subdivided into regions of high, low, and intermediate cell density/interstitial edema. Group 1 tumors contained greater volumes of habitats with low contrast enhancement but intermediate and high cell density (not fully necrotic) than group 2. Both leave-one-out and 10-fold cross-validation schemes demonstrated that individual patients could be correctly assigned to the short or long survival group with 81.25% accuracy. CONCLUSION: We demonstrate that novel image analytic techniques can characterize regional habitat variations in GBMs using combinations of MRI sequences. A preliminary study of 32 patients from the TCGA database found that the distribution of MRI-defined habitats varied significantly among the different survival groups. Radiologically defined ecological tumor analysis may provide valuable prognostic and predictive biomarkers in GBM and other tumors. PMID:24772202

  11. 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

  12. Multireference Level Set for the Characterization of Nuclear Morphology in Glioblastoma Multiforme

    PubMed Central

    Han, Ju; Spellman, Paul T.

    2013-01-01

    Histological tissue sections provide rich information and continue to be the gold standard for the assessment of tissue neoplasm. However, there are a significant amount of technical and biological variations that impede analysis of large histological datasets. In this paper, we have proposed a novel approach for nuclear segmentation in tumor histology sections, which addresses the problem of technical and biological variations by incorporating information from both manually annotated reference patches and the original image. Subsequently, the solution is formulated within a multireference level set framework. This approach has been validated on manually annotated samples and then applied to the TCGA glioblastoma multiforme (GBM) dataset consisting of 440 whole mount tissue sections scanned with either a 20× or 40× objective, in which, each tissue section varies in size from 40k × 40k pixels to 100k × 100k pixels. Experimental results show a superior performance of the proposed method in comparison with present state of art techniques. PMID:22987497

  13. Connection between Cell Phone use, p53 Gene Expression in Different Zones of Glioblastoma Multiforme and Survival Prognoses

    PubMed Central

    Akhavan-Sigari, Reza; Baf, Morteza Mazloum Farsi; Ariabod, Vahid; Rohde, Veit; Rahighi, Saeed

    2014-01-01

    The aim of this paper is to investigate p53 gene expression in the central and peripheral zones of glioblastoma multiforme using a real-time reverse transcription polymerase chain reaction (RT-PCR) technique in patients who use cell phones ≥3 hours a day and determine its relationship to clinicopathological findings and overall survival. Sixty-three patients (38 males and 25 females), diagnosed with glioblastoma multiforme (GBM), underwent tumor resection between 2008 and 2011. Patient ages ranged from 25 to 88 years, with a mean age of 55. The levels of expression of p53 in the central and peripheral zone of the GBM were quantified by RT-PCR. Data on p53 gene expression from the central and peripheral zone, the related malignancy and the clinicopatholagical findings (age, gender, tumor location and size), as well as overall survival, were analyzed. Forty-one out of 63 patients (65%) with the highest level of cell phone use (≥3 hours/day) had higher mutant type p53 expression in the peripheral zone of the glioblastoma; the difference was statistically significant (P=0.034). Results from the present study on the use of mobile phones for ≥3 hours a day show a consistent pattern of increased risk for the mutant type of p53 gene expression in the peripheral zone of the glioblastoma, and that this increase was significantly correlated with shorter overall survival time. The risk was not higher for ipsilateral exposure. We found that the mutant type of p53 gene expression in the peripheral zone of the glioblastoma was increased in 65% of patients using cell phones ≥3 hours a day. PMID:25276320

  14. ET-54IMMUNOTHERAPY BASED ON TUMOR TRANSPLANT ANTIGEN RECOGNITION EMERGES AS A PROMISING STRATEGY FOR RECURRENT GLIOBLASTOMA MULTIFORME (GBM) PATIENTS

    PubMed Central

    Schijns, Virgil; Pretto, Chrystel; Devillers, Laurent; Pierre, Denis; Hofman, Florence; Kruse, Carol; Chen, Thomas; Oertel, Joachim; Hantos, Peter; Bota, Daniela; Stathopoulos, Apostolos

    2014-01-01

    Glioblastoma multiforme (GBM) prognosis remains very poor. This is especially true when the tumors relapse on the current standard of care treatments. Our preclinical data, generated in a rat CNS-1 glioma model in Lewis rats, provided the scientific rationale for a prototype clinical vaccine preparation, named ERC 1671 (Gliovac). ERC1671 is composed of autologous antigens, derived from the patient's own tumour tissue, and administered in conjunction with allogeneic antigens from histologically confirmed glioma tumours removed from other glioma patients. This new treatment was administered to recurrent, treatment resistant GBM patients, and compared to historic controls. 12 GBM patients with recurrent disease who recurred after standard of care treatment, including surgery followed by concomitant radiotherapy and chemotherapy with temozolomide, and for US patients, bevacizumab as second line treatment were treated under compassionate use/ hospital exemption protocols. ERC 1671 was given intra-dermally, every three days. Each injection was administered together with human granulocyte macrophage colony stimulating factor (Leukine®), and preceded by a regimen of regulatory T cell-depleting, low-dose cyclophosphamide. Our data suggest that ERC1671 administration in patients that have failed standard of care therapies enhances both progression-free survival (PFS) and overall survival (OS). Median OS for all 12 ERC1671 treated patients was 36 weeks versus 13 weeks in the historical control group (p= 0.0076). Patients with a higher KPS at tumour recurrence (>60) had a longer OS (43 weeks). Six-month survival for the 12 patients was 60% versus 20% in the historical control groups. Six-month survival for the 7 patients with KPS > 60 was 100%. Our first results suggest that ERC1671 has low toxicity and very promising efficacy. A phase II trial has recently been initiated in recurrent, bevacizumab naïve GBM patients (NCT00122681).

  15. 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

  16. Initial care and outcome of glioblastoma multiforme patients in 2 diverse health care scenarios in Brazil: does public versus private health care matter?

    PubMed Central

    Loureiro, Luiz Victor Maia; Pontes, Lucíola de Barros; Callegaro-Filho, Donato; Koch, Ludmila de Oliveira; Weltman, Eduardo; Victor, Elivane da Silva; Santos, Adrialdo José; Borges, Lia Raquel Rodrigues; Segreto, Roberto Araújo; Malheiros, Suzana Maria Fleury

    2014-01-01

    Background The aim of this study was to describe the epidemiological and survival features of patients with glioblastoma multiforme treated in 2 health care scenarios—public and private—in Brazil. Methods We retrospectively analyzed clinical, treatment, and outcome characteristics of glioblastoma multiforme patients from 2003 to 2011 at 2 institutions. Results The median age of the 171 patients (117 public and 54 private) was 59.3 years (range, 18–84). The median survival for patients treated in private institutions was 17.4 months (95% confidence interval, 11.1–23.7) compared with 7.1 months (95% confidence interval, 3.8–10.4) for patients treated in public institutions (P < .001). The time from the first symptom to surgery was longer in the public setting (median of 64 days for the public hospital and 31 days for the private institution; P = .003). The patients at the private hospital received radiotherapy concurrent with chemotherapy in 59.3% of cases; at the public hospital, only 21.4% (P < .001). Despite these differences, the institution of treatment was not found to be an independent predictor of outcome (hazard ratio, 1.675; 95% confidence interval, 0.951–2.949; P = .074). The Karnofsky performance status and any additional treatment after surgery were predictors of survival. A hazard ratio of 0.010 (95% confidence interval, 0.003–0.033; P < .001) was observed for gross total tumor resection followed by radiotherapy concurrent with chemotherapy. Conclusions Despite obvious disparities between the hospitals, the medical assistance scenario was not an independent predictor of survival. However, survival was directly influenced by additional treatment after surgery. Therefore, increasing access to resources in developing countries like Brazil is critical. PMID:24463356

  17. 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.

  18. Myelin structure is a key difference in the x-ray scattering signature between meningioma, schwannoma and glioblastoma multiforme

    NASA Astrophysics Data System (ADS)

    Falzon, G.; Pearson, S.; Murison, R.; Hall, C.; Siu, K.; Round, A.; Schültke, E.; Kaye, A. H.; Lewis, R.

    2007-11-01

    Small angle x-ray scattering (SAXS) patterns of benign and malignant brain tumour tissue were examined. Independent component analysis was used to find a feature set representing the images collected. A set of coefficients was then used to describe each image, which allowed the use of the statistical technique of flexible discriminant analysis to discover a hidden order in the data set. The key difference was found to be in the intensity and spectral content of the second and fourth order myelin scattering peaks. This has clearly demonstrated that significant differences in the structure of myelin exist in the highly malignant glioblastoma multiforme as opposed to the benign: meningioma and schwannoma.

  19. Use of ERC-1671 Vaccine in a Patient with Recurrent Glioblastoma Multiforme after Progression during Bevacizumab Therapy: First Published Report.

    PubMed

    Bota, Daniela A; Alexandru-Abrams, Daniela; Pretto, Chrystel; Hofman, Florence M; Chen, Thomas C; Fu, Beverly; Carrillo, Jose A; Schijns, Virgil Ejc; Stathopoulos, Apostolos

    2015-01-01

    Glioblastoma multiforme is a highy aggressive tumor that recurs despite resection, focal beam radiation, and temozolamide chemotherapy. ERC-1671 is an experimental treatment strategy that uses the patient's own immune system to attack the tumor cells. The authors report preliminary data on the first human administration of ERC-1671 vaccination under a single-patient, compassionate-use protocol. The patient survived for ten months after the vaccine administration without any other adjuvant therapy and died of complications related to his previous chemotherapies. PMID:25785641

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. 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

  5. Serial analysis of imaging parameters in patients with newly diagnosed glioblastoma multiforme.

    PubMed

    Li, Yan; Lupo, Janine M; Polley, Mei-Yin; Crane, Jason C; Bian, Wei; Cha, Soonmee; Chang, Susan; Nelson, Sarah J

    2011-05-01

    The objective of this study was to test the predictive value of serial MRI data in relation to clinical outcome for patients with glioblastoma multiforme (GBM). Sixty-four patients with newly diagnosed GBM underwent conventional MRI and diffusion-weighted and perfusion-weighted imaging postsurgery and prior to radiation/chemotherapy (pre-RT), immediately after RT (post-RT), and every 1-2 months thereafter until tumor progression, up to a maximum of 1 year. Tumor volumes and perfusion and diffusion parameters were calculated and subject to time-independent and time-dependent Cox proportional hazards models that were adjusted for age and MR scanner field strength. Larger volumes of the T2 hyperintensity lesion (T2ALL) and nonenhancing lesion (NEL) at pre-RT, as well as increased anatomic volumes at post-RT, were associated with worse overall survival (OS). Higher normalized cerebral blood volumes (nCBVs), normalized peak height (nPH) and normalized recirculation factors (nRF) at pre-RT, and nCBV at post-RT, in the T2ALL and NEL, were associated with shorter progression-free survival (PFS). From pre- to post-RT, there was a reduction in nCBV and nPH and an increase in apparent diffusion coefficient (ADC). Patients with lower nRF values at pre-RT, or a larger increase in nRF from pre-RT to post-RT, had significantly longer PFS. Time-dependent analysis showed that patterns of changes in ADC and anatomic volumes were associated with OS, while changes in nCBV, nPH, and the contrast-enhancing volume were associated with PFS. Our studies suggest that quantitative MRI variables derived from anatomic and physiological MRI provide useful information for predicting outcome in patients with GBM. PMID:21297128

  6. 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

  7. Serial nonenhancing magnetic resonance imaging scans of high grade glioblastoma multiforme.

    PubMed Central

    Moore-Stovall, J.; Venkatesh, R.

    1993-01-01

    Magnetic resonance imaging (MRI) from clinical experience has proven to be superior to all other diagnostic imaging modalities, including computed tomography (CT) in the detection of intracranial neoplasms. Although glioblastoma multiforme presents a challenge for all diagnostic imaging modalities including MRI, MRI is paramount to CT in detecting subtle abnormal water accumulation in brain tissue caused by tumor even before there is disruption of the blood brain barrier. Currently, clinical research and investigational trials on nonionic gadolinium contrast agents have proven that nonionic gadolinium HP-DO3A (ProHance) contrast agents have lower osmolality and greater stability, which make them superior compounds to gadolinium diethylenetriamine-pentacetic acid (Gd-DTPA). Therefore, the nonionic gadolinium contrasts have been safely administered more rapidly, in higher or multiple doses for contrast enhanced MRI without adverse side effects or changes in serum iron or total bilirubin, and the intensity of the area of enhancement and number of lesions detected were superior to that of Gd-DTPA (Magnevist) at the standard dose (0.1 mmol/Kg). Perhaps if the nonionic gadolinium contrast agent, ProHance, had been approved by the Food and Drug Administration (FDA) when this MRI was performed in 1990 it would have aided in providing contrast enhancement and visualization of the tumor lesion to assist in patient diagnosis and management. Magnetic resonance imaging also provides unique multiplanar capabilities that allow for optimal visualization of the temporal and occipital lobes of the brain without bone interference.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9A Figure 9B Figure 10 Figure 11 Figure 12 Figure 13 PMID:8382751

  8. 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

  9. 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

  10. 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

  11. 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

  12. Focused ultrasound-aided immunomodulation in glioblastoma multiforme: a therapeutic concept.

    PubMed

    Cohen-Inbar, Or; Xu, Zhiyuan; Sheehan, Jason P

    2016-01-01

    Patients with glioblastoma multiforme (GBM) exhibit a deficient anti-tumor immune response. Both arms of the immune system were shown to be hampered in GBM, namely the local cellular immunity mediated by the Th1 subset of helper T cells and the systemic humoral immunity mediated by the Th2 subset of helper T cells. Immunotherapy is rapidly becoming one of the pillars of anti-cancer therapy. GBM has not received similar clinical successes as of yet, which may be attributed to its relative inaccessibility (the blood-brain barrier (BBB)), its poor immunogenicity, few characterized cancer antigens, or any of the many other immune mechanisms known to be hampered. Focused ultrasound (FUS) is emerging as a promising treatment approach. The effects of FUS on the tissue are not merely thermal. Mounting evidence suggests that in addition to thermal ablation, FUS induces mechanical acoustic cavitation and immunomodulation plays a key role in boosting the host anti-tumor immune responses. We separately discuss the different pertinent immunosuppressive mechanisms harnessed by GBM and the immunomodulatory effects of FUS. The effect of FUS and microbubbles in disrupting the BBB and introducing antigens and drugs to the tumor milieu is discussed. The FUS-induced pro-inflammatory cytokines secretion and stress response, the FUS-induced change in the intra-tumoral immune-cells populations, the FUS-induced augmentation of dendritic cells activity, and the FUS-induced increased cytotoxic cells potency are all discussed. We next attempt at offering a conceptual synopsis of the synergistic treatment of GBM utilizing FUS and immunotherapy. In conclusion, it is increasingly apparent that no single treatment modality will triumph on GBM. The reviewed FUS-induced immunomodulation effects can be harnessed to current and developing immunotherapy approaches. Together, these may overcome GBM-induced immune-evasion and generate a clinically relevant anti-tumor immune response. PMID:26807257

  13. 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

  14. 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

  15. 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

  16. A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Monjazeb, Arta M.; Ayala, Deandra; Jensen, Courtney; Case, L. Douglas; Bourland, J. Daniel; Ellis, Thomas L.; McMullen, Kevin P.; Chan, Michael D.; Tatter, Stephen B.; Lesser, Glen J.; Shaw, Edward G.

    2012-02-01

    Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4-5 acute neurotoxicity attributable to radiotherapy. Results: All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

  17. 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.

  18. Correlation between EGFR Amplification and the Expression of MicroRNA-200c in Primary Glioblastoma Multiforme

    PubMed Central

    Serna, Eva; Lopez-Gines, Concha; Monleon, Daniel; Muñoz-Hidalgo, Lisandra; Callaghan, Robert C.; Gil-Benso, Rosario; Martinetto, Horacio; Gregori-Romero, Aurelia; Gonzalez-Darder, Jose; Cerda-Nicolas, Miguel

    2014-01-01

    Extensive infiltration of the surrounding healthy brain tissue is a critical feature in glioblastoma. Several miRNAs have been related to gliomagenesis, some of them related with the EGFR pathway. We have evaluated whole-genome miRNA expression profiling associated with different EGFR amplification patterns, studied by fluorescence in situ hybridization in tissue microarrays, of 30 cases of primary glioblastoma multiforme, whose clinicopathological and immunohistochemical features have also been analyzed. MicroRNA-200c showed a very significant difference between tumors having or not EGFR amplification. This microRNA plays an important role in epithelial-mesenchymal transition, but its implication in the behavior of glioblastoma is largely unknown. With respect to EGFR status our cases were categorized into three groups: high level EGFR amplification, low level EGFR amplification, and no EGFR amplification. Our results showed that microRNA-200c and E-cadherin expression are down-regulated, while ZEB1 is up-regulated, when tumors showed a high level of EGFR amplification. Conversely, ZEB1 mRNA expression levels were significantly lower in the group of tumors without EGFR amplification. Tumors with a low level of EGFR amplification showed ZEB1 expression levels comparable to those detected in the group with a high level of amplification. In this study we provide what is to our knowledge the first report of association between microRNA-200c and EGFR amplification in glioblastomas. PMID:25058589

  19. Accelerated Hypofractionated Intensity-Modulated Radiotherapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma Multiforme: A Safety and Efficacy Analysis

    SciTech Connect

    Panet-Raymond, Valerie; Souhami, Luis; Roberge, David; Kavan, Petr; Shakibnia, Lily; Muanza, Thierry; Lambert, Christine; Leblanc, Richard; Del Maestro, Rolando; Guiot, Marie-Christine; Shenouda, George

    2009-02-01

    Purpose: Despite multimodality treatments, the outcome of patients with glioblastoma multiforme remains poor. In an attempt to improve results, we have begun a program of accelerated hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concomitant and adjuvant temozolomide (TMZ). Methods and Materials: Between March 2004 and June 2006, 35 unselected patients with glioblastoma multiforme were treated with hypo-IMRT. During a 4-week period, using a concomitant boost technique, a dose of 60 Gy and 40 Gy were delivered in 20 fractions prescribed to the periphery of the gross tumor volume and planning target volume, respectively. TMZ was administered according to the regimen of Stupp et al. Results: The median follow-up was 12.6 months. Of the 35 patients, 29 (82.8%) completed the combined modality treatment, and 25 (71.4%) received a median of four cycles of adjuvant TMZ. The median overall survival was 14.4 months, and the median disease-free survival was 7.7 months. The median survival time differed significantly between patients who underwent biopsy and those who underwent partial or total resection (7.1 vs. 16.1 months, p = 0.035). The median survival was also significantly different between patients with methylated vs. unmethylated 0-6-methylguanine-DNA methyltransferase promoters (14.4 vs. 8.7 months, p = 0.049). The pattern of failure was predominantly central, within 2 cm of the initial gross tumor volume. Grade 3-4 toxicity was limited to 1 patient with nausea and emesis during adjuvant TMZ administration. Conclusion: The results of our study have shown that hypo-IMRT with concomitant and adjuvant TMZ is well tolerated with a useful 2-week shortening of radiotherapy. Despite a high number of patients with poor prognostic features (74.3% recursive partitioning analysis class V or VI), the median survival was comparable to that after standard radiotherapy fractionation schedules plus TMZ.

  20. 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

  1. PET imaging of glioblastoma multiforme EGFR expression for therapeutic decision guidance.

    PubMed

    Wehrenberg-Klee, Eric; Redjal, Navid; Leece, Alicia; Turker, N Selcan; Heidari, Pedram; Shah, Khalid; Mahmood, Umar

    2015-01-01

    After initial therapy and total resection of glioblastoma multiforme (GBM), 80-90% of recurrences occur at the surgical margins. Insufficient sensitivity and specificity of current imaging techniques based on non-specific vascular imaging agents lead to delay in diagnosis of residual and/or recurrent disease. A tumor-specific imaging agent for GBM may improve detection of small residual disease in the post-operative period, and improve ability to distinguish tumor recurrence from its imaging mimics that can delay diagnosis. To this end, we developed an EGFR-targeted PET probe and assessed its ability to image EGFR WT (U87) and EGFRvIII (Gli36vIII) expressing GBMs in both murine intra-cranial xenografts and in a surgical-resection model. The developed imaging probe, (64)Cu-DOTAcetuximab-F(ab´)2, binds with a Kd of 11.2 nM to EGFR expressing GBM. (64)Cu-DOTA-cetuximab-F(ab´)2 specifically localized to intra-cranial tumor with a significant difference in SUVmean between tumor and contralateral brain for both Gli36vIII and U87 tumors (P<0.01 for both comparisons), with mean TBR of 22.5±0.7 for Gli36vIII tumors and 28.9±2.1 for U87 tumors (TBR±SEM). Tracer uptake by tumor was significantly inhibited by pre-injection with cetuximab (P<0.01 for both), with SUVmean reduced by 68% and 58% for Gli36vIII and U87 tumors, respectively. Surgical resection model PET-CT imaging demonstrates residual tumor and low nonspecific uptake in the resection site. We conclude that (64)Cu-DOTA-cetuximab-F(ab´)2 binds specifically to intracranial EGFR WT and EGFRvIII expressing GBM, demonstrates excellent TBR, and specifically images small residual tumor in a surgical model, suggesting future clinical utility in identifying true tumor recurrence. PMID:26269775

  2. Parameter optimization for constructing competing endogenous RNA regulatory network in glioblastoma multiforme and other cancers

    PubMed Central

    2015-01-01

    Background In addition to direct targeting and repressing mRNAs, recent studies reported that microRNAs (miRNAs) can bridge up an alternative layer of post-transcriptional gene regulatory networks. The competing endogenous RNA (ceRNA) regulation depicts the scenario where pairs of genes (ceRNAs) sharing, fully or partially, common binding miRNAs (miRNA program) can establish coexpression through competition for a limited pool of the miRNA program. While the dynamics of ceRNA regulation among cellular conditions have been verified based on in silico and in vitro experiments, comprehensive investigation into the strength of ceRNA regulation in human datasets remains largely unexplored. Furthermore, pan-cancer analysis of ceRNA regulation, to our knowledge, has not been systematically investigated. Results In the present study we explored optimal conditions for ceRNA regulation, investigated functions governed by ceRNA regulation, and evaluated pan-cancer effects. We started by investigating how essential factors, such as the size of miRNA programs, the number of miRNA program binding sites, and expression levels of miRNA programs and ceRNAs affect the ceRNA regulation capacity in tumors derived from glioblastoma multiforme patients captured by The Cancer Genome Atlas (TCGA). We demonstrated that increased numbers of common targeting miRNAs as well as the abundance of binding sites enhance ceRNA regulation and strengthen coexpression of ceRNA pairs. Also, our investigation revealed that the strength of ceRNA regulation is dependent on expression levels of both miRNA programs and ceRNAs. Through functional annotation analysis, our results indicated that ceRNA regulation is highly associated with essential cellular functions and diseases including cancer. Furthermore, the highly intertwined ceRNA regulatory relationship enables constitutive and effective intra-function regulation of genes in diverse types of cancer. Conclusions Using gene and microRNA expression

  3. Identification and characterization of alternative exon usage linked glioblastoma multiforme survival

    PubMed Central

    2012-01-01

    Background Alternative exon usage (AEU) is an important component of gene regulation. Exon expression platforms allow the detection of associations between AEU and phenotypes such as cancer. Numerous studies have identified associations between gene expression and the brain cancer glioblastoma multiforme (GBM). The few consistent gene expression biomarkers of GBM that have been reported may be due to the limited consideration of AEU and the analytical approaches used. The objectives of this study were to develop a model that accounts for the variations in expression present between the exons within a gene and to identify AEU biomarkers of GBM survival. Methods The expression of exons corresponding to 25,403 genes was related to the survival of 250 individuals diagnosed with GBM in a training data set. Genes exhibiting AEU in the training data set were confirmed in an independent validation data set of 78 patients. A hierarchical mixed model that allows the consideration of covariation between exons within a gene and of the effect of the epidemiological characteristics of the patients was developed to identify associations between exon expression and patient survival. This general model describes all three possible scenarios: multi-exon genes with and without AEU, and single-exon genes. Results AEU associated with GBM survival was identified on 2477 genes (P-value < 5.0E-04 or FDR-adjusted P-value < 0.05). G-protein coupled receptor 98 (Gpr98) and epidermal growth factor (Egf) were among the genes exhibiting AEU with 30 and 9 exons associated with GBM survival, respectively. Pathways enriched among the AEU genes included focal adhesion, ECM-receptor interaction, ABC transporters and pathways in cancer. In addition, 24 multi-exon genes without AEU and 8 single-exon genes were associated with GBM survival (FDR-adjusted P-value < 0.05). Conclusions The inferred patterns of AEU were consistent with in silico AS models. The hierarchical model used offered a flexible and

  4. PET imaging of glioblastoma multiforme EGFR expression for therapeutic decision guidance

    PubMed Central

    Wehrenberg-Klee, Eric; Redjal, Navid; Leece, Alicia; Turker, N Selcan; Heidari, Pedram; Shah, Khalid; Mahmood, Umar

    2015-01-01

    After initial therapy and total resection of glioblastoma multiforme (GBM), 80-90% of recurrences occur at the surgical margins. Insufficient sensitivity and specificity of current imaging techniques based on non-specific vascular imaging agents lead to delay in diagnosis of residual and/or recurrent disease. A tumor-specific imaging agent for GBM may improve detection of small residual disease in the post-operative period, and improve ability to distinguish tumor recurrence from its imaging mimics that can delay diagnosis. To this end, we developed an EGFR-targeted PET probe and assessed its ability to image EGFR WT (U87) and EGFRvIII (Gli36vIII) expressing GBMs in both murine intra-cranial xenografts and in a surgical-resection model. The developed imaging probe, 64Cu-DOTAcetuximab-F(ab´)2, binds with a Kd of 11.2 nM to EGFR expressing GBM. 64Cu-DOTA-cetuximab-F(ab´)2 specifically localized to intra-cranial tumor with a significant difference in SUVmean between tumor and contralateral brain for both Gli36vIII and U87 tumors (P<0.01 for both comparisons), with mean TBR of 22.5±0.7 for Gli36vIII tumors and 28.9±2.1 for U87 tumors (TBR±SEM). Tracer uptake by tumor was significantly inhibited by pre-injection with cetuximab (P<0.01 for both), with SUVmean reduced by 68% and 58% for Gli36vIII and U87 tumors, respectively. Surgical resection model PET-CT imaging demonstrates residual tumor and low nonspecific uptake in the resection site. We conclude that 64Cu-DOTA-cetuximab-F(ab´)2 binds specifically to intracranial EGFR WT and EGFRvIII expressing GBM, demonstrates excellent TBR, and specifically images small residual tumor in a surgical model, suggesting future clinical utility in identifying true tumor recurrence. PMID:26269775

  5. 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

  6. 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

  7. Asiatic acid induces endoplasmic reticulum stress and apoptotic death in glioblastoma multiforme cells both in vitro and in vivo.

    PubMed

    Kavitha, Chandagirikoppal V; Jain, Anil K; Agarwal, Chapla; Pierce, Angela; Keating, Amy; Huber, Kendra M; Serkova, Natalie J; Wempe, Michael F; Agarwal, Rajesh; Deep, Gagan

    2015-11-01

    Glioblastoma multiforme (GBM) is an untreatable malignancy. Existing therapeutic options are insufficient, and adversely affect functional and non-cancerous cells in the brain impairing different functions of the body. Therefore, there is an urgent need for additional preventive and therapeutic non-toxic drugs against GBM. Asiatic acid (AsA; 2,3,23-trihydroxy-12-ursen-28-oic acid, C30 H48 O5 ) is a natural small molecule widely used to treat various neurological disorders, and the present research investigates AsA's efficacy against GBM both in vitro and in vivo. Results showed that AsA treatment (10-100 µM) decreased the human GBM cell (LN18, U87MG, and U118MG) viability, with better efficacy than temozolomide at equimolar doses. Orally administered AsA (30 mg/kg/d) strongly decreased tumor volume in mice when administered immediately after ectopic U87MG xenograft implantation (54% decrease, P ≤ 0.05) or in mice with established xenografts (48% decrease, P ≤ 0.05) without any apparent toxicity. Importantly, AsA feeding (30 mg/kg/twice a day) also decreased the orthotopic U87MG xenografts growth in nude mice as measured by magnetic resonance imaging. Using LC/MS-MS methods, AsA was detected in mice plasma and brain tissue, confirming that AsA crosses blood-brain barrier. Mechanistic studies showed that AsA induces apoptotic death by modulating the protein expression of several apoptosis regulators (caspases, Bcl2 family members, and survivin) in GBM cells. Furthermore, AsA induced ER stress (increased GRP78 and Calpain, and decreased Calnexin and IRE1α expression), enhanced free intra-cellular calcium, and damaged cellular organization in GBM cells. These experimental results demonstrate that AsA is effective against GBM, and advocate further pre-clinical and clinical evaluations of AsA against GBM. PMID:25252179

  8. Phase I study of hypofractionated intensity modulated radiation therapy with concurrent and adjuvant temozolomide in patients with glioblastoma multiforme

    PubMed Central

    2013-01-01

    Purpose To determine the safety and efficacy of hypofractionated intensity modulated radiation therapy (Hypo-IMRT) using helical tomotherapy (HT) with concurrent low dose temozolomide (TMZ) followed by adjuvant TMZ in patients with glioblastoma multiforme (GBM). Methods and materials Adult patients with GBM and KPS > 70 were prospectively enrolled between 2005 and 2007 in this phase I study. The Fibonacci dose escalation protocol was implemented to establish a safe radiation fractionation regimen. The protocol defined radiation therapy (RT) dose level I as 54.4 Gy in 20 fractions over 4 weeks and dose level II as 60 Gy in 22 fractions over 4.5 weeks. Concurrent TMZ followed by adjuvant TMZ was given according to the Stupp regimen. The primary endpoints were feasibility and safety of Hypo-IMRT with concurrent TMZ. Secondary endpoints included progression free survival (PFS), pattern of failure, overall survival (OS) and incidence of pseudoprogression. The latter was defined as clinical or radiological suggestion of tumour progression within three months of radiation completion followed by spontaneous recovery of the patient. Results A total of 25 patients were prospectively enrolled with a median follow-up of 12.4 months. The median age at diagnosis was 53 years. Based on recursive partitioning analysis (RPA) criteria, 16%, 52% and 32% of the patients were RPA class III, class IV and class V, respectively. All patients completed concurrent RT and TMZ, and 19 patients (76.0%) received adjuvant TMZ. The median OS was 15.67 months (95% CI 11.56 - 20.04) and the median PFS was 6.7 months (95% CI 4.0 – 14.0). The median time between surgery and start of RT was 44 days (range of 28 to 77 days). Delaying radiation therapy by more than 6 weeks after surgery was an independent prognostic factor associated with a worse OS (4.0 vs. 16.1 months, P = 0.027). All recurrences occurred within 2 cm of the original gross tumour volume (GTV). No cases of pseudoprogression were

  9. A Thermodynamic-Based Interpretation of Protein Expression Heterogeneity in Different Glioblastoma Multiforme Tumors Identifies Tumor-Specific Unbalanced Processes.

    PubMed

    Kravchenko-Balasha, Nataly; Johnson, Hannah; White, Forest M; Heath, James R; Levine, R D

    2016-07-01

    We describe a thermodynamic-motivated, information theoretic analysis of proteomic data collected from a series of 8 glioblastoma multiforme (GBM) tumors. GBMs are considered here as prototypes of heterogeneous cancers. That heterogeneity is viewed here as manifesting in different unbalanced biological processes that are associated with thermodynamic-like constraints. The analysis yields a molecular description of a stable steady state that is common across all tumors. It also resolves molecular descriptions of unbalanced processes that are shared by several tumors, such as hyperactivated phosphoprotein signaling networks. Further, it resolves unbalanced processes that provide unique classifiers of tumor subgroups. The results of the theoretical interpretation are compared against those of statistical multivariate methods and are shown to provide a superior level of resolution for identifying unbalanced processes in GBM tumors. The identification of specific constraints for each GBM tumor suggests tumor-specific combination therapies that may reverse this imbalance. PMID:27035264

  10. 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.

  11. [Meningeal seeding of spinal cord glioblastoma multiforme without any signs of myelopathy].

    PubMed

    Chida, K; Konno, H; Sahara, M; Takase, S

    1995-11-01

    An autopsy case of meningeal spreading of glioblastoma multiforme (GBM) probably originating in the cervical cord was reported. In contrast to autopsy findings, main symptoms were similar to subacute meningitis, and any signs of myelopathy could not be detected during the clinical course. The patient was a 22-year-old man who was hospitalized because of a 2-week history of progressive headache following cough and slight fever. Vomiting and somnolence, developing 5 days before admission, were improved the day after a lumbar puncture performed at another hospital. On admission, meningeal signs, mild right abducens palsy, and depressed deep tendon reflexes were detected. There was no muscle weakness, sensory loss, or Babinski sign. Lumbar puncture yielded CSF with an opening pressure of 280 mmH2O, 21 mononuclear cells/mm3, a protein level of 645 mg/dl, and a glucose level of 7 mg/dl. Cytology for malignancy and multiple cultures were negative. Brain CT scan showed mild hydrocephalus and swelling of the brainstem and cerebellum. Intravenous administration of antimicrobial drugs was started and ventriculoperitoneal shunt surgery was performed. During the third hospital week, however, meningeal signs progressed and somnolence reappeared, followed by progressive multiple cranial neuropathy and polyradiculopathy characterized by flaccid tetraparesis, muscle atrophy, and sensory impairment without a level. Babinski sign could not be detected. MRI revealed an intramedullary lesion in the lower cervical cord, swelling of the brainstem, cerebellum, spinal cord and nerve roots, and a diffuse or nodular thickning of leptomeninges. Repeated CSF cytology disclosed atypical cells. Examinations for extraneural malignancies were negative. During the 9th hospital week, flaccid tetraplegia progressed and stupor developed, and the patient died 2 weeks later. The pathological study was limited to the brain. The brain showed a diffuse opalescent thickening of the leptomeninges, especially

  12. 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.

  13. 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

  14. 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

    NASA Astrophysics Data System (ADS)

    Ciofani, Gianni; Raffa, Vittoria; Menciassi, Arianna; Cuschieri, Alfred

    2009-02-01

    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 of 10B 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.

  15. 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

    Ciofani, Gianni; Raffa, Vittoria; Menciassi, Arianna; Cuschieri, Alfred

    2008-01-01

    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 of (10)B 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

  16. Assessing Response Using 99mTc-MIBI Early after Interstitial Chemotherapy with Carmustine-Loaded Polymers in Glioblastoma Multiforme: Preliminary Results

    PubMed Central

    Cecchin, D.; Schiorlin, I.; Della Puppa, A.; Lombardi, G.; Zucchetta, P.; Bodanza, V.; Gardiman, M. P.; Rolma, G.; Frigo, A. C.; Bui, F.

    2014-01-01

    Introduction. Early signs of response after applying wafers of carmustine-loaded polymers (gliadel) are difficult to assess with imaging because of time-related imaging changes. 99mTc-sestamibi (MIBI) brain single-photon emission tomography (SPET) has reportedly been used to reveal areas of cellularity distinguishing recurrent neoplasm from radionecrosis. Our aim was to explore the role of MIBI SPET in assessing response soon after gliadel application in glioblastoma multiforme (GBM). Methods. We retrospectively reviewed the charts on 28 consecutive patients with a radiological diagnosis of GBM who underwent MIBI SPET/CT before surgery (with intracavitary gliadel placement in 17 patients), soon after surgery, and at 4 months. The area of uptake was selected using a volume of interest that was then mirrored contralaterally to obtain a semiquantitative ratio. Results. After adjusting for ratio at the baseline, the effect of treatment (gliadel versus non-gliadel) was not statistically significant. Soon after surgery, however, 100% of patients treated with gliadel had a decreased ratio, as opposed to 62.5% of patients in the non-gliadel group (P = 0.0316). The difference between ratios of patients with radical versus partial resection reached statistical significance by a small margin (P = 0.0528). Conclusions. These data seem to suggest that the MIBI ratio could be a valuable tool for monitoring the effect of gliadel early after surgery. PMID:24800247

  17. Tumor cycling hypoxia induces chemoresistance in glioblastoma multiforme by upregulating the expression and function of ABCB1

    PubMed Central

    Chou, Chii-Wen; Wang, Chi-Chung; Wu, Chung-Pu; Lin, Yu-Jung; Lee, Yu-Chun; Cheng, Ya-Wen; Hsieh, Chia-Hung

    2012-01-01

    Tumor cycling hypoxia is now a well-recognized phenomenon in animal and human solid tumors. However, how tumor cycling hypoxia impacts chemotherapy is unclear. In the present study, we explored the impact and the mechanism of cycling hypoxia on tumor microenvironment-mediated chemoresistance. Hoechst 33342 staining and hypoxia-inducible factor–1 (HIF-1) activation labeling together with immunofluorescence imaging and fluorescence-activated cell sorting were used to isolate hypoxic tumor subpopulations from human glioblastoma xenografts. ABCB1 expression, P-glycoprotein function, and chemosensitivity in tumor cells derived from human glioblastoma xenografts or in vitro cycling hypoxic stress-treated glioblastoma cells were determined using Western blot analysis, drug accumulation and efflux assays, and MTT assay, respectively. ABCB1 expression and P-glycoprotein function were upregulated under cycling hypoxia in glioblastoma cells concomitant with decreased responses to doxorubicin and BCNU. However, ABCB1 knockdown inhibited these effects. Moreover, immunofluorescence imaging and flow cytometric analysis for ABCB1, HIF-1 activation, and Hoechst 3342 in glioblastoma revealed highly localized ABCB1 expression predominantly in potentially cycling hypoxic areas with HIF-1 activation and blood perfusion in the solid tumor microenvironment. The cycling hypoxic tumor cells derived from glioblastoma xenografts exhibited higher ABCB1 expression, P-glycoprotein function, and chemoresistance, compared with chronic hypoxic and normoxic cells. Tumor-bearing mice that received YC-1, an HIF-1α inhibitor, exhibited suppressed tumor microenvironment-induced ABCB1 induction and enhanced survival rate in BCNU chemotherapy. Cycling hypoxia plays a vital role in tumor microenvironment-mediated chemoresistance through the HIF-1–dependent induction of ABCB1. HIF-1 blockade before and concurrent with chemotherapy could suppress cycling hypoxia-induced chemoresistance. PMID:22946104

  18. 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

  19. Intrinsic radiation sensitivity may not be the major determinant of the poor clinical outcome of glioblastoma multiforme

    SciTech Connect

    Taghian, A.; Budach, W.; Gioioso, D.; Pardo, F.; Okunieff, P.; Suit, H. ); Ramsay, J.; Bleehen, N. ); Allalunis-Turner, J.; Urtasun, R. )

    1993-01-15

    Many radiobiologic mechanisms may contribute to the clinical radiation resistance of Glioblastoma Multiforme. One of them is considered to be an unusually low intrinsic radiation sensitivity. This is a collaborative study between three laboratories to evaluate the intrinsic radiation sensitivity of 85 cell lines derived from human malignant gliomas as the major cause of the poor clinical results of radiation treatment to these tumors. Fifty-one cell lines were early passage. The distribution by histologic type was: 58 glioblastoma, 17 anaplastic astrocytoma, six oligodendroglioma and four astrocytoma grade 2. The intrinsic radiation sensitivity will be expressed by the surviving fraction at 2 Gy (SF[sub 2]). The SF[sub 2] has been determined for single dose irradiation for cell lines on exponential phase, under aerobic conditions, growing on plastic. The patient age, Karnofski Status, histological grade, survival, dose or irradiation for 50 patients are investigated for correlations with SF[sub 2] of the corresponding newly established cell lines. These data on 85 malignant glioma cell lines show a very broad distribution of SF[sub 2] values for irradiation in vitro. SF[sub 2] reflected the difference in sensitivity between AA (Grade 3) and GBM (Grade) 4. This may suggest that the parameter SF[sub 2] is useful to discriminate between the sensitivity of different grades or types of histology in vitro. However, SF[sub 2] was not a predictor of the clinical outcome on individual basis for malignant gliomas. The in vitro studies will need to be supplemented by physiologic characterization of the tumors in vivo. Such conclusions would limit the predictive value of current radiation sensitivity assays based on in vitro dose-survival measurement for the least high grade malignant gliomas. 34 refs., 4 figs., 2 tabs.

  20. 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

  1. Piperlongumine selectively kills glioblastoma multiforme cells via reactive oxygen species accumulation dependent JNK and p38 activation.

    PubMed

    Liu, Ju Mei; Pan, Feng; Li, Li; Liu, Qian Rong; Chen, Yong; Xiong, Xin Xin; Cheng, Kejun; Yu, Shang Bin; Shi, Zhi; Yu, Albert Cheung-Hoi; Chen, Xiao Qian

    2013-07-19

    Piperlongumine (PL), a natural alkaloid isolated from the long pepper, may have anti-cancer properties. It selectively targets and kills cancer cells but leaves normal cells intact. Here, we reported that PL selectively killed glioblastoma multiforme (GBM) cells via accumulating reactive oxygen species (ROS) to activate JNK and p38. PL at 20μM could induce severe cell death in three GBM cell lines (LN229, U87 and 8MG) but not astrocytes in cultures. PL elevated ROS prominently and reduced glutathione levels in LN229 and U87 cells. Antioxidant N-acetyl-L-cysteine (NAC) completely reversed PL-induced ROS accumulation and prevented cell death in LN229 and U87 cells. In LN229 and U87 cells, PL-treatment activated JNK and p38 but not Erk and Akt, in a dosage-dependent manner. These activations could be blocked by NAC pre-treatment. JNK and p38 specific inhibitors, SB203580 and SP600125 respectively, significantly blocked the cytotoxic effects of PL in LN229 and U87 cells. Our data first suggests that PL may have therapeutic potential for one of the most malignant and refractory tumors GBM. PMID:23796709

  2. Hot melt extruded and injection moulded disulfiram-loaded PLGA millirods for the treatment of glioblastoma multiforme via stereotactic injection.

    PubMed

    McConville, Christopher; Tawari, Patricia; Wang, Weiguang

    2015-10-15

    Glioblastoma multiforme (GBM) has a poor prognosis and is one of the most common primary malignant brain tumours in adults. Stereotactic injections have been used to deliver chemotherapeutic drugs directly into brain tumours. This paper describes the development of disulfiram (DSF)-loaded biodegradable millirods manufactured using hot melt extrusion (HME) and injection moulding (IM). The paper demonstrates that the stability of the DSF within the millirods is dependent on the manufacturing technique used as well as the drug loading. The physical state of the DSF within the millirods was dependent on the fabrication process, with the DSF in the HME millirods being either completely amorphous within the PLGA, while the DSF within the IM millirods retained between 54 and 66% of its crystallinity. Release of DSF from the millirods was dependent on the degradation rate of the PLGA, the manufacturing technique used as well as the DSF loading. DSF in the 10% (w/w) DSF loaded HME millirods and the 20% (w/w) DSF-loaded HME and IM millirods had a similar cytotoxicity against a GBM cell line compared to the unprocessed DSF control. However, the 10% (w/w) DSF-loaded IM millirods had a significantly lower cytotoxicity when compared to the unprocessed control. PMID:26235918

  3. Development of siRNA-loaded chitosan nanoparticles targeting Galectin-1 for the treatment of glioblastoma multiforme via intranasal administration.

    PubMed

    Van Woensel, Matthias; Wauthoz, Nathalie; Rosière, Rémi; Mathieu, Véronique; Kiss, Robert; Lefranc, Florence; Steelant, Brecht; Dilissen, Ellen; Van Gool, Stefaan W; Mathivet, Thomas; Gerhardt, Holger; Amighi, Karim; De Vleeschouwer, Steven

    2016-04-10

    Galectin-1 (Gal-1) is a naturally occurring galactose-binding lectin, which is overexpressed in glioblastoma multiforme (GBM). Gal-1 is associated with tumor progression, and is a potent immune suppressor in the tumor micro-environment. To inhibit Gal-1 in GBM, an effective therapy is required that reaches the central nervous system tumor, with limited systemic effects. In this study, we report for the first time that concentrated chitosan nanoparticle suspensions can deliver small interfering RNA (siRNA) into the central nervous system tumor within hours after intranasal administration. These nanoparticles are able to complex siRNA targeting Gal-1 to a high percentage, and protect them from RNAse degradation. Moreover, a successful intracellular delivery of anti-Gal-1 siRNA resulted in a decreased expression of Gal-1 in both murine and human GBM cells. Sequence specific RNAinterference, resulted in more than 50% Gal-1 reduction in tumor bearing mice. This study indicates that the intranasal pathway is an underexplored transport route for delivering siRNA-based therapies targeting Gal-1 in the treatment of GBM. PMID:26902800

  4. High mobility group A1 expression shows negative correlation with recurrence time in patients with glioblastoma multiforme.

    PubMed

    Liu, Bin; Pang, Bo; Liu, Huajie; Arakawa, Yoshiki; Zhang, Rui; Feng, Bin; Zhong, Peng; Murata, Daiki; Fan, Haitao; Xin, Tao; Zhao, Guangyu; Liu, Wei; Guo, Hua; Luan, Liming; Xu, Shangchen; Miyamoto, Susumu; Pang, Qi

    2015-08-01

    The aim of this study was to explore the difference in high mobility group A1 (HMGA1) expression and isocitrate dehydrogenase (IDH) 1 R132H point mutation in initial and recurrent glioblastoma multiforme (GBM), and to further identify whether the expression of HMGA1 has a role in the malignant progression of GBM. Paired initial and recurrent GBM specimens from the same patient were evaluated using immunohistochemical analysis. The association between HMGA1 expression and progression-free survival time (PFST) was analyzed. Three patients were confirmed with IDH-1 R132H mutations in both initial and recurrent groups (3/25, 12%). There was a significant difference in HMGA1 expression between initial and recurrent GBM (P=0.002), and patients with tumors expressing HMGA1 at higher level had a significantly shorter PFST (7.3 months versus 11.1months; P=0.044). Our study indicates that recurrent GBM express HMGA1 at a higher level and that HMGA1 overexpressoin is associated with shorter PFST in patients with GBM. These findings suggest that HMGA1 potentially plays an important role in the treatment of GBM. PMID:26092597

  5. Therapy and progression--induced O6-methylguanine-DNA methyltransferase and mismatch repair alterations in recurrent glioblastoma multiforme.

    PubMed

    Agarwal, S; Suri, V; Sharma, M C; Sarkar, C

    2015-01-01

    Despite multimodality treatment protocol including surgical resection, radiotherapy, and chemotherapy in patients with glioblastoma multiforme (GBM), most suffer from treatment failure and tumor recurrence within a few months of initial surgery. The effectiveness of temozolomide (TMZ), the most commonly used chemotherapeutic agent, is largely dependent on the methylation status of the promoter of the gene O6-methylguanine-DNA methyltransferase (MGMT) and the integrity of the mismatch repair (MMR) system. Changes in these regulatory mechanisms at the time of recurrence may influence response to therapy. Deciphering the molecular mechanisms of resistance to these drugs may in future lead to improvised patient management. In this article, we provide an update of the spectrum of molecular changes that occur in recurrent GBMs, and thus may have an impact on patient survival and treatment response. For review, electronic search for the keywords "Recurrent GBM", "Recurrent GBM AND MGMT" "Recurrent glioma AND MGMT", "Recurrent GBM AND MMR" and "Recurrent glioma AND MMR", "Recurrent GBM AND MMR" and "Recurrent glioma AND MMR" was done on PubMed and relevant citations were screened including cross-references. PMID:26960480

  6. 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.

  7. 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

  8. Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).

    PubMed

    Elkamhawy, Ahmed; Viswanath, Ambily Nath Indu; Pae, Ae Nim; Kim, Hyeon Young; Heo, Jin-Chul; Park, Woo-Kyu; Lee, Chong-Ock; Yang, Heekyoung; Kim, Kang Ho; Nam, Do-Hyun; Seol, Ho Jun; Cho, Heeyeong; Roh, Eun Joo

    2015-10-20

    Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM. PMID:26355532

  9. 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. PMID:24072435

  10. Cyclic nucleotide phosphodiesterase-1C (PDE1C) drives cell proliferation, migration and invasion in glioblastoma multiforme cells in vitro.

    PubMed

    Rowther, Farjana B; Wei, Weinbin; Dawson, Timothy P; Ashton, Katherine; Singh, Anushree; Madiesse-Timchou, Mylene P; Thomas, D G T; Darling, John L; Warr, Tracy

    2016-03-01

    Cyclic nucleotides (cAMP & cGMP) are critical intracellular second messengers involved in the transduction of a diverse array of stimuli and their catabolism is mediated by phosphodiesterases (PDEs). We previously detected focal genomic amplification of PDE1C in >90 glioblastoma multiforme (GBM) cells suggesting a potential as a novel therapeutic target in these cells. In this report, we show that genomic gain of PDE1C was associated with increased expression in low passage GBM-derived cell cultures. We demonstrate that PDE1C is essential in driving cell proliferation, migration and invasion in GBM cultures since silencing of this gene significantly mitigates these functions. We also define the mechanistic basis of this functional effect through whole genome expression analysis by identifying down-stream gene effectors of PDE1C which are involved in cell cycle and cell adhesion regulation. In addition, we also demonstrate that Vinpocetine, a general PDE1 inhibitor, can also attenuate proliferation with no effect on invasion/migration. Up-regulation of at least one of this gene set (IL8, CXCL2, FOSB, NFE2L3, SUB1, SORBS2, WNT5A, and MMP1) in TCGA GBM cohorts is associated with worse outcome and PDE1C silencing down-regulated their expression, thus also indicating potential to influence patient survival. Therefore we conclude that proliferation, migration, and invasion of GBM cells could also be regulated downstream of PDE1C. PMID:25620587

  11. Quantitative proteomics reveals the novel co-expression signatures in early brain development for prognosis of glioblastoma multiforme

    PubMed Central

    Yu, Xuexin; Feng, Lin; Liu, Dianming; Zhang, Lianfeng; Wu, Bo; Jiang, Wei; Han, Zujing; Cheng, Shujun

    2016-01-01

    Although several researches have explored the similarity across development and tumorigenesis in cellular behavior and underlying molecular mechanisms, not many have investigated the developmental characteristics at proteomic level and further extended to cancer clinical outcome. In this study, we used iTRAQ to quantify the protein expression changes during macaque rhesus brain development from fetuses at gestation 70 days to after born 5 years. Then, we performed weighted gene co-expression network analysis (WGCNA) on protein expression data of brain development to identify co-expressed modules that highly expressed on distinct development stages, including early stage, middle stage and late stage. Moreover, we used the univariate cox regression model to evaluate the prognostic potentials of these genes in two independent glioblastoma multiforme (GBM) datasets. The results showed that the modules highly expressed on early stage contained more reproducible prognostic genes, including ILF2, CCT7, CCT4, RPL10A, MSN, PRPS1, TFRC and APEX1. These genes were not only associated with clinical outcome, but also tended to influence chemoresponse. These signatures identified from embryonic brain development might contribute to precise prediction of GBM prognosis and identification of novel drug targets in GBM therapies. Thus, the development could become a viable reference model for researching cancers, including identifying novel prognostic markers and promoting new therapies. PMID:26895104

  12. Quantitative proteomics reveals the novel co-expression signatures in early brain development for prognosis of glioblastoma multiforme.

    PubMed

    Yu, Xuexin; Feng, Lin; Liu, Dianming; Zhang, Lianfeng; Wu, Bo; Jiang, Wei; Han, Zujing; Cheng, Shujun

    2016-03-22

    Although several researches have explored the similarity across development and tumorigenesis in cellular behavior and underlying molecular mechanisms, not many have investigated the developmental characteristics at proteomic level and further extended to cancer clinical outcome. In this study, we used iTRAQ to quantify the protein expression changes during macaque rhesus brain development from fetuses at gestation 70 days to after born 5 years. Then, we performed weighted gene co-expression network analysis (WGCNA) on protein expression data of brain development to identify co-expressed modules that highly expressed on distinct development stages, including early stage, middle stage and late stage. Moreover, we used the univariate cox regression model to evaluate the prognostic potentials of these genes in two independent glioblastoma multiforme (GBM) datasets. The results showed that the modules highly expressed on early stage contained more reproducible prognostic genes, including ILF2, CCT7, CCT4, RPL10A, MSN, PRPS1, TFRC and APEX1. These genes were not only associated with clinical outcome, but also tended to influence chemoresponse. These signatures identified from embryonic brain development might contribute to precise prediction of GBM prognosis and identification of novel drug targets in GBM therapies. Thus, the development could become a viable reference model for researching cancers, including identifying novel prognostic markers and promoting new therapies. PMID:26895104

  13. Cryo-image Analysis of Tumor Cell Migration, Invasion, and Dispersal in a Mouse Xenograft Model of Human Glioblastoma Multiforme

    PubMed Central

    Qutaish, Mohammed Q.; Sullivant, Kristin E.; Burden-Gulley, Susan M.; Lu, Hong; Roy, Debashish; Wang, Jing; Basilion, James P.; Brady-Kalnay, Susann M.; Wilson, David L.

    2012-01-01

    Purpose The goals of this study were to create cryo-imaging methods to quantify characteristics (size, dispersal, and blood vessel density) of mouse orthotopic models of glioblastoma multiforme (GBM) and to enable studies of tumor biology, targeted imaging agents, and theranostic nanoparticles. Procedures Green fluorescent protein-labeled, human glioma LN-229 cells were implanted into mouse brain. At 20–38 days, cryo-imaging gave whole brain, 4-GB, 3D microscopic images of bright field anatomy, including vasculature, and fluorescent tumor. Image analysis/visualization methods were developed. Results Vessel visualization and segmentation methods successfully enabled analyses. The main tumor mass volume, the number of dispersed clusters, the number of cells/cluster, and the percent dispersed volume all increase with age of the tumor. Histograms of dispersal distance give a mean and median of 63 and 56 μm, respectively, averaged over all brains. Dispersal distance tends to increase with age of the tumors. Dispersal tends to occur along blood vessels. Blood vessel density did not appear to increase in and around the tumor with this cell line. Conclusion Cryo-imaging and software allow, for the first time, 3D, whole brain, microscopic characterization of a tumor from a particular cell line. LN-229 exhibits considerable dispersal along blood vessels, a characteristic of human tumors that limits treatment success. PMID:22125093

  14. 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.

  15. 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

  16. 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

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

    PubMed

    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

  18. 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

  19. 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.

  20. Equine Herpesvirus Type 1-Mediated Oncolysis of Human Glioblastoma Multiforme Cells

    PubMed Central

    Courchesne, Michael J.; White, Maria C.; Stanfield, Brent A.

    2012-01-01

    The cytolytic animal virus equine herpesvirus type 1 (EHV-1) was evaluated for its oncolytic potential against five human glioblastoma cell lines. EHV-1 productively infected four of these cell lines, and the degree of infection was positively correlated with glioma cell death. No human major histocompatibility complex class 1 (MHC-I) was detected in the resistant glioma line, while infection of the susceptible glioma cell lines, which expressed human MHC-I, were blocked with antibody to MHC-I, indicating that human MHC-I acts as an EHV-1 entry receptor on glioma cells. PMID:22205738

  1. 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.

  2. 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

  3. [First Mexican consensus on recommendations of the multidisciplinary care of patients with glioblastoma multiforme (GBM): Mexican Interdisciplinary Group on Neuro-Oncology Research (GIMINO)].

    PubMed

    Celis, Miguel Ángel; Alegría-Loyola, Marco Antonio; González-Aguilar, Alberto; Martínez-Tlahuel, Jorge; Green-Renner, Dan; Reyes-Soto, Gervith; Arellano-Reynoso, Alfonso; Flores-Castro, Jesús Manuel; Moreno-Jiménez, Sergio; Poitevin-Chacón, María Adela; Cacho-Díaz, Bernardo; Olvera-Manzanilla, Eduardo; Díaz-Victoria, Ana Ruth; Aguilar-Castañeda, Erika; Granados-García, Martín; Rodríguez-Orozco, Josana; Herrera-Goepfert, Roberto; Álvarez-Avitia, Miguel Ángel

    2015-01-01

    Glioblastoma multiforme is one of the most aggressive central nervous system tumors and with worse prognosis. Until now,treatments have managed to significantly increase the survival of these patients, depending on age, cognitive status, and autonomy of the individuals themselves. Based on these parameters, both initial or recurrence treatments are performed, as well as monitoring of disease by imaging studies. When the patient enters the terminal phase and curative treatments are suspended, respect for the previous wishes of the patient and development and implementation of palliative therapies must be guaranteed. PMID:26089278

  4. A phase II trial of accelerated radiotherapy using weekly stereotactic conformal boost for supratentorial glioblastoma multiforme: RTOG 0023

    SciTech Connect

    Cardinale, Robert; Choucair, Ali; Gillin, Michael; Chakravarti, Arnab; Schultz, Christopher; Souhami, Luis; Chen, Allan; Pham, Huong; Mehta, Minesh

    2006-08-01

    Purpose: This phase II trial was performed to assess the feasibility, toxicity, and efficacy of dose-intense accelerated radiation therapy using weekly fractionated stereotactic radiotherapy (FSRT) boost for patients with glioblastoma multiforme (GBM). Methods and Materials: Patients with histologically confirmed GBM with postoperative enhancing tumor plus tumor cavity diameter <60 mm were enrolled. A 50-Gy dose of standard radiation therapy (RT) was given in daily 2-Gy fractions. In addition, patients received four FSRT treatments, once weekly, during Weeks 3 to 6. FSRT dosing of either 5 Gy or 7 Gy per fraction was given for a cumulative dose of 70 or 78 Gy in 29 (25 standard RT + 4 FSRT) treatments over 6 weeks. After the RT course, carmustine (BCNU) at 80 mg/m{sup 2} was given for 3 days, every 8 weeks, for 6 cycles. Results: A total of 76 patients were analyzed. Toxicity included: 3 Grade 4 chemotherapy, 3 acute Grade 4 radiotherapy, and 1 Grade 3 late. The median survival time was 12.5 months. No survival difference is seen when compared with the RTOG historical database. Patients with gross total resection (41%) had a median survival time of 16.6 months vs. 12.0 months for historic controls with gross total resection (p = 0.14). Conclusion: This first, multi-institutional FSRT boost trial for GBM was feasible and well tolerated. There is no significant survival benefit using this dose-intense RT regimen. Subset analysis revealed a trend toward improved outcome for GTR patients suggesting that patients with minimal disease burden may benefit from this form of accelerated RT.

  5. Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme.

    PubMed

    Tivnan, Amanda; Zakaria, Zaitun; O'Leary, Caitrín; Kögel, Donat; Pokorny, Jenny L; Sarkaria, Jann N; Prehn, Jochen H M

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150 μM), vincristine (100 nM), and etoposide (2 μM). Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein) led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and multidrug resistance protein 4 (MRP4) led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 h period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients. PMID:26136652

  6. Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT) – phase I/II trial: study protocol

    PubMed Central

    Combs, Stephanie E; Heeger, Steffen; Haselmann, Renate; Edler, Lutz; Debus, Jürgen; Schulz-Ertner, Daniela

    2006-01-01

    Background The implementation of combined radiochemotherapy (RCHT) with temozolomide (TMZ) has lead to a significant increase in overall survival times in patients with Glioblastoma multiforme (GBM), however, outcome still remains unsatisfactory. The majority of GBMs show an overexpression and/or amplification of the epidermal growth factor receptor (EGFR). Therefore, addition of EGFR-inhibition with cetuximab to the current standard treatment approach with radiotherapy and TMZ seems promising. Methods/design GERT is a one-armed single-center phase I/II trial. In a first step, dose-escalation of TMZ from 50 mg/m2 to 75 mg/m2 together with radiotherapy and cetuximab will be performed. Should safety be proven, the phase II trial will be initiated with the standard dose of 75 mg/m2 of TMZ. Cetuximab will be applied in the standard application dose of 400 mg/m2 in week 1, thereafter at a dose of 250 mg/m2 weekly. A total of 46 patients will be included into this phase I/II trial. Primary endpoints are feasibility and toxicity, secondary endpoints are overall and progression-free survival. An interim analysis will be performed after inclusion of 15 patients into the main study. Patients' enrolment will be performed over a period of 2 years. The observation time will end 2 years after inclusion of the last patient. Discussion The goal of this study is to evaluate the safety and efficacy of combined RCHT-immunotherapy with TMZ and cetuximab as first-line treatment for patients with primary GBM. PMID:16709245

  7. OP33GLYCOGEN SYNTHASE KINASE INHIBITORS REDUCE 3D MIGRATION OF PATIENT DERIVED GLIOBLASTOMA MULTIFORME STEM CELLS

    PubMed Central

    Tams, Daniel M.; Murray, Clare; Barry, Simon T.; Lawler, Sean; Bruning-Richardson, Anke; Short, Susan

    2014-01-01

    INTRODUCTION: Glioblastoma multiforme (GBM) is a fast growing, highly invasive malignant brain tumour. Inhibition of tumour cell migration into normal brain tissue represents a major target for treatment. Glycogen synthase kinase (GSK-3) inhibition has been associated with reduced GBM invasion in in vitro and in vivo models. Targeting this pathway with established and/or novel drugs may elucidate more effective treatment combinations. METHOD: The effect of GSK-3 inhibitors BIO, AZD2858, AZ1293 and AZ1080 on GBM migration was assessed in patient derived GBM stem cells (GBM-1) and two established cell lines (U251 and U87) using a 3D collagen based assay. Multiple drug concentrations were investigated with up to 72 hours exposure. A migration index was determined using aggregate core size and cell migration area. Immunohistochemistry and immunocytochemistry were used to assess cell morphology and cytoskeletal changes. RESULTS: All compounds inhibit migration in this model. AZD2858 was the most potent, causing significant effects at 1 micro molar. All compounds were cytotoxic at between 10 and 20 micro molar. Cytoskeletal and nuclear abnormalities were noted following drug exposure in all cell lines. These data suggest that possible mechanisms for the anti-migratory effect of these compounds include effects on F-actin localization and microtubule polarity. Inhibition of migration and cell architecture changes occurred at non-toxic doses. CONCLUSION: Inhibition of GSK3 significantly reduced migration of this highly invasive tumour. It is evident from these data that inhibiting the complex biological mechanisms driven by GSK3 may aid treatment of GBM through a number of different mechanisms.

  8. 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.

  9. 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

  10. Use of ERC-1671 Vaccine in a Patient with Recurrent Glioblastoma Multiforme after Progression during Bevacizumab Therapy: First Published Report

    PubMed Central

    Bota, Daniela A; Alexandru-Abrams, Daniela; Pretto, Chrystel; Hofman, Florence M; Chen, Thomas C; Fu, Beverly; Carrillo, Jose A; Schijns, Virgil EJC; Stathopoulos, Apostolos

    2015-01-01

    Objectives: Glioblastoma multiforme (GBM) is a highly aggressive tumor, which recurs despite resection, focal beam radiation, and temozolomide chemotherapy. At recurrence, the only second-line treatment approved by the US Food and Drug Administration is bevacizumab (Avastin). To date, no single agent has shown to extend the life of patients with progressive malignant gliomas after bevacizumab failure. Once the tumor recurs during bevacizumab therapy, it is universally fatal, with death occurring within a few weeks. ERC-1671 is an experimental treatment strategy, which uses the patient’s own immune system to attack the tumor cells. We report preliminary data on the first human administration of ERC-1671 vaccination, under a single-patient, compassionate-use protocol, to a patient with progressive, bevacizumab-resistant GBM. Methods: Treatment involved sequential administration to the patient of GBM tumor cells and cell lysates combined from three different donors with GBM, followed by the patient’s own tumor cells and lysates. Results: The patient survived for ten months after the vaccine administration without any other adjuvant therapy and died of complications related to his previous chemotherapies. The tissues collected after two vaccination cycles and at the time of death showed a robust immune response and no viable tumor. Conclusion: These preliminary data strongly indicate that ERC-1671 could be effective in the treatment of progressive malignant gliomas. On the basis of these preliminary data, we are planning a larger study to assess the efficacy of ERC-1671 in the treatment of patients with recurrent GBM. PMID:25785641

  11. The interaction of bee products with temozolomide in human diffuse astrocytoma, glioblastoma multiforme and astroglia cell lines.

    PubMed

    Borawska, Maria H; Markiewicz-Żukowska, Renata; Naliwajko, Sylwia K; Moskwa, Justyna; Bartosiuk, Emilia; Socha, Katarzyna; Surażyński, Arkadiusz; Kochanowicz, Jan; Mariak, Zenon

    2014-01-01

    In the present study, we investigated the influence of extracts from Salix spp. honey (ESH), beebread (EBB), and royal jelly (ERJ) with and without temozolomide (TMZ) on cell lines derived from a patient with diffuse astrocytoma (DASC), human glioblastoma multiforme (U87MG), and normal human astroglia (SVGp12). DASC was identified by immunocytochemistry. TMZ (20 μM) in combination with ESH (30 μg/mL), EBB (50 μg/mL), and ERJ (30 μg/mL) has stronger cytotoxic activity on U87MG cells after 72 h (20.0, 26.5, and 29.3% of control, respectively) than TMZ alone (about 6% of control). An increase of the cytotoxic effect and inhibition of DNA synthesis in SVGp12 were detected after administering TMZ with the studied extracts. NF-κB p50 subunit was reduced in U87MG cells after treatment with ESH (70.9%) and ESH + TMZ (74.7%). A significant decline of MMP-9 and MMP-2 secretion in cultured U87MG was detected after incubation with EBB (42.9% and 73.0%, respectively) and EBB + TMZ (38.4% and 68.5%, respectively). In conclusion, the use of bee products may increase the cytotoxic effect of TMZ in U87MG but also in SVGp12 cell line. It is important to note that the U87MG cells were sensitive to natural bee products, although there was no influence of natural bee products on the DASC cells. PMID:25256634

  12. Association of {sup 11}C-Methionine PET Uptake With Site of Failure After Concurrent Temozolomide and Radiation for Primary Glioblastoma Multiforme

    SciTech Connect

    Lee, Irwin H.; Piert, Morand; Gomez-Hassan, Diana; Junck, Larry; Rogers, Lisa; Hayman, James; Ten Haken, Randall K.; Lawrence, Theodore S.; Cao Yue; Tsien, Christina

    2009-02-01

    Purpose: To determine whether increased uptake on 11C-methionine-PET (MET-PET) imaging obtained before radiation therapy and temozolomide is associated with the site of subsequent failure in newly diagnosed glioblastoma multiforme (GBM). Methods: Patients with primary GBM were treated on a prospective trial with dose- escalated radiation and concurrent temozolomide. As part of the study, MET-PET was obtained before treatment but was not used for target volume definition. Using automated image registration, we assessed whether the area of increased MET-PET activity (PET gross target volume [GTV]) was fully encompassed within the high-dose region and compared the patterns of failure for those with and without adequate high-dose coverage of the PET-GTV. Results: Twenty-six patients were evaluated with a median follow-up of 15 months. Nineteen of 26 had appreciable (>1 cm{sup 3}) volumes of increased MET-PET activity before treatment. Five of 19 patients had PET-GTV that was not fully encompassed within the high-dose region, and all five patients had noncentral failures. Among the 14 patients with adequately covered PET-GTV, only two had noncentral treatment failures. Three of 14 patients had no evidence of recurrence more than 1 year after radiation therapy. Inadequate PET-GTV coverage was associated with increased risk of noncentral failures. (p < 0.01). Conclusion: Pretreatment MET-PET appears to identify areas at highest risk for recurrence for patients with GBM. It would be reasonable to test a strategy of incorporating MET-PET into radiation treatment planning, particularly for identifying areas for conformal boost.

  13. 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.

  14. Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptide.

    PubMed

    Oji, Yusuke; Hashimoto, Naoya; Tsuboi, Akihiro; Murakami, Yui; Iwai, Miki; Kagawa, Naoki; Chiba, Yasuyoshi; Izumoto, Shuichi; Elisseeva, Olga; Ichinohasama, Ryo; Sakamoto, Junichi; Morita, Satoshi; Nakajima, Hiroko; Takashima, Satoshi; Nakae, Yoshiki; Nakata, Jun; Kawakami, Manabu; Nishida, Sumiyuki; Hosen, Naoki; Fujiki, Fumihiro; Morimoto, Soyoko; Adachi, Mayuko; Iwamoto, Masahiro; Oka, Yoshihiro; Yoshimine, Toshiki; Sugiyama, Haruo

    2016-09-15

    We previously evaluated Wilms' tumor gene 1 (WT1) peptide vaccination in a large number of patients with leukemia or solid tumors and have reported that HLA-A*24:02 restricted, 9-mer WT1-235 peptide (CYTWNQMNL) vaccine induces cellular immune responses and elicits WT1-235-specific cytotoxic T lymphocytes (CTLs). However, whether this vaccine induces humoral immune responses to produce WT1 antibody remains unknown. Thus, we measured IgG antibody levels against the WT1-235 peptide (WT1-235 IgG antibody) in patients with glioblastoma multiforme (GBM) receiving the WT1 peptide vaccine. The WT1-235 IgG antibody, which was undetectable before vaccination, became detectable in 30 (50.8%) of a total of 59 patients during 3 months of WT1 peptide vaccination. The dominant WT1-235 IgG antibody subclass was Th1-type, IgG1 and IgG3 . WT1-235 IgG antibody production was significantly and positively correlated with both progression-free survival (PFS) and overall survival (OS). Importantly, the combination of WT1-235 IgG antibody production and positive delayed type-hypersensitivity (DTH) to the WT1-235 peptide was a better prognostic marker for long-term OS than either parameter alone. These results suggested that WT1-235 peptide vaccination induces not only WT1-235-specific CTLs as previously described but also WT1-235-specific humoral immune responses associated with antitumor cellular immune response. Our results indicate that the WT1 IgG antibody against the WT1 peptide may be a useful predictive marker, with better predictive performance in combination with DTH to WT1 peptide, and provide a new insight into the antitumor immune response induction in WT1 peptide vaccine-treated patients. PMID:27170523

  15. 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

  16. 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. PMID:21896554

  17. 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.

  18. Knockdown of AKT3 (PKBγ) and PI3KCA Suppresses Cell Viability and Proliferation and Induces the Apoptosis of Glioblastoma Multiforme T98G Cells

    PubMed Central

    Paul-Samojedny, Monika; Suchanek, Renata; Borkowska, Paulina; Pudełko, Adam; Owczarek, Aleksander; Kowalczyk, Małgorzata; Machnik, Grzegorz; Fila-Daniłow, Anna; Kowalski, Jan

    2014-01-01

    Glioblastoma multiforme (GBM) is the most malignant and invasive human brain tumor that is difficult to treat and has a very poor prognosis. Thus, new therapeutic strategies that target GBM are urgently needed. The PI3K/AKT/PTEN signaling pathway is frequently deregulated in a wide range of cancers. The present study was designed to examine the inhibitory effect of AKT3 or PI3KCA siRNAs on GBM cell growth, viability, and proliferation.T98G cells were transfected with AKT3 and/or PI3KCA siRNAs. AKT3 and PI3KCA protein-positive cells were identified using FC and Western blotting. The influence of specific siRNAs on T98G cell viability, proliferation, cell cycle, and apoptosis was evaluated as well using FC. Alterations in the mRNA expression of AKT3, PI3KCA, and apoptosis-related genes were analyzed using QRT-PCR. Knockdown of AKT3 and/or PI3KCA genes in T98G cells led to a significant reduction in cell viability, the accumulation of subG1-phase cells and, a reduced fraction of cells in the S and G2/M phases. Additionally, statistically significant differences in the BAX/BCL-2 ratio and an increased percentage of apoptotic cells were found. The siRNA-induced AKT3 and PI3KCA mRNA knockdown may offer a novel therapeutic strategy to control the growth of human GBM cells. PMID:24967401

  19. 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

  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

    DOE PAGESBeta

    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

  2. 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

  3. Perfusion MR imaging and proton MR spectroscopic imaging in differentiating necrotizing cerebritis from glioblastoma multiforme.

    PubMed

    Pivawer, Gabriel; Law, Meng; Zagzag, David

    2007-02-01

    We describe a lesion with the magnetic resonance imaging (MRI) characteristics of a glioblastoma mutiforme and demonstrate how perfusion MRI and proton MR spectroscopic imaging can be used to differentiate necrotizing cerebritis from what appeared to be a high-grade glioma. A 43-year-old woman presented to her physician complaining of progressive visual disturbance and headache for several weeks. Conventional MRI demonstrated a parietal peripherally enhancing mass with central necrosis and moderate to severe surrounding T2 hyperintensity, suggesting an infiltrating high-grade glioma. However, advanced imaging, including dynamic susceptibility contrast MRI (DSC MRI) and magnetic resonance spectroscopic imaging (MRSI), suggested a nonneoplastic lesion. The DSC MRI data demonstrated no hyperperfusion within the lesion and surrounding T2 signal abnormality, and the MRSI data showed overall decrease in metabolites in this region, except for lactate. Because of the aggressive appearance to the lesion and the patients' worsening symptoms, a biopsy was performed. The pathologic diagnosis was necrotizing cerebritis. After the commencement of steroid therapy, imaging findings and patient symptoms improved. This report will review the utility of advanced imaging for differentiating inflammatory from neoplastic appearing lesions on conventional imaging. PMID:17275620

  4. DNA Damage of Glioblastoma Multiform Cells Induced by Beta Radiation of Iodine-131 in The Presence or Absence of Topotecan: A Picogreen and Colonogenic Assay

    PubMed Central

    Eyvazzadeh, Nazila; Neshasteh-Riz, Ali; Mahdavi, Seyed Rabee

    2015-01-01

    Objective Glioblastoma multiforme (GBM), one of the most common and aggressive malignant brain tumors, is highly resistant to radiotherapy. Numerous approaches have been pursued to find new radiosensitizers. We used a picogreen and colonogenic assay to appraise the DNA damage and cell death in a spheroid culture of GBM cells caused by iodine-131 (I-131) beta radiation in the presence of topotecan (TPT). Materials and Methods U87MG cells were cultured as spheroids with approximate diameters of 300 μm. Cells were treated with beta radiation of I-131 (at a dose of 2 Gy) and/ or TPT (1 μg/ml for 2 hours). The numbers of cells that survived were compared with untreated cells using a colonogenic assay. In addition, we evaluated possible DNA damages by the picogreen method. The relation between DNA damage and cell death was assessed in the experimental study of groups. Results The findings showed that survival fraction (SF) in the I-131+TPT group (39%) was considerably less than the I-131 group (58.92%; p<0.05). The number of single strand breaks (SSB) and double strand breaks (DSB), in the DNA of U87MG cells treated with beta radiation of I-131 and TPT (I-131+TPT) significantly increased compared to cells treated with only I-131 or TPT (p<0.05). The amount of SSB repair was more than DSB repair (p<0.05). The relationship between cell death and DNA damage was close (r≥0.6) and significant (p<0.05) in the irradiated and treated groups. Also the maximum rate of DNA repair occurred 24 hours after the treatments. A significant difference was not observed on other days of the restoration. Conclusion The findings in the present study indicated that TPT can sensitize U87MG cells to radiation and increase DNA damages. Potentially, TPT can cause an increase in damage from DSB and SSB by its inhibitory effects on topoisomerase enzyme and the cell cycle. The increased complex damages following the use of a genotoxic agent and beta I-131 radiation, causes a significant increase

  5. 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.

  6. 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

  7. Impact of [{sup 11}C]Methionine Positron Emission Tomography for Target Definition of Glioblastoma Multiforme in Radiation Therapy Planning

    SciTech Connect

    Matsuo, Masayuki; Miwa, Kazuhiro; Tanaka, Osamu; Shinoda, Jun; Nishibori, Hironori; Tsuge, Yusuke; Yano, Hirohito; Iwama, Toru; Hayashi, Shinya; Hoshi, Hiroaki; Yamada, Jitsuhiro; Kanematsu, Masayuki; Aoyama, Hidefumi

    2012-01-01

    Purpose: The purpose of this work was to define the optimal margins for gadolinium-enhanced T{sub 1}-weighted magnetic resonance imaging (Gd-MRI) and T{sub 2}-weighted MRI (T{sub 2}-MRI) for delineating target volumes in planning radiation therapy for postoperative patients with newly diagnosed glioblastoma multiforme (GBM) by comparison to carbon-11-labeled methionine positron emission tomography ([{sup 11}C]MET-PET) findings. Methods and Materials: Computed tomography (CT), MRI, and [{sup 11}C]MET-PET were separately performed for radiation therapy planning for 32 patients newly diagnosed with GBM within 2 weeks after undergoing surgery. The extent of Gd-MRI (Gd-enhanced clinical target volume [CTV-Gd]) uptake and that of T{sub 2}-MRI of the CTV (CTV-T{sub 2}) were compared with the extent of [{sup 11}C]MET-PET (CTV--[{sup 11}C]MET-PET) uptake by using CT--MRI or CT--[{sup 11}C]MET-PET fusion imaging. We defined CTV-Gd (x mm) and CTV-T{sub 2} (x mm) as the x-mm margins (where x = 0, 2, 5, 10, and 20 mm) outside the CTV-Gd and the CTV-T{sub 2}, respectively. We evaluated the relationship between CTV-Gd (x mm) and CTV-- [{sup 11}C]MET-PET and the relationship between CTV-T{sub 2} (x mm) and CTV-- [{sup 11}C]MET-PET. Results: The sensitivity of CTV-Gd (20 mm) (86.4%) was significantly higher than that of the other CTV-Gd. The sensitivity of CTV-T{sub 2} (20 mm) (96.4%) was significantly higher than that of the other CTV-T{sub 2} (x = 0, 2, 5, 10 mm). The highest sensitivity and lowest specificity was found with CTV-T{sub 2} (x = 20 mm). Conclusions: It is necessary to use a margin of at least 2 cm for CTV-T{sub 2} for the initial target planning of radiation therapy. However, there is a limit to this setting in defining the optimal margin for Gd-MRI and T{sub 2}-MRI for the precise delineation of target volumes in radiation therapy planning for postoperative patients with GBM.

  8. Prognostic factors in recurrent glioblastoma patients treated with bevacizumab.

    PubMed

    Schaub, Christina; Tichy, Julia; Schäfer, Niklas; Franz, Kea; Mack, Frederic; Mittelbronn, Michel; Kebir, Sied; Thiepold, Anna-Luisa; Waha, Andreas; Filmann, Natalie; Banat, Mohammed; Fimmers, Rolf; Steinbach, Joachim P; Herrlinger, Ulrich; Rieger, Johannes; Glas, Martin; Bähr, Oliver

    2016-08-01

    The value of bevacizumab (BEV) in recurrent glioblastoma is unclear. Imaging parameters and progression-free survival (PFS) are problematic endpoints. Few data exist on clinical factors influencing overall survival (OS) in unselected patients with recurrent glioblastoma exposed to BEV. We retrospectively analyzed 174 patients with recurrent glioblastoma treated with BEV at two German brain tumor centers. We evaluated general patient characteristics, MGMT status, pretreatment, concomitant oncologic treatment and overall survival. Karnofsky performance score, number of prior chemotherapies, number of prior recurrences and combined treatment with irinotecan (IRI) were significantly associated with OS in univariate analysis. We did not find differences in OS related to sex, age, histology, MGMT status, prior surgical treatment or number of prior radiotherapies. Combined treatment with IRI and higher KPS both remained significantly associated with prolonged survival in multivariate analysis, but patients receiving IRI co-treatment had less advanced disease. Grouping into clinically relevant categories revealed an OS of 16.9 months from start of BEV in patients with first recurrence and KPS ≥ 80 % (n = 25). In contrast, in patients with second recurrence and KPS < 80 %, OS was 3.6 months (n = 27). Our observational data support an early use of BEV in patients with good performance status. The benefit of co-treatment with IRI in our cohort seems to be the result of biased patient recruitment. PMID:27193554

  9. 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

  10. Is there hope to treat glioblastoma effectively?

    PubMed

    Mehrling, Thomas; Gunawardana, Roshaine

    2015-01-01

    Thomas Mehrling was appointed Managing Director of Mundipharma EDO GmbH, Basel, in January 2013 and brings extensive experience with more than 17 years in the industry to this role. During his career, he has held various senior positions in different companies across almost all functions in drug development and commercialization. Most recently, he held the position of International Director Oncology Strategy (2011-2013). From 2004 to 2011 he served as European Director Oncology at Mundipharma International Ltd. During his tenure the oncology business of the European Mundipharma network of independent associated companies was set up and two major products were launched in Europe, DepoCyte® and Levact® (Ribomustin®, Treanda®). He joined Mundipharma in 2000 as Head of Business Development. Prior to Mundipharma, he was Senior Vice President of the global CRO Medical Affairs at Staticon International, and prior to this he acted as Medical Leader at Takeda European R&D center. Dr. Mehrling is a certified Pharmacist with a PhD in pharmacology and a certified Physician trained in haemato-oncology. He obtained his PhD from Frankfurt University following work on developing a new 5-HT3 antagonist to treat nausea and vomiting and developed a particular interest in mechanisms of multidrug resistance into chemotherapy. Dr. Mehrling earned his MD degree through his work in the Department of Internal medicine at Frankfurt University (Hemato-oncology and Cardiology) where he worked for several years before starting his career in the pharmaceutical industry. PMID:26507499

  11. SU-C-BRE-03: Dual Compartment Mathematical Modeling of Glioblastoma Multiforme (GBM)

    SciTech Connect

    Yu, V; Nguyen, D; Kupelian, P; Kaprealian, T; Selch, M; Low, D; Pajonk, F; Sheng, K

    2014-06-15

    Purpose: To explore the aggressive recurrence and radioresistence of GBM with a dual compartment tumor survival mathematical model based on intrinsic tumor heterogeneity, cancer stem cells (CSC) and differentiated cancer cells (DCC). Methods: The repopulation and differentiation responses to radiotherapy of a solid tumor were simulated using an Ordinary Differential Equation (ODE). To obtain the tumor radiobiological parameters, we assumed that a tumor consists of two subpopulations, each with its distinctive linear quadratic parameters. The dual compartment cell survival model was constructed as SF(D)=F × exp(-α{sub 1} D-β{sub 1}D{sup 2}) + (1-F) × exp(-α{sub 2}D-β{sub 2}D{sup 2}) for a single fraction of treatment, with F as the fraction of CSC, and α and β describing the radiological properties of each population. Robust least square fitting was performed on clonogenic survival data from one GBM (U373MG) and one NSCLC (H460) cell line. The fit parameters were then used in the ODE model to predict treatment outcome of various treatment schemes. Results: The fit parameters from GBM cell survival data were (F, α{sub 1}, β{sub 1}, α{sub 2}, β{sub 2})=(0.0396, 0.0801, 0.0006, 0.1363, 0.0279), exhibiting two populations with distinctive radiological properties, CSC more radioresistant than DCC. The GBM cell line exhibited significantly poorer tumor control than its single compartment model prediction and NSCLC, which responded well to hypofrationation. The increased radioresistance was due to rapid regrowth of the DCC compartment triggered by its depletion while maintaining a viable CSC population. The rapid regrowth can be reduced by treating dose fractions ≤ 2 Gy with a prolonged treatment period. Conclusion: The interaction between a radioresistant CSC compartment and DCC compartment can explain the poor clinical outcome of GBM after radiotherapy despite dose escalation and hypofractionation attempts. Lower dose fractions result in better treatment

  12. The Role of a Single Angiogenesis Inhibitor in the Treatment of Recurrent Glioblastoma Multiforme: A Meta-Analysis and Systematic Review

    PubMed Central

    Wang, Yawei; Xing, Dan; Zhao, Meng; Wang, Jie; Yang, Yang

    2016-01-01

    Background Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients. Methods Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). Demographic data, treatment regimens, objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0). Results A total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR) 2.93, 95% CI 1.38–6.21; p = 0.025; and RR 2.36 95% CI 1.46–3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07). when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64–17.6, p<0.001), but not for 6-months PFS (p = 0.07) and 1-year OS (p = 0.31). As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence

  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. PMID:27595933

  14. 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

  15. First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity.

    PubMed

    Schijns, Virgil E J C; Pretto, Chrystel; Devillers, Laurent; Pierre, Denis; Hofman, Florence M; Chen, Thomas C; Mespouille, Pascal; Hantos, Peter; Glorieux, Philippe; Bota, Daniela A; Stathopoulos, Apostolos

    2015-05-28

    Glioblastoma multiforme (GBM) patients have a poor prognosis. After tumor recurrence statistics suggest an imminent death within 1-4.5 months. Supportive preclinical data, from a rat model, provided the rational for a prototype clinical vaccine preparation, named Gliovac (or ERC 1671) composed of autologous antigens, derived from the patient's surgically removed tumor tissue, which is administered together with allogeneic antigens from glioma tissue resected from other GBM patients. We now report the first results of the Gliovac treatment for treatment-resistant GBM patients. Nine (9) recurrent GBM patients, after standard of care treatment, including surgery radio- and chemotherapy temozolomide, and for US patients, also bevacizumab (Avastin™), were treated under a compassionate use/hospital exemption protocol. Gliovac was given intradermally, together with human GM-CSF (Leukine(®)), and preceded by a regimen of regulatory T cell-depleting, low-dose cyclophosphamide. Gliovac administration in patients that have failed standard of care therapies showed minimal toxicity and enhanced overall survival (OS). Six-month (26 weeks) survival for the nine Gliovac patients was 100% versus 33% in control group. At week 40, the published overall survival was 10% if recurrent, reoperated patients were not treated. In the Gliovac treated group, the survival at 40 weeks was 77%. Our data suggest that Gliovac has low toxicity and a promising efficacy. A phase II trial has recently been initiated in recurrent, bevacizumab naïve GBM patients (NCT01903330). PMID:25865468

  16. Integrated-boost IMRT or 3-D-CRT using FET-PET based auto-contoured target volume delineation for glioblastoma multiforme - a dosimetric comparison

    PubMed Central

    2009-01-01

    Background Biological brain tumor imaging using O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET combined with inverse treatment planning for locally restricted dose escalation in patients with glioblastoma multiforme seems to be a promising approach. The aim of this study was to compare inverse with forward treatment planning for an integrated boost dose application in patients suffering from a glioblastoma multiforme, while biological target volumes are based on FET-PET and MRI data sets. Methods In 16 glioblastoma patients an intensity-modulated radiotherapy technique comprising an integrated boost (IB-IMRT) and a 3-dimensional conventional radiotherapy (3D-CRT) technique were generated for dosimetric comparison. FET-PET, MRI and treatment planning CT (P-CT) were co-registrated. The integrated boost volume (PTV1) was auto-contoured using a cut-off tumor-to-brain ratio (TBR) of ≥ 1.6 from FET-PET. PTV2 delineation was MRI-based. The total dose was prescribed to 72 and 60 Gy for PTV1 and PTV2, using daily fractions of 2.4 and 2 Gy. Results After auto-contouring of PTV1 a marked target shape complexity had an impact on the dosimetric outcome. Patients with 3-4 PTV1 subvolumes vs. a single volume revealed a significant decrease in mean dose (67.7 vs. 70.6 Gy). From convex to complex shaped PTV1 mean doses decreased from 71.3 Gy to 67.7 Gy. The homogeneity and conformity for PTV1 and PTV2 was significantly improved with IB-IMRT. With the use of IB-IMRT the minimum dose within PTV1 (61.1 vs. 57.4 Gy) and PTV2 (51.4 vs. 40.9 Gy) increased significantly, and the mean EUD for PTV2 was improved (59.9 vs. 55.3 Gy, p < 0.01). The EUD for PTV1 was only slightly improved (68.3 vs. 67.3 Gy). The EUD for the brain was equal with both planning techniques. Conclusion In the presented planning study the integrated boost concept based on inversely planned IB-IMRT is feasible. The FET-PET-based automatically contoured PTV1 can lead to very complex geometric configurations, limiting the

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

    PubMed

    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

  18. 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

  19. Outcome and prognostic factors in cerebellar glioblastoma multiforme in adults: A retrospective study from the Rare Cancer Network

    SciTech Connect

    Weber, Damien C. . E-mail: damien.weber@hcuge.ch; Miller, Robert C.; Villa, Salvador; Hanssens, Patrick; Baumert, Brigitta G.; Castadot, Pierre; Varlet, Pascale; Abacioglu, Ufuk; Igdem, Sefik; Szutowicz, Ewa; Nishioka, Hiroshi; Hofer, Silvia; Rutz, Hans Peter; Ozsahin, Mahmut; Taghian, Alphonse; Mirimanoff, Rene O.

    2006-09-01

    Purpose: The aim of this study was to assess the outcome in patients with cerebellar glioblastoma (GBM) treated in 15 institutions of the Rare Cancer Network. Methods and Materials: Data from a series of 45 adult patients with cerebellar GBM were collected in a retrospective multicenter study. Median age was 50.3 years. Brainstem invasion was observed in 9 (20%) patients. Radiotherapy (RT) was administered to 36 patients (with concomitant chemotherapy, 7 patients). Adjuvant chemotherapy after RT was administered in 8 patients. Median RT dose was 59.4 Gy. Median follow-up was 7.2 months (range, 3.4-39.0). Results: The 1-year and 2-year actuarial overall survival rate was 37.8% and 14.7%, respectively, and was significantly influenced by salvage treatment (p = 0.048), tumor volume (p = 0.044), extent of neurosurgical resection (p = 0.019), brainstem invasion (p = 0.0013), additional treatment after surgery (p < 0.001), and completion of the initial treatment (p < 0.001) on univariate analysis. All patients experienced local progression: 8 and 22 had progression with and without a distant failure, respectively. The 1- and 2-year actuarial progression free survival was 25% and 10.7%, respectively, and was significantly influenced by brainstem invasion (p = 0.002), additional treatment after surgery (p = 0.0016), and completion of the initial treatment (p < 0.001). On multivariate analysis, survival was negatively influenced by the extent of surgery (p = 0.03) and brainstem invasion (p = 0.02). Conclusions: In this multicenter retrospective study, the observed pattern of failure was local in all cases, but approximately 1 patient of 4 presented with an extracerebellar component. Brainstem invasion was observed in a substantial number of patients and was an adverse prognostic factor.

  20. 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 ...

  1. 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

  2. Toroidal-Spiral Particles for Codelivery of Anti-VEGFR-2 Antibody and Irinotecan: A Potential Implant to Hinder Recurrence of Glioblastoma Multiforme

    PubMed Central

    2015-01-01

    Heterogeneous toroidal-spiral particles (TSPs) were generated by polymer droplet sedimentation, interaction, and cross-linking. TSPs provide a platform for encapsulation and release of multiple compounds of different sizes and physicochemical properties. As a model system, we demonstrate the encapsulation and independently controlled release of an anti-VEGFR-2 antibody and irinotecan for the treatment of glioblastoma multiforme. The anti-VEGFR-2 antibody was released from the TS channels and its binding to HUVECs was confirmed by confocal microscopy and flow cytometry, suggesting active antibody encapsulation and release. Irinotecan, a small molecule drug, was released from the dense polymer matrix of poly(ethylene glycol) diacrylate (MW ∼ 700 g/mol; PEGDA 700). Released irinotecan inhibited the proliferation of U251 malignant glioma cells. Since the therapeutic compounds are released through different pathways, specifically diffusion through the polymer matrix versus TS channels, the release rate can be controlled independently through the design of the structure and material of particle components. PMID:24460101

  3. Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogen-independent growth

    PubMed Central

    Olmez, Inan; Shen, Wangzhen; McDonald, Hayes; Ozpolat, Bulent

    2015-01-01

    Emerging evidence shows that glioblastoma multiforme (GBM) originates from cancer stem cells (CSCs). Characterization of CSC-specific signalling pathways would help identify new therapeutic targets and perhaps lead to the development of more efficient therapies selectively targeting CSCs. Here; we successfully dedifferentiated two patient-derived GBM cell lines into CSC-like cells (induced glioma stem cells, iGSCs) through expression of Oct4, Sox2 and Nanog transcription factors. Transformed cells exhibited significant suppression of epidermal growth factor receptor and its downstream pathways. Compared with parental GBM cells, iGSCs formed large neurospheres even in the absence of exogenous mitogens; they exhibited significant sensitivity to salinomycin and chemoresistance to temozolomide. Further characterization of iGSCs revealed induction of NOTCH1 and Wnt/β-catenin signalling and expression of CD133, CD44 and ALDH1A1. Our results indicate that iGSCs may help us understand CSC physiology and lead to development of potential therapeutic interventions aimed at differentiating tumour cells to render them more sensitive to chemotherapy or other standard agents. PMID:25787115

  4. Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogen-independent growth.

    PubMed

    Olmez, Inan; Shen, Wangzhen; McDonald, Hayes; Ozpolat, Bulent

    2015-06-01

    Emerging evidence shows that glioblastoma multiforme (GBM) originates from cancer stem cells (CSCs). Characterization of CSC-specific signalling pathways would help identify new therapeutic targets and perhaps lead to the development of more efficient therapies selectively targeting CSCs. Here; we successfully dedifferentiated two patient-derived GBM cell lines into CSC-like cells (induced glioma stem cells, iGSCs) through expression of Oct4, Sox2 and Nanog transcription factors. Transformed cells exhibited significant suppression of epidermal growth factor receptor and its downstream pathways. Compared with parental GBM cells, iGSCs formed large neurospheres even in the absence of exogenous mitogens; they exhibited significant sensitivity to salinomycin and chemoresistance to temozolomide. Further characterization of iGSCs revealed induction of NOTCH1 and Wnt/β-catenin signalling and expression of CD133, CD44 and ALDH1A1. Our results indicate that iGSCs may help us understand CSC physiology and lead to development of potential therapeutic interventions aimed at differentiating tumour cells to render them more sensitive to chemotherapy or other standard agents. PMID:25787115

  5. Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells

    PubMed Central

    Daniele, Simona; Costa, Barbara; Zappelli, Elisa; Da Pozzo, Eleonora; Sestito, Simona; Nesi, Giulia; Campiglia, Pietro; Marinelli, Luciana; Novellino, Ettore; Rapposelli, Simona; Martini, Claudia

    2015-01-01

    The poor prognosis of Glioblastoma Multiforme (GBM) is due to a high resistance to conventional treatments and to the presence of a subpopulation of glioma stem cells (GSCs). Combination therapies targeting survival/self-renewal signals of GBM and GSCs are emerging as useful tools to improve GBM treatment. In this context, the hyperactivated AKT/mammalian target of the rapamycin (AKT/mTOR) and the inhibited wild-type p53 appear to be good candidates. Herein, the interaction between these pathways was investigated, using the novel AKT/mTOR inhibitor FC85 and ISA27, which re-activates p53 functionality by blocking its endogenous inhibitor murine double minute 2 homologue (MDM2). In GBM cells, FC85 efficiently inhibited AKT/mTOR signalling and reactivated p53 functionality, triggering cellular apoptosis. The combined therapy with ISA27 produced a synergic effect on the inhibition of cell viability and on the reactivation of p53 pathway. Most importantly, FC85 and ISA27 blocked proliferation and promoted the differentiation of GSCs. The simultaneous use of these compounds significantly enhanced GSC differentiation/apoptosis. These findings suggest that FC85 actively enhances the downstream p53 signalling and that a combination strategy aimed at inhibiting the AKT/mTOR pathway and re-activating p53 signalling is potentially effective in GBM and in GSCs. PMID:25898313

  6. Genome-wide analysis of YB-1-RNA interactions reveals a novel role of YB-1 in miRNA processing in glioblastoma multiforme

    PubMed Central

    Wu, Shuai-Lai; Fu, Xing; Huang, Jinyan; Jia, Ting-Ting; Zong, Feng-Yang; Mu, Shi-Rong; Zhu, Hong; Yan, Yong; Qiu, Shuwei; Wu, Qun; Yan, Wei; Peng, Ying; Chen, Juxiang; Hui, Jingyi

    2015-01-01

    Altered miRNA expression is believed to play a crucial role in a variety of human cancers; however, the mechanisms leading to the dysregulation of miRNA expression remain elusive. In this study, we report that the human Y box-binding protein (YB-1), a major mRNA packaging protein, is a novel modulator of miRNA processing in glioblastoma multiforme (GBM). Using individual nucleotide-resolution crosslinking immunoprecipitation coupled to deep sequencing (iCLIP-seq), we performed the first genome-wide analysis of the in vivo YB-1-RNA interactions and found that YB-1 preferentially recognizes a UYAUC consensus motif and binds to the majority of coding gene transcripts including pre-mRNAs and mature mRNAs. Remarkably, our data show that YB-1 also binds extensively to the terminal loop region of pri-/pre-miR-29b-2 and regulates the biogenesis of miR-29b-2 by blocking the recruitment of microprocessor and Dicer to its precursors. Furthermore, we show that down-regulation of miR-29b by YB-1, which is up-regulated in GBM, is important for cell proliferation. Together, our findings reveal a novel function of YB-1 in regulating non-coding RNA expression, which has important implications in tumorigenesis. PMID:26240386

  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. 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

  9. 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. PMID:26683098

  10. 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

  11. 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

  12. 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

  13. 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

  14. Intracerebral abscess with dissecting pneumocephalus caused by a gas-producing gram-positive rod following craniotomy for glioblastoma multiforme resection.

    PubMed

    Sarkiss, Christopher A; Soleymani, Teo; Caplan, Justin M; Dorsi, Michael J; Huang, Judy

    2013-11-01

    Propionibacterium acnes (P. acnes), an indolent and slow-growing anaerobic gram-positive bacterium, has largely been known as a commensal organism of the normal skin flora. However, P. acnes is increasingly being recognized as the causative infectious organism complicating craniotomies and shunt insertions. To our knowledge, we present the first reported patient with an intracerebral abscess with dissecting pneumocephalus caused by P. acnes. A 58-year-old woman who was immunocompetent presented 3 weeks after a craniotomy for resection of a glioblastoma multiforme with worsening mental status, lethargy and left hemiparesis. Head CT scans and MRI demonstrated significant vasogenic edema and dissecting pneumocephalus in the resection cavity. A craniotomy was performed and purulent material was found in the subdural space and resection cavity. Cultures were positive for P. acnes. She completed a full course of intravenous antibiotics appropriate for the organism. The infection was eradicated and the patient survived albeit with persistent deficits. This case illustrates the importance of considering an underlying intracerebral abscess in patients with worsening neurological function and pneumocephalus on imaging several weeks after surgery. Our review of the literature underscores the great importance in early recognition and treatment with both surgical debridement and antibiotic therapy in achieving optimal patient recovery. PMID:23688444

  15. Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme.

    PubMed

    Sestito, Simona; Nesi, Giulia; Daniele, Simona; Martelli, Alma; Digiacomo, Maria; Borghini, Alice; Pietra, Daniele; Calderone, Vincenzo; Lapucci, Annalina; Falasca, Marco; Parrella, Paola; Notarangelo, Angelantonio; Breschi, Maria C; Macchia, Marco; Martini, Claudia; Rapposelli, Simona

    2015-11-13

    Aggressive behavior and diffuse infiltrative growth are the main features of Glioblastoma multiforme (GBM), together with the high degree of resistance and recurrence. Evidence indicate that GBM-derived stem cells (GSCs), endowed with unlimited proliferative potential, play a critical role in tumor development and maintenance. Among the many signaling pathways involved in maintaining GSC stemness, tumorigenic potential, and anti-apoptotic properties, the PDK1/Akt pathway is a challenging target to develop new potential agents able to affect GBM resistance to chemotherapy. In an effort to find new PDK1/Akt inhibitors, we rationally designed and synthesized a small family of 2-oxindole derivatives. Among them, compound 3 inhibited PDK1 kinase and downstream effectors such as CHK1, GS3Kα and GS3Kβ, which contribute to GCS survival. Compound 3 appeared to be a good tool for studying the role of the PDK1/Akt pathway in GCS self-renewal and tumorigenicity, and might represent the starting point for the development of more potent and focused multi-target therapies for GBM. PMID:26498573

  16. Identification of an EGFRvIII-JNK2-HGF/c-Met-Signaling Axis Required for Intercellular Crosstalk and Glioblastoma Multiforme Cell Invasion.

    PubMed

    Saunders, Vanessa C; Lafitte, Marie; Adrados, Isabel; Quereda, Victor; Feurstein, Daniel; Ling, YuanYuan; Fallahi, Mohammad; Rosenberg, Laura H; Duckett, Derek R

    2015-12-01

    Glioblastoma multiforme (GBM) is the most aggressive and common form of adult brain cancer. Current therapeutic strategies include surgical resection, followed by radiotherapy and chemotherapy. Despite such aggressive multimodal therapy, prognosis remains poor, with a median patient survival of 14 months. A proper understanding of the molecular drivers responsible for GBM progression are therefore necessary to instruct the development of novel targeted agents and enable the design of effective treatment strategies. Activation of the c-Jun N-terminal kinase isoform 2 (JNK2) is reported in primary brain cancers, where it associates with the histologic grade and amplification of the epidermal growth factor receptor (EGFR). In this manuscript, we demonstrate an important role for JNK2 in the tumor promoting an invasive capacity of EGFR variant III, a constitutively active mutant form of the receptor commonly found in GBM. Expression of EGFR variant III induces transactivation of JNK2 in GBM cells, which is required for a tumorigenic phenotype in vivo. Furthermore, JNK2 expression and activity is required to promote increased cellular invasion through stimulation of a hepatocyte growth factor-c-Met signaling circuit, whereby secretion of this extracellular ligand activates the receptor tyrosine kinase in both a cell autonomous and nonautonomous manner. Collectively, these findings demonstrate the cooperative and parallel activation of multiple RTKs in GBM and suggest that the development of selective JNK2 inhibitors could be therapeutically beneficial either as single agents or in combination with inhibitors of EGFR and/or c-Met. PMID:26452771

  17. 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

  18. 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.

  19. Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

    PubMed Central

    Kristoffersen, Karina; Nedergaard, Mette Kjølhede; Villingshøj, Mette; Borup, Rehannah; Broholm, Helle; Kjær, Andreas; Poulsen, Hans Skovgaard; Stockhausen, Marie-Thérése

    2014-01-01

    Background Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC. Methods Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice. Results By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control. Conclusion Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies. PMID

  20. A case of complete clearance of chronic subdural hematoma accompanied by recurrent glioblastoma multiforme after administration of bevacizumab.

    PubMed

    Suzuki, Keiko; Kawataki, Tomoyuki; Kanemaru, Kazuya; Mitsuka, Kentaro; Ogiwara, Masakazu; Sato, Hiroki; Kinouchi, Hiroyuki

    2016-07-01

    The efficacy of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), as an adjuvant therapy against various malignant tumors was recently established. Its pharmacological effects in malignant tumors, including gliomas, were speculated to involve neovascularization inhibition and vascular permeability. Recently, it has been reported that the outer membrane of chronic subdural hematoma (CSDH) contains high levels of VEGF, which were implicated in neovascularization of the outer membrane. Furthermore, studies suggested that VEGF has the etiology in CSDH development, although its involvement is not fully understood. Here, we report the first case of chronic subdural hematoma that was improved by bevacizumab administration for recurrent glioblastoma. The present case could contribute to the hypothesis that VEGF may be associated with CSDH. We also discuss the pathogenesis and mechanism of CSDH recurrence from the viewpoint of VEGF function. PMID:26919835

  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

    2014-01-01

    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. PMID:25325361

  2. 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

  3. 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

  4. Patterns of Recurrence Analysis in Newly Diagnosed Glioblastoma Multiforme After Three-Dimensional Conformal Radiation Therapy With Respect to Pre-Radiation Therapy Magnetic Resonance Spectroscopic Findings

    SciTech Connect

    Park, Ilwoo; Chuang, Cynthia F.; Chang, Susan M.; Berger, Mitchel S.; Nelson, Sarah J.

    2007-10-01

    Purpose: To determine whether the combined magnetic resonance imaging (MRI) and magnetic resonance spectroscopy imaging (MRSI) before radiation therapy (RT) is valuable for RT target definition, and to evaluate the feasibility of replacing the current definition of uniform margins by custom-shaped margins based on the information from MRI and MRSI. Methods and Materials: A total of 23 glioblastoma multiforme (GBM) patients underwent MRI and MRSI within 4 weeks after surgery but before the initiation of RT and at 2-month follow-up intervals thereafter. The MRSI data were quantified on the basis of a Choline-to-NAA Index (CNI) as a measure of spectroscopic abnormality. A combined anatomic and metabolic region of interest (MRI/S) consisting of T2-weighted hyperintensity, contrast enhancement (CE), resection cavity, and CNI2 (CNI {>=} 2) based on the pre-RT imaging was compared to the extent of CNI2 and the RT dose distribution. The spatial relationship of the pre-RT MRI/S and the RT dose volume was compared with the extent of CE at each follow-up. Results: Nine patients showed new or increased CE during follow-up, and 14 patients were either stable or had decreased CE. New or increased areas of CE occurred within CNI2 that was covered by 60 Gy in 6 patients and within the CNI2 that was not entirely covered by 60 Gy in 3 patients. New or increased CE resided within the pre-RT MRI/S lesion in 89% (8/9) of the patients with new or increased CE. Conclusion: These data indicate that the definition of RT target volumes according to the combined morphologic and metabolic abnormality may be sufficient for RT targeting.

  5. The homing of human cord blood stem cells to sites of inflammation: unfolding mysteries of a novel therapeutic paradigm for glioblastoma multiforme.

    PubMed

    Velpula, Kiran Kumar; Dasari, Venkata Ramesh; Rao, Jasti S

    2012-06-15

    Efficient homing of human umbilical cord blood mesenchymal stem cells (hUCBSC) to inflammation sites is crucial for therapeutic use. In glioblastoma multiforme, soluble factors released by the tumor facilitate the migratory capacity of mesenchymal stem cells toward glioma cells. These factors include chemokines and growth inducers. Nonetheless, the mechanistic details of these factors involved in hUCBSC homing have not been clearly delineated. The present study is aimed to deduce specific factors involved in hUCBSC homing by utilizing a glioma stem cell-induced inflammatory lesion model in the mouse brain. Our results show that hUCBSC do not form tumors in athymic nude mice brains and do not elicit immune responses in immunocompetent SKH1 mice. Further, hUCBSC spheroids migrate and invade glioma spheroids, while no effect was observed on rat fetal brain aggregates. Several cytokines, including GRO, MCP-1, IL-8, IL-3, IL-10, Osteopontin and TGF-β2, were constitutively secreted in the naive hUCBSC-conditioned medium, while significant increases of IL-8, GRO, GRO-α, MCP-1 and MCP-2 were observed in glioma stem cell-challenged hUCBSC culture filtrates. Furthermore, hUCBSC showed a stronger migration capacity toward glioma stem cells in vitro and exhibited enhanced migration to glioma stem cells in an intracranial human malignant glioma xenograft model. Our results indicate that multiple cytokines are involved in recruitment of hUCBSC toward glioma stem cells, and that hUCBSC are a potential candidate for glioma therapy. PMID:22684297

  6. 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

  7. Enhancing tumor apparent diffusion coefficient histogram skewness stratifies the postoperative survival in recurrent glioblastoma multiforme patients undergoing salvage surgery.

    PubMed

    Zolal, Amir; Juratli, Tareq A; Linn, Jennifer; Podlesek, Dino; Sitoci Ficici, Kerim Hakan; Kitzler, Hagen H; Schackert, Gabriele; Sobottka, Stephan B; Rieger, Bernhard; Krex, Dietmar

    2016-05-01

    Objective To determine the value of apparent diffusion coefficient (ADC) histogram parameters for the prediction of individual survival in patients undergoing surgery for recurrent glioblastoma (GBM) in a retrospective cohort study. Methods Thirty-one patients who underwent surgery for first recurrence of a known GBM between 2008 and 2012 were included. The following parameters were collected: age, sex, enhancing tumor size, mean ADC, median ADC, ADC skewness, ADC kurtosis and fifth percentile of the ADC histogram, initial progression free survival (PFS), extent of second resection and further adjuvant treatment. The association of these parameters with survival and PFS after second surgery was analyzed using log-rank test and Cox regression. Results Using log-rank test, ADC histogram skewness of the enhancing tumor was significantly associated with both survival (p = 0.001) and PFS after second surgery (p = 0.005). Further parameters associated with prolonged survival after second surgery were: gross total resection at second surgery (p = 0.026), tumor size (0.040) and third surgery (p = 0.003). In the multivariate Cox analysis, ADC histogram skewness was shown to be an independent prognostic factor for survival after second surgery. Conclusion ADC histogram skewness of the enhancing lesion, enhancing lesion size, third surgery, as well as gross total resection have been shown to be associated with survival following the second surgery. ADC histogram skewness was an independent prognostic factor for survival in the multivariate analysis. PMID:26830088

  8. 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

  9. Ultrastructural evidence for differentiation in a human glioblastoma cell line treated with inhibitors of eicosanoid metabolism

    SciTech Connect

    Wilson, D.E.; Anderson, K.M. ); Seed, T.M. )

    1990-01-01

    Human glioblastoma cells incubated in the presence of inhibitors of eicosanoid biosynthesis show decreased cellular proliferation without cytotoxicity. The authors studied the ultrastructural morphology of a human glioblastoma cell line cultured with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, or 5,8,11,14-eicosatetraynoic acid, a cyclooxygenase and lipoxygenase inhibitor. When glioblastoma cells were treated for 3 days with antiproliferative concentrations of either agent, they shared many morphological characteristics, including evidence for increased astrocytic differentiation with only limited signs of toxicity. The inhibited glioma cells demonstrated an increase in the number and length of astrocytic processes containing greater numbers of glial filaments, and the NDGA-treated cells also demonstrated extensive lateral pseudopod formation along the processes. The glioblastoma cell shape also become more elongated, losing the usual nuclear lobularity and nuclear inclusions, especially in NDGA-treated cells. Many cytoplasmic organelles packed the cytosol of the inhibited glioma cells, including prominent Golgi apparatus, dilated smooth endoplasmic reticulum evolving into dilated vesicles, cytoplasmic vacuoles, and numerous concentric laminations. There was limited evidence for toxicity, however, as the mitochondria were more pleomorphic with some mitochondrial distension and disruption of the cristae along with an increase in cytoplasmic vacuolization. The authors conclude that the inhibitors of eicosanoid biosynthesis. NDGA and 5,8,11,14-eicosatetraynoic acid, not only suppress glioblastoma cell proliferation, but also include increased astrocytic differentiation.

  10. 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 ...

  11. Increasing incidence of glioblastoma multiforme and meningioma, and decreasing incidence of Schwannoma (2000–2008): Findings of a multicenter Australian study

    PubMed Central

    Dobes, Martin; Khurana, Vini G.; Shadbolt, Bruce; Jain, Sanjiv; Smith, Sarah F.; Smee, Robert; Dexter, Mark; Cook, Raymond

    2011-01-01

    Background: The incidence of primary brain tumors by subtype is currently unknown in Australia. We report an analysis of incidence by tumor subtype in a retrospective multicenter study in the state of New South Wales (NSW) and the Australian Capital Territory (ACT), with a combined population of >7 million with >97% retention rate for medical care. Methods: Data from histologically confirmed primary brain tumors diagnosed from January 2000 through December 2008 were weighted for patient outflow and data completeness, and age standardized and analyzed using joinpoint analysis. Results: A significant increasing incidence in glioblastoma multiforme (GBM) was observed in the study period (annual percentage change [APC], 2.5; 95% confidence interval [CI], 0.4–4.6, n = 2275), particularly after 2006. In GBM patients in the ≥65-year group, a significantly increasing incidence for men and women combined (APC, 3.0; 95% CI, 0.5–5.6) and men only (APC, 2.9; 95% CI, 0.1–5.8) was seen. Rising trends in incidence were also seen for meningioma in the total male population (APC, 5.3; 95% CI, 2.6–8.1, n = 515) and males aged 20–64 years (APC, 6.3; 95% CI, 3.8–8.8). Significantly decreasing incidence trends were observed for Schwannoma for the total study population (APC, –3.5; 95% CI, –7.2 to –0.2, n = 492), significant in women (APC, –5.3; 95% CI, –9.9 to –0.5) but not men. Conclusion: This collection is the most contemporary data on primary brain tumor incidence in Australia. Our registries may observe an increase in malignant tumors in the next few years that they are not detecting now due to late ascertainment. We recommend a direct, uniform, and centralized approach to monitoring primary brain tumor incidence by subtype, including the introduction of nonmalignant data collection. PMID:22276231

  12. 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.

  13. 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

  14. 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

  15. Fludarabine phosphate selectively inhibits growth and modifies the antigenic phenotype of human glioblastoma-multiforme cells expressing a multidrug resistance phenotype.

    PubMed

    Jiang, H; Su, Z; Datta, S; Guarini, L; Waxman, S; Fisher, P

    1992-07-01

    Fludarabine phosphate (FLU), the 2-fluro derivative of Ara-A, 9-beta-D-arabino-furanosyl-2-fluoroadenine, has been shown to display both in vitro and in vivo antiproliferative activity toward a variety of murine tumors and human lymphoid malignancies. In the present study, we have determined the effect of FLU, alone and in combination with recombinant human fibroblast interferon (IFN-B), on in vitro growth, gene expression and the antigenic phenotype of human glioblastoma multiforme (GBM) cells displaying a multidrug sensitive and a multidrug resistant (MDR) phenotype. FLU exhibited a marked differential toxicity toward GBM-MDR cells versus the multidrug sensitive GBM parental cell line. Growth of GBM-MDR cells for seven days in 2.5 to 7.5 muM FLU resulted in a dose-dependent reduction or elimination of growth which persisted after removal of this agent. In contrast, recovery from FLU-induced growth suppression was observed in parental multidrug sensitive GBM cells. Acquisition of increased FLU sensitivity in GBM-MDR cells did not appear to result from selection for a subset of sensitive cells or an artifact associated with the DNA-transfection process. This conclusion is supported by the similar pattern of FLU resistance in GBM-18 clones isolated after transfection with a cloned hygromycin resistance gene and selection for resistance to hygromycin. The antiproliferative and toxic effect of FLU was increased in GBM-MDR cells by simultaneous growth in IFN-B and the toxic effect of FLU could be blocked in a dose-dependent manner by the simultaneous addition of deoxycytidine. In contrast, the toxicity of FLU toward GBM-MDR cells was not altered when cells were grown in the presence or absence of colchicine or by the administration of verapamil, which can reverse the MDR phenotype in GBM-MDR cells. The selective toxicity of FLU toward GBM-MDR versus GBM-18 cells was not associated with a consistent differential change in all of the GBM-18 MDR clones in the steady

  16. 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

  17. Recurrent Glioblastoma: Where we stand.

    PubMed

    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

  18. Treatment with Tumor-Treating Fields Therapy and Pulse Dose Bevacizumab in Patients with Bevacizumab-Refractory Recurrent Glioblastoma: A Case Series.

    PubMed

    Ansstas, George; Tran, David D

    2016-01-01

    Patients with bevacizumab-refractory recurrent glioblastoma multiforme (GBM) have a poor prognosis. We propose that instead of continuing on bevacizumab, patients should switch to treatment with Optune™, a novel antimitotic Tumor-Treating Fields (TTFields) therapy approved in the United States for newly diagnosed and recurrent GBM. This would reserve bevacizumab for subsequent disease progression. In this case series, we describe 8 patients with recurrent GBM who had disease progression on bevacizumab, discontinued bevacizumab treatment, and were treated with TTFields therapy alone. After subsequent radiographic or clinical progression, 5 patients were rechallenged with bevacizumab in a 'pulse dose' fashion, an approach not previously described. Following treatment with TTFields therapy, median overall survival (OS) was 216 days (7.2 months). Median OS from last dose of initial bevacizumab was 237 days (7.9 months), twice that of historical controls for bevacizumab failures, and median OS from the first dose of bevacizumab rechallenge was 172 days (5.7 months). TTFields therapy was well tolerated, with a mean adherence rate of 74.2% (range, 48.2-92.9%). These results support the use of TTFields therapy with pulse dose bevacizumab as an option in patients with refractory GBM. PMID:26889149

  19. 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

  20. Dioscin, a natural steroid saponin, induces apoptosis and DNA damage through reactive oxygen species: a potential new drug for treatment of glioblastoma multiforme.

    PubMed

    Lv, Linlin; Zheng, Lingli; Dong, Deshi; Xu, Lina; Yin, Lianhong; Xu, Youwei; Qi, Yan; Han, Xu; Peng, Jinyong

    2013-09-01

    Dioscin, a natural product obtained from medicinal plants shows lipid-lowering, anti-cancer and hepatoprotective effects. However, the effect of it on glioblastoma is unclear. In this study, dioscin significantly inhibited proliferation of C6 glioma cells and caused reactive oxygen species (ROS) generation and Ca²⁺ release. ROS accumulation affected levels of malondialdehyde, nitric oxide, glutathione disulfide and glutathione, and caused cell apoptosis. In addition, ROS generation caused mitochondrial damage including structural changes, increased mitochondrial permeability transition and decreased mitochondria membrane potential, which led to the release of cytochrome C, nuclear translation of programmed cell death-5 and increased activities of caspase-3,9. Simultaneously, dioscin down-regulated protein expression of Bcl-2, Bcl-xl, up-regulated expression of Bak, Bax, Bid and cleaved poly (ADP-ribose) polymerase. Also, oxygen stress induced S-phase arrest of cancer cells by way of regulating expression of DNA Topo I, p53, CDK2 and Cyclin A and caused DNA damage. In a rat allograft model, dioscin significantly inhibited tumor size and extended the life cycle of the rats. In conclusion, dioscin shows noteworthy anti-cancer activity on glioblastoma cells by promoting ROS accumulation, inducing DNA damage and activating mitochondrial signal pathways. Ultimately, we believe dioscin has promise as a new therapy for the treatment of glioblastoma. PMID:23871826

  1. Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: a phase I/II multi-institutional trial.

    PubMed

    Prados, Michael D; McDermott, Michael; Chang, Susan M; Wilson, Charles B; Fick, James; Culver, Kenneth W; Van Gilder, John; Keles, G Evren; Spence, Alex; Berger, Mitchel

    2003-12-01

    To determine the safety and evaluate the efficacy of repeated administration of virus-producing cells (GLI 328) containing the herpes simplex virus thymidine-kinase gene followed by ganciclovir treatment in adults with recurrent glioblastoma multiforme, we conducted a phase I/II multi-institutional trial. Eligible patients underwent surgical resection of tumor, followed by injections of vector producing cells (VPC) into the brain adjacent to the cavity. An Ommaya reservoir placed after surgery was used to inject a further dose of VPC seven days after surgery, followed seven days later by ganciclovir. Further gene therapy was given at 28-day intervals for up to a total of five cycles. Toxicity and anti-tumor effect were assessed. Of 30 patients who enrolled in the study, 16 experienced serious adverse events possibly related to the experimental therapy. Laboratory testing, including polymerase chain reaction analysis to detect replication-competent retrovirus in peripheral blood lymphocytes and tissues, as well as co-cultivation bioassays, were negative. Before receiving ganciclovir, 37% of the patients showed evidence of transduced peripheral blood leukocytes, but only 12% showed a persistence of transduced cells at the end of the first cycle of ganciclovir. Median survival was 8.4 months. Twenty percent of the patients (n = 6) survived more than 12 months from the date of study entry. This treatment modality is feasible and appears to have some evidence of efficacy. Toxicity may be related in part to the method of gene delivery. PMID:14682377

  2. [Retrospective analysis of 24 recurrent glioblastoma after chemoradiation and treated with nitrosoureas or irinotecan and bevacizumab].

    PubMed

    Vauleon, Elodie; Mesbah, Habiba; Gedouin, Daniel; Lecouillard, Isabelle; Louvel, Guillaume; Hamlat, Abderrahmane; Riffaud, Laurent; Carsin, Béatrice; Quillien, Véronique; Audrain, Odile; Lesimple, Thierry

    2012-02-01

    Despite progress in the initial management of glioblastoma (GB), the vast majority of patients will experience recurrence within 2-3 years. The medical treatment of these recurrences is being modified by the use of antiangiogenic therapies. Twenty-four patients, who relapsed from GB after chemoradiation followed by adjuvant temozolomide in Rennes, were treated by conventional chemotherapy (nitrosourea) or by the combination of irinotecan and bevacizumab. In this retrospective analysis, overall survival from diagnosis of recurrence was significantly longer in patients treated with the combination of bevacizumab and irinotecan than with nitrosourea (5 months versus 11.5 months). The combination of irinotecan and bevacizumab appeared to provide clinical benefit to patients with recurrent GB. PMID:22257744

  3. 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

  4. Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma

    PubMed Central

    Omar, Ayman I.

    2014-01-01

    A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA approved in April 2011 for the treatment of patients 22 years or older with rGBM. The device delivers alternating electric fields and is programmed to ensure maximal tumor cell kill1. Glioblastoma is the most common type of glioma and has an estimated incidence of approximately 10,000 new cases per year in the United States alone2. This tumor is particularly resistant to treatment and is uniformly fatal especially in the recurrent setting3-5. Prior to the approval of the TTF System, the only FDA approved treatment for rGBM was bevacizumab6. Bevacizumab is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF) protein that drives tumor angiogenesis7. By blocking the VEGF pathway, bevacizumab can result in a significant radiographic response (pseudoresponse), improve progression free survival and reduce corticosteroid requirements in rGBM patients8,9. Bevacizumab however failed to prolong overall survival in a recent phase III trial26. A pivotal phase III trial (EF-11) demonstrated comparable overall survival between physicians’ choice chemotherapy and TTF Therapy but better quality of life were observed in the TTF arm10. There is currently an unmet need to develop novel approaches designed to prolong overall survival and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the two currently approved treatment modalities namely bevacizumab and TTF Therapy. These two treatments are currently approved as monotherapy11,12, but their combination has never been evaluated in a clinical trial. We have developed an approach for combining those two treatment modalities and treated 2 rGBM patients. Here we describe a detailed methodology outlining this novel treatment protocol and present representative data from one of the

  5. Drug Resistance in Glioblastoma: A Mini Review

    PubMed Central

    Haar, Catherine P.; Hebbar, Preetha; Wallace, Gerald C.; Das, Arabinda; Vandergrift, William A.; Smith, Joshua A.; Giglio, Pierre; Patel, Sunil J.; Ray, Swapan K.; Banik, Naren L.

    2015-01-01

    Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. Currently used surgical techniques, chemotherapeutic agents, and radiotherapy strategies have done very little in extending the life expectancies of patients diagnosed with GBM. The difficulty in treating this malignant disease lies both in its inherent complexity and numerous mechanisms of drug resistance. In this review, we summarize several of the primary mechanisms of drug resistance. We reviewed available published literature in the English language regarding drug resistance in glioblastoma. The reasons for drug resistance in glioblastoma include drug efflux, hypoxic areas of tumor cells, cancer stem cells, DNA damage repair, and miRNAs. Many potential therapies target these mechanisms, including a series of investigated alternative and plant-derived agents. Future research and clinical trials in glioblastoma patients should pursue combination of therapies to help combat drug resistance. The emerging new data on the potential of plant-derived therapeutics should also be closely considered and further investigated. PMID:22228201

  6. Combined targeting of PDK1 and EGFR triggers regression of glioblastoma by reversing the Warburg effect.

    PubMed

    Velpula, Kiran Kumar; Bhasin, Arnima; Asuthkar, Swapna; Tsung, Andrew J

    2013-12-15

    Glioblastoma multiforme is the most aggressive primary brain tumor in adults. Overexpression of the EGF receptor (EGFR) is recognized as a widespread oncogenic signature in glioblastoma multiforme, but the complexity of its contributions is not fully understood, nor the most effective ways to leverage anti-EGFR therapy in this setting. Hypoxia is known to drive the aggressive character of glioblastoma multiforme by promoting aerobic glycolysis rather than pyruvate oxidation carried out in mitochondria (OXPHOS), a phenomenon termed the Warburg effect, which is a general feature of oncogenesis. In this study, we report that hypoxia drives expression of the pyruvate dehydrogenase kinase (PDK1) and EGFR along with the hypoxia-inducing factor (HIF)-1α in human glioblastoma multiforme cells. PDK1 is a HIF-1-regulated gene and our findings indicated that hypoxia-induced PDK1 expression may promote EGFR activation, initiating a feed-forward loop that can sustain malignant progression. RNAi-mediated attenuation of PDK1 and EGFR lowered PDK1-EGFR activation and decreased HIF-1α expression, shifting the Warburg phenotype to OXPHOS and inhibiting glioblastoma multiforme growth and proliferation. In clinical specimens of glioblastoma multiforme, we found that immunohistochemical expression of PDK1, EGFR, and HIF-1α were elevated in glioblastoma multiforme specimens when compared with normal brain tissues. Collectively, our studies establish PDK1 as a key driver and candidate therapeutic target in glioblastoma multiforme. PMID:24148623

  7. A functional polymorphism in the pre‑miR‑146a gene influences the prognosis of glioblastoma multiforme by interfering with the balance between Notch1 and Notch2.

    PubMed

    Liu, Rongyao; Li, Weihua; Wu, Chunming

    2015-10-01

    The aim of the present study was to evaluate the association between a polymorphism (rs2910164) in the microRNA (miR)‑146a precursor and the prognosis of glioblastoma multiforme (GBM), as well as to examine the possible underlying mechanism in a Chinese population. A total of 380 patients with histologically confirmed GBM were recruited between 2008 and 2012, and were genotyped for the rs2910164 polymorphism using Sanger sequencing. The Kaplan‑Meier method was used to estimate overall survival (OS), and univariate and multivariate Cox proportional hazard regression analyses were used to evaluate the effect of miR‑146a polymorphisms on OS. It was identified that the rs2910164 CC genotype was significantly associated with a decreased OS among the patients with GBM (P=0.002). It was confirmed that Notch1 and Notch2 were targets of miR‑146a and it was demonstrated that the introduction of miR‑146a mimic suppressed the levels of Notch1 and Notch2 to different extents, resulting in a reduced Notch1/Notch2 ratio with an increase in miR‑146a mimic concentration in U251 cells. Additionally, resected tumor specimens were collected from 138 GBM patients and the expression levels of miR‑146a, Notch1 and Notch2 were examined using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Consistent with the in vitro study, lower levels of miR‑146a, higher levels of Notch1 and Notch2, and a higher Notch1/Notch2 ratio were identified in the CC genotype group compared with those of the GG/GC group. In the present study, the rs2910164 C allele was found to be associated with a reduced survival rate in patients with GBM, and the observed association between the CC genotype and poorer prognosis of GBM was at least partially mediated by the decreased expression of miR‑146a, which interfered with the balance of Notch1 and Notch2. PMID:26165719

  8. Assessment of early response to tumor-treating fields in newly diagnosed glioblastoma using physiologic and metabolic MRI: initial experience.

    PubMed

    Mohan, Suyash; Chawla, Sanjeev; Wang, Sumei; Verma, Gaurav; Skolnik, Aaron; Brem, Steven; Peters, Katherine B; Poptani, Harish

    2016-07-01

    Tumor-treating fields (TTFields) is a novel antimitotic treatment modality for patients with glioblastoma. To assess response to TTFields, a newly diagnosed patient with glioblastoma underwent diffusion, perfusion and 3D echo-planar spectroscopic imaging prior to initiation of TTFields plus temozolamide (baseline) and at 1- and 2-month follow-up periods. Increased mean diffusivity along with decreased fractional anisotropy and maximum relative cerebral blood volume were noted at 2 months relative to baseline suggesting inhibition of tumor growth and angiogenesis. Additionally, a reduction in choline/creatine was also noted during this period. These preliminary data indicate the potential of physiologic and metabolic MRI in assessing early treatment response to TTFields in combination with temozolamide. PMID:27076281

  9. Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma

    PubMed Central

    2013-01-01

    The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (KD = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood–brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application. PMID:24900612

  10. Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma.

    PubMed

    Haftchenary, Sina; Luchman, H Artee; Jouk, Andriana O; Veloso, Anthony J; Page, Brent D G; Cheng, Xin Ran; Dawson, Sean S; Grinshtein, Natalie; Shahani, Vijay M; Kerman, Kagan; Kaplan, David R; Griffin, Carly; Aman, Ahmed M; Al-Awar, Rima; Weiss, Samuel; Gunning, Patrick T

    2013-11-14

    The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (K D = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood-brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application. PMID:24900612

  11. Neural stem cells, the subventricular zone and radiotherapy: implications for treating glioblastoma.

    PubMed

    Smith, Andrew W; Mehta, Minesh P; Wernicke, A Gabriella

    2016-06-01

    Over the past decade, advances in neuroscience have suggested that neural stem cells resident in specific regions of the adult brain may be involved in development of both primary and recurrent glioblastoma. Neurogenesis and malignant transformation occurs in the subventricular zone adjacent to the lateral ventricles. This region holds promise as a potential target for therapeutic intervention with radiotherapy. However, irradiation of a larger brain volume is not without risk, and significant side effects have been observed. The current literature remains contradictory regarding the efficacy of deliberate intervention with radiation to the subventricular zone. This critical review discusses the connection between neural stem cells and development of glioblastoma, explores the behavior of tumors associated with the subventricular zone, summarizes the discordant literature with respect to the effects of irradiation, and reviews other targeted therapies to this intriguing region. PMID:27108274

  12. Associations between polymorphisms in DNA repair genes and glioblastoma.

    PubMed

    McKean-Cowdin, Roberta; Barnholtz-Sloan, Jill; Inskip, Peter D; Ruder, Avima M; Butler, Maryann; Rajaraman, Preetha; Razavi, Pedram; Patoka, Joe; Wiencke, John K; Bondy, Melissa L; Wrensch, Margaret

    2009-04-01

    A pooled analysis was conducted to examine the association between select variants in DNA repair genes and glioblastoma multiforme, the most common and deadliest form of adult brain tumors. Genetic data for approximately 1,000 glioblastoma multiforme cases and 2,000 controls were combined from four centers in the United States that have conducted case-control studies on adult glioblastoma multiforme, including the National Cancer Institute, the National Institute for Occupational Safety and Health, the University of Texas M. D. Anderson Cancer Center, and the University of California at San Francisco. Twelve DNA repair single-nucleotide polymorphisms were selected for investigation in the pilot collaborative project. The C allele of the PARP1 rs1136410 variant was associated with a 20% reduction in risk for glioblastoma multiforme (odds ratio(CT or CC), 0.80; 95% confidence interval, 0.67-0.95). A 44% increase in risk for glioblastoma multiforme was found for individuals homozygous for the G allele of the PRKDC rs7003908 variant (odds ratio(GG), 1.44; 95% confidence interval, 1.13-1.84); there was a statistically significant trend (P = 0.009) with increasing number of G alleles. A significant, protective effect was found when three single-nucleotide polymorphisms (ERCC2 rs13181, ERCC1 rs3212986, and GLTSCR1 rs1035938) located near each other on chromosome 19 were modeled as a haplotype. The most common haplotype (AGC) was associated with a 23% reduction in risk (P = 0.03) compared with all other haplotypes combined. Few studies have reported on the associations between variants in DNA repair genes and brain tumors, and few specifically have examined their impact on glioblastoma multiforme. Our results suggest that common variation in DNA repair genes may be associated with risk for glioblastoma multiforme. PMID:19318434

  13. 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

  14. DGKI Methylation Status Modulates the Prognostic Value of MGMT in Glioblastoma Patients Treated with Combined Radio-Chemotherapy with Temozolomide

    PubMed Central

    Idbaih, Ahmed; Vauleon, Elodie; Marie, Yannick; Menei, Philippe; Boniface, Rachel; Figarella-Branger, Dominique; Karayan-Tapon, Lucie; Quillien, Veronique; Sanson, Marc; de Tayrac, Marie; Delattre, Jean-Yves; Mosser, Jean

    2014-01-01

    Background Consistently reported prognostic factors for glioblastoma (GBM) are age, extent of surgery, performance status, IDH1 mutational status, and MGMT promoter methylation status. We aimed to integrate biological and clinical prognostic factors into a nomogram intended to predict the survival time of an individual GBM patient treated with a standard regimen. In a previous study we showed that the methylation status of the DGKI promoter identified patients with MGMT-methylated tumors that responded poorly to the standard regimen. We further evaluated the potential prognostic value of DGKI methylation status. Methods 399 patients with newly diagnosed GBM and treated with a standard regimen were retrospectively included in this study. Survival modelling was performed on two patient populations: intention-to-treat population of all included patients (population 1) and MGMT-methylated patients (population 2). Cox proportional hazard models were fitted to identify the main prognostic factors. A nomogram was developed for population 1. The prognostic value of DGKI promoter methylation status was evaluated on population 1 and population 2. Results The nomogram-based stratification of the cohort identified two risk groups (high/low) with significantly different median survival. We validated the prognostic value of DGKI methylation status for MGMT-methylated patients. We also demonstrated that the DGKI methylation status identified 22% of poorly responding patients in the low-risk group defined by the nomogram. Conclusions Our results improve the conventional MGMT stratification of GBM patients receiving standard treatment. These results could help the interpretation of published or ongoing clinical trial outcomes and refine patient recruitment in the future. PMID:25233099

  15. GPU-Accelerated Compartmental Modeling Analysis of DCE-MRI Data from Glioblastoma Patients Treated with Bevacizumab

    PubMed Central

    Hsu, Yu-Han H.; Huang, Ziyin; Ferl, Gregory Z.; Ng, Chee M.

    2015-01-01

    The compartment model analysis using medical imaging data is the well-established but extremely time consuming technique for quantifying the changes in microvascular physiology of targeted organs in clinical patients after antivascular therapies. In this paper, we present a first graphics processing unit-accelerated method for compartmental modeling of medical imaging data. Using this approach, we performed the analysis of dynamic contrast-enhanced magnetic resonance imaging data from bevacizumab-treated glioblastoma patients in less than one minute per slice without losing accuracy. This approach reduced the computation time by more than 120-fold comparing to a central processing unit-based method that performed the analogous analysis steps in serial and more than 17-fold comparing to the algorithm that optimized for central processing unit computation. The method developed in this study could be of significant utility in reducing the computational times required to assess tumor physiology from dynamic contrast-enhanced magnetic resonance imaging data in preclinical and clinical development of antivascular therapies and related fields. PMID:25786263

  16. SU-D-BRB-06: Treating Glioblastoma Multiforme (GBM) as a Chronic Disease: Implication of Temporal-Spatial Dose Fractionation Optimization Including Cancer Stem Cell Dynamics

    SciTech Connect

    Yu, V; Nguyen, D; Pajonk, F; Kaprealian, T; Kupelian, P; Steinberg, M; Low, D; Sheng, K

    2015-06-15

    Purpose: To explore the feasibility of improving GBM treatment outcome with temporal-spatial dose optimization of an ordinary differential equation (ODE) that models the differentiation and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC). Methods: The ODE was formulated into a non-convex optimization problem with the objective to minimize remaining total cancer cells 500 days from the onset of radiotherapy when the total cancer cell number was 3.5×10{sup 7}, while maintaining normal tissue biological effective dose (BED) of 100Gy resulted from standard prescription of 2Gyx30. Assuming spatially separated CSC and DCC, optimization was also performed to explore the potential benefit from dose-painting the two compartments. Dose escalation to a sub-cell-population in the GTV was also examined assuming that a 2 cm margin around the GTV allows sufficient dose drop-off to 100Gy BED. The recurrence time was determined as the time at which the total cancer cell number regrows to 10{sup 9} cells. Results: The recurrence time with variable fractional doses administered once per week, bi-week and month for one year were found to be 615, 593 and 570 days, superior to the standard-prescription recurrence time of 418 days. The optimal dose-fraction size progression for both uniform and dose-painting to the tumor is low and relatively constant in the beginning and gradually increases to more aggressive fractions at end of the treatment course. Dose escalation to BED of 200Gy to the whole tumor alongside with protracted weekly treatment was found to further delay recurrence to 733 days. Dose-painting of 200 and 500Gy BED to CSC on a year-long weekly schedule further extended recurrence to 736 and 1076 days, respectively. Conclusion: GBM treatment outcome can possibly be improved with a chronic treatment approach. Further dose escalation to the entire tumor or CSC targeted killing is needed to achieve total tumor control. This work is supported by the NSF Graduate Research Fellowship (DGE-1144087)

  17. 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

  18. 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.

  19. Identification of ZCCHC8 as fusion partner of ROS1 in a case of congenital glioblastoma multiforme with a t(6;12)(q21;q24.3).

    PubMed

    Coccé, Mariela C; Mardin, Balca R; Bens, Susanne; Stütz, Adrian M; Lubieniecki, Fabiana; Vater, Inga; Korbel, Jan O; Siebert, Reiner; Alonso, Cristina N; Gallego, Marta S

    2016-09-01

    Congenital gliobastoma multiforme (GBM) is rare and little is known about the molecular defects underlying the initiation and progression of this tumor type. We present a case of congenital GBM analyzed by conventional cytogenetics, fluorescence in situ hybridization, array comparative genomic hybridization and next generation sequencing. On cytogenetic analysis we detected a reciprocal translocation t(6;12)(q21;q24.3). By sequencing, the translocation was shown to form a fusion between the 5' region of ZCCHC8 and the 3' region of ROS1. RT-PCR analyses confirmed the existence of an in-frame fusion transcript with ZCCHC8 exons 1-3 joined to ROS1 exons 36-43. In addition to the ZCCHC8-ROS1 fusion, we detected a deletion in the short arm of chromosome 9, including homozygous loss of the CDKN2A/2B locus in 9p21.3 and heterozygous deletion of the HAUS6 gene in 9p22.1. The latter encodes a protein involved in faithful chromosome segregation by regulating microtubule nucleation and its deletion might be associated with the marked subclonal changes of ploidy observed in the tumor. This report adds the ZCCHC8-ROS1 fusion as oncogenic driver in GBM and supports the role of ROS1 activation in the pathogenesis of a subset of GBM. © 2016 Wiley Periodicals, Inc. PMID:27121553

  20. MGMT Gene Promoter Methylation as a Potent Prognostic Factor in Glioblastoma Treated With Temozolomide-Based Chemoradiotherapy: A Single-Institution Study

    SciTech Connect

    Kim, Young Suk; Kim, Se Hoon; Cho, Jaeho; Kim, Jun Won; Chang, Jong Hee; Kim, Dong Suk; Lee, Kyu Sung; Suh, Chang-Ok

    2012-11-01

    Purpose: Recently, cells deficient in O{sup 6}-methylguanine-DNA methyltransferase (MGMT) were found to show increased sensitivity to temozolomide (TMZ). We evaluated whether hypermethylation of MGMT was associated with survival in patients with glioblastoma multiforme (GBM). Methods and Materials: We retrospectively analyzed 93 patients with histologically confirmed GBM who received involved-field radiotherapy with TMZ from 2001 to 2008. The median age was 58 years (range, 24-78 years). Surgical resection was total in 39 patients (42%), subtotal in 30 patients (32%), and partial in 17 patients (18%); only a biopsy was performed in 7 patients (8%). Postoperative radiotherapy began within 3 weeks of surgery in 87% of the patients. Radiotherapy doses ranged from 50 to 74 Gy (median, 70 Gy). MGMT gene methylation was determined in 78 patients; MGMT was unmethylated in 43 patients (55%) and methylated in 35 patients (45%). The median follow-up period was 22 months (range, 3-88 months) for all patients. Results: The median overall survival (OS) was 22 months, and progression-free survival (PFS) was 11 months. MGMT gene methylation was an independently significant prognostic factor for both OS (p = 0.002) and PFS (p = 0.008) in multivariate analysis. The median OS was 29 months for the methylated group and 20 months for the unmethylated group. In 35 patients with methylated MGMT genes, the 2-year and 5-year OS rates were 54% and 31%, respectively. Six patients with combined prognostic factors of methylated MGMT genes, age {<=}50 years, and total/subtotal resections are all alive 38 to 77 months after operation, whereas the median OS in 8 patients with unmethylated MGMT genes, age >50 years, and less than subtotal resection was 13.2 months. Conclusion: We confirmed that MGMT gene methylation is a potent prognostic factor in patients with GBM. Our results suggest that early postoperative radiotherapy and a high total/subtotal resection rate might further improve the

  1. GPU-accelerated nonparametric kinetic analysis of DCE-MRI data from glioblastoma patients treated with bevacizumab.

    PubMed

    Hsu, Yu-Han H; Ferl, Gregory Z; Ng, Chee M

    2013-05-01

    Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is often used to examine vascular function in malignant tumors and noninvasively monitor drug efficacy of antivascular therapies in clinical studies. However, complex numerical methods used to derive tumor physiological properties from DCE-MRI images can be time-consuming and computationally challenging. Recent advancement of computing technology in graphics processing unit (GPU) makes it possible to build an energy-efficient and high-power parallel computing platform for solving complex numerical problems. This study develops the first reported fast GPU-based method for nonparametric kinetic analysis of DCE-MRI data using clinical scans of glioblastoma patients treated with bevacizumab (Avastin®). In the method, contrast agent concentration-time profiles in arterial blood and tumor tissue are smoothed using a robust kernel-based regression algorithm in order to remove artifacts due to patient motion and then deconvolved to produce the impulse response function (IRF). The area under the curve (AUC) and mean residence time (MRT) of the IRF are calculated using statistical moment analysis, and two tumor physiological properties that relate to vascular permeability, volume transfer constant between blood plasma and extravascular extracellular space (K(trans)) and fractional interstitial volume (ve) are estimated using the approximations AUC/MRT and AUC. The most significant feature in this method is the use of GPU-computing to analyze data from more than 60,000 voxels in each DCE-MRI image in parallel fashion. All analysis steps have been automated in a single program script that requires only blood and tumor data as the sole input. The GPU-accelerated method produces K(trans) and ve estimates that are comparable to results from previous studies but reduces computational time by more than 80-fold compared to a previously reported central processing unit-based nonparametric method. Furthermore, it is at

  2. 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

  3. 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

  4. TORC1/2 Inhibitor MLN0128 and Bevacizumab in Treating Patients With Recurrent Glioblastoma or Advanced Solid Tumors

    ClinicalTrials.gov

    2016-06-17

    Adult Glioblastoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Solid Neoplasm; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  5. 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.

  6. 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. PMID:25117686

  7. 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

  8. 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

  9. An automated method for nonparametric kinetic analysis of clinical DCE-MRI data: application to glioblastoma treated with bevacizumab.

    PubMed

    Ferl, Gregory Z; Xu, Lu; Friesenhahn, Michel; Bernstein, Lisa J; Barboriak, Daniel P; Port, Ruediger E

    2010-05-01

    Here, we describe an automated nonparametric method for evaluating gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) kinetics, based on dynamic contrast-enhanced-MRI scans of glioblastoma patients taken before and after treatment with bevacizumab; no specific model or equation structure is assumed or used. Tumor and venous blood concentration-time profiles are smoothed, using a robust algorithm that removes artifacts due to patient motion, and then deconvolved, yielding an impulse response function. In addition to smoothing, robustness of the deconvolution operation is assured by excluding data that occur prior to the plasma peak; an exhaustive analysis was performed to demonstrate that exclusion of the prepeak plasma data does not significantly affect results. All analysis steps are executed by a single R script that requires blood and tumor curves as the sole input. Statistical moment analysis of the Impulse response function yields the area under the curve (AUC) and mean residence time (MRT). Comparison of deconvolution results to fitted Tofts model parameters suggests that AUCMRT and AUC of the Impulse response function closely approximate fractional clearance from plasma to tissue (K(trans)) and fractional interstitial volume (v(e)). Intervisit variability is shown to be comparable when using the deconvolution method (11% [AUCMRT] and 13%[AUC]) compared to the Tofts model (14%[K(trans)] and 24%[v(e)]). AUC and AUCMRT both exhibit a statistically significant decrease (P < 0.005) 1 day after administration of bevacizumab. PMID:20432307

  10. Novel Delivery Strategies for Glioblastoma

    PubMed Central

    Zhou, Jiangbing; Atsina, Kofi-Buaku; Himes, Benjamin T.; Strohbehn, Garth W.; Saltzman, W. Mark

    2012-01-01

    Brain tumors—particularly glioblastoma multiforme (GBM)—pose an important public health problem in the US. Despite surgical and medical advances, the prognosis for patients with malignant gliomas remains grim: current therapy for is insufficient with nearly universal recurrence. A major reason for this failure is the difficulty of delivering therapeutic agents to the brain: better delivery approaches are needed to improve treatment. In this article, we summarize recent progress in drug delivery to the brain, with an emphasis on convection-enhanced delivery of nanocarriers. We examine the potential of new delivery methods to permit novel drug- and gene-based therapies that target brain cancer stem cells (BCSCs) and discuss the use of nanomaterials for imaging of tumors and drug delivery. PMID:22290262

  11. 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

  12. A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy.

    PubMed

    Huang, Jiayi; Campian, Jian L; Gujar, Amit D; Tran, David D; Lockhart, A Craig; DeWees, Todd A; Tsien, Christina I; Kim, Albert H

    2016-06-01

    Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500-1000 mg once daily, in combination with 150-200 mg/m(2) temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2-3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells. PMID:26966095

  13. Microvesicles as a Biomarker for Tumor Progression versus Treatment Effect in Radiation/Temozolomide-Treated Glioblastoma Patients

    PubMed Central

    Koch, Cameron J.; Lustig, Robert A.; Yang, Xiang-Yang; Jenkins, Walter T.; Wolf, Ronald L.; Martinez-Lage, Maria; Desai, Arati; Williams, Dewight; Evans, Sydney M.

    2014-01-01

    The standard of care for glioblastoma (GB) is surgery followed by concurrent radiation therapy (RT) and temozolomide (TMZ) and then adjuvant TMZ. This regime is associated with increased survival but also increased occurrence of equivocal imaging findings, e.g., tumor progression (TP) versus treatment effect (TE), which is also referred to as pseudoprogression (PsP). Equivocal findings make decisions regarding further treatment difficult and often delayed. Because none of the current imaging assays have proven sensitive and specific for differentiation of TP versus TE/PsP, we investigated whether blood-derived microvesicles (MVs) would be a relevant assay. METHODS: 2.8 ml of citrated blood was collected from patients with GB at the time of their RT simulation, at the end of chemoradiation therapy (CRT), and multiple times following treatment. MVs were collected following multiple centrifugations (300g, 2500g, and 15,000g). The pellet from the final spin was analyzed using flow cytometry. A diameter of approximately 300 nm or greater and Pacific Blue–labeled Annexin V positivity were used to identify the MVs reported herein. RESULTS: We analyzed 19 blood samples from 11 patients with GB. MV counts in the patients with stable disease or TE/PsP were significantly lower than patients who developed TP (P = .014). CONCLUSION: These preliminary data suggest that blood analysis for MVs from GB patients receiving CRT may be useful to distinguish TE/PsP from TP. MVs may add clarity to standard imaging for decision making in patients with equivocal imaging findings. PMID:25500085

  14. GE-03GENOMIC CHARACTERIZATION OF SURVIVAL OUTLIERS IN GLIOBLASTOMA MULTIFORME

    PubMed Central

    Berens, Michael; Armstrong, Brock; Peng, Sen; Ross, Julianna; Salhia, Bodour; Byron, Sara; Virk, Selene; Dhruv, Harshil; Tran, Nhan; Sloan, Andrew; Ostrom, Quinn; Barnholtz-Sloan, Jill

    2014-01-01

    Despite the general poor prognosis for patients with GBM, a proportion survives well beyond the median survival of 12-14 months following diagnosis. To elucidate molecular features associated with disproportionately protracted survival, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide) wherein "GBM outliers" were identified: patients who responded (long-term survivor, LTS) versus those who failed rapidly (short-term survivor, STS). The datasets enabled interrogation for signatures indicative of tumor vulnerability. Whole genomic, epigenetic and transcriptomic analyses of 18 patients, including 8 LTS with an average 30 months overall survival (OS) and 10 STS with an average of 7 months OS were performed to capture single nucleotide variants (SNVs), indels, translocations, intra-chromosomal rearrangements, copy number variants, along with DNA methylation and mRNA expression. LTS and STS cases showed equal proportion of 7p11.2 (EGFR) amplification and 9p21.3 (CDKN2A) deletion. However, LTS GBM showed frequent chromosomal gains in 4q12 (PDGFRA and KIT) and 12q14.1 (CDK4) and deletion in 19q13.33 (BAX, BCAT2 and CD33), whereas, STS GBM showed frequent deletion in 9p11.2 (FOXD4L2 and AQP7P3) and 22q11.21 (HIC2). In addition, LTS GBM showed a 2-fold increased chromosomal instability as compared to STS GBM. By gene expression analysis, supervised clustering using the CIN70 chromosomal instability signature showed a decreased expression of these markers in LTS GBM, corroborating the genomic analysis. Finally, integrating DNA methylation data with gene expression revealed in STS GBM hypermethylation and downregulation of EPHA3, MEG, and PPP1R9A, linked to defective cell migration and adhesion. In contrast, LTS GBM showed hypomethylation and an increased gene expression of KIT. We posit that genomic instability predicts vulnerability of GBM to standard therapy and coupled with genetic and epigenetic signatures may identify patients where front-line entry into alternative, targeted regimens would be a preferred, more-efficacious management.

  15. 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

  16. 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

  17. Glioblastoma occurring after radiation therapy for meningioma: case report and review of literature

    SciTech Connect

    Zuccarello, M.; Sawaya, R.; deCourten-Meyers, G.

    1986-07-01

    A 32-year-old man developed an intracranial glioblastoma multiforme 10 years after irradiation for an incompletely resected convexity meningioma. The association of these two tumors is exceedingly rare. Therefore, we propose that this is a case of radiation-induced glioma and review the evidence supporting this view.

  18. AEG-1–AKT2: A novel complex controlling the aggressiveness of glioblastoma

    PubMed Central

    Emdad, Luni; Hu, Bin; Das, Swadesh K; Sarkar, Devanand; Fisher, Paul B

    2015-01-01

    Expression of AEG-1 (also known as MTDH or LYRIC) is elevated in many cancers including glioblastoma multiforme (GBM), in which it functions as an oncogene. AEG-1 activates AKT signaling and physically interacts with AKT2 in GBM. Disruption of this interaction reduces glioma cell survival and invasion, uncovering a novel potential target for development of an effective therapy against GBM.

  19. 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.

  20. Genotoxic Damage to Glioblastoma Cells Treated with 6 MV X-Radiation in The Presence or Absence of Methoxy Estradiol, IUDR or Topotecan

    PubMed Central

    Eyvazzadeh, Nazila; Neshasteh-Riz, Ali; Mahdavi, Seyed Rabee; Mohsenifar, Afshin

    2015-01-01

    Objective To explore the cumulative genotoxic damage to glioblastoma (GBM) cells, grown as multicellular spheroids, following exposure to 6 MV X-rays (2 Gy, 22 Gy) with or without, 2- methoxy estradiol (2ME2), iododeoxyuridine (IUDR) or topotecan (TPT), using the Picogreen assay. Materials and Methods The U87MG cells cultured as spheroids were treated with 6 MV X-ray using linear accelerator. Specimens were divided into five groups and irradiated using X-ray giving the dose of 2 Gy after sequentially incubated with one of the following three drug combinations: TPT, 2-ME2/TPT, IUDR/TPT or 2ME2/IUDR/ TPT. One specimen was used as the irradiated only sample (R). The last group was also irradiated with total dose of 22 Gy (each time 2 Gy) of 6 MV X-ray in 11 fractions and treated for three times. DNA damage was evaluated using the Picogreen method in the experimental study. Results R/TPT treated group had more DNA damage [double strand break (DSB)/single strand break (SSB)] compared with the untreated group (P<0.05). Moreover the R/ TPT group treated with 2ME2 followed by IUDR had maximum DNA damage in spheroid GBM indicating an augmented genotoxicity in the cells. The DNA damage was induced after seven fractionated irradiation and two sequential treatments with 2ME2/IUDR/TPT. To ensure accuracy of the slope of dose response curve the fractionated radiation was calculated as 7.36 Gy with respect to α/β ratio based on biologically effective dose (BED) formulae. Conclusion Cells treated with 2ME2/IUDR showed more sensitivity to radiation and accumulative DNA damage. DNA damage was significantly increased when GBM cells treated with TPT ceased at S phase due to the inhibition of topoisomerase enzyme and phosphorylation of Chk1 enzyme. These results suggest that R/TPT- treated cells increase sensitivity to 2ME2 and IUDR especially when they are used together. Therefore, due to an increase in the level of DNA damage (SSB vs. DSB) and impairment of DNA repair machinery

  1. 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

    2016-01-01

    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. PMID:26666269

  2. 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

  3. 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

  4. 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. PMID:25761648

  5. 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.

  6. MR Studies of Glioblastoma Models Treated with Dual PI3K/mTOR Inhibitor and Temozolomide:Metabolic Changes Are Associated with Enhanced Survival.

    PubMed

    Radoul, Marina; Chaumeil, Myriam M; Eriksson, Pia; Wang, Alan S; Phillips, Joanna J; Ronen, Sabrina M

    2016-05-01

    The current standard of care for glioblastoma (GBM) is surgical resection, radiotherapy, and treatment with temozolomide (TMZ). However, resistance to current therapies and recurrence are common. To improve survival, agents that target the PI3K signaling pathway, which is activated in approximately 88% of GBM, are currently in clinical trials. A challenge with such therapies is that tumor shrinkage is not always observed. New imaging methods are therefore needed to monitor response to therapy and predict survival. The goal of this study was to determine whether hyperpolarized (13)C magnetic resonance spectroscopic imaging (MRSI) and (1)H magnetic resonance spectroscopy (MRS) can be used to monitor response to the second-generation dual PI3K/mTOR inhibitor voxtalisib (XL765, SAR245409), alone or in combination with TMZ. We investigated GS-2 and U87-MG GBM orthotopic tumors in mice, and used MRI, hyperpolarized (13)C MRSI, and (1)H MRS to monitor the effects of treatment. In our study, (1)H MRS could not predict tumor response to therapy. However, in both our models, we observed a significantly lower hyperpolarized lactate-to-pyruvate ratio in animals treated with voxtalisib, TMZ, or combination therapy, when compared with controls. This metabolic alteration was observed prior to MRI-detectable changes in tumor size, was consistent with drug action, and was associated with enhanced animal survival. Our findings confirm the potential translational value of the hyperpolarized lactate-to-pyruvate ratio as a biomarker for noninvasively assessing the effects of emerging therapies for patients with GBM. Mol Cancer Ther; 15(5); 1113-22. ©2016 AACR. PMID:26883274

  7. Health-Related Quality of Life in Elderly Patients With Newly Diagnosed Glioblastoma Treated With Short-Course Radiation Therapy Plus Concomitant and Adjuvant Temozolomide

    SciTech Connect

    Minniti, Giuseppe; Scaringi, Claudia; Baldoni, Alessandra; Lanzetta, Gaetano; De Sanctis, Vitaliana; Esposito, Vincenzo; Enrici, Riccardo Maurizi

    2013-06-01

    Purpose: To describe the quality of life (QOL) in elderly patients with glioblastoma (GBM) treated with an abbreviated course of radiation therapy (RT; 40 Gy in 15 fractions) plus concomitant and adjuvant temozolomide (TMZ). Methods and Materials: Health-related QOL (HRQOL) was assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30, version 3) and EORTC Quality of Life Questionnaire Brain Cancer Module (QLQ-BN20). Changes from baseline in the score of 9 preselected domains (global QLQ, social functioning, cognitive functioning, emotional functioning, physical functioning, motor dysfunction, communication deficit, fatigue, insomnia) were determined 4 weeks after RT and thereafter every 8 weeks during the treatment until disease progression. The proportion of patients with improved HRQOL scores, defined as a change of 10 points or more, and duration of changes were recorded. Results: Sixty-five patients completed the questionnaires at baseline. The treatment was consistently associated with improvement or stability in most of the preselected HRQOL domains. Global health improved over time; mean score differed by 9.6 points between baseline and 6-month follow-up (P=.03). For social functioning and cognitive functioning, mean scores improved over time, with a maximum difference of 10.4 points and 9.5 points between baseline and 6-month follow-up (P=.01 and P=.02), respectively. By contrast, fatigue worsened over time, with a difference in mean score of 5.6 points between baseline and 4-month follow-up (P=.02). Conclusions: A short course of RT in combination with TMZ in elderly patients with GBM was associated with survival benefit without a negative effect on HRQOL until the time of disease progression.

  8. Quality of surgical care and readmission in elderly glioblastoma patients

    PubMed Central

    Nuño, Miriam; Ly, Diana; Mukherjee, Debraj; Ortega, Alicia; Black, Keith L.; Patil, Chirag G.

    2014-01-01

    Background Thirty-day readmissions post medical or surgical discharge have been analyzed extensively. Studies have shown that complex interactions of multiple factors are responsible for these hospitalizations. Methods A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) Medicare database of newly diagnosed elderly glioblastoma multiforme (GBM) patients who underwent surgical resection between 1991 and 2007. Hospitals were classified into high- or low-readmission rate cohorts using a risk-adjusted methodology. Bivariate comparisons of outcomes were conducted. Multivariate analysis evaluated differences in quality of care according to hospital readmission rates. Results A total of 1,273 patients underwent surgery in 338 hospitals; 523 patients were treated in 228 high-readmission hospitals and 750 in 110 low-readmission hospitals. Patient characteristics for high-versus low-readmission hospitals were compared. In a confounder-adjusted model, patients treated in high- versus low-readmission hospitals had similar outcomes. The hazard of mortality for patients treated at high- compared to low-readmission hospitals was 1.06 (95% CI, 0.095%–1.19%). While overall complications were comparable between high- and low-readmission hospitals (16.3% vs 14.3%; P = .33), more postoperative pulmonary embolism/deep vein thrombosis complications were documented in patients treated at high-readmission hospitals (7.5% vs 4.1%; P = .01). Adverse events and levels of resection achieved during surgery were comparable at high- and low-readmission hospitals. Conclusions For patients undergoing GBM resection, quality of care provided by hospitals with the highest adjusted readmission rates was similar to the care delivered by hospitals with the lowest rates. These findings provide evidence against the preconceived notion that 30-day readmissions can be used as a metric for quality of surgical and postsurgical care. PMID:26034614

  9. 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. PMID:26763536

  10. 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.

  11. 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

  12. 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.

  13. Phase II study of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine chemotherapy with radiotherapy for treating malignant glioma in children.

    PubMed Central

    Levin, V. A.; Lamborn, K.; Wara, W.; Davis, R.; Edwards, M.; Rabbitt, J.; Malec, M.; Prados, M. D.

    2000-01-01

    We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic

  14. 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. PMID:27048878

  15. mRNA expression levels of hypoxia-induced and stem cell-associated genes in human glioblastoma.

    PubMed

    Bache, Matthias; Rot, Swetlana; Keßler, Jacqueline; Güttler, Antje; Wichmann, Henri; Greither, Thomas; Wach, Sven; Taubert, Helge; Söling, Ariane; Bilkenroth, Udo; Kappler, Matthias; Vordermark, Dirk

    2015-06-01

    The roles of hypoxia-induced and stem cell-associated genes in the development of malignancy and tumour progression are well known. However, there are a limited number of studies analysing the impact of mRNA expression levels of hypoxia-induced and stem cell-associated genes in the tissues of brain tumours and glioblastoma patients. In this study, tumour tissues from patients with glioblastoma multiforme and tumour adjacent tissues were analysed. We investigated mRNA expression levels of hypoxia-inducible factor-1α (HIF-1α), hypoxia-inducible factor-2α (HIF-2α), carbonic anhydrase 9 (CA9), vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT-1) and osteopontin (OPN), and stem cell-associated genes survivin, epidermal growth factor receptor (EGFR), human telomerase reverse transcriptase (hTERT), Nanog and octamer binding transcription factor 4 (OCT4) using quantitative real-time polymerase chain reaction (qRT-PCR). Our data revealed higher mRNA expression levels of hypoxia-induced and stem cell-associated genes in tumour tissue than levels in the tumour adjacent tissues in patients with glioblastoma multiforme. A strong positive correlation between the mRNA expression levels of HIF-2α, CA9, VEGF, GLUT-1 and OPN suggests a specific hypoxia-associated profile of mRNA expression in glioblastoma multiforme. Additionally, the results indicate the role of stem-cell-related genes in tumour hypoxia. Kaplan-Maier analysis revealed that high mRNA expression levels of hypoxia-induced markers showed a trend towards shorter overall survival in glioblastoma patients (P=0.061). Our data suggest that mRNA expression levels of hypoxia-induced genes are important tumour markers in patients with glioblastoma multiforme. PMID:25963717

  16. Spatiotemporal Evolution of the Primary Glioblastoma Genome.

    PubMed

    Kim, Jinkuk; Lee, In-Hee; Cho, Hee Jin; Park, Chul-Kee; Jung, Yang-Soon; Kim, Yanghee; Nam, So Hee; Kim, Byung Sup; Johnson, Mark D; Kong, Doo-Sik; Seol, Ho Jun; Lee, Jung-Il; Joo, Kyeung Min; Yoon, Yeup; Park, Woong-Yang; Lee, Jeongwu; Park, Peter J; Nam, Do-Hyun

    2015-09-14

    Tumor recurrence following treatment is the major cause of mortality for glioblastoma multiforme (GBM) patients. Thus, insights on the evolutionary process at recurrence are critical for improved patient care. Here, we describe our genomic analyses of the initial and recurrent tumor specimens from each of 38 GBM patients. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor. In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk for TMZ-induced hypermutation for these tumors under the standard regimen. PMID:26373279

  17. Multidrug-induced erythema multiforme.

    PubMed

    Isik, S R; Karakaya, G; Erkin, G; Kalyoncu, A F

    2007-01-01

    Adverse skin reactions to drugs are frequent, with rates of reaction to many commonly used drugs exceeding 1%. We describe a 29-year-old woman admitted with a history of itching, rash, vesicles on her hands and soles, and edema on her tongue and oropharynx after trimethoprim-sulfamethoxazole, ciprofloxacin, methenamine anhydromethylene citrate, piroxicam, azithromycin, and ceftriaxone intake. Erythema multiforme (EM) was diagnosed by skin biopsy after oral challenge with piroxicam. EM lesions reappeared after oral challenge with levofloxacin. Although EM is quite common with trimethoprim-sulfamethoxazole and there are some reports of EM appearing after intake of ciprofloxacin, it has rarely been attributed to piroxicam and no reports have identified levofloxacin as a cause. PMID:17583109

  18. 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

  19. 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

  20. 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

    2016-01-01

    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

  1. 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

  2. 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. PMID:23099651

  3. Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells.

    PubMed Central

    Gladson, C L; Cheresh, D A

    1991-01-01

    Glioblastoma multiforme, the most malignant astroglial-derived tumor, grows as an adherent mass and locally invades normal brain. An examination of adult cerebral glioblastoma biopsy material for the expression of adhesive proteins that might potentiate adhesion and invasion demonstrated tumor cell-associated vitronectin (5/5). In contrast, vitronectin was not detected associated with glial cells in low grade astroglial tumors (0/4), reactive astrogliosis (0/4), or in normal adult cortex and cerebral white matter (0/5). Also, a wide variety of other adhesive ligands were absent from the glioblastoma tumor parenchyma. The alpha v beta 3 integrin was the only vitronectin receptor identified in glioblastoma tumors in situ, and was also not expressed on low grade astroglial-derived tumors, reactive astrogliosis, or on glia or neurons in normal adult cortex and cerebral white matter. In a cell attachment assay, cultured glioblastoma cells attached to the parenchyma of glioblastoma tumor cryostat sections at the sites of vitronectin expression, but failed to attach to normal brain. This adhesion was inhibited by antibodies directed against vitronectin, the alpha v beta 3 integrin, and with an Arg-Gly-Asp-containing peptide. These data provide evidence for a cell adhesion mechanism in glioblastoma tumors that might potentiate glioblastoma cell invasion of normal brain. Images PMID:1721625

  4. 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. PMID:25351918

  5. Protein tyrosine phosphatase mu regulates glioblastoma cell growth and survival in vivo

    PubMed Central

    Kaur, Harpreet; Burden-Gulley, Susan M.; Phillips-Mason, Polly J.; Basilion, James P.; Sloan, Andrew E.; Brady-Kalnay, Susann M.

    2012-01-01

    Glioblastoma multiforme (GBM) is the most lethal primary brain tumor. Extensive proliferation and dispersal of GBM tumor cells within the brain limits patient survival to approximately 1 year. Hence, there is a great need for the development of better means to treat GBM. Receptor protein tyrosine phosphatase (PTP)µ is proteolytically cleaved in GBM to yield fragments that promote dispersal of GBM cells. While normal brain tissue retains expression of full-length PTPµ, low-grade human astrocytoma samples have varying amounts of full-length PTPµ and cleaved PTPµ. In the highest-grade astrocytomas (i.e., GBM), PTPµ is completely proteolyzed into fragments. We demonstrate that short hairpin RNA mediated knockdown of full-length PTPµ and PTPµ fragments reduces glioma cell growth and survival in vitro. The reduction in growth and survival following PTPµ knockdown is enhanced when cells are grown in the absence of serum, suggesting that PTPµ may regulate autocrine signaling. Furthermore, we show for the first time that reduction of PTPµ protein expression decreases the growth and survival of glioma cells in vivo using mouse xenograft flank and i.c. tumor models. Inhibitors of PTPµ could be used to reduce the growth and survival of GBM cells in the brain, representing a promising therapeutic target for GBM. PMID:22505657

  6. 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. PMID:25501993

  7. Inhibition of Autophagy by Chloroquine Enhances the Antitumor Efficacy of Sorafenib in Glioblastoma.

    PubMed

    Liu, Xiangyu; Sun, Kangjian; Wang, Handong; Dai, Yuyuan

    2016-10-01

    Glioblastoma multiforme (GBM) is the most aggressive and common brain tumor in adults. Sorafenib, a multi-kinase inhibitor, has been shown to inhibit cell proliferation and induce apoptosis through inhibition of STAT3 signaling in glioblastoma cells and in intracranial gliomas. However, sorafenib also induces cell autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the therapeutic effect of sorafenib on glioblastoma is uncertain. Here, we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM. PMID:26971793

  8. Yes and PI3K bind CD95 to signal invasion of glioblastoma.

    PubMed

    Kleber, Susanne; Sancho-Martinez, Ignacio; Wiestler, Benedict; Beisel, Alexandra; Gieffers, Christian; Hill, Oliver; Thiemann, Meinolf; Mueller, Wolf; Sykora, Jaromir; Kuhn, Andreas; Schreglmann, Nina; Letellier, Elisabeth; Zuliani, Cecilia; Klussmann, Stefan; Teodorczyk, Marcin; Gröne, Hermann-Josef; Ganten, Tom M; Sültmann, Holger; Tüttenberg, Jochen; von Deimling, Andreas; Regnier-Vigouroux, Anne; Herold-Mende, Christel; Martin-Villalba, Ana

    2008-03-01

    Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo. PMID:18328427

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

    PubMed Central

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

    2014-01-01

    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. PMID:25034532

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

    PubMed

    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. PMID:25034532

  11. 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.

  12. Patterns of care and outcome for patients with glioblastoma diagnosed during 2008–2010 in Spain

    PubMed Central

    Graus, Francesc; Bruna, Jordi; Pardo, Javier; Escudero, Domingo; Vilas, Dolores; Barceló, Inés; Brell, Marta; Pascual, Carmen; Crespo, José A.; Erro, Elena; García-Romero, Juan C.; Estela, Jordi; Martino, Juan; García-Castaño, Almudena; Mata, Elena; Lema, Manuela; Gelabert, Miguel; Fuentes, Rafel; Pérez, Pedro; Manzano, Arancha; Aguas, Jesús; Belenguer, Antonio; Simón, Ana; Henríquez, Iván; Murcia, Mauricio; Vivanco, Rosa; Rojas-Marcos, Iñigo; Muñoz-Carmona, David; Navas, Inmaculada; de Andrés, Pablo; Mas, Gemma; Gil, Miguel; Verger, Eugènia

    2013-01-01

    Background To assess management patterns and outcome in patients with glioblastoma multiforme (GBM) treated during 2008–2010 in Spain. Methods Retrospective analysis of clinical, therapeutic, and survival data collected through filled questionnaires from patients with histologically confirmed GBM diagnosed in 19 Spanish hospitals. Results We identified 834 patients (23% aged >70 years). Surgical resection was achieved in 66% of patients, although the extent of surgery was confirmed by postoperative MRI in only 41%. There were major postoperative complications in 14% of patients, and age was the only independent predictor (Odds ratio [OR], 1.03; 95% confidence interval [CI],1.01–1.05; P = .006). After surgery, 57% received radiotherapy (RT) with concomitant and adjuvant temozolomide, 21% received other regimens, and 22% were not further treated. In patients treated with surgical resection, RT, and chemotherapy (n = 396), initiation of RT ≤42 days was associated with longer progression-free survival (hazard ratio [HR], 0.8; 95% CI, 0.64–0.99; P = .042) but not with overall survival (HR, 0.79; 95% CI, 0.62–1.00; P = .055). Only 32% of patients older than 70 years received RT with concomitant and adjuvant temozolomide. The median survival in this group was 10.8 months (95% CI, 6.8–14.9 months), compared with 17.0 months (95% CI, 15.5–18.4 months; P = .034) among younger patients with GBM treated with the same regimen. Conclusions In a community setting, 57% of all patients with GBM and only 32% of older patients received RT with concomitant and adjuvant temozolomide. In patients with surgical resection who were eligible for chemoradiation, initiation of RT ≤42 days was associated with better progression-free survival. PMID:23460319

  13. miR-155 is up-regulated in primary and secondary glioblastoma and promotes tumour growth by inhibiting GABA receptors.

    PubMed

    D'Urso, Pietro I; D'Urso, Oscar F; Storelli, Carlo; Mallardo, Massimo; Gianfreda, Cosimo Damiano; Montinaro, Antonio; Cimmino, Antonia; Pietro, Caliandro; Marsigliante, Santo

    2012-07-01

    An altered expression of microRNAs (miRNAs) contributes both to the development of cancer and to the progression of the disease. Malignant tumours and tumour cell lines have widespread deregulated expressions of miRNAs compared to normal tissues. In this study, we investigated the expression profiles of 340 mammalian miRNAs in 93 cases of multiform glioblastoma (primary and secondary glioblastoma tumours), by means of DNA microarrays. We show that the expression profiles of 10 miRNAs can distinguish primary from secondary glioblastoma types. Moreover, we found elevated miR-155 levels in primary and secondary glioblastoma tissues as well as in glioblastoma primary cultures. We hypothesised that γ-aminobutyric acid A receptor 1 (GABRA1) is a miR-155 target, and studied the correlation between miR-155 up-regulation and the GABRA1 protein in cultured glioblastoma cells by miRNA silencing. We show that a decrease in miR-155 expression to normal levels restores the expression of GABRA1, making glioblastoma cells sensitive to signals that inhibit cell proliferation mediated by GABRA1. In conclusion, the expression patterns of different miRNAs characterise primary and secondary glioblastomas. The aberrant overexpression of miR-155 contributes to the malignant phenotype of glioblastoma cells removing growth inhibition. PMID:22470130

  14. BI-08MICROVESICLES CAN DISTINGUISH BETWEEN TUMOR PROGRESSION AND TREATMENT EFFECT/PSEUDOPROGRESSION IN GLIOBLASTOMA PATIENTS TREATED WITH RADIATION AND TEMOZOLOMIDE

    PubMed Central

    Evans, Sydney M.; Koch, Cameron J.; Lustig, Robert

    2014-01-01

    The standard of care for glioblastoma (GB) is radiation therapy (RT) and temozolomide (TMZ) following optimal surgery. This regimen has been accompanied by an increase in the occurrence of equivocal imaging findings, e.g. tumor progression vs. treatment effect (TE), which includes pseudoprogression (PsP). Thus decisions regarding further treatment are difficult and often delayed. None of the current imaging methods for identifying TE/PsP have proven sensitive and specific. Therefore, we developed a method to isolate microvesicles (MV) from blood sample in patients with GB. MV are defined herein as lipid membrane-bound sacs with a diameter >300 nm. METHODS: 3 ml citrated blood was collected from GB patients at their RT simulation and at multiple times during and following treatment. MV were isolated during multiple centrifugations (300g, 2500g, 15,000g). The pellet from the final spin was analyzed using flow cytometry. Antibodies to phosphotidylserine were used to identify the MV. RESULTS: We analyzed 16 blood samples from 10 GB patients that met analysis criteria: the MV sample was obtained at or following the completion of CRT and, a definitive diagnosis (TP, TE or PSP) was reached within 60 days of the date of the sample. MV counts in the patients with stable disease or TE/PsP were significantly lower than patients who developed recurrence or died of their disease (p = 0.0385). Based on MRI and/or pathological assessment, 2 patients have died of their disease, 1 patient is alive with recurrence, 3 patients have stable disease and 4 patients are being followed for PsP vs. tumor progression (TP). SUMMARY/CONCLUSION: These preliminary data suggest that the analysis of blood (liquid biopsy) for MV may be useful to distinguish TE/PsP from TP in GB patients. MVs may be valuable in addition to standard imaging for decision making in patients with equivocal imaging findings.

  15. Sildenafil: A rare cause of erythema multiforme

    PubMed Central

    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

  16. 1H NMR Metabolomics Analysis of Glioblastoma Subtypes

    PubMed Central

    Cuperlovic-Culf, Miroslava; Ferguson, Dean; Culf, Adrian; Morin, Pier; Touaibia, Mohamed

    2012-01-01

    Glioblastoma multiforme (GBM) is the most common form of malignant glioma, characterized by unpredictable clinical behaviors that suggest distinct molecular subtypes. With the tumor metabolic phenotype being one of the hallmarks of cancer, we have set upon to investigate whether GBMs show differences in their metabolic profiles. 1H NMR analysis was performed on metabolite extracts from a selection of nine glioblastoma cell lines. Analysis was performed directly on spectral data and on relative concentrations of metabolites obtained from spectra using a multivariate regression method developed in this work. Both qualitative and quantitative sample clustering have shown that cell lines can be divided into four groups for which the most significantly different metabolites have been determined. Analysis shows that some of the major cancer metabolic markers (such as choline, lactate, and glutamine) have significantly dissimilar concentrations in different GBM groups. The obtained lists of metabolic markers for subgroups were correlated with gene expression data for the same cell lines. Metabolic analysis generally agrees with gene expression measurements, and in several cases, we have shown in detail how the metabolic results can be correlated with the analysis of gene expression. Combined gene expression and metabolomics analysis have shown differential expression of transporters of metabolic markers in these cells as well as some of the major metabolic pathways leading to accumulation of metabolites. Obtained lists of marker metabolites can be leveraged for subtype determination in glioblastomas. PMID:22528487

  17. Valganciclovir and bevacizumab for recurrent glioblastoma: A single-institution experience

    PubMed Central

    PENG, CHENGWEI; WANG, JIALING; TANKSLEY, JARRED P.; MOBLEY, BRET C.; AYERS, GREGORY D.; MOOTS, PAUL L.; CLARK, STEPHEN W.

    2016-01-01

    Prolonged treatment with adjuvant valganciclovir has been shown in one retrospective study to exert a significant effect on overall survival (OS) in newly diagnosed patients with glioblastoma multiforme (GBM). However, studies evaluating the effectiveness of valganciclovir in the treatment of recurrent GBM have not been performed. We evaluated the effect of valganciclovir in the recurrent setting in combination with bevacizumab therapy. A retrospective analysis was performed on patients treated for recurrent GBM with off-label valganciclovir and bevacizumab at Vanderbilt University. We identified 13 patients who received valganciclovir plus bevacizumab at some point during their treatment, 8 of whom were started on valganciclovir and bevacizumab concurrently upon first recurrence, whereas 5 had valganciclovir added to their bevacizumab regimen prior to a second recurrence. of these patients, 12 were pathologically confirmed to have GBM, and 1 patient was diagnosed with gliosarcoma. We also identified an institutional cohort of 50 patients who had not been exposed to valganciclovir, but were treated with bevacizumab for first recurrence. The progression-free survival (PFS) at 6 months (PF6) and median OS (mOS) in the valganciclovir plus bevacizumab group was 62% and 13.1 months, respectively, for all 13 patients, and 50% and 11.3 months, respectively, for the 8 concurrently treated patients. In the institutional bevacizumab cohort, the PF6 and mOS were 34% and 8.7 months, respectively. In this retrospective analysis, valganciclovir in combination with bevacizumab exhibited a trend toward improved survival in patients with recurrent GBM. However, given the small sample size and the retrospective nature of this study, a larger prospective study is required to confirm these results. PMID:26893852

  18. Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II/III gliomas treated with temozolomide.

    PubMed

    Redjal, Navid; Reinshagen, Clemens; Le, Andrew; Walcott, Brian P; McDonnell, Erin; Dietrich, Jorg; Nahed, Brian V

    2016-05-01

    Valproic acid (VPA) is an anti-epileptic drug with properties of a histone deacetylase inhibitor (HDACi). HDACi play a key role in epigenetic regulation of gene expression and have been increasingly used as anticancer agents. Recent studies suggest that VPA is associated with improved survival in high-grade gliomas. However, effects on lower grade gliomas have not been examined. This study investigates whether use of VPA correlates with tumor grade, histological progression, progression-free and overall survival (OS) in grade II, III, and IV glioma patients. Data from 359 glioma patients (WHO II-IV) treated with temozolomide plus an antiepileptic drug (VPA or another antiepileptic drug) between January 1997 and June 2013 at the Massachusetts General Hospital was analyzed retrospectively. After confounder adjustment, VPA was associated with a 28 % decrease in hazard of death (p = 0.031) and a 28 % decrease in the hazard of progression or death (p = 0.015) in glioblastoma. Additionally, VPA dose correlated with reduced hazard of death by 7 % (p = 0.002) and reduced hazard of progression or death by 5 % (p < 0.001) with each 100 g increase in total dose. Conversely, in grade II and III gliomas VPA was associated with a 118 % increased risk of tumor progression or death (p = 0.014), and every additional 100 g of VPA raised the hazard of progression or death by 4 %, although not statistically significant (p = 0.064). Moreover, grade II and III glioma patients taking VPA had 2.17 times the risk of histological progression (p = 0.020), although this effect was no longer significant after confounder adjustment. In conclusion, VPA was associated with improved survival in glioblastoma in a dose-dependent manner. However, in grade II and III gliomas, VPA was linked to histological progression and decrease in progression-free survival. Prospective evaluation of VPA treatment for glioma patients is warranted to confirm these findings. PMID:26830093

  19. 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. PMID:27101800

  20. Extracellular vesicle-transported Semaphorin3A promotes vascular permeability in glioblastoma.

    PubMed

    Treps, L; Edmond, S; Harford-Wright, E; Galan-Moya, E M; Schmitt, A; Azzi, S; Citerne, A; Bidère, N; Ricard, D; Gavard, J

    2016-05-19

    Glioblastoma are malignant highly vascularized brain tumours, which feature large oedema resulting from tumour-promoted vascular leakage. The pro-permeability factor Semaphorin3A (Sema3A) produced within glioblastoma has been linked to the loss of endothelial barrier integrity. Here, we report that extracellular vesicles (EVs) released by patient-derived glioblastoma cells disrupt the endothelial barrier. EVs expressed Sema3A at their surface, which accounted for in vitro elevation of brain endothelial permeability and in vivo vascular permeability, in both skin and brain vasculature. Blocking Sema3A or its receptor Neuropilin1 (NRP1) hampered EV-mediated permeability. In vivo models using ectopically and orthotopically xenografted mice revealed that Sema3A-containing EVs were efficiently detected in the blood stream. In keeping with this idea, sera from glioblastoma multiforme (GBM) patients also contain high levels of Sema3A carried in the EV fraction that enhanced vascular permeability, in a Sema3A/NRP1-dependent manner. Our results suggest that EV-delivered Sema3A orchestrates loss of barrier integrity in glioblastoma and may be of interest for prognostic purposes. PMID:26364614

  1. The role of IDH1 mutated tumour cells in secondary glioblastomas: an evolutionary game theoretical view

    NASA Astrophysics Data System (ADS)

    Basanta, David; Scott, Jacob G.; Rockne, Russ; Swanson, Kristin R.; Anderson, Alexander R. A.

    2011-02-01

    Recent advances in clinical medicine have elucidated two significantly different subtypes of glioblastoma which carry very different prognoses, both defined by mutations in isocitrate dehydrogenase-1 (IDH-1). The mechanistic consequences of this mutation have not yet been fully clarified, with conflicting opinions existing in the literature; however, IDH-1 mutation may be used as a surrogate marker to distinguish between primary and secondary glioblastoma multiforme (sGBM) from malignant progression of a lower grade glioma. We develop a mathematical model of IDH-1 mutated secondary glioblastoma using evolutionary game theory to investigate the interactions between four different phenotypic populations within the tumor: autonomous growth, invasive, glycolytic, and the hybrid invasive/glycolytic cells. Our model recapitulates glioblastoma behavior well and is able to reproduce two recent experimental findings, as well as make novel predictions concerning the rate of invasive growth as a function of vascularity, and fluctuations in the proportions of phenotypic populations that a glioblastoma will experience under different microenvironmental constraints.

  2. Expression of dynein, cytoplasmic 2, heavy chain 1 (DHC2) associated with glioblastoma cell resistance to temozolomide

    PubMed Central

    Wang, Hai; Feng, Wenfeng; Lu, Yuntao; Li, Hezhen; Xiang, Wei; Chen, Ziyang; He, Minyi; Zhao, Liang; Sun, Xuegang; Lei, Bingxi; Qi, Songtao; Liu, Yawei

    2016-01-01

    Temozolomide (TMZ) is the main chemotherapeutic drug utilized for the treatment of glioblastoma multiforme (GMB), however, drug resistance often leads to tumor recurrence and poor outcomes. GMB cell lines were treated with TMZ for up to two weeks and then subjected to proteomics analysis to identify the underlying molecular pathology that is associated with TMZ resistance. Proteomics data showed that TMZ altered expression of proteins that related to cytoskeleton structure and function, such as DHC2 and KIF2B. qRT-PCR and immunofluorescence were used to verify expression of DHC2 and KIF2B in these cells. Immunohistochemistry was used to verify expression of these two proteins in xenografts of a nude mouse model, and ex vivo GBM tissue samples. Their expression was knocked down using siRNA to confirm their role in the regulation of GBM cell sensitivity to TMZ. Knockdown of DHC2 expression enhanced sensitivity of U87 cells to TMZ treatment. Ex vivo data showed that DHC2 expression in GBM tissue samples was associated with tumor recurrence after TMZ chemotherapy. These results indicated cytoskeleton related protein DHC2 reduced sensitivity of GBM cells to TMZ treatment. Further studies should assess DHC2 as a novel target in GBM for TMZ combination treatment. PMID:27375225

  3. β-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway.

    PubMed

    Liu, Siwei; Zhou, Lei; Zhao, Yongshun; Yuan, Yuhui

    2015-08-01

    Glioblastoma multiforme (GBM), a tumor associated with poor prognosis, is known to be resistant to radiotherapy and alkylating agents such as temozolomide (TMZ). β-elemene, a monomer found in Chinese traditional herbs extracted from Curcuma wenyujin, is currently being used as an antitumor drug for different types of tumors including GBM. In the present study, we investigated the roles of β-elemene in the radiosensitivity and chemosensitivity of GBM cells. Human GBM cell lines U87-MG, T98G, U251, LN229 and rat C6 cells were treated with β-elemene combined with radiation or TMZ. We used MTT and colony forming assays to evaluate the proliferation and survival of the cells, and the comet assay to observe DNA damage. Expression of proteins was analyzed by immunoblotting. In the present study, we found that β-elemene inhibited the proliferation and survival of different GBM cell lines when combined with radiotherapy or TMZ via inhibition of DNA damage repair. Treatment of GBM cells with β-elemene decreased the phosphorylation of ataxia telangiectasia mutated (ATM), AKT and ERK following radiotherapy or chemotherapy. These results revealed that β-elemene could significantly increase the radiosensitivity and chemosensitivity of GBM. β-elemene may be used as a potential drug in combination with the radiotherapy and chemotherapy of GBM. PMID:26062577

  4. Expression of dynein, cytoplasmic 2, heavy chain 1 (DHC2) associated with glioblastoma cell resistance to temozolomide.

    PubMed

    Wang, Hai; Feng, Wenfeng; Lu, Yuntao; Li, Hezhen; Xiang, Wei; Chen, Ziyang; He, Minyi; Zhao, Liang; Sun, Xuegang; Lei, Bingxi; Qi, Songtao; Liu, Yawei

    2016-01-01

    Temozolomide (TMZ) is the main chemotherapeutic drug utilized for the treatment of glioblastoma multiforme (GMB), however, drug resistance often leads to tumor recurrence and poor outcomes. GMB cell lines were treated with TMZ for up to two weeks and then subjected to proteomics analysis to identify the underlying molecular pathology that is associated with TMZ resistance. Proteomics data showed that TMZ altered expression of proteins that related to cytoskeleton structure and function, such as DHC2 and KIF2B. qRT-PCR and immunofluorescence were used to verify expression of DHC2 and KIF2B in these cells. Immunohistochemistry was used to verify expression of these two proteins in xenografts of a nude mouse model, and ex vivo GBM tissue samples. Their expression was knocked down using siRNA to confirm their role in the regulation of GBM cell sensitivity to TMZ. Knockdown of DHC2 expression enhanced sensitivity of U87 cells to TMZ treatment. Ex vivo data showed that DHC2 expression in GBM tissue samples was associated with tumor recurrence after TMZ chemotherapy. These results indicated cytoskeleton related protein DHC2 reduced sensitivity of GBM cells to TMZ treatment. Further studies should assess DHC2 as a novel target in GBM for TMZ combination treatment. PMID:27375225

  5. Outcome of patients with glioblastoma in Saudi Arabia: Single center experience

    PubMed Central

    ALTWAIRGI, ABDULLAH K.; ALGAREEB, WALEED; YAHYA, GAAEM; MAKLAD, AHMED M.; ALY, MOAMEN MOM; AL SHAKWEER, WAFA; BALBAID, ALI; ALSAEED, EYAD; ALHUSSAIN, HUSSAIN; ORZ, YASSIR; LARY, AHMED; ELYAMANY, ASHRAF

    2016-01-01

    Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is associated with one of the worst 5 year survival rates among all human cancer types. To date, no published data are available for the outcome of this disease in Saudi Arabia. The present study performed a single-center, retrospective cohort study to evaluate the outcome of patients with GBM in Saudi Arabia. The Comprehensive Cancer Center at King Fahad Medical city (Riyadh, Saudi Arabia) was used in the present study. All adult patients (≥18 years) diagnosed with histologically proven GBM between January 2008 and December 2013 were included in the present study. A total of 90 patients were treated during the specified period. Of this, 73 (81%) patients underwent resection and 17 (19%) had biopsy only. The majority of patients (n=88; 98%) received radiotherapy (XRT): 67 (76%) with standard and 21 (24%) with hypo-fractionated dosage. Of the total patients, 65 (72%) received combined modality therapy [standard XRT concurrently with Temozolmide (TMZ)]. The 6 month progression-free survival rate was 43% for all patients and 55% for the combined modality subgroup. The median overall survival (OS) for all patients was 13.7 months. However, the median OS for patients treated with combined modality was 19.7 months. In this single-center retrospective study, the outcomes of patients with GBM were similar to those in previously reported studies. An improved outcome was associated with an improved performance status, absence of residual disease and use of adjuvant TMZ. PMID:27123275

  6. [Erythema exudativum multiforme--case report].

    PubMed

    Kantorowicz, Małgorzata; Olszewska-Czyz, Iwona; Chomyszyn-Gajewska, Maria

    2015-01-01

    Erythema exudativum multiforme (EM) is an acute mucocutaneous disease. Etiology of this disease is not clear. 50% - 60% cases of EM is induced by HSV infection (herpes simplex virus 1, herpes simplex virus 2). EM lesions may appear as red macules, erosions, ulcerations and hemorrhagic crusts. The study describes the case of 22 - year - old male who had characteristic lesions for EM after HSV infection. PMID:26817344

  7. 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

  8. 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

  9. 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

  10. Master Regulators, Regulatory Networks, and Pathways of Glioblastoma Subtypes

    PubMed Central

    Bozdag, Serdar; Li, Aiguo; Baysan, Mehmet; Fine, Howard A

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor. GBM samples are classified into subtypes based on their transcriptomic and epigenetic profiles. Despite numerous studies to better characterize GBM biology, a comprehensive study to identify GBM subtype- specific master regulators, gene regulatory networks, and pathways is missing. Here, we used FastMEDUSA to compute master regulators and gene regulatory networks for each GBM subtype. We also ran Gene Set Enrichment Analysis and Ingenuity Pathway Analysis on GBM expression dataset from The Cancer Genome Atlas Project to compute GBM- and GBM subtype-specific pathways. Our analysis was able to recover some of the known master regulators and pathways in GBM as well as some putative novel regulators and pathways, which will aide in our understanding of the unique biology of GBM subtypes. PMID:25368508

  11. 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

  12. 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

  13. Genomic Analysis of the BMP Family in Glioblastomas

    PubMed Central

    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 The 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. PMID:25987829

  14. DIETARY ISOTHIOCYANATE IBERIN INHIBITS GROWTH AND INDUCES APOPTOSIS IN HUMAN GLIOBLASTOMA CELLS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, we evaluated the antiproliferative and proapoptotic effects of the isothiocyanate iberin, a bioactive agent in Brassicaceae species, in human glioblastoma cells. The human glioblastoma cell cultures were treated with different concentrations of iberin and tested for growth inhibition...

  15. 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

  16. 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.

  17. Cucurbitacin I Induces Protective Autophagy in Glioblastoma in Vitro and in Vivo*

    PubMed Central

    Yuan, Guang; Yan, Shao-Feng; Xue, Hao; Zhang, Ping; Sun, Jin-Tang; Li, Gang

    2014-01-01

    There is an urgent need for new therapeutic avenues to improve the outcome of patients with glioblastoma multiforme (GBM). Current studies have suggested that cucurbitacin I, a natural selective inhibitor of JAK2/STAT3, has a potent anticancer effect on a variety of cancer cell types. This study showed that autophagy and apoptosis were induced by cucurbitacin I. Exposure of GBM cells to cucurbitacin I resulted in pronounced apoptotic cell death through activating bcl-2 family proteins. Cells treatment with cucurbitacin I up-regulated Beclin 1 and triggered autophagosome formation and accumulation as well as conversion of LC3I to LC3II. Activation of the AMP-activated protein kinase/mammalian target of rapamycin/p70S6K pathway, but not the PI3K/AKT pathway, occurred in autophagy induced by cucurbitacin I, which was accompanied by decreased hypoxia-inducible factor 1α. Stable overexpression of hypoxia-inducible factor 1α induced by FG-4497 prevented cucurbitacin I-induced autophagy and down-regulation of bcl-2. Knockdown of beclin 1 or treatment with the autophagy inhibitor 3-methyladenine also inhibited autophagy induced by cucurbitacin I. A coimmunoprecipitation assay showed that the interaction of Bcl-2 and Beclin 1/hVps34 decreased markedly in cells treated with cucurbitacin I. Furthermore, knockdown of beclin 1 or treatment with the lysosome inhibitor chloroquine sensitized cancer cells to cucurbitacin I-induced apoptosis. Finally, a xenograft model provided additional evidence for the occurrence of cucurbitacin I-induced apoptosis and autophagy in vitro. Our findings provide new insights into the molecular mechanisms underlying cucurbitacin I-mediated GBM cell death and may provide an efficacious therapy for patients harboring GBM. PMID:24599950

  18. Survival analysis in patients with newly diagnosed glioblastoma using pre- and postradiotherapy MR spectroscopic imaging†

    PubMed Central

    Li, Yan; Lupo, Janine M.; Parvataneni, Rupa; Lamborn, Kathleen R.; Cha, Soonmee; Chang, Susan M.; Nelson, Sarah J.

    2013-01-01

    Background The objective of this study was to examine the predictive value of parameters of 3D 1H magnetic resonance spectroscopic imaging (MRSI) prior to treatment with radiation/chemotherapy (baseline) and at a postradiation 2-month follow-up (F2mo) in relationship to 6-month progression-free survival (PFS6) and overall survival (OS). Methods Sixty-four patients with newly diagnosed glioblastoma multiforme (GBM) being treated with radiation and concurrent chemotherapy were involved in this study. Evaluated were metabolite indices and metabolite ratios. Logistic linear regression and Cox proportional hazards models were utilized to evaluate PFS6 and OS, respectively. These analyses were adjusted by age and MR scanner field strength (1.5 T or 3 T). Stepwise regression was performed to determine a subset of the most relevant variables. Results Associated with shorter PFS6 were a decrease in the ratio of N-acetyl aspartate to choline-containing compounds (NAA/Cho) in the region with a Cho-to-NAA index (CNI) >3 at baseline and an increase of the CNI within elevated CNI regions (>2) at F2mo. Patients with higher normalized lipid and lactate at either time point had significantly worse OS. Patients who had larger volumes with abnormal CNI at F2mo had worse PFS6 and OS. Conclusions Our study found more 3D MRSI parameters that predicted PFS6 and OS for patients with GBM than did anatomic, diffusion, or perfusion imaging, which were previously evaluated in the same population of patients. PMID:23393206

  19. CXCL12 Mediates Trophic Interactions between Endothelial and Tumor Cells in Glioblastoma

    PubMed Central

    Choe, Eun Joo; Woerner, B. Mark; Jackson, Erin; Sun, Tao; Leonard, Jeffrey; Piwnica-Worms, David; Rubin, Joshua B.

    2012-01-01

    Emerging evidence suggests endothelial cells (EC) play a critical role in promoting Glioblastoma multiforme (GBM) cell proliferation and resistance to therapy. The molecular basis for GBM-EC interactions is incompletely understood. We hypothesized that the chemokine CXCL12 and its receptor CXCR4 could mediate direct interactions between GBM cells and tumor-associated endothelial cells and that disruption of this interaction might be the molecular basis for the anti-tumor effects of CXCR4 antagonists. We investigated this possibility in vivo and in an in vitro co-culture model that incorporated extracellular matrix, primary human brain microvascular ECs (HBMECs) and either an established GBM cell line or primary GBM specimens. Depletion of CXCR4 in U87 GBM cells blocked their growth as intracranial xenografts indicating that tumor cell CXCR4 is required for tumor growth in vivo. In vitro, co-culture of either U87 cells or primary GBM cells with HBMECs resulted in their co-localization and enhanced GBM cell growth. Genetic manipulation of CXCL12 expression and pharmacological inhibition of its receptors CXCR4 and CXCR7 revealed that the localizing and trophic effects of endothelial cells on GBM cells were dependent upon CXCL12 and CXCR4. These findings indicate that the CXCL12/CXCR4 pathway directly mediates endothelial cell trophic function in GBMs and that inhibition of CXCL12-CXCR4 signaling may uniquely target this activity. Therapeutic disruption of endothelial cell trophic functions could complement the structural disruption of anti-angiogenic regimens and, in combination, might also improve the efficacy of radiation and chemotherapy in treating GBMs. PMID:22427929

  20. Do Long-Term Survivor Primary Glioblastoma Patients Harbor IDH1 Mutations?

    PubMed

    Sarmiento, J Manuel; Mukherjee, Debraj; Black, Keith L; Fan, Xuemo; Hu, Jethro L; Nuno, Miriam Aracely; Patil, Chirag G

    2016-05-01

    Background Approximately 3 to 16% of glioblastoma multiforme (GBM) patients are considered long-term survivors (LTS: 3+ years). Objective Given the improved survival conferred by IDH1 mutations and the fact that these mutations are detected in 12% of newly diagnosed GBM cases, could long-term survivorship be explained by IDH1 mutation status? Our aim was to describe GBM LTS with IDH1 mutations and explore its association with overall survival (OS). Methods Records of 453 newly diagnosed adult GBM patients treated at a single institution from 2004 to 2010 were reviewed retrospectively for patients who survived at least 36 months postsurgery. Descriptive statistics for clinical characteristics, treatments received, and tumor biomarkers were reported. Estimates for progression-free survival (PFS) and OS were provided. Results Forty (8.8%) LTS GBM patients were identified, with a median age of 50 years and a median preoperative Karnofsky Performance Score (KPS) of 80. Most patients underwent near-total/gross-total resection (72.5%), postoperative radiation (97.5%), and adjuvant temozolomide (95%). PFS rates at 12, 36, 48, and 72 months were 67.5%, 40%, 32.7%, and 26.2%, respectively. Median OS has not yet been reached; however, the survival rate at 48 months was 62.1%. Among 35 patients with available tumor samples, only 8 (22.9%) had IDH1 mutations. No significant difference in median PFS was found between IDH1 mutation and wild-type patients (46.6 versus 26.3 months; p =0.45). Conclusions Less than a quarter of our patients' long-term survivorship was associated with favorable IDH1 status. Therefore, IDH1 status does not explain most of the long-term survivorship in the temozolomide era. PMID:26935296

  1. Enhanced neutrophil activity is associated with shorter time to tumor progression in glioblastoma patients

    PubMed Central

    Rahbar, Afsar; Cederarv, Madeleine; Wolmer-Solberg, Nina; Tammik, Charlotte; Stragliotto, Giuseppe; Peredo, Inti; Fornara, Olesja; Xu, Xinling; Dzabic, Mensur; Taher, Chato; Skarman, Petra; Söderberg-Nauclér, Cecilia

    2016-01-01

    ABSTRACT Glioblastoma multiforme (GBM) is a highly malignant tumor with a poor outcome that is often positive for human cytomegalovirus (HCMV). GBM patients often have excessive numbers of neutrophils and macrophages near and within the tumor. Here, we characterized the cytokine patterns in the blood of GBM patients with and without Valganciclovir treatment. Furthermore, we determined whether neutrophil activation is related to HCMV status and patient outcome. Blood samples for analyses of cytokines and growth factors were collected from 42 GBM patients at the time of diagnosis (n = 42) and at weeks 12 and 24 after surgery. Blood neutrophils of 28 GBM patients were examined for CD11b expression. The levels of pro- and anti-inflammatory cytokines and chemokines—including interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, transforming growth factor (TGF)-β1, interferon-γ, interferon-α, tumor necrosis factor α, and monocyte chemoattractant protein (MCP)-1were analyzed with a bead-based flow cytometry assay. During the first six months after surgery, neutrophil activity was increased in 12 patients and was unchanged or decreased in 16. Patients with increased neutrophil activity had enhanced IL-12p70, high grade HCMV and a shorter time to tumor progression (TTP) than patients without or decreased neutrophil activity (median TTP; 5.4 vs. 12 months, 95% confidence interval; 1.6–10 vs. 0.1–0.6, hazard ratio = 3 vs. 0.4, p = 0.004). The levels of IL-12p70 were significantly decreased in Valganciclovir treated patients (n = 22, T 12W vs. T 24W, p = 0.03). In conclusion, our findings suggest that neutrophil activation is an early sign of tumor progression in GBM patients. PMID:27057448

  2. In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma

    PubMed Central

    Sagiyama, Koji; Mashimo, Tomoyuki; Togao, Osamu; Vemireddy, Vamsidhara; Hatanpaa, Kimmo J.; Maher, Elizabeth A.; Mickey, Bruce E.; Pan, Edward; Sherry, A. Dean; Bachoo, Robert M.; Takahashi, Masaya

    2014-01-01

    Glioblastoma multiforme (GBM), which account for more than 50% of all gliomas, is among the deadliest of all human cancers. Given the dismal prognosis of GBM, it would be advantageous to identify early biomarkers of a response to therapy to avoid continuing ineffective treatments and to initiate other therapeutic strategies. The present in vivo longitudinal study in an orthotopic mouse model demonstrates quantitative assessment of early treatment response during short-term chemotherapy with temozolomide (TMZ) by amide proton transfer (APT) imaging. In a GBM line, only one course of TMZ (3 d exposure and 4 d rest) at a dose of 80 mg/kg resulted in substantial reduction in APT signal compared with untreated control animals, in which the APT signal continued to increase. Although there were no detectable differences in tumor volume, cell density, or apoptosis rate between groups, levels of Ki67 (index of cell proliferation) were substantially reduced in treated tumors. In another TMZ-resistant GBM line, the APT signal and levels of Ki67 increased despite the same course of TMZ treatment. As metabolite changes are known to occur early in the time course of chemotherapy and precede morphologic changes, these results suggest that the APT signal in glioma may be a useful functional biomarker of treatment response or degree of tumor progression. Thus, APT imaging may serve as a sensitive biomarker of early treatment response and could potentially replace invasive biopsies to provide a definitive diagnosis. This would have a major impact on the clinical management of patients with glioma. PMID:24616497

  3. Lipid metabolism enzyme ACSVL3 supports glioblastoma stem cell maintenance and tumorigenicity

    PubMed Central

    2014-01-01

    Background Targeting cell metabolism offers promising opportunities for the development of drugs to treat cancer. We previously found that the fatty acyl-CoA synthetase VL3 (ACSVL3) is elevated in malignant brain tumor tissues and involved in tumorigenesis. This study investigates the role of ACSVL3 in the maintenance of glioblastoma multiforme (GBM) stem cell self-renewal and the capacity of GBM stem cells to initiate tumor xenograft formation. Methods We examined ACSVL3 expression during differentiation of several GBM stem cell enriched neurosphere cultures. To study the function of ACSVL3, we performed loss-of-function by using small interfering RNAs to target ACSVL3 and examined stem cell marker expression, neurosphere formation and tumor initiation properties. Results ACSVL3 expression levels were substantially increased in GBM stem cell enriched neurosphere cultures and decreased after differentiation of the neurospheres. Down-regulating ACSVL3 with small inhibiting RNAs decreased the expression of markers and regulators associated with stem cell self-renewal, including CD133, ALDH, Musashi-1 and Sox-2. ACSVL3 knockdown in neurosphere cells led to increased expression of differentiation markers GFAP and Tuj1. Furthermore, ACSVL3 knockdown reduced anchorage-independent neurosphere cell growth, neurosphere-forming capacity as well as self-renewal of these GBM stem cell enriched neurosphere cultures. In vivo studies revealed that ACSVL3 loss-of-function substantially inhibited the ability of neurosphere cells to propagate orthotopic tumor xenografts. A link between ACSVL3 and cancer stem cell phenotype was further established by the findings that ACSVL3 expression was regulated by receptor tyrosine kinase pathways that support GBM stem cell self-renewal and tumor initiation, including EGFR and HGF/c-Met pathways. Conclusions Our findings indicate that the lipid metabolism enzyme ACSVL3 is involved in GBM stem cell maintenance and the tumor-initiating capacity of

  4. High expression of miR-9 in CD133+ glioblastoma cells in chemoresistance to temozolomide

    PubMed Central

    Munoz, Jessian L.; Rodriguez-Cruz, Vivian; Rameshwar, Pranela

    2016-01-01

    Glioblastoma Multiforme (GBM), a uniformly lethal stage IV astrocytoma, is currently treated with a combination of surgical and radiation therapy as well as Temozolomide (TMZ) chemotherapy. Resistance to TMZ is rapidly acquired by GBM cells and overcoming this resistance has been an area of signi?cant research. GBM 'cancer stem cells' (CSC) also known as 'cancer initiating cells' are often positively selected by CD133 expression and TMZ resistance. In this project, we selected GBM CSC from two cell lines based on CD133 expression. CD133+ and CD133− GBM cells showed comparable cell cycle status. The expression of genes within the Sonic Hedgehog Signaling pathway, PTCH1 (SHH receptor/basal signaling repressor) and Gli1 (effector transcription factor) were increased. The recent literature indicated a decreased in PTCH expression by miRNA and this was independent of SHH expression. We analyzed 5 potential PTCH-targeting miRNA and identi?ed an increase in miRNA-9-2. The CD133+ cells showed an increase in the Multiple Drug Resistance 1 gene (MDR1). Knockdown of Gli1 and MDR1 with siRNA enhanced TMZ induced cell death. Taken together, these studies show CD133+ GBM CSCs expressed greater levels of miR-9 and activation of the SHH/PTCH1/MDR1 axis. This axis has been shown to impart TMZ resistance. In the case of the CD133+ cells, the resistance is not acquires but seems to be inherent. Identi?cation of this pathway as well as the identi?cation of miR-9 may allow for the development of miRNA-targeted approach to Cancer Stem Cell therapy in GBM. PMID:27347493

  5. A nanostructure of functional targeting epirubicin liposomes dually modified with aminophenyl glucose and cyclic pentapeptide used for brain glioblastoma treatment

    PubMed Central

    Zhang, Cheng-Xiang; Zhao, Wei-Yu; Liu, Lei; Ju, Rui-Jun; Mu, Li-Min; Zhao, Yao; Zeng, Fan; Xie, Hong-Jun; Yan, Yan; Lu, Wan-Liang

    2015-01-01

    The objectives of the present study were to develop functional targeting epirubicin liposomes for transferring drugs across the blood-brain barrier (BBB), treating glioblastoma, and disabling neovascularization. The studies were performed on glioblastoma cells in vitro and on glioblastoma-bearing mice. The results showed that the constructed liposomes had a high encapsulation efficiency for drugs (>95%), suitable particle size (109 nm), and less leakage in the blood component-containing system; were significantly able to be transported across the BBB; and exhibited efficacies in killing glioblastoma cells and in destroying glioblastoma neovasculature in vitro and in glioblastoma-bearing mice. The action mechanisms of functional targeting epirubicin liposomes correlated with the following features: the long circulation in the blood system, the ability to be transported across the BBB via glucose transporter-1, and the targeting effects on glioblastoma cells and on the endothelial cells of the glioblastoma neovasculature via the integrin β3 receptor. In conclusion, functional targeting epirubicin liposomes could be used as a potential therapy for treating brain glioblastoma and disabling neovascularization in brain glioblastomas. PMID:26418720

  6. B Cells Are Critical to T-cell-Mediated Antitumor Immunity Induced by a Combined Immune-Stimulatory/Conditionally Cytotoxic Therapy for Glioblastoma12

    PubMed Central

    Candolfi, Marianela; Curtin, James F; Yagiz, Kader; Assi, Hikmat; Wibowo, Mia K; Alzadeh, Gabrielle E; Foulad, David; Muhammad, AKM G; Salehi, Sofia; Keech, Naomi; Puntel, Mariana; Liu, Chunyan; Sanderson, Nicholas R; Kroeger, Kurt M; Dunn, Robert; Martins, Gislaine; Lowenstein, Pedro R; Castro, Maria G

    2011-01-01

    We have demonstrated that modifying the tumor microenvironment through intratumoral administration of adenoviral vectors (Ad) encoding the conditional cytotoxic molecule, i.e., HSV1-TK and the immune-stimulatory cytokine, i.e., fms-like tyrosine kinase 3 ligand (Flt3L) leads to T-cell-dependent tumor regression in rodent models of glioblastoma. We investigated the role of B cells during immune-mediated glioblastoma multiforme regression. Although treatment with Ad-TK+Ad-Flt3L induced tumor regression in 60% of wild-type (WT) mice, it completely failed in B-cell-deficient Igh6-/- mice. Tumor-specific T-cell precursors were detected in Ad-TK+Ad-Flt3L-treated WT mice but not in Igh6-/- mice. The treatment also failed in WT mice depleted of total B cells or marginal zone B cells. Because we could not detect circulating antibodies against tumor cells and the treatment was equally efficient in WT mice and in mice with B-cell-specific deletion of Prdm 1 (encoding Blimp-1), in which B cells are present but unable to fully differentiate into antibody-secreting plasma cells, tumor regression in this model is not dependent on B cells' production of tumor antigen-specific immunoglobulins. Instead, B cells seem to play a role as antigen-presenting cells (APCs). Treatment with Ad-TK+Ad-Flt3L led to an increase in the number of B cells in the cervical lymph nodes, which stimulated the proliferation of syngeneic T cells and induced clonal expansion of antitumor T cells. Our data show that B cells act as APCs, playing a critical role in clonal expansion of tumor antigen-specific T cells and brain tumor regression. PMID:22028620

  7. Proton Magnetic Resonance Spectroscopic Imaging in Newly Diagnosed Glioblastoma: Predictive Value for the Site of Postradiotherapy Relapse in a Prospective Longitudinal Study

    SciTech Connect

    Laprie, Anne Catalaa, Isabelle; Cassol, Emmanuelle; McKnight, Tracy R.; Berchery, Delphine; Marre, Delphine; Bachaud, Jean-Marc; Berry, Isabelle; Moyal, Elizabeth Cohen-Jonathan

    2008-03-01

    Purpose: To investigate the association between magnetic resonance spectroscopic imaging (MRSI)-defined, metabolically abnormal tumor regions and subsequent sites of relapse in data from patients treated with radiotherapy (RT) in a prospective clinical trial. Methods and Materials: Twenty-three examinations were performed prospectively for 9 patients with newly diagnosed glioblastoma multiforme studied in a Phase I trial combining Tipifarnib and RT. The patients underwent magnetic resonance imaging (MRI) and MRSI before treatment and every 2 months until relapse. The MRSI data were categorized by the choline (Cho)/N-acetyl-aspartate (NAA) ratio (CNR) as a measure of spectroscopic abnormality. CNRs corresponding to T1 and T2 MRI for 1,207 voxels were evaluated before RT and at recurrence. Results: Before treatment, areas of CNR2 (CNR {>=}2) represented 25% of the contrast-enhancing (T1CE) regions and 10% of abnormal T2 regions outside T1CE (HyperT2). The presence of CNR2 was often an early indicator of the site of relapse after therapy. In fact, 75% of the voxels within the T1CE+CNR2 before therapy continued to exhibit CNR2 at relapse, compared with 22% of the voxels within the T1CE with normal CNR (p < 0.05). The location of new contrast enhancement with CNR2 corresponded in 80% of the initial HyperT2+CNR2 vs. 20.7% of the HyperT2 voxels with normal CNR (p < 0.05). Conclusion: Metabolically active regions represented a small percentage of pretreatment MRI abnormalities and were predictive for the site of post-RT relapse. The incorporation of MRSI data in the definition of RT target volumes for selective boosting may be a promising avenue leading to increased local control of glioblastomas.

  8. 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

  9. Wnt inhibitory factor-1 regulates glioblastoma cell cycle and proliferation.

    PubMed

    Wu, Jun; Fang, Jiasheng; Yang, Zhuanyi; Chen, Fenghua; Liu, Jingfang; Wang, Yanjin

    2012-10-01

    Wnt proteins are powerful regulators of cell proliferation and differentiation, and activation of the Wnt signalling pathway is involved in the pathogenesis of several types of human tumours. Wnt inhibitory factor-1 (WIF-1) acts as a Wnt antagonist and tumour suppressor. Previous studies have shown that reducing expression of the WIF-1 gene aberrantly activates Wnt signalling and induces the development of certain types of cancers. In the present study, we examined the expression of WIF-1 in human primary glioblastoma multiforme (GBM) tumours. Studies using semiquantitative reverse transcription-polymerase chain reaction and immunohistochemical analysis revealed that WIF-1 expression is lower in human GBM than in normal brain tissue. To clarify the role of WIF-1, we transfected U251 human glioblastoma-derived cells, which do not express WIF-1, with the pcDNA3.1-WIF1 vector to restore WIF-1 expression. The results of cell proliferation, colony formation and apoptosis assays, as well as flow cytometry, indicate that exogenous WIF-1 has no effect on U251 cell apoptosis, but does arrest cells at the G(0)/G(1) phase and inhibit cell growth. Collectively, our data suggest that WIF-1 is a potent inhibitor of GBM growth. PMID:22901505

  10. MGMT Promoter Methylation Correlates with an Overall Survival Benefit in Chinese High-Grade Glioblastoma Patients Treated with Radiotherapy and Alkylating Agent-Based Chemotherapy: A Single-Institution Study

    PubMed Central

    Shen, Dong; Liu, Tao; Lin, Qingfen; Lu, Xiangdong; Wang, Qiong; Lin, Feng; Mao, Weidong

    2014-01-01

    Promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has been considered a prognostic marker and has become more important in the treatment of glioblastoma. However, reports on the correlation between MGMT and clinical outcomes in Chinese glioblastoma patients are very scarce. In this study, quantitative methylation data were obtained by the pyrosequencing of tumor tissues from 128 GBM patients. The median overall survival (OS) was 13.1 months, with a 1-year survival of 45.3%. The pyrosequencing data were reproducible based on archived samples yielding data for all glioblastomas. MGMT promoter methylation was detected in 75/128 cases (58.6%), whereas 53/128 (41.4%) cases were unmethylated. Further survival analysis also revealed that methylation was an independent prognostic factor associated with prolonged OS but not with progression-free survival (PFS) (p = 0.029 and p = 0.112, respectively); the hazard radios were 0.63 (95% CI: 0.42–0.96) and 0.72 (95% CI: 0.48–1.09), respectively. These data indicated that MGMT methylation has prognostic significance in patients with newly diagnosed high-grade glioblastoma undergoing alkylating agent-based chemotherapy after surgical resection. PMID:25211033

  11. 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

  12. Targeting strategies on miRNA-21 and PDCD4 for glioblastoma.

    PubMed

    Wang, Gang; Wang, Jun Jie; Tang, Hong Ming; To, Shing Shun Tony

    2015-08-15

    MicroRNAs (miRNAs) are often deregulated in glioblastoma multiforme (GBM). Downregulation of microRNA-21 (miR-21), especially in GBM, is responsible for increased apoptosis, decreased cell proliferation and invasion, increased G0/G1 cell cycle arrest, and reduced chemotherapeutic resistance to doxorubicin. Furthermore, it is a critical regulator of multiple downstream genes and signaling pathways involved in gliomagenesis. Programmed cell death 4 (PDCD4) is critical in mediating apoptosis in GBM, and is downregulated by miR-21, which may mediate the resistance of glioblastoma cells against chemotherapy or radiation via its target genes PDCD4. Evidence is mounting that how alterations of these miRNAs transcription factors provide initiation, maintenance, or progression of tumors. This review will focus on the roles of miRNAs family members (particularly miR-21 and its target gene PDCD4) in tumors like glioblastoma and new targeting strategies, as examples some new targeting therapeutic methods and molecular mechanisms of signal pathways in glioblastoma therapeutics, to give the reader the current trends of approach to target regulation of these miRNA and genes for future glioma therapies. PMID:26142886

  13. Toxic Epidermal Necrolysis in Polymedicated Patient Treated With Radiotherapy

    PubMed Central

    Pérez-Calderón, Remedios; Corrales-Vargas, Silvia; Jiménez-Ferrera, Gloria; Rodríguez-Nevado, Isabel; Díaz-Delgado, Mario

    2015-01-01

    Temozolomide is an oral alkylating agent indicated for the treatment of patients with glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment. We report the case of a patient who developed toxic epidermal necrolysis (TEN) while she was being treated with chemoradiotherapy and several drugs. Cutaneous tests were performed with the drugs involved with negative result. Although the occurrence of TEN contraindicates suspected drug readministration, we based the decision to perform the controlled administration of temozolomide on the following reasons: (1) the poor prognosis of the underlying disease, (2) the lack of therapeutic alternatives, (3) the suspicion that other drugs taken by the patient simultaneously may be responsible (as anticonvulsants and trimethoprim sulfamethoxazole [TMP-SMX]), and (4) temozolomide was the first choice for treating the patient's disease. The administration of a cumulative dose of 60 mg of temozolomide caused a slight skin reaction. Given this result, we conducted controlled administration of other drugs involved. Dexamethasone, codeine, omeprazole and levetiracetam were well tolerated. However, TMP-SMX produced a similar reaction to that caused by temozolomide. In conclusion, we present the first case of TEN induced by temozolomide and TMP-SMX associated with cranial radiotherapy confirmed by controlled administration. Radiotherapy in combination with these drugs could have favored TEN, as some authors have postulated, but we cannot prove this. PMID:25729629

  14. 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

  15. A retrospective study of the safety of BCNU wafers with concurrent temozolomide and radiotherapy and adjuvant temozolomide for newly diagnosed glioblastoma patients.

    PubMed

    Pan, Edward; Mitchell, Susan B; Tsai, Jerry S

    2008-07-01

    Despite aggressive therapy, most patients with glioblastoma multiforme (GBM) die within 2 years of diagnosis. The efficacy and safety of carmustine (BCNU) wafers followed by radiotherapy have been demonstrated in patients with malignant glioma. However, there is a reluctance to recommend them for newly diagnosed GBM patients due to the potential toxicity of BCNU wafers combined with temozolomide (TMZ) chemotherapy and radiotherapy. The purpose of this study was to assess the safety of BCNU wafers implanted at initial surgery, followed by concurrent TMZ and radiotherapy, and then adjuvant TMZ for the treatment of newly diagnosed GBM. We conducted a retrospective analysis of clinic and hospital records of 21 newly diagnosed GBM patients who received multimodal therapy at Florida Hospital Cancer Institute from January 2003 to December 2005. Three of 21 patients had grade 3 toxicities (two with cerebritis, one with psychosis). Grade 4 toxicities were not observed. Median overall survival was 17 months, median progression-free survival was 8.5 months, and 2-year survival was 39%. Multimodal treatment with surgery, BCNU wafers, radiotherapy, and TMZ did not result in a notable increase in significant toxicities. Survival outcomes were comparable to those in other studies in which patients were treated with concurrent TMZ and radiotherapy followed by adjuvant TMZ. Thus, the implantation of BCNU wafers prior to TMZ and radiotherapy appears safe in newly diagnosed GBM patients. PMID:18389176

  16. Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: from bedside to bench.

    PubMed

    Burkhardt, Jan-Karl; Hofstetter, Christoph P; Santillan, Alejandro; Shin, Benjamin J; Foley, Conor P; Ballon, Douglas J; Pierre Gobin, Y; Boockvar, John A

    2012-11-01

    Bevacizumab (BV), a humanized monocolonal antibody directed against vascular endothelial growth factor (VEGF), is a standard intravenous (IV) treatment for recurrent glioblastoma multiforme (GBM), that has been introduced recently as an intra-arterial (IA) treatment modality in humans. Since preclinical models have not been reported, we sought to develop a tumor stem cell (TSC) xenograft model to investigate IA BV delivery in vivo. Firefly luciferase transduced patient TSC were injected into the cortex of 35 nude mice. Tumor growth was monitored weekly using bioluminescence imaging. Mice were treated with either intraperitoneal (IP) or IA BV, with or without blood-brain barrier disruption (BBBD), or with IP saline injection (controls). Tumor tissue was analyzed using immunohistochemistry and western blot techniques. Tumor formation occurred in 31 of 35 (89%) mice with a significant signal increase over time (p=0.018). Post mortem histology revealed an infiltrative growth of TSC xenografts in a similar pattern compared to the primary human GBM. Tumor tissue analyzed at 24 hours after treatment revealed that IA BV treatment with BBBD led to a significantly higher intratumoral BV concentration compared to IA BV alone, IP BV or controls (p<0.05). Thus, we have developed a TSC-based xenograft mouse model that allows us to study IA chemotherapy. However, further studies are needed to analyze the treatment effects after IA BV to assess tumor progression and overall animal survival. PMID:22985932

  17. Early clinical experience of boron neutron capture therapy for glioblastoma multiforme

    SciTech Connect

    Joel, D.D.; Bergland, R.; Capala, J.

    1995-12-31

    Boron neutron capture therapy (BNCT) is a binary treatment modality that can selectively irradiate tumor tissue. BNCT uses drugs containing a stable isotope of boron. {sup 10}B, to sensitize tumor cells to irradiation by low energy (thermal) neutrons. The interaction of the {sup 10}B with a thermal neutron (neutron capture) causes the {sup 10}B nucleus to split, releasing an alpha particle and a lithium nucleus. These products of the {sup 10}B(n, {alpha}){sup 7}Li reaction are very damaging to cells but have a combined path length in tissue of approximately 14 {mu}m, or roughly the diameter of one or two cells. Thus, most of the ionizing energy imparted to tissue is localized to {sup 10}B-loaded cells.

  18. 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.

  19. 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

  20. Epidermal growth factor receptor and glioblastoma multiforme: molecular basis for a new approach.

    PubMed

    Belda-Iniesta, Cristóbal; de Castro Carpeño, Javier; Sereno, María; González-Barón, Manuel; Perona, Rosario

    2008-02-01

    High-grade gliomas are the most common primary malignant brain tumours. Surgery, radiotherapy and chemotherapy are the cornerstone of actual treatment. In spite of large therapeutic efforts, overall survival is still poor. New molecular data allow a new molecular classification for high-grade gliomas and open a therapeutic window for targeted therapy. Molecular diagnostic tools may provide a basis for receptor-based therapies and enough information to personalise future treatments. In this regard, epidermal growth factor receptor (EGFR) is a target that will play a critical role in the management of glioma patients. This review summarises basic and preclinical data that support future use of therapies against EGFR. PMID:18258505

  1. 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

  2. Wnt activation promotes neuronal differentiation of Glioblastoma

    PubMed Central

    Rampazzo, E; Persano, L; Pistollato, F; Moro, E; Frasson, C; Porazzi, P; Della Puppa, A; Bresolin, S; Battilana, G; Indraccolo, S; Te Kronnie, G; Argenton, F; Tiso, N; Basso, G

    2013-01-01

    One of the biggest challenges in tumour research is the possibility to reprogram cancer cells towards less aggressive phenotypes. In this study, we reprogrammed primary Glioblastoma multiforme (GBM)-derived cells towards a more differentiated and less oncogenic phenotype by activating the Wnt pathway in a hypoxic microenvironment. Hypoxia usually correlates with malignant behaviours in cancer cells, but it has been recently involved, together with Wnt signalling, in the differentiation of embryonic and neural stem cells. Here, we demonstrate that treatment with Wnt ligands, or overexpression of β-catenin, mediate neuronal differentiation and halt proliferation in primary GBM cells. An hypoxic environment cooperates with Wnt-induced differentiation, in line with our finding that hypoxia inducible factor-1α (HIF-1α) is instrumental and required to sustain the expression of β-catenin transcriptional partners TCF-1 and LEF-1. In addition, we also found that Wnt-induced GBM cell differentiation inhibits Notch signalling, and thus gain of Wnt and loss of Notch cooperate in the activation of a pro-neuronal differentiation program. Intriguingly, the GBM sub-population enriched of cancer stem cells (CD133+ fraction) is the primary target of the pro-differentiating effects mediated by the crosstalk between HIF-1α, Wnt, and Notch signalling. By using zebrafish transgenics and mutants as model systems to visualize and manipulate in vivo the Wnt pathway, we confirm that Wnt pathway activation is able to promote neuronal differentiation and inhibit Notch signalling of primary human GBM cells also in this in vivo set-up. In conclusion, these findings shed light on an unsuspected crosstalk between hypoxia, Wnt and Notch signalling in GBM, and suggest the potential to manipulate these microenvironmental signals to blunt GBM malignancy. PMID:23429286

  3. PTEN Loss Does Not Predict for Response to RAD001 (Everolimus) in a Glioblastoma Orthotopic Xenograft Test Panel

    PubMed Central

    Yang, Lin; Clarke, Michelle J.; Carlson, Brett L.; Mladek, Ann C.; Schroeder, Mark A.; Decker, Paul; Wu, Wenting; Kitange, Gaspar J.; Grogan, Patrick T.; Goble, Jennie M.; Uhm, Joon; Galanis, Evanthia; Giannini, Caterina; Lane, Heidi A.; James, C. David; Sarkaria, Jann N.

    2014-01-01

    Purpose Hyperactivation of the phosphatidylinositol 3-kinase/Akt signaling through disruption of PTEN function is common in glioblastoma multiforme, and these genetic changes are predicted to enhance sensitivity to mammalian target of rapamycin (mTOR) inhibitors such as RAD001 (everolimus). Experimental Design To test whether PTEN loss could be used as a predictive marker for mTOR inhibitor sensitivity, the response of 17 serially transplantable glioblastoma multiforme xenografts was evaluated in an orthotopic therapy evaluation model. Of these 17 xenograft lines, 7 have either genomic deletion or mutation of PTEN. Results Consistent with activation of Akt signaling, there was a good correlation between loss of PTEN function and elevated levels of Akt phosphorylation. However, of the 7 lines with disrupted PTEN function, only 1 tumor line (GBM10) was significantly sensitive to RAD001 therapy (25% prolongation in median survival), whereas1 of 10 xenograft lines with wild-type PTEN was significantly sensitive to RAD001 (GS22; 34% prolongation in survival). Relative to placebo, 5 days of RAD001 treatment was associated with a marked 66% reduction in the MIB1 proliferation index in the sensitive GBM10 line (deleted PTEN) compared with a 25% and 7% reduction in MIB1 labeling index in the insensitive GBM14 (mutant PTEN) and GBM15 (wild-type PTEN) lines, respectively. Consistent with a cytostatic antitumor effect, bioluminescent imaging of luciferase-transduced intracranial GBM10 xenografts showed slowed tumor growth without significant tumor regression during RAD001 therapy. Conclusion These data suggest that loss of PTEN function is insufficient to adequately predict responsiveness to mTOR inhibitors in glioblastoma multiforme. PMID:18559622

  4. 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

  5. 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

  6. Is There Pseudoprogression in Secondary Glioblastomas?

    SciTech Connect

    Juratli, Tareq A.; Engellandt, Kay; Lautenschlaeger, Tim; Kummer, Rüdiger von; Cerhova, Jana; Chakravarti, Arnab

    2013-12-01

    Purpose: Pseudoprogression (PP) during adjuvant treatment of glioblastoma (GBM) is frequent and is a clinically and radiologically challenging problem. While there are several reports of the frequency of PP in GBM cohorts including mainly patients with primary GBM, there are few data on the incidence of PP in patients with secondary glioblastomas (sGBM). Therefore, the goal of this study was to evaluate the frequency of PP in sGBM. Methods and Materials: We retrospectively evaluated the incidence of PP in adult patients with sGBM treated with chemoradiation therapy (CRTx) using temozolomide (TMZ) and sought to assess if there was an association between PP and MGMT promoter methylation status, IDH mutations status, or 1p/19q codeletion. The definition of PP according to the Response Assessment in Neuro-Oncology Working Group was used. Results: None of the evaluable 15 sGBM patients in our series demonstrated a PP. Of the 9 sGBM patients who received concomitant CRTx with TMZ, 6 patients had the methylated MGMT promoter, and 6 patients had IDH mutations. There also was no PP identified in sGBM patients who received sequential CRTx, irrespective of MGMT or IDH status. The median time of follow-up was 3.4 years after diagnosis of an sGBM, and the median overall survival was 18.2 months (range, 14.3-45.2 months). Three of 15 patients had previously received radiation therapy for their World Health Organization low-grade 2 glioma, while none of them had received chemotherapy at that stage. Conclusions: Based on this small series of sGBM patients treated with CRTx (concomitantly or sequentially) the frequency of PP appears to be very low in sGBM, even in those patients with methylated MGMT promoter or IDH mutations. Our results highlight the differences between primary glioblastomas and sGBM in particular as they relate to PP.

  7. Melatonin inhibits tumorigenicity of glioblastoma stem-like cells via the AKT-EZH2-STAT3 signaling axis.

    PubMed

    Chen, Xueran; Hao, Aijun; Li, Xian; Du, Zhaoxia; Li, Hao; Wang, Hongzhi; Yang, Haoran; Fang, Zhiyou

    2016-09-01

    Glioblastoma stem-like cells (GSCs) displaying self-renewing and tumor-propagating capacity play a particularly important role in maintaining tumor growth, therapeutic resistance, and tumor recurrence. Therefore, new therapeutic strategies focusing on impairing GSC maintenance are urgently needed. Here, we used GSCs isolated from surgical specimens from patients with glioblastoma multiforme (GBM) to study the roles and underlying mechanisms associated with melatonin in GSC biology. The results showed that melatonin directly targeted glioma tumor cells by altering GSC biology and inhibiting GSC proliferation. Additionally, melatonin altered profile of transcription factors to inhibit tumor initiation and propagation. Furthermore, EZH2 S21 phosphorylation and EZH2-STAT3 interaction in GSCs were impaired following melatonin treatment. These results suggested that melatonin attenuated multiple key signals involved in GSC self-renewal and survival, and further supported melatonin as a promising GBM therapeutic. PMID:27121240

  8. Phase II Study of Short-Course Radiotherapy Plus Concomitant and Adjuvant Temozolomide in Elderly Patients With Glioblastoma

    SciTech Connect

    Minniti, Giuseppe; Lanzetta, Gaetano; Scaringi, Claudia; Caporello, Paola; Salvati, Maurizio; Arcella, Antonella; De Sanctis, Vitaliana; Giangaspero, Felice; Enrici, Riccardo Maurizi

    2012-05-01

    Purpose: Radiotherapy (RT) and chemotherapy may prolong survival in older patients (age {>=}70 years) with glioblastoma multiforme (GBM), although the survival benefits remain poor. This Phase II multicenter study was designed to evaluate the efficacy and safety of an abbreviated course of RT plus concomitant and adjuvant temozolomide (TMZ) in older patients with GBM. Patients and Methods: Seventy-one eligible patients 70 years of age or older with newly diagnosed GBM and a Karnofsky performance status {>=}60 were treated with a short course of RT (40 Gy in 15 fractions over 3 weeks) plus TMZ at the dosage of 75 mg/m{sup 2} per day followed by 12 cycles of adjuvant TMZ (150-200 mg/m{sup 2} for 5 days during each 28-day cycle). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival and toxicity. Results: The Median OS was 12.4 months, and the 1-year and 2-year OS rates were 58% and 20%, respectively. The median and 1-year rates of progression-free survival were 6 months and 20%, respectively. All patients completed the planned programme of RT. Grade 3 or 4 adverse events occurred in 16 patients (22%). Grade 3 and 4 neutropenia and/or thrombocytopenia occurred in 10 patients (15%), leading to the interruption of treatment in 6 patients (8%). Nonhematologic Grade 3 toxicity was rare, and included fatigue in 4 patients and cognitive disability in 1 patient. Conclusions: A combination of an abbreviated course of RT plus concomitant and adjuvant TMZ is well tolerated and may prolong survival in elderly patients with GBM. Future randomized studies need to evaluate the efficacy and toxicity of different schedules of RT in association with chemotherapy.

  9. Heat-shock protein peptide complex–96 vaccination for recurrent glioblastoma: a phase II, single-arm trial

    PubMed Central

    Bloch, Orin; Crane, Courtney A.; Fuks, Yelena; Kaur, Rajwant; Aghi, Manish K.; Berger, Mitchel S.; Butowski, Nicholas A.; Chang, Susan M.; Clarke, Jennifer L.; McDermott, Michael W.; Prados, Michael D.; Sloan, Andrew E.; Bruce, Jeffrey N.; Parsa, Andrew T.

    2014-01-01

    Background Outcomes for patients with recurrent glioblastoma multiforme (GBM) are poor and may be improved by immunotherapy. We investigated the safety and efficacy of an autologous heat-shock protein peptide complex–96 (HSPPC-96) vaccine for patients with recurrent GBM. Methods In this open-label, single-arm, phase II study, adult patients with surgically resectable recurrent GBM were given vaccine after gross total resection. The primary endpoint was overall survival at 6 months. Secondary endpoints included overall survival, progression-free survival, safety, and immune profiling. Outcome analyses were performed in the intention-to-treat and efficacy populations. Results Between October 3, 2007 and October 24, 2011, 41 patients underwent gross total resection of recurrent GBM and received a median of 6 doses of HSPPC-96 vaccine. Following treatment, 90.2% of patients were alive at 6 months (95% confidence interval [CI]: 75.9–96.8) and 29.3% were alive at 12 months (95% CI: 16.6–45.7). Median overall survival was 42.6 weeks (95% CI: 34.7–50.5). Twenty-seven (66%) patients were lymphopenic prior to therapy, and patients with lymphocyte counts below the cohort median demonstrated decreased overall survival (hazard ratio: 4.0; 95% CI: 1.4–11.8; P = .012). There were no treatment-related deaths. There were 37 serious (grades 3–5) adverse events reported, with 17 attributable to surgical resection and a single grade 3 constitutional event related to the vaccine. Conclusion The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent GBM. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation. PMID:24335700

  10. Synergistic targeting tenascin C and neuropilin-1 for specific penetration of nanoparticles for anti-glioblastoma treatment.

    PubMed

    Kang, Ting; Zhu, Qianqian; Jiang, Di; Feng, Xingye; Feng, Jingxian; Jiang, Tianze; Yao, Jianhui; Jing, Yixian; Song, Qingxiang; Jiang, Xinguo; Gao, Xiaoling; Chen, Jun

    2016-09-01

    The pathological and physiological barriers of glioblastoma multiforme (GBM) lead to insufficient extravasation and penetration of nano-sized therapeutics. As the main driver of interstitial fluid pressure-related drug efflux, the aberrant extracellular matrix (ECM) appears to be a valuable target that plays a crucial role in forming pathological barriers of GBM. Herein, a new Ft peptide was synthesized by coupling FHK and tLyp-1 sequence together via a cysteine to synergistically target glioma-associated tenascin C (extracellular matrix component) and neuropilin-1 on neovasculature and glioma cells to enable specific penetration of nanoparticles for anti-glioblastoma treatment. In vitro, Ft peptide-functionalization not only enabled the internalization of poly (ethyleneglycol)-poly (lactic acid) nanoparticulate system in 2D U87 MG cells and HUVEC cells but also facilitated its deep penetration in 3D glioma spheroids. Similarly, in vivo real-time 2D and 3D imaging clearly showed a substantial accumulation of the Ft-functionalized nanoparticles (Ft-NP) in the glioma foci of intracranial U87 glioma-bearing mice. Glioma distribution assay demonstrated a tenascin C-mediated accumulation in glioma foci and neuropilin-1-mediated transportation through glioma cells. Paclitaxel-loaded Ft-NP (Ft-NP-PTX) induced higher cytotoxic effect and apoptosis rate compared with FHK or tLyp-1-modified ones. The highest anti-glioma efficacy was also achieved following the i.v. administration of Ft-NP-PTX, with a median survival promotion of 269% than that of the saline-treated mice, while only limited life span promotion was obtained after the treatment of other formulations (31.3%, 59.4%, 134.4% and 109.3% respectively for Taxol(®), NP-PTX, tLyp-1-NP-PTX and FHK-NP-PTX). In conclusion, all these evidences together verified the improved therapeutic effect of Ft-NP-PTX for anti-glioma drug delivery via neuropilin-1- and tenascin C-mediated specific penetration of nanoparticles in to

  11. [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

  12. Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy

    NASA Astrophysics Data System (ADS)

    Shao, Huilin; Chung, Jaehoon; Balaj, Leonora; Weissleder, Ralph; Lee, Hakho

    2013-03-01

    Glioblastomas shed large quantities of small, membrane-bound microvesicles (MVs) into the circulation. While these hold promise as potential biomarkers of therapeutic response, there remain hurdles to their identification and quantitation. Here, we describe a highly sensitive and rapid analytical technique for profiling circulating MVs directly from blood samples of glioblastoma patients. MVs, introduced onto a dedicated microfluidic chip, are labeled with target-specific magnetic nanoparticles and detected by a miniaturized nuclear magnetic resonance system. Compared with current standard assays (e.g., Western blotting, ELISA and flow cytometry), this integrated system has a much higher detection sensitivity, and can differentiate glioblastoma multiforme (GBM) MVs from non-tumor host cell-derived MVs. The system further showed that circulating GBM MVs could serve as a surrogate for primary tumor by reflecting its molecular signature and a predictor of treatment-induced changes. We expect that this converging nanotechnology platform would have a wide range of applications, providing both an earlier indicator of drug efficacy and a potential molecular stratifier for human clinical trials.

  13. 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

  14. 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.

  15. TARGETING SPHINGOSINE KINASE 1 INHIBITS AKT SIGNALING, INDUCES APOPTOSIS, AND SUPPRESSES GROWTH OF HUMAN GLIOBLASTOMA CELLS AND XENOGRAFTS

    PubMed Central

    Kapitonov, Dmitri; Allegood, Jeremy C.; Mitchell, Clint; Hait, Nitai C.; Almenara, Jorge A.; Adams, Jeffrey K.; Zipkin, Robert E.; Dent, Paul; Kordula, Tomasz; Milstien, Sheldon; Spiegel, Sarah

    2009-01-01

    Sphingosine-1-phosphate (S1P) is a potent sphingolipid mediator of diverse processes important for brain tumors, including cell growth, survival, migration, invasion, and angiogenesis. Sphingosine kinase 1 (SphK1), one of the two isoenzymes that produce S1P, is upregulated in glioblastoma and has been linked to poor prognosis in patients with glioblastoma multiforme (GBM). In the present study, we found that a potent isotype-specific SphK1 inhibitor, SK1-I, suppressed growth of LN229 and U373 glioblastoma cell lines and non-established human GBM6 cells. SK1-I also enhanced GBM cell death and inhibited their migration and invasion. SK1-I rapidly reduced phosphorylation of Akt but had no significant effect on activation of ERK1/2, another important survival pathway for GBM. Inhibition of the concomitant activation of the JNK pathway induced by SK1-I attenuated death of GBM cells. Importantly, SK1-I markedly reduced tumor growth rate of glioblastoma xenografts, inducing apoptosis and reducing tumor vascularization and enhanced the survival of mice harboring LN229 intracranial tumors. Our results support the notion that SphK1 may be an important factor in GBM and suggest that an isozyme-specific inhibitor of SphK1 deserves consideration as a new therapeutic agent for this disease. PMID:19723667

  16. Glioblastoma microvesicles promote endothelial cell proliferation through Akt/beta-catenin pathway.

    PubMed

    Liu, Shihai; Sun, Junfeng; Lan, Qing

    2014-01-01

    Glioblastoma tumor cells release microvesicles, which contain mRNA, miRNA and angiogenic proteins. These tumor-derived microvesicles transfer genetic information and proteins to normal cells. Previous reports demonstrated that the increased microvesicles in cerebrospinal fluid (CSF) of patients with glioblastoma up-regulate procoagulant activity. The concentration of microvesicles was closely related to thromboembolism incidence and clinical therapeutic effects of glioblastoma patients. However, it is still not clear how CSF microvesicles and what factors affect glioblastoma development. In this study, we collected the plasma and CSF from glioblastoma patients and healthy volunteers. Microvesicles acquired from serum or CSF were added to cultured endothelial cells. And the effects of these microvesicles on endothelial cells were examined. Our results showed that microvesicles from CSF of patients, but not from circulating blood, promoted endothelial cells migration and proliferation in vitro. In addition, the degree of endothelial cell proliferation triggered by microvesicles from CSF was reduced when treated with siRNA targeting Akt/beta-catenin, suggesting that the Akt/beta-catenin pathway is involved in the microvesicle-initiated endothelial cell proliferation. In conclusion, glioblastoma mainly affects microvesicles within CSF without showing significant impact on microvesicles in circulating blood. Microvesicles from the CSF of glioblastoma patients may initiate endothelial cell growth and thus promote cell invasion. This effect may be directly exerted by activated Akt/beta-catenin pathway. PMID:25197356

  17. 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

  18. Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival

    PubMed Central

    2011-01-01

    associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death. Conclusions Known biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme. PMID:21649900

  19. 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

  20. Novel multiform morphologies of hydroxyapatite: Synthesis and growth mechanism

    NASA Astrophysics Data System (ADS)

    Mary, I. Reeta; Sonia, S.; Viji, S.; Mangalaraj, D.; Viswanathan, C.; Ponpandian, N.

    2016-01-01

    Morphological evolution of materials becomes a prodigious challenge due to their key role in defining their functional properties and desired applications. Herein, we report the synthesis of hydroxyapatite (HAp) microstructures with multiform morphologies, such as spheres, cubes, hexagonal rods and nested bundles constructed from their respective nanoscale building blocks via a simple cost effective hydro/solvothermal method. A possible formation mechanism of diverse morphologies of HAp has been presented. Structural analysis based on X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy confirms the purity of the HAp microstructures. The multiform morphologies of HAp were corroborated by using Field emission scanning electron microscope (FESEM).

  1. Erythema multiforme as first sign of incomplete Kawasaki disease

    PubMed Central

    2013-01-01

    Incomplete Kawasaki disease represents a diagnostic challenge for pediatricians. In the absence of classical presentation, the laboratoristic evaluation of systemic inflammation can help in placing the correct diagnosis to promptly start adequate therapy. Erythema multiforme is an acute, self-limiting condition considered to be a hypersensitivity reaction commonly associated with various infections or medications. This aspecific skin condition has been rarely described as a sign of Kawasaki disease. We report on the case of a 4 years old boy presenting high-grade fever associated with erythema multiforme and evidence of systemic inflammation who showed a good response to prompt treatment with intravenous immunoglobulins. PMID:23406772

  2. Tumor cohesion and glioblastoma cell dispersal

    PubMed Central

    Foty, Ramsey A

    2013-01-01

    Patients with glioblastoma typically present when tumors are at an advanced stage. Surgical resection, radiotherapy and adjuvant chemotherapy are currently the standard of care for glioblastoma. However, due to the infiltrative and dispersive nature of the tumor, recurrence rate remains high and typically results in very poor prognosis. Efforts to treat the primary tumor are, therefore, palliative rather than curative. From a practical perspective, controlling growth and dispersal of the recurrence may have a greater impact on disease-free survival, In order for cells to disperse, they must first detach from the mass. Preventing detachment may keep tumors that recur more localized and perhaps more amenable to therapy. Here we introduce a new perspective in which a quantifiable mechanical property, namely tissue surface tension, can provide novel information on tumor behavior. The overall theme of the discussion will attempt to integrate how adhesion molecules can alter a tumor’s mechanical properties and how, in turn, these properties can be modified to prevent tumor cell detachment and dispersal. PMID:23902244

  3. Role of bevacizumab therapy in the management of glioblastoma

    PubMed Central

    Peak, Scott J; Levin, Victor A

    2010-01-01

    Glioblastoma is one of the most common primary brain tumors and one of the most difficult to treat. In population-based studies only 30% of patients will survive 1 year and in the most efficacious surgery, irradiation, and chemotherapy clinical trials approximately 20% will live 2 years. Bevacizumab is a recombinant, antivascular epidermal growth factor receptor (VEGF) monoclonal antibody with 6 VEGF-binding residues that binds to VEGF, preventing VEGF from binding to its target, VEGFR-1 and VEGFR-2, on endothelial cells. Through its binding to VEGF ligands bevacizumab reduces tumor angiogenesis and vasogenic brain edema; the consequences are that bevacizumab reduces the rate of glioblastoma tumor growth and its associated tumoral edema, thereby improving quality of life and survival for patients suffering from cerebral glioblastoma. In this review, we will summarize the studies that led to the use of bevacizumab in glioblastoma and the potential side-effects and complications that can be associated with its use and, finally, new opportunities for drug combinations with bevacizumab. PMID:21188100

  4. Comprehensive genomic characterization defines human glioblastoma genes and core pathways.

    PubMed

    2008-10-23

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas--the most common type of adult brain cancer--and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer. PMID:18772890

  5. 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

  6. Sustained Radiosensitization of Hypoxic Glioma Cells after Oxygen Pretreatment in an Animal Model of Glioblastoma and In Vitro Models of Tumor Hypoxia

    PubMed Central

    Clarke, Ryon H.; Moosa, Shayan; Anzivino, Matthew; Wang, Yi; Floyd, Desiree Hunt; Purow, Benjamin W.; Lee, Kevin S.

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal form of brain cancer and these tumors are highly resistant to chemo- and radiotherapy. Radioresistance is thought to result from a paucity of molecular oxygen in hypoxic tumor regions, resulting in reduced DNA damage and enhanced cellular defense mechanisms. Efforts to counteract tumor hypoxia during radiotherapy are limited by an attendant increase in the sensitivity of healthy brain tissue to radiation. However, the presence of heightened levels of molecular oxygen during radiotherapy, while conventionally deemed critical for adjuvant oxygen therapy to sensitize hypoxic tumor tissue, might not actually be necessary. We evaluated the concept that pre-treating tumor tissue by transiently elevating tissue oxygenation prior to radiation exposure could increase the efficacy of radiotherapy, even when radiotherapy is administered after the return of tumor tissue oxygen to hypoxic baseline levels. Using nude mice bearing intracranial U87-luciferase xenografts, and in vitro models of tumor hypoxia, the efficacy of oxygen pretreatment for producing radiosensitization was tested. Oxygen-induced radiosensitization of tumor tissue was observed in GBM xenografts, as seen by suppression of tumor growth and increased survival. Additionally, rodent and human glioma cells, and human glioma stem cells, exhibited prolonged enhanced vulnerability to radiation after oxygen pretreatment in vitro, even when radiation was delivered under hypoxic conditions. Over-expression of HIF-1α reduced this radiosensitization, indicating that this effect is mediated, in part, via a change in HIF-1-dependent mechanisms. Importantly, an identical duration of transient hyperoxic exposure does not sensitize normal human astrocytes to radiation in vitro. Taken together, these results indicate that briefly pre-treating tumors with elevated levels of oxygen prior to radiotherapy may represent a means for selectively targeting radiation

  7. Durable response of glioblastoma to adjuvant therapy consisting of temozolomide and a weekly dose of AMD3100 (plerixafor), a CXCR4 inhibitor, together with lapatinib, metformin and niacinamide

    PubMed Central

    Rios, Adan; Hsu, Sigmund H.; Blanco, Angel; Buryanek, Jamie; Day, Arthur L.; McGuire, Mary F.; Brown, Robert E.

    2016-01-01

    Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site.[3]. This SDF-1 hypoxia-dependent effect can be blocked by AMD3100 (plerixafor) [4]. We report a GBM case treated after chemo- radiotherapy with plerixafor and a combination of an mTOR, a Sirt1 and an EGFRvIII inhibitor. After one year temozolomide and the EGFRvIII inhibitor were stopped. Plerixafor, and the MTOR and Sirt-1 inhibitors were continued. He is in clinical and radiologic remission 30 months from the initiation of his adjuvant treatment. To our knowledge, this is the first report of a patient treated for over two years with a CXCR4 inhibitor (plerixafor), as part of his adjuvant treatment. We believe there is sufficient experimental evidence to consider AMD3100 (plerixafor) part of the adjuvant treatment of GBM. Significance The adjuvant inhibition of GBM vasculogenesis(a process different from local angiogenesis) by specifically blocking the migration of BMDCs to the primary tumor site with inhibitors of the CXCR4/SDF-1 axis represents a potential novel therapeutic approach to GBM. There is significant pre-clinical evidence and validation for its use as demonstrated in a patient derived tumor xenograft model of GBM. Together with other specific anti-tumoral therapies, the active inhibition of vasculogenesis in the adjuvant treatment of GBM is deserving of further exploration. PMID:27489862

  8. Drug induced oral erythema multiforme: A rare and less recognized variant of erythema multiforme

    PubMed Central

    Joseph, T Isaac; Vargheese, Geetha; George, Deepu; Sathyan, Pradeesh

    2012-01-01

    Oral erythema multiforme (EM) is considered as a third category of EM other than EM minor and major. Patients present with oral and lip ulcerations typical of EM but without any skin target lesions. It has been reported that primary attacks of oral EM is confined to the oral mucosa but the subsequent attacks can produce more severe forms of EM involving the skin. Hence, it is important to identify and distinguish them from other ulcerative disorders involving oral cavity for early management. This article reports two cases of oral EM that presented with oral and lip ulcerations typical of EM without any skin lesions and highlights the importance of early diagnosis and proper management. PMID:22434953

  9. 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

  10. SEMA6A is a prognostic biomarker in glioblastoma.

    PubMed

    Zhao, Jiaxin; Tang, Haitao; Zhao, Hong; Che, Wanli; Zhang, Lei; Liang, Peng

    2015-11-01

    Glioblastoma multiforme (GBM) is one of the most aggressive tumors in the central nervous system. SEMA6A, the first identified class 6 semaphorin, is contributed to regulate vascular development and adult angiogenesis. However, the function of SEMA6A in GBM is still undefined. In the present study, we investigated the expression of SEMA6A protein in 200 GBM tissues using immunohistochemistry (IHC). SEMA6A expression was associated with time to progression (P = 0.001) and mean tumor diameter (P = 0.038). Kaplan-Meier analysis revealed that patients expressing high SEMA6A protein levels had a significantly longer overall survival (OS, P = 0.013) and progression-free survival (PFS, P = 0.005) compared to those with low SEMA6A expression level. Cox multivariate regression analysis confirmed that low SEMA6A expression was an independent unfavorable prognostic factors for PFS (HR, 1.896; 95% CI, 1.147-2.768; P = 0.009) and OS (HR, 1.712; 95% CI, 1.011-2.657; P = 0.012). Furthermore, in vitro experiments showed that SEMA6A could inhibit proliferation, migration, and invasion in different glioma cell lines. In conclusion, our findings indicated that SEMA6A may be a potential prognostic biomarker in the treatment of GBM. PMID:26014517

  11. Targeting NF-κB in glioblastoma: A therapeutic approach

    PubMed Central

    Friedmann-Morvinski, Dinorah; Narasimamurthy, Rajesh; Xia, Yifeng; Myskiw, Chad; Soda, Yasushi; Verma, Inder M.

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)–binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-κB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-κB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-κB activity or targeting of inducible NF-κB genes is an attractive therapeutic approach for GBM. PMID:26824076

  12. 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. PMID:23408428

  13. 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

  14. Targeting DUSPs in glioblastomas - wielding a double-edged sword?

    PubMed

    Prabhakar, Sheila; Asuthkar, Swapna; Lee, William; Chigurupati, Srinivasulu; Zakharian, Eleonora; Tsung, Andrew J; Velpula, Kiran Kumar

    2014-02-01

    Several dual-specificity phosphatases (DUSPs) that play key roles in the direct or indirect inactivation of different MAP kinases (MAPKs) have been implicated in human cancers over the past decade. This has led to a growing interest in identifying DUSPs and their specific inhibitors for further testing and validation as therapeutic targets in human cancers. However, the lack of understanding of the complex regulatory mechanisms and cross-talks between MAPK signaling pathways, combined with the fact that DUSPs can act as a double-edged sword in cancer progression, calls for a more careful and thorough investigation. Among the various types of brain cancer, glioblastoma multiforme (GBM) is notorious for its aggressiveness and resistance to current treatment modalities. This has led to the search for new molecular targets, particularly those involving various signaling pathways. DUSPs appear to be a promising target, but much more information on DUSP targets and their effects on GBM is needed before potential therapies can be developed, tested, and validated. This review identifies and summarize the specific roles of DUSP1, DUSP4, DUSP6 and DUSP26 that have been implicated in GBM. PMID:24155099

  15. Targeting NF-κB in glioblastoma: A therapeutic approach.

    PubMed

    Friedmann-Morvinski, Dinorah; Narasimamurthy, Rajesh; Xia, Yifeng; Myskiw, Chad; Soda, Yasushi; Verma, Inder M

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-κB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-κB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-κB activity or targeting of inducible NF-κB genes is an attractive therapeutic approach for GBM. PMID:26824076

  16. 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.

  17. 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

  18. Predicting the efficacy of radiotherapy in individual glioblastoma patients in vivo: a mathematical modeling approach

    NASA Astrophysics Data System (ADS)

    Rockne, R.; Rockhill, J. K.; Mrugala, M.; Spence, A. M.; Kalet, I.; Hendrickson, K.; Lai, A.; Cloughesy, T.; Alvord, E. C., Jr.; Swanson, K. R.

    2010-06-01

    Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumors known as gliomas. They proliferate and invade extensively and yield short life expectancies despite aggressive treatment. Response to treatment is usually measured in terms of the survival