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Sample records for radiation-induced malignant gliomas

  1. Radiation-induced intracranial malignant gliomas

    SciTech Connect

    Shapiro, S.; Mealey, J. Jr.; Sartorius, C.

    1989-07-01

    The authors present seven cases of malignant gliomas that occurred after radiation therapy administered for diseases different from the subsequent glial tumor. Included among these seven are three patients who were treated with interstitial brachytherapy. Previously reported cases of radiation-induced glioma are reviewed and analyzed for common characteristics. Children receiving central nervous system irradiation appear particularly susceptible to induction of malignant gliomas by radiation. Interstitial brachytherapy may be used successfully instead of external beam radiotherapy in previously irradiated, tumor-free brain, and thus may reduce the risk of radiation necrosis. 31 references.

  2. Radiation-induced gliomas

    PubMed Central

    Prasad, Gautam; Haas-Kogan, Daphne A.

    2013-01-01

    Radiation-induced gliomas represent a relatively rare but well-characterized entity in the neuro-oncologic literature. Extensive retrospective cohort data in pediatric populations after therapeutic intracranial radiation show a clearly increased risk in glioma incidence that is both patient age- and radiation dose/volume-dependent. Data in adults are more limited but show heightened risk in certain groups exposed to radiation. In both populations, there is no evidence linking increased risk associated with routine exposure to diagnostic radiation. At the molecular level, recent studies have found distinct genetic differences between radiation-induced gliomas and their spontaneously-occurring counterparts. Clinically, there is understandable reluctance on the part of clinicians to re-treat patients due to concern for cumulative neurotoxicity. However, available data suggest that aggressive intervention can lead to improved outcomes in patients with radiation-induced gliomas. PMID:19831840

  3. Radiation-Induced Malignant Gliomas: Is There a Role for Reirradiation?

    SciTech Connect

    Paulino, Arnold C. Mai, Wei Y.; Chintagumpala, Murali; Taher, Abida; Teh, Bin S.

    2008-08-01

    Purpose: To review the literature regarding the role of radiotherapy (RT) in the treatment of patients with radiation-induced malignant gliomas (RIMGs). Methods and Materials: A PubMed search of English-language articles dealing with RIMG was performed, yielding 52 articles with 92 patients available for review. Results: Initial tumor types treated with RT included brain tumor in 37 patients (40%), acute lymphoblastic leukemia in 33 (36%), benign disease in 11 (12%), and other in 11 (12%). Median time from RT to development of an RIMG was 8.75 years (range, 2.5-61 years). The RIMG occurred within 10 years after RT in 81% of patients with acute lymphoblastic leukemia/lymphoma, 59% of patients with brain/other, and 18% of patients with benign conditions (p = 0.002). Type of RIMG was glioblastoma in 69 (75%) and anaplastic astrocytoma in 23 (25%). One-, 2-, and 5-year overall survival rates were 29.3%, 7.3%, and 0% for patients with glioblastoma and 59.7%, 30.3%, and 20.2% for patients with anaplastic astrocytoma. For the 85 patients with data regarding treatment for RIMG, 35 underwent reirradiation to a median dose of 50 Gy (range, 30-76 Gy). For patients undergoing reirradiation, 1-, 2- and 5-year overall survival rates were 58.9%, 20.5%, and 6.8%. For those not undergoing reirradiation, they were 15.1%, 3%, and 0% (p = 0.0009). Conclusions: The RIMG appeared earlier in patients treated for leukemia and lymphoma and latest for those treated for a benign condition. Patients who underwent reirradiation for RIMG have longer survival times compared with those not receiving RT.

  4. Radiation-induced meningiomas after BNCT in patients with malignant glioma.

    PubMed

    Kageji, T; Sogabe, S; Mizobichi, Y; Nakajima, K; Shinji, N; Nakagawa, Y

    2015-12-01

    Of the 180 patients with malignant brain tumors whom we treated with boron neutron capture therapy (BNCT) since 1968, only one (0.56%) developed multiple radiation-induced meningiomas. The parasagittal meningioma that had received 42 Gy (w) for BNCT showed more rapid growth on Gd-enhanced MRI scans and more atypical features on histopathologic studies than the temporal convexity tumor that had received 20 Gy (w). Long-term follow up MRI studies are necessary in long-survivors of malignant brain tumors treated by BNCT. PMID:26122975

  5. A report on radiation-induced gliomas

    SciTech Connect

    Salvati, M.; Artico, M.; Caruso, R.; Rocchi, G.; Orlando, E.R.; Nucci, F. )

    1991-01-15

    Radiation-induced gliomas are uncommon, with only 73 cases on record to date. The disease that most frequently occasioned radiation therapy has been acute lymphoblastic leukemia (ALL). Three more cases are added here, two after irradiation for ALL and one after irradiation for tinea capitis. In a review of the relevant literature, the authors stress the possibility that the ALL-glioma and the retinoblastoma-glioma links point to syndromes in their own right that may occur without radiation therapy.56 references.

  6. Radiation-induced upregulation of telomerase activity escapes PI3-kinase inhibition in two malignant glioma cell lines

    PubMed Central

    MILLET, P.; GRANOTIER, C.; ETIENNE, O.; BOUSSIN, F.D.

    2013-01-01

    Tumor relapse after radiotherapy is a great concern in the treatment of high-grade gliomas. Inhibition of the PI3-kinase/AKT pathway is known to radiosensitize cancer cells and to delay their DNA repair after irradiation. In this study, we show that the radiosensitization of CB193 and T98G, two high-grade glioma cell lines, by the PI3K inhibitor LY294002, correlates with the induction of G1 and G2/M arrest, but is inconsistently linked to a delayed DNA double-strand break (DSBs) repair. The PI3K/AKT pathway has been shown to activate radioprotective factors such as telomerase, whose inhibition may contribute to the radiosensitization of cancer cells. However, we show that radiation upregulates telomerase activity in LY-294002-treated glioma cells as well as untreated controls, demonstrating a PI3K/AKT-independent pathway of telomerase activation. Our study suggests that radiosensitizing strategies based on PI3-kinase inhibition in high-grade gliomas may be optimized by additional treatments targeting either telomerase activity or telomere maintenance. PMID:23727752

  7. Immunotherapy for malignant glioma

    PubMed Central

    Suryadevara, Carter M.; Verla, Terence; Sanchez-Perez, Luis; Reap, Elizabeth A.; Choi, Bryan D.; Fecci, Peter E.; Sampson, John H.

    2015-01-01

    Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12–15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM. PMID:25722935

  8. Molecular biology of malignant gliomas.

    PubMed

    Belda-Iniesta, Cristóbal; de Castro Carpeño, Javier; Casado Sáenz, Enrique; Cejas Guerrero, Paloma; Perona, Rosario; González Barón, Manuel

    2006-09-01

    Gliomas are the most common primary brain tumours. In keeping with the degree of aggressiveness, gliomas are divided into four grades, with different biological behaviour. Furthermore, as different gliomas share a predominant histological appearance, the final classification includes both, histological features and degree of malignancy. For example, gliomas of astrocytic origin (astrocytomas) are classified into pilocytic astrocytoma (grade I), astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GMB) (grade IV). Tumors derived from oligodendrocytes include grade II (oliogodendrogliomas) and grade III neoplasms (oligoastrocytoma). Each subtype has a specific prognosis that dictates the clinical management. In this regard, a patient diagnosed with an oligodendroglioma totally removed has 10-15 years of potential survival. On the opposite site, patients carrying a glioblastoma multiforme usually die within the first year after the diagnosis is made. Therefore, different approaches are needed in each case. Obviously, prognosis and biological behaviour of malignant gliomas are closely related and supported by the different molecular background that possesses each type of glioma. Furthermore, the ability that allows several low-grade gliomas to progress into more aggressive tumors has allowed cancer researchers to elucidate several pathways implicated in molecular biology of these devastating tumors. In this review, we describe classical pathways involved in human malignant gliomas with special focus with recent advances, such as glioma stem-like cells and expression patterns from microarray studies. PMID:17005465

  9. Malignant glioma following radiotherapy for unrelated primary tumors

    SciTech Connect

    Marus, G.; Levin, C.V.; Rutherfoord, G.S.

    1986-08-15

    Four cases are documented where a glioma was histologically verified in the irradiation field of a previously treated malignancy of a different cell line. Radiation-induced neoplasia in the central nervous system now has been established in the induction of meningioma and sarcoma. The association between therapeutic irradiation and glioma in the reported cases lends to the evidence that a causal relation does exist. This incidence is small and does not detract from the overall benefit of irradiation as a therapeutic modality.

  10. Tumor Metabolism of Malignant Gliomas

    PubMed Central

    Ru, Peng; Williams, Terence M.; Chakravarti, Arnab; Guo, Deliang

    2013-01-01

    Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation. PMID:24217114

  11. Immunological Aspects of Malignant Gliomas.

    PubMed

    Cohen-Inbar, Or; Zaaroor, Menashe

    2016-07-01

    Glioblastoma Multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival time of <24 months. This figure remains constant, despite significant progress in medical research and treatment. The lack of an efficient anti-tumor immune response and the micro-invasive nature of the glioma malignant cells have been explained by a multitude of immune-suppressive mechanisms, proven in different models. These immune-resistant capabilities of the tumor result in a complex interplay this tumor shares with the immune system. We present a short review on the immunology of GBM, discussing the different unique pathological and molecular features of GBM, current treatment modalities, the principles of cancer immunotherapy and the link between GBM and melanoma. Current knowledge on immunological features of GBM, as well as immunotherapy past and current clinical trials, is discussed in an attempt to broadly present the complex and formidable challenges posed by GBM. PMID:27324313

  12. Vaccine Therapies in Malignant Glioma

    PubMed Central

    Oh, Taemin; Sayegh, Eli T.; Fakurnejad, Shayan; Oyon, Daniel; Lamano, Jonathan Balquiedra; DiDomenico, Joseph David; Bloch, Orin; Parsa, Andrew T.

    2015-01-01

    Glioblastoma is a grade IV astrocytoma that is widely accepted in clinical neurosurgery as being an extremely lethal diagnosis. Long-term survival rates remain dismal and, even when tumors undergo gross resection with confirmation of total removal on neuroimaging, they invariably recur with even greater virulence. Standard therapeutic modalities as well as more contemporary treatments have largely resulted in disappointing improvements. However, the therapeutic potential of vaccine immunotherapy for malignant glioma should not be underestimated. In contrast to many of the available treatments, vaccine immunotherapy is unique because it offers the means of delivering treatment that is highly specific to both the patient and the tumor. Peptide, heat-shock proteins, and dendritic cell vaccines collectively encapsulate the majority of research efforts involving vaccine-based treatment modalities. In this review, important recent findings for these vaccine types are discussed in the context of ongoing clinical trials. Broad challenges to immunotherapy are also considered. PMID:25431096

  13. Radiation-induced malignant and atypical peripheral nerve sheath tumors

    SciTech Connect

    Foley, K.M.; Woodruff, J.M.; Ellis, F.T.; Posner, J.B.

    1980-04-01

    The reported peripheral nerve complications of therapeutic irradiation in humans include brachial and lumbar plexus fibrosis and cranial and peripheral nerve atrophy. We have encountered 9 patients with malignant (7) and atypical (2) peripheral nerve tumors occurring in an irradiated site suggesting that such tumors represent another delayed effect of radiation treatment on peripheral nerve. In all instances the radio-theray was within an acceptable radiation dosage, yet 3 patients developed local radiation-induced skin and bony abnormalities. The malignant peripheral nerve sheath tumors developed only in the radiation port. Animal studies support the clinical observation that malignant peripheral nerve sheath tumors can occur as a delayed effect of irradiation.

  14. Improving vaccine efficacy against malignant glioma.

    PubMed

    Ladomersky, Erik; Genet, Matthew; Zhai, Lijie; Gritsina, Galina; Lauing, Kristen L; Lulla, Rishi R; Fangusaro, Jason; Lenzen, Alicia; Kumthekar, Priya; Raizer, Jeffrey J; Binder, David C; James, C David; Wainwright, Derek A

    2016-08-01

    The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored. We conclude by proposing new strategies that are built on current vaccine technologies and improved upon with novel combinatorial approaches. PMID:27622066

  15. Radiation-Inducible Caspase-8 Gene Therapy for Malignant Brain Tumors

    SciTech Connect

    Tsurushima, Hideo Yuan Xuan; Dillehay, Larry E.; Leong, Kam W.

    2008-06-01

    Purpose: Patients with malignant gliomas have a poor prognosis. To explore a novel and more effective approach for the treatment of patients with malignant gliomas, we designed a strategy that combines caspase-8 (CSP8) gene therapy and radiation treatment (RT). In addition, the specificity of the combined therapy was investigated to decrease the unpleasant effects experienced by the surrounding normal tissue. Methods and Materials: We constructed the plasmid pEGR-green fluorescence protein that included the radiation-inducible early growth response gene-1 (Egr-1) promoter and evaluated its characteristics. The pEGR-CSP8 was constructed and included the Egr-1 promoter and CSP8 complementary DNA. Assays that evaluated the apoptosis inducibility and cytotoxicity caused by CSP8 gene therapy combined with RT were performed using U251 and U87 glioma cells. The pEGR-CSP8 was transfected into the subcutaneous U251 glioma cells of nude mice by means of in vivo electroporation. The in vivo effects of CSP8 gene therapy combined with RT were evaluated. Results: The Egr-1 promoter yielded a better response with fractionated RT than with single-dose RT. In the assay of apoptosis inducibility and cytotoxicity, pEGR-CSP8 showed response for RT. The pEGR-CSP8 combined with RT is capable of inducing cell death effectively. In mice treated with pEGR-CSP8 and RT, apoptotic cells were detected in pathologic sections, and a significant difference was observed in tumor volumes. Conclusions: Our results indicate that radiation-inducible gene therapy may have great potential because this can be spatially or temporally controlled by exogenous RT and is safe and specific.

  16. Nitrosoureas in the Management of Malignant Gliomas.

    PubMed

    Brandes, Alba A; Bartolotti, Marco; Tosoni, Alicia; Franceschi, Enrico

    2016-02-01

    Nitrosoureas represent one of the most active classes of agents in the treatment of high-grade gliomas and glioblastoma. In clinical practice, the most commonly used compounds are lomustine (either alone or in combination with procarbazine and vincristine), carmustine, and fotemustine. Given their toxicity profile and subsequent to the introduction of temozolomide in clinical practice, most of these agents were moved to the recurrent setting. This review focuses on the role of the nitrosoureas currently used in clinical practice for the treatment of malignant gliomas. PMID:26750128

  17. Economics of Malignant Gliomas: A Critical Review

    PubMed Central

    Raizer, Jeffrey J.; Fitzner, Karen A.; Jacobs, Daniel I.; Bennett, Charles L.; Liebling, Dustin B.; Luu, Thanh Ha; Trifilio, Steven M.; Grimm, Sean A.; Fisher, Matthew J.; Haleem, Meraaj S.; Ray, Paul S.; McKoy, Judith M.; DeBoer, Rebecca; Tulas, Katrina-Marie E.; Deeb, Mohammed; McKoy, June M.

    2015-01-01

    Purpose: Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society. Methods: A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the study's publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another. Results: Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from $50,600 to $92,700. The addition of temozolomide (TMZ) and bevacizumab to glioblastoma treatment regimens has resulted in increased overall costs for glioma care. Although health care costs are now less front-loaded, they have increased over the course of illness. Analysis using a willingness-to-pay threshold of $50,000 per quality-adjusted life-year suggests that the benefits of TMZ fall on the edge of acceptable therapies. Furthermore, indirect medical costs, such as productivity losses, are not trivial. Conclusion: With increased chemotherapy use for malignant glioma, the paradigm for treatment and associated out-of-pocket and total medical costs continue to evolve. Larger out-of-pocket costs may influence the choice of chemotherapeutic agents, the economic implications of which should be evaluated prospectively. PMID:25466707

  18. Tumor initiating cells in malignant gliomas

    PubMed Central

    Hadjipanayis, Costas G.; Van Meir, Erwin G.

    2009-01-01

    A rare subpopulation of cells within malignant gliomas, which shares canonical properties with neural stem cells (NSCs), may be integral to glial tumor development and perpetuation. These cells, also known as tumor initiating cells (TICs), have the ability to self-renew, develop into any cell in the overall tumor population (multipotency), and proliferate. A defining property of TICs is their ability to initiate new tumors in immunocompromised mice with high efficiency. Mounting evidence suggests that TICs originate from the transformation of NSCs and their progenitors. New findings show that TICs may be more resistant to chemotherapy and radiation than the bulk of tumor cells, thereby permitting recurrent tumor formation and accounting for the failure of conventional therapies. The development of new therapeutic strategies selectively targeting TICs while sparing NSCs may provide for more effective treatment of malignant gliomas. PMID:19189072

  19. Malignant gliomas: old and new systemic treatment approaches

    PubMed Central

    Mesti, Tanja

    2016-01-01

    Abstract Background Malignant (high-grade) gliomas are rapidly progressive brain tumours with very high morbidity and mortality. Until recently, treatment options for patients with malignant gliomas were limited and mainly the same for all subtypes of malignant gliomas. The treatment included surgery and radiotherapy. Chemotherapy used as an adjuvant treatment or at recurrence had a marginal role. Conclusions Nowadays, the treatment of malignant gliomas requires a multidisciplinary approach. The treatment includes surgery, radiotherapy and chemotherapy. The chosen approach is more complex and individually adjusted. By that, the effect on the survival and quality of life is notable higher. PMID:27247544

  20. Countermeasures for Space Radiation Induced Malignancies and Acute Biological Effects

    NASA Astrophysics Data System (ADS)

    Kennedy, Ann

    The hypothesis being evaluated in this research program is that control of radiation induced oxidative stress will reduce the risk of radiation induced adverse biological effects occurring as a result of exposure to the types of radiation encountered during space travel. As part of this grant work, we have evaluated the protective effects of several antioxidants and dietary supplements and observed that a mixture of antioxidants (AOX), containing L-selenomethionine, N-acetyl cysteine (NAC), ascorbic acid, vitamin E succinate, and alpha-lipoic acid, is highly effective at reducing space radiation induced oxidative stress in both in vivo and in vitro systems, space radiation induced cytotoxicity and malignant transformation in vitro [1-7]. In studies designed to determine whether the AOX formulation could affect radiation induced mortality [8], it was observed that the AOX dietary supplement increased the 30-day survival of ICR male mice following exposure to a potentially lethal dose (8 Gy) of X-rays when given prior to or after animal irradiation. Pretreatment of animals with antioxidants resulted in significantly higher total white blood cell and neutrophil counts in peripheral blood at 4 and 24 hours following exposure to doses of 1 Gy and 8 Gy. Antioxidant treatment also resulted in increased bone marrow cell counts following irradiation, and prevented peripheral lymphopenia following 1 Gy irradiation. Supplementation with antioxidants in irradiated animals resulted in several gene expression changes: the antioxidant treatment was associated with increased Bcl-2, and decreased Bax, caspase-9 and TGF-β1 mRNA expression in the bone marrow following irradiation. These results suggest that modulation of apoptosis may be mechanistically involved in hematopoietic system radioprotection by antioxidants. Maintenance of the antioxidant diet was associated with improved recovery of the bone marrow following sub-lethal or potentially lethal irradiation. Taken together

  1. Trends in Malignant Glioma Monoclonal Antibody Therapy

    PubMed Central

    Chekhonin, Ivan; Gurina, Olga

    2015-01-01

    Although new passive and active immunotherapy methods are emerging, unconjugated monoclonal antibodies remain the only kind of biological preparations approved for high-grade glioma therapy in clinical practice. In this review, we combine clinical and experimental data discussion. As antiangiogenic therapy is the standard of care for recurrent glioblastoma multiforme (GBM), we analyze major clinical trials and possible therapeutic combinations of bevacizumab, the most common monoclonal antibody to vascular endothelial growth factor (VEGF). Another humanized antibody to gain recognition in GBM is epidermal growth factor (EGFR) antagonist nimotuzumab. Other antigens (VEGF receptor, platelet-derived growth factor receptor, hepatocyte growth factor and c-Met system) showed significance in gliomas and were used to create monoclonal antibodies applied in different malignant tumors. We assess the role of genetic markers (isocitrate dehydrogenase, O6-methylguanine-DNA methyltransnsferase) in GBM treatment outcome prediction. Besides antibodies studied in clinical trials, we focus on perspective targets and briefly list other means of passive immunotherapy.

  2. Virotherapy against malignant glioma stem cells.

    PubMed

    Dey, Mahua; Ulasov, Ilya V; Lesniak, Maciej S

    2010-03-01

    Glioblastoma multiforme, the most common primary intracranial malignancy, is associated with very poor outcome despite advances in surgical techniques and chemo- and radiation therapy. Many novel treatment modalities are being investigated with varying amount of success. Evolution of cancer stem cell hypothesis provides a new venue for developmental therapeutics. In this review, we highlight the literature regarding the existence of glioma stem cells and their characteristics. We also discuss the potential for virotherapy, a novel therapeutic approach utilizing conditionally replicative viruses, to directly target this population of self-renewing cancer stem cells. PMID:19643532

  3. Virotherapy Against Malignant Glioma Stem Cells

    PubMed Central

    Dey, Mahua; Ulasov, Ilya V.; Lesniak, Maciej S.

    2009-01-01

    Glioblastoma multiforme, the most common primary intracranial malignancy, is associated with very poor outcome despite advances in surgical techniques and chemo- and radiation therapy. Many novel treatment modalities are being investigated with varying amount of success. Evolution of cancer stem cell hypothesis provides a new venue for developmental therapeutics. In this review, we highlight the literature regarding the existence of glioma stem cells and their characteristics. We also discuss the potential for virotherapy, a novel therapeutic approach utilizing conditionally replicative viruses, to directly target this population of self-renewing cancer stem cells. PMID:19643532

  4. Survival after stereotactic biopsy of malignant gliomas

    SciTech Connect

    Coffey, R.J.; Lunsford, L.D.; Taylor, F.H.

    1988-03-01

    For many patients with malignant gliomas in inaccessible or functionally important locations, stereotactic biopsy followed by radiation therapy (RT) may be a more appropriate initial treatment than craniotomy and tumor resection. We studied the long term survival in 91 consecutive patients with malignant gliomas diagnosed by stereotactic biopsy: 64 had glioblastoma multiforme (GBM) and 27 had anaplastic astrocytoma (AA). Sixty-four per cent of the GBMs and 33% of the AAs involved deep or midline cerebral structures. The treatment prescribed after biopsy, the tumor location, the histological findings, and the patient's age at presentation (for AAs) were statistically important factors determining patient survival. If adequate RT (tumor dose of 5000 to 6000 cGy) was not prescribed, the median survival was less than or equal to 11 weeks regardless of tumor histology or location. The median survival for patients with deep or midline tumors who completed RT was similar in AA (19.4 weeks) and GBM (27 weeks) cases. Histology was an important predictor of survival only for patients with adequately treated lobar tumors. The median survival in lobar GBM patients who completed RT was 46.9 weeks, and that in lobar AA patients who completed RT was 129 weeks. Cytoreductive surgery had no statistically significant effect on survival. Among the clinical factors examined, age of less than 40 years at presentation was associated with prolonged survival only in AA patients. Constellations of clinical features, tumor location, histological diagnosis, and treatment prescribed were related to survival time.

  5. [The immunosuppressive microenvironment of malignant gliomas].

    PubMed

    Borisov, K E; Sakaeva, D D

    2015-01-01

    The dogma of the central nervous system (CNS) as an immune-privileged site has been substantially revised in recent years. CNS is an immunocompetent organ and actively interacts with the immune system. Microglia plays a leading role in a CNS immune response. However, in malignant gliomas, there is M2-polarization of microglia acquiring immunosuppressive and tumor-supportive properties. It occurs under the influence of tumor cytokines, such as transforming growth factor-β, interleukin-10, and prostaglandin E2. M2-polarized microglia exhibits reduced phagocytic activity, changes in the expression of many cellular determinants, or inverse of their functions, STAT3 activation, and production of immunosuppressive cytokines that suppress the function of cytotoxic CD8+ T cells or CD4+ T-helper cells type I. Myeloid-derived suppressor cells and regulatory T-lymphocytes, which have been recruited from peripheral blood into tumor tissue, also have immunosuppressive properties. The development of new treatment options for malignant gliomas must consider the role of the microenvironment in maintaining tumor vitality and progression. PMID:26841651

  6. Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization.

    PubMed

    Kim, Young-Heon; Yoo, Ki-Chun; Cui, Yan-Hong; Uddin, Nizam; Lim, Eun-Jung; Kim, Min-Jung; Nam, Seon-Young; Kim, In-Gyu; Suh, Yongjoon; Lee, Su-Jae

    2014-11-01

    Given its contribution to malignant phenotypes of cancer, tumor hypoxia has been considered as a potential therapeutic problem. In the stressful microenvironment condition, hypoxia inducible factor 1 (HIF1) is well known to mediate the transcriptional adaptation of cells to hypoxia and acts as a central player for the process of hypoxia-driven malignant cancer progression. Here, we found that irradiation causes the HIF1α protein to stabilize, even in normoxia condition through activation of p38 MAPK, thereby promoting angiogenesis in tumor microenvironment and infiltrative property of glioma cells. Notably, irradiation reduced hydroxylation of HIF1α through destabilization of prolyl hydroxylases (PHD)-2. Moreover, radiation also decreased the half-life of protein von Hippel-Lindau (pVHL), which is a specific E3 ligase for HIF1α. Of note, inhibition of p38 MAPK attenuated radiation-induced stabilization of HIF1α through destabilization of PHD-2 and pVHL. In agreement with these results, targeting of either p38 MAPK, HIF1α, pVHL or PHD-2 effectively mitigated the radiation-induced tube formation of human brain-derived micro-vessel endothelial cells (HB-MEC) and infiltration of glioma cells. Taken together, our findings suggest that targeting HIF1α in combination with ionizing radiation might increase the efficacy of radiotherapy for glioma treatment. PMID:25109450

  7. Mechanisms of Chemoresistance in Malignant Glioma

    PubMed Central

    Sarkaria, Jann N.; Kitange, Gaspar J.; James, C. David; Plummer, Ruth; Calvert, Hilary; Weller, Michael; Wick, Wolfgang

    2008-01-01

    Intrinsic or acquired chemoresistance is a major cause of treatment failure in patients with malignant brain tumors. Alkylating agents, the mainstay of treatment for brain tumors, damage the DNA and induce apoptosis, but the cytotoxic activity of these agents is dependent on DNA repair pathways. For example, O6-methylguanine DNA adducts can cause double-strand breaks, but this is dependent on a functional mismatch repair (MMR) pathway. Thus, tumor cell lines deficient in MMR are resistant to alkylating agents. Perhaps the most important mechanism of resistance to alkylating agents is the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), which can eliminate the cytotoxic O6-methylguanine DNA adduct before it causes harm. Another mechanism of resistance to alkylating agents is the base excision repair (BER) pathway. Consequently, efforts are ongoing to develop effective inhibitors of BER. Poly(ADP-ribose)polymerase (PARP-1) plays a pivotal role in BER and is an important therapeutic target. Developing effective strategies to overcome chemoresistance requires the identification of reliable preclinical models that recapitulate human disease and can be used to facilitate drug development. This manuscript describes the diverse mechanisms of chemoresistance operating in malignant glioma and efforts to develop reliable preclinical models and novel pharmacologic approaches to overcome resistance to alkylating agents. PMID:18483356

  8. Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species

    PubMed Central

    Alan Mitteer, R.; Wang, Yanling; Shah, Jennifer; Gordon, Sherika; Fager, Marcus; Butter, Param-Puneet; Jun Kim, Hyun; Guardiola-Salmeron, Consuelo; Carabe-Fernandez, Alejandro; Fan, Yi

    2015-01-01

    Glioblastoma multiforme (GBM) is among the most lethal of human malignancies. Most GBM tumors are refractory to cytotoxic therapies. Glioma stem cells (GSCs) significantly contribute to GBM progression and post-treatment tumor relapse, therefore serving as a key therapeutic target; however, GSCs are resistant to conventional radiation therapy. Proton therapy is one of the newer cancer treatment modalities and its effects on GSCs function remain unclear. Here, by utilizing patient-derived GSCs, we show that proton radiation generates greater cytotoxicity in GSCs than x-ray photon radiation. Compared with photon radiation, proton beam irradiation induces more single and double strand DNA breaks, less H2AX phosphorylation, increased Chk2 phosphorylation, and reduced cell cycle recovery from G2 arrest, leading to caspase-3 activation, PARP cleavage, and cell apoptosis. Furthermore, proton radiation generates a large quantity of reactive oxygen species (ROS), which is required for DNA damage, cell cycle redistribution, apoptosis, and cytotoxicity. Together, these findings indicate that proton radiation has a higher efficacy in treating GSCs than photon radiation. Our data reveal a ROS-dependent mechanism by which proton radiation induces DNA damage and cell apoptosis in GSCs. Thus, proton therapy may be more efficient than conventional x-ray photon therapy for eliminating GSCs in GBM patients. PMID:26354413

  9. Fluorescence-Guided Resection of Malignant Glioma with 5-ALA

    PubMed Central

    Kaneko, Sadahiro

    2016-01-01

    Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD. PMID:27429612

  10. Fluorescence-Guided Resection of Malignant Glioma with 5-ALA.

    PubMed

    Kaneko, Sadahiro; Kaneko, Sadao

    2016-01-01

    Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD. PMID:27429612

  11. [Oncolytic viruses for therapy of malignant glioma].

    PubMed

    Sosnovtceva, A O; Grinenko, N F; Lipatova, A V; Chumakov, P M; Chekhonin, V P

    2016-05-01

    Effective treatment of malignant brain tumors is still an open problem. Location of tumor in vital areas of the brain significantly limits capasities of surgical treatment. The presence of tumor stem cells resistant to radiation and anticancer drugs in brain tumor complicates use of chemoradiotherapy and causes a high rate of disease recurrence. A technological improvement in bioselection and production of recombinant resulted in creation of viruses with potent oncolytic properties against glial tumors. Recent studies, including clinical trials, showed, that majority of oncolytic viruses are safe. Despite the impressive results of the viral therapy in some patients, the treatment of other patients is not effective; therefore, further improvement of the methods of oncolytic virotherapy is necessary. High genetic heterogeneity of glial tumor cells even within a single tumor determines differences in individual sensitivity of tumor cells to oncolytic viruses. This review analyses the most successful oncolytic virus strains, including those which had reached clinical trials, and discusses the prospects for new approaches to virotherapy of gliomas. PMID:27562991

  12. MicroRNAs and cell cycle of malignant glioma.

    PubMed

    Ouyang, Qing; Xu, Lunshan; Cui, Hongjuan; Xu, Minhui; Yi, Liang

    2016-01-01

    The control of malignant glioma cell cycle by microRNAs (miRNAs) is well established. The deregulation of miRNAs in glioma may contribute to tumor proliferation by directly targeting the critical cell-cycle regulators. Tumor suppressive miRNAs inhibit cell cycle through repressing the expression of positive cell-cycle regulators. However, oncogenic miRNAs promote the cell-cycle progression by targeting cell-cycle negative regulators. Recent studies have identified that transcription factors had involved in the expression of miRNAs. Transcription factors and miRNAs are implicated in regulatory network of glioma cell cycle, the deregulation of these transcription factors might be a cause of the deregulation of miRNAs. Abnormal versions of miRNAs have been implicated in the cell cycle of glioma. Based on those, miRNAs are excellent biomarker candidates and potential targets for therapeutic intervention in glioma. PMID:26000816

  13. Malignant glioma - timing of response to radiation therapy

    SciTech Connect

    Gaspar, L.E.; Fisher, B.J.; MacDonald, D.R.; Cairncross, J.G. London Regional Cancer Centre, Ontario ); LeBer, D.V. ); Halperin, E.C.; Schold, S.C. Jr. )

    1993-04-02

    The response of malignant gliomas to radiation was examined retrospectively in 71 patients with newly diagnosed supratentorial malignant gliomas. Questions asked included frequency, timing and clinical significance of response. After surgery, all were treated with whole brain plus boost radiotherapy followed 8 weeks later by chemotherapy. The rate, degree, and timing of response to radiation were determined by comparing postoperative, end of radiation, and prechemotherapy CT scans on each patient. Postoperative residual tumor was evident on 63/71 postoperative scans. Twenty-two of 63 tumors (35%) had a partial or complete response to radiation. Twenty (32%) had responded by the end of radiation; 17 maximally. Six to 8 weeks later, three responding tumors had responded further and two previously stable ones had begun to respond. Only three tumors (5%) responded completely. A greater proportion of anaplastic gliomas than glioblastomas responded to radiation (52% vs. 26%). Protracted or delayed responses were only observed in patients with anaplastic glioma. Patients who responded to radiation did not live significantly longer than non-responders. However, tumor progression prior to chemotherapy was associated with significantly shorter survival. This CT scan-based analysis demonstrates that malignant gliomas are only moderately radioresponsive tumors and also demonstrates that response to radiation, if it is going to occur, is usually evident by the end of treatment. 6 refs., 1 fig., 1 tab.

  14. Mutant tristetraprolin: a potent inhibitor of malignant glioma cell growth

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Malignant gliomas rely on the production of certain critical growth factors including VEGF, interleukin (IL)-6 and IL-8, to fuel rapid tumor growth, angiogenesis, and treatment resistance. Post-transcriptional regulation through adenine and uridine-rich elements of the 3' untranslated region is one ...

  15. Evolved Cellular Mechanisms to Respond to Genotoxic Insults: Implications for Radiation-Induced Hematologic Malignancies.

    PubMed

    Fleenor, Courtney J; Higa, Kelly; Weil, Michael M; DeGregori, James

    2015-10-01

    Human exposure to ionizing radiation is highly associated with adverse health effects, including reduced hematopoietic cell function and increased risk of carcinogenesis. The hematopoietic deficits manifest across blood cell types and persist for years after radiation exposure, suggesting a long-lived and multi-potent cellular reservoir for radiation-induced effects. As such, research has focused on identifying both the immediate and latent hematopoietic stem cell responses to radiation exposure. Radiation-associated effects on hematopoietic function and malignancy development have generally been attributed to the direct induction of mutations resulting from radiation-induced DNA damage. Other studies have illuminated the role of cellular programs that both limit and enhance radiation-induced tissue phenotypes and carcinogenesis. In this review, distinct but collaborative cellular responses to genotoxic insults are highlighted, with an emphasis on how these programmed responses impact hematopoietic cellular fitness and competition. These radiation-induced cellular programs include apoptosis, senescence and impaired self-renewal within the hematopoietic stem cell (HSC) pool. In the context of sporadic DNA damage to a cell, these cellular responses act in concert to restore tissue function and prevent selection for adaptive oncogenic mutations. But in the contexts of whole-tissue exposure or whole-body exposure to genotoxins, such as radiotherapy or chemotherapy, we propose that these programs can contribute to long-lasting tissue impairment and increased carcinogenesis. PMID:26414506

  16. Interrelationship between differentiation and malignancy-associated properties in glioma.

    PubMed Central

    Frame, M. C.; Freshney, R. I.; Vaughan, P. F.; Graham, D. I.; Shaw, R.

    1984-01-01

    The phenotypic expression of cells derived from human anaplastic astrocytomas, rat glioma, normal human adult and foetal brain tissue have been examined for differentiated and malignancy-associated properties. Glial fibrillary acidic protein (GFAP), high affinity glutamate and gamma-amino butyric acid (GABA) uptake and glutamine synthetase were used as indicators of astroglial differentiation. Plasminogen activator and tumour angiogenesis factor were the malignancy-associated markers. The normal adult brain-derived lines showed some differentiated astroglial features and expressed low levels of the malignancy-associated properties. The foetal cultures contained highly differentiated astroglia while the glioma lines showed considerable phenotypic heterogeneity from highly differentiated to undifferentiated. The least differentiated glioma cells exhibited the highest plasminogen activator activities. The density-dependent control of phenotypic expression was also investigated. High affinity GABA uptake, and GFAP in rat C6 glioma cultures, increased with increasing monolayer cell density, events probably mediated by an increase in the formation of cell-cell contacts at confluence. Plasminogen activator activity decreased with increasing cell density. Images Figure 2 Figure 6 PMID:6200130

  17. Treatment With Bevacizumab Plus Carboplatin for Recurrent Malignant Glioma

    PubMed Central

    Thompson, Eric M.; Dosa, Edit; Kraemer, Dale F.; Neuwelt, Edward A.

    2016-01-01

    Objective To estimate overall survival (OS), progression-free survival (PFS), imaging responses, and toxicities of bevacizumab plus carboplatin for the treatment of recurrent malignant glioma. The secondary objective was to estimate the agreement between post-contrast T1-weighted and T2-weighted magnetic resonance imaging. Methods A retrospective analysis of 9 patients who received bevacizumab (10 mg/kg intravenously) and carboplatin (AUC 5 intravenously) for recurrent malignant glioma (World Health Organization grades III and IV) is presented. Eight of 9 patients received this regimen at first recurrence. Results The median age and Karnofsky performance score were 51 years and 70, respectively. For the 5 patients with grade III gliomas, the median PFS was 126 days, whereas median OS was not attained at 517 days of follow-up. Six-month PFS was 40%, whereas 6-month OS was 60%. For the 4 patients with grade IV gliomas, the median PFS was 216 days, whereas the median OS was not attained at 482 days of follow-up. Six-month PFS was 50%, whereas 6-month OS was 75%. The agreement between contrast-enhanced T1-weighted and T2-weighted images to determine recurrence was moderate (kappa = 0.5714). Three patients had grade 3 and 4 toxicities including hyponatremia and thrombocytopenia. Conclusion Patients who received the combination of bevacizumab plus carboplatin for recurrent malignant glioma had reasonable PFS, OS, and toxicities. The median OS in our series is promising at well over 1 year. Agreement between postcontrast T1- and T2-weighted images is only moderate in the context of bevacizumab therapy. PMID:20559095

  18. MR assessment of radiation-induced blood-brain barrier permeability changes in a rat glioma model

    SciTech Connect

    Krueck, W.G. Univ. of Washington School of Medicine, Seattle, WA ); Schmiedl, U.P.; Maravilla, K.R.; Starr, F.L.; Kenney, J. )

    1994-04-01

    To assess the potential of a T1-weighted, gadolinium-enhanced MR technique for quantifying radiation-induced changes of blood-brain barrier permeability in a model of stereotactically implanted intracerebral gliomas in rats. We calculated the gadolinium blood-to-tissue transport coefficient for gadopentetate dimeglumine from signal intensities in sequential MR images in nine control animals that were not irradiated and in five and three animals that had received 2500 cGy and 1500 cGy whole-brain irradiation, respectively, at 2 days before imaging. The average blood-to-tissue transport coefficient values were 9.76 mL[center dot]kg[sup [minus]1][center dot]min[sup [minus]1] in the control group, 23.41 mL[center dot]kg[sup [minus]1][center dot]min[sup [minus]1] in the 2500-cGy group, and 25.63 mL[center dot]kg[sup [minus]1][center dot]min[sup [minus]1] in the 1500-cGy group. Blood-to-tissue transport coefficients were significantly higher after irradiation, indicating increased radiation-induced blood-brain barrier permeability. Similar increased blood-brain barrier leakiness in brain tumors after high-dose irradiation has been shown by previous nuclear medicine studies using quantitative autoradiography. Contrast-enhanced dynamic MR of brain gliomas is a sensitive method to document radiation-induced blood-brain barrier breakdown. Quantitative gadolinium-enhanced MR may become a useful tool for the management of patients with brain tumors undergoing radiation therapy. 28 refs., 4 figs., 1 tab.

  19. Risk of Radiation-Induced Malignancy With Heterotopic Ossification Prophylaxis: A Case–Control Analysis

    SciTech Connect

    Sheybani, Arshin; TenNapel, Mindi J.; Lack, William D.; Clerkin, Patrick; Hyer, Daniel E.; Sun, Wenqing; Jacobson, Geraldine M.

    2014-07-01

    Purpose: To determine the risk of radiation-induced malignancy after prophylactic treatment for heterotopic ossification (HO). Methods and Materials: A matched case–control study was conducted within a population-based cohort of 3489 patients treated either for acetabular fractures with acetabular open reduction internal fixation or who underwent total hip arthroplasty from 1990 to 2009. Record-linkage techniques identified patients who were diagnosed with a malignancy from our state health registry. Patients with a prior history of malignancy were excluded from the cohort. For each documented case of cancer, 2 controls were selected by stratified random sampling from the cohort that did not develop a malignancy. Matching factors were sex, age at time of hip treatment, and duration of follow-up. Results: A total of 243 patients were diagnosed with a malignancy after hip treatment. Five patients were excluded owing to inadequate follow-up time in the corresponding control cohort. A cohort of 238 cases (control, 476 patients) was included. Mean follow-up was 10 years, 12 years in the control group. In the cancer cohort, 4% of patients had radiation therapy (RT), compared with 7% in the control group. Of the 9 patients diagnosed with cancer after RT, none occurred within the field. The mean latency period was 5.9 years in the patients who received RT and 6.6 years in the patients who did not. Median (range) age at time of cancer diagnosis in patients who received RT was 62 (43-75) years, compared with 70 (32-92) years in the non-RT patients. An ad hoc analysis was subsequently performed in all 2749 patients who were not matched and found neither an increased incidence of malignancy nor a difference in distribution of type of malignancy. Conclusion: We were unable to demonstrate an increased risk of malignancy in patients who were treated with RT for HO prophylaxis compared with those who were not.

  20. Integrated genomic characterization of IDH1-mutant glioma malignant progression

    PubMed Central

    Bai, Hanwen; Harmanci, Akdes Serin; Erson-Omay, E Zeynep; Li, Jie; Coşkun, Süleyman; Simon, Matthias; Krischek, Boris; Özduman, Koray; Omay, S Bülent; Sorensen, Eric A; Turcan, Şevin; Bakırcığlu, Mehmet; Carrión-Grant, Geneive; Murray, Phillip B; Clark, Victoria E; Ercan-Sencicek, A Gulhan; Knight, James; Sencar, Leman; Altınok, Selin; Kaulen, Leon D; Gülez, Burcu; Timmer, Marco; Schramm, Johannes; Mishra-Gorur, Ketu; Henegariu, Octavian; Moliterno, Jennifer; Louvi, Angeliki; Chan, Timothy A; Tannheimer, Stacey L; Pamir, M Necmettin; Vortmeyer, Alexander O; Bilguvar, Kaya; Yasuno, Katsuhito; Günel, Murat

    2016-01-01

    Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors1. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach. PMID:26618343

  1. Radiation-induced malignant fibrous histiocytoma of the occipital: a case report.

    PubMed

    Zhang, Guo-Bin; Li, Jian; Zhang, Peng-Fei; Han, Li-Jiang; Zhang, Jun-Ting

    2014-01-01

    Malignant fibrous histiocytoma (MFH) is a rare neoplasm exhibiting a propensity for aggressive clinical behavior. Effective treatment modality is surgical resection with wide margins, but its rate of recurrence and metastasis is still high. Early detection and complete excision of the tumor is necessary. A MFH of the occipital developed in a 51-year-old woman eight years after surgery and radiation for medulloblastoma of the cerebellar vermis. The secondary neoplasm arose at the site of tumor resection within the irradiated field, and was resected. The development of sarcomas is a recognized complication of radiation therapy. The final diagnosis after the operation was MFH. Radiation-induced sarcoma (RIS) is well known, but radiation-induced MFH is relatively rare in the head and neck region, especially in the occipital. The imaging findings are not diagnosis specific, but strict follow-up within the radiation field by computerized tomography (CT) and magnetic resonance imaging (MRI) and appreciation of the expected latency period may help in providing the diagnosis of RIS. PMID:24742094

  2. [The issue of low doses in radiation therapy and impact on radiation-induced secondary malignancies].

    PubMed

    Chargari, Cyrus; Cosset, Jean-Marc

    2013-12-01

    Several studies have well documented that the risk of secondary neoplasms is increasing among patients having received radiation therapy as part of their primary anticancer treatment. Most frequently, radiation-induced neoplasms occur in volume exposed to high doses. However, the impact of "low" doses (<5 Gy) in radiation-induced carcinogenesis should be clinically considered because modern techniques of intensity-modulated radiation therapy (IMRT) or stereotactic irradiation significantly increase tissue volumes receiving low doses. The risk inherent to these technologies remains uncertain and estimates closely depend on the chosen risk model. According to the (debated) linear no-threshold model, the risk of secondary neoplasms could be twice higher with IMRT, as compared to conformal radiation therapy. It seems that only proton therapy could decrease both high and low doses delivered to non-target volumes. Except for pediatric tumors, for which the unequivocal risk of second malignancies (much higher than in adults) should be taken into account, epidemiological data suggest that the risk of secondary cancer related to low doses could be very low, even negligible in some cases. However, clinical follow-up remains insufficient and a marginal increase in secondary tumors could counterbalance the benefit of a highly sophisticated irradiation technique. It therefore remains necessary to integrate the potential risk of new irradiation modalities in a risk-adapted strategy taking into account therapeutic objectives but also associated risk factors, such as age (essentially), chemotherapy, or life style. PMID:24257106

  3. [Current situation and future prospects of radiotherapy for malignant gliomas].

    PubMed

    Terahara, Atsuro

    2013-10-01

    Prognosis of malignant gliomas remains poor, although adjuvant radiotherapy increases survival time. To improve treatment outcomes, high-precision radiotherapy techniques such as three-dimensional conformal radiotherapy, stereotactic irradiation, intensity modulated radiotherapy, and charged particle radiotherapy have been developed for dose distribution optimization and dose escalation. Improvements in clinical outcomes with these new treatment strategies have been reported; however, the efficacy of these treatment strategies has not yet been verified in randomized trials. Further development of radiation delivery techniques, including boron neutron capture therapy, and ways of achieving more adequate target volume delineation using modern multimodality imaging technology are currently being intensively investigated to further improve patient outcomes. PMID:24105051

  4. Experimental approaches for the treatment of malignant gliomas

    PubMed Central

    Arko, Leopold; Katsyv, Igor; Park, Grace E.; Luan, William Patrick; Park, John K.

    2010-01-01

    Malignant gliomas, which include glioblastomas and anaplastic astrocytomas, are the most common primary tumors of the brain. Over the past 30 years, the standard treatment for these tumors has evolved to include maximal safe surgical resection, radiation therapy and temozolomide chemotherapy. While the median survival of patients with glioblastomas has improved from 6 months to 14.6 months, these tumors continue to be lethal for the vast majority of patients. There has, however, been recent substantial progress in our mechanistic understanding of tumor development and growth. The translation of these genetic, epigenetic and biochemical findings into therapies that have been tested in clinical trials is the subject of this review. PMID:20546782

  5. A malignant cellular network in gliomas: potential clinical implications.

    PubMed

    Osswald, Matthias; Solecki, Gergely; Wick, Wolfgang; Winkler, Frank

    2016-04-01

    The recent discovery of distinct, ultra-long, and highly functional membrane protrusions in gliomas, particularly in astrocytomas, extends our understanding of how these tumors progress in the brain and how they resist therapies. In this article, we will focus on ideas on how to target these membrane protrusions, for which we have suggested the term "tumor microtubes" (TMs), and the malignant multicellular network they form. First, we discuss TM-specific features and their differential biological functions known so far. Second, the connection between 1p/19q codeletion and the inability to form functional TMs via certain neurodevelopmental pathways is presented; this could provide an explanation for the distinct clinical features of oligodendrogliomas. Third, the role of TMs for primary and potentially also adaptive resistance to cytotoxic therapies is highlighted. Fourth, avenues for therapeutic approaches to inhibit TM formation and/or function are discussed, with a focus on disruption (or exploitation) of network functionality. Finally, we propose ideas on how to use TMs as a biomarker in glioma patients. An increasing understanding of TMs in clinical and preclinical settings will show us whether they really are a long-sought-after Achilles' heel of treatment-resistant gliomas. PMID:26995789

  6. Emerging methods for disease monitoring in malignant gliomas

    PubMed Central

    Ambady, Prakash; Bettegowda, Chetan; Holdhoff, Matthias

    2016-01-01

    Summary MRI remains the backbone of measuring disease burden and treatment response in individuals with malignant gliomas. Traditional radiographic approaches, however, are largely limited to depicting anatomic changes and are not a direct measure of disease burden. For example, contrast enhancement is related to blood–brain barrier integrity rather than actual tumor size. Without accurate measures of disease, common clinical dilemmas include ‘pseudo-progression’ (e.g., after chemoradiation) or ‘pseudo-response’ (e.g., with steroid treatment and antiangiogenic agents), which can lead to delays in therapy, premature discontinuation of successful treatments and to unnecessary surgical procedures. This overview focuses on novel, minimally invasive approaches in the area of imaging and blood-based biomarkers that aim to more accurately determine disease status and response to treatment in malignant brain tumors. PMID:25054821

  7. Hypofractionated stereotactic radiotherapy combined with topotecan in recurrent malignant glioma

    SciTech Connect

    Wurm, Reinhard E. . E-mail: Reinhard.Wurm@charite.de; Kuczer, David A.; Schlenger, Lorenz; Matnjani, Gesa; Scheffler, Dirk; Cosgrove, Vivian P.; Ahlswede, Julia; Woiciechowsky, Christian; Budach, Volker

    2006-11-15

    Purpose: To assess hypofractionated stereotactic radiotherapy (H-SRT) with concurrent topotecan in patients with recurrent malignant glioma. Methods and Materials: Between February 1998 and December 2001, 25 patients with recurrent malignant glioma were treated in a phase I-II study (8 females and 17 males; median age, 45 years; range, 11-66 years; median Karnofsky performance status, 80%, range, 50-100%; median Mini Mental Standard Examination score, 25 points; range, 10-30 points). Of the 25 patients, 20% had World Health Organization Grade III and 80% World Health Organization Grade IV glioma. All patients had been treated previously by external beam radiotherapy with 54.4 Gy in 34 fractions twice daily, at least 6 h apart, within 3.5 weeks or 60 Gy in 30 fractions within 6 weeks. In addition, 84% had already received at least one chemotherapy regimen for recurrence. The median H-SRT dose at the 80% isodose was 25 Gy, and the maximal dose was 30 Gy delivered in five to six fractions on consecutive days. Topotecan (1.1 mg/m{sup 2}/d) was given as a continuous i.v. infusion during H-SRT. Depending on the toxicity and compliance, patients received an additional 48 topotecan courses. Results: For all patients, the actuarial median progression-free survival was 10.5 months (range, 1.4-47.8 months), the median functional survival was 12.6 months (range, 1.6-49.5 months), and the median overall survival was 14.5 months (range, 3-56.4 months). Twelve percent of patients developed presumed adverse radiation effects (Radiation Therapy Oncology Group Grade 2). According to the Common Toxicity Criteria, version 2.0, no topotecan-related Grade 4 toxicity was noted. Grade 3 neutropenia was documented after 14 and Grade 3 thrombopenia after 12 courses. Conclusion: H-SRT with topotecan is feasible and well-tolerated in patients with recurrent high-grade glioma and results in similar survival compared with other repeat treatment modalities.

  8. Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas

    SciTech Connect

    Hegarty, T.J.; Thornton, A.F.; Diaz, R.F.; Chandler, W.F.; Ensminger, W.D.; Junck, L.; Page, M.A.; Gebarski, S.S.; Hood, T.W.; Stetson, P.L. )

    1990-08-01

    In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas.

  9. Photochemical internalization for the treatment of malignant gliomas

    NASA Astrophysics Data System (ADS)

    Madsen, Steen J.; Kharkhuu, Khishigzaya; Berg, Kristian; Hirschberg, Henry

    2007-02-01

    Photochemical internalization (PCI) is a technique to improve the utilization of macromolecules (e.g. chemotherapeutic agents) in cancer therapy in a site-specific manner. The concept is based on the use of specially designed photosensitizers which localize preferentially in the membranes of endocytic vesicles. Upon exposure to light the photosensitizers induce the formation of reactive oxygen species such as singlet molecular oxygen. The photooxidation of the endocytic membranes leads to the release of the contents of the vesicles into the cytosol. In this way, macromolecules encapsulated by the vesicles will reach the cytosol and exert their biological activity instead of being degraded by lysosomal hydrolases. The utility of PCI for the treatment of malignant gliomas was investigated in vitro using an F98 rat glioma cell line. The cytotoxicity of 5-aminolevulinic acid (ALA) based PCI of bleomycin was compared to: (1) ALA-PDT, and (2) bleomycin. In all cases, monolayers were incubated in ALA, bleomycin, or ALA + bleomycin for 4 hours and were subsequently exposed to 635 nm light. Toxicity was evaluated using colony formation assays. F98 rat glioma cells in monolayer were found to be susceptible to the effects of both ALA-PDT and bleomycin. ALA-PDT was found to be particularly effective when light was delivered at a low irradiance of 5 mW cm -2. In this case, a radiant exposure of 20 J cm -2 resulted in only 4% survival. Bleomycin was found to be toxic at relatively low concentrations, incubation of F98 cells in 10 μg ml -1 for 4 hours resulted in 1% survival. The PCI effect was found to be negligible for the parameters investigated in the F98 cell line suggesting that: (1) the incubation time was sub-optimal and/or (2) ALA was inappropriate for this application.

  10. Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies

    PubMed Central

    Thaker, Nikhil G; Pollack, Ian F

    2010-01-01

    Median survival of patients with malignant glioma (MG) from time of diagnosis is approximately 1 year, despite surgery, irradiation and conventional chemotherapy. Improving patient outcome relies on our ability to develop more effective therapies that are directed against the unique molecular aberrations within a patient’s tumor. Such molecularly targeted therapies may provide novel treatments that are more effective than conventional chemotherapeutics. Recently developed therapeutic strategies have focused on targeting several core glioma signaling pathways, including pathways mediated by growth-factors, PI3K/Akt/PTEN/mTOR, Ras/Raf/MEK/MAPK and other vital pathways. However, given the molecular diversity, heterogeneity and diverging and converging signaling pathways associated with MG, it is unlikely that any single agent will have efficacy in more than a subset of tumors. Overcoming these therapeutic barriers will require multiple agents that can simultaneously inhibit these processes, providing a rationale for combination therapies. This review summarizes the currently implemented single-agent and combination molecularly targeted therapies for MG. PMID:19951140

  11. Practical guidelines for the treatment of malignant gliomas.

    PubMed Central

    Chamberlain, M C; Kormanik, P A

    1998-01-01

    The treatment of patients with malignant gliomas is palliative and encompasses surgery, radiotherapy, and chemotherapy. Outcome measures have demonstrated improvement in both survival and neurologic performance in patients undergoing complete or near-complete tumor resection. After surgery, involved-field radiotherapy (radiotherapy administered to the tumor and to the tissue in a 3-cm radius surrounding the tumor) has been shown to further improve survival rates when given in a total dose of 6000-6500 cGy. Survival is further improved by the coadministration of the chemoradiopotentiator hydroxycarbamide (hydroxyurea). The role of adjuvant or boost stereotactic radiotherapy is unclear, despite its frequent use. In addition, adjuvant chemotherapy has been shown to improve survival rates in approximately one-quarter of patients with glioblastoma multiforme and in the majority of patients with anaplastic astrocytoma. No a priori method exists, however, to predict which patient will benefit from adjuvant chemotherapy. As a consequence, all physiological young patients with good performance status or limited neurologic disability are treated with chemotherapy. The best results of adjuvant chemotherapy are achieved with a nitrosourea chemotherapy, either carmustine (BCNU) or a combination of procarbazine and lomustine (CCNU) and vincristine, known as PCV-3 therapy. Salvage chemotherapy is reserved for patients with tumor progression, some of whom benefit from a re-operation. Occasional patients with recurrent gliomas may be palliated by stereotactic radiotherapy. PMID:9499745

  12. Bevacizumab for Malignant Brain Gliomas. Which is the Current Evidence?

    PubMed

    Koukourakis, Georgios V

    2015-01-01

    Recently, the improvement of innovative medications named focused treatments represents the consequence of a superior knowledge of the procedures implicated in the modification of physiological tissues in tumor. Focused treatment is known as the therapy which uses specific substances that affect selective mechanisms implicated in tumorigenesis and tumor development. Angiogenesis is important for tumor development and distant metastatic disease and represents a significant aim for modern biological substances. Bevacizumab belongs to humanized recombinant antibody family which obviates vascular endothelial growth factor (VEGF) receptor fastening, and suspending genesis of new vessels and tumor development. Bevacizumab represents the primary antiangiogenic treatment authorized for usage in tumor and has FDA authorization to treat the recurrent glioblastoma multiform since 2009. Bevacizumab's efficiency for treating malignant brain gliomas along with correlated patent appliances related to this agent is discussed below. PMID:26256461

  13. MicroRNA profiling in the malignant progression of gliomas

    NASA Astrophysics Data System (ADS)

    Stupak, E. V.; Veryaskina, Yu. A.; Titov, S. E.; Achmerova, L. G.; Stupak, V. V.; Ivanov, M. K.; Zhimulev, I. F.; Kolesnikov, N. N.

    2016-08-01

    Wealth of data indicates that microRNAs (miRNAs) are directly involved in carcinogenesis and that miRNA can, on their own, act as diagnostic and prognostic markers for various types of cancers, including gliomas. The aim of this study was to conduct a comparative analysis of expression profile for 10 microRNAs (miR-124, -125b, -16, -181b, -191, -21, -221, -223, -31, and -451) in surgical specimens of various hystotypes of glioimatissues vs adjacent normal tissues from the same patient (n = 77). The study identified specific microRNA expression profiles for different histotypes of tumors that are related to their degree of malignancy. We have outlined approaches to development of miRNA-based diagnostic and prognostic panel, which may be used to compensate for the lack of appropriate screening methods.

  14. [Glutamate and malignant gliomas, from epilepsia to biological aggressiveness: therapeutic implications].

    PubMed

    Blecic, Serge; Rynkowski, Michal; De Witte, Olivier; Lefranc, Florence

    2013-09-01

    In this review article, we describe the unrecognized roles of glutamate and glutamate receptors in malignant glioma biology. The neurotransmitter glutamate released from malignant glioma cells in the extracellular matrix is responsible for seizure induction and at higher concentration neuronal cell death. This neuronal cell death will create vacated place for tumor growth. Glutamate also stimulates the growth and the migration of glial tumor cells by means of the activation of glutamate receptors on glioma cells in a paracrine and autocrine manner. The multitude of effects of glutamate in glioma biology supports the rationale for pharmacological targeting of glutamate receptors and transporters in the adjuvant treatment of malignant gliomas in neurology and neuro-oncology. Using the website www.clinicaltrials.gov/ as a reference - a service developed by the National Library of Medicine for the National Health Institute in USA - we have evoked the few clinical trials completed and currently ongoing with therapies targeting the glutamate receptors. PMID:23883552

  15. BI-11PROGNOSTIC microRNAS IN MALIGNANT GLIOMA

    PubMed Central

    Hayes, Josie; Thygesen, Helene; Droop, Alastair; Boissinot, Marjorie; Bellamy, Charlotte; Hughes, Thomas; Westhead, David; Shaw, Lisa; Wurdak, Heiko; Lawler, Sean; Short, Susan

    2014-01-01

    MicroRNAs are short non-coding RNAs that act as micro-managers of cellular function. Their dysregulation is well documented in many cancers. TCGA microRNA expression data is available to identify the prognostic potential of microRNAs in malignant glioma. Using the LASSO statistical approach for 475 glioblastomas in the TCGA dataset we identified a nine-microRNA signature that predicts overall (p = 2.26e-09) and progression-free survival (p = 9.91e-08) with superior power than conventional molecular markers, including MGMT methylation status. This signature has significance in all molecular subtypes of glioblastoma with the exception of the non-G-CIMP proneural group and validated in a separate validation cohort (p = 4.50E-02). The signature also predicts survival in grade II and III disease (p = 5.20e-03). The great majority of microRNAs in the signature have previously been shown to play a role in glioma biology. In addition, when we compared patient groups at the extremes of survival in grade III astrocytoma (poor prognosis n = 10, survival <18 months; good prognosis n = 6, survival > 48 months) and glioblastoma (poor prognosis n = 14, survival <4 months; good prognosis n = 13, survival > 48 months), we found that microRNA profiles aligned with specific neuro-developmental pathways were associated with outcomes. Specifically, poorer prognosis disease was associated with profiles aligned towards glial-restricted and oligodendrocyte precursor (OP) cells. Furthermore, correlation of microRNA expression patterns of OPs with expression of 39 grade III astrocytomas and 558 glioblastomas predicts survival with high significance (p= 5.50e-06), indicating that the more tightly a grade III or IV tumor correlates with an OP profile, the poorer the outcome. These observations indicate that microRNAs have predictive power in malignant glioma. MicroRNA expression patterns may also reveal important aspects of underlying tumor biology. This data, coupled with the superior

  16. Over-expression of tetraspanin 8 in malignant glioma regulates tumor cell progression

    SciTech Connect

    Pan, Si-Jian; Wu, Yue-Bing; Cai, Shang; Pan, Yi-Xin; Liu, Wei; Bian, Liu-Guan; Sun, Bomin; Sun, Qing-Fang

    2015-03-13

    Tumor cell invasion and proliferation remain the overwhelming causes of death for malignant glioma patients. To establish effective therapeutic methods, new targets implied in these processes have to be identified. Tetraspanin 8 (Tspn8) forms complexes with a large variety of trans-membrane and/or cytosolic proteins to regulate several important cellular functions. In the current study, we found that Tspn8 was over-expressed in multiple clinical malignant glioma tissues, and its expression level correlated with the grade of tumors. Tspn8 expression in malignant glioma cells (U251MG and U87MG lines) is important for cell proliferation and migration. siRNA-mediated knockdown of Tspn8 markedly reduced in vitro proliferation and migration of U251MG and U87MG cells. Meanwhile, Tspn8 silencing also increased the sensitivity of temozolomide (TMZ), and significantly increased U251MG or U87MG cell death and apoptosis by TMZ were achieved with Tspn8 knockdown. We observed that Tspn8 formed a complex with activated focal adhesion kinase (FAK) in both human malignant glioma tissues and in above glioma cells. This complexation appeared required for FAK activation, since Tspn8 knockdown inhibited FAK activation in U251MG and U87MG cells. These results provide evidence that Tspn8 contributes to the pathogenesis of glioblastoma probably by promoting proliferation, migration and TMZ-resistance of glioma cells. Therefore, targeting Tspn8 may provide a potential therapeutic intervention for malignant glioma. - Highlights: • Tspn8 is over-expressed in multiple clinical malignant glioma tissues. • Tspn8 expression is correlated with the grade of malignant gliomas. • Tspn8 knockdown suppresses U251MG/U87MG proliferation and in vitro migration. • Tspn8 knockdown significantly increases TMZ sensitivity in U251MG/U87MG cells. • Tspn8 forms a complex with FAK, required for FAK activation.

  17. Genomic dynamics associated with malignant transformation in IDH1 mutated gliomas.

    PubMed

    Park, Chul-Kee; Park, Inho; Lee, Seungmook; Sun, Choong-Hyun; Koh, Youngil; Park, Sung-Hye; Kim, Ja Eun; Yun, Hongseok; Lee, Se-Hoon

    2015-12-22

    The genomic mechanism responsible for malignant transformation remains an open question for glioma researchers, where differing conclusions have been drawn based on diverse study conditions. Therefore, it is essential to secure direct evidence using longitudinal samples from the same patient. Moreover, malignant transformation of IDH1-mutated gliomas is of potential interest, as its genomic mechanism under influence of oncometabolite remains unclear, and even higher rate of malignant transformation was reported in IDH1-mutated low grade gliomas than in wild-type IDH1 tumors. We have analyzed genomic data using next-generation sequencing technology for longitudinal samples from 3 patients with IDH1-mutated gliomas whose disease had progressed from a low grade to a high grade phenotype. Comprehensive analysis included chromosomal aberrations as well as whole exome and transcriptome sequencing, and the candidate driver genes for malignant transformation were validated with public database. Integrated analysis of genomic dynamics in clonal evolution during the malignant transformation revealed alterations in the machinery regulating gene expression, including the spliceosome complex (U2AF2), transcription factors (TCF12), and chromatin remodelers (ARID1A). Moreover, consequential expression changes implied the activation of genes associated with the restoration of the stemness of cancer cells. The alterations in genetic regulatory mechanisms may be the key factor for the major phenotypic changes in IDH1 mutated gliomas. Despite being limited to a small number of cases, this analysis provides a direct example of the genomic changes responsible for malignant transformation in gliomas. PMID:26524630

  18. Genomic dynamics associated with malignant transformation in IDH1 mutated gliomas

    PubMed Central

    Sun, Choong-Hyun; Koh, Youngil; Park, Sung-Hye; Kim, Ja Eun; Yun, Hongseok; Lee, Se-Hoon

    2015-01-01

    The genomic mechanism responsible for malignant transformation remains an open question for glioma researchers, where differing conclusions have been drawn based on diverse study conditions. Therefore, it is essential to secure direct evidence using longitudinal samples from the same patient. Moreover, malignant transformation of IDH1-mutated gliomas is of potential interest, as its genomic mechanism under influence of oncometabolite remains unclear, and even higher rate of malignant transformation was reported in IDH1-mutated low grade gliomas than in wild-type IDH1 tumors. We have analyzed genomic data using next-generation sequencing technology for longitudinal samples from 3 patients with IDH1-mutated gliomas whose disease had progressed from a low grade to a high grade phenotype. Comprehensive analysis included chromosomal aberrations as well as whole exome and transcriptome sequencing, and the candidate driver genes for malignant transformation were validated with public database. Integrated analysis of genomic dynamics in clonal evolution during the malignant transformation revealed alterations in the machinery regulating gene expression, including the spliceosome complex (U2AF2), transcription factors (TCF12), and chromatin remodelers (ARID1A). Moreover, consequential expression changes implied the activation of genes associated with the restoration of the stemness of cancer cells. The alterations in genetic regulatory mechanisms may be the key factor for the major phenotypic changes in IDH1 mutated gliomas. Despite being limited to a small number of cases, this analysis provides a direct example of the genomic changes responsible for malignant transformation in gliomas. PMID:26524630

  19. Malignant brainstem gliomas in adults: clinicopathological characteristics and prognostic factors

    PubMed Central

    Babu, Ranjith; Kranz, Peter G.; McLendon, Roger E.; Thomas, Steven; Friedman, Allan H.; Bigner, Darell D.; Adamson, Cory

    2015-01-01

    Adult malignant brainstem gliomas (BSGs) are poorly characterized due to their relative rarity. We have examined histopathologically confirmed cases of adult malignant BSGs to better characterize the patient and tumor features and outcomes, including the natural history, presentation, imaging, molecular characteristics, prognostic factors, and appropriate treatments. A total of 34 patients were identified, consisting of 22 anaplastic astrocytomas (AAs) and 12 glioblastomas (GBMs). The overall median survival for all patients was 25.8 months, with patients having GBMs experiencing significantly worse survival (12.1 vs. 77.0 months, p = 0.0011). The majority of tumors revealed immunoreactivity for EGFR (93.3 %) and MGMT (64.7 %). Most tumors also exhibited chromosomal abnormalities affecting the loci of epidermal growth factor receptor (92.9 %), MET (100 %), PTEN (61.5 %), and 9p21 (80 %). AAs more commonly appeared diffusely enhancing (50.0 vs. 27.3 %) or diffusely nonenhancing (25.0 vs. 0.0 %), while GBMs were more likely to exhibit focal enhancement (54.6 vs. 10.0 %). Multivariate analysis revealed confirmed histopathology for GBM to significantly affect survival (HR 4.80; 95 % CI 1.86–12.4; p = 0.0012). In conclusion, adult malignant BSGs have an overall poor prognosis, with GBM tumors faring significantly worse than AAs. As AAs and GBMs have differing imaging characteristics, tissue diagnosis may be necessary to accurately determine patient prognosis and identify molecular characteristics which may aid in the treatment of these aggressive tumors. PMID:24838419

  20. Clinicopathological and molecular features of malignant optic pathway glioma in an adult.

    PubMed

    Nagaishi, Masaya; Sugiura, Yoshiki; Takano, Issei; Tanaka, Yoshihiro; Suzuki, Kensuke; Yokoo, Hideaki; Hyodo, Akio

    2015-01-01

    Malignant gliomas of the optic pathway are rare, and their genetic alterations are poorly understood. We describe a 64-year-old woman with anaplastic astrocytoma originating from the optic pathway, together with the molecular features. She presented with progressive visual field loss, and a biopsy sample was obtained from the lesion in the optic chiasm. She underwent radiosurgery concomitant with temozolomide chemotherapy, and subsequently remained stable for 10 months after initial presentation. Molecular analysis indicated that the mass may have shared common molecular genetic features with conventional primary astrocytic gliomas but not pilocytic gliomas, which supported the morphologic diagnosis of anaplastic astrocytoma. Molecular analysis of malignant optic pathway gliomas in adults is useful for distinguishing between high-grade gliomas and anaplastic pilocytic astrocytomas, and for determining further therapy. PMID:25150758

  1. Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process

    PubMed Central

    Galvao, Rui Pedro; Kasina, Anita; McNeill, Robert S.; Harbin, Jordan E.; Foreman, Oded; Verhaak, Roel G. W.; Nishiyama, Akiko; Miller, C. Ryan; Zong, Hui

    2014-01-01

    How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas. PMID:25246577

  2. Challenges in Clinical Design of Immunotherapy Trials for Malignant Glioma

    PubMed Central

    Rolle, Cleo E.; Sengupta, Sadhak; Lesniak, Maciej S.

    2009-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. The traditional treatments for GBM, including surgery, radiation, and chemotherapy, only modestly improve patient survival. Therefore, immunotherapy has emerged as a novel therapeutic modality. Immunotherapeutic strategies exploit the immune system's ability to recognize and mount a specific response against tumor cells, but not normal cells. Current immunotherapeutic approaches for glioma can be divided into three categories: immune priming (active immunotherapy), immunomodulation (passive immunotherapy), and adoptive immunotherapy. Immune priming sensitizes the patient's immune cells to tumor antigens using various vaccination protocols. In the case of immunomodulation, strategies are aimed at reducing suppressive cytokines in the tumor microenvironment or using immune molecules to specifically target tumor cells. Adoptive immunotherapy involves harvesting the patient's immune cells, followed by ex vivo activation and expansion prior to re-infusion. This review will provide an overview of the interactions between the central nervous system and the immune system and discuss the challenges facing current immunotherapeutic strategies. PMID:19944979

  3. Surgery for malignant gliomas: mechanistic reasoning and slippery statistics.

    PubMed

    Mitchell, Patrick; Ellison, David W; Mendelow, A David

    2005-07-01

    Current surgical treatment of malignant gliomas largely depends on mechanistic reasoning and data collected in non-randomised studies. Technological advance has enabled more accurate resection of tumours and preservation of eloquent brain areas but ethical considerations have restricted randomised trials on the efficacy of surgery to one small trial that found a 3 month survival advantage for patients over age 65 years who received surgery and interim analysis of a larger trial. There is an argument for surgery as a palliative measure in patients with symptoms caused by mechanisms that are surgically remediable. Whether there is any survival advantage from surgery in patients other than those with immediately life-threatening, surgically remediable complications, such as raised intracranial pressure, is unclear. The available data show that if such an advantage does exist, it is modest at best. Adjuvant treatments given surgically are being studied. Chemotherapy wafers are the most prominent of the adjuvant treatments but the evidence available is insufficient to recommend their use in routine practice. In this review we examine the prevailing mechanistic model and observational data; we assess how these are applied and the priorities they indicate for future research. PMID:15963444

  4. Radiosensitization effect of zidovudine on human malignant glioma cells

    SciTech Connect

    Zhou Fuxiang; Liao Zhengkai; Dai Jing; Xiong Jie; Xie CongHua; Luo Zhiguo; Liu Shiquan; Zhou Yunfeng . E-mail: yfzhouwhu@163.com

    2007-03-09

    Telomeres are shortened with each cell division and play an important role in maintaining chromosomal integrity and function. Telomerase, responsible for telomere synthesis, is activated in 90% of human tumor cells but seldom in normal somatic cells. Zidovudine (AZT) is a reverse transcriptase inhibitor. In this study, we have investigated the effects of {gamma}-radiation in combination with AZT on telomerase activity (TA), telomere length, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and the changes in radiosensitivity of human malignant glioma cell line U251. The results showed that the TA was suppressed by AZT but enhanced by irradiation, resulting in a deceleration of restored rate of shortened telomere, decreased repair rate of DNA strand breaks, and increased radiosensitivity of U251 cells. Our results suggested that telomerase activity and telomere length may serve as markers for estimating the efficacy of cancer radiotherapy and reverse transcriptase inhibitors, such as AZT, may be used clinically as a new radiosensitizer in cancer radiotherapy.

  5. Magnetic resonance analysis of malignant transformation in recurrent glioma

    PubMed Central

    Jalbert, Llewellyn E.; Neill, Evan; Phillips, Joanna J.; Lupo, Janine M.; Olson, Marram P.; Molinaro, Annette M.; Berger, Mitchel S.; Chang, Susan M.; Nelson, Sarah J.

    2016-01-01

    Background Patients with low-grade glioma (LGG) have a relatively long survival, and a balance is often struck between treating the tumor and impacting quality of life. While lesions may remain stable for many years, they may also undergo malignant transformation (MT) at the time of recurrence and require more aggressive intervention. Here we report on a state-of-the-art multiparametric MRI study of patients with recurrent LGG. Methods One hundred and eleven patients previously diagnosed with LGG were scanned at either 1.5 T or 3 T MR at the time of recurrence. Volumetric and intensity parameters were estimated from anatomic, diffusion, perfusion, and metabolic MR data. Direct comparisons of histopathological markers from image-guided tissue samples with metrics derived from the corresponding locations on the in vivo images were made. A bioinformatics approach was applied to visualize and interpret these results, which included imaging heatmaps and network analysis. Multivariate linear-regression modeling was utilized for predicting transformation. Results Many advanced imaging parameters were found to be significantly different for patients with tumors that had undergone MT versus those that had not. Imaging metrics calculated at the tissue sample locations highlighted the distinct biological significance of the imaging and the heterogeneity present in recurrent LGG, while multivariate modeling yielded a 76.04% accuracy in predicting MT. Conclusions The acquisition and quantitative analysis of such multiparametric MR data may ultimately allow for improved clinical assessment and treatment stratification for patients with recurrent LGG. PMID:26911151

  6. Misonidazole combined with hyperfractionation in the management of malignant glioma

    SciTech Connect

    Fulton, D.S.; Urtasun, R.C.; Shin, K.H.; Geggie, P.H.S.; Thomas, H.; Muller, P.J.; Moody, J.; Tanasichuk, H.; Mielke, B.; Johnson, E.

    1984-09-01

    Multiple daily fractionated radiation therapy (MDF) may be more effective than conventionally fractionated radiation therapy (CF) in the treatment of malignant glioma. The hypoxic cell sensitizer misonidazole (MISO) could be more effective when employed with small fractions of radiation every 4 hours to take advantage of the long half-life of the drug. To evaluate MDF and MDF in combination with MISO, a randomized prospective trial was initiated. Between January 1981, and December 1982, patients with histologically verified astrocytoma with anaplastic foci or glioblastoma multiforme were randomized to CF, MDF and MDF in combination with MISO. In January 1983, the CF arm was dropped and a high dose MDF arm added. CCNU chemotherapy was given at the time of tumor progression. Median survival was 29 weeks for CF, 45 weeks for MDF and 50 weeks for MDF plus MISO. Survival was significantly improved for patients treated with MDF compared to patients treated with CF. The addition of MISO to MDF did not result in further improvement in survival. Acute toxicity was acceptable.

  7. Reduced Expression of the Hyaluronan and Proteoglycan Link Proteins in Malignant Gliomas*

    PubMed Central

    Sim, Hosung; Hu, Bin; Viapiano, Mariano S.

    2009-01-01

    Malignant gliomas have a distinctive ability to infiltrate the brain parenchyma and disrupt the neural extracellular matrix that inhibits motility of axons and normal neural cells. Chondroitin sulfate proteoglycans (CSPGs) are among the major inhibitory components in the neural matrix, but surprisingly, some are up-regulated in gliomas and act as pro-invasive signals. In the normal brain, CSPGs are thought to associate with hyaluronic acid and glycoproteins such as the tenascins and link proteins to form the matrix scaffold. Here, we examined for the first time the expression of link proteins in human brain and malignant gliomas. Our results indicate that HAPLN4 and HAPLN2 are the predominant members of this family in the adult human brain but are strongly reduced in the tumor parenchyma. To test if their absence was related to a pro-invasive gain of function of CSPGs, we expressed HAPLN4 in glioma cells in combination with the CSPG brevican. Surprisingly, HAPLN4 increased glioma cell adhesion and migration and even potentiated the motogenic effect of brevican. Further characterization revealed that HAPLN4 expressed in glioma cells was largely soluble and did not reproduce the strong, hyaluronan-independent association of the native protein to brain subcellular membranes. Taken together, our results suggest that the tumor parenchyma is rich in CSPGs that are not associated to HAPLNs and could instead interact with other extracellular matrix proteins produced by glioma cells. This dissociation may contribute to changes in the matrix scaffold caused by invasive glioma cells. PMID:19633295

  8. Role of microRNAs Located on Chromosome Arm 10q in Malignant Gliomas.

    PubMed

    Wolter, Marietta; Werner, Thomas; Malzkorn, Bastian; Reifenberger, Guido

    2016-05-01

    Deletions of chromosome arm 10q are found in most glioblastomas and subsets of lower grade gliomas. Mutations in the PTEN gene at 10q23.3 are restricted to less than half of the 10q-deleted gliomas, suggesting additional glioma-associated tumor suppressors on 10q. We investigated 64 astrocytic gliomas of different malignancy grades for aberrant expression of 16 microRNAs (miRNAs) on 10q. Thereby, we identified four miRNAs (miR-107, miR-146b-5p, miR-346, miR-1287-5p) whose expression was frequently down-regulated in anaplastic astrocytomas and/or glioblastomas. DNA methylation analyses revealed 5'-CpG site hypermethylation of miR-346 in more than two-thirds of primary glioblastomas, while aberrant 5'-CpG site methylation of miR-146b-5p was frequent in IDH1-mutant astrocytomas and secondary glioblastomas. Overexpression of either of the four miRNAs in glioma cell lines reduced cell proliferation and/or increased caspase-3/7 activity. Expression analyses of miRNA overexpressing glioma cells and 3'-untranslated region luciferase reporter gene assays revealed evidence that these miRNAs post-transcriptionally regulate expression of glioma-relevant genes, including CDK6 (miR-107), EGFR (miR-146b-5p, miR-1287-5p), TERT and SEMA6A (miR-346), all of which are overexpressed in malignant gliomas in situ. In summary, we show that the 10q-located miRNAs miR-107, miR-146b-5p, miR-346 and miR-1287-5p are frequently down-regulated in malignant gliomas and thereby may support overexpression of important glioma growth-promoting genes. PMID:26223576

  9. Eckol suppresses maintenance of stemness and malignancies in glioma stem-like cells

    SciTech Connect

    Hyun, Kyung-Hwan; Yoon, Chang-Hwan; Kim, Rae-Kwon; Lim, Eun-Jung; An, Sungkwan; Park, Myung-Jin; Hyun, Jin-Won; Suh, Yongjoon; Kim, Min-Jung; Lee, Su-Jae

    2011-07-01

    A subpopulation of cancer cells with stem cell properties is responsible for tumor maintenance and progression, and may contribute to resistance to anticancer treatments. Thus, compounds that target cancer stem-like cells could be usefully applied to destroy cancer. In this study, we investigated the effect of Eckol, a phlorotannin compound, on stemness and malignancies in glioma stem-like cells. To determine whether Eckol targets glioma stem-like cells, we examined whether Eckol treatment could change the expression levels of glioma stem-like cell markers and self-renewal-related proteins as well as the sphere forming ability, and the sensitivity to anticancer treatments. Alterations in the malignant properties of sphere-derived cells by Eckol were also investigated by soft-agar colony forming assay, by xenograft assay in nude mice, and by cell invasion assay. Treatment of sphere-forming glioma cells with Eckol effectively decreased the sphere formation as well as the CD133{sup +} cell population. Eckol treatment suppressed expression of the glioma stem-like cell markers and the self-renewal-related proteins without cell death. Moreover, treatment of glioma stem-like cells with Eckol significantly attenuated anchorage-independent growth on soft agar and tumor formation in xenograft mice. Importantly, Eckol treatment effectively reduced the resistance of glioma stem-like cells to ionizing radiation and temozolomide. Treatment of glioma stem-like cells with Eckol markedly blocked both phosphoinositide 3-kinase-Akt and Ras-Raf-1-Erk signaling pathways. These results indicate that the natural phlorotannin Eckol suppresses stemness and malignancies in glioma stem-like cells, and thereby makes glioma stem-like cells more sensitive to anticancer treatments, providing novel therapeutic strategies targeting specifically cancer stem-like cells.

  10. Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells.

    PubMed

    Seol, Ho Jun; Chang, Jong Hee; Yamamoto, Junkoh; Romagnuolo, Rocco; Suh, Youngchul; Weeks, Adrienne; Agnihotri, Sameer; Smith, Christian A; Rutka, James T

    2012-09-01

    The malignant glioma is the most common primary human brain tumor, and its migration and invasiveness away from the primary tumor mass are considered a leading cause of tumor recurrence and treatment failure. Recently, gene expression profiling revealed that the transmembrane glycoprotein CD99 is more highly expressed in malignant glioma than in normal brain. Although its function is not completely understood, CD99 is implicated in cell adhesion and migration in a variety of different cell types. CD99 has wild-type and splice variant isoforms. Previous studies have shown that wild-type CD99 may be an oncosuppressor in some tumors, distinct from the role of the splice variant isoform. In this study, our data reveal that only wild-type CD99 is expressed in human glioma cells and tissues. Using a tissue microarray, we validated that gliomas demonstrate higher expression of CD99 compared with nonneoplastic brain. To assess the role of CD99 in glioma migration and invasion, we inhibited CD99 expression by siRNA and demonstrated decreased glioma migration and invasion. In contrast, when CD99 was overexpressed in glioma cells, we observed enhancement of cell migration and invasiveness. An orthotopic brain tumor model demonstrates that CD99 overexpression significantly increases invasiveness and decreases survival rate. Interestingly, Rac activity was decreased and Rho activity was increased in CD99 overexpressing glioma cells, and the proportion of amoeboid cells to mesenchymal cells was significantly increased. Taken together, our findings suggest that CD99 may play an important role in the migration and invasion of human gliomas independent of Akt, ERK, or JNK signaling pathways. Moreover, CD99 might be involved in amoeboid-mesenchymal transition in glioma migration. CD99 may be an important future target to inhibit migration and invasion, especially in CD99-expressing gliomas. PMID:23486730

  11. Sunitinib in Treating Patients With Recurrent Malignant Gliomas

    ClinicalTrials.gov

    2016-01-29

    Adult Anaplastic Astrocytoma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pineal Gland Astrocytoma

  12. The Challenges and the Promise of Molecular Targeted Therapy in Malignant Gliomas1

    PubMed Central

    Wang, Hongxiang; Xu, Tao; Jiang, Ying; Xu, Hanchong; Yan, Yong; Fu, Da; Chen, Juxiang

    2015-01-01

    Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional treatment, the outcome for patients remains almost universally fatal. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. However, over the past decade, molecular targeted therapy has held the promise of transforming the care of malignant glioma patients. Significant progress in understanding the molecular pathology of gliomagenesis and maintenance of the malignant phenotypes will open opportunities to rationally develop new molecular targeted therapy options. Recently, therapeutic strategies have focused on targeting pro-growth signaling mediated by receptor tyrosine kinase/RAS/phosphatidylinositol 3-kinase pathway, proangiogenic pathways, and several other vital intracellular signaling networks, such as proteasome and histone deacetylase. However, several factors such as cross-talk between the altered pathways, intratumoral molecular heterogeneity, and therapeutic resistance of glioma stem cells (GSCs) have limited the activity of single agents. Efforts are ongoing to study in depth the complex molecular biology of glioma, develop novel regimens targeting GSCs, and identify biomarkers to stratify patients with the individualized molecular targeted therapy. Here, we review the molecular alterations relevant to the pathology of malignant glioma, review current advances in clinical targeted trials, and discuss the challenges, controversies, and future directions of molecular targeted therapy. PMID:25810009

  13. Use of thallium-201 SPECT to quantitate malignancy grade of gliomas

    SciTech Connect

    Black, K.L.; Hawkins, R.A.; Kim, K.T.; Becker, D.P.; Lerner, C.; Marciano, D. )

    1989-09-01

    A quantitative preoperative technique using thallium-201 single-photon emission computerized tomography is described which predicts whether specific gliomas are of high- or low-grade malignancy. An index, based on the ratio of thallium uptake in the tumor versus the homologous contralateral brain, was calculated and compared with tumor histology. The index in 14 patients with low-grade malignant gliomas was 1.27 {plus minus} 0.40 in contrast to an index of 2.40 {plus minus} 0.61 in 11 patients with high-grade malignant gliomas (p less than 0.0005). Whether gliomas were of low- or high-grade malignancy could be predicted with 89% accuracy using a threshold of 1.5. Low-grade gliomas with an index higher than 1.5 acted biologically more like high-grade tumors, and no tumor histologically classified as being of high-grade malignancy had an index lower than 1.7. This technique could help to reduce unrecognized sampling errors during needle biopsies of brain tumors, particularly of high-grade lesions classified in error as low-grade tumors due to inadequate biopsy material.

  14. Fibulin-3 is uniquely upregulated in malignant gliomas and promotes tumor cell motility and invasion.

    PubMed

    Hu, Bin; Thirtamara-Rajamani, Keerthi K; Sim, Hosung; Viapiano, Mariano S

    2009-11-01

    Malignant gliomas are highly invasive tumors with an almost invariably rapid and lethal outcome. Surgery and chemoradiotherapy fail to remove resistant tumor cells that disperse within normal tissue, which are a major cause for disease progression and therapy failure. Infiltration of the neural parenchyma is a distinctive property of malignant gliomas compared with other solid tumors. Thus, glioma cells are thought to produce unique molecular changes that remodel the neural extracellular matrix and form a microenvironment permissive for their motility. Here, we describe the unique expression and proinvasive role of fibulin-3, a mesenchymal matrix protein specifically upregulated in gliomas. Fibulin-3 is downregulated in peripheral tumors and is thought to inhibit tumor growth. However, we found fibulin-3 highly upregulated in gliomas and cultured glioma cells, although the protein was undetectable in normal brain or cultured astrocytes. Overexpression and knockdown experiments revealed that fibulin-3 did not seem to affect glioma cell morphology or proliferation, but enhanced substrate-specific cell adhesion and promoted cell motility and dispersion in organotypic cultures. Moreover, orthotopic implantation of fibulin-3-overexpressing glioma cells resulted in diffuse tumors with increased volume and rostrocaudal extension compared with controls. Tumors and cultured cells overexpressing fibulin-3 also showed elevated expression and activity of matrix metalloproteases, such as MMP-2/MMP-9 and ADAMTS-5. Taken together, our results suggest that fibulin-3 has a unique expression and protumoral role in gliomas, and could be a potential target against tumor progression. Strategies against this glioma-specific matrix component could disrupt invasive mechanisms and restrict the dissemination of these tumors. PMID:19887559

  15. Financial burden experienced by patients undergoing treatment for malignant gliomas

    PubMed Central

    Kumthekar, Priya; Stell, Becky V.; Jacobs, Daniel I.; Helenowski, Irene B.; Rademaker, Alfred W.; Grimm, Sean A.; Bennett, Charles L.; Raizer, Jeffrey J.

    2014-01-01

    Background Patients undergoing treatment for malignant gliomas (MGs) can encounter medical costs beyond what their insurance covers. The magnitude and type of costs experienced by patients are unknown. The purpose of this study was to have patients or their families report on the medical costs incurred during the patients MG treatment. Methods Patients with MG were eligible if they were within 6 months of diagnosis or tumor recurrence. Patients had to be ≥18 years of age, fluent in English, and not aphasic. Weekly logbooks were issued to patients for recording associated costs for ∼6 months or until tumor progression. “Out-of-pocket” (OOP) costs included medical and nonmedical expenses that were not reimbursed by insurance. Direct medical costs included hospital and physician bills. Direct nonmedical costs included transportation, parking, and other related items. Indirect medical costs included lost wages. Costs were analyzed to provide mean and medians with range of expenses. Results Forty-three patients provided cost data for a median of 12 weeks. There were 25 men and 18 women with a median age of 57 years (range, 24y–73y); 79% were married, and 49% reported annual income >$75 000. Health insurance coverage was preferred provider organizations for 58% of patients, and median deductible was $1 500. Median monthly OOP cost was $1 342 (mean, $2 451; range, $333.41–$17 267.16). The highest OOP median costs were medication copayments ($710; range, $0–13 611.20), transportation ($327; range, $0–$1 927), and hospital bill copayments ($403; range, $0–$4 000). Median lost wages were $7 500, and median lost days of work were 12.8. Conclusions OOP costs for MG patients can be significant and comprise direct and indirect costs across several areas. Informing patients about expected costs could limit additional duress and allow financial support systems to be implemented. PMID:26034619

  16. Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

    PubMed Central

    Sarin, Hemant; Kanevsky, Ariel S; Wu, Haitao; Brimacombe, Kyle R; Fung, Steve H; Sousa, Alioscka A; Auh, Sungyoung; Wilson, Colin M; Sharma, Kamal; Aronova, Maria A; Leapman, Richard D; Griffiths, Gary L; Hall, Matthew D

    2008-01-01

    Background Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells. Methods Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured in vivo with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed ex vivo with fluorescence imaging. Results We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells. Conclusion The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives. PMID:19094226

  17. De novo cerebellar malignant glioma: A case report

    PubMed Central

    Matsumoto, Hiroaki; Yoshida, Yasuhisa

    2016-01-01

    Introduction Gliomas of the cerebellum are rare in adults, and their natural history and clinical behavior are not well known. Because cerebellar glioma is not usually diagnosed until clinical symptoms have appeared, no reports have described the developmental process of new cerebellar gliomas. We describe a case of de novo cerebellar anaplastic astrocytoma in which the developmental process was detected on magnetic resonance imaging (MRI). Presentation of case A 78-year-old man with a history of cerebral infarction was undergoing follow-up MRI every 6 months. This follow-up revealed a small abnormality in the left cerebellar hemisphere without clinical symptoms. Subsequent MRI showed lesion growth accompanying clinical symptoms. As cerebellar tumor was suspected, the lesion was extirpated. The histological diagnosis was anaplastic astrocytoma. Local recurrence developed and the patient died 20 months postoperatively. Discussion Cerebellar gliomas sometimes do not exhibit the common MRI findings of supratentorial gliomas, leading to difficulty with preoperative diagnosis. In this case, we initially diagnosed asymptomatic cerebellar infarction because the lesion was small and asymptomatic. The abnormal lesion gradually grew and clinical symptoms appeared. Cerebellar glioma may show few signs characteristic of tumor on MRI in the initial stages. Conclusion When MRI detects a new, faint abnormality in the cerebellum, close follow-up of clinical symptoms and MRI on suspicion of glioma is warranted PMID:27017277

  18. Erlotinib and Temsirolimus in Treating Patients With Recurrent Malignant Glioma

    ClinicalTrials.gov

    2015-05-29

    Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymal Giant Cell Astrocytoma; Recurrent Adult Brain Tumor

  19. Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas

    PubMed Central

    Wakimoto, Hiroaki; Tanaka, Shota; Curry, William T.; Loebel, Franziska; Zhao, Dan; Tateishi, Kensuke; Chen, Juxiang; Klofas, Lindsay K.; Lelic, Nina; Kim, James C.; Dias-Santagata, Dora; Ellisen, Leif W.; Borger, Darrell R.; Fendt, Sarah-Maria; Heiden, Matthew G. Vander; Batchelor, Tracy T.; Iafrate, A. John; Cahill, Daniel P.; Chi, Andrew S.

    2014-01-01

    PURPOSE Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. METHODS We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. RESULTS By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non-xenograft-forming gliomas (P=.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT or PTEN mutation or PDGFRA, MET or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations while IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months, P=.0011). CONCLUSION A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. PMID:24714777

  20. RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma

    ClinicalTrials.gov

    2015-09-28

    Acoustic Schwannoma; Adult Anaplastic (Malignant) Meningioma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Brain Stem Glioma; Adult Choroid Plexus Neoplasm; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Primary Melanocytic Lesion of Meninges; Adult Subependymal Giant Cell Astrocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor; Malignant Adult Intracranial Hemangiopericytoma

  1. P01.23NEUROTENSIN PROMOTES THE PROGRESSION OF MALIGNANT GLIOMA THROUGH NTSR1 AND IMPACTS THE PROGNOSIS OF GLIOMA PATIENTS

    PubMed Central

    Yi, L.; Xu, M.; Xu, L.; Feng, H.; Cui, H.

    2014-01-01

    BACKGROUND: Neurotensin (NTS) functions as a neuromodulator and induces cellular proliferation and migration in various solid tumors. However, whether NTS can promote the progression of malignant glioma and its prognostic significance for glioma patients remain unclear. METHODS: NTS and its high-affinity receptor (NTSR1) expression levels in clinical glioma samples were detected by immunohistochemistry and immunobloting. The prognostic analysis in glioma patients were conducted online by R2 microarray analysis and the visualization platform. The proliferation of glioma cells were evaluated by CCK8 and BrdU incorporation assay. The celluar invasiveness were tested by wound healing model and the Matrigel transwell assay. A neutralizing antibody to NTS, NTSR1-selective antagonist SR48692 and NTSR1-siRNA were used to suppress the NTS stimulation. Erk1/2 phosphorylation was tested by immunobloting. The orthotopic glioma implantation model was established to examine the role of NTS and NTSR1 in the progression of glioma in vivo. RESULTS: Positive correlations were shown between the expression levels of NTS and NTSR1 with the pathological grade of gliomas. The high levels of NTS and NTSR1 expression indicate a worse prognosis in glioma patients. The proliferation and invasiveness of glioma cells could be enhanced by NTS stimulation and impaired by the inhibition of NTSR1 functions. NTS stimulated Erk1/2 phosphorylation in glioma cells, which could be reversed by treatment with SR48692 or NTSR1-siRNA. In vivo experiments showed that therapy with SR48692 significantly prolonged the survival length of glioma-bearing mice and inhibited glioma cell invasiveness in vivo. CONCLUSIONS: NTS promotes the proliferation and invasion of glioma via the activation of NTSR1 and its downstream signaling molecules, resulting in Erk1/2 phosphorylation. High levels of NTS and NTSR1 expression predict a bad prognosis in glioma patients.

  2. The Guanine Nucleotide Exchange Factor SWAP-70 Modulates the Migration and Invasiveness of Human Malignant Glioma Cells12

    PubMed Central

    Seol, Ho Jun; Smith, Christian A; Salhia, Bodour; Rutka, James T

    2009-01-01

    The malignant glioma is the most common primary human brain tumor. Its tendency to invade away from the primary tumor mass is considered a leading cause of tumor recurrence and treatment failure. Accordingly, the molecular pathogenesis of glioma invasion is currently under investigation. Previously, we examined a gene expression array database comparing human gliomas to nonneoplastic controls and identified several Rac guanine nucleotide exchange factors with differential expression. Here, we report that the guanine nucleotide exchange factor SWAP-70 has increased expression in malignant gliomas and strongly correlates with lowered patient survival. SWAP-70 is a multifunctional signaling protein involved in membrane ruffling that works cooperatively with activated Rac. Using a glioma tissue microarray, we validated that SWAP-70 demonstrates higher expression in malignant gliomas compared with low-grade gliomas or nonneoplastic brain tissue. Through immunofluorescence, SWAP-70 localizes to membrane ruffles in response to the growth factor, epidermal growth factor. To assess the role of SWAP-70 in glioma migration and invasion, we inhibited its expression withsmall interfering RNAs and observed decreased glioma cell migration and invasion. SWAP-70 overexpression led to increased levels of active Rac even in low-serum conditions. In addition, when SWAP-70 was overexpressed in glioma cells, we observed enhanced membrane ruffle formation followed by increased cellmigration and invasiveness. Taken together, our findings suggest that the guanine nucleotide exchange factor SWAP-70 plays an important role in the migration and invasion of human gliomas into the surrounding tissue. PMID:19956392

  3. Fluorescence-guided resections and photodynamic therapy for malignant gliomas using 5-aminolevulinic acid

    NASA Astrophysics Data System (ADS)

    Stepp, Herbert G.; Beck, Tobias; Beyer, Wolfgang; Pongratz, Thomas; Sroka, Ronald; Baumgartner, Reinhold; Stummer, Walter; Olzowy, Bernhard; Mehrkens, Jan H.; Tonn, Joerg C.; Reulen, Hans J.

    2005-04-01

    Oral application of 20 mg/kg bw of 5-aminolevulinic acid results in a highly specific accumulation of fluorescent and phototoxic Protoporphyrin IX in malignant glioma tissue. Surgical removal with fluorescence guidance is studied in a phase III clinical trial, adjuvant Photodynamic Therapy (PDT) to the surgical cavity is in phase II and for interstitial PDT of recurrent gliomas, a phase I/II study has started. Fluorescence guided resections have been shown to be safe and effective in augmenting neurosurgical removal of malignant gliomas in 52 consecutive patients. Intra-operative fluorescence spectroscopy showed statistically significant higher sensitizer accumulation in vital brain tumor versus the infiltration zone and in the infiltration zone versus adjacent normal brain, which contained very little PPIX. This is promisingly exploited for PDT - both to the surgical cavity by surface irradiation and for stereotactically guided interstitial irradiation.

  4. MAGI3 negatively regulates Wnt/β-catenin signaling and suppresses malignant phenotypes of glioma cells.

    PubMed

    Ma, Qian; Yang, Ying; Feng, Duiping; Zheng, Shuai; Meng, Ran; Fa, Pengyan; Zhao, Chunjuan; Liu, Hua; Song, Ran; Tao, Tao; Yang, Longyan; Dai, Jie; Wang, Songlin; Jiang, Wen G; He, Junqi

    2015-11-01

    Gliomas are the most common primary brain malignancies and are associated with a poor prognosis. Here, we showed that the PDZ domain-containing protein membrane-associated guanylate kinase inverted 3 (MAGI3) was downregulated at the both mRNA and protein levels in human glioma samples. MAGI3 inhibited proliferation, migration, and cell cycle progression of glioma cells in its overexpression and knockdown studies. By using GST pull-down and co-immunoprecipitation assays, we found that MAGI3 bound to β-catenin through its PDZ domains and the PDZ-binding motif of β-catenin. MAGI3 overexpression inhibited β-catenin transcriptional activity via its interaction with β-catenin. Consistently, MAGI3 overexpression in glioma cells C6 suppressed expression of β-catenin target genes including Cyclin D1 and Axin2, whereas MAGI3 knockdown in glioma cells U373 and LN229 enhanced their expression. MAGI3 overexpression decreased growth of C6 subcutaneous tumors in mice, and inhibited expression of β-catenin target genes in xenograft tumors. Furthermore, analysis based on the Gene Expression Omnibus (GEO) glioma dataset showed association of MAGI3 expression with overall survival and tumor grade. Finally, we demonstrated negative correlation between MAGI3 expression and activity of Wnt/β-catenin signaling through GSEA of three public glioma datasets and immunohistochemical staining of clinical glioma samples. Taken together, these results identify MAGI3 as a novel tumor suppressor and provide insight into the pathogenesis of glioma. PMID:26452219

  5. Myxoma Virus Infection Promotes NK Lysis of Malignant Gliomas In Vitro and In Vivo

    PubMed Central

    Ogbomo, Henry; Zemp, Franz J.; Lun, Xueqing; Zhang, Jiqing; Stack, Danuta; Rahman, Masmudur M.; Mcfadden, Grant; Mody, Christopher H.; Forsyth, Peter A.

    2013-01-01

    Myxoma virus (MYXV) is a well-established oncolytic agent against different types of tumors. MYXV is also known for its immunomodulatory properties in down-regulating major histocompatibility complex (MHC) I surface expression (via the M153R gene product, a viral E3-ubiquitin ligase) and suppressing T cell killing of infected target cells. MHC I down-regulation, however, favors NK cell activation. Brain tumors including gliomas are characterized by high MHC I expression with impaired NK activity. We thus hypothesized that MYXV infection of glioma cells will promote NK cell-mediated recognition and killing of gliomas. We infected human gliomas with MYXV and evaluated their susceptibility to NK cell-mediated cytotoxicity. MYXV enhanced NK cell-mediated killing of glioma cells (U87 cells, MYXV vs. Mock: 51.73% vs. 28.63%, P = .0001, t test; U251 cells, MYXV vs. Mock: 40.4% vs. 20.03%, P .0007, t test). Using MYXV M153R targeted knockout (designated vMyx-M153KO) to infect gliomas, we demonstrate that M153R was responsible for reduced expression of MHC I on gliomas and enhanced NK cell-mediated antiglioma activity (U87 cells, MYXV vs. vMyx-M153KO: 51.73% vs. 25.17%, P = .0002, t test; U251 cells, MYXV vs. vMyx-M153KO: 40.4% vs. 19.27, P = .0013, t test). Consequently, NK cell-mediated lysis of established human glioma tumors in CB-17 SCID mice was accelerated with improved mouse survival (log-rank P = .0072). These results demonstrate the potential for combining MYXV with NK cells to effectively kill malignant gliomas. PMID:23762498

  6. A New Hope in Immunotherapy for Malignant Gliomas: Adoptive T Cell Transfer Therapy

    PubMed Central

    Chung, Dong-Sup; Shin, Hye-Jin; Hong, Yong-Kil

    2014-01-01

    Immunotherapy emerged as a promising therapeutic approach to highly incurable malignant gliomas due to tumor-specific cytotoxicity, minimal side effect, and a durable antitumor effect by memory T cells. But, antitumor activities of endogenously activated T cells induced by immunotherapy such as vaccination are not sufficient to control tumors because tumor-specific antigens may be self-antigens and tumors have immune evasion mechanisms to avoid immune surveillance system of host. Although recent clinical results from vaccine strategy for malignant gliomas are encouraging, these trials have some limitations, particularly their failure to expand tumor antigen-specific T cells reproducibly and effectively. An alternative strategy to overcome these limitations is adoptive T cell transfer therapy, in which tumor-specific T cells are expanded ex vivo rapidly and then transferred to patients. Moreover, enhanced biologic functions of T cells generated by genetic engineering and modified immunosuppressive microenvironment of host by homeostatic T cell expansion and/or elimination of immunosuppressive cells and molecules can induce more potent antitumor T cell responses and make this strategy hold promise in promoting a patient response for malignant glioma treatment. Here we will review the past and current progresses and discuss a new hope in adoptive T cell therapy for malignant gliomas. PMID:25009822

  7. Regression of Recurrent Malignant Gliomas With Convection-Enhanced Delivery of Topotecan

    PubMed Central

    Bruce, Jeffrey N.; Fine, Robert L.; Canoll, Peter; Yun, Jonathan; Kennedy, Benjamin C.; Rosenfeld, Steven S.; Sands, Stephen A.; Surapaneni, Krishna; Lai, Rose; Yanes, Candix L.; Bagiella, Emilia; DeLaPaz, Robert L.

    2016-01-01

    BACKGROUND Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through continuous, low-grade positive-pressure infusion. This allows high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs. OBJECTIVE To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and secondarily to assess radiographic response and survival. METHODS We performed a prospective, dose-escalation phase Ib study of the topoisomerase-I inhibitor topotecan given by convection-enhanced delivery in patients with recurrent malignant gliomas. RESULTS Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies. CONCLUSION Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials. PMID:21562434

  8. Myosin VI contributes to malignant proliferation of human glioma cells

    PubMed Central

    Xu, Rong; Fang, Xu-hao

    2016-01-01

    Previously characterized as a backward motor, myosin VI (MYO6), which belongs to myosin family, moves toward the minus end of the actin track, a direction opposite to all other known myosin members. Recent researches have illuminated the role of MYO6 in human cancers, particularly in prostate cancer. However, the role of MYO6 in glioma has not yet been determined. In this study, to explore the role of MYO6 in human glioma, lentivirus-delivered short hairpin RNA (shRNA) targeting MYO6 was designed to stably down-regulate its endogenous expression in glioblastoma cells U251. Knockdown of MYO6 signifi cantly inhibited viability and proliferation of U251 cells in vitro. Moreover, the cell cycle of U251 cells was arrested at G0/G1 phase with the absence of MYO6, which could contribute to the suppression of cell proliferation. In conclusion, we firstly identified the crucial involvement of MYO6 in human glioma. The inhibition of MYO6 by shRNA might be a potential therapeutic method in human glioma. PMID:26937209

  9. Malignant gliomas induce and exploit astrocytic mesenchymal-like transition by activating canonical Wnt/β-catenin signaling.

    PubMed

    Lu, Ping; Wang, Yajing; Liu, Xiuting; Wang, Hong; Zhang, Xin; Wang, Kequan; Wang, Qing; Hu, Rong

    2016-07-01

    The complex microenvironment of malignant gliomas plays a dynamic and usually cancer-promoting role in glioma progression. Astrocytes, the major stromal cells in the brain, can be activated by glioma microenvironment, resulting in a layer of reactive astrocytes surrounding the gliomas. Reactive astrocytes are universally characterized with the upregulation of glial fibrillary protein and glycoprotein podoplanin. In this work, we investigated the role of reactive astrocytes on malignant glioma microenvironment and the potential mechanism by which glioma cells activated the tumor-associated astrocytes (TAAs). The reactive astrocytes were observed around gliomas in the intracranial syngeneic implantation of rat C6 and mouse GL261 glioma cells in vivo, as well as primary astrocytes cultured with glioma cells condition medium in vitro. Besides, reactive astrocytes exhibited distinct epithelial-to-mesenchymal (-like) transition and enhanced migration and invasion activity, with the decrease of E-cadherin and concomitant increase of vimentin and matrix metalloproteinases. Furthermore, canonical Wnt/β-catenin signaling was activated in TAAs. The Wnt/β-catenin pathway inhibitor XAV939 and β-catenin plasmid were used to verify the regulation of Wnt/β-catenin signaling on TAAs and their invasion ability. Taken together, our findings established that glioma cells remarkably activated astrocytes via upregulating Wnt/β-catenin signaling, with obviously mesenchymal-like transition and increased migration and invasion ability, indicating that glioma cells may stimulate adjacent astrocytes to degrade extracellular matrix and thereby promoting tumor invasiveness. PMID:27236327

  10. The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas.

    PubMed

    Pyrko, Peter; Schönthal, Axel H; Hofman, Florence M; Chen, Thomas C; Lee, Amy S

    2007-10-15

    Poor chemosensitivity and the development of chemoresistance remain major obstacles to successful chemotherapy of malignant gliomas. GRP78 is a key regulator of the unfolded protein response (UPR). As a Ca2+-binding molecular chaperone in the endoplasmic reticulum (ER), GRP78 maintains ER homeostasis, suppresses stress-induced apoptosis, and controls UPR signaling. We report here that GRP78 is expressed at low levels in normal adult brain, but is significantly elevated in malignant glioma specimens and human malignant glioma cell lines, correlating with their rate of proliferation. Down-regulation of GRP78 by small interfering RNA leads to a slowdown in glioma cell growth. Our studies further reveal that temozolomide, the chemotherapeutic agent of choice for treatment of malignant gliomas, leads to induction of CHOP, a major proapoptotic arm of the UPR. Knockdown of GRP78 in glioblastoma cell lines induces CHOP and activates caspase-7 in temozolomide-treated cells. Colony survival assays further establish that knockdown of GRP78 lowers resistance of glioma cells to temozolomide, and, conversely, overexpression of GRP78 confers higher resistance. Knockdown of GRP78 also sensitizes glioma cells to 5-fluorouracil and CPT-11. Treatment of glioma cells with (-)-epigallocatechin gallate, which targets the ATP-binding domain of GRP78 and blocks its protective function, sensitizes glioma cells to temozolomide. These results identify a novel chemoresistance mechanism in malignant gliomas and show that combination of drugs capable of suppressing GRP78 with conventional agents such as temozolomide might represent a novel approach to eliminate residual tumor cells after surgery and increase the effectiveness of malignant glioma chemotherapy. PMID:17942911

  11. Akt2 and Akt3 play a pivotal role in malignant gliomas

    PubMed Central

    Mure, Hideo; Matsuzaki, Kazuhito; Kitazato, Keiko T.; Mizobuchi, Yoshifumi; Kuwayama, Kazuyuki; Kageji, Teruyoshi; Nagahiro, Shinji

    2010-01-01

    Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase, is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ and their functional roles in malignant glioma are not well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas, glioblastomas, and non-neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knock-down and the over-expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas. PMID:20167810

  12. Characterization of highly proliferative secondary tumor clusters along host blood vessels in malignant glioma

    PubMed Central

    WANG, TING-CHUNG; CHENG, CHUN-YU; YANG, WEI-HSUN; CHEN, WEN-CHENG; CHANG, PEY-JIUM

    2015-01-01

    The aim of the present study was to investigate the extensive invasion of tumor cells into normal brain tissue, a life-threatening feature of malignant gliomas. How invasive tumor cells migrate into normal brain tissue and form a secondary tumor structure remains to be elucidated. In the present study, the morphological and phenotypic changes of glioma cells during invasion in a C6 glioma model were investigated. C6 glioma cells were stereotactically injected into the right putamen region of adult Sprague-Dawley rats. The brain tissue sections were then subjected to hematoxylin and eosin, immunohistochemical or immunofluorescent staining. High magnification views of the tissue sections revealed that C6 cells formed tumor spheroids following implantation and marked invasion was observed shortly after spheroid formation. In the later stages of invasion, certain tumor cells invaded the perivascular space and formed small tumor clusters. These small tumor clusters exhibited certain common features, including tumor cell multilayers surrounding an arteriole, which occurred up to several millimeters away from the primary tumor mass; a high proliferation rate; and similar gene expression profiles to the primary tumor. In conclusion, the present study revealed that invading tumor cells are capable of forming highly proliferative cell clusters along arterioles near the tumor margin, which may be a possible cause of the recurrence of malignant glioma. PMID:26299849

  13. The EGF Receptor Promotes the Malignant Potential of Glioma by Regulating Amino Acid Transport System xc(-).

    PubMed

    Tsuchihashi, Kenji; Okazaki, Shogo; Ohmura, Mitsuyo; Ishikawa, Miyuki; Sampetrean, Oltea; Onishi, Nobuyuki; Wakimoto, Hiroaki; Yoshikawa, Momoko; Seishima, Ryo; Iwasaki, Yoshimi; Morikawa, Takayuki; Abe, Shinya; Takao, Ayumi; Shimizu, Misato; Masuko, Takashi; Nagane, Motoo; Furnari, Frank B; Akiyama, Tetsu; Suematsu, Makoto; Baba, Eishi; Akashi, Koichi; Saya, Hideyuki; Nagano, Osamu

    2016-05-15

    Extracellular free amino acids contribute to the interaction between a tumor and its microenvironment through effects on cellular metabolism and malignant behavior. System xc(-) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. Here, we show that the EGFR interacts with xCT and thereby promotes its cell surface expression and function in human glioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake, as well as increased glutamate, which promotes matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells, as well as tumor growth and invasiveness. Our findings establish a new functional role for EGFR in promoting the malignant potential of glioma cells through interaction with xCT at the cell surface. Cancer Res; 76(10); 2954-63. ©2016 AACR. PMID:26980765

  14. p27 modulates cell cycle progression and chemosensitivity in human malignant glioma.

    PubMed

    Naumann, U; Weit, S; Rieger, L; Meyermann, R; Weller, M

    1999-08-11

    The cell cycle regulatory protein p27, an inhibitor of cyclin-dependent kinases (CDK), has been attributed a role in (i) prognosis in breast and colon cancer, (ii) induction of apoptosis in cancer cells, and (iii) resistance to cancer chemotherapy. Here we report that p27 is widely expressed in human malignant gliomas in vivo and in glioma cell lines in vitro. Serum deprivation or confluency promotes p27 protein accumulation in vitro. Neither baseline p27 levels nor p27 levels induced by confluency or serum deprivation correlate with p53 status or drug sensitivity of human glioma cell lines. Expression of antisense p27 mRNA increased the doubling times in T98G glioma cells, whereas sense p27 mRNA had no such effect. There was a density-dependent and drug-specific modulation of chemosensitivity by sense or antisense mRNA expression in T98G cells. Taken together, these data define a strong p27 response to altered growth conditions and suggest a role for p27 in modulating response to chemotherapy in human malignant glioma cells. PMID:10441521

  15. Controlled Payload Release by Magnetic Field Triggered Neural Stem Cell Destruction for Malignant Glioma Treatment.

    PubMed

    Muroski, Megan E; Morshed, Ramin A; Cheng, Yu; Vemulkar, Tarun; Mansell, Rhodri; Han, Yu; Zhang, Lingjiao; Aboody, Karen S; Cowburn, Russell P; Lesniak, Maciej S

    2016-01-01

    Stem cells have recently garnered attention as drug and particle carriers to sites of tumors, due to their natural ability to track to the site of interest. Specifically, neural stem cells (NSCs) have demonstrated to be a promising candidate for delivering therapeutics to malignant glioma, a primary brain tumor that is not curable by current treatments, and inevitably fatal. In this article, we demonstrate that NSCs are able to internalize 2 μm magnetic discs (SD), without affecting the health of the cells. The SD can then be remotely triggered in an applied 1 T rotating magnetic field to deliver a payload. Furthermore, we use this NSC-SD delivery system to deliver the SD themselves as a therapeutic agent to mechanically destroy glioma cells. NSCs were incubated with the SD overnight before treatment with a 1T rotating magnetic field to trigger the SD release. The potential timed release effects of the magnetic particles were tested with migration assays, confocal microscopy and immunohistochemistry for apoptosis. After the magnetic field triggered SD release, glioma cells were added and allowed to internalize the particles. Once internalized, another dose of the magnetic field treatment was administered to trigger mechanically induced apoptotic cell death of the glioma cells by the rotating SD. We are able to determine that NSC-SD and magnetic field treatment can achieve over 50% glioma cell death when loaded at 50 SD/cell, making this a promising therapeutic for the treatment of glioma. PMID:26734932

  16. The involvement of heparan sulfate proteoglycans in stem cell differentiation and in malignant glioma

    NASA Astrophysics Data System (ADS)

    Kundu, Soumi; Xiong, Anqi; Forsberg-Nilsson, Karin

    2016-04-01

    Heparan sulfate (HS) proteoglycans (HSPG) are major components of the extracellular matrix. They interact with a plethora of macromolecules that are of physiological importance. The pattern of sulfation of the HS chain determines the specificity of these interactions. The enzymes that synthesize and degrade HS are thus key regulators of processes ranging from embryonic development to tissue homeostasis and tumor development. Formation of the nervous system is also critically dependent on appropriate HSPGs as shown by several studies on the role of HS in neural induction from embryonic stem cells. High-grade glioma is the most common primary malignant brain tumor among adults, and the prognosis is poor. Neural and glioma stem cells share several traits, including sustained proliferation and highly efficient migration in the brain. There are also similarities between the neurogenic niche where adult neural stem cells reside and the tumorigenic niche, including their interactions with components of the extracellular matrix (ECM). The levels of many of these components, for example HSPGs and enzymes involved in the biosynthesis and modification of HS are attenuated in gliomas. In this paper, HS regulation of pathways involved in neural differentiation and how these may be of importance for brain development are discussed. The literature suggesting that modifications of HS could regulate glioma growth and invasion is reviewed. Targeting the invasiveness of glioma cells by modulating HS may improve upon present therapeutic options, which only marginally enhance the survival of glioma patients.

  17. Controlled Payload Release by Magnetic Field Triggered Neural Stem Cell Destruction for Malignant Glioma Treatment

    PubMed Central

    Muroski, Megan E.; Morshed, Ramin A.; Cheng, Yu; Vemulkar, Tarun; Mansell, Rhodri; Han, Yu; Zhang, Lingjiao; Aboody, Karen S.; Cowburn, Russell P.; Lesniak, Maciej S.

    2016-01-01

    Stem cells have recently garnered attention as drug and particle carriers to sites of tumors, due to their natural ability to track to the site of interest. Specifically, neural stem cells (NSCs) have demonstrated to be a promising candidate for delivering therapeutics to malignant glioma, a primary brain tumor that is not curable by current treatments, and inevitably fatal. In this article, we demonstrate that NSCs are able to internalize 2 μm magnetic discs (SD), without affecting the health of the cells. The SD can then be remotely triggered in an applied 1 T rotating magnetic field to deliver a payload. Furthermore, we use this NSC-SD delivery system to deliver the SD themselves as a therapeutic agent to mechanically destroy glioma cells. NSCs were incubated with the SD overnight before treatment with a 1T rotating magnetic field to trigger the SD release. The potential timed release effects of the magnetic particles were tested with migration assays, confocal microscopy and immunohistochemistry for apoptosis. After the magnetic field triggered SD release, glioma cells were added and allowed to internalize the particles. Once internalized, another dose of the magnetic field treatment was administered to trigger mechanically induced apoptotic cell death of the glioma cells by the rotating SD. We are able to determine that NSC-SD and magnetic field treatment can achieve over 50% glioma cell death when loaded at 50 SD/cell, making this a promising therapeutic for the treatment of glioma. PMID:26734932

  18. Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

    PubMed Central

    Cardama, Georgina A; Gonzalez, Nazareno; Ciarlantini, Matias; Gandolfi Donadío, Lucia; Comin, María Julieta; Alonso, Daniel F; Menna, Pablo Lorenzano; Gomez, Daniel E

    2014-01-01

    Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180–Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models. PMID:25378937

  19. Epigenetic silencing of KAZALD1 confers a better prognosis and is associated with malignant transformation/progression in glioma.

    PubMed

    Wang, Hongjun; Feng, Ying; Bao, Zhaoshi; Jiang, Chuanlu; Yan, Wei; Wang, Yongzhi; Zhang, Chuanbao; Liu, Yanwei; Zhang, Quangeng; Zhang, Wei; Jiang, Chuanlu

    2013-11-01

    In order to more thoroughly analyze aberrant DNA methylation in glioma, we applied a large cohort methylation microarray including 119 glioma samples. Six genes, ADCY1, KAZALD1, KLF4, SLMAP, TETRAN and TP53INP1, were screened out through significance analysis of microarray (SAM), survival Cox-regression and certain other pre-set conditions. We focused on the KAZALD1 oncogene. KAZALD1, also known as IGFBP-rP10, belongs to the IGFBP family. We found that KAZALD1 was hypomethylated in high-grade glioma (anaplastic gliomas and glioblastomas) compared to low-grade glioma (astrocytoma, oligodendrocytoma and oligoastrocytoma) using methylation microarrays (p<0.001). Immunohistochemistry (IHC) of 91 glioma samples showed that the KAZALD1 expression scores of high-grade glioma samples were higher compared to the scores of low-grade gliomas (p<0.001). In high-grade gliomas, overall survival (OS) was shorter for patients with KAZALD1 hypomethylation or overexpression compared to those without. Decreased KAZALD1 expression in glioma inhibited cell proliferation and invasion both in vitro and in vivo. On the basis of these observations and the results from subset analysis, it is reasonable to conclude that KAZALD1 promoter hypomethylation is an important prognostic biomarker in glioma. KAZALD1 promotes glioma malignant progression through invasion and proliferation. PMID:24002581

  20. Bevacizumab is active as a single agent against recurrent malignant gliomas.

    PubMed

    Agha, Caroline A; Ibrahim, Saman; Hassan, Ahmed; Elias, Dean A; Fathallah-Shaykh, Hassan M

    2010-02-01

    Bevacizumab, a humanized monoclonal antibody designed to inhibit vascular endothelial growth factor, is effective in combination with chemotherapy against malignant gliomas. We examined the therapeutic effects and toxicity of bevacizumab as a single agent for the treatment of recurrent malignant glioma. This is a retrospective analysis of a case series of 18 adult patients, diagnosed with recurrent WHO grade III and IV gliomas. Patients were divided into two groups: group A (n=8) received bevacizumab at a dose of 10 mg/kg every two weeks; group B patients (n=10) were treated with salvage chemotherapy of lomustine (n=4), liposomal doxorubicin (n=4), temozolomide (n=1), or the combination of procarbazine, lomustine, and vincristine (n=1). The main study outcome measure was the 12-month progression-free survival probability; the objective radiological response was a secondary endpoint. Half of the patients treated with bevacizumab remained progression-free at 12 months as compared to none in group B (log-rank p=0.0067). In addition, 7/8 patients in group A showed a radiological response as compared to 4/10 in group B. Toxicity was mild and no intracranial hemorrhage was observed. The finding that bevacizumab has significant activity as a single agent against malignant glioma is important, particularly for those patients who are unable to tolerate traditional chemotherapy. PMID:20332478

  1. Malignant gliomas: current perspectives in diagnosis, treatment, and early response assessment using advanced quantitative imaging methods

    PubMed Central

    Ahmed, Rafay; Oborski, Matthew J; Hwang, Misun; Lieberman, Frank S; Mountz, James M

    2014-01-01

    Malignant gliomas consist of glioblastomas, anaplastic astrocytomas, anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, and some less common tumors such as anaplastic ependymomas and anaplastic gangliogliomas. Malignant gliomas have high morbidity and mortality. Even with optimal treatment, median survival is only 12–15 months for glioblastomas and 2–5 years for anaplastic gliomas. However, recent advances in imaging and quantitative analysis of image data have led to earlier diagnosis of tumors and tumor response to therapy, providing oncologists with a greater time window for therapy management. In addition, improved understanding of tumor biology, genetics, and resistance mechanisms has enhanced surgical techniques, chemotherapy methods, and radiotherapy administration. After proper diagnosis and institution of appropriate therapy, there is now a vital need for quantitative methods that can sensitively detect malignant glioma response to therapy at early follow-up times, when changes in management of nonresponders can have its greatest effect. Currently, response is largely evaluated by measuring magnetic resonance contrast and size change, but this approach does not take into account the key biologic steps that precede tumor size reduction. Molecular imaging is ideally suited to measuring early response by quantifying cellular metabolism, proliferation, and apoptosis, activities altered early in treatment. We expect that successful integration of quantitative imaging biomarker assessment into the early phase of clinical trials could provide a novel approach for testing new therapies, and importantly, for facilitating patient management, sparing patients from weeks or months of toxicity and ineffective treatment. This review will present an overview of epidemiology, molecular pathogenesis and current advances in diagnoses, and management of malignant gliomas. PMID:24711712

  2. Exploring the role of inflammation in the malignant transformation of low-grade gliomas.

    PubMed

    Michelson, Nicole; Rincon-Torroella, Jordina; Quiñones-Hinojosa, Alfredo; Greenfield, Jeffrey P

    2016-08-15

    Studies of inflammatory mediators have established the tumor micro-environment as a driver of oncogenesis. This inflammatory milieu often precedes cancer, however recent data also point to the ability of oncogenic changes to induce inflammatory responses that are later harnessed by the tumor to survive and proliferate. In this review, we propose that the IDH1 mutation, present in the majority of low-grade gliomas (LGGs), initiates an inflammatory cascade that is ultimately hijacked by the tumor. Glioma infiltrating macrophages and microglia (GIMs) are polarized to the M2 phenotype, subverting the host's adaptive immune response, and fostering a tumor milieu ripe for angiogenesis, migration, and metastasis. As data continue to expand the role of inflammation in low-grade gliomas, new molecular pathways may emerge as therapeutic targets that offer a window of opportunity to intervene before the malignant transformation (MT) of LGGs occurs. PMID:27397086

  3. T Cells Enhance Stem-Like Properties and Conditional Malignancy in Gliomas

    PubMed Central

    Irvin, Dwain K.; Jouanneau, Emmanuel; Duvall, Gretchen; Zhang, Xiao-xue; Zhai, Yuying; Sarayba, Danielle; Seksenyan, Akop; Panwar, Akanksha; Black, Keith L.; Wheeler, Christopher J.

    2010-01-01

    Background Small populations of highly tumorigenic stem-like cells (cancer stem cells; CSCs) can exist within, and uniquely regenerate cancers including malignant brain tumors (gliomas). Many aspects of glioma CSCs (GSCs), however, have been characterized in non-physiological settings. Methods We found gene expression similarity superiorly defined glioma “stemness”, and revealed that GSC similarity increased with lower tumor grade. Using this method, we examined stemness in human grade IV gliomas (GBM) before and after dendritic cell (DC) vaccine therapy. This was followed by gene expression, phenotypic and functional analysis of murine GL26 tumors recovered from nude, wild-type, or DC-vaccinated host brains. Results GSC similarity was specifically increased in post-vaccine GBMs, and correlated best to vaccine-altered gene expression and endogenous anti-tumor T cell activity. GL26 analysis confirmed immune alterations, specific acquisition of stem cell markers, specifically enhanced sensitivity to anti-stem drug (cyclopamine), and enhanced tumorigenicity in wild-type hosts, in tumors in proportion to anti-tumor T cell activity. Nevertheless, vaccine-exposed GL26 cells were no more tumorigenic than parental GL26 in T cell-deficient hosts, though they otherwise appeared similar to GSCs enriched by chemotherapy. Finally, vaccine-exposed GBM and GL26 exhibited relatively homogeneous expression of genes expressed in progenitor cells and/or differentiation. Conclusions T cell activity represents an inducible physiological process capable of proportionally enriching GSCs in human and mouse gliomas. Stem-like gliomas enriched by strong T cell activity, however, may differ from other GSCs in that their stem-like properties may be disassociated from increased tumor malignancy and heterogeneity under specific host immune conditions. PMID:20539758

  4. Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study

    PubMed Central

    de Groot, John F.; Lamborn, Kathleen R.; Chang, Susan M.; Gilbert, Mark R.; Cloughesy, Timothy F.; Aldape, Kenneth; Yao, Jun; Jackson, Edward F.; Lieberman, Frank; Robins, H. Ian; Mehta, Minesh P.; Lassman, Andrew B.; DeAngelis, Lisa M.; Yung, W.K. Alfred; Chen, Alice; Prados, Michael D.; Wen, Patrick Y.

    2011-01-01

    Purpose Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma. Patients and Methods Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle. Results The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance. Conclusion Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma. PMID:21606416

  5. Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids.

    PubMed

    Panosyan, Eduard H; Lasky, Joseph L; Lin, Henry J; Lai, Albert; Hai, Yang; Guo, Xiuqing; Quinn, Michael; Nelson, Stanley F; Cloughesy, Timothy F; Nghiemphu, P Leia

    2016-05-01

    Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one  % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2-4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1(WT) gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development. PMID:26922345

  6. Inhibition of transient receptor potential canonical channels impairs cytokinesis in human malignant gliomas

    PubMed Central

    Bomben, V. C.; Sontheimer, H. W.

    2009-01-01

    Objectives Glial-derived primary brain tumours, gliomas, are among the fastest growing malignancies and present a huge clinical challenge. Research suggests an important, yet poorly understood, role of ion channels in growth control of normal and malignant cells. In this study, we sought to functionally characterize Transient Receptor Potential Canoncial (TRPC) channels in glioma cell proliferation. TRPC channels form non-selective cation channels that have been suggested to represent a Ca2+ influx pathway impacting cellular growth. Materials and Methods Employing a combination of molecular, biochemical and biophysical techniques, we characterized TRPC channels in glioma cells. Results We showed consistent expression of four channel family members (TRPC-1, -3, -5, -6) in glioma cell lines and acute patient-derived tissues. These channels gave rise to small, non-voltage-dependent cation currents that were blocked by the TRPC inhibitors GdCl3, 2-APB, or SKF96365. Importantly, TRPC channels contributed to the resting conductance of glioma cells and their acute pharmacological inhibition caused an ~10 mV hyperpolarization of the cells’ resting potential. Additionally, chronic application of the TRPC inhibitor SKF96365 caused near complete growth arrest. A detailed analysis, by fluorescence-activated cell sorting and time-lapse microscopy, showed that growth inhibition occurred at the G2 + M phase of the cell cycle with cytokinesis defects. Cells underwent incomplete cell divisions and became multinucleate, enlarged cells. Conclusions Nuclear atypia and enlarged cells are histopathological hallmarks for glioblastoma multiforme, the highest grade glioma, suggesting that a defect in TRPC channel function may contribute to cellular abnormalities in these tumours. PMID:18211288

  7. Selective enrichment of hypericin in malignant glioma: pioneering in vivo results.

    PubMed

    Noell, Susan; Mayer, Daniel; Strauss, Wolfgang S L; Tatagiba, Marcos S; Ritz, Rainer

    2011-05-01

    Malignant gliomas are diffuse infiltrative growing tumors with a poor prognosis despite treatment with a combination of surgery, radiotherapy and chemotherapy. It has been shown recently that complete tumor resection improves the survival time significantly. Hypericin, a component of St. Johns Wort, is one of the most powerful photosensitizers in nature. The aim of the present study was to investigate accumulation of hypericin in intracerebral implanted malignant glioma in vivo. Rats underwent stereotactic implantation of C6 glioma cells. After intravenous administration of hypericin (5 mg per kg body weight), accumulation of the compound was studied in tumor, the infiltration zone surrounding the tumor and healthy brain (contralateral hemisphere) by fluorescence microscopy between 0 and 48 h after injection. Results were compared by one-way analysis of variance. For post hoc pair-wise comparison the Tukey-Kramer HSD test was used. Accumulation of hypericin was significantly higher in C6 glioma as compared to normal tissue. Maximum hypericin uptake was achieved at 24 h after injection. Ratios of fluorescence intensity between tumor and normal tissue as well as infiltration zone and normal tissue of about 6.1:1 and 1.4:1 were found. Considering tissue auto-fluorescence, fluorescence ratios of about 19.8:1 and 2.5:1 were calculated, respectively. Therefore, hypericin seems to be quite an effective fluorescence marker for the detection of glioma in vivo. To the best of our knowledge, the present study demonstrates for the first time that hypericin accumulates selectively in intracerebral implanted C6 glioma in vivo after systemic (intravenous) administration. PMID:21399870

  8. Radiation-induced malignant meningioma following proton beam therapy for a choroidal melanoma.

    PubMed

    Scaringi, Claudia; Minniti, Giuseppe; Bozzao, Alessandro; Giangaspero, Felice; Falco, Teresa; Greco, Alessandro; De Sanctis, Vitaliana; Romano, Andrea; Enrici, Riccardo Maurizi

    2015-06-01

    We report a woman with malignant meningioma diagnosed 9 years after the treatment of a choroidal melanoma with proton beam therapy. The risk of secondary cancers is a well-known adverse late effect of radiation therapy, especially with the use of advanced techniques such as intensity-modulated radiation therapy. However, this risk may be less with the use of proton beam therapy. A 79-year-old woman presented with symptoms of enophthalmos, ptosis and paralysis of the left medial rectus muscle. She had previously been successfully treated for a choroidal melanoma of the left eye with proton beam therapy (total dose: 60 cobalt gray equivalents) following local resection. MRI showed a lesion in the left cavernous sinus with extension into the orbit and a subsequent biopsy revealed a papillary meningioma. The cavernous tumor was treated with photon radiotherapy (total dose: 54Gy) which achieved an initial partial response. However, 8 months later the tumor extensively metastasized to the skull and the spine and the patient died 1 year after the treatment. The incidence of secondary malignancies after proton beam therapy is low but not negligible, therefore, it must be taken into account when planning a treatment as secondary tumors may present with a highly aggressive behaviour. PMID:25861886

  9. Malignant transformation of bone marrow stromal cells induced by the brain glioma niche in rats.

    PubMed

    He, Qiuping; Zou, Xifeng; Duan, Deyi; Liu, Yujun; Xu, Qunyuan

    2016-01-01

    Normal human embryonic stem cells (hESCs) can develop neoplastic cancer stem cell (CSC) properties after coculture with transformed hESCs in vitro. In the present study, the influence of the tumor microenvironment on malignant transformation of bone marrow stromal cells (BMSCs) was studied after allografting a mixture of enhanced green fluorescent protein (EGFP)-labeled BMSCs and C6 glioma cells into the rat brain to understand the influence of the cellular environment, especially the tumor environment, on the transformation of grafted BMSCs in the rat brain. We performed intracerebral transplantation in the rat brain using EGFP-labeled BMSCs coinjected with C6 tumor cells. After transplantation, the EGFP-labeled cells were isolated from the tumor using fluorescence-activated cell sorting, and the characteristics of the recovered cells were investigated. Glioma-specific biomarkers of the sorted cells and the biological characteristics of the tumors were analyzed. The BMSCs isolated from the cografts were transformed into glioma CSCs, as indicated by the marked expression of the glioma marker GFAP in glioma cells, and of Nestin and CD133 in neural stem cells and CSCs, as well as rapid cell growth, decreased level of the tumor suppressor gene p53, increased level of the oncogene murine double minute gene 2 (MDM2), and recapitulation of glioma tissues in the brain. These data suggest that BMSCs can be transformed into CSCs, which can be further directed toward glioma formation under certain conditions, supporting the notion that the tumor microenvironment is involved in transforming normal BMSCs into glial CSCs. PMID:26590986

  10. Intraoperative vascular DIVA surgery reveals angiogenic hotspots in tumor zones of malignant gliomas

    PubMed Central

    Eyüpoglu, Ilker Y.; Hore, Nirjhar; Fan, Zheng; Buslei, Rolf; Merkel, Andreas; Buchfelder, Michael; Savaskan, Nicolai E.

    2015-01-01

    Malignant gliomas belong to the most threatening tumor entities and are hallmarked by rapid proliferation, hypervascularization and an invasive growth pattern. The primary obstacle in surgical treatment lies in differentiation between healthy and pathological tissue at the tumor margins, where current visualization methods reach their limits. Here, we report on a novel technique (vascular dual intraoperative visualization approach - vDIVA) enabling visualization of different tumor zones (TZ I–III) on the basis of angiogenic hotspots. We investigated glioblastoma patients who underwent 5-ALA fluorescence-guided surgery with simultaneous intraoperative ICG fluorescence angiography. This vDIVA technique revealed hypervascularized areas which were further histologically investigated. Neuropathological assessments revealed tissue areas at the resection margins corresponding to TZ II, and postoperative CD34- and Map2 immunostaining confirmed these angiogenic hotspots to be occupied by glioma cells. Hence, the vascular architecture in this transitional zone could be well differentiated from both primary tumor bulk and healthy brain parenchyma. These data demonstrate that ICG fluorescence angiography improves state-of-the-art glioma surgery techniques and facilitates the future characterization of polyclonal attributes of malignant gliomas. PMID:25609379

  11. Clinical outcome assessment in malignant glioma trials: measuring signs, symptoms, and functional limitations.

    PubMed

    Blakeley, Jaishri O; Coons, Stephen Joel; Corboy, John R; Leidy, Nancy Kline; Mendoza, Tito R; Wefel, Jeffrey S

    2016-03-01

    The shared goal of all parties developing therapeutics against malignant gliomas is to positively impact the lives of people affected by these cancers. Clinical outcome assessment (COA) tools, including measures of patient-reported outcome, performance outcome, clinician-reported outcome, and observer-reported outcome, allow patient-focused assessments to complement traditional efficacy measures such as overall survival and radiographic endpoints. This review examines the properties of various COA measures used in malignant glioma clinical trials to date and cross references their content to the priority signs, symptoms, and functional limitations defined through a community survey conducted by the National Brain Tumor Society. The overarching goal of this initiative is to identify COA measures that are feasible and have appropriate psychometric properties for use in this patient population as well as highlight where further development is needed. PMID:26989128

  12. Demethoxycurcumin Retards Cell Growth and Induces Apoptosis in Human Brain Malignant Glioma GBM 8401 Cells

    PubMed Central

    Huang, Tzuu-Yuan; Hsu, Che-Wen; Chang, Weng-Cheng; Wang, Miin-Yau; Wu, June-Fu; Hsu, Yi-Chiang

    2012-01-01

    Demethoxycurcumin (DMC; a curcumin-related demethoxy compound) has been recently shown to display antioxidant and antitumor activities. It has also produced a potent chemopreventive action against cancer. In the present study, the antiproliferation (using the MTT assay, DMC was found to have cytotoxic activities against GBM 8401 cell with IC50 values at 22.71 μM) and induced apoptosis effects of DMC have been investigated in human brain malignant glioma GBM 8401 cells. We have studied the mitochondrial membrane potential (MMP), DNA fragmentation, caspase activation, and NF-κB transcriptional factor activity. By these approaches, our results indicated that DMC has produced an inhibition of cell proliferation as well as the activation of apoptosis in GBM 8401 cells. Both effects were observed to increase in proportion with the dosage of DMC treatment, and the apoptosis was induced by DMC in human brain malignant glioma GBM 8401 cells via mitochondria- and caspase-dependent pathways. PMID:22454662

  13. Bevacizumab and irinotecan in recurrent malignant glioma, a single institution experience

    PubMed Central

    Mesti, Tanja; Moltara, Maja Ebert; Boc, Marko; Rebersek, Martina; Ocvirk, Janja

    2015-01-01

    Background Treatment options of recurrent malignant gliomas are very limited and with a poor survival benefit. The results from phase II trials suggest that the combination of bevacizumab and irinotecan is beneficial. Patients and methods. The medical documentation of 19 adult patients with recurrent malignant gliomas was retrospectively reviewed. All patients received bevacizumab (10 mg/kg) and irinotecan (340 mg/m2 or 125 mg/m2) every two weeks. Patient clinical characteristics, drug toxicities, response rate, progression free survival (PFS) and overall survival (OS) were evaluated. Results Between August 2008 and November 2011, 19 patients with recurrent malignant gliomas (median age 44.7, male 73.7%, WHO performance status 0–2) were treated with bevacizumab/irinotecan regimen. Thirteen patients had glioblastoma, 5 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. With exception of one patient, all patients had initially a standard therapy with primary resection followed by postoperative chemoradiotherapy. Radiological response was confirmed after 3 months in 9 patients (1 complete response, 8 partial responses), seven patients had stable disease and three patients have progressed. The median PFS was 6.8 months (95% confidence interval [CI]: 5.3–8.3) with six-month PFS rate 52.6%. The median OS was 7.7 months (95% CI: 6.6–8.7), while six-month and twelve-month survival rates were 68.4% and 31.6%, respectively. There were 16 cases of hematopoietic toxicity grade (G) 1–2. Non-hematopoietic toxicity was present in 14 cases, all G1-2, except for one patient with proteinuria G3. No grade 4 toxicities, no thromboembolic event and no intracranial hemorrhage were observed. Conclusions In recurrent malignant gliomas combination of bevacizumab and irinotecan might be an active regimen with acceptable toxicity. PMID:25810706

  14. Current status of local therapy in malignant gliomas--a clinical review of three selected approaches.

    PubMed

    Juratli, Tareq A; Schackert, Gabriele; Krex, Dietmar

    2013-09-01

    Malignant gliomas are the most frequently occurring, devastating primary brain tumors, and are coupled with a poor survival rate. Despite the fact that complete neurosurgical resection of these tumors is impossible in consideration of their infiltrating nature, surgical resection followed by adjuvant therapeutics, including radiation therapy and chemotherapy, is still the current standard therapy. Systemic chemotherapy is restricted by the blood-brain barrier, while methods of local delivery, such as with drug-impregnated wafers, convection-enhanced drug delivery, or direct perilesional injections, present attractive ways to circumvent these barriers. These methods are promising ways for direct delivery of either standard chemotherapeutic or new anti-cancer agents. Several clinical trials showed controversial results relating to the influence of a local delivery of chemotherapy on the survival of patients with both recurrent and newly diagnosed malignant gliomas. Our article will review the development of the drug-impregnated release, as well as convection-enhanced delivery and the direct injection into brain tissue, which has been used predominantly in gene-therapy trials. Further, it will focus on the use of convection-enhanced delivery in the treatment of patients with malignant gliomas, placing special emphasis on potential shortcomings in past clinical trials. Although there is a strong need for new or additional therapeutic strategies in the treatment of malignant gliomas, and although local delivery of chemotherapy in those tumors might be a powerful tool, local therapy is used only sporadically nowadays. Thus, we have to learn from our mistakes in the past and we strongly encourage future developments in this field. PMID:23694764

  15. Hypofractionated stereotactic radiotherapy in combination with bevacizumab or fotemustine for patients with progressive malignant gliomas.

    PubMed

    Minniti, Giuseppe; Agolli, Linda; Falco, Teresa; Scaringi, Claudia; Lanzetta, Gaetano; Caporello, Paola; Osti, Mattia Falchetto; Esposito, Vincenzo; Enrici, Riccardo Maurizi

    2015-05-01

    To evaluate the efficacy of hypofractionated stereotactic radiotherapy performed as reirradiation in combination with fotemustine or bevacizumab as salvage treatment in patients with recurrent malignant glioma. Between May 2006 and December 2013, 54 patients with recurrent malignant glioma received hypofractionated stereotactic radiotherapy (HSRT, 25 Gy in 5-Gy fractions) plus either fotemustine or bevacizumab at University of Rome Sapienza, Sant'Andrea Hospital. All patients had Karnofsky performance score (KPS) ≥ 60 and were previously treated with standard chemoradiotherapy. Forty-two patients had a GBM and 12 patients had an anaplastic astrocytoma (AA). The median overall survival (OS) time and 12-month OS rates after HSRT was 11 months and 30 % for patients treated with HSRT plus bevacizumab and 8.3 months and 5 % for those treated with HSRT plus fotemustine (p = 0.01). Median PFS times were 4 and 6 months for patients treated with HSRT plus fotemustine or bevacizumab, respectively (p = 0.01). KPS > 70 (p = 0.04), AA histology, and the treatment with bevacizumab were independent favourable prognostic factors for OS. In general, both treatments were well tolerated with relatively low treatment-related toxicity. HSRT combined with bevacizumab or fotemustine may represent a feasible treatment option for patients with progressive malignant gliomas, although most of the tumors recur in a few months. Efficacy of bevacizumab or alkylating agents in combination with different radiation schedules needs to be evaluated in prospective studies. PMID:25702193

  16. Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601).

    PubMed

    Mamelak, Adam N; Jacoby, Douglas B

    2007-03-01

    Targeted therapies for cancer is a rapidly advancing field, but the identification of tumor-specific ligands has proven difficult. Chlorotoxin (CTX) is a small, 36 amino acid neurotoxin isolated from the venom of the Giant Yellow Israeli scorpion Leiurus Quinquestriatus. Interestingly, the peptide has been found to preferentially bind to a variety of human malignancies, but shows little or no binding to normal human tissues. A synthetic version of this peptide (TM-601) has been manufactured and covalently linked to iodine 131 (131I-TM-601) as a means of targeting radiation to tumor cells. Preclinical studies and Phase I clinical trials have been completed in patients with recurrent glioma, a type of malignant brain tumor. These studies demonstrated that intracavitary dosing of 131I-TM-601 appears safe, minimally toxic, and binds malignant glioma with high affinity and for long durations. A Phase II trial of this agent using higher doses of radioactivity and repeated local administrations is underway. In addition, enrolment has begun in a Phase I trial evaluating whether systemically delivered 131I-TM-601 can be used to image metastatic solid tumors and primary gliomas. Due to its small size, selective tumor binding properties, minimal toxicity and relative ease of manipulation, CTX represents a potentially important targeting agent for many cancers. PMID:17335414

  17. The Potential of Tetrandrine against Gliomas.

    PubMed

    Chen, Yun; Tseng, Sheng-Hong

    2010-09-01

    Patients with malignant gliomas have poor prognoses, and the majority of the patients have local tumor recurrence after various treatments including surgery, radiotherapy, and chemotherapy. Thus it is mandatory to develop better therapies for treatment of these malignant brain tumors. Tetrandrine, a bisbenzylisoquinoline alkaloid, has antitumor effects against some cancers. Tetrandrine affects the cell cycle, production of reactive oxygen species, mitogen-activated protein kinase activity, and reverses multidrug resistance in various cancer cells. Since tetrandrine is a highly lipid-soluble and hydrophobic molecule with a low molecular weight, it may cross the blood brain barrier; thus, it could be used for the treatment of gliomas. Tetrandrine inhibits the large-conductance, calcium-activated potassium (BK) channels and the expression of BK channel has a positive correlation with tumor malignancy grade in human gliomas. Furthermore, tetrandrine also exerts cytotoxic effects, and induces apoptosis and radiosensitization in glioma cells by elimination of radiation-induced cell cycle perturbation. It also has anti-angiogenesis effects in gliomas, and exerts an antitumor effect on subcutaneous and intracerebral gliomas. Tetrandrine is a radiosensitizer and also a multidrug resistance reversing agent. Tetrandrine can probably be combined with radiotherapy or other chemotherapeutic agents to treat gliomas. Nonetheless, it is important to determine the balance between the safety and efficacy of tetrandrine in patients with malignant gliomas before any clinical application. PMID:20879981

  18. Spectral karyotyping (SKY) analysis of heritable effects of radiation-induced malignant transformation

    NASA Astrophysics Data System (ADS)

    Zitzelsberger, Horst; Fung, Jingly; Janish, C.; McNamara, George; Bryant, P. E.; Riches, A. C.; Weier, Heinz-Ulli G.

    1999-05-01

    Radiocarcinogenesis is widely recognized as occupational, environmental and therapeutical hazard, but the underlying mechanisms and cellular targets have not yet been identified. We applied SKY to study chromosomal rearrangements leading to malignant transformation of irradiated thyroid epithelial cells. SKY is a recently developed technique to detect translocations involving non-homologous based on unique staining of all 24 human chromosomes by hybridization with a mixture of whole chromosome painting probes. A tuneable interferometer mounted on a fluorescence microscope in front of a CCD camera allows to record the 400 nm - 1000 nm fluorescence spectrum for each pixel in the image. After background correction, spectra recorded for each pixel are compared to reference spectra stored previously for each chromosome-specific probe. Thus, pixel spectra can be associated with specific chromosomes and displayed in 'classification' colors, which are defined so that even small translocations become readily discernible. SKY analysis was performed on several radiation-transformed cell lines. Line S48T was generated from a primary tumor of a child exposed to elevated levels of radiation following the Chernobyl nuclear accident. Subclones were generated from the human thyroid epithelial cell line (HTori-3) by exposure to gamma or alpha irradiation. SKY analysis revealed multiple translocations and, combined with G-banding, allowed the definition of targets for positional cloning of tumor related genes.

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

    SciTech Connect

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

    2009-09-01

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

  20. Histologically Proven Radiation-Induced Brainstem Glioma 93 Months After External Beam Radiotherapy for Pituitary Macroadenoma: Radiation Treatment Dose and Volume Correlation.

    PubMed

    Abboud, Salim E; Wolansky, Leo J; Manjila, Sunil V; Lo, Simon S; Arafah, Baha M; Selman, Warren R; Couce, Marta E; Rogers, Lisa R

    2015-01-01

    Patient is a 29-year-old with a history of recurrent growth hormone-secreting pituitary macroadenoma diagnosed 12 years prior to presentation. Eight years prior to current presentation, the patient underwent re-resection and received 50.4 Gy external beam radiotherapy (EBRT) in 28 fractions of 1.8 Gy each. Serial postradiation MRIs demonstrated regression in pituitary tumor size. Patient presented with new headaches 7.5 years after completing EBRT. Brain MRI demonstrated new FLAIR hyperintensity and contrast enhancement within the pons and medulla, corresponding to the 36 Gy isodose line of each radiation dose fraction. Differential diagnosis included radiation necrosis and radiation-induced glioma (RIG). The patient's neurologic exam worsened over the following 4 months. MRI showed progressive increase in mass effect, extent of FLAIR hyperintensity, and contrast enhancement in the brainstem. Stereotactic-assisted biopsy showed infiltrating astrocytoma with moderate atypia. A PubMed search showed this is the first case of histologically verified brainstem RIG correlated with 3-dimensional conformational radiation therapy dose and volume planning following EBRT for a pituitary adenoma. The rare occurrence of brainstem RIG after radiation therapy for pituitary tumor supports the need for long-term imaging monitoring of such patients. PMID:25345677

  1. Safety and Efficacy of Stereotactic Radiosurgery and Adjuvant Bevacizumab in Patients With Recurrent Malignant Gliomas

    SciTech Connect

    Cuneo, Kyle C.; Vredenburgh, James J.; Sampson, John H.; Reardon, David A.; Desjardins, Annick; Peters, Katherine B.; Friedman, Henry S.; Willett, Christopher G.; Kirkpatrick, John P.

    2012-04-01

    Purpose: Patients with recurrent malignant gliomas treated with stereotactic radiosurgery (SRS) and multiagent systemic therapies were reviewed to determine the effects of patient- and treatment-related factors on survival and toxicity. Methods and Materials: A retrospective analysis was performed on patients with recurrent malignant gliomas treated with salvage SRS from September 2002 to March 2010. All patients had experienced progression after treatment with temozolomide and radiotherapy. Salvage SRS was typically administered only after multiple postchemoradiation salvage systemic therapies had failed. Results: 63 patients were treated with SRS for recurrent high-grade glioma; 49 patients had World Health Organization (WHO) Grade 4 disease. Median follow-up was 31 months from primary diagnosis and 7 months from SRS. Median overall survival from primary diagnosis was 41 months for all patients. Median progression-free survival (PFS) and overall survival from SRS (OS-SRS) were 6 and 10 months for all patients, respectively. The 1-year OS-SRS for patients with Grade 4 glioma who received adjuvant (concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant bevacizumab (p = 0.005). Median PFS for patients with a WHO Grade 4 glioma who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for patients who did not receive adjuvant bevacizumab (p = 0.014). Karnofsky performance status (KPS) and age were not significantly different between treatment groups. Treatment-related Grade 3/4 toxicity for patients receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58).On multivariate analysis, the relative risk of death and progression with adjuvant bevacizumab was 0.37 (confidence interval [CI] 0.17-0.82) and 0.45 (CI 0.21-0.97). KPS >70 and age <50 years were significantly associated with improved survival. Conclusions: The combination of salvage radiosurgery and bevacizumab to treat recurrent malignant

  2. THOR METHYLATION PROVIDES INSIGHT INTO THE TELOMERE MAINTENANCE LANDSCAPE OF MALIGNANT GLIOMAS

    PubMed Central

    Tabori, Uri; Castelo-Branco, Pedro; Lee, Donghyun; Gallo, Marco; Limpan, Tatiana; Mangerel, Joshua; Price, Aryeh; Remke, Marc; Zhang, Cindy; Heidari, Abolfazl; Wani, Khalida; Vanner, Robert; Zadeh, Gelareh; Karamchandani, Jason; Das, Sunit; Taylor, michael; Hawkins, Cynthia; Yan, Hai; Aldape, Kenneth; Dirks, Peter B.

    2014-01-01

    BACKGROUND: Gliomas are a deadly group of childhood and adult cancers associated with high relapse rate following current therapies. Limitless self-renewal is a hallmark of cancer recurrence and is controlled by telomerase activation and telomere maintenance. We have recently uncovered THOR (TERT Hypermethylated Oncological Region) which is paradoxically hypermethylated in gliomas with telomerase activation. In order to further explore the biological impact of THOR hypermethylation on self renewal and telomere maintenance of gliomas we undertook a stepwise approach. METHODS: RESULTS: Mapping of the human TERT promoter reveals that THOR spans 432 BP and comprises 52 CG sites. In contrast, the area where mutations in TERT promoter were uncovered is permanently hypomethylated. Promoter driven expression was analysed through luciferase assays and unveiled a repressive effect of THOR on the TERT promoter. Moreover, TERT mutations promoted hyperactivation of the reporter gene providing explanations for the methylation pattern observed in malignant gliomas. THOR methylation increases in gliomas as they transform from low to high grade and from primary tumor to established cell lines (p < 0.001). Analysis of allelic Tert expression reveals that THOR is initally methylated in the mutant allele and throughout tumor progression, the other allele eventually becomes methylated. This correlates with higher TERT expression. In contrast, tumors utilizing alternative lengthening of telomeres (ALT) lack THOR methylation and TERT mutations. Glioma stem cells (n = 32) are addicted to telomerase and have higher THOR methylation than the bulk tumor. Strikingly, glioblastomas which activate ALT lack this phenotype in their stem cells compartment. Whole exome sequencing reveals multiple ALT related mutations (TP53 and ATRX) which are present in the mature tumor cells subpopulation and absent in the TERT expressing stem cell subpopulation. THOR demethylation with Decitabine results in loss

  3. Concurrent Chemotherapy of Malignant Glioma in Rats by Using Multidrug-Loaded Biodegradable Nanofibrous Membranes

    PubMed Central

    Tseng, Yuan-Yun; Huang, Yin-Chen; Yang, Tao-Chieh; Yang, Shun-Tai; Liu, Shou-Cheng; Chang, Tzu-Min; Kau, Yi-Chuan; Liu, Shih-Jung

    2016-01-01

    Glioblastoma multiforme has a poor prognosis and is highly chemoresistant. In this study, we implanted biodegradable 1,3-bis[2-chloroethyl]-1-nitroso-urea-, irinotecan-, and cisplatin-eluting poly[(d,l)-lactide-co-glycolide] (BIC/PLGA) and virgin nanofibrous membranes on the brain surface of C6 glioma-bearing rats in concurrent and virgin groups, respectively. The concentrations of all applied drugs were significantly higher in the brain than in the blood for more than 8 weeks in all studied rats. Tumor growth was more rapid in the vehicle-treated group, and tumor volumes were significantly higher in the vehicle-treated group. Moreover, the average survival time was significantly shorter in the vehicle-treated group (P = 0.026), and the BIC/PLGA nanofibrous membranes significantly reduced the risk of mortality (P < 0.001). Furthermore, the results suggested that the BIC/PLGA nanofibers reduced the malignancy of C6 glioma. The experimental findings indicate that the multianticancer drug (i.e., BIC)-eluting PLGA nanofibers are favorable candidates for treating malignant glioma. PMID:27471070

  4. Concurrent Chemotherapy of Malignant Glioma in Rats by Using Multidrug-Loaded Biodegradable Nanofibrous Membranes.

    PubMed

    Tseng, Yuan-Yun; Huang, Yin-Chen; Yang, Tao-Chieh; Yang, Shun-Tai; Liu, Shou-Cheng; Chang, Tzu-Min; Kau, Yi-Chuan; Liu, Shih-Jung

    2016-01-01

    Glioblastoma multiforme has a poor prognosis and is highly chemoresistant. In this study, we implanted biodegradable 1,3-bis[2-chloroethyl]-1-nitroso-urea-, irinotecan-, and cisplatin-eluting poly[(d,l)-lactide-co-glycolide] (BIC/PLGA) and virgin nanofibrous membranes on the brain surface of C6 glioma-bearing rats in concurrent and virgin groups, respectively. The concentrations of all applied drugs were significantly higher in the brain than in the blood for more than 8 weeks in all studied rats. Tumor growth was more rapid in the vehicle-treated group, and tumor volumes were significantly higher in the vehicle-treated group. Moreover, the average survival time was significantly shorter in the vehicle-treated group (P = 0.026), and the BIC/PLGA nanofibrous membranes significantly reduced the risk of mortality (P < 0.001). Furthermore, the results suggested that the BIC/PLGA nanofibers reduced the malignancy of C6 glioma. The experimental findings indicate that the multianticancer drug (i.e., BIC)-eluting PLGA nanofibers are favorable candidates for treating malignant glioma. PMID:27471070

  5. Concurrent Chemotherapy of Malignant Glioma in Rats by Using Multidrug-Loaded Biodegradable Nanofibrous Membranes

    NASA Astrophysics Data System (ADS)

    Tseng, Yuan-Yun; Huang, Yin-Chen; Yang, Tao-Chieh; Yang, Shun-Tai; Liu, Shou-Cheng; Chang, Tzu-Min; Kau, Yi-Chuan; Liu, Shih-Jung

    2016-07-01

    Glioblastoma multiforme has a poor prognosis and is highly chemoresistant. In this study, we implanted biodegradable 1,3-bis[2-chloroethyl]-1-nitroso-urea-, irinotecan-, and cisplatin-eluting poly[(d,l)-lactide-co-glycolide] (BIC/PLGA) and virgin nanofibrous membranes on the brain surface of C6 glioma-bearing rats in concurrent and virgin groups, respectively. The concentrations of all applied drugs were significantly higher in the brain than in the blood for more than 8 weeks in all studied rats. Tumor growth was more rapid in the vehicle-treated group, and tumor volumes were significantly higher in the vehicle-treated group. Moreover, the average survival time was significantly shorter in the vehicle-treated group (P = 0.026), and the BIC/PLGA nanofibrous membranes significantly reduced the risk of mortality (P < 0.001). Furthermore, the results suggested that the BIC/PLGA nanofibers reduced the malignancy of C6 glioma. The experimental findings indicate that the multianticancer drug (i.e., BIC)-eluting PLGA nanofibers are favorable candidates for treating malignant glioma.

  6. The deadly connection between endoplasmic reticulum, Ca2+, protein synthesis, and the endoplasmic reticulum stress response in malignant glioma cells

    PubMed Central

    Johnson, Guyla G.; White, Misti C.; Wu, Jian-He; Vallejo, Matthew; Grimaldi, Maurizio

    2014-01-01

    Background The endoplasmic reticulum (ER) is involved in Ca2+ signaling and protein processing. Accumulation of unfolded proteins following ER Ca2+ depletion triggers the ER stress response (ERSR), which facilitates protein folding and removal of damaged proteins and can induce cell death. Unfolded proteins bind to chaperones, such as the glucose-regulated protein (GRP)78 and cause the release of GRP78-repressed proteins executing ERSR. Methods Several glioma cell lines and primary astrocytes were used to analyze ERSR using standard western blots, reverse transcription–PCR, viability assays, and single cell Ca2+ imaging. Results ERSR induction with thapsigargin results in a more intense ERSR associated with a larger loss of ER Ca2+, activation of ER-associated caspases (4/12) and caspase 3, and a higher rate of malignant glioma cell death than in normal glial cells. Malignant glioma cells have higher levels of protein synthesis and expression of the translocon (a component of the ribosomal complex, guiding protein entry in the ER), the activity of which is associated with the loss of ER Ca2+. Our experiments confirm increased expression of the translocon in malignant glioma cells. In addition, blockade of the ribosome-translocon complex with agents differently affecting translocon Ca2+ permeability causes opposite effects on ERSR deployment and death of malignant glioma cells. Conclusions Excessive ER Ca2+ loss due to translocon activity appears to be responsible for the enhancement of ERSR, leading to the death of glioma cells. The results reveal a characteristic of malignant glioma cells that could be exploited to develop new therapeutic strategies to treat incurable glial malignancies. PMID:24569545

  7. Predictive value of MGMT promoter methylation status in Asian and Caucasian patients with malignant gliomas: a meta-analysis

    PubMed Central

    Chen, Chao; Wang, Feng; Cheng, Yuan; Cheng, Yin; Ren, Xueying; Huai, Haiqing

    2015-01-01

    Background: The prognostic significance of O6-methylguanine-DNA methyltransferase (MGMT) promoter status for survival of patients with malignant gliomas remains controversial. Thus, the meta-analysis was performed in order to identify the impact of MGMT expression on prognosis of malignant gliomas. Method: An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases. Version 12.0 STATA software was used for the current meta-analysis. Hazard ratios (HRs) with their corresponding 95% confidence interval (95% CI) were also calculated to clarify the correlation between MGMT expression and the prognosis of malignant gliomas. Results: Final analysis of 2,377 malignant gliomas patients from 32 clinical studies was performed. The meta-analysis results show that MGMT promoter group and unmethylated MGMT group has a significant difference (all P < 0.01). Combined HR of MGMT suggests that the methylated MGMT group has a longer overall survival than the unmethylated MGMT group (P < 0.01), but the Asians don’t present a difference between the two groups. Conclusion: The meta-analysis study shows that the elevated MGMT promoter group may have a better prognosis in malignant gliomas patients, but the Asians don’t have a better prognosis. PMID:26131285

  8. Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma.

    PubMed

    Doucette, Tiffany A; Kong, Ling-Yuan; Yang, Yuhui; Ferguson, Sherise D; Yang, Jinbo; Wei, Jun; Qiao, Wei; Fuller, Gregory N; Bhat, Krishna P; Aldape, Kenneth; Priebe, Waldemar; Bögler, Oliver; Heimberger, Amy B; Rao, Ganesh

    2012-09-01

    Signal transducer and activator of transcription (STAT) 3 has been described as a "master regulator" of signaling pathways involved in the transition from low-grade glioma (LGG) to high-grade glioma (HGG). Although STAT3 is overexpressed in HGGs, it remains unclear whether its overexpression is sufficient to induce or promote the malignant progression of glioma. To characterize the effect of STAT3 expression on tumor progression in vivo, we expressed the STAT3 gene in glioneuronal progenitor cells in mice. STAT3 was expressed alone or concurrently with platelet-derived growth factor B (PDGFB), a well-described initiator of LGG. STAT3 alone was insufficient to induce tumor formation; however, coexpression of STAT3 with PDGFB in mice resulted in a significantly higher incidence of HGGs than PDGFB alone. The median symptomatic tumor latency in mice coexpressing STAT3 and PDGFB was significantly shorter, and mice that developed symptomatic tumors demonstrated significantly higher expression of phosphorylated STAT3 intratumorally. In HGGs, expression of STAT3 was associated with suppression of apoptosis and an increase in tumor cell proliferation. HGGs induced by STAT3 and PDGFB also displayed frequent foci of necrosis and microvascular proliferation. The expression of CD31 (a marker of endothelial proliferation) was significantly higher in tumors induced by coexpression of STAT3 and PDGFB. When mice injected with PDGFB and STAT3 were treated with a STAT3 inhibitor, median survival increased and the incidence of HGG and CD31 expression decreased significantly. These results demonstrate that STAT3 promotes the malignant progression of glioma. Inhibiting STAT3 expression mitigates tumor progression and improves survival, validating it as a therapeutic target. PMID:22753228

  9. Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma

    PubMed Central

    Doucette, Tiffany A.; Kong, Ling-Yuan; Yang, Yuhui; Ferguson, Sherise D.; Yang, Jinbo; Wei, Jun; Qiao, Wei; Fuller, Gregory N.; Bhat, Krishna P.; Aldape, Kenneth; Priebe, Waldemar; Bögler, Oliver; Heimberger, Amy B.; Rao, Ganesh

    2012-01-01

    Signal transducer and activator of transcription (STAT) 3 has been described as a “master regulator” of signaling pathways involved in the transition from low-grade glioma (LGG) to high-grade glioma (HGG). Although STAT3 is overexpressed in HGGs, it remains unclear whether its overexpression is sufficient to induce or promote the malignant progression of glioma. To characterize the effect of STAT3 expression on tumor progression in vivo, we expressed the STAT3 gene in glioneuronal progenitor cells in mice. STAT3 was expressed alone or concurrently with platelet-derived growth factor B (PDGFB), a well-described initiator of LGG. STAT3 alone was insufficient to induce tumor formation; however, coexpression of STAT3 with PDGFB in mice resulted in a significantly higher incidence of HGGs than PDGFB alone. The median symptomatic tumor latency in mice coexpressing STAT3 and PDGFB was significantly shorter, and mice that developed symptomatic tumors demonstrated significantly higher expression of phosphorylated STAT3 intratumorally. In HGGs, expression of STAT3 was associated with suppression of apoptosis and an increase in tumor cell proliferation. HGGs induced by STAT3 and PDGFB also displayed frequent foci of necrosis and microvascular proliferation. The expression of CD31 (a marker of endothelial proliferation) was significantly higher in tumors induced by coexpression of STAT3 and PDGFB. When mice injected with PDGFB and STAT3 were treated with a STAT3 inhibitor, median survival increased and the incidence of HGG and CD31 expression decreased significantly. These results demonstrate that STAT3 promotes the malignant progression of glioma. Inhibiting STAT3 expression mitigates tumor progression and improves survival, validating it as a therapeutic target. PMID:22753228

  10. Isolation and characterization of human malignant glioma cells from histologically normal brain.

    PubMed

    Silbergeld, D L; Chicoine, M R

    1997-03-01

    Brain invasion prevents complete surgical extirpation of malignant gliomas; however, invasive cells from distant, histologically normal brain previously have not been isolated, cultured, and characterized. To evaluate invasive human malignant glioma cells, the authors established cultures from gross tumor and histologically normal brain. Three men and one woman, with a mean age of 67 years, underwent two frontal and two temporal lobectomies for tumors, which yielded specimens of both gross tumor and histologically normal brain. Each specimen was acquired a minimum of 4 cm from the gross tumor. The specimens were split: a portion was sent for neuropathological evaluation (three glioblastomas multiforme and one oligodendroglioma) and a portion was used to establish cell lines. Morphologically, the specimens of gross tumor and histologically normal brain were identical in three of the four cell culture pairs. Histochemical staining characteristics were consistent both within each pair and when compared with the specimens sent for neuropathological evaluation. Cultures demonstrated anchorage-independent growth in soft agarose and neoplastic karyotypes. Growth rates in culture were greater for histologically normal brain than for gross tumor in three of the four culture pairs. Although the observed increases in growth rates of histologically normal brain cultures do not correlate with in vivo behavior, these findings corroborate the previously reported stem cell potential of invasive glioma cells. Using the radial dish assay, no significant differences in motility between cultures of gross tumor and histologically normal brain were found. In summary, tumor cells were cultured from histologically normal brain acquired from a distance greater than 4 cm from the gross tumor, indicating the relative insensitivity of standard histopathological identification of invasive glioma cells (and hence the inadequacy of frozen-section evaluation of resection margins). Cell lines

  11. Profound tumor-specific Th2 bias in patients with malignant glioma

    PubMed Central

    2012-01-01

    Background Vaccination against tumor-associated antigens is one promising approach to immunotherapy against malignant gliomas. While previous vaccine efforts have focused exclusively on HLA class I-restricted peptides, class II-restricted peptides are necessary to induce CD4+ helper T cells and sustain effective anti-tumor immunity. In this report we investigated the ability of five candidate peptide epitopes derived from glioma-associated antigens MAGE and IL-13 receptor α2 to detect and characterize CD4+ helper T cell responses in the peripheral blood of patients with malignant gliomas. Methods Primary T cell responses were determined by stimulating freshly isolated PBMCs from patients with primary glioblastoma (GBM) (n = 8), recurrent GBM (n = 5), meningioma (n = 7), and healthy controls (n = 6) with each candidate peptide, as well as anti-CD3 monoclonal antibody (mAb) and an immunodominant peptide epitope derived from myelin basic protein (MBP) serving as positive and negative controls, respectively. ELISA was used to measure IFN-γ and IL-5 levels, and the ratio of IFN-γ/IL-5 was used to determine whether the response had a predominant Th1 or Th2 bias. Results We demonstrate that novel HLA Class-II restricted MAGE-A3 and IL-13Rα2 peptides can detect T cell responses in patients with GBMs as well as in healthy subjects. Stimulation with a variety of peptide antigens over-expressed by gliomas is associated with a profound reduction in the IFN-γ/IL-5 ratio in GBM patients relative to healthy subjects. This bias is more pronounced in patients with recurrent GBMs. Conclusions Therapeutic vaccine strategies to shift tumor antigen-specific T cell response to a more immunostimulatory Th1 bias may be needed for immunotherapeutic trials to be more successful clinically. PMID:23186108

  12. Brain PDD and PDT unlocking the mystery of malignant gliomas.

    PubMed

    Eljamel, M Sam

    2004-12-01

    Malignant brain tumours (MBTs) have one of the worst outcomes of human cancers today and their incidence is on the increase. Current treatment failure is usually due to local recurrence of the tumour rather than distant metastasis. In the last three decades we have seen many novel and potentially effective treatment strategies rise rapidly to the rescue. Sadly, however, the majority of these approaches were not good enough to withstand the harsh reality of the sceptical gaze of the scientific eye or the stringent health economics of this millennium. PDD and PDT, however, is one of the few therapies fighting back and still standing today. The results of its randomised controlled trials are eagerly awaited. To date the literature suggests that both PDD and PDT significantly prolong the time to tumour progression, reduce local recurrence, increase radical resection and prolong overall survival of MBTs. PDD and PDT are well tolerated by patients and worthwhile pursuing. PMID:25048434

  13. Malignant Transformation in Glioma Steered by an Angiogenic Switch: Defining a Role for Bone Marrow-Derived Cells.

    PubMed

    Xu, Raymond; Pisapia, David; Greenfield, Jeffrey P

    2016-01-01

    Low-grade gliomas, such as pilocytic astrocytoma and subependymoma, are often characterized as benign tumors due to their relative circumscription radiologically and typically non-aggressive biologic behavior. In contrast, low-grades that are by their nature diffusely infiltrative, such as diffuse astrocytomas and oligodendrogliomas, have the potential to transform into malignant high-grade counterparts and, given sufficient time, invariably do so. These high-grade gliomas carry very poor prognoses and are largely incurable, warranting a closer look at what causes this adverse transition. A key characteristic that distinguishes low- and high-grade gliomas is neovascularization: it is absent in low-grade gliomas, but prolific in high-grade gliomas, providing the tumor with ample blood supply for exponential growth. It has been well described in the literature that bone marrow-derived cells (BMDCs) may contribute to the angiogenic switch that is responsible for malignant transformation of low-grade gliomas. In this review, we will summarize the current literature on BMDCs and their known contribution to angiogenesis-associated tumor growth in gliomas. PMID:26973806

  14. Collaborative labeling of malignant glioma with WebMILL: a first look

    NASA Astrophysics Data System (ADS)

    Singh, Eesha; Asman, Andrew J.; Xu, Zhoubing; Chambless, Lola; Thompson, Reid; Landman, Bennett A.

    2012-02-01

    Malignant gliomas are the most common form of primary neoplasm in the central nervous system, and one of the most rapidly fatal of all human malignancies. They are treated by maximal surgical resection followed by radiation and chemotherapy. Herein, we seek to improve the methods available to quantify the extent of tumors using newly presented, collaborative labeling techniques on magnetic resonance imaging. Traditionally, labeling medical images has entailed that expert raters operate on one image at a time, which is resource intensive and not practical for very large datasets. Using many, minimally trained raters to label images has the possibility of minimizing laboratory requirements and allowing high degrees of parallelism. A successful effort also has the possibility of reducing overall cost. This potentially transformative technology presents a new set of problems, because one must pose the labeling challenge in a manner accessible to people with little or no background in labeling medical images and raters cannot be expected to read detailed instructions. Hence, a different training method has to be employed. The training must appeal to all types of learners and have the same concepts presented in multiple ways to ensure that all the subjects understand the basics of labeling. Our overall objective is to demonstrate the feasibility of studying malignant glioma morphometry through statistical analysis of the collaborative efforts of many, minimally-trained raters. This study presents preliminary results on optimization of the WebMILL framework for neoplasm labeling and investigates the initial contributions of 78 raters labeling 98 whole-brain datasets.

  15. Phase I Dose Escalation Trial of Vandetanib With Fractionated Radiosurgery in Patients With Recurrent Malignant Gliomas

    SciTech Connect

    Fields, Emma C.; Damek, Denise; Gaspar, Laurie E.; Liu, Arthur K.; Kavanagh, Brian D.; Waziri, Allen; Lillehei, Kevin; Chen, Changhu

    2012-01-01

    Purpose: To determine the maximum tolerated dose (MTD) of vandetanib with fractionated stereotactic radiosurgery (SRS) in patients with recurrent malignant gliomas. Methods and Materials: Patients with a recurrent malignant glioma and T1-enhancing recurrent tumor {<=}6 cm were eligible. Vandetanib was given orally, once per day, 7 days a week, starting at least 7 days before SRS and continued until a dose-limiting toxicity (DLT) or disease progression. The planned vandetanib daily dose was 100 mg, 200 mg, and 300 mg for the cohorts 1, 2, and 3, respectively, and was escalated using a standard 3+3 design. A total SRS dose of 36 Gy, 12 Gy per fraction, was delivered over 3 consecutive days. The MTD was defined as the dose of vandetanib at which less than 33% of patients developed DLTs, defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3 as any Grade 3 or greater nonhematologic toxicity and Grade 4 or greater hematologic toxicity. Results: Ten patients were treated, 6 on cohort 1 and 4 on cohort 2. Treatment characteristics were: 7 men, 3 women; median age, 40 years (range, 22-72); 7 GBM, 3 anaplastic astrocytoma (AA); median initial radiation (RT) dose, 60 Gy (range, 59.4-70); median interval since initial RT, 14.5 months (range, 7-123); All patients received SRS per protocol. The median follow-up time was 4 months (range, 1-10 months). Median time on vandetanib was 3 months (range 1-11). One of 6 patients in the first cohort developed a DLT of Grade 3 hemothorax while on anticoagulation. The MTD was reached when 2 of the 4 patients enrolled in the second cohort developed DLTs. Six patients had radiographic response, 2 with stable disease. Conclusion: The MTD of vandetanib, with SRS in recurrent malignant glioma, is 100 mg daily. Further evaluation of safety and efficacy is warranted.

  16. PD-1 marks dysfunctional regulatory T cells in malignant gliomas

    PubMed Central

    Lowther, Daniel E.; Goods, Brittany A.; Lucca, Liliana E.; Lerner, Benjamin A.; Raddassi, Khadir; van Dijk, David; Hernandez, Amanda L.; Duan, Xiangguo; Gunel, Murat; Coric, Vlad; Krishnaswamy, Smita; Love, J. Christopher; Hafler, David A.

    2016-01-01

    Immunotherapies targeting the immune checkpoint receptor programmed cell death protein 1 (PD-1) have shown remarkable efficacy in treating cancer. CD4+CD25hiFoxP3+ Tregs are critical regulators of immune responses in autoimmunity and malignancies, but the functional status of human Tregs expressing PD-1 remains unclear. We examined functional and molecular features of PD-1hi Tregs in healthy subjects and patients with glioblastoma multiforme (GBM), combining functional assays, RNA sequencing, and cytometry by time of flight (CyTOF). In both patients with GBM and healthy subjects, circulating PD-1hi Tregs displayed reduced suppression of CD4+ effector T cells, production of IFN-γ, and molecular signatures of exhaustion. Transcriptional profiling of tumor-resident Tregs revealed that several genes coexpressed with PD-1 and associated with IFN-γ production and exhaustion as well as enrichment in exhaustion signatures compared with circulating PD-1hi Tregs. CyTOF analysis of circulating and tumor-infiltrating Tregs from patients with GBM treated with PD-1-blocking antibodies revealed that treatment shifts the profile of circulating Tregs toward a more exhausted phenotype reminiscent of that of tumor-infiltrating Tregs, further increasing IFN-γ production. Thus, high PD-1 expression on human Tregs identifies dysfunctional, exhausted Tregs secreting IFN-γ that exist in healthy individuals and are enriched in tumor infiltrates, possibly losing function as they attempt to modulate the antitumoral immune responses. PMID:27182555

  17. Glioma

    MedlinePlus

    ... problems, as well as changes in behavior and personality, are also fairly common in mixed glioma patients. ... Cerebri: Symptoms are often nonspecific and can include personality and behavioral changes, memory disturbance, increased intracranial pressure ...

  18. Rotating magnetic field induced oscillation of magnetic particles for in vivo mechanical destruction of malignant glioma.

    PubMed

    Cheng, Yu; Muroski, Megan E; Petit, Dorothée C M C; Mansell, Rhodri; Vemulkar, Tarun; Morshed, Ramin A; Han, Yu; Balyasnikova, Irina V; Horbinski, Craig M; Huang, Xinlei; Zhang, Lingjiao; Cowburn, Russell P; Lesniak, Maciej S

    2016-02-10

    Magnetic particles that can be precisely controlled under a magnetic field and transduce energy from the applied field open the way for innovative cancer treatment. Although these particles represent an area of active development for drug delivery and magnetic hyperthermia, the in vivo anti-tumor effect under a low-frequency magnetic field using magnetic particles has not yet been demonstrated. To-date, induced cancer cell death via the oscillation of nanoparticles under a low-frequency magnetic field has only been observed in vitro. In this report, we demonstrate the successful use of spin-vortex, disk-shaped permalloy magnetic particles in a low-frequency, rotating magnetic field for the in vitro and in vivo destruction of glioma cells. The internalized nanomagnets align themselves to the plane of the rotating magnetic field, creating a strong mechanical force which damages the cancer cell structure inducing programmed cell death. In vivo, the magnetic field treatment successfully reduces brain tumor size and increases the survival rate of mice bearing intracranial glioma xenografts, without adverse side effects. This study demonstrates a novel approach of controlling magnetic particles for treating malignant glioma that should be applicable to treat a wide range of cancers. PMID:26708022

  19. Optimization of combination therapy of arsenic trioxide and fractionated radiotherapy for malignant glioma

    SciTech Connect

    Ning Shoucheng; Knox, Susan J. . E-mail: sknox@stanford.edu

    2006-06-01

    Purpose: The primary objective was to optimize the combined treatment regimen using arsenic trioxide (ATO) and fractionated radiotherapy for the treatment of malignant glioma. Methods and Materials: Nude mice with human glioma xenograft tumors were treated with fractionated local tumor radiation of 250 cGy/fraction/day and 5 mg/kg ATO for 5-10 days. Results: Time course experiments demonstrated that maximal tumor growth delay occurred when ATO was administered between 0 and 4 h after radiation. The combination treatment of ATO and radiation synergistically inhibited tumor growth and produced a tumor growth delay time of 13.2 days, compared with 1.4 days and 6.5 days for ATO and radiation alone (p < 0.01), respectively. The use of concurrent therapy of radiation and ATO initially, followed by ATO as maintenance therapy, was superior to the use of preloading with ATO before combined therapy and produced a tumor growth delay time of 22.7 days as compared with 11.7 days for the ATO preloading regimen (p < 0.01). The maintenance dose of ATO after concurrent therapy was effective and important for continued inhibition of tumor growth. Conclusions: The combined use of fractionated radiation and ATO is effective for the treatment of glioma xenograft tumors. ATO was most effective when administered 0-4 h after radiation without pretreatment with ATO. These results have important implications for the optimization of treatment regimen using ATO and fractionated radiotherapy for the treatment of brain tumors.

  20. Analgesic-antitumor peptide inhibits proliferation and migration of SHG-44 human malignant glioma cells.

    PubMed

    Zhao, Youlong; Cai, Xueting; Ye, Tingmei; Huo, Jiege; Liu, Chao; Zhang, Shuangquan; Cao, Peng

    2011-09-01

    Malignant gliomas, the most common subtype of primary brain tumors, are characterized by high proliferation, great invasion, and neurological destruction and considered to be the deadliest of human cancers. Analgesic-antitumor peptide (AGAP), one of scorpion toxic polypeptides, has been shown to have antitumor activity. Here, we show that recombinant AGAP (rAGAP) not only inhibits the proliferation of gliomas cell SHG-44 and rat glioma cell C6, but also suppresses the migration of SHG-44 cells during wound healing. To explain these phenomena, we find that rAGAP leads to cell cycle of SHG-44 arrested in G1 phase accompanied by suppressing G1 cell cycle regulatory proteins CDK2, CDK6, and p-RB by means of the down-regulated protein expression of p-AKT. Meanwhile, rAGAP significantly decreases the production of NF-κB, BCL-2, p-p38, p-c-Jun, and p-Erk1/2 and further suppresses the activation of VEGF and MMP-9 in SHG-44 cells. These findings suggest rAGAP inhibit proliferation and migration of SHG-44 cells by arresting cell cycle and interfering p-AKT, NF-κB, BCL-2, and MAPK signaling pathways. PMID:21538480

  1. Macrophage migration inhibitory factor (MIF) expression in human malignant gliomas contributes to immune escape and tumour progression.

    PubMed

    Mittelbronn, Michel; Platten, Michael; Zeiner, Pia; Dombrowski, Yvonne; Frank, Brigitte; Zachskorn, Cornelia; Harter, Patrick N; Weller, Michael; Wischhusen, Jörg

    2011-09-01

    Macrophage migration inhibitory factor (MIF), which inhibits apoptosis and promotes angiogenesis, is expressed in cancers suppressing immune surveillance. Its biological role in human glioblastoma is, however, only poorly understood. We examined in-vivo expression of MIF in 166 gliomas and 23 normal control brains by immunohistochemistry. MIF immunoreactivity was enhanced in neoplastic astrocytes in WHO grade II glioma and increased significantly in higher tumour grades (III-IV). MIF expression was further assessed in 12 glioma cell lines in vitro. Quantitative RT-PCR showed that MIF mRNA expression was elevated up to 800-fold in malignant glioma cells compared with normal brain. This translated into high protein levels as assessed by immunoblotting of total cell lysates and by ELISA-based measurement of secreted MIF. Wild-type p53-retaining glioma cell lines expressed higher levels of MIF, which may be connected with the previously described role of MIF as a negative regulator of wild-type p53 signalling in tumour cells. Stable knockdown of MIF by shRNA in glioma cells significantly increased tumour cell susceptibility towards NK cell-mediated cytotoxicity. Furthermore, supernatant from mock-transfected cells, but not from MIF knockdown cells, induced downregulation of the activating immune receptor NKG2D on NK and CD8+ T cells. We thus propose that human glioma cell-derived MIF contributes to the immune escape of malignant gliomas by counteracting NK and cytotoxic T-cell-mediated tumour immune surveillance. Considering its further cell-intrinsic and extrinsic tumour-promoting effects and the availability of small molecule inhibitors, MIF seems to be a promising candidate for future glioma therapy. PMID:21773885

  2. Immunosuppressive Mechanisms of Malignant Gliomas: Parallels at Non-CNS Sites

    PubMed Central

    Perng, Powell; Lim, Michael

    2015-01-01

    The central nervous system (CNS) possesses powerful local and global immunosuppressive capabilities that modulate unwanted inflammatory reactions in nervous tissue. These same immune-modulatory mechanisms are also co-opted by malignant brain tumors and pose a formidable challenge to brain tumor immunotherapy. Routes by which malignant gliomas coordinate immunosuppression include the mechanical and functional barriers of the CNS; immunosuppressive cytokines and catabolites; immune checkpoint molecules; tumor-infiltrating immune cells; and suppressor immune cells. The challenges to overcoming tumor-induced immunosuppression, however, are not unique to the brain, and several analogous immunosuppressive mechanisms also exist for primary tumors outside of the CNS. Ultimately, the immune responses in the CNS are linked and complementary to immune processes in the periphery, and advances in tumor immunotherapy in peripheral sites may therefore illuminate novel approaches to brain tumor immunotherapy, and vice versa. PMID:26217588

  3. New therapeutic approaches for malignant glioma: in search of the Rosetta stone

    PubMed Central

    Auffinger, Brenda; Thaci, Bart; Nigam, Pragati; Rincon, Esther; Cheng, Yu

    2012-01-01

    Malignant gliomas are heterogeneous, diffuse and highly infiltrating by nature. Despite wide surgical resection and improvements in radio- and chemotherapies, the prognosis of patients with glioblastoma multiforme remains extremely poor, with a median survival time of only 14.5 months from diagnosis to death. Particular challenges for glioblastoma multiforme therapy are posed by limitations in the extent of feasible surgical resections, distinct tumor heterogeneity, difficulties in drug delivery across the blood-brain barrier and low drug distribution within the tumor. Therefore, new paradigms permitting tumor-specific targeting and extensive intratumoral distribution must be developed to allow an efficient therapeutic delivery. This review highlights the latest advances in the treatment of glioblastoma multiforme and the recent developments that have resulted from the interchange between preclinical and clinical efforts. We also summarize and discuss novel therapies for malignant glioma, focusing on advances in the following main topics of glioblastoma multiforme therapy: immunotherapy, gene therapy, stem cell-based therapies and nanotechnology. We discuss strategies and outcomes of emerging therapeutic approaches in these fields, and the main challenges associated with the integration of discoveries that occur in the laboratory into clinical practice. PMID:22991580

  4. Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma.

    PubMed

    Lu, Fanghui; Chen, Ying; Zhao, Chuntao; Wang, Haibo; He, Danyang; Xu, Lingli; Wang, Jincheng; He, Xuelian; Deng, Yaqi; Lu, Ellen E; Liu, Xue; Verma, Ravinder; Bu, Hong; Drissi, Rachid; Fouladi, Maryam; Stemmer-Rachamimov, Anat O; Burns, Dennis; Xin, Mei; Rubin, Joshua B; Bahassi, El Mustapha; Canoll, Peter; Holland, Eric C; Lu, Q Richard

    2016-05-01

    Malignant gliomas exhibit extensive heterogeneity and poor prognosis. Here we identify mitotic Olig2-expressing cells as tumor-propagating cells in proneural gliomas, elimination of which blocks tumor initiation and progression. Intriguingly, deletion of Olig2 resulted in tumors that grow, albeit at a decelerated rate. Genome occupancy and expression profiling analyses reveal that Olig2 directly activates cell-proliferation machinery to promote tumorigenesis. Olig2 deletion causes a tumor phenotypic shift from an oligodendrocyte precursor-correlated proneural toward an astroglia-associated gene expression pattern, manifest in downregulation of platelet-derived growth factor receptor-α and reciprocal upregulation of epidermal growth factor receptor (EGFR). Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends the lifespan of animals. Thus, Olig2-orchestrated receptor signaling drives mitotic growth and regulates glioma phenotypic plasticity. Targeting Olig2 may circumvent resistance to EGFR-targeted drugs. PMID:27165742

  5. Up-regulation of microRNA-15b correlates with unfavorable prognosis and malignant progression of human glioma

    PubMed Central

    Pang, Chao; Guan, Yanlei; Zhao, Kai; Chen, Ling; Bao, Yijun; Cui, Run; Li, Guangyu; Wang, Yunjie

    2015-01-01

    Recent studies have demonstrated that microRNA-15b (miR-15b) regulates cell cycle progression, proliferationnd apoptosis in glioma cells by targeting Cyclins. However, the clinical significance of miR-15b in human glioma remains unclear. Therefore, the aim of this study was to investigate the significance of miR-15b expression in diagnosis, prognosis and malignant progression of glioma. Quantitative real-time reverse transcriptive-PCR (qRT-PCR) was performed to examine miR-15b expression levels in 76 glioma tissues (13 grade II, 13 grade III and 50 grade IV gliomas) and seven glioma cell lines, as well as 10 non-neoplastic brain tissues and human astrocyte as control. MiR-15b showed significant increased expression in high-grade gliomas (P ≤ 0.001) and glioma cells (fold change 2.8-7.6) relative to non-neoplastic brains and astrocyte, respectively. Additionally, high miR-15b expression was significantly associated with advanced WHO grade (P ≤ 0.001), advanced patient age (P ≤ 0.001) and low Karnofsky performance score (KPS, P ≤ 0.001). Furthermore, Kaplan-Meier survival analysis and Cox regression analysis showed that patients with high miR-15b expression had significantly poor overall survival rate (P ≤ 0.001) and miR-15b expression was an independent prognosis-predicting factor for glioma patients (P ≤ 0.001; risk ratio = 5.6), respectively. Moreover, miR-15b expression was examined in seven independent patients with primary grade II or III gliomas that spontaneously progressed to grade III or IV gliomas. Statistically significant higher expression (P = 0.01) in the recurrent tumor compared with the corresponding primary tumor was observed in all of the seven patients. Our results suggest that miR-15b may be a prognostic predictor and be involved in malignant progression of glioma. PMID:26191187

  6. A novel bispecific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells to target blood vessels and vasculogenic mimicry of malignant gliomas

    PubMed Central

    Zhang, Yonghong; Sun, Xinlin; Huang, Min; Ke, Yiquan; Wang, Jihui; Liu, Xiao

    2015-01-01

    Background In previous years, immunotoxins have been shown to be a greatly promising therapeutic tool for brain malignancies, such as gliomas. Human mesenchymal stem cells (hMSCs) exhibit tropism to tumor tissue. However, the effect of bispecific immunotoxins in malignant gliomas is still unknown. The aim of this study was to investigate the function of bispecific immunotoxins in human malignant gliomas. Materials and methods In the present study, the bispecific immunotoxin VEGF165-ephrin A1-PE38KDEL was established using deoxyribonucleic acid shuffling and cloning techniques. The VEGF165-ephrin A1-PE38KDEL was delivered by hMSCs to mouse malignant gliomas. The effects of the bispecific immunotoxins on glioma-derived blood vessels and vasculogenic mimicry to elucidate the molecular mechanisms underlying the antitumorigenic effects of immunotoxins were examined in vivo. Results In vitro, transfected hMSCs significantly inhibited the cell viability of gliomas cell lines U87 and U251 in a dose-dependent manner compared with untransfected hMSCs (P<0.01). In vivo, the intratumoral injection of engineered hMSCs was effective at inhibiting tumor growth in a malignant glioma tumor model. Conclusion The bispecific immunotoxin secreted from hMSCs acts as a novel strategy for improving treatment options for malignant gliomas in the clinic. PMID:26089644

  7. Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

    PubMed Central

    Li, Rong; Zhang, Wenbin; Yang, Xiuhua; Wheeler, Crystal G.; Friedman, Gregory K.; Province, Paula; Ding, Qiang; You, Zhiying; Fathallah-Shaykh, Hassan M.; Gillespie, G. Yancey; Zhao, Xinyang; King, Peter H.; Nabors, L. Burt

    2014-01-01

    Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N'G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth. PMID:24664369

  8. Hypofractionated stereotactic radiotherapy and continuous low-dose temozolomide in patients with recurrent or progressive malignant gliomas.

    PubMed

    Minniti, Giuseppe; Scaringi, Claudia; De Sanctis, Vitaliana; Lanzetta, Gaetano; Falco, Teresa; Di Stefano, Domenica; Esposito, Vincenzo; Enrici, Riccardo Maurizi

    2013-01-01

    To evaluate the efficacy of reirradiation and systemic chemotherapy as salvage treatment in patients with recurrent malignant glioma. Between May 2006 and December 2011, 54 patients with recurrent malignant glioma received hypofractionated stereotactic radiotherapy (HSRT) plus systemic therapy at University of Rome Sapienza, Sant' Andrea Hospital. All patients had Karnofsky performance score ≥60 and were previously treated with standard conformal RT (60 Gy) with concomitant and adjuvant temozolomide (TMZ) up to 12 cycles. Thirty-eight patients had a GBM and 16 patients had a grade 3 glioma. The median time interval between primary RT and reirradiation was 15.5 months. At the time of recurrence all patients received HSRT (30 Gy in 6-Gy fractions) plus concomitant TMZ (75 mg/m(2)/day) followed by continuous TMZ at 50 mg/m(2) everyday up to 1 year or until progression. Median overall survival after HSRT was 12.4 months, and the 12- and 24-month survival rates were 53 and 16 %, respectively. The median progression-free survival (PFS) was 6 months, and the 12- and 24-month PFS rates were 24 and 10 %, respectively. KPS >70 (P = 0.04) and grade 3 glioma were independent favourable prognostic factors for survival. In general chemoradiation regimen was well tolerated with relatively low treatment-related toxicity. HSRT plus concomitant TMZ followed by continuous dose-intense TMZ is a feasible treatment option associated with survival benefits and low risk of complications in selected patients with recurrent malignant glioma. The potential advantages of combined chemoradiation schedules in patients with recurrent malignant gliomas need to be explored in future studies. PMID:23129347

  9. Radiation-induced osteochondromas

    SciTech Connect

    Libshitz, H.I.; Cohen, M.A.

    1982-03-01

    Radiation-induced osteochondromas, either single or multiple, occur more commonly than is generally recognized. The incidence following irradiation for childhood malignancy is approximately 12%. Any open epiphysis is vulnerable. Age at irradiation, time of appearance following therapy, dose and type of radiation, and clinical course in 14 cases are dicussed. Due to growth of the lesion and/or pain, 3 tumors were excised. None revealed malignant degeneration.

  10. Human Cytomegalovirus Antigens in Malignant Gliomas as Targets for Adoptive Cellular Therapy

    PubMed Central

    Landi, Daniel; Hegde, Meenakshi; Ahmed, Nabil

    2014-01-01

    Malignant gliomas are the most common primary brain tumor in adults, with over 12,000 new cases diagnosed in the United States each year. Over the last decade, investigators have reliably identified human cytomegalovirus (HCMV) proteins, nucleic acids, and virions in most high-grade gliomas, including glioblastoma (GBM). This discovery is significant because HCMV gene products can be targeted by immune-based therapies. In this review, we describe the current level of understanding regarding the presence and role in pathogenesis of HCMV in GBM. We describe our success detecting and expanding HCMV-specific cytotoxic T lymphocytes to kill GBM cells and explain how these cells can be used as a platform for enhanced cellular therapies. We discuss alternative approaches that capitalize on HCMV infection to treat patients with HCMV-positive tumors. Adoptive cellular therapy for HCMV-positive GBM has been tried in a small number of patients with some benefit, but we reason why, to date, these approaches generally fail to generate long-term remission or cure. We conjecture how cellular therapy for GBM can be improved and describe the barriers that must be overcome to cure these patients. PMID:25505736

  11. A novel manganese complex selectively induces malignant glioma cell death by targeting mitochondria

    PubMed Central

    Geng, Ji; Li, Jing; Huang, Tao; Zhao, Kaidi; Chen, Qiuyun; Guo, Wenjie; Gao, Jing

    2016-01-01

    Despite advances in treatment, malignant glioma commonly exhibits recurrence, subsequently leading to a poor prognosis. As manganese (Mn) compounds can be transported by the transferrin-transferrin receptor system, the present study synthesized and examined the potential use of Adpa-Mn as a novel antitumor agent. Adpa-Mn time and dose-dependently inhibited U251 and C6 cell proliferation; however, it had little effect on normal astrocytes. Apoptosis was significantly elevated following treatment with Adpa-Mn, as detected by chromatin condensation, Annexin V/propidium iodide staining, cytochrome c release from mitochondria to the cytoplasm, and the activation of caspases-9, -7 and -3 and poly (ADP-ribose) polymerase. In addition, Adpa-Mn enhanced fluorescence intensity of monodansylcadaverine and elevated the expression levels of the autophagy-related protein microtubule-associated protein 1 light chain 3. Pretreatment with the autophagy inhibitors 3-methyladenine and chloroquine enhanced Adpa-Mn-induced cell inhibition, thus indicating that autophagy has an essential role in this process. Furthermore, evidence of mitochondrial dysfunction was detected in the Adpa-Mn-treated group, including disrupted membrane potential, elevated levels of reactive oxygen species (ROS) and depleted adenosine triphosphate. Conversely, treatment with the mitochondrial permeability transition inhibitor cyclosporin A reversed Adpa-Mn-induced ROS production, mitochondrial damage and cell apoptosis, thus suggesting that Adpa-Mn may target the mitochondria. Taken together, these data suggested that Adpa-Mn may be considered for use as a novel anti-glioma therapeutic option. PMID:27432745

  12. Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study.

    PubMed

    Chakraborty, Shamik; Filippi, Christopher G; Wong, Tamika; Ray, Ashley; Fralin, Sherese; Tsiouris, A John; Praminick, Bidyut; Demopoulos, Alexis; McCrea, Heather J; Bodhinayake, Imithri; Ortiz, Rafael; Langer, David J; Boockvar, John A

    2016-07-01

    Objective To establish a maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of Cetuximab after osmotic disruption of the blood-brain barrier (BBB) with mannitol, and examine safety of the procedure in patients with recurrent malignant glioma. Methods A total of 15 patients with recurrent malignant glioma were included in the current study. The starting dose of Cetuximab was 100 mg/m(2) and dose escalation was done to 250 mg/m(2). All patients were observed for 28 days post-infusion for any side effects. Results There was no dose-limiting toxicity from a single dose of SIACI of Cetuximab up to 250 mg/m(2) after osmotic BBB disruption with mannitol. A tolerable rash was seen in 2 patients, anaphylaxis in 1 patient, isolated seizure in 1 patient, and seizure and cerebral edema in 1 patient. Discussion SIACI of mannitol followed by Cetuximab (up to 250 mg/m(2)) for recurrent malignant glioma is safe and well tolerated. A Phase I/II trial is currently underway to determine the efficacy of SIACI of cetuximab in patients with high-grade glioma. PMID:26945581

  13. MicroRNA-93 promotes the malignant phenotypes of human glioma cells and induces their chemoresistance to temozolomide

    PubMed Central

    Chen, Rui; Liu, Huan; Cheng, Quan; Jiang, Bing; Peng, Renjun; Zou, Qin; Yang, Wenren; Yang, Xiaosheng; Wu, Xiaobing; Chen, Zigui

    2016-01-01

    ABSTRACT MicroRNAs (miRNAs), a class of small non-coding RNAs, can induce mRNA degradation or repress translation by binding to the 3′-untranslated region (UTR) of its target mRNA. Recently, some specific miRNAs, e.g. miR-93, have been found to be involved in pathological processes by targeting some oncogenes or tumor suppressors in glioma. However, the regulatory mechanism of miR-93 in the biological behaviors and chemoresistance of glioma cells remains unclear. In the present study, in situ hybridization and real-time RT-PCR data indicated that miR-93 was significantly upregulated in glioma patients (n=43) compared with normal brain tissues (n=8). Moreover, the upregulated miR-93 level was significantly associated with the advanced malignancy. We also found that upregulation of miR-93 promoted the proliferation, migration and invasion of glioma cells, and that miR-93 was involved in the regulation of cell cycle progression by mediating the protein levels of P21, P27, P53 and Cyclin D1. P21 was further identified as a direct target of miR-93. Knockdown of P21 attenuated the suppressive effects of miR-93 inhibition on cell cycle progression and colony formation. In addition, inhibition of miR-93 enhanced the chemosensitization of glioma cells to temozolomide (TMZ). Based on these above data, our study demonstrates that miR-93, upregulated in glioma, promotes the proliferation, cell cycle progression, migration and invasion of human glioma cells and suppresses their chemosensitivity to TMZ. Therefore, miR-93 may become a promising diagnostic marker and therapeutic target for glioma. PMID:27185265

  14. IDH mutation is associated with higher risk of malignant transformation in low-grade glioma.

    PubMed

    Leu, Severina; von Felten, Stefanie; Frank, Stephan; Boulay, Jean-Louis; Mariani, Luigi

    2016-04-01

    Acquisition of IDH1 or IDH2 mutation (IDHmut) is among the earliest genetic events that take place in the development of most low-grade glioma (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. A collection of 210 archived adult LGG previously stratified by IDHmut, MGMT methylation (MGMTmet), 1p/19q combined loss of heterozygosity (1p19qloh) and TP53 immunopositivity (TP53pos) status was analyzed. We used multistate models to assess MT-free survival, considering one initial, one transient (MT), and one absorbing state (death). Missing explanatory variables were multiply imputed. Overall, although associated with a lower risk of death (HR(DEATH) = 0.35, P = 0.0023), IDHmut had a non-significantly higher risk of MT (HR(MT) = 1.84; P = 0.1683) compared to IDH wild type (IDHwt). The double combination of IDHmut and MGMTmet and the triple combination of IDHmut, MGMTmet and 1p/19qloh, despite significantly lower hazards for death (HR(DEATH) versus IDHwt: 0.35, P = 0.0194 and 0.15, P = 0.0008, respectively), had non-significantly different hazards for MT. Conversely, the triple combination of IDHmut/MGMTmet/TP53pos, with a non-significantly different hazard for death, had a significantly higher hazard for MT than IDHwt (HR(MT) versus IDHwt: 2.83; P = 0.0452). Although IDHmut status is associated with longer overall patient survival, all IDHmut/MGMTmet subsets consistently showed higher risks of MT than of death, compared to IDHwt LGG. This supports the findings that molecular events relevant to IDH mutations impact early glioma development prior to malignant transformation. PMID:26780338

  15. Mismatch Repair Deficiency Does Not Mediate Clinical Resistance to Temozolomide in Malignant Glioma

    PubMed Central

    Maxwell, Jill A.; Johnson, Stewart P.; McLendon, Roger E.; Lister, David W.; Horne, Krystle S.; Rasheed, Ahmed; Quinn, Jennifer A.; Ali-Osman, Francis; Friedman, Allan H.; Modrich, Paul L.; Bigner, Darell D.; Friedman, Henry S.

    2010-01-01

    Purpose A major mechanism of resistance to methylating agents, including temozolomide, is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Preclinical data indicates that defective DNA mismatch repair (MMR) results in tolerance to temozolomide regardless of AGT activity. The purpose of this study was to determine the role of MMR deficiency in mediating resistance in samples from patients with both newly diagnosed malignant gliomas and those who have failed temozolomide therapy. Experimental Design The roles of AGT and MMR deficiency in mediating resistance in glioblastoma multiforme were assessed by immunohistochemistry and microsatellite instability (MSI), respectively. The mutation status of the MSH6 gene, a proposed correlate of temozolomide resistance, was determined by direct sequencing and compared with data from immunofluorescent detection of MSH6 protein and reverse transcription-PCR amplification of MSH6 RNA. Results Seventy percent of newly diagnosed and 78 % of failed-therapy glioblastoma multiforme samples expressed nuclear AGT protein in ≥20% of cells analyzed, suggesting alternate means of resistance in 20% to 30% of cases. Single loci MSI was observed in 3% of patient samples; no sample showed the presence of high MSI. MSI was not shown to correlate with MSH6 mutation or loss of MSH6 protein expression. Conclusions Although high AGT levels may mediate resistance in a portion of these samples, MMR deficiency does not seem to be responsible for mediating temozolomide resistance in adult malignant glioma. Accordingly, the presence of a fraction of samples exhibiting both lowAGT expression and MMR proficiency suggests that additional mechanisms of temozolomide resistance are operational in the clinic. PMID:18676759

  16. Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy.

    PubMed

    Khan, Zahidul; Knecht, Wolfgang; Willer, Mette; Rozpedowska, Elzbieta; Kristoffersen, Peter; Clausen, Anders Ranegaard; Munch-Petersen, Birgitte; Almqvist, Per M; Gojkovic, Zoran; Piskur, Jure; Ekström, Tomas J

    2010-06-01

    The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the nucleoside analog prodrug zidovudine (azidothymidine, AZT), which is known to penetrate the blood-brain barrier. An important feature of toTK1 is that it efficiently phosphorylates its substrate AZT not only to AZT monophosphate, but also to AZT diphosphate, with excellent kinetics. The efficiency of the toTK1/AZT system was confirmed when toTK1-transduced human glioblastoma (GBM) cells displayed a 500-fold increased sensitivity to AZT compared with wild-type cells. In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT suicide gene therapy system in combination with stem cell-mediated gene delivery promises new treatment of malignant gliomas. PMID:20154339

  17. Pediatric Cranio-spinal Axis Irradiation: Comparison of Radiation-induced Secondary Malignancy Estimations Based on Three Methods of Analysis for Three Different Treatment Modalities.

    PubMed

    Myers, P A; Mavroidis, P; Komisopoulos, G; Papanikolaou, N; Stathakis, S

    2015-04-01

    Pediatric cranio-spinal axis irradiation (CSI) is a valuable treatment for many central nervous system (CNS) diseases, but due to the life expectancies and quality of life expectations for children, the minimization of the risk for radiation-induced secondary malignancies must be a high priority. This study compared the estimated CSI-induced secondary malignancy risks of three radiation therapy modalities using three different models. Twenty-four (n = 24) pediatric patients previously treated with CSI for tumors of the CNS were planned using three different treatment modalities: three-dimensional conformal radiation therapy (3D-CRT), volume modulated arc therapy (VMAT), and Tomotherapy. Each plan was designed to deliver 23.4 Gy (1.8 Gy/fraction) to the target which was defined as the entire brain and spinal column with a 0.7 cm expansion. The mean doses as well as the dose volume histograms (DVH) of specific organs were analyzed for secondary malignancy risk according to three different methods: the effective dose equivalent (EDE), the excess relative risk (ERR), and the linear quadratic (LQ) models. Using the EDE model, the average secondary risk was highest for the 3D-CRT plans (37.60%), compared to VMAT (28.05%) and Tomotherapy (27.90%). The ERR model showed similarly that the 3D-CRT plans had considerably higher risk (10.84%) than VMAT and Tomotherapy, which showed almost equal risks (7.05 and 7.07%, respectively). The LQ model requires organ-specific cell survival parameters, which for the lungs, heart, and breast relevant values were found and applied. The lung risk for secondary malignancy was found to be 1.00, 1.96, and 2.07% for 3D-CRT, VMAT, and Tomotherapy, respectively. The secondary cancer risk for breast was estimated to be 0.09, 0.21, and 0.27% and for heart it was 9.75, 6.02 and 6.29% for 3D-CRT, VMAT, and Tomotherapy, respectively. Based on three methods of secondary malignancy estimation, the 3D-CRT plans produced highest radiation-induced

  18. Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics.

    PubMed

    Kronik, Natalie; Kogan, Yuri; Vainstein, Vladimir; Agur, Zvia

    2008-03-01

    Glioblastoma (GBM), a highly aggressive (WHO grade IV) primary brain tumor, is refractory to traditional treatments, such as surgery, radiation or chemotherapy. This study aims at aiding in the design of more efficacious GBM therapies. We constructed a mathematical model for glioma and the immune system interactions, that may ensue upon direct intra-tumoral administration of ex vivo activated alloreactive cytotoxic-T-lymphocytes (aCTL). Our model encompasses considerations of the interactive dynamics of aCTL, tumor cells, major histocompatibility complex (MHC) class I and MHC class II molecules, as well as cytokines, such as TGF-beta and IFN-gamma, which dampen or increase the pro-inflammatory environment, respectively. Computer simulations were used for model verification and for retrieving putative treatment scenarios. The mathematical model successfully retrieved clinical trial results of efficacious aCTL immunotherapy for recurrent anaplastic oligodendroglioma and anaplastic astrocytoma (WHO grade III). It predicted that cellular adoptive immunotherapy failed in GBM because the administered dose was 20-fold lower than required for therapeutic efficacy. Model analysis suggests that GBM may be eradicated by new dose-intensive strategies, e.g., 3 x 10(8) aCTL every 4 days for small tumor burden, or 2 x 10(9) aCTL, infused every 5 days for larger tumor burden. Further analysis pinpoints crucial bio-markers relating to tumor growth rate, tumor size, and tumor sensitivity to the immune system, whose estimation enables regimen personalization. We propose that adoptive cellular immunotherapy was prematurely abandoned. It may prove efficacious for GBM, if dose intensity is augmented, as prescribed by the mathematical model. Re-initiation of clinical trials, using calculated individualized regimens for grade III-IV malignant glioma, is suggested. PMID:17823798

  19. A novel manganese complex selectively induces malignant glioma cell death by targeting mitochondria.

    PubMed

    Geng, Ji; Li, Jing; Huang, Tao; Zhao, Kaidi; Chen, Qiuyun; Guo, Wenjie; Gao, Jing

    2016-09-01

    Despite advances in treatment, malignant glioma commonly exhibits recurrence, subsequently leading to a poor prognosis. As manganese (Mn) compounds can be transported by the transferrin‑transferrin receptor system, the present study synthesized and examined the potential use of Adpa‑Mn as a novel antitumor agent. Adpa‑Mn time and dose‑dependently inhibited U251 and C6 cell proliferation; however, it had little effect on normal astrocytes. Apoptosis was significantly elevated following treatment with Adpa‑Mn, as detected by chromatin condensation, Annexin V/propidium iodide staining, cytochrome c release from mitochondria to the cytoplasm, and the activation of caspases‑9, ‑7 and ‑3 and poly (ADP‑ribose) polymerase. In addition, Adpa‑Mn enhanced fluorescence intensity of monodansylcadaverine and elevated the expression levels of the autophagy‑related protein microtubule‑associated protein 1 light chain 3. Pretreatment with the autophagy inhibitors 3‑methyladenine and chloroquine enhanced Adpa‑Mn‑induced cell inhibition, thus indicating that autophagy has an essential role in this process. Furthermore, evidence of mitochondrial dysfunction was detected in the Adpa‑Mn‑treated group, including disrupted membrane potential, elevated levels of reactive oxygen species (ROS) and depleted adenosine triphosphate. Conversely, treatment with the mitochondrial permeability transition inhibitor cyclosporin A reversed Adpa‑Mn‑induced ROS production, mitochondrial damage and cell apoptosis, thus suggesting that Adpa‑Mn may target the mitochondria. Taken together, these data suggested that Adpa‑Mn may be considered for use as a novel anti‑glioma therapeutic option. PMID:27432745

  20. MiR-135a and MRP1 play pivotal roles in the selective lethality of phenethyl isothiocyanate to malignant glioma cells

    PubMed Central

    Zhang, Taolan; Shao, Yingying; Chu, Tang-Yuan; Huang, Hsuan-Shun; Liou, Yu-Ligh; Li, Qing; Zhou, Honghao

    2016-01-01

    Amounting evidence has demonstrated that phenethyl isothiocyanate (PEITC) is a strong inducer of reactive oxygen species (ROS) and functions as a selective killer to various human cancer cells. However, it remains obscure whether PEITC has potential selective lethality to malignant glioma cells. Thus in this study, we performed multiple analysis such as MTT assay, Hoechst 33258 staining, flow cytometry, foci formation, RT-PCR, Western blot, and transfection to explore the selective lethality of PEITC to malignant glioma cells and the underlying mechanisms. We found that PEITC induced a selective apoptosis and suppressed tumorigenicity and migration of malignant glioma cells. Furthermore, we found PEITC significantly induced GSH depletion, ROS production, caspase-9 and caspase-3 activation, and miR-135a upregulation in malignant glioma cells but not in normal cells. Moreover, PEITC activated the miR-135a-mitochondria dependent apoptosis pathway as demonstrated by downregulation of STAT6, SMAD5 and Bcl-xl while upregulation of Bax expression and Cytochrome-C release in malignant glioma cell lines but not in the immortalized human normal glial HEB cells. Correspondingly, the above PEITC-induced activation of the ROS-MiR-135a-Mitochondria dependent apoptosis pathways in malignant glioma was attenuated by pre-transfection with miR-135a inhibitor, pre-treatment with multidrug resistance-associated protein 1 (MRP1) inhibitor Sch B, or combination with glutathione (GSH). These results revealed that PEITC selectively induced apoptosis of malignant glioma cells through MRP1-mediated export of GSH to activate ROS-MiR-135a-Mitochondria dependent apoptosis pathway, suggesting a potential application of PEITC for treating glioma. PMID:27293991

  1. MiR-135a and MRP1 play pivotal roles in the selective lethality of phenethyl isothiocyanate to malignant glioma cells.

    PubMed

    Zhang, Taolan; Shao, Yingying; Chu, Tang-Yuan; Huang, Hsuan-Shun; Liou, Yu-Ligh; Li, Qing; Zhou, Honghao

    2016-01-01

    Amounting evidence has demonstrated that phenethyl isothiocyanate (PEITC) is a strong inducer of reactive oxygen species (ROS) and functions as a selective killer to various human cancer cells. However, it remains obscure whether PEITC has potential selective lethality to malignant glioma cells. Thus in this study, we performed multiple analysis such as MTT assay, Hoechst 33258 staining, flow cytometry, foci formation, RT-PCR, Western blot, and transfection to explore the selective lethality of PEITC to malignant glioma cells and the underlying mechanisms. We found that PEITC induced a selective apoptosis and suppressed tumorigenicity and migration of malignant glioma cells. Furthermore, we found PEITC significantly induced GSH depletion, ROS production, caspase-9 and caspase-3 activation, and miR-135a upregulation in malignant glioma cells but not in normal cells. Moreover, PEITC activated the miR-135a-mitochondria dependent apoptosis pathway as demonstrated by downregulation of STAT6, SMAD5 and Bcl-xl while upregulation of Bax expression and Cytochrome-C release in malignant glioma cell lines but not in the immortalized human normal glial HEB cells. Correspondingly, the above PEITC-induced activation of the ROS-MiR-135a-Mitochondria dependent apoptosis pathways in malignant glioma was attenuated by pre-transfection with miR-135a inhibitor, pre-treatment with multidrug resistance-associated protein 1 (MRP1) inhibitor Sch B, or combination with glutathione (GSH). These results revealed that PEITC selectively induced apoptosis of malignant glioma cells through MRP1-mediated export of GSH to activate ROS-MiR-135a-Mitochondria dependent apoptosis pathway, suggesting a potential application of PEITC for treating glioma. PMID:27293991

  2. Modulation of Radiation-Induced Genetic Damage by HCMV in Peripheral Blood Lymphocytes from a Brain Tumor Case-Control Study

    PubMed Central

    Rourke, Elizabeth A.; Lopez, Mirtha S.; Monroy, Claudia M.; Scheurer, Michael E.; Etzel, Carol J.; Albrecht, Thomas; Bondy, Melissa L.; El-Zein, Randa A.

    2010-01-01

    Human cytomegalovirus (HCMV) infection occurs early in life and viral persistence remains through life. An association between HCMV infection and malignant gliomas has been reported, suggesting that HCMV may play a role in glioma pathogenesis and could facilitate an accrual of genotoxic damage in the presence of γ-radiation; an established risk factor for gliomas. We tested the hypothesis that HCMV infection modifies the sensitivity of cells to γ-radiation-induced genetic damage. We used peripheral blood lymphocytes (PBLs) from 110 glioma patients and 100 controls to measure the level of chromosome damage and cell death. We evaluated baseline, HCMV-, γ-radiation and HCMV + γ-radiation induced genetic instability with the comprehensive Cytokinesis-Blocked Micronucleus Cytome (CBMN-CYT). HCMV, similar to radiation, induced a significant increase in aberration frequency among cases and controls. PBLs infected with HCMV prior to challenge with γ-radiation led to a significant increase in aberrations as compared to baseline, γ-radiation and HCMV alone. With regards to apoptosis, glioma cases showed a lower percentage of induction following in vitro exposure to γ-radiation and HCMV infection as compared to controls. This strongly suggests that, HCMV infection enhances the sensitivity of PBLs to γ-radiation-induced genetic damage possibly through an increase in chromosome damage and decrease in apoptosis. PMID:24281077

  3. Phase 1 Clinical Trial of Intratumoral Reovirus Infusion for the Treatment of Recurrent Malignant Gliomas in Adults

    PubMed Central

    Kicielinski, Kimberly P; Chiocca, E Antonio; Yu, John S; Gill, George M; Coffey, Matt; Markert, James M

    2014-01-01

    Reovirus, an oncolytic RNA virus exhibiting antiglioma activity, was shown in a previous single institution phase 1 study found that the inoculation of the virus to be well tolerated in patients with recurrent malignant glioma (MG). The goals of multicenter study reported herein were to determine the dose-limiting toxicity, maximum tolerated dose, and target lesion response rate when reovirus was administered in a novel fashion via intratumoral infusion for 72 hours in patients with recurrent malignant glioma. Fifteen adult patients were treated in a dose escalation study ranging from 1 × 108 to 1 × 1010 tissue culture infectious dose 50, tentimes the dose achieved in the previous trial. Neurological, functional examinations, and imaging studies were completed pre- and postinfusion. There was one grade 3 adverse event (convulsions) felt to be possibly related to treatment, but no grade 4 adverse events considered probably or definitely related to treatment. Dose-limiting toxicity were not identified and a maximum tolerated dose was not reached. Evidence of antiglioma activity was seen in some patients. This first report of intratumoral infusion of reovirus in patients with recurrent malignant glioma demonstrated the approach to be safe and well tolerated, warranting further studies. PMID:24553100

  4. Embryonic stem cell (ESC)-mediated transgene delivery induces growth suppression, apoptosis and radiosensitization, and overcomes temozolomide resistance in malignant gliomas.

    PubMed

    Germano, I M; Emdad, L; Qadeer, Z A; Binello, E; Uzzaman, M

    2010-09-01

    High-grade gliomas are among the most lethal of all cancers. Despite considerable advances in multimodality treatment, including surgery, radiotherapy and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for malignant gliomas is promising, as it allows in situ delivery and selectively targets brain tumor cells while sparing the adjacent normal brain tissue. Viral vectors that deliver proapoptotic genes to malignant glioma cells have been investigated. Although tangible results on patients' survival remain to be further documented, significant advances in therapeutic gene transfer strategies have been made. Recently, cell-based gene delivery has been sought as an alternative method. In this paper, we report the proapoptotic effects of embryonic stem cell (ESC)-mediated mda-7/IL-24 delivery to malignant glioma cell lines. Our data show that these are similar to those observed using a viral vector. In addition, acknowledging the heterogeneity of malignant glioma cells and their signaling pathways, we assessed the effects of conventional treatment for high-grade gliomas, ionizing radiation and temozolomide, when combined with ESC-mediated transgene delivery. This combination resulted in synergistic effects on tumor cell death. The mechanisms involved in this beneficial effect included activation of both apoptosis and autophagy. Our in vitro data support the concept that ESC-mediated gene delivery might offer therapeutic advantages over standard approaches to malignant gliomas. Our results corroborate the theory that combined treatments exploiting different signaling pathways are needed to succeed in the treatment of malignant gliomas. PMID:20523363

  5. YThe BigH3 Tumor Suppressor Gene in Radiation-Induced Malignant Transformation of Human Bronchial Epithelial Cells

    NASA Astrophysics Data System (ADS)

    Zhao, Y.; Shao, G.; Piao, C.; Hei, T.

    Carcinogenesis is a multi-stage process with sequences of genetic events governing the phenotypic expression of a series of transformation steps leading to the development of metastatic cancer Previous studies from this laboratory have identified a 7 fold down- regulation of the novel tumor suppressor Big-h3 among radiation induced tumorigenic BEP2D cells Furthermore ectopic re-expression of this gene suppresses tumorigenic phenotype and promotes the sensitivity of these tumor cells to etoposide-induced apoptosis To extend these studies using a genomically more stable bronchial cell line we ectopically expresses the catalytic subunit of telomerase hTERT in primary human small airway epithelial SAE cells and generated several clonal cell lines that have been continuously in culture for more than 250 population doublings and are considered immortal Comparably-treated control SAE cells infected with only the viral vector senesced after less than 10 population doublings The immortalized clones demonstrated anchorage dependent growth and are non-tumorigenic in nude mice These cells show no alteration in the p53 gene but a decrease in p16 expression Exponentially growing SAEh cells were exposed to graded doses of 1 GeV nucleon of 56 Fe ions accelerated at the Brookhaven National Laboratory Irradiated cells underwent gradual phenotypic alterations after extensive in vitro cultivation Transformed cells developed through a series of successive steps before becoming anchorage independent in semisolid medium These findings indicate

  6. Bevacizumab changes vascular structure and modulates the expression of angiogenic factors in recurrent malignant gliomas.

    PubMed

    Okamoto, Saori; Nitta, Masayuki; Maruyama, Takashi; Sawada, Tatsuo; Komori, Takashi; Okada, Yoshikazu; Muragaki, Yoshihiro

    2016-04-01

    Bevacizumab (BV), a monoclonal antibody against vascular endothelial growth factor (VEGF), is currently used in the treatment of malignant glioma. To understand mechanisms of resistance to BV, we investigated morphological changes in tumor vessels and expression of angiogenic factors, such as VEGF, Flt-1, basic fibroblast growth factor (bFGF), and platelet-derived growth factor-BB (PDGF-BB), in four autopsied tumors after BV treatment. Three patients had glioblastomas; the fourth had a secondary glioblastoma that developed from a diffuse astrocytoma. BV was administered because of recurrence following the use of the Stupp regimen in these four patients. We compared the initial surgical specimen with that obtained after death following BV treatment. Immunohistochemical staining of the autopsied tumors showed that Flt-1 expression increased while VEGF expression was significantly reduced. Additionally, other angiogenic factors, particularly bFGF, were enhanced. Interestingly, the proliferation of endothelial cells was reduced, but remarkable proliferation of pericytes was observed. These results suggest that following BV treatment, glioblastomas can grow tumor vessels by expressing various angiogenic factors. These mechanisms might be important for rapid regrowth and blood brain barrier repair after BV treatment. Inhibition of multiple angiogenic factors will be required to control tumor vessels in glioblastoma. PMID:26826105

  7. Application of Convection-Enhanced Drug Delivery in the Treatment of Malignant Gliomas.

    PubMed

    Tykocki, Tomasz; Miękisiak, Grzegorz

    2016-06-01

    Convection-enhanced delivery (CED) is a promising new method of local drug delivery therapy for a diverse type of antitumor agents. CED offers significant advantages over systemic chemotherapy by bypassing the blood-brain barrier and obtaining adequate drug concentration with limited systemic toxicity. Actually, there is no effective treatment of malignant gliomas (MGs); survival rates remain poor despite decades of clinical trials. Conventional chemotherapy has been found to be minimally effective in the control of MG progression. CED involves the implantation of catheters through which conventional and novel therapeutic formulations can be delivered directly to the tumor using continuous, low-positive-pressure bulk flow. On the basis of the preclinical and clinical studies, we demonstrated that CED could produce effective drug delivery to large brain and tumor areas. However, clinical studies to date have not found any substantial improvement in overall survival in the treatment of MG. This overview presents up-to-date clinical results in the treatment of MG by the application of CED. PMID:26898499

  8. Effect of flupirtine on the growth and viability of U373 malignant glioma cells

    PubMed Central

    Panchanathan, Elango; Ramanathan, Gnanasambandan; Lakkakula, Bhaskar Venkata Kameswara Subrahmanya

    2013-01-01

    Objective Flupirtine is a non-opioid analgesic without antipyretic or antiphlogistic properties but with favorable tolerability in humans. This analgesic also exhibits neuroprotective activities. Furthermore, flupirtine antagonizes glutamate- and NMDA-induced intracellular levels of Ca2+ and counteracts the effects of focal cerebral ischemia. Although flupirtine has been used to relieve pain caused by different diseases and clinical procedures, information on the safety and efficacy of flupirtine is limited. The present study was conducted to investigate the neuroprotective effects of flupirtine on U373 malignant glioma (MG) cell lines. Methods Cell viability and cell cycle analysis was performed by MTT assay and flow cytometry, respectively. Results Variations in the growth of U373 MG cells in 5 mM N-methyl-D-aspartate (NMDA), 1 mM flupirtine, and combined treatment indicated the antagonistic effects of NMDA and flupirtine on MG cell lines. The variation in the percentage of gated cell population in different cell cycle phases showed significant variations after 48 h of treatment. Conclusion Flupirtine has neuroprotective effect of on U373 MG cells, which limits its use in the pain management of brain tumors. This property warrants further studies using animal models and large-scale clinical trials. PMID:24379989

  9. Raman spectroscopy for in situ- evaluation of high-grade malignant gliomas induced in SCID mice

    NASA Astrophysics Data System (ADS)

    Clary, Candace E.; Dergachev, Alex Y.; Mirov, Sergey B.; Gillespie, G. Yancey

    1997-05-01

    Each year, more people at younger ages are diagnosed with primary brain tumors. Current histological discrimination between normal and diseased tissue occurs after tissue excision. A reliable optical biopsy for open craniotomy would optimize the amount and types of tissue removal by making an accurate evaluation before excision. The presented work is part of a study investigating the clinical diagnostic potential of Raman spectroscopy for gliomas. It has been shown that the optical properties of in vitro tissue are strongly dependent upon sample preparation. The investigation of the effects of time latency, paraformalin tissue fixation, and tissue perfusion with carbogen-bubbled cortical transport solution on their respective Raman spectra of brain tissue and tumors will be discussed, as well as their implications on the study of neurological tissue. The studies are conducted with in situ tissue samples from scid mice and 785 nm pulsed alexandrite laser excitation. Results illustrating positive qualitative and quantitative variations between Raman spectra of normal and malignant brain tissue will be presented.

  10. Light-controlled inhibition of malignant glioma by opsin gene transfer

    PubMed Central

    Yang, F; Tu, J; Pan, J-Q; Luo, H-L; Liu, Y-H; Wan, J; Zhang, J; Wei, P-F; Jiang, T; Chen, Y-H; Wang, L-P

    2013-01-01

    Glioblastomas are aggressive cancers with low survival rates and poor prognosis because of their highly proliferative and invasive capacity. In the current study, we describe a new optogenetic strategy that selectively inhibits glioma cells through light-controlled membrane depolarization and cell death. Transfer of the engineered opsin ChETA (engineered Channelrhodopsin-2 variant) gene into primary human glioma cells or cell lines, but not normal astrocytes, unexpectedly decreased cell proliferation and increased mitochondria-dependent apoptosis, upon light stimulation. These optogenetic effects were mediated by membrane depolarization-induced reductions in cyclin expression and mitochondrial transmembrane potential. Importantly, the ChETA gene transfer and light illumination in mice significantly inhibited subcutaneous and intracranial glioma growth and increased the survival of the animals bearing the glioma. These results uncover an unexpected effect of opsin ion channels on glioma cells and offer the opportunity for the first time to treat glioma using a light-controllable optogenetic approach. PMID:24176851

  11. Risk, Outcomes, and Costs of Radiation-Induced Oral Mucositis Among Patients With Head-and-Neck Malignancies

    SciTech Connect

    Elting, Linda S. . E-mail: lelting@mdanderson.org; Cooksley, Catherine D.; Chambers, Mark S.; Garden, Adam S.

    2007-07-15

    Purpose: To study the risk, outcomes, and costs of radiation-induced oral mucositis (OM) among patients receiving radiotherapy (RT) to head and neck primary cancers. Methods and Materials: A retrospective cohort consisting of 204 consecutive head-and-neck cancer patients who received RT with or without chemotherapy during 2002 was formed; their records were reviewed for clinical and resource use information. Patients who had received prior therapy, had second primary cancers, or received palliative radiation therapy were excluded. The risk of OM was analyzed by multiple variable logistic regression. The cost of care was computed from the provider's perspective in 2006 U.S. dollars and compared among patients with and without OM. Results: Oral mucositis occurred in 91% of patients; in 66% it was severe (Grade 3-4). Oral mucositis was more common among patients with oral cavity or oropharynx primaries (odds ratio [OR], 44.5; 95% confidence interval [CI], 5.2 to >100; p < 0.001), those who received chemotherapy (OR = 7.8; 95% CI, 1.5-41.6; p 0.02), and those who were treated with altered fractionation schedules (OR 6.3; 95% CI, 1.1-35.1; p = 0.03). Patients with OM were significantly more likely to have severe pain (54% vs. 6%; p < 0.001) and a weight loss of {>=}5% (60% vs. 17%; p < 0.001). Oral mucositis was associated with an incremental cost of $1700-$6000, depending on the grade. Conclusions: Head-and-neck RT causes OM in virtually all patients. Oral mucositis is associated with severe pain, significant weight loss, increased resource use, and excess cost. Preventive strategies are needed.

  12. Temsirolimus and Perifosine in Treating Patients With Recurrent or Progressive Malignant Glioma

    ClinicalTrials.gov

    2016-07-06

    Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Recurrent Adult Brain Neoplasm

  13. Erlotinib Hydrochloride and Isotretinoin in Treating Patients With Recurrent Malignant Glioma

    ClinicalTrials.gov

    2015-07-27

    Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Recurrent Adult Brain Tumor

  14. A Case of Congenital Malignant Spinal Cord Glioma as a Cause of Congenital Ascites in a Neonate.

    PubMed

    Karber, Bianca; Omesi, Lenore; Chang, Sunny; Handel, Andrew; Hegedus, Monica; Maduekwe, Echezona

    2016-01-01

    Congenital ascites is rare, but when it occurs, urinary ascites secondary to posterior urethral valve obstruction is the most common, and tumors are the least. Among the tumors in the pediatric population, the central nervous system tumors are common, but spinal cord tumors are rare. We describe a very rare case of congenital malignant spinal cord glioma presenting as isolated congenital ascites secondary to neurogenic bladder. A female infant was diagnosed sonographically with isolated congenital ascites at 40 weeks' gestational age, with uneventful development prior to 40 weeks' gestational age. Magnetic resonance imaging of the spine done within the first week of life identified a lobulated spinal mass with heterogeneous enhancement within the conus medullaris. Spinal fluid analysis showed evidence of small round blue cells and the pathology from the excision biopsy of the mass confirmed a WHO grade III or IV malignant glioma. The postoperative course was uneventful with resolution of the ascites and spontaneous micturition. The patient was discharged home without an indwelling urinary catheter. We report the first documented case of a newborn infant with isolated congenital ascites from neurogenic bladder secondary to a spinal cord glioma. PMID:27597917

  15. A Case of Congenital Malignant Spinal Cord Glioma as a Cause of Congenital Ascites in a Neonate

    PubMed Central

    Omesi, Lenore; Chang, Sunny; Handel, Andrew; Hegedus, Monica; Maduekwe, Echezona

    2016-01-01

    Congenital ascites is rare, but when it occurs, urinary ascites secondary to posterior urethral valve obstruction is the most common, and tumors are the least. Among the tumors in the pediatric population, the central nervous system tumors are common, but spinal cord tumors are rare. We describe a very rare case of congenital malignant spinal cord glioma presenting as isolated congenital ascites secondary to neurogenic bladder. A female infant was diagnosed sonographically with isolated congenital ascites at 40 weeks' gestational age, with uneventful development prior to 40 weeks' gestational age. Magnetic resonance imaging of the spine done within the first week of life identified a lobulated spinal mass with heterogeneous enhancement within the conus medullaris. Spinal fluid analysis showed evidence of small round blue cells and the pathology from the excision biopsy of the mass confirmed a WHO grade III or IV malignant glioma. The postoperative course was uneventful with resolution of the ascites and spontaneous micturition. The patient was discharged home without an indwelling urinary catheter. We report the first documented case of a newborn infant with isolated congenital ascites from neurogenic bladder secondary to a spinal cord glioma. PMID:27597917

  16. Nogo-A inhibits the migration and invasion of human malignant glioma U87MG cells.

    PubMed

    Jin, Shu-Guang; Ryu, Hyang-Hwa; Li, Song-Yuan; Li, Chun-Hao; Lim, Sa-Hoe; Jang, Woo-Youl; Jung, Shin

    2016-06-01

    Nogo or reticulon-4 (RTN4), also known as neurite outgrowth inhibitor, is a member of the reticulon family of genes. Nogo-A, one of the three isoforms, is enriched in the central nervous system (CNS). The extracellular domain of Nogo-A, Nogo-66, has neurite growth inhibitory activity that is specific for neurons and is mediated by the Nogo receptor. However, most of its functions are not known yet. We investigated whether Nogo-A modulates the migration and invasion of a glioblastoma cell line, as well as the factors that have an effect on Nogo-A. The expression of Nogo-A was evaluated using western blotting and immunohistochemistry in human brain tumor specimens. U87MG cells were transfected with a sense-Nogo-A cDNA construct (U87-Nogo-A cells expressing Nogo-A) and an empty vector (U87MG-E cells not expressing Nogo-A). The migration and invasion abilities of these cells were investigated using simple scratch and Matrigel invasion assays. Morphologic and cytoskeletal changes were documented by confocal microscopy. The proliferation rate was estimated using doubling time assay. The effects of Nogo-A on Rho activity and phosphorylated cofilin were determined by a Rho activity assay and western blotting. Among primary brain tumors, Nogo-A expression was found in a higher percentage of oligodendrogliomas (90.0%) compared with the percentage in the glioblastomas (68.4%). In addition, the percentage in mixed gliomas was 42.9%, while it was not expressed in pituitary adenomas or schwannomas. The migration and invasion abilities of the U87-Nogo-A cells were decreased compared with the control. In the U87-Nogo-A cell line, Rho activity and phosphorylated cofilin expression were also decreased and morphology became more flat in comparison with the U87MG-E cell line. Nogo-A may inhibit the migration and invasion of human malignant glioma cells via the downregulation of RhoA-cofilin signaling. PMID:27109183

  17. Metabolic Targeting of Lactate Efflux by Malignant Glioma Inhibits Invasiveness and Induces Necrosis: An In Vivo Study1

    PubMed Central

    Colen, Chaim B; Shen, Yimin; Ghoddoussi, Farhad; Yu, Pingyang; Francis, Todd B; Koch, Brandon J; Monterey, Michael D; Galloway, Matthew P; Sloan, Andrew E; Mathupala, Saroj P

    2011-01-01

    Glioblastoma multiforme (GBM) are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rate. To survive, GBMs efflux lactic acid to the tumor microenvironment through transmembrane transporters denoted monocarboxylate transporters (MCTs). We hypothesized that inhibition of MCT function would impair the glycolytic metabolism and affect both glioma invasiveness and survival. We examined the effect on invasiveness with α-cyano-4-hydroxy-cinnamic acid (ACCA, 4CIN, CHCA), a small-molecule inhibitor of lactate transport, through Matrigel-based and organotypic (brain) slice culture invasive assays using U87-MG and U251-MG glioma cells. We then conducted studies in immunodeficient rats by stereotaxic intracranial implantation of the glioma cells followed by programmed orthotopic application of ACCA through osmotic pumps. Effect on the implanted tumor was monitored by small-animal magnetic resonance imaging. Our assays indicated that glioma invasion was markedly impaired when lactate efflux was inhibited. Convection-enhanced delivery of inhibitor to the tumor bed caused tumor necrosis, with 50% of the animals surviving beyond the experimental end points (3 months after inhibitor exhaustion). Most importantly, control animals did not display any adverse neurologic effects during orthotopic administration of ACCA to brain through programmed delivery. These results indicate the clinical potential of targeting lactate efflux in glioma through delivery of small-molecule inhibitors of MCTs either to the tumor bed or to the postsurgical resection cavity. PMID:21750656

  18. The cellular origin for malignant glioma and prospects for clinical advancements

    PubMed Central

    Zong, Hui; Verhaak, Roel GW; Canoll, Peter

    2012-01-01

    Glioma remains incurable despite great advancements in medicine. Targeting the cell of origin for gliomas could bring great hope for patients. However, as a collection of diverse diseases, each subtype of glioma could derive from a distinct cell of origin. To resolve such a complex problem, one must use multiple research approaches to gain deep insights. Here we review current evidence regarding the cell of origin from clinical observations, whole-genome molecular pathology and glioma animal models. We conclude that neural stem cells, glial progenitors (including oligodendrocyte progenitor cells) and astrocytes could all serve as cells of origin for gliomas, and that cells incurring initial mutations (cells of mutation) might not transform, while their progeny cells could instead transform and act as cells of origin. Further studies with multidisciplinary approaches are needed to link each subtype to a particular cell of origin, and to develop effective therapies that target the signaling network within these cells. PMID:22616703

  19. miR-148b-3p inhibits malignant biological behaviors of human glioma cells induced by high HOTAIR expression

    PubMed Central

    Wang, Guan; Li, Zhaohui; Tian, Nan; Han, Liang; Fu, Yao; Guo, Zhigang; Tian, Yu

    2016-01-01

    Increasing evidence suggests that long non coding (lnc)RNA and microRNA (miRNA/miR) both regulate the expression of key genes in tumorigenesis and have considerable theranostic potential. Rapid advances in bioinformatics indicate that miRNA may potentially interact with lncRNA to modulate their regulatory roles. miR-148b-3p has been reported to have a vital role in regulating tumor progression. However, the expression pattern of miR-148b-3p in glioma remains largely unknown, and interactions between miR-148b-3p and lncRNA has yet to be identified. The aim of the present study was to insight into the regulatory role of miR-148b-3p in glioma. Using online software, the HOTAIR gene was identified as a possible lncRNA target of miR-148b-3p in the present study. siRNA was used to suppress the expression of HOTAIR and reverse transcription-quantitative polymerase chain reaction was used to detect the expression of miR-148b-3p. The results confirmed that HOTAIR mRNA expression was inversely correlated with miR-148b-3p expression in A172 glioma cells. Furthermore, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the viability of cells, flow cytometry was performed to test cell cycle and a matrigel invasion assay was performed to test cell invasion. The results showed that HOTAIR promotes factors associated with malignancy, including cell proliferation, cell cycle progression and invasion, whereas miR-148b-3p suppresses malignancy. Bioinformatics and luciferase reporter assays showed that miR-148b-3p modulates HOTAIR expression by directly targeting the HOTAIR gene sequence. In summary, the results indicated that miR-148b-3p inhibits malignant biological behaviors of glioma cells by directly targeting HOTAIR. The current data provide important evidence for understanding the key roles of the lncRNA miRNA functional network in glioma. PMID:27446363

  20. Malignant Glioma with Neuronal Marker Expression : A Clinicopathological Study of 18 Cases

    PubMed Central

    Kim, Hong Rye; Lee, Jae Jun; Lee, Jung-Il; Nam, Do Hyun; Suh, Yeon-Lim

    2016-01-01

    Objective Malignant gliomas with neuronal marker expression (MGwNM) are rare and poorly characterized. Increasingly diverse types of MGwNM have been described and these reported cases underscore the dilemmas in the classification and diagnosis of those tumors. The aim of this study is to provide additional insights into MGwNM and present the clinicopathological features of 18 patients. Methods We reviewed the medical records of 18 patients diagnosed as MGwNM at our institute between January 2006 and December 2012. Macroscopic total resection was performed in 11 patients (61%). We evaluated the methylation status of O6-methylguanine-DNA methyltransferase (MGMT) and expression of isocitrate dehydrogenase 1 (IDH-1) in all cases, and deletions of 1p and 19q in available cases. Results The estimated median overall survival was 21.2 months. The median progression-free survival was 6.3 months. Six patients (33%) had MGMT methylation but IDH1 mutation was found in only one patient (6%). Gene analysis for 1p19q performed in nine patients revealed no deletion in six, 19q deletion only in two, and 1p deletion only in one. The extent of resection was significantly correlated with progression free survival on both univariate analysis and multivariate analysis (p=0.002 and p=0.013, respectively). Conclusion In this study, the overall survival of MGwNM was not superior to glioblastoma. The extent of resection has a significant prognostic impact on progression-free survival. Further studies of the prognostic factors related to chemo-radio therapy, similar to studies with glioblastoma, are mandatory to improve survival. PMID:26885285

  1. Concurrent Stereotactic Radiosurgery and Bevacizumab in Recurrent Malignant Gliomas: A Prospective Trial

    SciTech Connect

    Cabrera, Alvin R.; Cuneo, Kyle C.; Desjardins, Annick; Sampson, John H.; McSherry, Frances; Herndon, James E.; Peters, Katherine B.; Allen, Karen; Hoang, Jenny K.; Chang, Zheng; Craciunescu, Oana; Vredenburgh, James J.; Friedman, Henry S.; Kirkpatrick, John P.

    2013-08-01

    Purpose: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. Methods and Materials: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. Results: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. Conclusions: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.

  2. The effects of sequential treatments on hippocampal volumes in malignant glioma patients.

    PubMed

    Nolen, Shantell C; Lee, Brian; Shantharam, Shruti; Yu, Hon J; Su, Lydia; Billimek, John; Bota, Daniela A

    2016-09-01

    Malignant gliomas (MG) are very aggressive tumors. In an effort to improve the outcome, the patients receive multi-modal therapies such as surgery, radiation and chemotherapy (temozolomide followed in many cases by bevacizumab). The survivors are affected by multiple learning and memory deficits. Greater deterioration over time in hippocampal specific cognitive tasks was shown in patients receiving bevacizumab in addition to radiation and temozolomide for a longer period of time (RTOG 0825). The rate of hippocampal atrophy in patients treated with radiation and temozolomide followed by bevacizumab is not yet determined, and is the goal of the present study. We used the serial MRIs obtained as parts of standard clinical care in patients with MG. Measurements were done using the Medical Image Processing, Analysis and Visualization (MIPAV) software. The hippocampus in the contralateral hemisphere was manually traced and measured, to avoid morphological structure changes induced by the tumor, radiation fields or surgical markers. We determined a longitudinal progression of hippocampal atrophy-with the maximum volume loss (33.26 %) for the patients that were on treatment for 5 years. There was no detectable hippocampal atrophy during the chemo-radiation followed by adjuvant temozolomide. A significant decrease in the absolute hippocampus volume was noted after 6 months of continuous bevacizumab treatment (p < 0.05). The hippocampal volume loss progressed over the next 3 years, and was higher than the one previously reported in Alzheimer disease patients. The hippocampal volume loss is minimal during the 1 month after diagnosis, when the patients receive chemo-radiation and adjuvant temozolomide. However, prolonged treatment including bevacizumab is associated with a significant rate of hippocampal volume loss. PMID:27393350

  3. Oncolytic virotherapy for malignant glioma: translating laboratory insights into clinical practice.

    PubMed

    Auffinger, Brenda; Ahmed, Atique U; Lesniak, Maciej S

    2013-01-01

    Glioblastoma multiforme, one of the most common and aggressive brain tumors in adults, is highly resistant to currently available therapies and often recurs. Due to its poor prognosis and difficult management, there is an urgent need for the development and translation of new anti-glioma therapeutic approaches into the clinic. In this context, oncolytic virotherapy arises as an exciting treatment option for glioma patients. These natural or genetically engineered viruses are able to effectively infect cancer cells, inducing a specific anti-tumor cytotoxic effect. In addition, some viruses have been redesigned to modulate glioma microenvironment, to express cytokines to boost a systemic anti-glioma immune response and to incorporate angiostatic genes to decrease glioma vasculature. Although recent clinical trials have confirmed the safety of oncolytic virotherapies in the brain, their moderate clinical efficacy has not yet matched the encouraging preclinical laboratory results. In this review, we will discuss the leading anti-glioma virotherapy approaches that are presently under preclinical and clinical evaluation. We will also review different delivery methods, in vivo virus behavior, fate, replication, intratumoral spread, activation of anti-tumor immune response, and targeting of glioma stem cells. We will focus on the advantages and limitations of each therapeutic approach and how to overcome these hurdles to effectively translate exciting laboratory results into promising clinical trials. PMID:23443138

  4. Oncolytic virotherapy for malignant glioma: translating laboratory insights into clinical practice

    PubMed Central

    Auffinger, Brenda; Ahmed, Atique U.; Lesniak, Maciej S.

    2013-01-01

    Glioblastoma multiforme, one of the most common and aggressive brain tumors in adults, is highly resistant to currently available therapies and often recurs. Due to its poor prognosis and difficult management, there is an urgent need for the development and translation of new anti-glioma therapeutic approaches into the clinic. In this context, oncolytic virotherapy arises as an exciting treatment option for glioma patients. These natural or genetically engineered viruses are able to effectively infect cancer cells, inducing a specific anti-tumor cytotoxic effect. In addition, some viruses have been redesigned to modulate glioma microenvironment, to express cytokines to boost a systemic anti-glioma immune response and to incorporate angiostatic genes to decrease glioma vasculature. Although recent clinical trials have confirmed the safety of oncolytic virotherapies in the brain, their moderate clinical efficacy has not yet matched the encouraging preclinical laboratory results. In this review, we will discuss the leading anti-glioma virotherapy approaches that are presently under preclinical and clinical evaluation. We will also review different delivery methods, in vivo virus behavior, fate, replication, intratumoral spread, activation of anti-tumor immune response, and targeting of glioma stem cells. We will focus on the advantages and limitations of each therapeutic approach and how to overcome these hurdles to effectively translate exciting laboratory results into promising clinical trials. PMID:23443138

  5. Targeting the RTK-PI3K-mTOR Axis in Malignant Glioma: Overcoming Resistance

    PubMed Central

    Fan, Qi-Wen

    2010-01-01

    Gliomas represent the most common primary brain tumor and among the most aggressive of cancers. Patients with glioma typically relapse within a year of initial diagnosis. Recurrent glioma is associated with acquired therapeutic resistance. Although neurosurgical resection, radiation and chemotherapy provide clear benefit, survival remains disappointing. It is, therefore, critical that we identify effective medical therapies and appropriate tumor biomarkers in patients at initial presentation, to promote durable responses in glioma. Pathways linking receptor tyrosine kinases, PI3 kinase, Akt, and mTOR feature prominently in this disease and represent therapeutic targets. Small molecules that inhibit one or more of these kinases are now being introduced into the clinic and may have some activity. Disappointingly, however, preclinical studies demonstrate these agents to be primarily cytostatic rather than cytotoxic to glioma cells. Here, we detail activation of the EGFR-PI3K-Akt-mTOR signaling network in glioma, review class I PI3K inhibitors, discuss roles for Akt, PKC and mTOR, and the importance of biomarkers. We further delineate attempts to target both single and multiple components within the EGFR-PI3K-Akt-mTOR axes. Lastly, we discuss the need to combine targeted therapies with cytotoxic chemotherapy, radiation and with inhibitors of survival signaling to improve outcomes in glioma. PMID:20535652

  6. Design and synthesis of a MAO-B-selectively activated prodrug based on MPTP: a mitochondria-targeting chemotherapeutic agent for treatment of human malignant gliomas.

    PubMed

    Sharpe, Martyn A; Han, Junyan; Baskin, Alexandra M; Baskin, David S

    2015-04-01

    Malignant gliomas, including glioblastomas, are extremely difficult to treat. The median survival for glioblastoma patients with optimal therapeutic intervention is 15 months. We developed a novel MAO-B-selectively activated prodrug, N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propanamide (MP-MUS), for the treatment of gliomas based on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The design of neutral MP-MUS involved the use of a seeker molecule capable of binding to mitochondrial MAO-B, which is up-regulated ≥fourfold in glioma cells. Once the binding occurs, MP-MUS is converted into a positively charged moiety, P(+) -MUS, which accumulates inside mitochondria at a theoretical maximal value of 1000:1 gradient. The LD50 of MP-MUS against glioma cells is 75 μM, which is two- to threefold more potent than temozolomide, a primary drug for gliomas. Importantly, MP-MUS was found to be selectively toxic toward glioma cells. In the concentration range of 150-180 μM MP-MUS killed 90-95 % of glioma cells, but stimulated the growth of normal human astrocytes. Moreover, maturation of MP-MUS is highly dependent on MAO-B, and inhibition of MAO-B activity with selegiline protected human glioma cells from apoptosis. PMID:25677185

  7. AEG-1/MTDH-activated autophagy enhances human malignant glioma susceptibility to TGF-β1-triggered epithelial-mesenchymal transition

    PubMed Central

    Zou, Meijuan; Zhu, Wei; Wang, Li; Shi, Lei; Gao, Rui; Ou, Yingwei; Chen, Xuguan; Wang, Zhongchang; Jiang, Aiqin; Liu, Kunmei; Xiao, Ming; Ni, Ping; Wu, Dandan; He, Wenping; Sun, Geng; Li, Ping; Zhai, Sulan; Wang, Xuerong; Hu, Gang

    2016-01-01

    Autophagy is a tightly regulated process activated in response to metabolic stress and other microenvironmental changes. Astrocyte elevated gene 1 (AEG-1) reportedly induces protective autophagy. Our results indicate that AEG-1 also enhances the susceptibility of malignant glioma cells to TGF-β1-triggered epithelial-mesenchymal transition (EMT) through induction of autophagy. TGF-β1 induced autophagy and activated AEG-1 via Smad2/3 phosphorylation in malignant glioma cells. Also increased was oncogene cyclin D1 and EMT markers, which promoted tumor progression. Inhibition of autophagy using siRNA-BECN1 and siRNA-AEG-1 suppressed EMT. In tumor samples from patients with malignant glioma, immunohistochemical assays showed that expression levels of TGF-β1, AEG-1, and markers of autophagy and EMT, all gradually increase with glioblastoma progression. In vivo siRNA-AEG-1 administration to rats implanted with C6 glioma cells inhibited tumor growth and increased the incidence of apoptosis among tumor cells. These findings shed light on the mechanisms underlying the invasiveness and progression of malignant gliomas. PMID:26909607

  8. Erlotinib in Treating Patients With Recurrent Malignant Glioma or Recurrent or Progressive Meningioma

    ClinicalTrials.gov

    2014-07-09

    Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Grade III Meningioma; Adult Mixed Glioma; Recurrent Adult Brain Tumor

  9. Sunitinib Malate in Treating Younger Patients With Recurrent, Refractory, or Progressive Malignant Glioma or Ependymoma

    ClinicalTrials.gov

    2015-08-18

    Childhood Cerebellar Anaplastic Astrocytoma; Childhood Cerebral Anaplastic Astrocytoma; Childhood Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma

  10. Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340.

    PubMed

    Price, A; Shi, Q; Morris, D; Wilcox, M E; Brasher, P M; Rewcastle, N B; Shalinsky, D; Zou, H; Appelt, K; Johnston, R N; Yong, V W; Edwards, D; Forsyth, P

    1999-04-01

    Synthetic matrix metalloproteinase (MMP) inhibitors have activity against a variety of tumors in preclinical models but have not been studied in gliomas. We determined the effect of AG3340, a novel synthetic MMP inhibitor with Ki values against gelatinases in the low picomolar range, on the growth of a human malignant glioma cell line (U87) in SCID-NOD mice. Mice were injected s.c. with U87 cells. Tumors were allowed to grow to a size of approximately 0.5 x 0.5 cm (after about 3 weeks), and the mice were randomized to receive either: (a) 100 mg/kg AG3340 in vehicle; or (b) vehicle control (0.5% carboxymethyl cellulose, 0.1% pluronic F68), both given daily i.p. Tumor area was measured twice weekly, and animals were sacrificed when moribund, or earlier if premorbid histology was examined. In vivo inhibition of tumor growth was profound, with AG3340 decreasing tumor size by 78% compared with controls after 31 days (when controls were sacrificed; P < 0.01, Wilcoxon test). Control animals survived 31 days after the i.p. injections began, and AG3340 mice survived 71 days, representing a >2-fold increase in survival associated with tumor growth delay. Histological examination found that AG3340-treated tumors were smaller, had lower rates of proliferation, and significantly less invasion than control-treated tumors. Hepatic or pulmonary metastases were not seen in either group. In a separate experiment, the tumors were smaller and sampled after a shorter duration of treatment; the changes in proliferation were more marked and occurred earlier than differences in tumor invasion between the two groups. Furthermore, in vitro cell growth was not inhibited at AG3340 concentrations of <1 mM. AG3340 plasma concentrations in vivo, 1 h after administration, ranged from 67 to 365 nM. Thus, AG3340 produced a profound inhibition of glioma tumor growth and invasion. AG3340 markedly increased survival in this in vivo glioma model. Treatment with AG3340 may be potentially useful in

  11. Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats

    PubMed Central

    Tyler, Betty; Wadsworth, Scott; Recinos, Violette; Mehta, Vivek; Vellimana, Ananth; Li, Khan; Rosenblatt, Joel; Do, Hiep; Gallia, Gary L.; Siu, I-Mei; Wicks, Robert T.; Rudek, Michelle A.; Zhao, Ming; Brem, Henry

    2011-01-01

    Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated. PMID:21727209

  12. Aurantiamide acetate suppresses the growth of malignant gliomas in vitro and in vivo by inhibiting autophagic flux

    PubMed Central

    Yang, Yi; Zhang, Li-hui; Yang, Bing-xian; Tian, Jin-kui; Zhang, Lin

    2015-01-01

    We aim to investigate the effect of aurantiamide acetate isolated from the aerial parts of Clematis terniflora DC against gliomas. Human malignant glioma U87 and U251 cells were incubated with different concentrations (0–100 μM) of aurantiamide acetate. Aurantiamide acetate greatly decreased the cell viability in a dose- and time-dependent manner. It induced moderate mitochondrial fragmentation and the loss of mitochondrial membrane potential. No significant difference was found in the alternation of other intracellular organelles, although F-actin structure was slightly disturbed. Apparent ultrastructure alternation with increased autophagosome and autolysosome accumulation was observed in aurantiamide acetate-treated cells. The expression of LC3-II was greatly up-regulated in cells exposed to aurantiamide acetate (P < 0.05 compared with control). The cytoplasmic accumulation of autophagosomes and autolysosomes induced by aurantiamide acetate treatment was confirmed by fluorescent reporter protein labelling. Administration of chloroquine (CQ), which inhibits the fusion step of autophagosomes, further increased the accumulation of autophagosomes in the cytoplasm of U87 cells. Autophagy inhibition by 3-methyladenine, Bafilomycin A1 or CQ had no influence on aurantiamide acetate-induced cytotoxicity, whereas autophagy stimulator rapamycin significantly suppressed aurantiamide acetate-induced cell death. The anti-tumour effects of aurantiamide acetate were further evaluated in tumour-bearing nude mice. Intratumoural injection of aurantiamide acetate obviously suppressed tumour growth, and increased number of autophagic vacuoles was observed in tumour tissues of animals receiving aurantiamide acetate. Our findings suggest that aurantiamide acetate may suppress the growth of malignant gliomas by blocking autophagic flux. PMID:25704599

  13. Aurantiamide acetate suppresses the growth of malignant gliomas in vitro and in vivo by inhibiting autophagic flux.

    PubMed

    Yang, Yi; Zhang, Li-hui; Yang, Bing-xian; Tian, Jin-kui; Zhang, Lin

    2015-05-01

    We aim to investigate the effect of aurantiamide acetate isolated from the aerial parts of Clematis terniflora DC against gliomas. Human malignant glioma U87 and U251 cells were incubated with different concentrations (0-100 μM) of aurantiamide acetate. Aurantiamide acetate greatly decreased the cell viability in a dose- and time-dependent manner. It induced moderate mitochondrial fragmentation and the loss of mitochondrial membrane potential. No significant difference was found in the alternation of other intracellular organelles, although F-actin structure was slightly disturbed. Apparent ultrastructure alternation with increased autophagosome and autolysosome accumulation was observed in aurantiamide acetate-treated cells. The expression of LC3-II was greatly up-regulated in cells exposed to aurantiamide acetate (P < 0.05 compared with control). The cytoplasmic accumulation of autophagosomes and autolysosomes induced by aurantiamide acetate treatment was confirmed by fluorescent reporter protein labelling. Administration of chloroquine (CQ), which inhibits the fusion step of autophagosomes, further increased the accumulation of autophagosomes in the cytoplasm of U87 cells. Autophagy inhibition by 3-methyladenine, Bafilomycin A1 or CQ had no influence on aurantiamide acetate-induced cytotoxicity, whereas autophagy stimulator rapamycin significantly suppressed aurantiamide acetate-induced cell death. The anti-tumour effects of aurantiamide acetate were further evaluated in tumour-bearing nude mice. Intratumoural injection of aurantiamide acetate obviously suppressed tumour growth, and increased number of autophagic vacuoles was observed in tumour tissues of animals receiving aurantiamide acetate. Our findings suggest that aurantiamide acetate may suppress the growth of malignant gliomas by blocking autophagic flux. PMID:25704599

  14. Pharmacokinetic and Tumor Distribution Characteristics of Temsirolimus in Patients with Recurrent Malignant Glioma

    PubMed Central

    Kuhn, John G.; Chang, Susan M.; Wen, Patrick Y.; Cloughesy, Timothy F.; Greenberg, Harry; Schiff, David; Conrad, Charles; Fink, Karen L.; Robins, H. Ian; Mehta, Minesh; DeAngelis, Lisa; Raizer, Jeffrey; Hess, Kenneth; Lamborn, Kathleen R.; Dancey, Janet; Prados, Michael D.

    2016-01-01

    Purpose To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue. Experimental Design Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis. Results Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus. Conclusions Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of

  15. Blood-brain barrier permeable gold nanoparticles: an efficient delivery platform for enhanced malignant glioma therapy and imaging.

    PubMed

    Cheng, Yu; Dai, Qing; Morshed, Ramin A; Fan, Xiaobing; Wegscheid, Michelle L; Wainwright, Derek A; Han, Yu; Zhang, Lingjiao; Auffinger, Brenda; Tobias, Alex L; Rincón, Esther; Thaci, Bart; Ahmed, Atique U; Warnke, Peter C; He, Chuan; Lesniak, Maciej S

    2014-12-29

    The blood-brain barrier (BBB) remains a formidable obstacle in medicine, preventing efficient penetration of chemotherapeutic and diagnostic agents to malignant gliomas. Here, a transactivator of transcription (TAT) peptide-modified gold nanoparticle platform (TAT-Au NP) with a 5 nm core size is demonstrated to be capable of crossing the BBB efficiently and delivering cargoes such as the anticancer drug doxorubicin (Dox) and Gd(3+) contrast agents to brain tumor tissues. Treatment of mice bearing intracranial glioma xenografts with pH-sensitive Dox-conjugated TAT-Au NPs via a single intravenous administration leads to significant survival benefit when compared to the free Dox. Furthermore, it is demonstrated that TAT-Au NPs are capable of delivering Gd(3+) chelates for enhanced brain tumor imaging with a prolonged retention time of Gd(3+) when compared to the free Gd(3+) chelates. Collectively, these results show promising applications of the TAT-Au NPs for enhanced malignant brain tumor therapy and non-invasive imaging. PMID:25104165

  16. Blood-Brain Barrier Permeable Gold Nanoparticles: An Efficient Delivery Platform for Enhanced Malignant Glioma Therapy and Imaging

    PubMed Central

    Cheng, Yu; Dai, Qing; Morshed, Ramin; Fan, Xiaobing; Wegscheid, Michelle L.; Wainwright, Derek A.; Han, Yu; Zhang, Lingjiao; Auffinger, Brenda; Tobias, Alex L.; Rincón, Esther; Thaci, Bart; Ahmed, Atique U.; Warnke, Peter; He, Chuan

    2014-01-01

    The blood-brain barrier (BBB) remains a formidable obstacle in medicine, preventing efficient penetration of chemotherapeutic and diagnostic agents to malignant gliomas. Here, we demonstrate that a transactivator of transcription (TAT) peptide-modified gold nanoparticle platform (TAT-Au NP) with a 5 nm core size is capable of crossing the BBB efficiently and delivering cargoes such as the anticancer drug doxorubicin (Dox) and Gd3+ contrast agents to brain tumor tissues. Treatment of mice bearing intracranial glioma xenografts with pH-sensitive Dox-conjugated TAT-Au NPs via a single intravenous administration leads to significant survival benefit when compared to the free Dox. Furthermore, we demonstrate that TAT-Au NPs are capable of delivering Gd3+ chelates for enhanced brain tumor imaging with a prolonged retention time of Gd3+ when compared to the free Gd3+ chelates. Collectively, these results show promising applications of the TAT-Au NPs for enhanced malignant brain tumor therapy and non-invasive imaging. PMID:25104165

  17. PME-1 protects ERK pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma

    PubMed Central

    Puustinen, Pietri; Junttila, Melissa R.; Vanhatupa, Sari; Sablina, Anna A.; Hector, Melissa E.; Teittinen, Kaisa; Raheem, Olayinka; Ketola, Kirsi; Lin, Shujun; Kast, Juergen; Haapasalo, Hannu; Hahn, William C.; Westermarck, Jukka

    2010-01-01

    ERK/MAPK pathway activity is regulated by the antagonist function of activating kinases and inactivating protein phosphatases. Sustained ERK pathway activity is commonly observed in human malignancies, however the mechanisms by which the pathway is protected from phosphatase-mediated inactivation in the tumor tissue remain obscure. Here we show that methylesterase PME-1-mediated inhibition of the protein phosphatase 2A (PP2A) promotes basal ERK pathway activity, and is required for efficient growth factor response. Mechanistically PME-1 is shown to support ERK pathway signaling upstream of Raf, but downstream of growth factor receptors and PKC. In malignant glioblastoma, PME-1 expression levels correlate with both ERK activity and cell proliferation in vivo. Moreover, PME-1 expression significantly correlates with disease progression in human astrocytic gliomas (N=222). Together, these observations identify PME-1 expression as one mechanism by which ERK pathway activity is maintained in cancer cells, and suggest important functional role for PME-1 in the disease progression of human astrocytic gliomas. PMID:19293187

  18. Temozolomide Modifies Caveolin-1 Expression in Experimental Malignant Gliomas In Vitro and In Vivo1

    PubMed Central

    Bruyère, Céline; Abeloos, Laurence; Lamoral-Theys, Delphine; Senetta, Rebecca; Mathieu, Véronique; Le Mercier, Marie; Kast, Richard E; Cassoni, Paola; Vandenbussche, Guy; Kiss, Robert; Lefranc, Florence

    2011-01-01

    BACKGROUND: Caveolin-1 is a protein that displays promotive versus preventive roles in cancer progression according to circumstances. Temozolomide (TMZ) is the standard chemotherapeutic to treat glioma patients. The present work aims to characterizeTMZ-induced effects on caveolin-1 expression in glioma cells. METHODS: Human astroglioma (U373 and T98G) and oligodendroglioma (Hs683) cell lines were used in vitro as well as in vivo orthotopic xenografts (Hs683 and U373) into the brains of immunocompromisedmice. In vitro TMZ-induced effects on protein expression and cellular localization were determined by Western blot analysis and on the actin cytoskeleton organization by means of immunofluorescence approaches. In vivo TMZ-induced effects in caveolin-1 expression in human glioma xenografts were monitored by means of immunohistochemistry. RESULTS: TMZ modified caveolin-1 expression and localization in vitro and in vivo after an administration schedule that slightly, if at all, impaired cell growth characteristics in vitro. Caveolin-1 by itself (at a 100-ng/ml concentration) was able to significantly reduce invasiveness (Boyden chambers) of the three human glioma cell lines. The TMZ-inducedmodification in caveolin-1 expression in flotation/raft compartments was paralleled by altered Cyr61 and β1 integrin expression, two elements that have already been reported to collaborate with caveolin-1 in regulating glioma cell biology, and all these features led to profound reorganization of the actin cytoskeleton. An experimental Src kinase inhibitor, AZD0530, almost completely antagonized the TMZ-induced modulation in caveolin-1 expression. CONCLUSION: TMZ modifies caveolin-1 expression in vitro and in vivo in glioma cells, a feature that directly affects glioma cell migration properties. PMID:21461172

  19. A Phase I and Biology Study of Gefitinib and Radiation in Children with Newly Diagnosed Brain Stem Gliomas or Supratentorial Malignant Gliomas

    PubMed Central

    Geyer, J. Russell; Stewart, Clinton F.; Kocak, Mehmet; Broniscer, Alberto; Phillips, Peter; Douglas, James G.; Blaney, Susan M.; Packer, Roger J.; Gururangan, Sri; Banerjee, Anu; Kieran, Mark W.; Kun, Larry E.; Gilbertson, Richard J.; Boyett, James M.

    2010-01-01

    Purpose To estimate the maximum tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ≤21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG. Patients and methods Three strata were identified: Stratum 1A - BSG; Stratum IB - incompletely resected STMG not receiving enzyme inducing anti-convulsant drugs (EIACD); and Stratum II - incompletely resected STMG receiving EIACD. Dose escalation using a modified 3 + 3 cohort design was performed in strata IA & II. The initial gefitinib dosage was 100mg/m2/day commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients. Results Of 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral hemorrhage (ITH); 2 during and 2 post dose-finding. ITH was observed in 0 of 11 patients treated at 100mg/m2/day, 1 of 10 at 250mg/m2/day, and 3 of 12 at 375mg/m2/day. Subsequently a second patient at 250mg/m2/day experienced ITH. PK analysis showed the median gefitinib systemic exposure increased with dosage (p=0.04). EGFR was overexpressed in 5 of 11 STMG and amplified in 4 (36%) samples. Conclusion This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250mg/m2/day was selected for the Phase II trial. PMID:20708924

  20. Hypotaurine evokes a malignant phenotype in glioma through aberrant hypoxic signaling.

    PubMed

    Gao, Peng; Yang, Chunzhang; Nesvick, Cody L; Feldman, Michael J; Sizdahkhani, Saman; Liu, Huailei; Chu, Huiying; Yang, Fengxu; Tang, Ling; Tian, Jing; Zhao, Shiguang; Li, Guohui; Heiss, John D; Liu, Yang; Zhuang, Zhengping; Xu, Guowang

    2016-03-22

    Metabolomics has shown significant potential in identifying small molecules specific to tumor phenotypes. In this study we analyzed resected tissue metabolites using capillary electrophoresis-mass spectrometry and found that tissue hypotaurine levels strongly and positively correlated with glioma grade. In vitro studies were conducted to show that hypotaurine activates hypoxia signaling through the competitive inhibition of prolyl hydroxylase domain-2. This leads to the activation of hypoxia signaling as well as to the enhancement of glioma cell proliferation and invasion. In contrast, taurine, the oxidation metabolite of hypotaurine, decreased intracellular hypotaurine and resulted in glioma cell growth arrest. Lastly, a glioblastoma xenograft mice model was supplemented with taurine feed and exhibited impaired tumor growth. Taken together, these findings suggest that hypotaurine is an aberrantly produced oncometabolite, mediating tumor molecular pathophysiology and progression. The hypotaurine metabolic pathway may provide a potentially new target for glioblastoma diagnosis and therapy. PMID:26934654

  1. Hypotaurine evokes a malignant phenotype in glioma through aberrant hypoxic signaling

    PubMed Central

    Nesvick, Cody L.; Feldman, Michael J.; Sizdahkhani, Saman; Liu, Huailei; Chu, Huiying; Yang, Fengxu; Tang, Ling; Tian, Jing; Zhao, Shiguang; Li, Guohui; Heiss, John D.; Liu, Yang; Zhuang, Zhengping; Xu, Guowang

    2016-01-01

    Metabolomics has shown significant potential in identifying small molecules specific to tumor phenotypes. In this study we analyzed resected tissue metabolites using capillary electrophoresis-mass spectrometry and found that tissue hypotaurine levels strongly and positively correlated with glioma grade. In vitro studies were conducted to show that hypotaurine activates hypoxia signaling through the competitive inhibition of prolyl hydroxylase domain-2. This leads to the activation of hypoxia signaling as well as to the enhancement of glioma cell proliferation and invasion. In contrast, taurine, the oxidation metabolite of hypotaurine, decreased intracellular hypotaurine and resulted in glioma cell growth arrest. Lastly, a glioblastoma xenograft mice model was supplemented with taurine feed and exhibited impaired tumor growth. Taken together, these findings suggest that hypotaurine is an aberrantly produced oncometabolite, mediating tumor molecular pathophysiology and progression. The hypotaurine metabolic pathway may provide a potentially new target for glioblastoma diagnosis and therapy. PMID:26934654

  2. [Radiation-induced cancers].

    PubMed

    Dutrillaux, B

    1998-01-01

    The induction of malignant diseases is one of the most concerning late effects of ionising radiation. A large amount of information has been collected form atomic bomb survivors, patients after therapeutic irradiation, occupational follow-up and accidentally exposed populations. Major uncertainties persist in the (very) low dose range i.e., population and workers radioprotection. A review of the biological mechanisms leading to cancer strongly suggests that the vast majority of radiation-induced malignancies arise as a consequence of recessive mutations of tumour-suppressor genes. These mutations can be unveiled by ageing, this process being possibly furthered by constitutional or acquired genomic instability. The individual risk is likely to be very low, probably because of the usual dose level. However, the magnitude of medical exposure and the reliance of our societies on nuclear industry are so high that irreproachable decision-making processes and standards for practice are inescapable. PMID:9868399

  3. A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas.

    PubMed

    Odia, Yazmin; Iwamoto, Fabio M; Moustakas, Argirios; Fraum, Tyler J; Salgado, Carlos A; Li, Aiguo; Kreisl, Teri N; Sul, Joohee; Butman, John A; Fine, Howard A

    2016-03-01

    We evaluated the efficacy of combination enzastaurin (LY317615) and bevacizumab for recurrent malignant gliomas and explored serologic correlates. We enrolled 81 patients with glioblastomas (GBM, n = 40) and anaplastic gliomas (AG, n = 41). Patients received enzastaurin as a loading dose of 1125 mg, followed by 500 or 875 mg daily for patients on non-enzyme-inducing or enzyme-inducing antiepileptics, respectively. Patients received bevacizumab 10 mg/kg intravenously biweekly. Clinical evaluations were repeated every 4 weeks. Magnetic resonance imaging was obtained at baseline and every 8 weeks from treatment onset. Phosphorylated glycogen synthase kinase (GSK)-3 levels from peripheral blood mononuclear cells (PBMCs) were checked with each MRI. Median overall survival was 7.5 and 12.4 months for glioblastomas and anaplastic glioma cohorts, with median progression-free survivals of 2.0 and 4.4 months, respectively. Of GBM patients, 3/40 (7.5 %) were not evaluable, while 8/37 (22 %) had partial or complete response and 20/37 (54 %) had stable disease for 2+ months. Of the 39 evaluable AG patients, 18 (46 %) had an objective response, and 16 (41 %) had stable disease for 2+ months. The most common grade 3+ toxicities were lymphopenia (15 %), hypophosphatemia (8.8 %) and thrombotic events (7.5 %). Two (2.5 %) GBM patients died suddenly; another death (1.3 %) occurred from intractable seizures. Phosphorylated GSK-3 levels from PBMCs did not correlate with treatment response. A minimally important improvement in health-related quality of life was self-reported in 7-9/24 (29.2-37.5 %). Early response based on Levin criteria was significantly associated with significantly longer progression free survival for glioblastomas. Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy. PMID:26643807

  4. Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression

    SciTech Connect

    Chang, C.-J.; Hsu, C.-C.; Yung, M.-C.; Chen, K.-Y.; Tzao Ching; Wu, W.-F.; Chou, H.-Y.; Lee, Y.-Y.; Lu, K.-H.; Chiou, S.-H.; Ma, H.-I

    2009-03-06

    CD133-expressing glioma cells play a critical role in tumor recovery after treatment and are resistant to radiotherapy. Herein, we demonstrated that glioblastoma-derived CD133-positive cells (GBM-CD133{sup +}) are capable of self-renewal and express high levels of embryonic stem cell genes and SirT1 compared to GBM-CD133{sup -} cells. To evaluate the role of SirT1 in GBM-CD133{sup +}, we used a lentiviral vector expressing shRNA to knock-down SirT1 expression (sh-SirT1) in GBM-CD133{sup +}. Silencing of SirT1 significantly enhanced the sensitivity of GBM-CD133{sup +} to radiation and increased the level of radiation-mediated apoptosis. Importantly, knock-down of SirT1 increased the effectiveness of radiotherapy in the inhibition of tumor growth in nude mice transplanted with GBM-CD133{sup +}. Kaplan-Meier survival analysis indicated that the mean survival rate of GBM-CD133{sup +} mice treated with radiotherapy was significantly improved by Sh-SirT1 as well. In sum, these results suggest that SirT1 is a potential target for increasing the sensitivity of GBM and glioblastoma-associated cancer stem cells to radiotherapy.

  5. Estimation of Radiobiologic Parameters and Equivalent Radiation Dose of Cytotoxic Chemotherapy in Malignant Glioma

    SciTech Connect

    Jones, Bleddyn . E-mail: b.jones.1@bham.ac.uk; Sanghera, Paul

    2007-06-01

    Purpose: To determine the radiobiologic parameters for high-grade gliomas. Methods and Materials: The biologic effective dose concept is used to estimate the {alpha}/{beta} ratio and K (dose equivalent for tumor repopulation/d) for high-grade glioma patients treated in a randomized fractionation trial. The equivalent radiation dose of temozolomide (Temodar) chemotherapy was estimated from another randomized study. The method assumes that the radiotherapy biologic effective dose is proportional to the adjusted radiotherapy survival duration of high-grade glioma patients. Results: The median tumor {alpha}/{beta} and K estimate is 9.32 Gy and 0.23 Gy/d, respectively. Using the published surviving fraction after 2-Gy exposure (SF{sub 2}) data, and the above {alpha}/{beta} ratio, the estimated median {alpha} value was 0.077 Gy{sup -1}, {beta} was 0.009 Gy{sup -2}, and the cellular doubling time was 39.5 days. The median equivalent biologic effective dose of temozolomide was 11.03 Gy{sub 9.3} (equivalent to a radiation dose of 9.1 Gy given in 2-Gy fractions). Random sampling trial simulations based on a cure threshold of 70 Gy in high-grade gliomas have shown the potential increase in tumor cure with dose escalation. Partial elimination of hypoxic cells (by chemical hypoxic cell sensitizers or carbon ion therapy) has suggested that considerable gains in tumor control, which are further supplemented by temozolomide, are achievable. Conclusion: The radiobiologic parameters for human high-grade gliomas can be estimated from clinical trials and could be used to inform future clinical trials, particularly combined modality treatments with newer forms of radiotherapy. Other incurable cancers should be studied using similar radiobiologic analysis.

  6. Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the children’s oncology group

    PubMed Central

    Hamilton, Ronald L.; Murdoch, Geoffrey H.; Burger, Peter C.; Brat, Daniel J.; Rosenblum, Marc K.; Nikiforova, Marina N.; Holmes, Emiko J.; Zhou, Tianni; Cohen, Kenneth J.; Jakacki, Regina I.

    2010-01-01

    Aberrant activation of Akt is a common finding in adult malignant gliomas, resulting in most cases from mutations or deletions involving PTEN, which allows constitutive Akt phosphorylation. In contrast, we have previously reported that pediatric malignant gliomas, which are morphologically similar to lesions arising in adults, have a substantially lower incidence of genomic alterations of PTEN. The objective of this study was to determine whether Akt activation was also an uncommon finding in childhood malignant gliomas and whether this feature was associated with survival. To address this issue, we examined the frequency of Akt activation, determined by overexpression of the activated phosphorylated form of Akt (Se473) on immunohistochemical analysis, in a series of 53 childhood malignant gliomas obtained from newly diagnosed patients treated on the Children’s Oncology Group ACNS0126 and 0423 studies. The relationship between Akt activation and p53 over-expression, MIB1 labeling, and tumor histology was evaluated. The association between Akt activation and survival was also assessed. Overexpression of activated Akt was observed in 42 of 53 tumors, far in excess of the frequency of PTEN mutations we have previously observed. There was no association between Akt activation and either histology, p53 overexpression, or MIB1 proliferation indices. Although tumors that lacked Akt overexpression had a trend toward more favorable event-free survival and overall survival (p = 0.06), this association reflected that non-overexpressing tumors were significantly more likely to have undergone extensive tumor removal, which was independently associated with outcome. Activation of Akt is a common finding in pediatric malignant gliomas, although it remains uncertain whether this is an independent adverse prognostic factor. In view of the frequency of Akt activation, the evaluation of molecularly targeted therapies that inhibit this pathway warrants consideration for these tumors

  7. Artemether Combined with shRNA Interference of Vascular Cell Adhesion Molecule-1 Significantly Inhibited the Malignant Biological Behavior of Human Glioma Cells

    PubMed Central

    Wang, Ping; Xue, Yi-Xue; Yao, Yi-Long; Yu, Bo; Liu, Yun-Hui

    2013-01-01

    Artemether is the derivative extracted from Chinese traditional herb and originally used for malaria. Artemether also has potential therapeutic effects against tumors. Vascular cell adhesion molecule-1 (VCAM-1) is an important cell surface adhesion molecule associated with malignancy of gliomas. In this work, we investigated the role and mechanism of artemether combined with shRNA interference of VCAM-1 (shRNA-VCAM-1) on the migration, invasion and apoptosis of glioma cells. U87 human glioma cells were treated with artemether at various concentrations and shRNA interfering technology was employed to silence the expression of VCAM-1. Cell viability, migration, invasiveness and apoptosis were assessed with MTT, wound healing, Transwell and Annexin V-FITC/PI staining. The expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and phosphorylated Akt (p-Akt) was checked by Western blot assay. Results showed that artemether and shRNA-VCAM-1 not only significantly inhibited the migration, invasiveness and expression of MMP-2/9 and p-Akt, but also promoted the apoptosis of U87 cells. Combined treatment of both displayed the maximum inhibitory effects on the malignant biological behavior of glioma cells. Our work revealed the potential therapeutic effects of artemether and antiVCAM-1 in the treatments of gliomas. PMID:23593320

  8. Malignant gliomas with primitive neuroectodermal tumor-like components: a clinicopathologic and genetic study of 53 cases.

    PubMed

    Perry, Arie; Miller, C Ryan; Gujrati, Meena; Scheithauer, Bernd W; Zambrano, Sandro Casavilca; Jost, Sarah C; Raghavan, Ravi; Qian, Jiang; Cochran, Elizabeth J; Huse, Jason T; Holland, Eric C; Burger, Peter C; Rosenblum, Marc K

    2009-01-01

    Central nervous system neoplasms with combined features of malignant glioma and primitive neuroectodermal tumor (MG-PNET) are rare, poorly characterized, and pose diagnostic as well as treatment dilemmas. We studied 53 MG-PNETs in patients from 12 to 80 years of age (median = 54 years). The PNET-like component consisted of sharply demarcated hypercellular nodules with evidence of neuronal differentiation. Anaplasia, as seen in medulloblastomas, was noted in 70%. Within the primitive element, N-myc or c-myc gene amplifications were seen in 43%. In contrast, glioma-associated alterations involved both components, 10q loss (50%) being most common. Therapy included radiation (78%), temozolomide (63%) and platinum-based chemotherapy (31%). Cerebrospinal fluid (CSF) dissemination developed in eight patients, with response to PNET-like therapy occurring in at least three. At last follow-up, 27 patients died, their median survival being 9.1 months. We conclude that the primitive component of the MG-PNET: (i) arises within a pre-existing MG, most often a secondary glioblastoma; (ii) may represent a metaplastic process or expansion of a tumor stem/progenitor cell clone; (iii) often shows histologic anaplasia and N-myc (or c-myc) amplification; (iv) has the capacity to seed the CSF; and (v) may respond to platinum-based chemotherapy regimens. PMID:18452568

  9. Intake of high-fat diet stimulates the risk of ultraviolet radiation-induced skin tumors and malignant progression of papillomas to carcinoma in SKH-1 hairless mice

    SciTech Connect

    Vaid, Mudit; Singh, Tripti; Prasad, Ram; Katiyar, Santosh K.

    2014-01-01

    Previously, we showed that administration of a high-fat diet (HF-diet) to C57BL/6 mice exacerbates their response to short-term UVB radiation-induced inflammation in the skin. To explore the effects of an HF-diet on UVB-induced tumorigenesis, we have used the SKH-1 hairless mouse model in which the mice are exposed to UVB radiation (180 mJ/cm{sup 2}) three times a week for 24 weeks. The development of UVB-induced skin tumors was rapid and the tumor multiplicity and tumor size were significantly higher (P < 0.01–0.005) in the mice fed an HF-diet than the mice fed a control-diet (C-diet). Moreover, the malignant progression of UVB-induced papillomas to carcinomas was higher in HF-diet-fed mice. On analysis of tumors and tumor-uninvolved skin samples from the tumor-bearing mice, we found that administration of an HF-diet significantly enhanced the levels of UVB-induced expression of cyclooxygenase-2 (COX-2), prostaglandin E{sub 2} (P < 0.01), and PGE{sub 2} receptors, and activation of NF-κB in the UVB-exposed skin as well as in tumors. In addition the HF-diet enhanced the expression of proinflammatory cytokines, including tumor necrosis factor-α (P < 0.01), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.05) in the UVB-exposed skin as well as in tumors. Western blot analysis revealed that HF-diet enhanced the levels of epidermal cell proliferation, phosphatidylinositol 3-kinase and phosphorylation of Akt at Ser{sup 473} in UVB-exposed skin and skin tumors. Collectively, these data demonstrate that the regular consumption of an HF-diet increases the risk of photocarcinogenesis in mice and that this is associated with enhanced expression of inflammatory mediators in the UVB-exposed skin and tumors. - Highlights: • Consumption of high-fat diet increases UVB-induced skin tumor development in mice. • Intake of high-fat diet stimulates progression of UV-induced papilloma to carcinoma. • Intake of high-fat diet enhances inflammation in UV-exposed skin • Regular

  10. Growth-inhibitory and chemosensitizing effects of the glutathione-S-transferase-π-activated nitric oxide donor PABA/NO in malignant gliomas.

    PubMed

    Kogias, Evangelos; Osterberg, Nadja; Baumer, Brunhilde; Psarras, Nikolaos; Koentges, Christoph; Papazoglou, Anna; Saavedra, Joseph E; Keefer, Larry K; Weyerbrock, Astrid

    2012-03-01

    Glutathione-S-transferases (GSTs) are upregulated in malignant gliomas and contribute to their chemoresistance. The nitric oxide (NO) donor PABA/NO (O(2) -{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) generates NO upon selective enzymatic activation by GST-π-inducing selective biological effects in tumors. Tumor cell killing and chemosensitization were observed in a variety of tumors after exposure to GST-activated NO donor drugs. In our project, cytotoxic and chemosensitizing effects of PABA/NO in combination with carboplatin (CPT) and temozolomide (TMZ) were studied in human U87 glioma cells in vitro and in vivo. U87 glioma cells were exposed to PABA/NO alone or in combination with CPT or TMZ for 24 hr. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 24-hr incubation and 48 hr after drug removal. The antiproliferative effect of PABA/NO was assessed in an intracranial U87 glioma nude rat model comparing subcutaneous administration and intratumoral delivery by convection-enhanced delivery. PABA/NO monotherapy showed a strong dose-dependent growth-inhibitory effect in U87 glioma cells in vitro, and a strong synergistic effect was observed after concomitant treatment with TMZ, but not with CPT. Systemic and intratumoral PABA/NO administration significantly reduced cell proliferation, but this did not result in prolonged survival in nude rats with intracranial U87 gliomas. PABA/NO has potent antiproliferative effects, sensitizes U87 glioma cells to TMZ in vitro and shows some in vivo efficacy. Further studies are still required to consolidate the role of NO donor therapy in glioma treatment. PMID:21455987

  11. Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma1

    PubMed Central

    Prados, Michael D.; Lamborn, Kathleen R.; Chang, Susan; Burton, Eric; Butowski, Nicholas; Malec, Mary; Kapadia, Ami; Rabbitt, Jane; Page, Margaretta S.; Fedoroff, Ann; Xie, Dong; Kelley, Sean K.

    2006-01-01

    The purpose of this study was to define the maximum tolerated dose of erlotinib and characterize its pharmacokinetics and safety profile, alone and with temozolomide, with and without enzyme-inducing antiepileptic drugs (EIAEDs), in patients with malignant gliomas. Patients with stable or progressive malignant primary glioma received erlotinib alone or combined with temozolomide in this dose-escalation study. In each treatment group, patients were stratified by coadministration of EIAEDs. Erlotinib was started at 100 mg orally once daily as a 28-day treatment cycle, with dose escalation by 50 mg/day up to 500 mg/day. Temozolomide was administered at 150 mg/m2 for five consecutive days every 28 days, with dose escalation up to 200 mg/m2 at the second cycle. Eighty-three patients were evaluated. Rash, fatigue, and diarrhea were the most common adverse events and were generally mild to moderate. The recommended phase 2 dose of erlotinib is 200 mg/day for patients with glioblastoma multiforme who are not receiving an EIAED, 450 mg/day for those receiving temozolomide plus erlotinib with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED. Of the 57 patients evaluable for response, eight had a partial response (PR). Six of the 57 patients had a progression-free survival of longer than six months, including four patients with a PR. Coadministration of EIAEDs reduced exposure to erlotinib as compared with administration of erlotinib alone (33%–71% reduction). There was a modest pharmacokinetic interaction between erlotinib and temozolomide. The favorable tolerability profile and evidence of antitumor activity indicate that further investigation of erlotinib is warranted. PMID:16443950

  12. To what extent will 5-aminolevulinic acid change the face of malignant glioma surgery?

    PubMed

    Díez Valle, Ricardo; Tejada Solis, Sonia

    2015-01-01

    Glioma surgery is an essential part of glioma management; however, fully achieving the goal of surgery has been uncommon. The goal of surgery is 'maximal safe resection' with the accepted target for maximal being complete resection of the contrast-enhancing tumor. This ideal result was obtained in less than 30% of cases in centers of excellence until a few years ago. The development of fluorescence-guided surgery using 5-aminolevulinic acid has initiated a radical change. Over the past 5 years, various groups have published rates of complete resection of the enhancing tumor that exceed 80%. In the coming years, as the use of the technology expands, complete resection should become a common, predictable result at many centers. Consequently, adjuvant therapies that benefit from resection could play a bigger role, resection could be incorporated as a variable in randomized trials and distant recurrence might become a more common problem. PMID:26118538

  13. Immunotherapeutic approach with oligodeoxynucleotides containing CpG motifs (CpG-ODN) in malignant glioma.

    PubMed

    Ursu, Renata; Carpentier, Antoine F

    2012-01-01

    Bacterial DNA and synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODNs) are strong activators of both innate and specific immunity, driving the immune response towards the Th1 phenotype. In cancer patients, CpG-ODNs can be used to activate the innate immunity and trigger a tumor-specific immune response. Several clinical trials are on-going worldwide in various cancers. In this chapter, we will focus on the potential applications of CpG-ODNs in glioma. So far, CpG-ODN has mainly been used by intratumoral injections. Indeed, human gliomas display a locally invasive pattern of growth and rarely metastasize, making local treatment clinically relevant. PMID:22639162

  14. Differential Effects of Cold Atmospheric Plasma in the Treatment of Malignant Glioma

    PubMed Central

    Siu, Alan; Volotskova, Olga; Cheng, Xiaoqian; Khalsa, Siri S.; Bian, Ka; Murad, Ferid; Keidar, Michael; Sherman, Jonathan H.

    2015-01-01

    Objective Cold atmospheric plasma (CAP) has recently been shown to selectively target cancer cells with minimal effects on normal cells. We systematically assessed the effects of CAP in the treatment of glioblastoma. Methods Three glioma cell lines, normal astrocytes, and endothelial cell lines were treated with CAP. The effects of CAP were then characterized for viability, cytotoxicity/apoptosis, and cell cycle effects. Statistical significance was determined with student's t-test. Results CAP treatment decreases viability of glioma cells in a dose dependent manner, with the ID50 between 90-120 seconds for all glioma cell lines. Treatment with CAP for more than 120 seconds resulted in viability less than 35% at 24-hours posttreatment, with a steady decline to less than 20% at 72-hours. In contrast, the effect of CAP on the viability of NHA and HUVEC was minimal, and importantly not significant at 90 to 120 seconds, with up to 85% of the cells remained viable at 72-hours post-treatment. CAP treatment produces both cytotoxic and apoptotic effects with some variability between cell lines. CAP treatment resulted in a G2/M-phase cell cycle pause in all three cell lines. Conclusions This preliminary study determined a multi-focal effect of CAP on glioma cells in vitro, which was not observed in the non-tumor cell lines. The decreased viability depended on the treatment duration and cell line, but overall was explained by the induction of cytotoxicity, apoptosis, and G2/M pause. Future studies will aim at further characterization with more complex pre-clinical models. PMID:26083405

  15. ALA-mediated photodynamic therapy of experimental malignant glioma in the BD-IX rat model

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Angell-Petersen, Even; Peng, Qian; Sun, Chung-Ho; Sorensen, Dag R.; Carper, Steven W.; Madsen, Steen J.

    2005-04-01

    Introduction: Failure of treatment for high grade gliomas is usually due to local recurrence at the site of surgical resec-tion indicating that a more aggressive form of local therapy could be of benefit. Photodynamic therapy (PDT) is a local form of treatment involving the administration of a tumor-localizing photosensitizing drug that is activated by light of a specific wavelength The results of in vitro experiments indicated that PDT, given at low fluence rates was substantially more effective at inhibiting glioma spheroid growth than short term high fluence rate regimes. This prompted the initia-tion of in vivo studies of low fluence rate 5-aminolevulinic acid (ALA) PDT in a rat glioma model. Methods:BT4C cell line tumors were established in the brains of inbred BD- IX rats. Eighteen days following tumor induction the animals were injected with 125 mg/kg ALA ip. and four hours later light treatment at various fluences and fluence rates were given after the introduction of an optical fiber. Tumor histology and animal survival were examined. Results: In vitro experiments verified that the cell line was sensitive to ALA PDT. Microfluorometry of frozen tissue sections showed that PpIX is produced with a greater than 20:1 tumor to normal tissue selectivity ratio four hours after ALA injection. Histological examination demonstrated neutrophil infiltration and tumor central necrosis in low fluence rate treated tumors. Conclusions: Low fluence rate long term ALA mediated PDT had a more pronounced effect on tumor histology than single shot short duration treatments at similar total fluence levels.

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

    PubMed Central

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

    2010-01-01

    The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 × 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where ≤1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs. PMID:20150371

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

    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 D; Wen, Patrick Y; Fine, Howard A; Mehta, Minesh; Deangelis, Lisa M; Lieberman, Frank; Cloughesy, Timothy F; Robins, H Ian; Dancey, Janet; Prados, Michael D

    2010-01-01

    The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 x 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where < or = 1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs. PMID:20150371

  18. [Results of radical removal of malignant cerebral gliomas, by using computer-assisted navigation, followed by adjuvant therapy].

    PubMed

    Krivoshapkin, A L; Kanygin, V V; Semin, P A; Melidi, E G

    2006-01-01

    A retrospective cohort analysis of the results of treatment of patients with malignant gliomas was made in 2 groups, each comprising 43 patients. In Group 1, the tumors were radically removed under neuronavigation guidance ("Voyager SX"). In Group 2 where the patients were operated on by the same team of surgeons who did not employ computer-assisted navigation technologies. The results of different adjuvant therapy regimens were analyzed in patients after radical tumor removal under navigation guidance (Group 1). In its first subgroup, 24 patients with anaplastic astrocytes were postoperatively irradiated (60 Gy), followed by treatment with temodal (200 mg/m2 (mean 6 courses). In the second subgroup, 12 patients received chemoradiotherapy (temodal, 75 mg/m2 daily + irradiation), followed by courses (n=6) of temodal, 200 mg/m2). In the third subgroup, 7 patients were treated with fotemustin (200 mg/m2 (induction) + 5 cycles). The computer-assisted technologies substantially improve a postoperative outcome in patients with malignant glionas. Current chemoradiotherapy is relatively safe and prolongs a relapse-free interval with a high quality of life. Further studies call for the efficiency of different adjuvant therapy regimens after radical surgery. PMID:17195370

  19. Identification of histological markers for malignant glioma by genome-wide expression analysis: dynein, alpha-PIX and sorcin.

    PubMed

    Yokota, Takashi; Kouno, Jun; Adachi, Koji; Takahashi, Hiroshi; Teramoto, Akira; Matsumoto, Koshi; Sugisaki, Yuichi; Onda, Masamitsu; Tsunoda, Tatsuhiko

    2006-01-01

    Glioblastoma multiforme (GBM), the most malignant class of glial neoplasm (grade IV in WHO criteria), carries the worst clinical prognosis among primary brain tumors in adults. To identify a set of genes involved in the tumorigenesis of GBM, we evaluated expression profiles of GBM tissues from 11 patients using a cDNA microarray representing 25,344 human genes. By comparing the profiles with those of normal brain tissue, we identified a number of differentially expressed genes: 54 with increased expression and 45 with reduced expression in GBMs. Semi-quantitative RT-PCR experiments with 6 of those genes confirmed higher expression of DNCH2, ARHGEF6, NPM1 and SRI and lower expression of NRGN and TM4SF2 in GBM tumors. Immunohistochemical staining for 3 of the respective gene products, dynein (product of DNCH2), alpha-PIX (product of ARHGEF6), and sorcin (product of SRI) indicated that this technique might be useful for histological grading of glial tumors. To establish criteria for this diagnostic approach, we scored glial tumor tissues of different histological grades according to the staining results; the scores were significantly higher in anaplastic astrocytomas and GBMs than in diffuse astrocytomas or normal brain tissues. These findings indicated that levels of these three proteins might serve as histological markers for malignant glioma classification. PMID:16320026

  20. Bex2 regulates cell proliferation and apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase pathway

    SciTech Connect

    Zhou, Xiuping; Meng, Qingming; Xu, Xuebin; Zhi, Tongle; Shi, Qiong; Wang, Yong; Yu, Rutong

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer The expression levels of Bex2 markedly increased in glioma tissues. Black-Right-Pointing-Pointer Bex2 over-expression promoted cell proliferation, while its down-regulation inhibited cell growth. Black-Right-Pointing-Pointer Bex2 down-regulation promoted cell apoptosis via JNK/c-Jun signaling pathway. -- Abstract: The function of Bex2, a member of the Brain Expressed X-linked gene family, in glioma is controversial and its mechanism is largely unknown. We report here that Bex2 regulates cell proliferation and apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase (JNK) pathway. The expression level of Bex2 is markedly increased in glioma tissues. We observed that Bex2 over-expression promotes cell proliferation, while down-regulation of Bex2 inhibits cell growth. Furthermore, Bex2 down-regulation promotes cell apoptosis and activates the JNK pathway; these effects were abolished by administration of the JNK specific inhibitor, (SP600125). Thus, Bex2 may be an important player during the development of glioma.

  1. TERT promoter mutations and telomere length in adult malignant gliomas and recurrences

    PubMed Central

    Heidenreich, Barbara; Rachakonda, P. Sivaramakrishna; Hosen, Ismail; Volz, Florian; Hemminki, Kari; Weyerbrock, Astrid; Kumar, Rajiv

    2015-01-01

    In this report on 303 gliomas we show the highest frequency of TERT promoter mutations in gliobastomas (80%) followed by oligodendrogliomas (70%) and astrocytomas (39%). We observed positive association between TERT promoter and IDH mutations in oligodendroglial tumors (OR = 26.3; 95% CI 2.5–250.2) and inverse association in primary glioblastomas (OR = 0.13; 95% CI 0.03–0.58). Tumors with TERT promoter mutations compared to those without showed increased TERT transcription; we also showed difference in the transcription levels due to the two main mutations. Tumors with TERT promoter mutations had shorter telomeres than those without. The patients with only TERT promoter mutations showed worst survival (median survival 14.6 months) and patients with both IDH and TERT promoter mutations showed best survival (246.5 months). In patients with astrocytoma, the TERT promoter mutations only associated with poor survival (P < 0.0001); IDH mutations and 1p/19q deletions associated with increased survival (P = 0.0004). TERT promoter mutations in low grade gliomas associated with reduced progression free survival (HR 10.2; 95% CI 1.9 – 55.9). While our data affirm the role of TERT promoter mutations in glial tumors, effects on transcription and telomere length emphasise the importance of telomere biology in disease genesis and outcome. PMID:25797251

  2. 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

  3. 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

  4. Use of the functional imaging modalities, f MRI r CBV and PET FDG, alters radiation therapy 3-D treatment planning in patients with malignant gliomas

    SciTech Connect

    Fitzek, M.; Pardo, F.S.; Busierre, M.

    1995-12-31

    Malignant gliomas present one of the most difficult challenges to definitive radiation therapy, not only with respect to local control, but also with respect to clinical functional status. While tumor target volume definitions for malignant gliomas are often based on CT and conventional MRI, the functional imaging modalities, echo planar rCBV (regional cerebral blood volume mapping) and 18F-fluorodeoxyglucose PET, are more sensitive modalities for the detection of neovascularization, perhaps one of the earliest signs of glial tumor initiation and progression. In order to address the clinical utility of functional imaging in radiation therapy 3-D treatment planning, we compared tumor target volume definitions and overall dosimetry in patients either undergoing co-registration of conventional Gadolinium-enhanced MRI, or co-registration of functional imaging modalities, prior to radiation therapy 3-D treatment planning.

  5. Fatty acid induced glioma cell growth is mediated by the acyl-CoA synthetase 5 gene located on chromosome 10q25.1-q25.2, a region frequently deleted in malignant gliomas.

    PubMed

    Yamashita, Y; Kumabe, T; Cho, Y Y; Watanabe, M; Kawagishi, J; Yoshimoto, T; Fujino, T; Kang, M J; Yamamoto, T T

    2000-11-30

    Acyl-CoA synthetase (ACS) ligates fatty acid and CoA to produce acyl-CoA, an essential molecule in fatty acid metabolism and cell proliferation. ACS5 is a recently characterized ACS isozyme highly expressed in proliferating 3T3-L1 cells. Molecular characterization of the human ACS5 gene revealed that the gene is located on chromosome 10q25.1-q25.2, spans approximately 46 kb, comprises 21 exons and 22 introns, and encodes a 683 amino acid protein. Two major ACS5 transcripts of 2.5- and 3.7-kb are distributed in a wide range of tissues with the highest expression in uterus and spleen. Markedly increased levels of ACS5 transcripts were detected in a glioma line, A172 cells, and primary gliomas of grade IV malignancy, while ACS5 expression was found to be low in normal brain. Immunohistochemical analysis also revealed strong immunostaining with an anti-ACS5 antibody in glioblastomas. U87MG glioma cells infected with an adenovirus encoding ACS5 displayed induced cell growth on exposure to palmitate. Consistent with the induction of cell growth, the virus infected cells displayed induced uptake of palmitate. These results demonstrate a novel fatty acid-induced glioma cell growth mediated by ACS5. PMID:11127823

  6. RHPN2 Drives Mesenchymal Transformation in Malignant Glioma by Triggering RhoA Activation

    PubMed Central

    Danussi, Carla; Akavia, Uri David; Niola, Francesco; Jovic, Andreja; Lasorella, Anna; Pe’er, Dana; Iavarone, Antonio

    2013-01-01

    Summary Mesenchymal (MES) transformation is a hallmark of aggressive glioblastoma (GBM). Here we report the development of an unbiased method for computational integration of copy number variation, expression and mutation data from large datasets. Using this method we identified RHPN2 as a central genetic determinant of the MES phenotype of human GBM. Notably, amplification of the human RHPN2 gene on chromosome 19 correlates with a dramatic decrease in the survival of glioma patients. Ectopic expression of RHPN2 in neural stem cells and astrocytes triggered the expression of MES genes and promoted an invasive phenotype without impacting cell proliferation. Mechanistically, these effects were implemented through RHPN2-mediated activation of RhoA, a master regulator of cell migration and invasion. Our results define RHPN2 amplification as a central genetic determinant of a highly aggressive phenotype that directs the worst clinical outcomes in GBM patients. PMID:23774217

  7. Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer

    PubMed Central

    Andersson, Ulrika; Wibom, Carl; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Armstrong, Georgina N.; Shete, Sanjay; Lau, Ching C.; Bainbridge, Matthew N.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Lai, Rose; Il'yasova, Dora; Houlston, Richard S.; Schildkraut, Joellen; Bernstein, Jonine L.; Olson, Sara H.; Jenkins, Robert B.; Lachance, Daniel H.; Wrensch, Margaret; Davis, Faith G.; Merrell, Ryan; Johansen, Christoffer; Sadetzki, Siegal; Bondy, Melissa L.; Melin, Beatrice S.; Adatto, Phyllis; Morice, Fabian; Payen, Sam; McQuinn, Lacey; McGaha, Rebecca; Guerra, Sandra; Paith, Leslie; Roth, Katherine; Zeng, Dong; Zhang, Hui; Yung, Alfred; Aldape, Kenneth; Gilbert, Mark; Weinberger, Jeffrey; Colman, Howard; Conrad, Charles; de Groot, John; Forman, Arthur; Groves, Morris; Levin, Victor; Loghin, Monica; Puduvalli, Vinay; Sawaya, Raymond; Heimberger, Amy; Lang, Frederick; Levine, Nicholas; Tolentino, Lori; Saunders, Kate; Thach, Thu-Trang; Iacono, Donna Dello; Sloan, Andrew; Gerson, Stanton; Selman, Warren; Bambakidis, Nicholas; Hart, David; Miller, Jonathan; Hoffer, Alan; Cohen, Mark; Rogers, Lisa; Nock, Charles J; Wolinsky, Yingli; Devine, Karen; Fulop, Jordonna; Barrett, Wendi; Shimmel, Kristen; Ostrom, Quinn; Barnett, Gene; Rosenfeld, Steven; Vogelbaum, Michael; Weil, Robert; Ahluwalia, Manmeet; Peereboom, David; Staugaitis, Susan; Schilero, Cathy; Brewer, Cathy; Smolenski, Kathy; McGraw, Mary; Naska, Theresa; Rosenfeld, Steven; Ram, Zvi; Blumenthal, Deborah T.; Bokstein, Felix; Umansky, Felix; Zaaroor, Menashe; Cohen, Avi; Tzuk-Shina, Tzeela; Voldby, Bo; Laursen, René; Andersen, Claus; Brennum, Jannick; Henriksen, Matilde Bille; Marzouk, Maya; Davis, Mary Elizabeth; Boland, Eamon; Smith, Marcel; Eze, Ogechukwu; Way, Mahalia; Lada, Pat; Miedzianowski, Nancy; Frechette, Michelle; Paleologos, Nina; Byström, Gudrun; Svedberg, Eva; Huggert, Sara; Kimdal, Mikael; Sandström, Monica; Brännström, Nikolina; Hayat, Amina; Tihan, Tarik; Zheng, Shichun; Berger, Mitchel; Butowski, Nicholas; Chang, Susan; Clarke, Jennifer; Prados, Michael; Rice, Terri; Sison, Jeannette; Kivett, Valerie; Duo, Xiaoqin; Hansen, Helen; Hsuang, George; Lamela, Rosito; Ramos, Christian; Patoka, Joe; Wagenman, Katherine; Zhou, Mi; Klein, Adam; McGee, Nora; Pfefferle, Jon; Wilson, Callie; Morris, Pagan; Hughes, Mary; Britt-Williams, Marlin; Foft, Jessica; Madsen, Julia; Polony, Csaba; McCarthy, Bridget; Zahora, Candice; Villano, John; Engelhard, Herbert; Borg, Ake; Chanock, Stephen K; Collins, Peter; Elston, Robert; Kleihues, Paul; Kruchko, Carol; Petersen, Gloria; Plon, Sharon; Thompson, Patricia; Johansen, C.; Sadetzki, S.; Melin, B.; Bondy, Melissa L.; Lau, Ching C.; Scheurer, Michael E.; Armstrong, Georgina N.; Liu, Yanhong; Shete, Sanjay; Yu, Robert K.; Aldape, Kenneth D.; Gilbert, Mark R.; Weinberg, Jeffrey; Houlston, Richard S.; Hosking, Fay J.; Robertson, Lindsay; Papaemmanuil, Elli; Claus, Elizabeth B.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Sloan, Andrew E.; Barnett, Gene; Devine, Karen; Wolinsky, Yingli; Lai, Rose; McKean-Cowdin, Roberta; Il'yasova, Dora; Schildkraut, Joellen; Sadetzki, Siegal; Yechezkel, Galit Hirsh; Bruchim, Revital Bar-Sade; Aslanov, Lili; Sadetzki, Siegal; Johansen, Christoffer; Kosteljanetz, Michael; Broholm, Helle; Bernstein, Jonine L.; Olson, Sara H.; Schubert, Erica; DeAngelis, Lisa; Jenkins, Robert B.; Yang, Ping; Rynearson, Amanda; Andersson, Ulrika; Wibom, Carl; Henriksson, Roger; Melin, Beatrice S.; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Merrell, Ryan; Lada, Patricia; Wrensch, Margaret; Wiencke, John; Wiemels, Joe; McCoy, Lucie; McCarthy, Bridget J.; Davis, Faith G.

    2014-01-01

    Background Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes. PMID:24723567

  8. Optic glioma

    MedlinePlus

    Glioma - optic; Optic nerve glioma; Juvenile pilocytic astrocytoma; Brain cancer - optic glioma ... Optic gliomas are rare. The cause of optic gliomas is unknown. Most optic gliomas are slow-growing ...

  9. Neurosphere and adherent culture conditions are equivalent for malignant glioma stem cell lines.

    PubMed

    Rahman, Maryam; Reyner, Karina; Deleyrolle, Loic; Millette, Sebastien; Azari, Hassan; Day, Bryan W; Stringer, Brett W; Boyd, Andrew W; Johns, Terrance G; Blot, Vincent; Duggal, Rohit; Reynolds, Brent A

    2015-03-01

    Certain limitations of the neurosphere assay (NSA) have resulted in a search for alternative culture techniques for brain tumor-initiating cells (TICs). Recently, reports have described growing glioblastoma (GBM) TICs as a monolayer using laminin. We performed a side-by-side analysis of the NSA and laminin (adherent) culture conditions to compare the growth and expansion of GBM TICs. GBM cells were grown using the NSA and adherent culture conditions. Comparisons were made using growth in culture, apoptosis assays, protein expression, limiting dilution clonal frequency assay, genetic affymetrix analysis, and tumorigenicity in vivo. In vitro expansion curves for the NSA and adherent culture conditions were virtually identical (P=0.24) and the clonogenic frequencies (5.2% for NSA vs. 5.0% for laminin, P=0.9) were similar as well. Likewise, markers of differentiation (glial fibrillary acidic protein and beta tubulin III) and proliferation (Ki67 and MCM2) revealed no statistical difference between the sphere and attachment methods. Several different methods were used to determine the numbers of dead or dying cells (trypan blue, DiIC, caspase-3, and annexin V) with none of the assays noting a meaningful variance between the two methods. In addition, genetic expression analysis with microarrays revealed no significant differences between the two groups. Finally, glioma cells derived from both methods of expansion formed large invasive tumors exhibiting GBM features when implanted in immune-compromised animals. A detailed functional, protein and genetic characterization of human GBM cells cultured in serum-free defined conditions demonstrated no statistically meaningful differences when grown using sphere (NSA) or adherent conditions. Hence, both methods are functionally equivalent and remain suitable options for expanding primary high-grade gliomas in tissue culture. PMID:25806119

  10. Local interstitial delivery of z-butylidenephthalide by polymer wafers against malignant human gliomas

    PubMed Central

    Harn, Horng-Jyh; Lin, Shinn-Zong; Lin, Po-Cheng; Liu, Cyong-Yue; Liu, Po-Yen; Chang, Li-Fu; Yen, Ssu-Yin; Hsieh, Dean-Kuo; Liu, Fu-Chen; Tai, Dar-Fu; Chiou, Tzyy-Wen

    2011-01-01

    We have shown that the natural compound z-butylidenephthalide (Bdph), isolated from the chloroform extract of Angelica sinensis, has antitumor effects. Because of the limitation of the blood-brain barrier, the Bdph dosage required for treatment of glioma is relatively high. To solve this problem, we developed a local-release system with Bdph incorporated into a biodegradable polyanhydride material, p(CPP-SA; Bdph-Wafer), and investigated its antitumor effects. On the basis of in vitro release kinetics, we demonstrated that the Bdph-Wafer released 50% of the available Bdph by the sixth day, and the release reached a plateau phase (90% of Bdph) by the 30th day. To investigate the in situ antitumor effects of the Bdph-Wafer on glioblastoma multiforme (GBM), we used 2 xenograft animal models—F344 rats (for rat GBM) and nude mice (for human GBM)—which were injected with RG2 and DBTRG-05MG cells, respectively, for tumor formation and subsequently treated subcutaneously with Bdph-Wafers. We observed a significant inhibitory effect on tumor growth, with no significant adverse effects on the rodents. Moreover, we demonstrated that the antitumor effect of Bdph on RG2 cells was via the PKC pathway, which upregulated Nurr77 and promoted its translocation from the nucleus to the cytoplasm. Finally, to study the effect of the interstitial administration of Bdph in cranial brain tumor, Bdph-Wafers were surgically placed in FGF-SV40 transgenic mice. Our Bdph-Wafer significantly reduced tumor size in a dose-dependent manner. In summary, our study showed that p(CPP-SA) containing Bdph delivered a sufficient concentration of Bdph to the tumor site and effectively inhibited the tumor growth in the glioma. PMID:21565841

  11. Radiation injury of boron neutron capture therapy using mixed epithermal- and thermal neutron beams in patients with malignant glioma.

    PubMed

    Kageji, T; Nagahiro, S; Mizobuchi, Y; Toi, H; Nakagawa, Y; Kumada, H

    2004-11-01

    The purpose of this study was to clarify the radiation injury in acute or delayed stage after boron neutron capture therapy (BNCT) using mixed epithermal- and thermal neutron beams in patients with malignant glioma. Eighteen patients with malignant glioma underwent mixed epithermal- and thermal neutron beam and sodium borocaptate between 1998 and 2004. The radiation dose (i.e. physical dose of boron n-alpha reaction) in the protocol used between 1998 and 2000 (Protocol A, n = 8) prescribed a maximum tumor volume dose of 15 Gy. In 2001, a new dose-escalated protocol was introduced (Protocol B, n = 4); it prescribes a minimum tumor volume dose of 18 Gy or, alternatively, a minimum target volume dose of 15 Gy. Since 2002, the radiation dose was reduced to 80-90% dose of Protocol B because of acute radiation injury. A new Protocol was applied to 6 glioblastoma patients (Protocol C, n = 6). The average values of the maximum vascular dose of brain surface in Protocol A, B and C were 11.4+/-4.2 Gy, 15.7+/-1.2 and 13.9+/-3.6 Gy, respectively. Acute radiation injury such as a generalized convulsion within 1 week after BNCT was recognized in three patients of Protocol B. Delayed radiation injury such as a neurological deterioration appeared 3-6 months after BNCT, and it was recognized in 1 patient in Protocol A, 5 patients in Protocol B. According to acute radiation injury, the maximum vascular dose was 15.8+/-1.3 Gy in positive and was 12.6+/-4.3 Gy in negative. There was no significant difference between them. According to the delayed radiation injury, the maximum vascular dose was 13.8+/-3.8 Gy in positive and was 13.6+/-4.9 Gy in negative. There was no significant difference between them. The dose escalation is limited because most patients in Protocol B suffered from acute radiation injury. We conclude that the maximum vascular dose does not exceed over 12 Gy to avoid the delayed radiation injury, especially, it should be limited under 10 Gy in the case that tumor

  12. Potentiation of treosulfan toxicity by the glutathione-depleting agent buthionine sulfoximine in human malignant glioma cells: the role of bcl-2.

    PubMed

    Reber, U; Wüllner, U; Trepel, M; Baumgart, J; Seyfried, J; Klockgether, T; Dichgans, J; Weller, M

    1998-02-01

    Median survival of human malignant glioma patients is less than one year even with cytoreductive surgery and postoperative radiotherapy. Adjuvant chemotherapy has been rather ineffective. Here, we studied the potentiation by L-buthionine-[S,R]-sulfoximine (BSO), a glutathione-depleting agent, of anticancer drug actions on two human malignant glioma cell lines, LN-229 and T98G. LN-229 has wild-type p53 status, T98G is mutant for p53. Glutathione levels were depleted by BSO with similar kinetics in both cell lines. Only LN-229 cells were growth-inhibited by BSO. BSO had minor effects on the toxicity of doxorubicin, ACNU (1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosou rea, nimustine) and vincristine. BSO failed to alter teniposide or cytarabine toxicity. BSO induced prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides. In the absence of BSO, treosulfan had little acute cytotoxic and moderate antiproliferative effects. Synergistic glioma cell cytotoxicity induced by treosulfan and BSO was not associated with reactive oxygen species formation. Ectopic expression of bcl-2 did not alter basal glutathione levels but attenuated glutathione depletion induced by BSO. Bcl-2 provided only moderate protection from synergistic induction of glioma cell death by treosulfan and BSO. Glutathione depletion may play a role in BSO-mediated chemosensitization, but other mechanisms are probably involved as well. BSO may be a useful agent for glioma cell sensitization to specific chemotherapeutic drugs such as treosulfan. PMID:9484802

  13. Radiation-induced neoplasms of the brain

    SciTech Connect

    Kumar, P.P.; Good, R.R.; Skultety, F.M.; Leibrock, L.G.; Severson, G.S.

    1987-04-01

    The histopathology of two patients with radiation-induced neoplasms of the brain following therapeutic irradiation for intracranial malignancies is described. The second neoplasms were an atypical meningioma and a polymorphous cell sarcoma, respectively. They occurred 12 and 23 years after irradiation (4000 rad), within the original field of irradiation. In both cases, the radiation-induced tumors were histologically distinct from the initial medulloblastomas. Both patients were retreated with local irradiation using permanent implantation of radioactive iodine-125 seeds.

  14. QL-09TRAJECTORY OF QUALITY OF LIFE AT END OF LIFE IN MALIGNANT GLIOMA: SUPPORT FOR THE TERMINAL DROP THEORY

    PubMed Central

    Farace, Elana; Sheehan, Jonas

    2014-01-01

    Very little is known about quality of life (QOL) at end-of-life (EOL) in malignant brain tumor patients, which limits clinicians ability to best to help patients at this stage. The QOL trajectory at EOL has commonly been hypothesized to be "terminal decline," a linear relationship to time before death with a relatively gradual decline. Alternately, QOL at EOL could be hypothesized to be analogous to the "terminal drop" theory of cognitive aging, wherein the patient QOL has a curvilinear relationship to time before death; a relatively flat curve with a rapid decline a short time before death. 89 patients with malignant glioma were enrolled in this NCI funded study of QOL and neurocognition. Patients completed the EORTC-QLQ-C30 at three month intervals until death. Mean length of follow-up was 224 days (median 155 days). Mean age of patients was 52 years (range 18-80). The gender ratio was 49% men and 51% women. One patient was Latino (so 97% Non-Hispanic), 69 participants were Caucasian, one was African American, and one was Native American. The mean educational level was 13 years (range 8-20). Twenty-eight patients had glioblastoma (grade IV), nine had a grade III oligodendroglioma, and six had a grade III oligoastrocytoma. Data were plotted over time to determine if the shape of the curve resembles terminal decline or terminal drop. Interestingly, as can be seen from the graph, Global QOL slightly improved over time. Growth Curve Analysis confirms this finding. Results of this study may supporting the terminal drop theory but may also illustrate response shift, a conundrum for QOL researchers in which patients' perspective changes and thus they report improved QOL. Longer follow-up is necessary to delineate this pattern. A better understanding of QOL at EOL will improve medical and psychosocial palliative care.

  15. The Role of Bcl-2 Family Proteins in Therapy Responses of Malignant Astrocytic Gliomas: Bcl2L12 and Beyond

    PubMed Central

    Kouri, Fotini M.; Jensen, Samuel A.; Stegh, Alexander H.

    2012-01-01

    Glioblastoma (GBM) is a highly aggressive and lethal brain cancer with a median survival of less than two years after diagnosis. Hallmarks of GBM tumors include soaring proliferative indices, high levels of angiogenesis, diffuse invasion into normal brain parenchyma, resistance toward therapy-induced apoptosis, and pseudopallisading necrosis. Despite the recent advances in neurosurgery, radiation therapy, and the development of targeted chemotherapeutic regimes, GBM remains one of the deadliest types of cancer. Particularly, the alkylating agent temozolomide (TMZ) in combination with radiation therapy prolonged patient survival only marginally, and clinical studies assessing efficacies of targeted therapies, foremost ATP mimetics inhibiting the activity of receptor tyrosine kinases (RTKs), revealed only few initial responders; tumor recurrence is nearly universal, and salvage therapies to combat such progression remain ineffective. Consequently, myriad preclinical and clinical studies began to define the molecular mechanisms underlying therapy resistance of GBM tumors, and pointed to the Bcl-2 protein family, in particular the atypical member Bcl2-Like 12 (Bcl2L12), as important regulators of therapy-induced cell death. This review will discuss the multi-faceted modi operandi of Bcl-2 family proteins, describe their roles in therapy resistance of malignant glioma, and outline current and future drug development efforts to therapeutically target Bcl-2 proteins. PMID:22431925

  16. Comparative Genomic Hybridization of Human Malignant Gliomas Reveals Multiple Amplification Sites and Nonrandom Chromosomal Gains and Losses

    PubMed Central

    Schròck, Evelin; Thiel, Gundula; Lozanova, Tanka; du Manoir, Stanislas; Meffert, Marie-Christine; Jauch, Anna; Speicher, Michael R.; Nürnberg, Peter; Vogel, Siegfried; Janisch, Werner; Donis-Keller, Helen; Ried, Thomas; Witkowski, Regine; Cremer, Thomas

    1994-01-01

    Nine human malignant gliomas (2 astrocytomas grade III and 7 glioblastomas) were analyzed using comparative genomic hybridization (CGH). In addition to the amplification of the EGFR gene at 7p12 in 4 of 9 cases, six new amplification sites were mapped to 1q32, 4q12, 7q21.1, 7q21.2-3, 12p, and 22q12. Nonrandom chromosomal gains and losses were identified with overrepresentation of chromosome 7 and underrepresentation of chromosome 10 as the most frequent events (1 of 2 astrocytomas, 7 of 7 glioblastomas). Gain of a part or the whole chromosome 19 and losses of chromosome bands 9pter-23 and 22q13 were detected each in five cases. Loss of chromosome band 17p13 and gain of chromosome 20 were revealed each in three cases. The validity of the CGH data was confirmed using interphase cytogenetics with YAC clones, chromosome painting in tumor metaphase spreads, and DNA fingerprinting. A comparison of CGH data with the results of chromosome banding analyses indicates that metaphase spreads accessible in primary tumor cell cultures may not represent the clones predominant in the tumor tissue ImagesFigure 1Figure 4Figure 6 PMID:8203461

  17. Tamoxifen-Induced Cell Death of Malignant Glioma Cells Is Brought About by Oxidative-Stress-Mediated Alterations in the Expression of BCL2 Family Members and Is Enhanced on miR-21 Inhibition.

    PubMed

    Harmalkar, Mugdha; Upraity, Shailendra; Kazi, Sadaf; Shirsat, Neelam Vishwanath

    2015-10-01

    High-grade gliomas are refractory to the current mode of treatment primarily due to their inherent resistance to cell death. Tamoxifen has been reported to inhibit growth and induce cell death of glioma cells in vitro, in an estrogen-receptor-independent manner. Delineating the molecular mechanism underlying tamoxifen-induced cell death of human glioma cells would help in identifying pathways/genes that could be targeted to induce tumor-cell-specific cell death. In the present study, tamoxifen was found to bring about autophagic cell death of human glioma cells that was accompanied by oxidative stress induction, JNK activation, downregulation of anti-autophagic BCL2 family members, viz. BCL2 and BCL-XL, and increased expression of the pro-autophagic members BCL-Xs and BAK. Oxidative stress induction appears to be primarily responsible for the tamoxifen-induced cell death since the cell death, JNK activation, and the alterations in the expression levels of BCL2 family members were abrogated on pretreatment with antioxidant vitamin E. MiR-21, an oncogenic miRNA, is known to be highly upregulated in malignant glioma. Inhibition of miR-21 activity was found to enhance tamoxifen-induced cell death of U87 MG malignant glioma cells. Tamoxifen treatment coupled with miR-21 inhibition could therefore be an effective strategy for the treatment of malignant gliomas. PMID:26109525

  18. Human Phospholipase D Activity Transiently Regulates Pyrimidine Biosynthesis in Malignant Gliomas

    PubMed Central

    Mathews, Thomas P.; Hill, Salisha; Rose, Kristie L.; Ivanova, Pavlina T.; Lindsley, Craig W.; Brown, H. Alex

    2015-01-01

    Cancer cells reorganize their metabolic pathways to fuel demanding rates of proliferation. Oftentimes, these metabolic phenotypes lie downstream of prominent oncogenes. The lipid signaling molecule phosphatidic acid (PtdOH), which is produced by the hydrolytic enzyme phospholipase D (PLD), has been identified as a critical regulatory molecule for oncogenic signaling in many cancers. In an effort to identify novel regulatory mechanisms for PtdOH, we screened various cancer cell lines, assessing whether treatment of cancer models with PLD inhibitors altered production of intracellular metabolites. Preliminary findings lead us to focus on how deoxyribonucleoside triphosphates (dNTPs) are altered upon PLD inhibitor treatment in gliomas. Using a combination of proteomics and small molecule intracellular metabolomics, we show herein that PtdOH acutely regulates the production of these pyrimidine metabolites through activation of CAD via mTOR signaling pathways independently of Akt. These changes are responsible for decreases in dNTP production after PLD inhibitor treatment. Our data identify a novel regulatory role for PLD activity in specific cancer types. PMID:25646564

  19. Heparan sulfate sulfatase SULF2 regulates PDGFRα signaling and growth in human and mouse malignant glioma

    PubMed Central

    Phillips, Joanna J.; Huillard, Emmanuelle; Robinson, Aaron E.; Ward, Anna; Lum, David H.; Polley, Mei-Yin; Rosen, Steven D.; Rowitch, David H.; Werb, Zena

    2012-01-01

    Glioblastoma (GBM), a uniformly lethal brain cancer, is characterized by diffuse invasion and abnormal activation of multiple receptor tyrosine kinase (RTK) signaling pathways, presenting a major challenge to effective therapy. The activation of many RTK pathways is regulated by extracellular heparan sulfate proteoglycans (HSPG), suggesting these molecules may be effective targets in the tumor microenvironment. In this study, we demonstrated that the extracellular sulfatase, SULF2, an enzyme that regulates multiple HSPG-dependent RTK signaling pathways, was expressed in primary human GBM tumors and cell lines. Knockdown of SULF2 in human GBM cell lines and generation of gliomas from Sulf2–/– tumorigenic neurospheres resulted in decreased growth in vivo in mice. We found a striking SULF2 dependence in activity of PDGFRα, a major signaling pathway in GBM. Ablation of SULF2 resulted in decreased PDGFRα phosphorylation and decreased downstream MAPK signaling activity. Interestingly, in a survey of SULF2 levels in different subtypes of GBM, the proneural subtype, characterized by aberrations in PDGFRα, demonstrated the strongest SULF2 expression. Therefore, in addition to its potential as an upstream target for therapy of GBM, SULF2 may help identify a subset of GBMs that are more dependent on exogenous growth factor–mediated signaling. Our results suggest the bioavailability of growth factors from the microenvironment is a significant contributor to tumor growth in a major subset of human GBM. PMID:22293178

  20. Modeling mass transfer from carmustine-loaded polymeric implants for malignant gliomas.

    PubMed

    Pereira, David Y; Yip, Allison T; Lee, Brian S; Kamei, Daniel T

    2014-02-01

    Significant advances in the encapsulation and release of drugs from degradable polymers have led to the Food and Drug Administration approval of Gliadel wafers for controlled local delivery of the chemotherapeutic drug carmustine to high-grade gliomas following surgical resection. Due to the localized nature of the delivery method, no pharmacokinetic measurements have been taken in humans. Rather, pharmacokinetic studies in animals and associated modeling have indicated the capability of carmustine to be delivered in high concentrations within millimeters from the implant site over approximately 5 days. Mathematical models have indicated that diffusion has a primary role in transport, which may be complemented by enhanced fluid convection from postsurgical edema in the initial 3 days following implantation. Carmustine's penetration distance is also presumably limited by its lipophilicity and permeability in the capillaries. This review discusses the mathematical models that have been used to predict the release and distribution of carmustine from a polymeric implant. These models provide a theoretical framework for greater understanding of systems for localized drug delivery while highlighting factors that should be considered in clinical applications. In effect, Gliadel wafers and similar drug delivery implants can be optimized with reduction in required time and resources with such a quantitative and integrative approach. PMID:23975389

  1. Suppressing the malignant phenotypes of glioma cells by lentiviral delivery of small hairpin RNA targeting hypoxia-inducible factor-1α

    PubMed Central

    Dong, Chang Gui; Wu, William K K; Feng, Su Yin; Yu, Jun; Shao, Jun Fei; He, Gui Mei

    2013-01-01

    Hypoxic microenvironment of solid tumors is known to shape malignant phenotypes of cancer cells through the dimeric transcription factor hypoxia-inducible factor (HIF)-1. In the present study, the therapeutic effect of targeting α subunit of HIF-1 in glioma cells via lentiviral delivery of small hairpin RNA (shRNA) was evaluated. Data from quantitative real-time PCR and immunohistochemistry demonstrated that HIF-1α was progressively upregulated during the development of gliomas. Lentiviral shRNA targeting HIF-1α led to substantial loss of cell viability, G0/G1-phase cell cycle arrest, apoptosis, and impairment of cell motility and invasiveness in human glioma U87MG cells. Xenograft experiments in nude mice further showed that HIF-1α-shRNA inhibited tumor growth and caused persistent repression of HIF-1α and its target genes, including VEGF, GLUT1 and MMP2, up to 25 days post-inoculation. Taken together, lentiviral delivery of shRNA is a promising therapeutic approach for targeting HIF-1α in glioma. PMID:24228093

  2. 18F-FDOPA and 18F-FLT positron emission tomography parametric response maps predict response in recurrent malignant gliomas treated with bevacizumab.

    PubMed

    Harris, Robert J; Cloughesy, Timothy F; Pope, Whitney B; Nghiemphu, Phioanh L; Lai, Albert; Zaw, Taryar; Czernin, Johannes; Phelps, Michael E; Chen, Wei; Ellingson, Benjamin M

    2012-08-01

    The current study examined the use of voxel-wise changes in (18)F-FDOPA and (18)F-FLT PET uptake, referred to as parametric response maps (PRMs), to determine whether they were predictive of response to bevacizumab in patients with recurrent malignant gliomas. Twenty-four patients with recurrent malignant gliomas who underwent bevacizumab treatment were analyzed. Patients had MR and PET images acquired before and at 2 time points after bevacizumab treatment. PRMs were created by examining the percentage change in tracer uptake between time points in each image voxel. Voxel-wise increase in PET uptake in areas of pretreatment contrast enhancement defined by MRI stratified 3-month progression-free survival (PFS) and 6-month overall survival (OS) according to receiver-operating characteristic curve analysis. A decrease in PET tracer uptake was associated with longer PFS and OS, whereas an increase in PET uptake was associated with short PFS and OS. The volume fraction of increased (18)F-FDOPA PET uptake between the 2 posttreatment time points also stratified long- and short-term PFS and OS (log-rank, P < .05); however, (18)F-FLT uptake did not stratify OS. This study suggests that an increase in FDOPA or FLT PET uptake on PRMs after bevacizumab treatment may be a useful biomarker for predicting PFS and that FDOPA PET PRMs are also predictive of OS in recurrent gliomas treated with bevacizumab. PMID:22711609

  3. Radiographic and Histopathologic Observations After Combined EGFR Inhibition and Hypofractionated Stereotactic Radiosurgery in Patients With Recurrent Malignant Gliomas

    SciTech Connect

    Schwer, Amanda L.; Kavanagh, Brian D.; McCammon, Robert; Gaspar, Laurie E.; Kleinschmidt-De Masters, B.K.; Stuhr, Kelly; Chen Changhu

    2009-04-01

    Purpose: To describe the radiographic and histopathologic changes after stereotactic radiosurgery (SRS) and epidermal growth factor receptor inhibition in patients with recurrent malignant gliomas. Methods and Materials: A total of 15 patients with recurrent high-grade gliomas were treated on a prospective Phase I trial combining SRS and gefitinib. The SRS dose was escalated from 18 to 36 Gy in three fractions. The planning target volume was the T{sub 1}-weighted contrast-enhancing (T{sub 1}C) lesion plus 2 mm. Gefitinib was given at 250 mg daily. Serial brain magnetic resonance imaging scans were analyzed to characterize the volumetric changes in the T{sub 1}C and T{sub 2} abnormalities after treatment. Two patients underwent resection for suspected recurrence. Results: The median pretreatment magnetic resonance imaging T{sub 1}C and T{sub 2} volume was 40.9 and 184.1 cm{sup 3}, respectively. The median post-SRS percentage of increases in the T{sub 1}C volume at 1, 2-4, and 5-7 months was 8.9%, 41.3%, and 99.6%, respectively. The median percentage increase in the T{sub 2} volume likewise showed a trend upward after SRS, from 18.0% at 1 month to 37.8% at 5-7 months. For the 2 patients who underwent resection after SRS for an increasing T{sub 1}C volume, the histopathologic analysis revealed therapy-induced vascular injury and necrosis. One patient with an asymptomatic increase in the T{sub 1}C volume after SRS was treated conservatively. After a peak T{sub 1}C volume increase at 9 months, the T{sub 1}C volume had declined to 50% of the maximal volume at 15 months. The patients with the most dramatic increase in T{sub 1}C volume experienced the longest overall survival. Conclusion: Patients experienced a notable increase in magnetic resonance imaging T{sub 1}C and T{sub 2} volumes after the combination of SRS and epidermal growth factor receptor inhibition. The tissue changes were consistent with a potent treatment effect.

  4. Brain-Penetrating Nanoparticles Improve Paclitaxel Efficacy in Malignant Glioma Following Local Administration

    PubMed Central

    2015-01-01

    Poor drug distribution and short drug half-life within tumors strongly limit efficacy of chemotherapies in most cancers, including primary brain tumors. Local or targeted drug delivery via controlled-release polymers is a promising strategy to treat infiltrative brain tumors, which cannot be completely removed surgically. However, drug penetration is limited with conventional local therapies since small-molecule drugs often enter the first cell they encounter and travel only short distances from the site of administration. Nanoparticles that avoid adhesive interactions with the tumor extracellular matrix may improve drug distribution and sustain drug release when applied to the tumor area. We have previously shown model polystyrene nanoparticles up to 114 nm in diameter were able to rapidly diffuse in normal brain tissue, but only if coated with an exceptionally dense layer of poly(ethylene glycol) (PEG) to reduce adhesive interactions. Here, we demonstrate that paclitaxel (PTX)-loaded, poly(lactic-co-glycolic acid) (PLGA)-co-PEG block copolymer nanoparticles with an average diameter of 70 nm were able to diffuse 100-fold faster than similarly sized PTX-loaded PLGA particles (without PEG coatings). Densely PEGylated PTX-loaded nanoparticles significantly delayed tumor growth following local administration to established brain tumors, as compared to PTX-loaded PLGA nanoparticles or unencapsulated PTX. Delayed tumor growth combined with enhanced distribution of drug-loaded PLGA-PEG nanoparticles to the tumor infiltrative front demonstrates that particle penetration within the brain tumor parenchyma improves therapeutic efficacy. The use of drug-loaded brain-penetrating nanoparticles is a promising approach to achieve sustained and more uniform drug delivery to treat aggressive gliomas and potentially other brain disorders. PMID:25259648

  5. A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas.

    PubMed

    Raizer, Jeffrey J; Chandler, James P; Ferrarese, Roberto; Grimm, Sean A; Levy, Robert M; Muro, Kenji; Rosenow, Joshua; Helenowski, Irene; Rademaker, Alfred; Paton, Martin; Bredel, Markus

    2016-08-01

    One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m(2) IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m(2) PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m(2) on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycles post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor. PMID:27300524

  6. Analysis of equivalent uniform dose (EUD) and conventional radiation treatment parameters after primary and re-irradiation of malignant glioma

    PubMed Central

    2013-01-01

    Background Re-irradiation is a reasonable second treatment option for patients with recurrent malignant glioma (MG) after previous radio(chemo)therapy. However, only limited data is available allowing for a precise selection of patients suitable for re-treatment in regard to safety and efficacy. Methods Using the department database, 58 patients with two courses of percutaneous radiation were identified. Besides classical dose-volume histogram (DVH) parameters equivalent uniform dose (EUD) values were calculated for the tumor and organs at risk (OARs), retrospectively analyzed and correlated to survival outcome parameters. Cumulative EUD values were also calculated in all cases where previous OAR DVHs were available. Results Median follow-up was 265 days and no relevant toxicity was observed after re-irradiation in our patient cohort during follow-up. Time interval between first and second irradiation was regularly above 6 months. As a conservative estimation of the cumulative EUD to the OARs, the EUDs of first and second irradiation were added. Median cumulative EUD to the optic chiasm was 48.8 Gy (range, 2.5–76.5 Gy), 57.4 Gy (range, 2.7–75.3 Gy) to the brainstem, 20.9/22.1 Gy (range, 0.0–68.3 Gy) to the right/left optic nerve and 73.8 Gy (range, 64.9–77.3 Gy) to the brain. No correlation between treated volume and survival was seen. Conclusions This study provides retrospective estimates on cumulative doses at the OARs. EUD values are derived and may serve as reference for further studies, including planning studies where specific constraints are needed. PMID:24330746

  7. Prolongation of survival for high-grade malignant gliomas with adjuvant high-dose BCNU and autologous bone marrow transplantation.

    PubMed

    Johnson, D B; Thompson, J M; Corwin, J A; Mosley, K R; Smith, M T; de los Reyes, R A; Daly, M B; Petty, A M; Lamaster, D; Pierson, W P

    1987-05-01

    Employment of postoperative brain irradiation in the initial management of high-grade malignant glial tumors has now become standard. The addition of conventional chemotherapy to irradiation has not significantly improved median survival beyond 1 year. We treated 25 consecutive patients (13 pilot patients and 12 protocol patients) with histologically confirmed unresectable grade 3 or 4 malignant gliomas with high-dose BCNU (carmustine) followed by autologous bone marrow transplantation and whole brain irradiation. Within 3 weeks of initial surgery, each patient had autologous bone marrow stored (median 2 X 10(8) nucleated cells/kg), and then received BCNU 1,050 mg/m2 intravenously (IV). Peripheral granulocytes recovered (greater than 500/microL) at a median of 19 days (range, 10 to 37 days), and platelets recovered (greater than 20,000/microL) at a median of 18 days (range, 13 to 40 days), following bone marrow infusion. Patients received 60 Gy whole brain irradiation when granulocytes were greater than 1,500/microL. Toxicity was well tolerated. Nausea occurred in 19 patients (76%); however, only eight patients (32%) experienced vomiting (mild in three, moderate in five). Eleven patients (44%) did not require empiric antibiotics, six of whom never developed an absolute granulocyte count less than 500/microL. Three patients with a poor performance status died early (one seizure with vomiting and asphyxiation; one, klebsiella urinary tract infection (UTI) with bacteremia; one, candidal pneumonia), and one additional patient who was performing well died of pulmonary hemorrhage. The 13 pilot patients have now been followed for a median of 23 months, with a significant survival advantage compared with the 52 consecutive historical control patients who received similar surgery and radiotherapy without high-dose BCNU (P = .037). The overall study group of 25 patients also has a significant survival advantage when compared with the same historical control group, with a

  8. L-Boronophenylalanine-Mediated Boron Neutron Capture Therapy for Malignant Glioma Progressing After External Beam Radiation Therapy: A Phase I Study

    SciTech Connect

    Kankaanranta, Leena; Seppaelae, Tiina; Koivunoro, Hanna; Vaelimaeki, Petteri; Beule, Annette; Collan, Juhani; Kortesniemi, Mika; Uusi-Simola, Jouni; Kotiluoto, Petri; Auterinen, Iiro; Seren, Tom; Paetau, Anders; Saarilahti, Kauko; Savolainen, Sauli; Joensuu, Heikki

    2011-06-01

    Purpose: To investigate the safety of boronophenylalanine-mediated boron neutron capture therapy (BNCT) in the treatment of malignant gliomas that progress after surgery and conventional external beam radiation therapy. Methods and Materials: Adult patients who had histologically confirmed malignant glioma that had progressed after surgery and external beam radiotherapy were eligible for this Phase I study, provided that >6 months had elapsed from the last date of radiation therapy. The first 10 patients received a fixed dose, 290 mg/kg, of L-boronophenylalanine-fructose (L-BPA-F) as a 2-hour infusion before neutron irradiation, and the remaining patients were treated with escalating doses of L-BPA-F, either 350 mg/kg, 400 mg/kg, or 450 mg/kg, using 3 patients on each dose level. Adverse effects were assessed using National Cancer Institute Common Toxicity Criteria version 2.0. Results: Twenty-two patients entered the study. Twenty subjects had glioblastoma, and 2 patients had anaplastic astrocytoma, and the median cumulative dose of prior external beam radiotherapy was 59.4 Gy. The maximally tolerated L-BPA-F dose was reached at the 450 mg/kg level, where 4 of 6 patients treated had a grade 3 adverse event. Patients who were given >290 mg/kg of L-BPA-F received a higher estimated average planning target volume dose than those who received 290 mg/kg (median, 36 vs. 31 Gy [W, i.e., a weighted dose]; p = 0.018). The median survival time following BNCT was 7 months. Conclusions: BNCT administered with an L-BPA-F dose of up to 400 mg/kg as a 2-hour infusion is feasible in the treatment of malignant gliomas that recur after conventional radiation therapy.

  9. Phase I/II Clinical Trial of Carbon Ion Radiotherapy for Malignant Gliomas: Combined X-Ray Radiotherapy, Chemotherapy, and Carbon Ion Radiotherapy

    SciTech Connect

    Mizoe, Jun-Etsu Tsujii, Hirohiko; Hasegawa, Azusa D.D.S.; Yanagi, Tsuyoshi; Takagi, Ryo D.D.S.; Kamada, Tadashi; Tsuji, Hiroshi; Takakura, Kintomo

    2007-10-01

    Purpose: To report the results of a Phase I/II clinical trial for patients with malignant gliomas, treated with combined X-ray radiotherapy (XRT), chemotherapy, and carbon ion radiotherapy (CRT). Methods and Materials: Between October 1994 and February 2002, 48 patients with histologically confirmed malignant gliomas (16 anaplastic astrocytoma (AA) and 32 glioblastoma multiforme (GBM) were enrolled in a Phase I/II clinical study. The treatment involved the application of 50 Gy/25 fractions/5 weeks of XRT, followed by CRT at 8 fractions/2 weeks. Nimustine hydrochloride (ACNU) were administered at a dose of 100 mg/m{sup 2} concurrently in weeks 1, 4, or 5 of XRT. The carbon ion dose was increased from 16.8 to 24.8 Gray equivalent (GyE) in 10% incremental steps (16.8, 18.4, 20.0, 22.4, and 24.8 GyE, respectively). Results: There was no Grade 3 or higher acute reaction in the brain. The late reactions included four cases of Grade 2 brain morbidity and four cases of Grade 2 brain reaction among 48 cases. The median survival time (MST) of AA patients was 35 months and that of GBM patients 17 months (p = 0.0035). The median progression-free survival and MST of GBM showed 4 and 7 months for the low-dose group, 7 and 19 months for the middle-dose group, and 14 and 26 months for the high-dose group. Conclusion: The results of combined therapy using XRT, ACNU chemotherapy, and CRT showed the potential efficacy of CRT for malignant gliomas in terms of the improved survival rate in those patients who received higher carbon doses.

  10. Neurocognitive functioning and quality of life in patients with recurrent malignant gliomas treated on a phase Ib trial evaluating topotecan by convection-enhanced delivery

    PubMed Central

    Oberg, Jennifer A.; Dave, Amie N.; Bruce, Jeffrey N.; Sands, Stephen A.

    2014-01-01

    Background Malignant gliomas are highly proliferative, invasive tumors that are resistant to conventional treatment, and disease progression is often accompanied by physical and mental debilitation. Neurocognitive functioning (NCF) and quality of life (QoL) were evaluated as part of a prospective phase Ib dose-escalation study of topotecan by convection-enhanced delivery (CED) for adult patients with recurrent malignant gliomas. Methods Sixteen patients were enrolled, and NCF and QoL were evaluated using the Cognitive Stability Index and SF-36 at baseline and monthly for 4 months post treatment. Descriptive analyses included the reliable change index for serial evaluations and correlations for associations between outcome variables and age, tumor volume, total topotecan dose, and treatment effect. Results Individual classifications of response to treatment indicated that a majority of patients reported stable scores over the follow-up period. Demographic and treatment-related variables were not associated with outcomes. Baseline processing speed scores were invalid for 6 subjects. Higher rates of valid scores were observed on subsequent administrations. Conclusions As the first study to use CED of any kind to evaluate the impact of CED on NCF or QoL, there was no evidence of severe detriment to either outcome. Long-term evaluation is necessary to track changes in NCF and QoL related to disease progression. Invalid scores suggest that computer-based assessments may not be suitable for all patients with malignant gliomas, especially those with cognitive deficits secondary to their disease. Future trials should include a wider range of sensitive measures to assess the impact of CED on patient NCF and QoL. PMID:26034621